CA2135669A1 - Ribavirin as hepato (liver) protecting agent - Google Patents
Ribavirin as hepato (liver) protecting agentInfo
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- CA2135669A1 CA2135669A1 CA002135669A CA2135669A CA2135669A1 CA 2135669 A1 CA2135669 A1 CA 2135669A1 CA 002135669 A CA002135669 A CA 002135669A CA 2135669 A CA2135669 A CA 2135669A CA 2135669 A1 CA2135669 A1 CA 2135669A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
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Abstract
Use of Ribavirin as a hepato (liver) protecting agent.
Description
~135669 TITLE OF INVENTION
RIBAVIRIN AS HEPATO (LIVER) PROTECTING AGENT
This invention relates to new uses for Ribavirin, novel uses of Ribavirin for the treatment of chronic hepatitis C, novel methods for treating hepatitis C, and new dosages suitable for use when treating hepatitis C.
Ribavirin was taught in both United States Patents 3,798,209, 3,927,216, and 4,211,771 teaches the processes for treating viral diseases in humans which comprises administering to human patients an antiviral agent which has as its active component the compound Ribavirin. Canadian Patent 1,261,265 relates to formulations and the manufacture of formulations for the medical treatment of viral diseases in humans which are caused by, among other viruses, Arboviruses which included hepatitis C. The formulations taught in that patent comprise an effective non-toxic amount of a composition containing from .01% to 50% by weight of the total weight of the composition of a compound Ribavirin.
In "Pilot study of Ribavirin Therapy for Chronic Hepatitis C"
accepted for publication April 28, 1992 in Hepatology at page 649, the areticle discussed the treatment of a small number of patients with chronic hepatitis C using Ribavirin. In the pilot study itself, Ribavirin was given for six months in doses that increased at two-month intervals from 600 mg to 1,000 mg to 1,200 mg per day. The serum alanine aminotransferase (ALT) levels gradually decreased in all 13 treated patients. In the three to six month periodafter cessation of Ribavirin therapy, serum aminotransferase activities gradually rose to near pre-treatment levels in all but one patient. No significant improvement was seen in liver histological appearance. The article went on to say that these findings suggest that Ribavirin has a beneficial effect in patients with chronic hepatitis C.
Another article entitled "Ribavirin Treatment for Chronic Hepatitis C" published in Lancet,; 1991 (May 4); volume 337: at pages 1058 ~135669 to 1061, discussed the treatment of ten patients in a pilot study, all of whom had biopsy-proven chronic non-A, non-B hepatitis and were repeatedly positive for antibodies to hepatitis C virus. The treatment was with oral Ribavirin, 1,000 to 1,200 mg per day in two divided doses for twelve weeks.
Once again, serum ALT levels fell when treated. However, within six weeks of the end of treatment, the median serum alanine aminotransferase concentration was not significantly different from that before treatment.
In Hepatology, 1993; volume 18, number 4, pt. 2, a summary entitled "Randomized, Double-Blind Placebo-Controlled Trial of Ribavirin Therapy for Chronic Hepatitis C" is provided wherein 58 patients with chronic hepatitis C entered a randomized, double-blind controlled trial of Ribavirin (600 mg BID orally for twelve months) versus placebo. As in the previous studies, serum ALT values fell, but rose after the cessation of therapy in all but two of four responders. The conclusion from the trial was that prolonged Ribavirin therapy was associated with significant improvement in serum ALT levels (despite unchanged serum HCV RNA
levels) and hepatic lobular mucosis.
The prior patents and articles referred to do not lead the reader to the appreciation that the Ribavirin reduce serum ALT levels in some patients to normal levels where they remain for a prolonged period of time after the suspension of treatment with Ribavirin. Further, there is no appreciation of the ability to treat a patient for a prolonged period of time with Ribavirin, and that as a result of that treatment the serum ALT levels remain normal even after cessation of treatment. Furthermore, there is no teaching that the use of Ribavirin may protect the liver, acting as a hepato-protecting agent, thus at least preventing worsening of the condition of the patient's liver, and, in many cases, improving the condition of the patient's liver.
In treating chronic hepatitis C with the antiviral agent Ribavirin, it would also have been expected by persons skilled in the art that the level of hepatitis C virus would diminish in the liver because Rlbavirin is identified as an antiviral agent. This is surprisingly not the case, however, even though the serum ALT levels reduced.
In the Ribavirin studies carried out in accordance with this invention, the primary response parameter was reduction in serum ALT
levels. Elevation of ALT indicates biochemical evidence of hepatic inflammation, and reduction of the ALT level is an accepted response criterion in clinical studies of therapeutic agents in hepatitis C. In all of the studies in the Ribavirin clinical program, phase II and phase III Ribavirin was significantly superior to placebo in normalizing and reducing ALT levels during treatment. Using the integrated definition of ALT response, which includes normalization of ALT at the end of treatment and a clinically meaningful definition of partial response, 46% of Ribavirin-treated patients were responders compared to 4% of placebo controls (p~0.001). Following withdrawal of Ribavirin, the ALT levels of the majority of responders reverted to baseline levels. However 12% of the patients did maintain the ALT response throughout the follow-up period, and we have discovered that there is a correlation between the rate of sustained response and duration of treatment. The rate of sustained resonse was greater in the study of the longest duration (i.e., 48 weeks) and we expect even a greater sustained response after longer treatment. According to our invention, the effect of treatment on liver histology was assessed in the same manner in each of the phase III studies. The Knodell scoring system was strictly adhered to throughout. For each patient the effect of treatment was determined by the change in score from baseline to the end of therapy. All liver biopsy assessments (taken before and after treatment) were performed in a blinded fashion, by a single pathologist in each of two studies (92-001 and CT00/002), or, in the case of another study (91-DK-178), by two pathologists who agreed on each specimen. In each study, analysis of Knodell scores by the methods specified in the analysis plans did not reveal a statistically significant difference between the treatment groups. In each study, however, there is a consistent numerical trend in favour of Ribavirin in the changes in total scores and in many of the component scores. This same trend is thus apparent when the data from the three studies is combined. The methods of collection of the liver biopsy data described above justify combining the data in this way. It is of interest that the trend applies not only to improvement ofscores but also to worsening, indicating that even if no patients in either treatment group improve, then fewer patients in the Ribavirin group are worsening. This is an important observation considering that one objective of treatment is to prevent deterioration of a chronic and progressive condition. Analysis of the combined data by analysis of covariance using baseline Knodell score as covariate reveals statistically significant differences in favour of Ribavirin for the total Knodell score and for each of the four subscores. This analysis takes into account the baseline variability in Knodell scores, and the tendency for baseline scores at the extremes of the scale to regress to the mean without any treatment effect.
The mean changes in the scores for Ribavirin-treated patients are only small, but due to small variances the differences from placebo are statistically significant. It is of interest to note that the only Knodell sub-score that does not improve is fibrosis, and that there is less deterioration in the Ribavirin group than in the placebo group.
Within the Ribavirin group, comparison of ALT responders and non-responders revealed that ALT responders experienced a significantly greater improvement in liver histology as compared to ALT non-responders.
The mean fall in total Knodell score was approximately two points for ALT
responders as compared to one point for all Ribavirin-treated patients. A fall in total Knodell score of two points is generally considered by hepatologists tobe clinically significant. There was thus a statistically significant positive correlation between ALT response and a clinically significant degree of improvement in liver histology. This is an important finding, as ,2135669 measurement of ALT levels is an accepted, non-invasive method of monitoring the degree of hepatic inflammation, while improvement of liver histology, or at least prevention of further deterioration, is the ultimate clinical objective.
Regarding reduction and elimination of HCV-RNA, response rates were generally low in all of the phase II and phase III studies, with no significant differences between Ribavirin and placebo (or any evidence of a trend in favour of Ribavirin). This was an unexpected result, especially considering the positive effects of Ribavirin therapy on ALT reduction and the finding herein of the improvement in liver histology. Higher rates of HCV-RNA elimination have been reported during interferon therapy of hepatitis C, but following withdrawal of therapy the great majority of patients eventually become HCV-RNA positive again. It is not known how elimination of HCV-RNA relates to improvement in liver histology, which is the ultimate clinical objective. Until recently it has been generally accepted that the primary objective should be eradication of viremia, the assumption being that clinical benefit cannot be expected if viremia persists. The efficacyof Ribavirin against the biochemical and histological parameters of hepatic inflammation without an accompanying reduction of viremia we found changes this assumption. While the eradication of viremia would appear to be a logical objective of treatment, we have found that such eradication is clearly not a prerequisite for clinical improvement in all patients. As the hepatitis C virus, like other RNA viruses, does not exist as a single entity butas a mixture of sub-species, it is, we believe, that Ribavirin inhibits the mostpathogenic subpopulation of viruses while leaving other populations relatively unaffected. The liver cell and cells and, thus, the liver is thus protected against the chronic pro-inflammatory effect of viremia. Also, the practicality of eradication of viremia as the primary objective of treatment cannow be considered in light of our discovery and developments.
2l35669 While interferon can be effective in the short term, this agent is not suitable for the long term maintenance therapy required to prevent relapse, due to poor tolerability, some serious adverse reactions and the unacceptability of long term injection therapy. Thus long-term control of the hepatitis C disease process and prevention of liver damage should be the primary objective of treatment, at least in those patients in whom attempts to eradicate viremia have failed. Due to its oral administration and good tolerability Ribavirin is a suitable agent for the long-term amelioration of theeffects of chronic hepatitis C infection on the liver (beyond a year). As we have found positive correlation between ALT reduction and improvement in liver histology, routine monitoring of the response to treatment is simple and non-invasive. ~hese same properties facilitate the introduction of active treatment at an earlier stage of disease, the objective being to prevent the progression of even minimal liver damage.
In the phase III clinical program, the efficacy of Ribavirin in terms of reducing ALT levels appeared to be dose-related. In one study (CT00/002) dose was determined at baseline according to weight, and in all studies the variation in patients' weight, permitted discrimination between patients on the basis of the daily dose calculated as mg per kg. It was thus possible to perform an analysis of dose response. Guidance for the choice of the standard daily dose of Ribavirin for the phase III studies (1200mg) was provided by the results of -he phase II study (90-DK-49), in which the dose varied from 600 mg to 1200 mg according to efficacy and tolerability (with no adjustment by patient weight). This study was small but indicated that efficacy in reducing ALT levels was dose-related within the dose range employed in the study, while the high dose was as well tolerated as the low dose. We have descovered that the pharmacokinetics of Ribavirin are linear over the dose range 600-2400 mg/day.
The effect of Ribavirin on symptoms of hepatitis was assessed in two of the phase III studies. In one study (92-001), Ribavirin improved fatigue ~135669 in comparison to placebo. There were no significant differences for other symptoms. In another study (91-DK-178), Ribavirin did not differ from placebo in the effect on symptoms.
There was no apparent effect of age, but females had a higher response rate than males (60% versus 40%, p=0.046). We determined this was in fact a dose effect, due to the lower weights of females. Regarding baseline characteristics, there were trends towards lower response rates in patients with the highest baseline ALT levels and total Knodell scores because we believe these patients probably had more severe disease in the first place.
There was no apparent effect of duration of hepatitis or previous exposure to interferon on ALT response.
Furthermore, there is no evidence we have found of loss of ALT
response with increasing duration of treatment. Therefore, we predict on the basis of our tests that treatment can be carried out indefinitely to protect theliver.
We have therefore found that Ribavirin in the treatment of hepatitis C is, according to one important aspect of our invention, a hepato-protecting agent, which acts to protect the liver even if the Ribavirin is unable to eradicate or eliminate the virus from the liver. The liver is protected. As aresult, because Ribavirin is well tolerated and can be taken for a substantial period of time (for example, for years), the applicants have discovered that thetreatment of hepatitis C, and, in one embodiment, chronic hepatitis C, would involve the administration of an effective hepato protecting amount of Ribavirin to the patient (for example, 1200 mg of Ribavirin in a suitable oral dosage form per day) for a substantial period (for example, for in excess of 12 months). For the protection of the liver, other dosage amounts can be given according to our invention. The tests have found the above amounts well-tolerated and successful, and the duration of treatment appropriate. The dosage forms themselves may comprise the known 200 mg capsules [containing 200 mg Ribavirin, 50 mg Avicel, 46 mg Lactose, and 4 mg Magnesium Stearate in a #1 shell 21 mm long by 71/2 mm in width] taken three at a time twice a day, or better still two, according to our invention twoat a time, a total of 300 mg capsules taken (for a total of 12 mg) twice daily for 1200 mg per day, three 400 mg capsules each taken three times daily (for a total of 1200 mg), or two 600 mg capsules taken twice daily all for better patient compliance. Patients, after taking three 200 mg capsules twice daily formonths tire of taking medication. Patients compliance becomes more difficult. Furthermore, it si important not to make the larger dosage sizes too large so that the patient is uncomfortable taking the medication.
Furthermore, immediate release formulations are desired with preferably large amounts of Ribavirin being included in each formulation relative to the total weight of the formulation, for example, greater than 70% of the formulation by weight (excluding the weight of any covering, for example, capsule shell) being Ribavirin with the maximum amount of about less than 80% by weight of the formulation. In a number of formulations, they may be manufactured according to aspects of embodiments of our invention as follows:
STRENGTH OF CAPSULE: 300 mg 400 mg 600 mg COMPOSITION:
(a) Ribavirin - active medicine 300 mg 400 mg 600 mg (b) Diluent, for example: 75 mg 100 mg 150 mg Avicel - a type of cellulose for diluting the active (c) Filler and Diluent, Lactose 29 mg 62 mg 63 mg (d) Dispersant - Magnesium Stearate 6 mg 8 mg 12 mg - dispersant, Lubricant F;ll Wt. 410mg 570mg 825mg Shell SizeforCapsule: # # #
Length 23 mm 25 mm 28 mm Width 8 mm 9 mm 10 mm , 2l3~669 Ribavirin (VirazoleTM) 300 mg, 400 mg & 600 mg Capsules: theoretical, immediate release formula.
Benefits: patient compliance - both sizes and amounts, for example:
300 mg: 2 capsules in the morning, 2 capsules in the evening 400 mg:
one capsule three times a day 600 mg: one capsule twice a day For assisting doctors or patients with patient compliance, the capsules may be put on a strip and provided in seven-day dosage amounts on, for example, tear strips (blister packages) from which individual doses (for example) may be removed one at a time, so that the patient knows whether or not he/she has taken the appropriate dosage that day. In this regard, see Figures 1 to 6 which are discussed hereinafter. The material shown in the strips are blister packs in which one capsule is located in each blister. Each strip is perforated so that one capsule can be removed at one time from the strip. The packaging components used for manufacturing, for example, the four strips of six capsules per strip (totalling 24 capsules shown in FIgure 2) may consist of a polyvinyl chloride blister, with a punch out foil backing.
The finished package will be four strips of six capsules per strip or 24 capsules.
Each blister may be made with the following material: the blister material may be Genotherm 1001 C Natural; Foil Backing may be a thin aluminium foil with an outside lacquer of of polyester and an inside lacquer of VCVDC
(vinyl chloride vinylidenchloride (copolymer)). The strips may be packed in a carton which may be a pre-printed chip-board carton to enclose the four strips of blister capsules.
Additionally, the strips can be provided in specified daily amounts, for example, a four day amount which a doctor may give to a patient for testing over a four-day period to help determine whether or not the patient is sensitive to Ribavirin and is able to take the desired dosage amount of Ribavirin. For example, a four-day test strip may amount to twenty-four 200 mg capsules provided in a blister pack which is handed to the 21~5669 patient thereby providing a dosage amount of six capsules in four rows, three capsules taken at each dosage administration, giving 600 mg twice daily for four days. The blister package strips of Ribavirin may also constitute a week supply, two weeks supply, etc. to ensure patient compliance. In this way the patient is easily able to comply knowing what strip should be removed from what row as rows may be numbered and removing the appropriate amount at each dosage time.
The analyses of safety indicate that Ribavirin is a well-tolerated therapy. This low toxicity profile is demonstrated through analyses of the clinical studies in the treatment of hepatitis C as well as through review of individual study reports and review of published literature. No patients died during Ribavirin therapy; one patient died in the follow-up phase due to a condition which pre-dated exposure to Ribavirin. Out of 159 patients with chronic hepatitis C exposed to Ribavirin for periods ranging from 12-48 weeks, only 5 (3%) were withdrawn due to adverse events. Apart from one patient who developed anemia, none of the serious adverse events or withdrawals appeared to be related to Ribavirin. There was no pattern in the events occurring in these patients, and the events could not be explained by any known pharmacological effects of Ribavirin.
The most common side effect of Ribavirin is a mild, reversible hemolytic anemia which occurs in a substantial proportion of patients treated. This anemia can be a serious event in patients with impaired renal function, but in the great majority of patients with normal renal function it isa benign, self-limiting condition which is often asymptomatic, and is easy to recognize and manage. Ribavirin is contraindicated in patients with chronic anemia and a hemoglobin level below 10 gm/dL.
Apart from anemia, the only adverse event which was statistically significant more frequent in the Ribavirin group compared to the placebo group was pruritus. There appeared to be a non-statistically , ~13S669 significant trend towards a higher frequency of certain central nervous system events (e.g., depression, nervousness) in the Ribavirin group.
Ribavirin therapy was associated with a slight elevation of the serus uric acid level and of the platelet count. The size of these elevations was not clinically significant and there were no reports of gout attacks or any effects related to elevated platelet count. The effect on the serum uric acid level may relate to metabolism of Ribavirin to urates. The effect on the platelet count had been observed in animal toxicology studies and the significance of the finding is not known.
No other effects of treatment on laboratory parameters were identified. Apart from the one patient who withdrew from treatment due to anemia, there were no withdrawals due to laboratory abnormalities.
Ribavirin has no known drug interactions, although interactions with agents other than theophylline have not been studied. No long-term adverse effects or withdrawal effects have been identified. There is no known potential for abuse, and no experience for overdose. Thus Ribavirin can be used for long periods of time.
Therefore, according to one aspect of the invention, Applicants have developed a new use for ribavarin namely, the use of ribavirin as ~1 hepato(liver) protecting agent (for example, when treating hepatitis C).
In this regard, while the administration of ribavirin doe~ - ot eradicate the hepatitis C virus from the liver, its administration protects the L.~er, (as for example, determined from liver biopsies). In protecting the liver, the ribavirin prevents the condition of the liver from worsening and, in many cases, improves the condition of the liver. Thus, ribavarin protects the liver.
According to another aspect of the invention, a method of protecting the liver from viral diseases comprises administering an effective amount of ribavarin (for example, 1200 mg daily) to a patient in need of such protection (for example, a patient suffering from chronic hepatitis C) for a 21~s669 prolonged period of time (for example, for in excess of one year) to protect thepatient's liver.
According to another aspect of the invention, the use of ribavarin is provided in the manufacture a pharmaceutical composition for the use as a hepato (liver) protecting agent. The ribavirin may be used to manufacture dosage forms which can be administered in effective dosage amounts (for example, 1200 mg daily) to the patient whose liver is in need of protection (because the patient is for example, suffering from chronic hepatitis C). The pharmaceutical composition may comprise suitable excipients (such as fillers, diluents, flow enhancers). However, preferably each dosage form comprises ribavirin in excess of 70% (by weight) of the dosage amount of the active and excipients to ensure that the amount of ribavirin administered is maximized while minimizing the size of the dosage form so that the patient can take a minimum dosage size containing a maximum amount of ribavarin to ease patient compliance (who must take dosages every day). Preferably, the amount of ribavirin in the dosage exceeds 70% for example, the amount of ribavarin is 80% or more of the dosage amount of active and excipients (by weight) while ensuring the filling has the appropriate amount of excipients to ensure proper dispersion in the patient's system.
The invention does not just have application to patients infected with hepatitis C. The inventors aiso envisage application to the treatment of patients having other viruses which viruses affect the liver. Thus, the use ribavarin as a hepato (liver) protecting agent is not limited to patients suffering from hepatitis C.
Furthermore, because of Applicants' invention, a maintenance therapy can be provided which involves the use of ribavarin for maintenance of the condition of a patient's liver, even when the patient is being treated with other medicines.
~35669 An overview of clinical studies is provided hereinafter:
Adequate and well-controlled studies have shown that oral Ribavirin can produce clinically meaningful effects in patients with chronic hepatitis C, including normalization or reduction of ALT levels and improvement in liver histology.
Three placebo-controlled studies of Ribavirin in the treatment of chronic hepatitis C were conducted. These studies included 134 patients treated with Ribavirin and 97 patients who received placebo. There were also two uncontrolled Phase II studies including a total of 23 patients treated with Ribavirin. The primary response parameter was normalization or reduction of serum ALT levels. Response was also assessed in terms of elimination or reduction of serum HCV RNA levels, and improvement in liver histology as assessed by changes in Knodell scores.
In all of the controlled and uncontrolled studies, using the definitions of response specified in the protocols and analysis plans, Ribavirinwas statistically significantly superior to placebo in normalizing and reducing ALT levels during treatment. In the integrated analyses based on all patients in the controlled studies, using a uniform definition of response including normalization of ALT at the end of treatment or a clinically meaningful level of partial response, 46% of Ribavirin patients were responders compared to 4% of placebo controls (p<0.001). Patients generally responded after two to three months of treatment and the response was maintained as long as treatment was continued. There was no evidence of loss of ALT response with increasing duration of treatment. Following withdrawal of Ribavirin at the end of the active treatment phase, 11.5% of responders had a sustained response throughout the follow-up period.
Regarding improvement in liver histology, in each of the controlled studies there was a non-significant trend in favour of Ribavirin in the changes in total Knodell scores and many of the component scores.
Analysis of the combined data by analysis of covariance using the baseline , 213~669 Knodell score as covariate resulted in statistically significant differences in favour of Ribavirin for the total score and each of the component scores.
Thus in the controlled studies, in comparing all Ribavirin-treated patients with placebo recipients, Ribavirin had a modest but real effect in improving liver histology. Within the Ribavirin group, comparison of ALT responders and non-responders revealed that ALT responders experienced a significantly greater improvement in liver histology as compared to ALT non-responders.
The mean fall in total Knodell score was approximately two points for ALT
responders as compared to one point for all Ribavirin-treated patients. A fall in total Knodell score of two points is generally considered by hepatologists tobe clinically significant. There was thus a statistically significant positive correlation between ALT -esponse and a clinically significant degree of improvement in liver histology.
In all studies, the primary end point was defined as a reduction in ALT level. In all studies a complete ALT response was defined as normalization of the ALT level at the end of treatment. A partial ALT
response was defined as either a 50% or greater reduction at the end of treatment from the patient's baseline value, or a 50% or greater reduction to a level not higher than 1.5 times the upper limit of normal.
Table 1 (see page 15) displays the response rates in terms of improvement in liver histology. There were no statistically significant differences between the treatment groups in the changes in Knodell scores in any of the studies, although there were numerical trends in favour of Ribavirin. In study CT00/002 there was a difference in favour of Ribavirin in one of the secondary parameters (lymphoid aggregates, p.=0.05).
In studies 92-001 and 91-DK-178, the treatment groups were compared with respect to the effect of the study medication on symptoms relevant to hepatitis. This could not be done in study CT00/002 because the case report form did not permit the systematic collection of symptom data.
, 2135669 In study 92-001, there was a statistically significant difference in favour of Ribavirin for decreased fatigue. At the end of treatment and at the end of the follow-up period, a higher proportion of Ribavirin patients showed some improvement from baseline in fatigue compared to placebo patients (p=0.04 for end of treatment and p=0.006 for end of follow-up). In this study there were no slgnificant differences between the treatment groups for any other symptoms.
In study 91-DK-178, there were isolated significant differences between the treatment groups in individual symptoms at individual visits, some favouring the placebo group and some the Ribavirin group, but there were no overall trends favouring either treatment group.
2l~5669 Table 1. Comparison of Results of Controlled Studies - Liver Histology Protocol Protocol Definition of Analysis Plan Result Response Definition of Response 92-001 C o m p a r i s o n o f Same No significant treatment groups difference with respect to the between changes from pre- to treatment post-treatment in groups each patient's Knodell scores 91-DK- Long-term response: C o m p a r i s o n o-f No significant 178 Improvement in liver treatment grou~s difference histopathology by with respect to ~ne between "blinded ranking of changes from pre- to treatment all liver biopsies for post-treatment in groups the degree of current e a c h p a t i e n t ' s hepatic injury using Knodell scores the Wilcoxon rank sum test"
CT00/002 Improvement in Comparison of No significant d e g r e e o f treatment groups difference inflammatory activity with respect to the between from pre- to post- changes from pre- to treatment treatment as assessed post-treatment in groups by Knodell scores e a c h p a t i e n t ' s Knodell scores Pre- to post- Reduction in treatment changes in lymphoid other histological aggregates in parameters thought Ribavirin to be relevant to group hepatitis C
Further analyses were performed in respect of the different studies. However, to make the results of these analyses more meaningful, the control studies data were combined to make the sample sizes larger.
~13S669 Results of Integrated Analyses a. Analysis of Response to Ribavirin According to the Relevant Effectiveness Criteria 1. ALT Response During Ribavirin Therapy For the purposes of the integrated effectiveness analyses, the following definitions of ALT response were used:
Complete Response = return to within the normal range at the end of treatment.
Partial Response = 50% or greater reduction from the patient's baseline level to within 1.5 times the upper limit of normal at the end of treatment.
"Responder" = meets above definitions of either complete or partial response.
The definition of "responder" was determined by plotting the ALT
values over time for the groups of patients fitting various definitions of response employed within each study. The data were fitted with a cubic spline smoothing function (Reinsch 1967). Three definitions of response were used:
a. Complete response = ALT in normal range at end of treatment.
b. Partial response(A) = 50% or greater reduction from the patient's baseline level to within 1.5 times the upper limit of normal at the end of treatment.
2I3566~9 c. Partial response(B) = 50% or greater reduction from the patient'sbaseline level at the end of treatment.
All other patients were considered non-responders. Plots were alsc. constructed for Ribavirin-treated non-responders within each stuày and for all placebo patients (responders and non-responders) within each study.
The three curves for "complete response" demonstrated that this response was achieved after approximately one third of the treatment period and was maintained thereafter. The three curves for "partial response(A)" demonstrated a similar pattern of response. The three curves for "partial response(B)" demonstrated distinctly more variability of ALT levels during the treatment periods. The plots for Ribavirin-treated non-responders and the plots for placebo patients demonstrated, as expected, a dispersion of the data points which did not change in any recognizable pattern across the treatment and follow-up periods. It was decided that the "partial response(B)" definition was inappropriate for the purpose of the integrated effectiveness analyses.
Due to the consistent pattern of response demonstrated by the "complete response" and "partial response(A)" definitions, and the fact that these definitions are clinically meaningful, it was decided that for the purpose of the integrated effectiveness analyses a "response" be defined as either "complete response" or "partial response(A)."
Table 2 displays the results for each study and for the combined database, using the above definition of ALT response. The proportions of responders in the two treatment groups were compared using either a Chi-square or Fisher's Exact test.
213~69 Table 2. Percent ALT Response Rates Study Ribavirin Placebo p Value n/N (%) n/N (%) 92-001 15/28 (53.6) 1/30 (3.3) <0.001 91-DK-178 11/29 (37.9) 1/29 (3.4) <0.001 CT00/002 32/70 (45.7) 2/36 (5.6) <0.001 Combined 58/127 (45.7) 4/95 (4.2) <0.001 database n = Number of pat ents with an ALT response (integrated def nition) N = All patients treated (intent-to-treat population) minus those without valid non-missing observations.
For the purpose of identifying the ALT value corresponding to the end of treatment, the last valid, non-missing observation, going back a maximum of two visits, was carried forward for those patients missing such a true value. This same policy was employed in two out of the three controlled studies (91-DK-178 and CT00/002). Nine patients in the Ribavirin group and two placebo patients did not have such a valid non-missing observation available.
The ALT response rates were consistent across the three controlled studies and ranged from 37.9 to 53.6%. When the data were combined the ALT response rate was 45.7%. In all instances, the ALT
response rates for patients treated with Ribavirin were statistically significantly superior to the rates in patients treated with placebo. In the placebo group, ALT response rates were consistently low and ranged from 3.3 to 5.6% and 4.2% when the data were combined.
2. ALT Response in the Follow-Up Period Table 3 summarizes the rates of sustained response in studies 92-001 and 91-DK-178 and in these two studies combined. The individual study analysis plan definitions of sustained response are used. A
~1356~9 sustained responder is essentially a patient with either normalization of ALT or a partial response at the end of treatment, who still meets either of these criteria throughout the follow-up period. It was not possible to provide this same analysis for study CT00/002 because too few patients had complete ALT data throughout the follow-up period.
Table 3. Percent ALT Sustained Response Rates - Protocol Definitions Study Ribavirin Placebo n/N (%) n/N (%) 92-001 1/15 (6.7) 0/1 (0.0) 91-DK-178 2/11(18.2) 0/1 (0.0) Combined database 3/26 (11.5) 0/2 (0.0) n = Number of patients w th a sustained ALT response N = Number of patients with complete or partial response at the end of treatment (study analysis plan definitions) In the two studies analyzed, the sustained ALT response rates were 6.7 and 18.2% for Ribavirin-treated patients compared with 0% for patients receiving placebo.
Due to the low sample size and the very low number of placebo responders a statistical analysis was not performed.
Improvement in Knodell Scores Within each of the three controlled studies, there was a consist~nt numerical trend in favour of Ribavirin in the changes in total scores and in many of the component scores. This same trend was thus apparent when the data from the three studies was combined. The trend applies not only to improvement of scores but also to worsening, indicating that even if no patients in either treatment group improve, then fewer patients in the Ribavirin group are worsening. This is an important observation considering that one objective of treatment is to prevent deterioration of a chronic and progressive condition. Analysis of the combined data by the CMH chi-square test does not reveal any statistically significant differences. Analysis of the combined data by analysis of variance (as used in studies 92-001 and 91-DK-178) revealed a statistically significant difference in favour of Ribavirin for the total Knodell score but not for any ofthe component scores.
The liver histology data was examined further by analysis of covariance, using the baseline Knodell score as covariate. Regression analysis of the baseline Knodell scores versus the end of treatment scores for all Ribavirin-treated and placebo patients combined resulted in a slope of less than 1.0 but greater than zero. This indicated that the baseline Knodell score influenced the expectation of outcome of treatment, regardless of any difference between Ribavirin and placebo. Where the regression slope differs markedly from 1.0, analysis of covariance is a more appropriate test than analysis of variance (Fisher 1951). The result of the analysis of covariance is displayed in Table 4. The mean changes in the scores for Ribavirin-treated patients are only small, but due to small variances the differences from placebo are statistically significant. It is of interest to note that the only Knodell sub-score that does not improve is fibrosis, and that there is less deterioration in the Ribavirin group than in the placebo group.
~135669 Table 4. Comparison of Ribavirin and Placebo in Terms of Changes in Knodell Scores from Baseline to End of Treatment -- Analysis of Covariance Using Baseline Knodell Score as Covariate All Phase III Studies Combined Mean Change in Score from Baseline to End of Treatment Knodell Ribavirin Placebo Component N = 107 N = 78 p Value Periportal Activity and -0.40 -0.01 0.0004 Necrosis Portal -0.30 -0.10 0.0206 Inflammation Lobular -0.33 -0.13 0.0019 Necrosis Fibrosis +0.07 +0.25 0.0071 Total score -1.11 -0.05 0.0001 E~amination of Correlation Between ALT Response and Improvement in Knodell Scores In each of the three controlled studies, Ribavirin was significantly more effective than placebo in normalizing and reducing ALT
levels. (An elevated serum ALT level is a biochemical indicator of hepatic inflammation.) Was there also a correlation between response to Ribavirin therapy in terms of normalization or reduction of ALT level within individual patients and by an improvement in liver histology as determined by Knodell scores. We found that there was indeed a consistent trend towards a positive relationship between ALT response and improvement in Knodell scores when both parameters are treated in a categorical manner. In the combined database, this trend was statistically significant for the Total Knodell score (p = 0.008), Fibrosis (p = 0.014), and Portal Inflammation (p =
0.022) using the Cochran-Mantel-Haenszel (CMH) chi-square test (Table 5 through Table 7).
- 23 - ~135 6 6 9 Table 5. Knodell Response Status by Controlled Studies --Total by ALT Response Responder Non-responder Protocol Response n % n % P-Value 1 92-001 Improved 7 46.7 4 33.3 0.099 Unchanged 7 46.7 3 25.0 Worsened 1 6.7 5 41.7 91-DK-178 Improved 10 90.9 7 38.9 0.021 *
Unchanged 1 9.1 5 27.8 Worsened O 0.00 6 33.3 CT00/002 Improved 11 42.3 12 48.0 0.171 Unchanged 11 42.3 5 20.0 Worsened 4 15.4 8 32.0 Integrated Improved 28 53.8 23 41.8 0.008 $
Unchanged 19 36.5 13 23.6 Worsened 5 9.6 19 34.5 N = Number of patients in study n - Number of patients in response category % = (n/N)*100 1 Cochran-Mantel-Haenszel Statistic * P<0.05 ~13566g Table 6. Knodell Response Status by Controlled Studies --Fibrosis by ALT Response Responder Non-responder Protocol Response n % n % P-Value 1 92-001 Improved 2 13.3 1 0.0 0.434 Unchanged 12 80.0 11 91.7 Worsened 1 6.7 1 8.3 91-DK-178 Improved 5 45.5 2 11.1 0.119 Unchanged 4 36.4 11 61.1 Worsened 2 18.2 5 27.8 CT00/002 Improved 6 23.1 1 4.0 0.120 Unchanged 18 69.2 20 80.0 Worsened 2 7.7 4 16.0 Integrated Improved 13 25.0 3 5.5 0.014 *
Unchanged 34 65.4 42 76.4 Worsened 5 9.6 10 18.2 N = Number of patients in study n - Number of patients in response category % = (n/N)*100 1 Cochran-Mantel-Haenszel Statistic * PcO.05 ~c~l3s669 Table 7. Knodell Response Status by Controlled Studies --Portal Tnflammation by ALT Response Responder Non-responder Protocol Response n % n % P-Value 1 92-001 Improved 5 33.3 3 25.0 0.220 Unchanged 9 60.0 5 41.7 Worsened 1 6.7 4 33.3 91-DK-178 Improved 5 45.5 4 22.2 0.227 Unchanged 6 54.5 11 61.1 Worsened 0 0.0 3 16.7 CT00/002 Improved 5 19.2 6 24.0 0.159 Unchanged 21 80.8 16 64.0 Worsened 0 0.0 3 12.0 Integrated Improved 15 28.8 13 23.6 0.022 *
Unchanged 36 69.2 32 58.2 Worsened 1 1.9 10 18.2 N = Number of patients in study n - Number of patients in response category % = (n/N)*100 1 Cochran-Mantel-Haenszel Statistic * P<0.05 The relationship between ALT response and improvement in liver histology was studied further in order to quantify the improvement in liver histology in patients responding to Ribavirin, and to determine if there was a subgroup of patients who derive a more substantial clinical benefit from treatment with Ribavirin. In each of the three controlled studies, Ribavirin-treated ALT responders and non-responders were compared in terms of the mean changes in total Knodell scores over the course of treatment. This analysis, displayed in Table 8 thus quantifies the directional changes displayed in Table 5.
~135669 It can be seen that in each study there was a correlation between ALT response and improvement in liver histology, in that ALT
response was associated with a greater improvement in liver histology as compared to ALT non-responders. This effect was particularly striking in study 91-DK-178, where there was a mean Knodell score reduction of 4.09 in ALT responders as compared to 0.17 in ALT non-responders. A regression model was employed to examine the relationship between ALT response and Knodell score changes. This revealed that in all three studies ALT Response was a significant predictor of improvement in liver histology. Thus, ALT
normalization or reduction correlates with improvement in liver histology in patients with hepatitis C treated with Ribavirin, and patients who achieve an ALT response are likely to derive a substantial clinical benefit. In patients treated with Ribavirin who do not achieve an ALT response, there does not appear to be any clinical benefit in comparison to patients who received placebo.
~13~6S9 Table 8.
Study CT00/002 92-001 91-DK-178 Combined Database Duration 24 36 48 of Treatment (Weeks) Mean -1.23 -1.47 -4.09 -1.90 Knodell (-7,4) (-8,2) (-9,0) (-9,4) Change (Range) n = 26 n = 15 n = 11 n = 52 in ALT
Responder s*
Mean -0.96 +0.58 -0.17 -0.36 Knodell (~9'4) (-3.6) (-6,7) (-9,7) Change (Range) n = 25 n = 12 n = 18 n = 55 in ALT
Non-responders P Value ** 0.004 0.0001 0.002 0.0001 Mean -1.10 -0.56 -1.65 -1.11 Knodell (-9,4) (-8,6) (-9.7) (-9.7) Change (Range) n = 51 n = 27 n = 29 n = 107 all Ribavirin Patients Mean -0.09 +0.44 -0.52 -0.51 Knodell (-4.4) (~3'5) (-8,4) (-8,5) Change (Range) n = 23 n = 27 n = 27 n = 77 All Placebo Patients P Value NS NS NS 0.01 * ALT response was defined as normalization at the end of treatment or reduction of 50% or more from baseline to within 1.5 times the upper limit of normal at the end of treatment.
** Regression analysis.
Thus, in summary, the phase III program on Ribavirin in chronic hepatitis C consisted of three randomized, double-blind, placebo-controlled, parallel group studies. A total of 134 patients were randomized to receive Ribavirin and 97 to receive placebo. Response to treatment was assessed using three parameters:
1. Reduction or normalization of the ALT level (elevation of ALT is a biochemical marker of hepatic inflammation).
2. Improvement in liver histology as evidenced by a reduction in the Knodell score (the Knodell scoring system quantifies the degree of liver damage by assigning scores to various relevant microscopic characteristics and summing these sub-scores to give a total score).
3. Elimination of hepatitis C virus from the blood, or a reduction in the amount of virus present.
Of the 134 patients in the phase III studies, there were 101 with complete data on ALT levels, Knodell scores and virus levels. Among these 101 patients, there were 24 patients who met the criteria for an optimal clinical response to Ribavirin therapy. These criteria are:
(a) Normalization or clinically significant reduction of the ALT level, and reduction in total Knodell score of two or more points.
For these 24 patients, the clinical response was obtained without an accompanying reduction in the virus level in the blood. The table below summarizes the data on ALT levels and Knodell scores for the 24 responding patients as compared to the remaining 77 patients who demonstrated lesser degrees of response.
Responders Non-Responders N-24 N=77 Mean baseline ALT 142.5 (52-269) 176.9 (35-629) (range) U/L
Mean end-of-treatment ALT 36.8 (21-62) 91.7 (13-286) (range)~
U/L
Mean Knodell score reduction 4.1 (2-9) 0.15 (-7 to+9) (range) * upper limit or normal is 40 U/L
- 29 ~ 1 35 6 6 9 As many changes can be made to the examples without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.
RIBAVIRIN AS HEPATO (LIVER) PROTECTING AGENT
This invention relates to new uses for Ribavirin, novel uses of Ribavirin for the treatment of chronic hepatitis C, novel methods for treating hepatitis C, and new dosages suitable for use when treating hepatitis C.
Ribavirin was taught in both United States Patents 3,798,209, 3,927,216, and 4,211,771 teaches the processes for treating viral diseases in humans which comprises administering to human patients an antiviral agent which has as its active component the compound Ribavirin. Canadian Patent 1,261,265 relates to formulations and the manufacture of formulations for the medical treatment of viral diseases in humans which are caused by, among other viruses, Arboviruses which included hepatitis C. The formulations taught in that patent comprise an effective non-toxic amount of a composition containing from .01% to 50% by weight of the total weight of the composition of a compound Ribavirin.
In "Pilot study of Ribavirin Therapy for Chronic Hepatitis C"
accepted for publication April 28, 1992 in Hepatology at page 649, the areticle discussed the treatment of a small number of patients with chronic hepatitis C using Ribavirin. In the pilot study itself, Ribavirin was given for six months in doses that increased at two-month intervals from 600 mg to 1,000 mg to 1,200 mg per day. The serum alanine aminotransferase (ALT) levels gradually decreased in all 13 treated patients. In the three to six month periodafter cessation of Ribavirin therapy, serum aminotransferase activities gradually rose to near pre-treatment levels in all but one patient. No significant improvement was seen in liver histological appearance. The article went on to say that these findings suggest that Ribavirin has a beneficial effect in patients with chronic hepatitis C.
Another article entitled "Ribavirin Treatment for Chronic Hepatitis C" published in Lancet,; 1991 (May 4); volume 337: at pages 1058 ~135669 to 1061, discussed the treatment of ten patients in a pilot study, all of whom had biopsy-proven chronic non-A, non-B hepatitis and were repeatedly positive for antibodies to hepatitis C virus. The treatment was with oral Ribavirin, 1,000 to 1,200 mg per day in two divided doses for twelve weeks.
Once again, serum ALT levels fell when treated. However, within six weeks of the end of treatment, the median serum alanine aminotransferase concentration was not significantly different from that before treatment.
In Hepatology, 1993; volume 18, number 4, pt. 2, a summary entitled "Randomized, Double-Blind Placebo-Controlled Trial of Ribavirin Therapy for Chronic Hepatitis C" is provided wherein 58 patients with chronic hepatitis C entered a randomized, double-blind controlled trial of Ribavirin (600 mg BID orally for twelve months) versus placebo. As in the previous studies, serum ALT values fell, but rose after the cessation of therapy in all but two of four responders. The conclusion from the trial was that prolonged Ribavirin therapy was associated with significant improvement in serum ALT levels (despite unchanged serum HCV RNA
levels) and hepatic lobular mucosis.
The prior patents and articles referred to do not lead the reader to the appreciation that the Ribavirin reduce serum ALT levels in some patients to normal levels where they remain for a prolonged period of time after the suspension of treatment with Ribavirin. Further, there is no appreciation of the ability to treat a patient for a prolonged period of time with Ribavirin, and that as a result of that treatment the serum ALT levels remain normal even after cessation of treatment. Furthermore, there is no teaching that the use of Ribavirin may protect the liver, acting as a hepato-protecting agent, thus at least preventing worsening of the condition of the patient's liver, and, in many cases, improving the condition of the patient's liver.
In treating chronic hepatitis C with the antiviral agent Ribavirin, it would also have been expected by persons skilled in the art that the level of hepatitis C virus would diminish in the liver because Rlbavirin is identified as an antiviral agent. This is surprisingly not the case, however, even though the serum ALT levels reduced.
In the Ribavirin studies carried out in accordance with this invention, the primary response parameter was reduction in serum ALT
levels. Elevation of ALT indicates biochemical evidence of hepatic inflammation, and reduction of the ALT level is an accepted response criterion in clinical studies of therapeutic agents in hepatitis C. In all of the studies in the Ribavirin clinical program, phase II and phase III Ribavirin was significantly superior to placebo in normalizing and reducing ALT levels during treatment. Using the integrated definition of ALT response, which includes normalization of ALT at the end of treatment and a clinically meaningful definition of partial response, 46% of Ribavirin-treated patients were responders compared to 4% of placebo controls (p~0.001). Following withdrawal of Ribavirin, the ALT levels of the majority of responders reverted to baseline levels. However 12% of the patients did maintain the ALT response throughout the follow-up period, and we have discovered that there is a correlation between the rate of sustained response and duration of treatment. The rate of sustained resonse was greater in the study of the longest duration (i.e., 48 weeks) and we expect even a greater sustained response after longer treatment. According to our invention, the effect of treatment on liver histology was assessed in the same manner in each of the phase III studies. The Knodell scoring system was strictly adhered to throughout. For each patient the effect of treatment was determined by the change in score from baseline to the end of therapy. All liver biopsy assessments (taken before and after treatment) were performed in a blinded fashion, by a single pathologist in each of two studies (92-001 and CT00/002), or, in the case of another study (91-DK-178), by two pathologists who agreed on each specimen. In each study, analysis of Knodell scores by the methods specified in the analysis plans did not reveal a statistically significant difference between the treatment groups. In each study, however, there is a consistent numerical trend in favour of Ribavirin in the changes in total scores and in many of the component scores. This same trend is thus apparent when the data from the three studies is combined. The methods of collection of the liver biopsy data described above justify combining the data in this way. It is of interest that the trend applies not only to improvement ofscores but also to worsening, indicating that even if no patients in either treatment group improve, then fewer patients in the Ribavirin group are worsening. This is an important observation considering that one objective of treatment is to prevent deterioration of a chronic and progressive condition. Analysis of the combined data by analysis of covariance using baseline Knodell score as covariate reveals statistically significant differences in favour of Ribavirin for the total Knodell score and for each of the four subscores. This analysis takes into account the baseline variability in Knodell scores, and the tendency for baseline scores at the extremes of the scale to regress to the mean without any treatment effect.
The mean changes in the scores for Ribavirin-treated patients are only small, but due to small variances the differences from placebo are statistically significant. It is of interest to note that the only Knodell sub-score that does not improve is fibrosis, and that there is less deterioration in the Ribavirin group than in the placebo group.
Within the Ribavirin group, comparison of ALT responders and non-responders revealed that ALT responders experienced a significantly greater improvement in liver histology as compared to ALT non-responders.
The mean fall in total Knodell score was approximately two points for ALT
responders as compared to one point for all Ribavirin-treated patients. A fall in total Knodell score of two points is generally considered by hepatologists tobe clinically significant. There was thus a statistically significant positive correlation between ALT response and a clinically significant degree of improvement in liver histology. This is an important finding, as ,2135669 measurement of ALT levels is an accepted, non-invasive method of monitoring the degree of hepatic inflammation, while improvement of liver histology, or at least prevention of further deterioration, is the ultimate clinical objective.
Regarding reduction and elimination of HCV-RNA, response rates were generally low in all of the phase II and phase III studies, with no significant differences between Ribavirin and placebo (or any evidence of a trend in favour of Ribavirin). This was an unexpected result, especially considering the positive effects of Ribavirin therapy on ALT reduction and the finding herein of the improvement in liver histology. Higher rates of HCV-RNA elimination have been reported during interferon therapy of hepatitis C, but following withdrawal of therapy the great majority of patients eventually become HCV-RNA positive again. It is not known how elimination of HCV-RNA relates to improvement in liver histology, which is the ultimate clinical objective. Until recently it has been generally accepted that the primary objective should be eradication of viremia, the assumption being that clinical benefit cannot be expected if viremia persists. The efficacyof Ribavirin against the biochemical and histological parameters of hepatic inflammation without an accompanying reduction of viremia we found changes this assumption. While the eradication of viremia would appear to be a logical objective of treatment, we have found that such eradication is clearly not a prerequisite for clinical improvement in all patients. As the hepatitis C virus, like other RNA viruses, does not exist as a single entity butas a mixture of sub-species, it is, we believe, that Ribavirin inhibits the mostpathogenic subpopulation of viruses while leaving other populations relatively unaffected. The liver cell and cells and, thus, the liver is thus protected against the chronic pro-inflammatory effect of viremia. Also, the practicality of eradication of viremia as the primary objective of treatment cannow be considered in light of our discovery and developments.
2l35669 While interferon can be effective in the short term, this agent is not suitable for the long term maintenance therapy required to prevent relapse, due to poor tolerability, some serious adverse reactions and the unacceptability of long term injection therapy. Thus long-term control of the hepatitis C disease process and prevention of liver damage should be the primary objective of treatment, at least in those patients in whom attempts to eradicate viremia have failed. Due to its oral administration and good tolerability Ribavirin is a suitable agent for the long-term amelioration of theeffects of chronic hepatitis C infection on the liver (beyond a year). As we have found positive correlation between ALT reduction and improvement in liver histology, routine monitoring of the response to treatment is simple and non-invasive. ~hese same properties facilitate the introduction of active treatment at an earlier stage of disease, the objective being to prevent the progression of even minimal liver damage.
In the phase III clinical program, the efficacy of Ribavirin in terms of reducing ALT levels appeared to be dose-related. In one study (CT00/002) dose was determined at baseline according to weight, and in all studies the variation in patients' weight, permitted discrimination between patients on the basis of the daily dose calculated as mg per kg. It was thus possible to perform an analysis of dose response. Guidance for the choice of the standard daily dose of Ribavirin for the phase III studies (1200mg) was provided by the results of -he phase II study (90-DK-49), in which the dose varied from 600 mg to 1200 mg according to efficacy and tolerability (with no adjustment by patient weight). This study was small but indicated that efficacy in reducing ALT levels was dose-related within the dose range employed in the study, while the high dose was as well tolerated as the low dose. We have descovered that the pharmacokinetics of Ribavirin are linear over the dose range 600-2400 mg/day.
The effect of Ribavirin on symptoms of hepatitis was assessed in two of the phase III studies. In one study (92-001), Ribavirin improved fatigue ~135669 in comparison to placebo. There were no significant differences for other symptoms. In another study (91-DK-178), Ribavirin did not differ from placebo in the effect on symptoms.
There was no apparent effect of age, but females had a higher response rate than males (60% versus 40%, p=0.046). We determined this was in fact a dose effect, due to the lower weights of females. Regarding baseline characteristics, there were trends towards lower response rates in patients with the highest baseline ALT levels and total Knodell scores because we believe these patients probably had more severe disease in the first place.
There was no apparent effect of duration of hepatitis or previous exposure to interferon on ALT response.
Furthermore, there is no evidence we have found of loss of ALT
response with increasing duration of treatment. Therefore, we predict on the basis of our tests that treatment can be carried out indefinitely to protect theliver.
We have therefore found that Ribavirin in the treatment of hepatitis C is, according to one important aspect of our invention, a hepato-protecting agent, which acts to protect the liver even if the Ribavirin is unable to eradicate or eliminate the virus from the liver. The liver is protected. As aresult, because Ribavirin is well tolerated and can be taken for a substantial period of time (for example, for years), the applicants have discovered that thetreatment of hepatitis C, and, in one embodiment, chronic hepatitis C, would involve the administration of an effective hepato protecting amount of Ribavirin to the patient (for example, 1200 mg of Ribavirin in a suitable oral dosage form per day) for a substantial period (for example, for in excess of 12 months). For the protection of the liver, other dosage amounts can be given according to our invention. The tests have found the above amounts well-tolerated and successful, and the duration of treatment appropriate. The dosage forms themselves may comprise the known 200 mg capsules [containing 200 mg Ribavirin, 50 mg Avicel, 46 mg Lactose, and 4 mg Magnesium Stearate in a #1 shell 21 mm long by 71/2 mm in width] taken three at a time twice a day, or better still two, according to our invention twoat a time, a total of 300 mg capsules taken (for a total of 12 mg) twice daily for 1200 mg per day, three 400 mg capsules each taken three times daily (for a total of 1200 mg), or two 600 mg capsules taken twice daily all for better patient compliance. Patients, after taking three 200 mg capsules twice daily formonths tire of taking medication. Patients compliance becomes more difficult. Furthermore, it si important not to make the larger dosage sizes too large so that the patient is uncomfortable taking the medication.
Furthermore, immediate release formulations are desired with preferably large amounts of Ribavirin being included in each formulation relative to the total weight of the formulation, for example, greater than 70% of the formulation by weight (excluding the weight of any covering, for example, capsule shell) being Ribavirin with the maximum amount of about less than 80% by weight of the formulation. In a number of formulations, they may be manufactured according to aspects of embodiments of our invention as follows:
STRENGTH OF CAPSULE: 300 mg 400 mg 600 mg COMPOSITION:
(a) Ribavirin - active medicine 300 mg 400 mg 600 mg (b) Diluent, for example: 75 mg 100 mg 150 mg Avicel - a type of cellulose for diluting the active (c) Filler and Diluent, Lactose 29 mg 62 mg 63 mg (d) Dispersant - Magnesium Stearate 6 mg 8 mg 12 mg - dispersant, Lubricant F;ll Wt. 410mg 570mg 825mg Shell SizeforCapsule: # # #
Length 23 mm 25 mm 28 mm Width 8 mm 9 mm 10 mm , 2l3~669 Ribavirin (VirazoleTM) 300 mg, 400 mg & 600 mg Capsules: theoretical, immediate release formula.
Benefits: patient compliance - both sizes and amounts, for example:
300 mg: 2 capsules in the morning, 2 capsules in the evening 400 mg:
one capsule three times a day 600 mg: one capsule twice a day For assisting doctors or patients with patient compliance, the capsules may be put on a strip and provided in seven-day dosage amounts on, for example, tear strips (blister packages) from which individual doses (for example) may be removed one at a time, so that the patient knows whether or not he/she has taken the appropriate dosage that day. In this regard, see Figures 1 to 6 which are discussed hereinafter. The material shown in the strips are blister packs in which one capsule is located in each blister. Each strip is perforated so that one capsule can be removed at one time from the strip. The packaging components used for manufacturing, for example, the four strips of six capsules per strip (totalling 24 capsules shown in FIgure 2) may consist of a polyvinyl chloride blister, with a punch out foil backing.
The finished package will be four strips of six capsules per strip or 24 capsules.
Each blister may be made with the following material: the blister material may be Genotherm 1001 C Natural; Foil Backing may be a thin aluminium foil with an outside lacquer of of polyester and an inside lacquer of VCVDC
(vinyl chloride vinylidenchloride (copolymer)). The strips may be packed in a carton which may be a pre-printed chip-board carton to enclose the four strips of blister capsules.
Additionally, the strips can be provided in specified daily amounts, for example, a four day amount which a doctor may give to a patient for testing over a four-day period to help determine whether or not the patient is sensitive to Ribavirin and is able to take the desired dosage amount of Ribavirin. For example, a four-day test strip may amount to twenty-four 200 mg capsules provided in a blister pack which is handed to the 21~5669 patient thereby providing a dosage amount of six capsules in four rows, three capsules taken at each dosage administration, giving 600 mg twice daily for four days. The blister package strips of Ribavirin may also constitute a week supply, two weeks supply, etc. to ensure patient compliance. In this way the patient is easily able to comply knowing what strip should be removed from what row as rows may be numbered and removing the appropriate amount at each dosage time.
The analyses of safety indicate that Ribavirin is a well-tolerated therapy. This low toxicity profile is demonstrated through analyses of the clinical studies in the treatment of hepatitis C as well as through review of individual study reports and review of published literature. No patients died during Ribavirin therapy; one patient died in the follow-up phase due to a condition which pre-dated exposure to Ribavirin. Out of 159 patients with chronic hepatitis C exposed to Ribavirin for periods ranging from 12-48 weeks, only 5 (3%) were withdrawn due to adverse events. Apart from one patient who developed anemia, none of the serious adverse events or withdrawals appeared to be related to Ribavirin. There was no pattern in the events occurring in these patients, and the events could not be explained by any known pharmacological effects of Ribavirin.
The most common side effect of Ribavirin is a mild, reversible hemolytic anemia which occurs in a substantial proportion of patients treated. This anemia can be a serious event in patients with impaired renal function, but in the great majority of patients with normal renal function it isa benign, self-limiting condition which is often asymptomatic, and is easy to recognize and manage. Ribavirin is contraindicated in patients with chronic anemia and a hemoglobin level below 10 gm/dL.
Apart from anemia, the only adverse event which was statistically significant more frequent in the Ribavirin group compared to the placebo group was pruritus. There appeared to be a non-statistically , ~13S669 significant trend towards a higher frequency of certain central nervous system events (e.g., depression, nervousness) in the Ribavirin group.
Ribavirin therapy was associated with a slight elevation of the serus uric acid level and of the platelet count. The size of these elevations was not clinically significant and there were no reports of gout attacks or any effects related to elevated platelet count. The effect on the serum uric acid level may relate to metabolism of Ribavirin to urates. The effect on the platelet count had been observed in animal toxicology studies and the significance of the finding is not known.
No other effects of treatment on laboratory parameters were identified. Apart from the one patient who withdrew from treatment due to anemia, there were no withdrawals due to laboratory abnormalities.
Ribavirin has no known drug interactions, although interactions with agents other than theophylline have not been studied. No long-term adverse effects or withdrawal effects have been identified. There is no known potential for abuse, and no experience for overdose. Thus Ribavirin can be used for long periods of time.
Therefore, according to one aspect of the invention, Applicants have developed a new use for ribavarin namely, the use of ribavirin as ~1 hepato(liver) protecting agent (for example, when treating hepatitis C).
In this regard, while the administration of ribavirin doe~ - ot eradicate the hepatitis C virus from the liver, its administration protects the L.~er, (as for example, determined from liver biopsies). In protecting the liver, the ribavirin prevents the condition of the liver from worsening and, in many cases, improves the condition of the liver. Thus, ribavarin protects the liver.
According to another aspect of the invention, a method of protecting the liver from viral diseases comprises administering an effective amount of ribavarin (for example, 1200 mg daily) to a patient in need of such protection (for example, a patient suffering from chronic hepatitis C) for a 21~s669 prolonged period of time (for example, for in excess of one year) to protect thepatient's liver.
According to another aspect of the invention, the use of ribavarin is provided in the manufacture a pharmaceutical composition for the use as a hepato (liver) protecting agent. The ribavirin may be used to manufacture dosage forms which can be administered in effective dosage amounts (for example, 1200 mg daily) to the patient whose liver is in need of protection (because the patient is for example, suffering from chronic hepatitis C). The pharmaceutical composition may comprise suitable excipients (such as fillers, diluents, flow enhancers). However, preferably each dosage form comprises ribavirin in excess of 70% (by weight) of the dosage amount of the active and excipients to ensure that the amount of ribavirin administered is maximized while minimizing the size of the dosage form so that the patient can take a minimum dosage size containing a maximum amount of ribavarin to ease patient compliance (who must take dosages every day). Preferably, the amount of ribavirin in the dosage exceeds 70% for example, the amount of ribavarin is 80% or more of the dosage amount of active and excipients (by weight) while ensuring the filling has the appropriate amount of excipients to ensure proper dispersion in the patient's system.
The invention does not just have application to patients infected with hepatitis C. The inventors aiso envisage application to the treatment of patients having other viruses which viruses affect the liver. Thus, the use ribavarin as a hepato (liver) protecting agent is not limited to patients suffering from hepatitis C.
Furthermore, because of Applicants' invention, a maintenance therapy can be provided which involves the use of ribavarin for maintenance of the condition of a patient's liver, even when the patient is being treated with other medicines.
~35669 An overview of clinical studies is provided hereinafter:
Adequate and well-controlled studies have shown that oral Ribavirin can produce clinically meaningful effects in patients with chronic hepatitis C, including normalization or reduction of ALT levels and improvement in liver histology.
Three placebo-controlled studies of Ribavirin in the treatment of chronic hepatitis C were conducted. These studies included 134 patients treated with Ribavirin and 97 patients who received placebo. There were also two uncontrolled Phase II studies including a total of 23 patients treated with Ribavirin. The primary response parameter was normalization or reduction of serum ALT levels. Response was also assessed in terms of elimination or reduction of serum HCV RNA levels, and improvement in liver histology as assessed by changes in Knodell scores.
In all of the controlled and uncontrolled studies, using the definitions of response specified in the protocols and analysis plans, Ribavirinwas statistically significantly superior to placebo in normalizing and reducing ALT levels during treatment. In the integrated analyses based on all patients in the controlled studies, using a uniform definition of response including normalization of ALT at the end of treatment or a clinically meaningful level of partial response, 46% of Ribavirin patients were responders compared to 4% of placebo controls (p<0.001). Patients generally responded after two to three months of treatment and the response was maintained as long as treatment was continued. There was no evidence of loss of ALT response with increasing duration of treatment. Following withdrawal of Ribavirin at the end of the active treatment phase, 11.5% of responders had a sustained response throughout the follow-up period.
Regarding improvement in liver histology, in each of the controlled studies there was a non-significant trend in favour of Ribavirin in the changes in total Knodell scores and many of the component scores.
Analysis of the combined data by analysis of covariance using the baseline , 213~669 Knodell score as covariate resulted in statistically significant differences in favour of Ribavirin for the total score and each of the component scores.
Thus in the controlled studies, in comparing all Ribavirin-treated patients with placebo recipients, Ribavirin had a modest but real effect in improving liver histology. Within the Ribavirin group, comparison of ALT responders and non-responders revealed that ALT responders experienced a significantly greater improvement in liver histology as compared to ALT non-responders.
The mean fall in total Knodell score was approximately two points for ALT
responders as compared to one point for all Ribavirin-treated patients. A fall in total Knodell score of two points is generally considered by hepatologists tobe clinically significant. There was thus a statistically significant positive correlation between ALT -esponse and a clinically significant degree of improvement in liver histology.
In all studies, the primary end point was defined as a reduction in ALT level. In all studies a complete ALT response was defined as normalization of the ALT level at the end of treatment. A partial ALT
response was defined as either a 50% or greater reduction at the end of treatment from the patient's baseline value, or a 50% or greater reduction to a level not higher than 1.5 times the upper limit of normal.
Table 1 (see page 15) displays the response rates in terms of improvement in liver histology. There were no statistically significant differences between the treatment groups in the changes in Knodell scores in any of the studies, although there were numerical trends in favour of Ribavirin. In study CT00/002 there was a difference in favour of Ribavirin in one of the secondary parameters (lymphoid aggregates, p.=0.05).
In studies 92-001 and 91-DK-178, the treatment groups were compared with respect to the effect of the study medication on symptoms relevant to hepatitis. This could not be done in study CT00/002 because the case report form did not permit the systematic collection of symptom data.
, 2135669 In study 92-001, there was a statistically significant difference in favour of Ribavirin for decreased fatigue. At the end of treatment and at the end of the follow-up period, a higher proportion of Ribavirin patients showed some improvement from baseline in fatigue compared to placebo patients (p=0.04 for end of treatment and p=0.006 for end of follow-up). In this study there were no slgnificant differences between the treatment groups for any other symptoms.
In study 91-DK-178, there were isolated significant differences between the treatment groups in individual symptoms at individual visits, some favouring the placebo group and some the Ribavirin group, but there were no overall trends favouring either treatment group.
2l~5669 Table 1. Comparison of Results of Controlled Studies - Liver Histology Protocol Protocol Definition of Analysis Plan Result Response Definition of Response 92-001 C o m p a r i s o n o f Same No significant treatment groups difference with respect to the between changes from pre- to treatment post-treatment in groups each patient's Knodell scores 91-DK- Long-term response: C o m p a r i s o n o-f No significant 178 Improvement in liver treatment grou~s difference histopathology by with respect to ~ne between "blinded ranking of changes from pre- to treatment all liver biopsies for post-treatment in groups the degree of current e a c h p a t i e n t ' s hepatic injury using Knodell scores the Wilcoxon rank sum test"
CT00/002 Improvement in Comparison of No significant d e g r e e o f treatment groups difference inflammatory activity with respect to the between from pre- to post- changes from pre- to treatment treatment as assessed post-treatment in groups by Knodell scores e a c h p a t i e n t ' s Knodell scores Pre- to post- Reduction in treatment changes in lymphoid other histological aggregates in parameters thought Ribavirin to be relevant to group hepatitis C
Further analyses were performed in respect of the different studies. However, to make the results of these analyses more meaningful, the control studies data were combined to make the sample sizes larger.
~13S669 Results of Integrated Analyses a. Analysis of Response to Ribavirin According to the Relevant Effectiveness Criteria 1. ALT Response During Ribavirin Therapy For the purposes of the integrated effectiveness analyses, the following definitions of ALT response were used:
Complete Response = return to within the normal range at the end of treatment.
Partial Response = 50% or greater reduction from the patient's baseline level to within 1.5 times the upper limit of normal at the end of treatment.
"Responder" = meets above definitions of either complete or partial response.
The definition of "responder" was determined by plotting the ALT
values over time for the groups of patients fitting various definitions of response employed within each study. The data were fitted with a cubic spline smoothing function (Reinsch 1967). Three definitions of response were used:
a. Complete response = ALT in normal range at end of treatment.
b. Partial response(A) = 50% or greater reduction from the patient's baseline level to within 1.5 times the upper limit of normal at the end of treatment.
2I3566~9 c. Partial response(B) = 50% or greater reduction from the patient'sbaseline level at the end of treatment.
All other patients were considered non-responders. Plots were alsc. constructed for Ribavirin-treated non-responders within each stuày and for all placebo patients (responders and non-responders) within each study.
The three curves for "complete response" demonstrated that this response was achieved after approximately one third of the treatment period and was maintained thereafter. The three curves for "partial response(A)" demonstrated a similar pattern of response. The three curves for "partial response(B)" demonstrated distinctly more variability of ALT levels during the treatment periods. The plots for Ribavirin-treated non-responders and the plots for placebo patients demonstrated, as expected, a dispersion of the data points which did not change in any recognizable pattern across the treatment and follow-up periods. It was decided that the "partial response(B)" definition was inappropriate for the purpose of the integrated effectiveness analyses.
Due to the consistent pattern of response demonstrated by the "complete response" and "partial response(A)" definitions, and the fact that these definitions are clinically meaningful, it was decided that for the purpose of the integrated effectiveness analyses a "response" be defined as either "complete response" or "partial response(A)."
Table 2 displays the results for each study and for the combined database, using the above definition of ALT response. The proportions of responders in the two treatment groups were compared using either a Chi-square or Fisher's Exact test.
213~69 Table 2. Percent ALT Response Rates Study Ribavirin Placebo p Value n/N (%) n/N (%) 92-001 15/28 (53.6) 1/30 (3.3) <0.001 91-DK-178 11/29 (37.9) 1/29 (3.4) <0.001 CT00/002 32/70 (45.7) 2/36 (5.6) <0.001 Combined 58/127 (45.7) 4/95 (4.2) <0.001 database n = Number of pat ents with an ALT response (integrated def nition) N = All patients treated (intent-to-treat population) minus those without valid non-missing observations.
For the purpose of identifying the ALT value corresponding to the end of treatment, the last valid, non-missing observation, going back a maximum of two visits, was carried forward for those patients missing such a true value. This same policy was employed in two out of the three controlled studies (91-DK-178 and CT00/002). Nine patients in the Ribavirin group and two placebo patients did not have such a valid non-missing observation available.
The ALT response rates were consistent across the three controlled studies and ranged from 37.9 to 53.6%. When the data were combined the ALT response rate was 45.7%. In all instances, the ALT
response rates for patients treated with Ribavirin were statistically significantly superior to the rates in patients treated with placebo. In the placebo group, ALT response rates were consistently low and ranged from 3.3 to 5.6% and 4.2% when the data were combined.
2. ALT Response in the Follow-Up Period Table 3 summarizes the rates of sustained response in studies 92-001 and 91-DK-178 and in these two studies combined. The individual study analysis plan definitions of sustained response are used. A
~1356~9 sustained responder is essentially a patient with either normalization of ALT or a partial response at the end of treatment, who still meets either of these criteria throughout the follow-up period. It was not possible to provide this same analysis for study CT00/002 because too few patients had complete ALT data throughout the follow-up period.
Table 3. Percent ALT Sustained Response Rates - Protocol Definitions Study Ribavirin Placebo n/N (%) n/N (%) 92-001 1/15 (6.7) 0/1 (0.0) 91-DK-178 2/11(18.2) 0/1 (0.0) Combined database 3/26 (11.5) 0/2 (0.0) n = Number of patients w th a sustained ALT response N = Number of patients with complete or partial response at the end of treatment (study analysis plan definitions) In the two studies analyzed, the sustained ALT response rates were 6.7 and 18.2% for Ribavirin-treated patients compared with 0% for patients receiving placebo.
Due to the low sample size and the very low number of placebo responders a statistical analysis was not performed.
Improvement in Knodell Scores Within each of the three controlled studies, there was a consist~nt numerical trend in favour of Ribavirin in the changes in total scores and in many of the component scores. This same trend was thus apparent when the data from the three studies was combined. The trend applies not only to improvement of scores but also to worsening, indicating that even if no patients in either treatment group improve, then fewer patients in the Ribavirin group are worsening. This is an important observation considering that one objective of treatment is to prevent deterioration of a chronic and progressive condition. Analysis of the combined data by the CMH chi-square test does not reveal any statistically significant differences. Analysis of the combined data by analysis of variance (as used in studies 92-001 and 91-DK-178) revealed a statistically significant difference in favour of Ribavirin for the total Knodell score but not for any ofthe component scores.
The liver histology data was examined further by analysis of covariance, using the baseline Knodell score as covariate. Regression analysis of the baseline Knodell scores versus the end of treatment scores for all Ribavirin-treated and placebo patients combined resulted in a slope of less than 1.0 but greater than zero. This indicated that the baseline Knodell score influenced the expectation of outcome of treatment, regardless of any difference between Ribavirin and placebo. Where the regression slope differs markedly from 1.0, analysis of covariance is a more appropriate test than analysis of variance (Fisher 1951). The result of the analysis of covariance is displayed in Table 4. The mean changes in the scores for Ribavirin-treated patients are only small, but due to small variances the differences from placebo are statistically significant. It is of interest to note that the only Knodell sub-score that does not improve is fibrosis, and that there is less deterioration in the Ribavirin group than in the placebo group.
~135669 Table 4. Comparison of Ribavirin and Placebo in Terms of Changes in Knodell Scores from Baseline to End of Treatment -- Analysis of Covariance Using Baseline Knodell Score as Covariate All Phase III Studies Combined Mean Change in Score from Baseline to End of Treatment Knodell Ribavirin Placebo Component N = 107 N = 78 p Value Periportal Activity and -0.40 -0.01 0.0004 Necrosis Portal -0.30 -0.10 0.0206 Inflammation Lobular -0.33 -0.13 0.0019 Necrosis Fibrosis +0.07 +0.25 0.0071 Total score -1.11 -0.05 0.0001 E~amination of Correlation Between ALT Response and Improvement in Knodell Scores In each of the three controlled studies, Ribavirin was significantly more effective than placebo in normalizing and reducing ALT
levels. (An elevated serum ALT level is a biochemical indicator of hepatic inflammation.) Was there also a correlation between response to Ribavirin therapy in terms of normalization or reduction of ALT level within individual patients and by an improvement in liver histology as determined by Knodell scores. We found that there was indeed a consistent trend towards a positive relationship between ALT response and improvement in Knodell scores when both parameters are treated in a categorical manner. In the combined database, this trend was statistically significant for the Total Knodell score (p = 0.008), Fibrosis (p = 0.014), and Portal Inflammation (p =
0.022) using the Cochran-Mantel-Haenszel (CMH) chi-square test (Table 5 through Table 7).
- 23 - ~135 6 6 9 Table 5. Knodell Response Status by Controlled Studies --Total by ALT Response Responder Non-responder Protocol Response n % n % P-Value 1 92-001 Improved 7 46.7 4 33.3 0.099 Unchanged 7 46.7 3 25.0 Worsened 1 6.7 5 41.7 91-DK-178 Improved 10 90.9 7 38.9 0.021 *
Unchanged 1 9.1 5 27.8 Worsened O 0.00 6 33.3 CT00/002 Improved 11 42.3 12 48.0 0.171 Unchanged 11 42.3 5 20.0 Worsened 4 15.4 8 32.0 Integrated Improved 28 53.8 23 41.8 0.008 $
Unchanged 19 36.5 13 23.6 Worsened 5 9.6 19 34.5 N = Number of patients in study n - Number of patients in response category % = (n/N)*100 1 Cochran-Mantel-Haenszel Statistic * P<0.05 ~13566g Table 6. Knodell Response Status by Controlled Studies --Fibrosis by ALT Response Responder Non-responder Protocol Response n % n % P-Value 1 92-001 Improved 2 13.3 1 0.0 0.434 Unchanged 12 80.0 11 91.7 Worsened 1 6.7 1 8.3 91-DK-178 Improved 5 45.5 2 11.1 0.119 Unchanged 4 36.4 11 61.1 Worsened 2 18.2 5 27.8 CT00/002 Improved 6 23.1 1 4.0 0.120 Unchanged 18 69.2 20 80.0 Worsened 2 7.7 4 16.0 Integrated Improved 13 25.0 3 5.5 0.014 *
Unchanged 34 65.4 42 76.4 Worsened 5 9.6 10 18.2 N = Number of patients in study n - Number of patients in response category % = (n/N)*100 1 Cochran-Mantel-Haenszel Statistic * PcO.05 ~c~l3s669 Table 7. Knodell Response Status by Controlled Studies --Portal Tnflammation by ALT Response Responder Non-responder Protocol Response n % n % P-Value 1 92-001 Improved 5 33.3 3 25.0 0.220 Unchanged 9 60.0 5 41.7 Worsened 1 6.7 4 33.3 91-DK-178 Improved 5 45.5 4 22.2 0.227 Unchanged 6 54.5 11 61.1 Worsened 0 0.0 3 16.7 CT00/002 Improved 5 19.2 6 24.0 0.159 Unchanged 21 80.8 16 64.0 Worsened 0 0.0 3 12.0 Integrated Improved 15 28.8 13 23.6 0.022 *
Unchanged 36 69.2 32 58.2 Worsened 1 1.9 10 18.2 N = Number of patients in study n - Number of patients in response category % = (n/N)*100 1 Cochran-Mantel-Haenszel Statistic * P<0.05 The relationship between ALT response and improvement in liver histology was studied further in order to quantify the improvement in liver histology in patients responding to Ribavirin, and to determine if there was a subgroup of patients who derive a more substantial clinical benefit from treatment with Ribavirin. In each of the three controlled studies, Ribavirin-treated ALT responders and non-responders were compared in terms of the mean changes in total Knodell scores over the course of treatment. This analysis, displayed in Table 8 thus quantifies the directional changes displayed in Table 5.
~135669 It can be seen that in each study there was a correlation between ALT response and improvement in liver histology, in that ALT
response was associated with a greater improvement in liver histology as compared to ALT non-responders. This effect was particularly striking in study 91-DK-178, where there was a mean Knodell score reduction of 4.09 in ALT responders as compared to 0.17 in ALT non-responders. A regression model was employed to examine the relationship between ALT response and Knodell score changes. This revealed that in all three studies ALT Response was a significant predictor of improvement in liver histology. Thus, ALT
normalization or reduction correlates with improvement in liver histology in patients with hepatitis C treated with Ribavirin, and patients who achieve an ALT response are likely to derive a substantial clinical benefit. In patients treated with Ribavirin who do not achieve an ALT response, there does not appear to be any clinical benefit in comparison to patients who received placebo.
~13~6S9 Table 8.
Study CT00/002 92-001 91-DK-178 Combined Database Duration 24 36 48 of Treatment (Weeks) Mean -1.23 -1.47 -4.09 -1.90 Knodell (-7,4) (-8,2) (-9,0) (-9,4) Change (Range) n = 26 n = 15 n = 11 n = 52 in ALT
Responder s*
Mean -0.96 +0.58 -0.17 -0.36 Knodell (~9'4) (-3.6) (-6,7) (-9,7) Change (Range) n = 25 n = 12 n = 18 n = 55 in ALT
Non-responders P Value ** 0.004 0.0001 0.002 0.0001 Mean -1.10 -0.56 -1.65 -1.11 Knodell (-9,4) (-8,6) (-9.7) (-9.7) Change (Range) n = 51 n = 27 n = 29 n = 107 all Ribavirin Patients Mean -0.09 +0.44 -0.52 -0.51 Knodell (-4.4) (~3'5) (-8,4) (-8,5) Change (Range) n = 23 n = 27 n = 27 n = 77 All Placebo Patients P Value NS NS NS 0.01 * ALT response was defined as normalization at the end of treatment or reduction of 50% or more from baseline to within 1.5 times the upper limit of normal at the end of treatment.
** Regression analysis.
Thus, in summary, the phase III program on Ribavirin in chronic hepatitis C consisted of three randomized, double-blind, placebo-controlled, parallel group studies. A total of 134 patients were randomized to receive Ribavirin and 97 to receive placebo. Response to treatment was assessed using three parameters:
1. Reduction or normalization of the ALT level (elevation of ALT is a biochemical marker of hepatic inflammation).
2. Improvement in liver histology as evidenced by a reduction in the Knodell score (the Knodell scoring system quantifies the degree of liver damage by assigning scores to various relevant microscopic characteristics and summing these sub-scores to give a total score).
3. Elimination of hepatitis C virus from the blood, or a reduction in the amount of virus present.
Of the 134 patients in the phase III studies, there were 101 with complete data on ALT levels, Knodell scores and virus levels. Among these 101 patients, there were 24 patients who met the criteria for an optimal clinical response to Ribavirin therapy. These criteria are:
(a) Normalization or clinically significant reduction of the ALT level, and reduction in total Knodell score of two or more points.
For these 24 patients, the clinical response was obtained without an accompanying reduction in the virus level in the blood. The table below summarizes the data on ALT levels and Knodell scores for the 24 responding patients as compared to the remaining 77 patients who demonstrated lesser degrees of response.
Responders Non-Responders N-24 N=77 Mean baseline ALT 142.5 (52-269) 176.9 (35-629) (range) U/L
Mean end-of-treatment ALT 36.8 (21-62) 91.7 (13-286) (range)~
U/L
Mean Knodell score reduction 4.1 (2-9) 0.15 (-7 to+9) (range) * upper limit or normal is 40 U/L
- 29 ~ 1 35 6 6 9 As many changes can be made to the examples without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.
Claims (17)
1. Use of ribavirin as a hepato (liver) protecting agent.
2. Use of a pharmaceutical composition containing ribavirin and pharmaceutically acceptable excipients as a hepato (liver) protecting agent.
3. Use of a pharmaceutical composition containing ribavirin and pharmaceutically acceptable excipients as a hepato (liver) protecting agent wherein the amount of ribavirin exceeds 70% by weight of the active and excipients in the pharmaceutical composition.
4. The use of Claim 3 wherein the amount of ribavirin is about 80% by weight of the active and excipients in the pharmaceutical composition.
5. The use of ribavirin in an amount equal to or exceeding 1200 mg daily for a period of at least a year as a hepato (liver) protecting agent.
6. The use of Claim 1, 2, 3, 4 or 5 wherein the ribavirin is substituted by a form of ribavirin in an amount equivalent to the amount of ribavirin.
7. The use of the pharmaceutical composition of Claim 3 or 4 for a period of at least about a year.
8. The use of the pharmaceutical composition of Claim 3, 4 or 7 wherein the ribavirin is in a dosage amount of at least about 1200 mg daily.
9. A pharmaceutical composition comprising ribavirin and pharmaceutically acceptable excipients wherein the amount of ribavirin exceeds 70% by weight of the active and excipients in the pharmaceutical composition.
10. A new use for ribavirin namely, the use of ribavirin as a hepato (liver) protecting agent (for example, when treating hepatitis C).
11. The use of Claim 10 wherein, while the administration of ribavirin does not eradicate the hepatitis C virus from the liver, its administration protects the liver, protecting the liver, wherein the ribavirin prevents the condition of the liver from worsening and, in many cases, improves the condition of the liver.
12. A method of protecting the liver from viral diseases comprising administering an effective amount of ribavirin (for example, 1200 mg daily) to a patient in need of such protection (for example, a patient suffering from chronic hepatitis C) for a prolonged period of time (for example, for in excess of one year) to protect the patient's liver.
13. The use of ribavirin in the manufacture of a pharmaceutical composition for the use as a hepato (liver) protecting agent.
14. The use of Claim 13 wherein the ribavirin may be used to manufacture dosage forms which can be administered in effective dosage amounts (for example, 1200 mg daily) to the patient whose liver is in need of protection (because the patient is for example, suffering from chronic hepatitis C).
15. The pharmaceutical composition of Claim 9 comprising suitable excipients (such as fillers, diluents, flow enhancers).
16. The pharmaceutical composition of Claim 15 wherein each dosage form comprises ribavirin in excess of 70% (by weight) of the dosage amount of the active and excipients to ensure that the amount of ribavirin administered is maximized while minimizing the size of the dosage form so that the patient can take a minimum dosage size containing a maximum amount of ribavirin to ease patient compliance.
17. A maintenance therapy involving the use of ribavirin for maintenance of the condition of a patient's liver, even when the patient is being treated with other medicines.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002135669A CA2135669A1 (en) | 1994-11-10 | 1994-11-10 | Ribavirin as hepato (liver) protecting agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002135669A CA2135669A1 (en) | 1994-11-10 | 1994-11-10 | Ribavirin as hepato (liver) protecting agent |
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| Publication Number | Publication Date |
|---|---|
| CA2135669A1 true CA2135669A1 (en) | 1996-05-11 |
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ID=4154657
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002135669A Abandoned CA2135669A1 (en) | 1994-11-10 | 1994-11-10 | Ribavirin as hepato (liver) protecting agent |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999032128A1 (en) * | 1997-12-22 | 1999-07-01 | Schering Corporation | Orally administrable solid ribavirin dosage forms and process for making them |
| US6720000B2 (en) | 2001-03-19 | 2004-04-13 | Three Rivers Pharmaceutical, Llc | Process for producing wet ribavirin pellets |
| EP1240899A3 (en) * | 1996-01-23 | 2004-05-19 | Ribapharm, Inc. | Modulation of Th1/Th2 Cytokine expression by Ribavirin and Ribavirin analogs in actived T-Lymphocytes for treating HCV infections |
| US7538094B2 (en) | 2002-09-19 | 2009-05-26 | Three Rivers Pharmacueticals, Llc | Composition containing ribavirin and use thereof |
| WO2011029868A1 (en) | 2009-09-11 | 2011-03-17 | Ratiopharm Gmbh | Pharmaceutical formulation containing ribavirin |
-
1994
- 1994-11-10 CA CA002135669A patent/CA2135669A1/en not_active Abandoned
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1240899A3 (en) * | 1996-01-23 | 2004-05-19 | Ribapharm, Inc. | Modulation of Th1/Th2 Cytokine expression by Ribavirin and Ribavirin analogs in actived T-Lymphocytes for treating HCV infections |
| WO1999032128A1 (en) * | 1997-12-22 | 1999-07-01 | Schering Corporation | Orally administrable solid ribavirin dosage forms and process for making them |
| US6051252A (en) * | 1997-12-22 | 2000-04-18 | Schering Corporation | Orally administrable solid dosage form |
| US6335032B1 (en) | 1997-12-22 | 2002-01-01 | Schering Corporation | Orally administrable solid dosage form |
| US6337090B1 (en) | 1997-12-22 | 2002-01-08 | Schering Corporation | Orally administrable solid ribavirin dosage forms and process for making them |
| EP1321147A1 (en) * | 1997-12-22 | 2003-06-25 | Schering Corporation | Orally administrable solid ribavirin dosage forms and process for making them |
| AU762826B2 (en) * | 1997-12-22 | 2003-07-03 | Schering Corporation | Orally administrable solid ribavirin dosage forms and process for making them |
| US6720000B2 (en) | 2001-03-19 | 2004-04-13 | Three Rivers Pharmaceutical, Llc | Process for producing wet ribavirin pellets |
| US7538094B2 (en) | 2002-09-19 | 2009-05-26 | Three Rivers Pharmacueticals, Llc | Composition containing ribavirin and use thereof |
| WO2011029868A1 (en) | 2009-09-11 | 2011-03-17 | Ratiopharm Gmbh | Pharmaceutical formulation containing ribavirin |
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