WO2010040113A1 - Compositions and methods for the treatment of bowel diseases with granulated mesalamine - Google Patents
Compositions and methods for the treatment of bowel diseases with granulated mesalamine Download PDFInfo
- Publication number
- WO2010040113A1 WO2010040113A1 PCT/US2009/059458 US2009059458W WO2010040113A1 WO 2010040113 A1 WO2010040113 A1 WO 2010040113A1 US 2009059458 W US2009059458 W US 2009059458W WO 2010040113 A1 WO2010040113 A1 WO 2010040113A1
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- WO
- WIPO (PCT)
- Prior art keywords
- subject
- granulated mesalamine
- formulation
- granulated
- mesalamine
- Prior art date
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
Definitions
- Ulcerative colitis is an idiopathic, chronic relapsing and remitting, non-specific inflammatory disease of the colonic mucosa. Acute episodes are characterized by chronic diarrhea, rectal bleeding and abdominal pain. Stool volume correlates directly with disease severity, since the colon becomes increasingly unable to reabsorb water and electrolytes as inflammation of the mucosa increases. Loss of water and electrolytes can lead to dehydration, weight loss and serum electrolyte disturbances. Inflammation of the mucosa leads to erosions, which eventually result in rectal bleeding. Anemia and hypoalbuminemia often develop as the disease progresses.
- Muscosal Inflammation also leads to smooth muscle spasm that, in turn, causes urgency to defecate and tenesmus.
- Systemic manifestations include anorexia, weight loss, fatigue, fever, increased sedimentation rate, arthritis, eye inflammation, anxiety, tachycardia, and elevation in liver function tests (LFTs).
- UC also has a profound emotional and social impact on the affected individual.
- the etiology and pathogenesis of UC are multifactorial and incompletely understood.
- One theory is that the disease results from inappropriate activation of the mucosal immune system, resulting in the inflammatory response.
- theories regarding the inappropriate activation suggest a role for genetic predisposition and/or environment triggers.
- UC ulcerative colitis
- Maintenance therapy refers to treatment given to subjects to enable them to stay in remission, to maintain their health in a disease-free, or limited-disease, state. Maintenance medications must be taken for a prolonged period of time.
- the clinical efficacy of oral mesalamine compounds to treat UC has related to delivery of the intact molecule to the colonic mucosa without breakdown during digestion.
- BD bowel diseases
- the present invention features compositions and related methods for treating gastrointestinal disorders, e.g., inflammatory gastrointestinal disorders, irritable bowel disease, gastrointestinal motility disorders, functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), Crohn's disease, ulcerative colitis, and diverticulitis, inflammatory bowel disease, and gastroparesis, with a granulated mesalamine formulation.
- gastrointestinal disorders e.g., inflammatory gastrointestinal disorders, irritable bowel disease, gastrointestinal motility disorders, functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), Crohn's disease, ulcerative colitis, and diverticulitis, inflammatory bowel disease, and gastroparesis
- provided herein are methods of treating a subject having a gastrointestinal disorder comprising administering to the subject an effective amount of a granulated mesalamine formulation; thereby treating the subject.
- a prior treatment of the subject with another formulation of mesalamine has failed.
- the gastrointestinal disorder is selected from the group consisting of: irritable bowel disease, gastrointestinal motility disorders, functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), Crohn's disease, ulcerative colitis (UC), active UC, UC in remission, diverticular disease, inflammatory bowel disease, and gastroparesis.
- the effective amount of granulated mesalamine formulation comprises from between about 0.5 to about 4 g per day.
- the effective amount of granulated mesalamine formulation comprises about 1.5 g per day. In one embodiment, the effective amount of granulated mesalamine formulation comprises about 3 g per day.
- the 1.5 g of granulated mesalamine formulation is administered as four 375mg dosage units.
- the subject maintains remission of the gastrointestinal disease. In one embodiment, the subject remains relapse free of the gastrointestinal disease.
- the granulated mesalamine formulation is administered as a single daily dosage.
- provided herein are methods of treating a subject having ulcerative colitis (active or in remission) comprising, administering to the subject an effective amount of a granulated mesalamine formulation as a single daily dosage; thereby treating the subject.
- the subject maintains remission of ulcerative colitis.
- the subject remains relapse free of ulcerative colitis.
- the granulated mesalamine formulation is a delayed and extended release formulation.
- "delayed and extended" release formulations comprise formulations that first release mesalamine in the ileum and continue to release mesalamine throughout the terminal ileum and colon.
- provided herein are methods of treating a subject having a gastrointestinal disorder comprising, determining treatment failure from a non-granulated 5- ASA mesalamine formulation; and responsive to such failure, administering to the subject an effective amount of a granulated mesalamine formulation; thereby treating the subject.
- provided herein are methods of treating a subject having a gastrointestinal disorder comprising, administering to the subject an effective amount of a granulated mesalamine formulation, wherein treatment of the subject with another formulation of mesalamine has failed; thereby treating the subject.
- provided herein are methods of treating a subject having a gastrointestinal disorder comprising administering to the subject an effective amount of a granulated mesalamine formulation orally, once daily, in the morning.
- provided herein are methods of treating or maintaining remission of ulcerative colitis, comprising, administering from between about 0.75 g and about 4g of a granulated mesalamine formulation orally to the subject once daily in the morning. In one embodiment, about 1.5 g of the granulated mesalamine formulation is administered. In one embodiment, about 3 g of the granulated mesalamine formulation is administered. In one embodiment, the granulated mesalamine formulation is taken without regard to meals. In one embodiment, the granulated mesalamine formulation is taken with or without food. In one embodiment, the granulated mesalamine formulation is not co-administered with antacids.
- the 1.5 g of granulated mesalamine formulation comprises four capsules. In one embodiment, the four capsules each comprise 0.375 g mesalamine. In one embodiment, the four capsules each comprise from between about 0.25 g to about 0.45 g mesalamine.
- the methods further comprise an evaluation of renal function prior to administration of the granulated mesalamine formulation.
- treatment is contraindicated if a subject has hypersensitivity to salicylates or aminosalicylates.
- the granulated mesalamine formulation is a locally-acting aminosalicylate. In one embodiment, the granulated mesalamine formulation is an extended release formulation.
- extended release comprises release throughout the lumen of a colon.
- delayed release comprises release at between about pH 5.7 to about pH 7.
- delayed release comprises release at about pH 6.
- treatment of the subject with another formulation of mesalamine has failed.
- the subject remains relapse free.
- a locally-acting aminosalicylate e.g., a granulated mesalamine formulation
- a granulated mesalamine formulation indicated for the maintenance of remission of ulcerative colitis in a subject, for example humans.
- the subject is an adult human.
- the subject is a juvenile or child human.
- a granulated mesalamine formulation is administered for the maintenance of remission of ulcerative colitis in subjects 18 years of age and older.
- four capsules of the granulated mesalamine formulation are administered once daily (e.g., 1.5 g/day) in the morning, afternoon or evening with or without food.
- the capsules of the granulated mesalamine formulation are administered once daily (e.g., 1.5 g/day) in the morning, with or without food.
- the granulated mesalamine formulation is not administered with antacids. Because the dissolution of the coating of the granulated mesalamine formulation, the dissolution of the formulation depends on pH.
- the granulated mesalamine formulation is administered as extended-release capsules 0.375 g each.
- the dose for maintenance of remission of ulcerative colitis in adult subjects comprises 1.5 g (four granulated mesalamine formulation) orally once daily in the morning without regard to meals.
- subject with hypersensitivity to salicylates, aminosalicylates, or any component of the granulated mesalamine formulation should not be administered the granulated mesalamine formulation.
- the subject is advised that when being administered granulated mesalamine formulation renal impairment may occur.
- the subject's renal function is assessed at the beginning of treatment.
- renal function is assessed before initiating therapy with mesalamine.
- subject's renal function is assessed periodically during therapy.
- the subject is advised that acute exacerbation of colitis symptoms can occur.
- the subject is advised that the granulated mesalamine formulation should be used with caution in subjects with renal disease.
- the blood cell counts are monitored in geriatric subjects being administered the granulated mesalamine formulation.
- the subject is advised that the granulated mesalamine formulation contains aspartame.
- the subject is advised that the granulated mesalamine formulation should be used with caution with pre-existing liver disease.
- the subject is advised that there are adverse reactions associated with administration of the granulated mesalamine formulation.
- the adverse reactions include, for example, (incidence >3%) are headache, diarrhea, upper abdominal pain, nausea, nasopharyngitis, flu or flu-like illness, sinusitis.
- the granulated mesalamine formulation comprises extended-release capsules containing 0.375 g mesalamine.
- the granulated mesalamine formulation comprises delayed and extended-release capsules containing 0.375 g mesalamine.
- the subject is advised that mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from a flare of inflammatory bowel disease.
- Symptoms include, for example, cramping, acute abdominal pain and bloody diarrhea, sometimes fever, headache, and rash.
- the subject is advised to promptly discontinue treatment with the granulated mesalamine formulation.
- the subject is advised that subjects who have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to the granulated mesalamine formulation.
- the subject is advised that based on in vitro studies, granulated mesalamine formulation is not expected to inhibit the metabolism of drugs that are substrates of CYPl A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.
- the subject is advised that low concentrations of mesalamine and higher concentrations of its N-acetyl metabolite have been detected in human breast milk.
- the subject is advised that the clinical studies of granulated mesalamine formulation did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects.
- the subject is advised that the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly subjects should be considered when prescribing granulated mesalamine formulation.
- the subject is advised that a higher incidence of blood dyscrasias, i.e., neutropenia, pancytopenia, in subjects who were 65 years or older who were taking mesalamine-containing products.
- the subject is advised that caution should be taken to closely monitor blood cell counts during mesalamine therapy.
- the subject is advised that reproduction studies with mesalamine have been performed in rats and rabbits and have revealed no evidence of impaired fertility or harm to the fetus due to mesalamine.
- the subject is advised that there is no specific antidotes for mesalamine overdose; however, therapy for salicylate toxicity may be beneficial in the event of acute overdosage.
- therapy for salicylate toxicity may be beneficial in the event of acute overdosage.
- Fluid and electrolyte imbalance should be corrected by the administration of appropriate intravenous therapy. Adequate renal function should be maintained.
- the subject and/or the healthcare provider is advised that granulated mesalamine formulation is a pH dependent delayed-release product and this factor should be considered when treating a suspected overdose.
- the granulated mesalamine formulation comprises a capsule comprising a delayed- and extended-release dosage form for oral administration.
- each capsule comprises 0.375 g of mesalamine USP (5 -amino salicylic acid, 5- ASA), an anti-inflammatory drug.
- the subject and/or the healthcare provider is advised not to take granulated mesalamine formulation capsules with antacids, because it could affect the way granulated mesalamine formulation dissolves.
- the subject is advised to contact a health care provider if they experience a worsening of ulcerative colitis symptoms, because it could be due to a reaction to granulated mesalamine formulation.
- renal impairment includes minimal change nephropathy, acute and chronic interstitial nephritis, and, rarely, renal failure.
- salicylate toxicity symptoms includes for example, hematemesis, tachypnea, hyperpnea, tinnitus, deafness, lethargy, seizures, confusion, or dyspnea. Severe intoxication may lead to electrolyte and blood pH imbalance and potentially to other organ (e.g., renal and liver) involvement.
- organ e.g., renal and liver
- the invention provides methods of administering granulated mesalamine as a treatment for a gastrointestinal disorder, by advising a health care worker and/or a subject that subjects previously prescribed corticosteroids followed by granulated mesalamine have a decreased incidence of adverse events; and administering the granulated mesalamine to the patient in order to treat the gastrointestinal disorder.
- the gastrointestinal disorder is ulcerative colitis.
- the adverse events are ulcerative colitis-related adverse events.
- the invention provides methods of decreasing the incidence of adverse events in the subject having a gastrointestinal disorder after the subject has been treated with corticosteroids, by administering granulated mesalamine to the subject, thereby decreasing the incidence of adverse events.
- the gastrointestinal disorder is ulcerative colitis.
- the adverse events are ulcerative colitis-related adverse events.
- the subject is administered a once daily dose of granulated mesalamine.
- the once daily does is 1.5g of granulated mesalamine and can be administered as, for example, four capsules of 375mg granulated mesalamine.
- the invention provides methods of treating a subject having a gastrointestinal disorder, by advising a health care worker and/or a subject that subjects having a low mucosal score are most likely remain in remission from the gastrointestinal disorder; and administering the granulated mesalamine to the patient in order to treat the gastrointestinal disorder.
- the gastrointestinal disorder is ulcerative colitis.
- the low mucosal score is 0.
- Figure 1 is a flow chart depicting patient disposition.
- Figure 2 shows percentage of patients relapse free at Month 6/end of treatment.
- FIG. 2A the primary efficacy analysis, patients were counted as treatment failures only if they withdrew for lack of efficacy or an ulcerative colitis-related adverse event.
- FIG. 2B patients withdrawing for any reason were counted as treatment failures.
- Figure 3 shows Kaplan-Meier estimates of time to relapse during the treatment period in the ITT population.
- GM dosed at 1.5g once daily significantly reduced the risk of relapse by 52% versus placebo (odds ratio, 0.48; 95% CI, 0.322-0.711; p 0.0003).
- the most influential prognostic factors for maintenance of remission in this covariate analysis were the DAI mucosal subscore (p 0.0014).
- administration includes routes of introducing a granulated mesalamine formulation to a subject to perform their intended function.
- routes of administration include injection (subcutaneous, intravenous, parenterally, intraperitoneally, intrathecal), oral, inhalation, rectal and transdermal.
- the pharmaceutical preparations may be given by forms suitable for each administration route. For example, these preparations are administered in tablets or capsule form, by injection, inhalation, eye lotion, eye drops, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories.
- the injection can be bolus or can be continuous infusion.
- a granulated mesalamine formulation can be coated with or disposed in a selected material to protect it from natural conditions that may detrimentally affect its ability to perform its intended function.
- a granulated mesalamine formulation can be administered alone, or in conjunction with either another agent or agents as described above or with a pharmaceutically- acceptable carrier, or both.
- a granulated mesalamine formulation can be administered prior to the administration of the other agent, simultaneously with the agent, or after the administration of the agent.
- a granulated mesalamine formulation can also be administered in a proform, which is converted into its active metabolite, or more active metabolite in vivo.
- Administration "in combination with" one or more further therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order.
- the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed.
- the determination of effective dosage levels can be accomplished by one skilled in the art using routine pharmacological methods. Typically, human clinical applications of products are commenced at lower dosage levels, with dosage level being increased until the desired effect is achieved.
- Carriers as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers which are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. Often the physiologically acceptable carrier is an aqueous pH buffered solution.
- physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEEN, polyethylene glycol (PEG).
- buffers such as phosphate, citrate, and other organic acids
- antioxidants including ascorbic acid
- proteins such as serum albumin, gelatin, or immunoglobulin
- an effective amount includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result, e.g., sufficient to treat or prevent UC or other mesalamine related disorders in a patient or subject.
- An effective amount of a granulated mesalamine formulation may vary according to factors such as the disease state, age, and weight of the subject, and the ability of a granulated mesalamine formulation to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response.
- An effective amount is also one in which any toxic or detrimental effects (e.g., side effects) of a granulated mesalamine formulation are outweighed by the therapeutically beneficial effects.
- “Ameliorate,” “amelioration,” “improvement” or the like refers to, for example, a detectable improvement or a detectable change consistent with improvement that occurs in a subject or in at least a minority of subjects, e.g., in at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 100% or in a range between about any two of these values.
- Such improvement or change may be observed in treated subjects as compared to subjects not treated with granulated mesalamine, where the untreated subjects have, or are subject to developing, the same or similar disease, condition, symptom or the like.
- Amelioration of a disease, condition, symptom or assay parameter may be determined subjectively or objectively, e.g., self assessment by a subject(s), by a clinician's assessment or by conducting an appropriate assay or measurement, including, e.g., a quality of life assessment, a slowed progression of a disease(s) or condition(s), a reduced severity of a disease(s) or condition(s), or a suitable assay(s) for the level or activity(ies) of a biomolecule(s), cell(s) or by detection of UC in a subject.
- Amelioration may be transient, prolonged or permanent or it may be variable at relevant times during or after a granulated mesalamine formulation is administered to a subject or is used in an assay or other method described herein or a cited reference, e.g., within timeframes described infra, or about 1 hour after the administration or use of a granulated mesalamine formulation to about 28 days, or 1, 3, 6, 9 months or more after a subject(s) has received such treatment.
- subject includes organisms which are capable of suffering from a bowel disease or other disease treatable by granulated mesalamine or who could otherwise benefit from the administration of a granulated mesalamine as described herein, such as human and non-human animals.
- Preferred human animals include human subjects.
- non-human animals of the invention includes all vertebrates, e.g., mammals, e.g., rodents, e.g., mice, and non-mammals, such as non-human primates, e.g., sheep, dog, cow, chickens, amphibians, reptiles, etc.
- Susceptible to a bowel disease is meant to include subjects at risk of developing a bowel disease.
- the granulated mesalamine formulation disclosed herein and used in the methods described herein may be formulated to release more (in comparison to Asacol® and other formulations of mesalamine) of the active agent, mesalamine, directly to the therapeutic site of action (e.g., terminal ileum and colon) over a more prolonged period, and to decrease systemic availability relative to unencapsulated mesalamine granules.
- the mesalamine is released over approximately 7 hours.
- the granulated mesalamine formulation for example in one embodiment, comprises a hard gelatin capsule shell containing a granulated mesalamine formulation which comprises, for example, an inner polymer matrix mesalamine core that is surrounded by an outer flavor coating, a middle coating, and an inner enteric pH dependent (delayed) release coating.
- the inner coating dissolves, for example, at pH >6, but resists dissolution in the stomach, where gastric fluid is pH 1 during fasting and approximately pH 4 during a meal.
- the polymer matrix core of the granulated mesalamine provides a mechanism by which mesalamine, the active therapeutic ingredient, is uniformly and slowly released and distributed in the lumen of the colon.
- the release profile and additional pharmacokinetic data show that the pellets of the granulated mesalamine formulation have a relatively low rate and extent of systemic absorption, and that 85% to 90% of drug reaches the diseased area.
- the direct and prolonged targeted release of the active agent from a granulated mesalamine formulation in UC subjects makes the formulation particularly effective as a once daily (QD) dosage regimen.
- Relapse or treatment failure included a rectal bleeding score of 1 or more as described in the Sutherland DAI and a mucosal appearance score of 2 or more as described in the Sutherland DAI.
- Another embodiment includes articles of manufacture that comprise, for example, a container holding a pharmaceutical composition suitable for oral administration of granulated mesalamine in combination with printed labeling instructions providing a discussion of when a particular dosage form should be administered if the patient has previously failed treatment for a gastrointestinal disorder, such as ulcerative colitis.
- the dosage can be modified for administration to a subject suffering from ulcerative colitis, or include labeling for administration to a subject suffering from ulcerative colitis.
- Exemplary dosage forms and administration protocols are described infra.
- the composition will be contained in any suitable container capable of holding and dispensing the dosage form and which will not significantly interact with the composition and will further be in physical relation with the appropriate labeling.
- the labeling instructions may be consistent with the methods of treatment as described hereinbefore.
- the labeling may be associated with the container by any means that maintain a physical proximity of the two, by way of non-limiting example, they may both be contained in a packaging material such as a box or plastic shrink wrap or may be associated with the instructions being bonded to the container such as with glue that does not obscure the labeling instructions or other bonding or holding means.
- Another aspect is an article of manufacture that comprises a container containing a pharmaceutical composition comprising granulated mesalamine wherein the container holds preferably granulated mesalamine compositions in unit dosage form and is associated with printed labeling instructions advising that administration of the granulated mesalamine may increase time to remission or relapse of ulcerative colitis.
- the instructions will inform or advise the prescribing physician, a pharmacist, or a subject that they should determine if the subject has previously failed treatment for ulcerative colitis or other gastrointestinal disorders before prescribing granulated mesalamine to treat ulcerative colitis in the subject.
- the instructions will inform the subject and/or the healthcare provider that there is an extended time to remission or relapse of subjects that take granulated mesalamine in comparison to placebos.
- kits are also provided herein, for example, kits for treating gastrointestinal diseases in a subject.
- the kits may contain, for example, granulated mesalamine capsules and instructions for use when treating a subject for an ulcerative colitis disorder who has previously failed using mesalamine treatment.
- the instructions for use may contain prescribing information, dosage information, storage information, and the like.
- the granulated mesalamine formulation comprises, for example, mesalamine, aspartame, citric acid, colloidal silicone dioxide, magnesium stearate, microcrystalline cellulose, povidone, simethicone emulsion, talc, titanium dioxide, triethyl citrate, vanilla flavoring, poly(methacrylic acid, methylmethacrylate) 1 :1, poly(ethylacrylate- methylmethacrylate), and hypromellose.
- the encapsulated granulated mesalamine formulation are subsequently encapsulated in capsules, for example, hard gelatin, size "00" capsule shells.
- each granulated mesalamine formulation capsule contains, for example, granules composed of mesalamine in a polymer matrix with an enteric coating that dissolves at pH 6 and above.
- Inactive ingredients of granulated mesalamine formulation capsules may include one or more of, for example, colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, simethicone emulsion ethylacrylate/methylmethacrylate copolymer nonoxynol 100 dispersion, hypromellose, methacrylic acid copolymer, talc, titanium dioxide, triethyl citrate, aspartame, anhydrous citric acid, povidone, vanilla flavor, and edible black ink.
- the composition of granulated mesalamine formulations may be contained in a hard-shell capsule, which is a delayed and extended release dosage form for oral administration.
- Each capsule may contain, for example, 0.375 g of mesalamine USP (5 -amino salicylic acid, 5 -ASA), an anti-inflammatory drug.
- mesalamine USP 5 -amino salicylic acid, 5 -ASA
- the structural formula of mesalamine is :
- Formulations of granulated mesalamine useful in the methods disclosed herein comprise, for example, granulated mesalamine with a pH dependant coating that dissolves at pH 6 or greater, reached in the terminal ileum and colon, and a polymer matrix core which distributes the mesalamine slowly and uniformly throughout the lumen of the terminal ileum and colon.
- the formulation is, for example, delayed because it does not release the mesalamine until the terminal ileum and it is also extended release because it continuously releases mesalamine throughout the terminal ileum and the colon.
- This release profile is particularly advantageous to treat bowel diseases such as uncreative colitis, Crohn' s disease and diverticulitis.
- the formulation may also contain inactive ingredients, for example, capsules comprising, for example, colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, dry substance of simethicone emulsion 30%, dry substance of poly(ethylacrylatemethylmethacrylate) 2% nonoxynol 100 dispersion (Eudragit NE40D), hypromellose, poly(methacrylic acid, methylmethacrylate) 1 : 1 (Eudragit LlOO), talc, titanium dioxide, triethyl citrate, aspartame, anhydrous citric acid, povidone (K25), vanilla flavoring agent, and edible black ink.
- capsules comprising, for example, colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, dry substance of simethicone emulsion 30%, dry substance of poly(ethylacrylatemethylmethacrylate) 2% nonoxynol 100 dispersion (Eudragit NE40D), hypromellose, poly(me
- 5 -AS A The mechanism of action of 5 -AS A is unknown, and without wishing to be bound by any particular scientific theory, it appears to be local to the intestinal mucosa rather than systemic. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase pathways, e.g., prostanoids, and through the lipoxygenase pathways, e.g., leukotrienes and hydroxyeicosatetraenoic acids, is increased in subjects with chronic inflammatory bowel disease, and it is possible that 5-ASA diminishes inflammation by blocking production of arachidonic acid metabolites.
- cyclooxygenase pathways e.g., prostanoids
- lipoxygenase pathways e.g., leukotrienes and hydroxyeicosatetraenoic acids
- Described herein are methods of treating subjects suffering from or susceptible to gastrointestinal disorders by administering a granulated mesalamine formulation to a subject.
- the administration of a granulated mesalamine formulation, as described herein increases the efficacy of treatment in subjects having gastrointestinal disorders. This includes both active disease and prevention of relapse or maintenance of remission of disease, for example, active UC or UC in remission.
- Exemplary gastrointestinal disorders that may be treated using the methods of the invention include, but are not limited to, inflammatory gastrointestinal disorders such as irritable bowel disease, gastrointestinal motility disorders, functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), Crohn's disease, ulcerative colitis, and diriticulitis, inflammatory bowel disease, and gastroparesis.
- inflammatory gastrointestinal disorders such as irritable bowel disease, gastrointestinal motility disorders, functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), Crohn's disease, ulcerative colitis, and diriticulitis, inflammatory bowel disease, and gastroparesis.
- Therapeutically effective amounts include doses from between about 0.5 g to about 4 g/day or from between about 1 g to about 3 g/day, specifically about 1.5 g/day or 3 g/day, of mesalamine formulation.
- Therapeutically effective amounts and dosage regimens include, administering four tablets, capsules, or granules of the formulation once each day, wherein each tablet, capsule, or granule (e.g., loose or in a sachet) comprises about 375 mg of mesalamine.
- 1.5 g of a mesalamine in a granulated mesalamine formulation is administered as four capsules which contain granulated mesalamine formulation granules.
- Yet another aspect of this invention relates to a method of treating a subject with a granulated mesalamine formulation who is in need thereof. Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method). In specific embodiments, the invention relates to identifying subjects in need of treatment with a granulated mesalamine formulation by identifying subjects who have previously had and failed treatment with another mesalamine formulation.
- a therapeutically effective amount means an amount effective, when administered to a human or non-human subject, to provide a therapeutic benefit such as an amelioration of symptoms, e.g., an amount effective to decrease the symptoms of ulcerative colitis or to maintain the remission of ulcerative colitis in a subject.
- a granulated mesalamine formulation may be administered once daily to a subject.
- Dosages range from between about Ig to about 4g of a granulated mesalamine formulation administered daily. Specifically, dosages of about 1.5 g/day or 3 g/day of a granulated mesalamine formulation are exemplified in the examples presented herein. Other appropriate dosages for methods according to this invention may be determined by health care professionals or by the subject. The amount of a granulated mesalamine formulation administered daily may be increased or decreased based on the weight, age, health, sex or medical condition of the subject. One of skill in the art would be able to determine the proper dose for a subject based on this disclosure.
- the amount of the granulated mesalamine formulation of the invention which will be effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques. The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each subject's circumstances.
- the total daily dosage of a granulated mesalamine formulation can range from about 1 g to about 4 g per day. For example, in general, the total daily adult dosage of a granulated mesalamine formulation of the present invention ranges from about 0.75 g to about 2g, or any whole number or fractional amount in between.
- a single capsule or tablet may be formulated to contain about 250, 275, 375, 450, 525, 550, 575, 750, 800 or 1000 mg of a granulated mesalamine formulation. In one embodiment, a single capsule or tablet contains about 375 mg of a granulated mesalamine.
- a granulated mesalamine formulation is administered to the subject using a pharmaceutically-acceptable formulation.
- a patient is administered granulated mesalamine as described in U.S. Patent 6,277,412; US Patent 6,551,620 or US Publication 2003/0133983, but wherein the granulated mesalamine is advantageously in a capsule dosage form.
- the granulated mesalamine formulation may be an extended-release capsule, containing, for example 0.375 g of mesalamine.
- the granulated mesalamine formulation may be a delayed and an extended- release formulation in capsules, containing, for example 0.375 g of mesalamine.
- the granulated mesalamine formulation is a locally-acting aminosalicylate.
- the granulated mesalamine formulation maintains the remission of ulcerative colitis.
- the maintenance of remission is, for example, in adults and children.
- Adult as used herein, includes, for example, subjects 18 years of age and older.
- the granulated mesalamine formulation may also be administered to treat active ulcerative colitis.
- the granulated mesalamine formulation is administered until active symptoms are alleviated.
- the granulated mesalamine formulation is administered during active disease and is continued to maintain remission.
- the granulated mesalamine formulation comprises four units of a dosage form (e.g., pills, capsules, tablets, sachets, granules) taken once daily.
- the once daily could be, for example, in the morning, in the afternoon, in the evening or in the night.
- morning comprises, for example, between about 3AM to about noon.
- Morning may also be, for example, the time after waking from sleep until noon.
- afternoon comprises, for example, between about noon to about 6PM.
- Afternoon may also be, for example, the time from lunch until about 6pm.
- evening comprises, for example, between about 6 PM to about 3AM. Evening may also be, for example, the time from dinner starting to sleep.
- night comprises, for example, between about 8PM to about 4AM. Night may also be, for example, the time during which the sun has gone down and it is dark outside.
- the granulated mesalamine formulation may be taken without regard to food.
- it may be taken with or without food.
- the granulated mesalamine formulation may not be co-administered with antacids. It may be advantageous to not take the granulated mesalamine formulation with antacids because it could affect the way granulated mesalamine formulation dissolves. In another embodiment, 1.5 g of a granulated mesalamine formulation is administered once daily in the morning.
- 1.5 g of a granulated mesalamine formulation is administered once daily in the morning with or without food.
- the granulated mesalamine formulation may be taken before, after, or during food consumption.
- the granulated mesalamine formulation may be taken, for example, on an empty or full stomach.
- 1.5 g of a granulated mesalamine formulation is administered once daily in the morning with or without food without antacids.
- N-acetyl-S-aminosalicylic acid N-Ac-5-ASA
- N-Ac-5-ASA N-acetyl-S-aminosalicylic acid
- 5-ASA was observed with a high fat meal.
- the overall extent of absorption of N-Ac-5-ASA was not affected by a high fat meal.
- granulated mesalamine formulation and mesalamine granules in sachet were bioequivalent, granulated mesalamine formulation can be taken without regard to food.
- N-Ac-5-ASA In an in vitro study, at 2.5 ⁇ g/mL, mesalamine and N-Ac-5-ASA are 43 + 6% and 78 + 1% bound, respectively, to plasma proteins. Protein binding of N-Ac-5-ASA does not appear to be concentration dependent at concentrations ranging from 1 to 10 ⁇ g/mL. Metabolism
- N-acetyl-5-aminosalicylic acid N-Ac -5-ASA
- N-Ac -5- ASA N-acetyl-5-aminosalicylic acid
- the mean half-lives were 9 to 10 hours for 5-ASA, and 12 to 14 hours for N-Ac-5-ASA. Of the approximately 32% of the dose absorbed, about 2% of the dose was excreted unchanged in the urine, compared with about 30% of the dose excreted as N-Ac-5-ASA.
- ASA ASA, were shown not to inhibit the major CYP enzymes evaluated (CYP 1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). Therefore, mesalamine and its metabolite are not expected to inhibit the metabolism of other drugs that are substrates of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.
- Dietary mesalamine was not carcinogenic in rats at doses as high as 480 mg/kg/day, or in mice at 2000 mg/kg/day. These doses are about 2.6 and 5.4 times the recommended human dose of granulated mesalamine capsules of 1.5 g/day (30 mg/kg if 50 kg body weight assumed or 1110 mg/m 2 ), respectively, based on body surface area.
- Mesalamine was negative in the Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, the sister chromatid exchange assay in the Chinese hamster bone marrow test, and the mouse bone marrow micronucleus test.
- Mesalamine at oral doses up to 320 mg/kg (about 1.7 times the recommended human dose based on body surface area) was found to have no effect on fertility or reproductive performance in rats.
- Oral doses of 60 mg/kg/day (about 1.1 times the human dose, on the basis of body surface area) or higher in dogs also produced renal lesions including tubular atrophy, interstitial cell infiltration, chronic nephritis, and papillary necrosis.
- Example 2 Mesalamine Granules Maintain Remission In Ulcerative Colitis Subjects Who Switch From Another 5-ASA Treatment
- Granulated mesalamine Improves Patient Adherence Fewer subjects taking granulated mesalamine (28 percent) withdrew from the study versus subjects who received placebo (43 percent) due to disease relapse (12 percent vs. 20 percent for placebo) or adverse events (11 percent vs. 16 percent for placebo). For granulated mesalamine versus placebo, the most common adverse events were UC flare (11 percent vs. 24 percent), headache (11 percent vs. 8 percent), and diarrhea (8 percent vs. 7 percent). Incidence of renal, hepatic, and pancreatic AEs was low and comparable in both the granulated mesalamine (6%) and placebo (5%) groups. The percentage of subjects who experienced serious adverse events was small in both the granulated mesalamine (1 percent) and placebo (two percent) groups, and no event reported in the granulated mesalamine group was considered drug-related.
- mesalamine Approximately 80% of an administered oral dose of mesalamine is estimated to be available in the colon, sigmoid, and rectum when dosed as mesalamine granules.
- DAI Sutherland Disease Activity Index 1
- the time to maximum drug concentrations was shorter for granulated mesalamine formulation administered QD than BID for 5-ASA (mean of 3.96 vs. 11.00 hours, respectively) and for N-Ac-5-ASA (mean of 5.21 vs. 11.68 hours, respectively).
- Treatment A Asacol® 800 mg (2 x 400 mg tablets) BID for 4 days;
- Treatment B Granulated mesalamine formulation 800 mg BID for 4 days; or
- Treatment C Granulated mesalamine formulation 1600 mg (2 x 800 mg) QD for 4 days.
- the time to maximum drug concentrations was shorter for granulated mesalamine formulation administered QD than BID for 5-ASA (mean of 3.96 vs. 11.00 hours, respectively) and for N-Ac-5-ASA (mean of 5.21 vs. 11.68 hours, respectively).
- AUC values for Treatments A and B are AUCC and for Treatment C are AUC 0 . 24 .
- AUC C AUC 0 . 12 X (1 + (AUC 12 - 24 /AUC 0 - 12 ). e Median (range).
- Asacol® was administered as 800 mg BID for 4 days, the granulated mesalamine formulation was administered as 800 mg BID for 4 days. The granulated mesalamine formulation was also administered as 1600 mg QD for 4 days. Intact and partially intact Asacol® tablets were observed in fecal samples and removed from the feces of approximately 50% of subjects who were administered Treatment A (Asacol®). Because of this, and the inability of the analysis method to differentiate between released and total mesalamine in fecal samples, quantitative comparisons between Treatment A (Asacol®) and the granulated mesalamine formulation regimens were not possible.
- the 16 h median T max means that maximum plasma concentration was reached approximately 4 h after the second of the 2 BID doses. This is consistent with maximum plasma concentration being reached approximately 3 h following the single QD dose.
- ASA and N-Ac-5-ASA as measured by C max were higher following granulated mesalamine formulations administered QD compared to BID. Plasma concentrations were assumed to be at steady state because the T 1/2 values for 5-ASA and N-Ac-5-ASA in study granulated mesalamine formulation PK1002, after a 1600 mg dose to fasted subjects, were 5.49 h and
- Treatment I Oral administration of Salofalk® granules 1.5 g once daily in the morning on Days 1, and 4 to 10. No administration on Days 2 and 3.
- Treatment II Oral administration of Salofalk® granules 3.0 g once daily in the morning on Days 1, and 4 to 10. No administration on Days 2 and 3.
- Treatment III Oral administration of Salofalk® granules 0.5 g thrice daily on Days 1 to 6. Last dosing in the morning of Day 7.
- Treatment IV Oral administration of Salofalk® granules 1.0 g thrice daily on Days 1 to 6. Last dosing in the morning of Day 7.
- Salofalk® granules were preferred by the study subjects over the previous use of tablets. The vast majority of the subjects preferred a QD regimen compared to the TID regimen.
- the three gram granulated mesalamine formulation administered once daily (QD) was safe and well tolerated. No disadvantage in safety and tolerability in comparison with 1 g granulated mesalamine formulation TID, especially with regard to potential tubulo-toxicity, could be observed.
- the clinical remission rates at the final/withdrawal visit were higher in subjects taking 3 g granulated mesalamine formulation QD than in subjects taking 1 g granulated mesalamine formulation TID in both the PP and the ITT analysis set.
- the shifted asymptotic ⁇ 2 test for comparing two rates yielded a one-sided overall p-value of ⁇ 0.0001 for both the PP and the ITT analysis set for all evaluable subjects.
- CAI Clinical Remission
- CAI > 8 Clinical Remission rates were higher in subjects with a CAI ⁇ 8 at baseline than in subjects with a CAI > 8 at baseline in both the PP and the ITT analysis set. Comparisons between treatment groups showed higher remission rates in subjects taking 3 g granulated mesalamine formulation QD than in subjects taking 1 g granulated mesalamine formulation TID in the subgroup of subjects with a CAI ⁇ 8 at baseline. No such difference was observed in subjects with a CAI > 8 at baseline.
- Clinical remission rates were fairly independent of the disease localization. The highest remission rates were observed in subjects with a proctosigmoiditis and subjects with a subtotal-/pancolitis compared to subjects with a left-sided colitis in the PP and ITT analysis set. Comparisons between treatment groups showed higher remission rates in subjects taking 3 g granulated mesalamine formulation QD than in subjects taking 1 g granulated mesalamine formulation TID in the subgroup of subjects with a proctosigmoiditis.
- a QD regimen may deliver more active substance into the more distal parts of the colon.
- remission rates were higher in the 3g granulated mesalamine formulation QD group than in the Ig granulated mesalamine formulation TID group.
- the median time to first resolution of clinical symptoms appeared to be lower in subjects taking 3 g granulated mesalamine formulation QD than in subjects taking 1 g granulated mesalamine formulation TID.
- Prognostic factors that may contribute to UC relapse include baseline demographics and disease characteristics such as age; sex; DAI total score, and subscores for stool frequency, mucosal appearance, physician's assessment; time to last flare; and disease duration. Covariate analysis was used to evaluate outcomes.
- GM dosed at 1.5 g once daily demonstrated a significant protective effect for long- term maintenance of remission of UC during the 6-month treatment period after controlling for prognostic factors.
- the most influential prognostic factor was the mucosal score at baseline.
- Example 9 Long Term Maintenance with Mesalamine Granules (1.5 g) in Patients Previously Treated with Corticosteroids is Associated with a Low Incidence of Ulcerative Colitis-Related Adverse Events
- TEAE emergent adverse events
- UC related symptoms hematochezia and increased bowel frequency
- Adverse event rates were comparable between GM and placebo treatments in this subpopulation for related treatment-emergent AEs (3.0 vs 2.1), serious AEs (0.025 vs 0.06), and AEs leading to premature withdrawal (0.075 vs 0.06) during RCT, and declined for the GM treated patients during OLT.
- Mean compliance with the once-daily regimen was >96.7% during the 6 months of double-blind treatment and >96.3% during OLT.
- GM in a 1.5g dose was found to be effective versus placebo with a favorable safety profile in the long-term maintenance of remission of ulcerative colitis.
- Patients took the 1.5g of GM as four capsules of 375mg GM.
- Treatment with GM maintained remission in approximately 80% of patients (165 of 209) for 6 months.
- Ulcerative colitis is a chronically relapsing and remitting inflammatory bowel disease that impairs patients' quality of life, disrupts the ability to undertake daily activities, and is associated with heightened risk of morbidity and mortality from other digestive diseases including colon cancer.
- Long-term maintenance of remission of symptoms and mucosal inflammation is a main goal of therapy Effective maintenance of remission reduces the risk of complications and the need for surgery and improves patients' well-being and functional ability.
- 5-aminosalicylic acid (5-ASA; mesalamine) acts topically on the gastrointestinal mucosa to inhibit multiple inflammatory processes.
- 5-ASA agents differentiated by their delivery systems have been developed with the aim of maximizing drug delivery to the colon and minimizing systemic absorption.
- Time- and pH-dependent delivery systems are available as are azo-bonded prodrugs that release 5-ASA in the colon upon exposure of the prodrug to colonic bacteria.
- 5-ASA agents are conventionally administered in multiple daily doses in various dosing schedules that may contribute to non-adherence to the therapeutic regimen, a major cause of ulcerative colitis relapse.
- the granulated mesalamine is dosed once daily as 4 extended- release capsules of 0.375 g mesalamine each.
- the gelatin capsules dissolve to release thousands of granules into the stomach.
- the delayed-release coating on each granule dissolves at a pH >6, a level frequently reached in the gastrointestinal tract.
- the extended-release polymer matrix core swells to distribute mesalamine gradually throughout the colon.
- a once-daily dose releases thousands of granules to provide substantial surface area for mesalamine release for 24-hour protection.
- Men and non-pregnant, non-lactating women >18 years of age were eligible for the study if they had a confirmed diagnosis of mild-to-moderate ulcerative colitis in remission for at least 1 month but not more than 12 months, a history of at least one flare with symptoms that required intervention within 1 to 12 months before screening, and had not taken steroids or immunosuppressive agents within 30 days before screening.
- Remission was defined as both a screening rectal bleeding score of 0 (no bleeding) and a screening sigmoidoscopy score for mucosal appearance of 0 (intact mucosa with preserved or distorted vessels) or 1 (erythema, decreased vascular pattern, granularity, no mucosal hemorrhage) on the revised Sutherland Disease Activity Index (SDAI), described below.
- SDAI Sutherland Disease Activity Index
- Exclusion criteria included evidence of impaired immune function; receipt of immunosuppressive therapy or corticosteroids within 30 days before screening; prior bowel surgery except appendectomy; positive serology results for human immunodeficiency virus or hepatitis B or C; presence of infectious, ischemic, or immunologic diseases involving the gastrointestinal tract; renal disease manifested by serum creatinine or blood urea nitrogen 1.5 times the upper limit of normal; liver disease manifested by values twice the upper limit of normal for alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or total bilirubin. All patients provided written informed consent.
- ALT alanine aminotransferase
- AST aspartate aminotransferase
- ALP alkaline phosphatase
- the protocol for this randomized, double-blind, placebo-controlled, Phase III study was approved by institutional review boards for the study sites.
- the study included a screening phase completed within a week before randomization and a treatment phase that lasted up to 6 months. Patients who met eligibility criteria during the screening phase were randomized 2:1 to receive GM 1.5 g once daily (dosed as 4 capsules, 0.375 g mesalamine each) or matching placebo in a double-blinded fashion for up to 6 months during the treatment phase.
- the treatment phase included 4 clinic visits at randomization (baseline) on Day 1 and at the end of Months 1, 3, and 6 to assess disease activity and monitor patients for adverse events.
- a sigmoidoscopy was performed at screening and at the end of Month 6 (or upon premature withdrawal from the study).
- SDAI saliva activity was assessed with the SDAI, which evaluates stool frequency, rectal bleeding, mucosal appearance, and physician's rating of disease severity on scales of 0 to 3 with a maximum total score of 12. All 4 components of SDAI were evaluated at screening and Month 6 (or upon premature withdrawal from the study); an abbreviated SDAI including all indices except mucosal appearance were evaluated on Day 1 (baseline) and at the end of Months 1 and 3. Medications prohibited during the treatment phase included, but were not limited to, immunosuppressants, chronic nonsteroidal anti-inflammatory drugs, corticosteroids, oral antibiotics except as 7- to 10-day courses for conditions unrelated to ulcerative colitis, psyllium-containing intestinal regulators, and 5- ASAs other than study medication.
- Efficacy data were analyzed for the In tent- to -Treat (ITT) population, defined as randomized patients who received at least 1 dose of study medication.
- the primary efficacy endpoint was the percentage of patients who remained relapse free after 6 months of treatment.
- Relapse or treatment failure was defined as a rectal bleeding score >1 and a mucosal appearance score >2 on the SDAI, an ulcerative colitis flare, or initiation of medication previously used to treat an ulcerative colitis flare.
- Other research in ulcerative colitis has employed similar, but less inclusive, definitions of relapse. 20
- premature withdrawal from the study was not considered to be a relapse unless the reason for early termination was lack of efficacy or an ulcerative colitis-related adverse event. For patients prematurely withdrawing from the study for other reasons, the last SDAI assessment was used to determine relapse status.
- Secondary efficacy endpoints were the percentages of patients with each level of change from baseline in rectal bleeding score, mucosal appearance score, physician' s rating of disease activity, and stool frequency on the SDAI at Months 1, 3, and 6/end of treatment; mean change from baseline in the SDAI at Month 6/end of treatment; the percentage of patients classified as treatment successes, defined as maintaining the SDAI total score ⁇ 2 with no individual component >1 and rectal bleeding score of 0 at Month 6/end of treatment; and relapse-free duration, defined as the number of days between the start of study medication and the date of first relapse or premature withdrawal from the study plus 1 day.
- the last- observation-carried-forward (LOCF) methodology was used for imputing missing values for secondary efficacy endpoints for patients who prematurely withdrew from the study.
- Safety data were summarized with descriptive statistics for the Safety population, defined as randomized patients who received at least 1 dose of study medication and provided at least 1 post-baseline safety assessment.
- the main safety measures were the percentages of patients with treatment-emergent adverse events (defined as any untoward medical occurrences with a start date on or after treatment Day 1 or, if pre-existing, worsening after treatment Day 1), serious adverse events (defined as adverse events that resulted in death, disability, or incapacity; were life threatening; required or prolonged hospitalization; or were a congenital anomaly or birth defect), adverse events leading to premature withdrawal from the study, and the results of clinical laboratory tests.
- Demographics and baseline disease characteristics were similar between the group receiving GM and the placebo group (Table 10). The majority of patients were white, and 44.0% (GM) to 55.2% (placebo) were male. The mean time since the most recent ulcerative colitis flare was 25.6 weeks in both groups, and the mean duration of remission was approximately 16 weeks. The mean baseline SDAI score was 0.8 (SD 0.8) in the group receiving GM and 1.0 (SD 1.3) in the placebo group.
- the mean compliance for the duration of the treatment period was 96.2% (SD 11.6) for the group receiving GM and 96.7% (SD 6.4) for the placebo group.
- the hazard ratio for the risk of relapse in the group receiving GM relative to that in the placebo group reflected a 58% reduction in the risk of relapse with GM compared with placebo over the 6-month treatment period (Figure 3).
- GM first statistically significantly separated from placebo during the first week of treatment.
- a number-needed-to-treat analysis revealed that 1 ulcerative colitis relapse was prevented for every 5 patients treated with GM.
- the percentage of patients with >1 treatment-emergent adverse event was 64% in each treatment group.
- Table 12 lists treatment-emergent adverse events reported in >3% of patients in a treatment group and reported more frequently with GM than placebo. Table 12.
- Treatment-emergent adverse events affecting the pancreatic, renal, or hepatic systems were rare in both treatment groups. Only 1 adverse event involving the pancreas was reported: a mild exacerbation of acute pancreatitis not considered to be caused by study medication in a patient receiving GM. Adverse events affecting the renal and hepatic systems were similarly infrequent. Elevations in liver associated laboratory chemistries reported as treatment- emergent adverse events were less frequent in patients receiving GM than in patients receiving placebo: ⁇ 1% of patients versus 4% of patients for elevated AST; 0% versus 4% for elevated ALT; and ⁇ 1% versus 2% for elevated alkaline phosphatase.
- GM had a favourable safety profile in this study.
- adverse events reported in >5% of patients in either treatment group the only adverse event occurring >2% more frequently with GM than placebo was headache (11% GM, 7% placebo).
- the incidence of adverse events leading to premature withdrawal from the study was nearly 2-fold lower in the group receiving GM (15%) than the placebo group (28%).
- the incidences of adverse events affecting the pancreatic, hepatic, and renal systems — which have been reported, albeit rarely, with other mesalamine formulations — were low in both groups and did not differ between GM and placebo. While antacids were permitted during the treatment period, only 5 patients reported concomitant antacid use in the GM group.
- GM capsules administered once daily had a favorable safety profile and was effective compared with placebo in the long-term maintenance of remission of ulcerative colitis; 8 of 10 patients maintained remission for the 6-month duration of the treatment period and GM treatment resulted in significantly better scores for rectal bleeding, physician's rating of disease activity, and stool frequency than placebo.
- the delayed-release coating dissolves at a pH >6 and exposes the extended-release core. The extended release core of each granule then slowly releases 5-ASA throughout the colon.
- Example 11 EFFECT OF PROGNOSTIC FACTORS ON MAINTENANCE OF REMISSION FROM ULCERATIVE COLITIS IN PATIENTS TREATED WITH ONCE- DAILY MESALAMINE GRANULES (1.5 G)
- remission was defined as both of the following, according to revised Sutherland Disease Activity Index (DAI): a sigmoidoscopy score (mucosal appearance index score) of 0 to 1 and a rectal bleeding score of 0.
- DAI Sutherland Disease Activity Index
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102319218A (en) * | 2011-09-22 | 2012-01-18 | 贝沃特医药技术(上海)有限公司 | Drug sustained and controlled release microparticle preparation for treating intestinal diseases, and preparation method thereof |
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EA201100565A1 (en) | 2011-10-31 |
CA2739465C (en) | 2017-01-31 |
EP2334178A1 (en) | 2011-06-22 |
AU2009298139B2 (en) | 2015-02-19 |
US8865688B2 (en) | 2014-10-21 |
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CA2739465A1 (en) | 2010-04-08 |
US20100086588A1 (en) | 2010-04-08 |
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JP2012504658A (en) | 2012-02-23 |
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