BRPI0706723A2 - process to treat a patient suffering from lung disease that requires the use of mechanical ventilation to sustain breathing - Google Patents

Abstract

PROCESS TO TREAT A PATIENT SUFFERING FROM LUNG DISEASE THAT REQUIRES THE USE OF MECHANICAL VENTILATION TO SUPPORT BREATH Patients suffering from acute respiratory failure syndrome or acute lung injury are treated by administering to patients a therapeutically effective dosage of a therapeutically effective dosage of a therapeutically effective dosage. surfactant that includes SP-B and phospholipid at a concentration of SP-B relative to the concentration of phospholipid that is sufficient to produce detectable SP-B dependent activity.

Description

"PROCESS TO TREAT A PATIENT SUFFERING FROM LUNG DISEASE REQUIRING THE USE OF MECHANICAL VENTILATION TO SUSTAIN BREATHING"

CROSS REFERENCE WITH RELATED APPLICATION

This application claims priority over U.S. Provisional Patent Application No. 60 / 761,250 filed January 23, 2006 and PCT / US2006 / 02423 filed January 23, 2006.

FIELD OF INVENTION

The present invention relates to the treatment of a patient suffering from acute lung injury (ALI) and / or acute respiratory failure syndrome (ARDS) by administering a pulmonary detensive preparation to the patient.

BACKGROUND OF THE INVENTION

Acute Respiratory Failure Syndrome (ARDS) was originally called adult respiratory failure syndrome because it resembled the clinical picture of Child Respiratory Failure Syndrome (IRDS), and both had hyaline membranes at autopsy (.Lancet. 1967; 2: 319- 323, Chest 1971; 60: 233-239). Avery and Mead {Am. J. Dis. Child 1959: 97: 517-523) first reported that the amount of pulmonary surfactant and its activity was abnormal in children with IRDS, and surfactant substitution became standard therapy for preterm infants at risk for IRDS or with IRDS. Petty and Ashbaugh {Chest. 1971; 60: 233-239) described equative qualitative surfactant deficiencies in their initial description of ARDS, and the subsequent scientific literature recently reviewed by Notter {Lung Surfactants. New York, NY: Mareei Dekker, 2000) corroborated the role of detective dysfunction in both ARDS and less severe Acute Lung Injury (ALI) {Am. J. Respir. Crit. CareMed 1994; 149: 818-824).

Human ARDS and ALI surfactant substitution has been shown to be largely unsuccessful. Three large prospective randomized controlled trials of surfactant replacement have shown little or no benefit in adults with ARDS or ALI who have been treated with synthetic aerosolized exosurf (Burroughs Wellcome, Kirkland, Quebec) (N. Engl. J. Med. 1996; 334: 1417-1421), Survanta (Abbott Laboratories, Abbott Park, IL) instilled semi-synthetic (Am. J. Respir.Crit. Care Med. 1997; 155: 1309- 1315), and Recombinant-Specific Recombinant Protein-Based Venticute (ALTANA) Pharma, Konstartz, Germany) instilled (N. Engl. J. Med. 2004; 351: 884-892).

Surfactant preparations differ in phospholipids, neutral lipids, and protein composition, and the failure of previous assays may be related to these differences. The importance of Bespecific protein for hydrophobic surfactant apoprotein surfactant has only recently been recognized (Pediatr. Res. 1986; 20: 460-467).

Calfactant is a modified natural surfactant with a ratio of phospholipids to apoprotein SP-B similar to that found in natural bovine notifiable (Expert Opin. Pharmacother. 2001; 2: 1479-1493). Biophysical and biological tests demonstrate activity similar to that of surfactant (Am. Rev Respir Dis Dis 1992; 145: 24-30) and resistance to inhibition by plasma and other proteins associated with lung or parecellular injury and lysophospholipids (Am. J. Respir. Crit Care Med. 1998; 15: 28-35)

It has been theorized that a natural surfactant containing high levels of SP-B as a calfactor could prove to be effective in ARDS or ALL. An acute positive response to calfactant administration in an open label trial in 29 ALI-ventilated children was reported in 1996 (Crit Care Med. 1996; 24: 1316-1322), and a subsequent unblinded but controlled study of 42 patients replicated this. acute improvement demonstrated a shortened ventilator and intensive care unit stroke (Crit. Care Med. 1999; 27: 188-195). Positive results in those preliminary studies led to a blinded, multicenter, controlled trial of calfactor compared with placebo in infants, children, and adolescents with ARDS or ALL respiratory failure.

SUMMARY OF THE INVENTION

The present invention relates to a process for treating a patient suffering from lung disease that requires the use of mechanical ventilation to maintain respiration. The process comprises the step of administering to the patient a therapeutically effective dosage of a surfactant comprising SP-B and phospholipid at a concentration of SP-Brelatively relative to the phospholipid concentration that is sufficient to produce detectable SP-B activity.

The preferred surfactant is calfactant.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1 is a graph illustrating the recruitment of patients randomly assigned to the calfactant and placebo groups.

Figure 2 is a graph comparing successful extubation of patients with calfactant and placebo during the study.

Figure 3 includes two graphs of the versus time oxygenation index for the calfactant and placebo patient groups.

Figure 4 contains Tables 1, 2, and 3, which are discussed in

Detailed Description of the Invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method for treating a patient suffering from acute respiratory failure syndrome (ARDS) or acute pulmonary injury (ALI), as well as other patients suffering from pulmonary disease requiring the use of mechanical ventilation of lung disease requiring The use of mechanical ventilation to support breathing, but which does not meet X-ray and / or severity criteria for ARDS or ALI. More specifically, the invention relates to the treatment of a selected patient from the group consisting of (a) patients suffer from acute lung injury, who are patients with acute respiratory failure requiring mechanical ventilation, collapse / severe bilateral X-ray pulmonary edema, and having a partial arterial oxygen pressure ratio, PaC> 2, for fractional oxygen fraction, F1O2, which is less than 300 (PaC> 2 / Fi02 <300); (b) patients suffering from acute respiratory distress syndrome (ARDS) who are a subset of ALI patients for whom their [ratio] PaC> 2 / Fi02 <200; and (c) patients suffering from lung disease requiring mechanical ventilation to support breathing but not meeting the X-ray and / or severity criteria for ARDS or ALI.

The method comprises the step of administering to the patient a therapeutically effective dosage of a SP-B phospholipid surfactant at a concentration of SP-B relative to the concentration of phospholipid that is sufficient to produce detectable SP-B-dependent activity, with the patient having a probability improvement compared to a comparable patient treated with a placebo.

With respect to this invention, the term "SP-B" is understood to refer to "apoprotein SP-B" or "a protein that exhibits SP-B-like activity".

In a preferred embodiment of the invention, the surfactant is administered by intratracheal instillation.

In another further preferred embodiment of the invention, therapeutically effective dosage comprises about 10 mg dephospholipid / kg body weight to about 200 mg phospholipid / kg body weight, which is equivalent to about 400 mg to about 8400 mg dephospholipid / m2 or about 11 ml to about 240 ml / m of a phospholipid-containing suspension at a concentration of about 35 mg / ml. In a further preferred embodiment of the invention, the surfactant comprises a saline suspension comprising about 25 mg. / ml to about 100 mg / ml phospholipid plus SP-B in an amount from about 0.1 wt% to about 4.0 wt%, based on the weight of the phospholipid.

In another further preferred embodiment of the invention, the surfactant is a pulmonary surfactant.

In a particularly preferred embodiment of the invention, the surfactant is calfactant.

SP-B activity can be measured as biophysical activity or biological activity. Biophysical activity is determined by observing that the surface tension of an inverted air "bubble" in the suspension in consideration reaches <3 mN / m and a minimum bubble volume within 5 minutes when oscillated on a Pulsating Bubble Surfactometer. ] (Electronetics, Amherst, NY) at 20 cycles / minute as described in Wang et al. (Am J Physiol Lung Cell MolPhysiol 2002; 283: L897). Biological activity is determined by observing the normal restoration of the deflation volume-pressure curve in an in situ or excised surfactant-deficient animal lung using the Bermel Method (.Lung 1984; 162: 99-113) or Mizuno CPediatr Res 1995,37: 271-276).

In another embodiment, the present invention is directed to supplementing the compositions of the invention with exogenous SP-B or SP-C alone or in combination, and particularly supplementation with SP-Bexogen. For example, the results of the present invention are counterintuitive in ARDS / ALI are not easily characterized as a state with surfactant deficiency, a term that would be more appropriately used to describe the prevailing situation in the lungs of a premature baby. Instead, while not wishing to stick to any particular theory, the results obtained here suggest that it might be more appropriate to refer to ARDS / ALI as a dysfunctional surfactant state, where normal surfactant function is interrupted, for example by proteins. and other materials and resulting in lung damage.

Again, while not wishing to stick to any particular theory, the results obtained here are strongly suggestive of surfactant protective aspects in situations such as detensive dysfunction, and also strongly suggest that the presence of SP-B and / or SP-C, however. particularly SP-B, in added surfactant may confer an advantageous effect on a patient suffering from ARDS / ALI, particularly in terms of reducing patient mortality for said ARDS / ALT patients.

Thus in light of the foregoing, one embodiment of the present invention is based on supplementation of the surfactants of the invention, including, but not limited to, lung-based surfactants of the invention, with exogenous SP-C or SP-B. For example, the surfactants of the invention may be supplemented by SP-B or SP-C obtained as described in U.S. Pat. 6,020,307 or 6,458,759, incorporated herein by reference in their entirety. Said compositions may have additional advantageous properties as described above or in addition to the above. Assays for determining these properties include clinical studies as well as physical and biochemical tests for pulmonary function, as described elsewhere herein. Assays will also include animal models that model the presence of various compounds in the lungs in cases of ARDS / ALI that may result in surfactant dysfunction, such that any exogenously supplied SP-C or SP-B-containing surfactant protective effects can be analyzed. in combination. In the embodiment of the above invention, it is possible to add SP-B in an amount such that the total amount of SP-B in the surfactant (ie, more exogenous endogenous) is from about 0.1 wt% to about 4.0 wt%, with base weight of phospholipids, and more preferably in an amount such that the total amount of SP-B in the surfactant is about 0.7% by weight, 0.8% by weight, 0.9% by weight, 1.0 wt%, 1.1 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 1.6 wt%, 1.7% by weight, 1.8% by weight, 1.9% by weight, 2.0% by weight, 2.1% by weight, 2.2% by weight, 2.3% by weight, 2.4% by weight 2.5 wt%, 2.6 wt%, 2.7 wt%, 2.8 wt%, 2.9 wt%, 3.0 wt%, 3.1 wt%, 3.2 wt%, 3.3 wt%, 3.4 wt%, 3.5 wt%, 3.6 wt%, 3.7 wt%, 3.8 wt%, 3 9 wt%, or 4.0 wt%, and more preferably greater than about 0.7 wt% based on the weight of the phospholipids. SP-C may be added in similar amounts.

The following description is illustrative of the process of the present invention. Those skilled in the art will appreciate that the scope of the invention is not limited by the specific examples and treatment protocols described herein.

Patients

According to the present invention, a patient undergoing treatment is preferably postneonatal, i.e. after 40 weeks of post-conception life and one week or more after birth.

Twenty-one Pediatric Intensive Care Units (PICUs) across the Pediatric Acute Pulmonary Injury network and patients included in the sepsis investigator network over a 3-year period from July 2000 to July 2003. Institutional Review Boards in each institution approved the study protocol. Informed consent was obtained from a parent or guardian prior to recruitment. Demographic information obtained included age, gender, race / ethnicity (white, black, Hispanic, or others) determined from the medical record.

Entry criteria included age from 1 week to 21 years, respiratory failure due to radiographically evident bilateral parenchymal lung disease; recruitment within 24 hours of initiation of mechanical ventilation (extended to 48 hours after the initial 50 patients); and an oxygenation index greater than 7 [oxygenation index = (fraction of oxygen breathed) X (mean airway pressure) X 100 / PaCy.

Exclusion criteria included prematurity (corrected gestational age <37 weeks); status asthmaticus; head injury with Glasgow Coma Scale [Glasgow Coma Scale] of <8; chronic lung disease defined by use of diuretic or domestic oxygen; death, orders not to resuscitate, cardiopulmonary resuscitation, and limitation of life support; significant airway disease that could delay extubation; uncorrected congenital heart disease, pre-existing myocardial dysfunction, or pulmonary-cardiogenic edema.

Randomization was stratified to balance the severity of lung injury between groups at study entry. Stratification was based on evidence of increased mortality in patients with a deoxygenation index of 13 or greater (rapid entry) compared to a deoxygenation index greater than 7 but less than 13 (slow entry) within 6 hours of onset of ventilation. mechanical.

Study Protocol

Patients were randomized to receive intratracheal instillation of 2 doses of 80 ml / m calfactant (35 mg / ml phospholipid suspension in saline) or an equal volume of placebo air. In the case of infants weighing less than 10 kg, the equivalent dose of paraneonate calfactant was 3 ml / kg. The treatment was administered in 4 equal fractions instilled intratracheally via a small catheter. Patient positions were switched between fractions (left lying, head up, then down; right lying, head up, then down), and sedation and neuromuscular blockade were administered for the procedure. Gas exchange was maintained by manual ventilation with 100% oxygen using pressures comparable to those previously used mechanical ventilation. Per protocol, a second intervention [] was performed an average (SD) of 12 (2) hours later if the oxygenation index remained greater than 7.

To conserve the binding, a pharmacist removed the following (opaque) envelope from the appropriate fast entry or slow entry file centrally randomized in blocks 2 and 4 and sent calfactant or placebo yeast to the PTCU in an opaque container. A respiratory therapist not otherwise involved in patient treatment applied opaque tape to the endotracheal tube and underwent the intervention. Physicians, investigators, and nurse caregivers remained blinded to the distribution of treatment throughout the study.

Participating physicians agreed to follow deviant guidelines by limiting the oscillating volume to less than 8 ml / kg; inspired oxygen fraction less than 0.6; peak inspiratory pressure below 40mm Hg; and Paco 2 greater than 40 and less than 60 mm Hg. Blood gases and ventilator adjustments were assessed until day 14 of the study.

Treatment with other surfactants was prohibited, and the clinical treatment team determined all other aspects of patient treatment. All data were collected prospectively.

Study Drugs

Calfactant (Infasurf produced by ONY Inc, Amherst, NY) is a modified natural lung surfactant approved by the Food and DrugAdministration for ERDS and produced by extraction of phospholipids, neutral lipids, and hydrophobic apoproteins obtained from bovine pulmonary detoxifying SP-B and SP-C by saline lavage of the newborn neonate lungs.

Study Outcome

The primary outcome of efficacy was the duration of respiratory failure as measured by days without ventilator within 28 days of study entry. A fanless day is a composite result that incorporates both mortality and mechanical ventilation duration. In the analysis, death or need for extracorporeal membrane oxygenation are equivalent to unresolved respiratory failure at 28 days, and equal to non-ventilator-free days. Death was identified prospectively as the most important outcome, and was carefully monitored for safety reasons. Based on differences in mortality in preliminary studies, the study was not expected to identify a benefit involving mortality (Crit Care Med.1996; 24: 1316-1322).

Additional efficacy outcome measures included PICU and length of hospital stay, hospital bills, duration of supplemental oxygen therapy, and conventional mechanical ventilation failure (defined a priori by the use of high frequency oscillatory, oxidonitric ventilation, or extracorporeal membrane oxygenation).

The acute effects of surfactant therapy were evaluated by comparing the oxygenation index in the treatment and placebo groups over 24 hours after treatment. Vital signs and oximetry were continuously monitored and recorded at 5-minute intervals for 30 minutes after the intervention.

Complications at the time of the study intervention included any significant change in vital signs (eg, bradycardia, hypotension) or sustained oxygen saturation (> 30 seconds) of less than 80%. Safety results included mortality, pulmonary complications (pulmonary air leaks). , pulmonary bleeding, and pneumoniacomial), and any unexpected adverse events.

Study Management

The original study project required the recruitment of 300 patients and completion in 2 years. Calculation of sample size based on pilot study data (Cr U. Care Med, 1999; 27: 188-195) suggested that a 25% reduction in mean 13-day ventilator stroke for pediatric respiratory failure would require 274 patients with a α level of 0.05 and a β level of 0.10. After the first year, it became apparent that four participants were recruiting fewer patients than expected.

The safety and data monitoring board endorsed a one-year study extension and study closure at year-end, regardless of recruitment. The safety and data monitoring board conducted an interim safety analysis when reaching 100 patients. There were no significant differences in adverse events or deaths. However, mortality was higher than in the two previous studies (Crit Care Med, 1996; 24: 1316-1322, Crit. CareMed. 1999; 27: 188-195), prompting the board to blindly review all deaths. The board concluded that the increase in deaths was due to the inclusion of immunocompromised children in the current study. With guidance from the Food and Drug Administration, the board continued to review the checks every 10 additional deaths. The study was discontinued within the 3-year limit and was not discontinued due to differences in mortality. The difference in mortality we found was only discovered when the study was terminated.

Statistical analysis

Χ2 tests were used to compare groups with relationship results by category. Wilcoxon's category sum test was used to compare groups with quantitative results. Healing rate models were used to compare time to successful extubation (Lung 1984; 162: 99-1). Repeated measurement models were used to compare the oxygenation index in the subjects over time. In post hoc analyzes, logistic regression models were used to assess treatment effects on mortality, which were adjusted for fast or slow stratification factor; study site (sites with <10 recruited patients were treated as a single site); age category (<1 year, 1-5 years, 6-13 years,> 13 years); and immunological condition (immunocompromised versus uncommitted). All variables and the subvariable subset were found to be significant when tested in multivariate models that included the treatment group. We use statistical software to fit the cure rate models (GAUSS, AptechSystems, Kent, Wash) and for other analyzes (SAS version 8.2, SAS Institute, Cary, NC). Statistical significance was considered to be P <0.05.

Results

A total of 153 patients provided consent, but a parent withdrew consent prior to treatment. Seventy-seven patients were randomized to the calfactant group, and 75 patients were randomized to the placebo group (FIGURE 1). All data were included in an intention-to-treat analysis.

At study entry, 91% of patients met ARDS criteria and all patients met ALI criteria (Am. J. Respir.Crit. Care Med. 1994; 149: 818-824). There were no significant differences between groups regarding demographic profile, severity of disease, randomization, or coexisting diagnoses or comorbidities (Table 1).

Although not statistically significant, there were five additional bone marrow transplant patients in the placebo group, and three additional near-drowning patients in the surfactant arm; both groups had high baseline mortality. Eight protocol violations were identified: six patients (three placebo and three calfactant) had an initial oxygenation index of less than 7, but met all other entry criteria, and two patients (one placebo and one decalfactor) received surfactant administration. non-protocol after study intervention. Adherence to ventilator parameters was comparable between groups. Inspired oxygen fraction and peak pressures remained within the parameters more than 90% of the time, and Paco2 was greater than 40mm Hg more than 80% of the time.

Unexpectedly, mortality was significantly higher in the placebo group compared to the calfactor group (27 / 75versus 15/77; odds ratio [OR, odds ratio], 2.32 [confidence interval] of 95% ), 1.15-4.85]) when all deaths were considered, and it was still significant when considering death without recovery from heart failure (Table 2). Breathing failure was indicated as the primary cause of death in 40% of patients and as a major contributor of death in 43% of patients. Decalfactant patients had an average (SD) of 13.2 (10) days off at 28 days, while placebo patients had an average of 11.5 (10.5) days off (P = 0.21). Cumulative percentages of extubated patients in each group over the first 28 days appear in FIGURE 2.

Oxygenation, as measured by the oxygenation index, improved significantly with both doses of calfactant (FIGURES). Improvement after the first intervention was not adequate to dispense with treatment in most patients, however, as most calfactant patients ( 70%) and placebo (79%) received a second intervention due to the study protocol because their oxygenation index remained above 7.

Babies under 12 months accounted for 26% of the population. Mortality in this subgroup of placebo patients was more than three times that of patients treated with calfactant (9/19 versus 3/21; P = 0.02). Fan-free days were also statistically less empathic on placebo (mean [SD] 5 7.0 [9.9] versus 15.2 [10.3]; P = 0.01).

Table 2 reports other clinical results. More patients with placebo did not respond to conventional mechanical ventilation after a study intervention. Comparisons of oxygen therapy duration, hospital length of stay and PICU, and hospital bills revealed no statistical differences between groups.

Immediate complications associated with instillation were more frequent in calfactant patients and were similar to acute newborn responses to surfactant instillation (.Pediatrics. 1997; 100: 31-38). Hypotension was observed in 9% of calfactant instillations compared with 1 % of placebo instillations (P = 0.005). All patients with hypotension responded to volume infusion. Hypo-transient occurred in 12% of calfactant instillations compared to 3% of placebo instillations (P = 0.08), but disappeared when decalfactant instillation was slowed and / or positive pressure ventilation was transiently increased. No patients were removed from the study due to treatment complications. The incidence of pulmonary air leakage was 13% in the calfactant group and 16% in the placebo group (P = 0.65). Nosocomial pneumonia was observed in 6% of calfactant patients and 11% of placebo patients ( P = 0.40). No systemic complications were attributed to intervention in either group. ORs and 95% of ICs associated with treatment effect on mortality served to adjust factors identified a priori (rapid versus slow entry, center) or a posteriori (age, immune status, number of recruitments) and are shown in TABLE 3. Although the group treatment is not significant in all models, particularly those adjusting for immunocompromised condition, the OR associated with treatment was at least 2.1 for all models listed in TABLE 3.

Infants, children, and adolescents with ALI who received calcification in this multicenter study had reduced mortality, faster improvement in oxygenation, and were more likely to respond to conventional mechanical ventilation. The primary outcome variable, ventilator-free days, was not significantly different between groups. Transient hypoxia and hypotension were more common with calfactant treatment, but these effects were mild and did not require withdrawal from the study. The acute positive effect of calfactant on ventilation in this trial is consistent with previous studies of calfactant in children {Crit. CareMed 1996; 24: 1316-1322, Crit CareMed. 1999; 27: 188-195).

Respiratory failure syndrome in the baby results in quantitative surfactant deficiency, leading to respiratory failure progressive deatelectasis. Surfactant is also deficient in ARDS and ALI, but is also inhibited by inflammatory mediators, plasma proteins, and cell leaks in the airspace. Consequently, the challenges for successful surfactant replacement in ARDS and ALI are more complex than for IRDS (.Biometrics. 2001; 57: 282-286). Effective IRDS surfactants have shown disappointing results when tested in large clinical trials on ARDS and ALI (N. Engl. J. MeA.1996; 334: 1417-1421, Am. J. Respir. Crit CareMed, 1997; 155: 1309-1315) .

The previously observed acute benefits of lung function-related calfactants have been replicated here {Crit Care Med.1996; 24: 1316-1322, Crit. Care Med. 1999; 27: 188-195). Both decalfactant doses improved oxygenation, demonstrating that they may form a functioning film in the injured lung. However, calfactant restored lung function to normal, and not all patients responded positively. Only 55% of calfactant patients (versus 33% of placebo patients) had a 25% or greater improvement in oxygenation index 12 hours after the first intervention.

The duration of respiratory failure was not improved with calcification as it was in a pilot study (Crit. Care Med. 1999; 27: 188-195). The mean duration of ventilation in placebo-treated calfactant patients was similar (11.3 versus 10.8 days), as were the lengths of hospital stays and hospital costs. The lack of benefit in these parameters may be a consequence of the unexpected disproportionate survival of patients treated with calfactant. As noted with the introduction of surfactant therapy in premature infants, increased survival may effectively increase the need for prolonged supportive treatment (J. Clin. Invest 1991 ; 88: 1976-1981).

The severity of the initial lung injury was expected to influence survival. Mortality rate was effectively higher in rapid subgroups (37%) compared to slow-entry subgroups (20%). Mortality in both extracts for calfactant (26% calfactanteversus 46% placebo for rapid entry and 14% versus 26% for entralent respectively). Unresolved respiratory failure was cited as primary cause or as the major contributor in 83% of deaths, and lack of improved oxygenation after intervention was strongly associated with mortality. Improvement in lung function offers a plausible mechanism with which treatment with calfactant could increase survival because respiratory failure was a significant cause of death in this trial.

Overall mortality in this study was higher than in the pilot study (Crit. Care Med. 1999; 27: 188-195) (14% in the pilot study versus 28% here), attributable to the inclusion of previously excluded immunocompromised patients whose rate of mortality (56%) was four times that of immunocompetent patients (13%). Mortality rates were lower for calfactant patients in both immunocompromised (50% versus 60%) and immunocompetent (7% versus 20%) subjects. The numerically larger number of immunocompromised patients in the placebo group (30 in the placebo group versus 22 in the calfactant group; P = 0.17) influenced the observed difference in overall mortality between the groups. ORs for placebo-treated mortality approached, but did not reach, statistical significance (P = 0.08) after hoc adjustment for immunological condition (TABLE 3). This study was not sufficiently subsidized to detect effects on specific patient subgroups.

There may be multiple reasons for the failure of other surfactants in the three major ARDS assays (N. Engl. J. Med. 1996; 334: 1417-1421, Am. J. Respir. Crit. Care Med. 1997; 155: 1309-1315 , N. Engl. J. Med. 2004; 351: 884-892), but in none of these trials was a pulmonary detensive preparation containing sufficient SP-B, which is an essential factor for full surfactant activity and of the resistance of a surfactant to inhibition by inflammatory protein and blood molecules present in the ARDS / ALI alveoli (J. Clin. Invest. 1991; 88: 1976-1981, Am. J. Respir. Crit. Care Med. 1996; 153: 176-184). Congenital absence of SP-B in humans causes lethal neonatal respiratory failure syndrome (J. Clin. Invest. 1994; 93: 1860-1863), and mice raised with SP-B deficiency die at birth from respiratory failure ( Proc. Natl. Acad. Sci. USA 1995; 92: 7794-7798). SP-B protein alone confers full biophysical and biological activity in surfactant phospholipids (J Lipid.Res, 1996; 37: 1749-1760). The surfactant used in the study has the highest level of inactivation resistance, as determined by in vitro and in vivo experimental tests, due to its high ratio of parapholipid SP-B (Expert Opin. Pharmacother. 2001; 2: 1479-1493, Am. Rev Respir Dis 1992; 145: 24-30, Eur Respir J. 1993: 6: 971-977). It has higher surface activity and physiological activity in animal lungs than Exosurf or Survanta, which are two surfactants previously used to treat ARDS in adults (Chem. Phys. Lipids, 2002; 114: 21-34).

In addition, the amount of calfactant administered in this assay was more than three times the estimated normal pulmonary surfactant content of 20mg / kg (Lung Surfactants, New York, NY: Mareei Dekker, 2000).

In this randomized, multicenter, blinded trial, early administration of calfactant in the course of pediatric acute respiratory failure resulted in acute oxygenation improvement, and unexpectedly produced lower mortality. Adverse effects of therapy were minimal.

Claims (12)

Method for treating a patient suffering from lung disease requiring the use of mechanical ventilation to support breathing, comprising: the step of administering to said patient a therapeutically effective dosage of a surfactant comprising SP-B and phospholipid; SP-B concentration relative to the phospholipid concentration that is sufficient to produce detectable SP-B dependent activity. A process according to claim 1 characterized in that the patient is selected from the group consisting of (a) patients suffering from acute respiratory failure (ARDS), (b) patients suffering from acute lung injury (ALI), and (c) other patients who do not meet the X-ray and / or severity criteria for ARDS or ALI. Process according to claim 1, characterized in that said surfactant is a pulmonary surfactant. Process according to claim 3, characterized in that said pulmonary surfactant is calfactant. Process according to Claim 1, characterized in that said administration step further comprises the step of administering said surfactant by intratracheal instillation. Process according to claim 1, characterized in that said patient is at least about one week old. Process according to claim 1, characterized in that said patient is post-neonatal. Process according to Claim 1, characterized in that said therapeutically effective dosage comprises from about 10 mg phospholipid / kg body weight to about 200 mg dephospholipid / kg body weight. Process according to Claim 1, characterized in that the surfactant comprises a saline suspension comprising about 25 mg / ml to about 100 mg / ml phospholipid, plus SP-B in an amount of about 0.1% by weight. weight to about 4.0% by weight based on the weight of phospholipid. Process according to Claim 9, characterized in that the SP-B comprises exogenous SP-B. Process according to Claim 10, characterized in that the exogenous SP-B is added such that the total amount of SP-B in the surfactant is at least about 0.7% by weight. A method for treating a patient suffering from lung disease requiring the use of mechanical ventilation to support breathing, wherein said method comprises: the step of administering to said patient a therapeutically effective dosage of a surfactant comprising SP-B and Phospholipid at a concentration of SP-B relative to the concentration of phospholipid which is sufficient to produce detectable SP-B-dependent activity, wherein said surfactant is calfactant, and being preferred SP-B comprises exogenous SP-B added such that the total amount of SP-B in the surfactant is at least about 0.7% by weight.