CA2637644A1 - Treatment of acute respiratory distress syndrome - Google Patents

Abstract

Patients suffering from acute respiratory distress syndrome or acute lung injury are treated by administering to the patients a therapeutically effective dosage of a surfactant that includes SP-B and phospholipid at a concentration of SP-B relative to concentration of phospholipid that is sufficient to produce detectable SP-B dependent activity.

Description

TREATVtENT OF ACUTE RESPI:RATOlE2Y DISTRESS SYNDRO~IIE
CROSS REFERENCE TO RELATED APPLICATION
100011 This application claims priority to U.S. Provisional Patent Application No.
60/761,250, filed January 23, 2006, and to PCT[US2006/02423, fil.ed Janciary 23, 2006.
FIELD OF INVENTION
[00021 The present invention. relates to the treata.nent of a patient sufferia3g from acute lung injury (ALI) and/or acute respiratory distress syaadroine (ARDS) by admi.nistering a lung surfactant preparation to the patient.

BACKGROUND OF TFiE TNVENTION
[0003] Acute respiratory distress syndrome (ARDS) was originally termed the adult respircrtory distress syndrome because it resembled the clinical pictur.e of infant respiratory distress syridrome (IRDS), and botli exhibitea liyaline mexnbranes at autopsy (Lancet. 1.967;2:319-323, Claest. 1971; 60:233-239). Avery and Mead (.4 z. J.
Dis. Child.
1959:97:517-523) first reported that luiag surfactant quantity and activity were abnormal in infants with IRDS, and surfactant rcplac8ment l.ias subsequently beconie standard therapy f'or premattire infan.ts at risk for or l-iaving IRDS. Petty and Ashbaug. (Chest.
1971; 60:233-239) described qualitative and quantitative surfactant deficiencies in thei.r initial description of ARDS, and the subsequent scientifc literatLire, recent.ly reviewed by Notter (Lurzg Sui;factants. New York, NY: Marcel Dekker, 2000), has supported the role of surfactant dysfunction in both ARDS and less severe acute ltmg iu~jury (ALI) (,4xl2.
J. Reslbir=. Crit. Ca.re llfecz'. 1994;1.49:818-824).
[00041 Surfactant replacement in ARDS and ALI in hunians has bccn largely urisuceessful. Tliree large prospective, randomized controlled clinica.l trials of surfactant replacement demonstrated little or iio benefit in adults wilb ARDS
or ALI
who were treated with aerosolized synthetic Exosurf (Btu-roughs Wellcome, Kirkland, Quebec)(1V. Etzgl. J.Afed. 1996;334: 1417-1421), instil.led, semisynthetic Survanta (Abbott Laboratories, Abbott Park, IL) (Atn. J. Respir. Crit. CrxreMcrl. 1997;
155:1.309-1315), and instilled recombinant surfactant-speci.fic protein C-based'VeiZticute (ALTANA
Ph.anna, Konstanz, Gerinany) (N. Lragl. J. Med. 2004;351:884-892).

[00051 Surfactant preparations differ in phospholipids, neutral lipid, and protein eoniposition and the failure of previous trials may relate to these differences. The i,rnportan.ce of the hydrophobic surfactant apoprotein surfactant-specific protein. B has only recently been r.ecognized. (Pecliatr.Res. 1986;20:460-467).
(0006] Calfactant is a rnodifiQd natural surfactant with a ratio of p.laosphol.ipids to apoprotein SP-B sunilar to ttiat found in natural bovine surfactant (Expc:rt Opin.
1'hcrrinacnther. 2001;2:1479-1493). Biophysical and biological testing demonstrates activity equal to natural surfactant (Am.Rev Respir. Dis. 1992;145;24-30) and resistance to inhibition by plasma and other profeins associatod with lung in}ury or 1U by cell wall. and lysophospholipids (Afn. J. Respir. C'rit Care Mer.i.
1998;158:28-35).
[0007] It was hypothesized that a natural surfactant coittaining high levels of SP-B, such as calfactant, naight prove effective in ARDS or ALI. A positive acute response to calfactant adna.inistration in. an open-label trial in. 29 children.
ventilated for ALI was reported in I996(C'rit Care Med. 1996;24_1376-1322), and a subsequent contxolled but un-blinded st-udy of 42 patients replicated tlris acute improvement and demonstrated a shortened ven.tilator and intensive care unit course (Crit. Ccire.Med.
1999;27;188-795).
The positive restilts in those prelinlinary studies led to a multicenter, blinded, controlled trial of calfactant coinpared with placebo in infants, children, and adolescents with respi ra.tor.y faa.lure from ARDS or AI.,I.
SUMMARY OF THE INVEN'TION
[0008] The present invention is directed to a process for treating a patient su.ffering from lung disease that requires the use of mechanical ventilation to sustain breathing. The process coniprises the stop of adzninislering to the pati.en.t a therapeuticail_y effective dosage of a surfactant coniprising SP-B and phospholipid at a concentration of SP-B
relative to concentrati.on of phospholipid that is sufficient to prodi.ice detectable SP-B
activity.
[00091 The preferred sLiTfacta-it is calfactant.

BRIEF DESCRIPTION OF THE DRAW INGS
[00010] Figure i is a chart depicting the enrolhment of patients rand.omly assigned to the cal.f:actant and placebo groups.
[000111 Figure 2 is a grapli coinpEuing the successfiil extubation of calfactan.t and placebo patients during the study.

[00012] Figure 3 includes two graph.s of oxygenation index vs tin-ie for the calfactant a:tld placebo patient groups.
[000131 Figure 4 contains Tables 1, 2, a.nd 3, which are discussed in the Detailed Description of the Inventior.z.

DETAILED DESCRIPTION OF THE IN'VENTION
1000141 The present invention relates to a process for treating a patient sufferi.ng frorn acute respiratory distress syndrome (ARDS) or acute lung injury (ALI), as well as other patients suffering from 1tu1g discasc that i-cquires the use of inechan.ical ventilation to sustain breathing but does not meet either the X-ray and/or the severity criteria for ARDS or ALI. More specifically, the invention, is directed to the treatnzent of a patient selected frona. the group consisting of (a) patients suffering from acute lung injury, who are patients with acute respiratory failure requiring mechajaical ventilation, witli severe bilateral Iiui.g ederna/collapse by chest X-Ray, and havin.g a ratio of arterial oxygen partial pressure, Pa0?, to fractior.t of irlspire:d oxygen, FiO2,that is less t111n 300 (PaO-)/Fi02 <300); (b) patieats suffering from acute respiratory distress syndroine (ARDS) who are a subset of ALI
patients in that their PaO2/FiO2 <200; and (c) patients suffering fronz lung disease that requires the use ofinechanical ventilation to sustai.n breathing but does ziot r7ieet either llie X-.ray and/or the severity criteria for ARDS or ALT.
[000151 The process comprises the step of administering to the patient a t.herapeuticaliy effective dosage of a surfactant coin.prisi.ng SP-B and phospholipid at a concentration of SP-B relative to concentration of phospholipid that is sufficient to produce detectable SP-B
dependent activity, whereby the patient has an improved likelihood of stu-vival relative to a coinparable patient treated with a placebo.
1000161 With respect to this invention, thc teiin "SP-B" is understood to refer either to "apoprotein SP-B" or "a protein that ex:hi.lii.ts SP-B-Iike activity."
[00017} I:n a preferred etY7Tcodirric:nt of the invention, the surfactant is admitzistered by in.tratracheal insti.liati.on.
[000181 In another preferred embodiment of the invention, the therapeutically effectivc dosage coniprises about 10 n1g phosphol.ipid/kg body weigllt to about 200 ing phospholipid /kg body rveiglit, which is equivalent to about 400 mg to about 8400 mg plzosphol.ipid / m2 of body surface area, or about 1.1 ml to about 240 rnlhn2 of a suspension containing pliospholipid in a concentrati.on of about 35 nzg/ml.

[00019[ In another preferred enibodiment of the invention, the surfactant comprises a saline sitspensioil comprising about 25 mg/nil to about 100 mg/inl ofphospholipid, plus SP-B in an azzoii.nt of about 0.1 wt. % to about 4.0 wt.%, based oii. the weight of phospholipid.
[00020] In another preferred embodiment of the invention, the surfactant i s a li.ang surfactant.
[00021] h1 a particularly prefe:rred ernbodirnent of the invention, the surfactant is calfactanL.
[00022] The activity of SP-B can be measured as biophysical activity or biologic act:ivity. Biophysical activity is determined by observing i:iia.t the surface ttension ofan inverted air "bubble" in the suspension under consider.ation reaches < i nliNlnl at mininltzm bubble volunze within 5 nzinutes when oscillated in a Pulsating Bubble Surfactoineter (Electronetics, Anzherst, NY) at 20 cycles/rninute as described in Wang et a1.
(Arrz JPdzysiol Lung C'ell.Mol Physiol 2002; 283: I,$97). Biologic activity is detennin.ed by observing restoration to n.on.-nal of the deflation pressure-volume curve in an excised or in situ surfactant deficient aiiimai liing using the method of Bermel (Lun.g 1984; 162-99-17 3) or Mizuno (Peiliatr Res 1.995, 37.271-276).
[00023] In another embodiment, the present invention is drawn. to the supplement.atiolz of the conapositions of the invention with exogenous SP-B or SP-C, alotie cir in combination, and particularly to the supplementation with exogenous SP-B.
For example, the results of the present invention are counterintuitive in that ARDS/ALI
is not readily characterized as a surfactaiit deficient state, a ten-n which would be most appropriately used to describe the situation that prevails in the lungs of a premature infarit. Insteaci, while not wishing to be bound by any particular theory, the results obtained herein suggest that it might be most appropriate to .refer to ARDS/ALI as a surfactant dysfuinctional state, where nornia.7 surfactant fiinction is disitiipted by, for example, pr.oteins and other materials resulting from lung damage.
[000241 Again while not wishing to be bound by a.ny particular theory, the results obtained herein are st7ongl.y suggestive of the protective aspects of surfactants in such situations of surfactant dysfunction, and also strongly suggest that the presence of SP-B
and/or SP-C, but particularly SP-B, in added surfactant znay confer an advantageoLis effect on a patie7lt suffering from ARDS/ALI, particularly in terzns of red:uction of patient mortality for suc1.1 ARDS/ALT patients.

[000251 Thi.i.s in light of the above, an ernbodiment of the present invention is based on the supplenient.ation of the surfactants of the invention, i:ncluding, but not linai.ted to the calf-lung based surfactants of the invention, with exogenous SP-B or SP-C.
.For exan-iple, the surfactants of the invention may be supplemented with SP-B or SP-C

5 obtained as described i.n United States Patents No. 6,020,307 or 6,458,759, herein incorporated in their entirctics by refercnce. Such compositions inay exhibit further advantageous properties as described above or in addition to the above. Assays for these properties will include cliidcal studies as well as physical and.
biochetn.ical assays for lung function such as desci-ibed elsewhere herein. Assays will also include aniinal models wliich znodel the presence ofvarious conipotulds in the lulzgs in ART)S/Ai..I
cases that nlay result in surfactant dysfitnction, such that any p'rotective effects surfactant containing exogenously provid.ed SP-B or SP-C alone or in combination may be assayed.
[000261 In the above embodimetit of the invention, SP-B may be added in an anloun.t such that the total amount of SP-B in the surfactan.t (i.e., endogenous plus exogenous) is about 0,1 wt. % to about 4.0 wt.%, based on the weiglit of pliospliolipids, and more preferably in an arziount such that the total aniount of SP-B in the surfactant is about 0.7 wt fo, 0.8 wt "/o, 0.9 wt Jo, 1.0 wt %, 1.1 wt Jo, 1.2 wt %, 1.3 wt %, 1.4 wt ofo, 1.5 wt %, 1.6 wt %, 1.7 wt %, 1.8 wt %, 1.9 wt /u, 2.0 wt %, 2.1 wt `%, 2.2 wt %, 2.3 wt /u, 2_4 wt %,2,5wt%,2.fiw't%,2.7wt%,.2.4wt%,2.9wt%,3.0wt%,3.1 Wt"/o,3.2wt%,3.3 wt%, 3.4wt0110,3.5wt 1o,3.6wt%,3.7wt.%,3.8 wt%,3.9wt%,or4.Owt%,and most preferably greater than about 0.7 wt % based on the weight of phospholipids. SP-C
may be added in similar aniounts, [00027] Tl:ie following description is illustrative of the process of the present invention.. Those skilled iri the arL will recognize that scope of the invention is not limited by the specific exan-iples and treatment protocols d.escribed herein.
Patients 1000281 In accordance with the present inventivn, a patient undergoing treatnlent is preferably post-neonatal, i.e., after 40 weeks post-conceptual age, and one wcclc 3o or more after birth, [00029] Twenty-o.ne pediatric inten.si.ve care units (PICUs) across the Pediatric Acute Lung liajLrry and Sepsis Investigator network enrolled patients over a 3-year period from July 2000 to :3'uly 2003. Institutional review boards at eacll institution approved the study protocol. Tnfornied consent was obtained from a parent or guardian prior to enrollz.nent. Demographie infonm.ationobtained included age, sex, and raee/
ethnicity (white, black, Hispanic, or other), determined from the nzedical record..
[00030E En.try criteria included age I weelc to 21 years; respiratory failure d.ue to radiograpliically eviclent bilateral parenchymal lung disease; enrolli-nent within 24 hours of initiation of niechanical ventilation (extended to 48 hours after the in.itial 50 patients);
and an oxygenation index higher than 7[oxygenation. index=(fraction of inspirecl oxygen) X (mean airway pressure) X l00/PaOz].
[00031] Exclu.sion criteria included prematurity (corrected gestational age <37 weeks); status asthmaticus; head injury with Glasgow Coma Scale of <$; chronic luiag disease defined by home oxygen or diuretic use; brain death, do not resuscitate orders, ongoing cardiopulmonary resuscitation, or limitation of life support;
siViificant airway disease that might delay extubation; uncorrected congenital heart disease, preexisting myocardial dysfi.inction, or cardiogenic pulmonary ede.ina.
[00032] Randoni:ization was sti-ati.Ced to bala-nce the severity of lting injury between groups at stttdy entry. Stratification was based on evidence of increllsed nlortality in. patients with an oxygenation index of 13 or high.er (fast entry) compared with an oxygenation index hi.ghcr than 7 but less than 13 (slow entry) within 6 hours of th.e initiation of mechanical ventilation.
Study Protocol [00033] Patients were randomized to receive in(ratracheal instillation of 2 doses of 80 mL/rr.mz calfactant (35 mg/rnL of phospholipid suspension in saline) or an equal volume of air placebo. For infants weighing less than 10 kg, the equivalent newborn dose of calfactant was 3 mL/kg. Treatment was administered in 4 equal aliquots instilled intratracheally via a srnall catheter. 1'ai:ient positions were changed between.
aliquots (left decubitus, head up tl=ieti down; right decubitus, head up then down) and sedation and neuron-iuscular blockade were given for the procedure. Gas exchange was inaintarned by manual ventilation with 100% oxygen using pressures comparable with.
those previously used on mechanical ventilation. By protocol, a second intervention was performed a mean (SD) of 12 (2) hours later if the oxygenation index rernained higlzcr than 7.

[00034] To niaintain blinding, a pharn-iacist drew the next (opaque) envelope frorn the appropriate fast entry or slow entry file previou.sly randomized centrally in bloclcs of 2 and 4 and seut the syringes of calfactant oz placebo to the PICU in an opaque container. A respiratory therapist not otherwise involved with the care of the pati.ent placed opaque tape on the endotracheal tube an.dperformed the intervention_ Physicians, investigators, and nurses caring for the patient reinained blinded. to treatment assignmen.t th.roughout the study.
1000351 Participating physicians agreed to follo~v ventilator guidelines limiting tidal volume of less than 8 mL/kg; fraction of inspired oxygen of less than 0.6;
peak inspiratory pressure of less than 40 nzrn Hg; ancl ;['UC02 of greater than 40 a.nd less than 60 nim I Ig.
Blood gases and ventilator settings were evaltiated through study day 14.
[00036] Treatment with other surfactants was pirohiUited and the clinical care teaii determined all other aspects of the patient's care. All data were collected prospectively.
Study Dr {00037J Calfactant (1i:i.fasurfproduced by NY Ine, Amherst, NY) is a nlodified natural lung surfactant approved by the Food and Brnxg Acia-ninistTation for :I1ZDS and produced by extracting the phospholipids, neutral lipids, and hydrophobic apoproteins SP-B and SP-C fion3 bovine lung st.irfa.ctant obtained by saline lavage of newbon2 calf lungs.
studv Out.conze [000381 The priniaiy efficacy outcome was the duration of respiratory failure as measured by ventilator-free days in the 28 days following study entry. A
ventilator-free day is a coixiposite ozi.lcoine Chat i.ncoi-porates both moi-tality an.d dtration. of n-ieclianical ventilati.on. Tn. the analysis, deatlz or the need for extracorporeal tne.tnbranc oxygcnation are equivalent to unresolved respiratory fai.lure at 28 days and equal to zlo ventilator-free days.
Death was prospectively identified as tlie nlost irsiportant oulcUme and was eareful.ly i-tionitored for sa.fety reasons. Based ota niortality differences in.
preliminary studies, the stlidy was not expected to identify a mort2lity benefit (CYit Care Nlecl.
1.996;24:131 U-1322).
[00039] Additional efficacy outconic mcasurements included PICU and hospital lengths of stay, hospital charges, duratkozl of supplemental oxygen therapy, and. failure of conven.tional nzechanical ventilation (defined a priori by the use of high-frequ.ency oscillatory ventilation, nitric oxide, or extracorporeal membrane oxygenation).

[000401 The acute effects of surfactant therapy were evaluated by comparing the oxygenation index in the treatment aiad placebo groups over the 24 hours after treatment. Vital signs and oxirnetry were monitored continuously and recorded at 5-min.ute intervals for 30 minutes after the intervention. Com.plicat7on.s at the time of study intcrvention included any si~,mi:C.cant change in vital signs (e.g., bradycardia, hypotension) oi- sustained (>30 seconds) oxygeti saturation of less than 80%.
Safety outcornes included mortality, pulmonary complications (air leaks, pulnionary hen7orrli.age, atad nosuc;orriidl plreLtmo:nia), and any unexpected adverse events.

Manczgemerr.t o,f Zhe St. ud~
[00041] T12e original study design called for enrol.linent of 300 patients and completion in 2 years. Sarnple size calculation based on pilot study data (Crit. Ctzre Meci. 1999;27:188-195) suggested a 25% reduction in the 13-day average ventilator cour.se for pediatric respiratory failure would require 274 patients with an a level of 05 and a j3l.evel of .10. Af-ter the f:rst year, it becarne apparent that participating centers were ezirolling fewer patients than expected. The data arid safety monitoring board endorsed a 1-year study extension and closure of the study at the end of that year regardless of enrollment. The data and safety rrzonitoiing board conducted an interim safety analysis when 1(}0 patients had beeri enrolled. No significant differences in adverse events or deaths were found. However, mortality was higher thai in the previous two studies (Crit Care Mecl. 1996;24:1316-1322, Crit. Care Med. 1999;27:188-195), proixlptiitg a blinded review of all deaths by the board. The board concluded that tl7e increase in deaths was due to the inclusion of immunoconzpromised.- children in the current study. At the di.rection of the Food arid Drug Adrninistration, the board continued to revicw the findings with each additional 10 d.eaths. The study was stopped at the predetem-l:i.ned 3-year limit and was not stopped because of mortality differences. 'i'he znortality diffcrcncc we found was not discovered until after tl-1e study was closed.
Stc.7tistica.l ~.na.lt>sis [000421 xz tests vver-e used to cuinpare groups w:ith respect to categorical outcomes.
The Wilcoxon rank swn test was used to compare groups witb quantitative outcomes.
Cure-rate models were used to compare time with successful ex.tubation (Lung 1984;
162:99-1). Repeated measures models were used to coni.pare the oxygenation index within subjects over time. In post hoc analyses, logistic regression niodels were used to assess treatr.n,ent effects otz r:nortality, which were adjusted for fast or slow entry stratification factor; study site (sites with < 10 patients enrolled were treated as one site);
age category (<t year, 1-5 years, 6-13 years, >13 years); and immune status (immunoco ipronzised. vs no .conipromised). All variables and the subset of variables found to be significant were thcn tcstcd in rnultivariate models that included the treatnient group. We used statistical software to fit the cure rate nzodels (GAUSS, Aptech Systerns, Keiit, Wash) ai-id for other analyses (SAS version 8.2, SA.S
Institute, Cary, NTC).
Statistical signi.ficance was considered to be P<.05.

IO
Results [00043] A total of 153 patients provided conseixt, but a parent withdrew consent prior to treatment. Seven.ty-seven patients were randomized to the calfactant group, and 75 patients were randoniized to the placebo group (Ftc.,'(ynt; 1). All data were included in an inten.tion-to-txeat analysi.s.
[00044] At study entry, 91 /a of patients nzet ARDS criteria and all patients met ALI
criteria (Am. JRespir. Cria. Cure Mecl. 1994;149:818-824). There were no significant differences between groups in demographic profile, severity of illness at randomization, or coexisting diagnoses o-i- co-morbidities (TABLE 1). Although not statFst]cally significant, th.ere were five additional bone rnarrow transplant patietits in the placebo group and three additional near-drowriingpatients in the surfaetant arm; both groups had I.iigh baselin.e mortality. Eight protocol violations were identified: six patients (tl-iree placebo and three calfactant) had an initial oxygenation index of less than 7 but met all other entry crileri<<, and two patients (one placebo and one calfactarlt) received nonprotoeol surfactant adnlin:istration after the study interventifln. Adherence to tlxe ventilator guid.elines was comparable between groups. Fraction of inspired oxygen and pea.l.c pressures were within guidel'uies more than. 90% of the titne and PaC02 was higher lhan 40 nuii. Hg more th.an. 80% of the tinie.
[000451 Unexpectedly, mortality was significantly greater in the placebo group compared with the calfactant group (27/75 vs 15/77; odds ratio [OR], 2.32 [95%
confidence interval {CI}, 1.15-4.85]) when all deaths were considered and was still significant when death without recovery from respi.ratory failure was considered (Tasr.,.E2). Respiratory failure was given as the priniary cause of death in 40% of patients and as a major contributor of death in 43% of patients. Calfactant patients averaged a mean (SD) of 13.2 (10) ventilator-free days at 28 days, while placebo patients averaged 11.5 (10.5) ventilator-free days (P= .21). The cumulative percentages of ext2ibated patients in each group over the first 28 days appear in rIGI.;~R.E
2.
5 f 00046] Oxygenation as measured. by oxygenatio.n index significantly improved with both doses ofcalfactan.t (FIGURI:3). Inaprovement after the first intervention was not adequate to precl.ude retreatment in most patients, however, as most calfactant (70%) and placebo patients (79 so) received a secon.d intet-vention per the study protocol becal.I.se their oxygenation index remained greater than 7, 10 [000471 Znfants younger than 12 nlontlzs constituted 26% of the population.
Mortality in th:is su.bgroup of placebo patients was more than three tirn.es tllat of calfactant-treated patients (9/19 vs 3/21; P=.02). Ventilator-free days were also statistically fewer in placebo patients (na.ean [SD], 7.0 [9.9] vs. 15.2 [10.3]; P=.01).
(00048] Table 2 reports other clinical otttcomes. M.ore placebo patients did not respond to convcntional mechanical ventilation after the study intervention.
Comparison. of duration of oxygen therapy, hospital and PrCLr lengths of stay, and hospital chxrges revealed no statistical differences betweeia groups.
[00049] Inlmediate connplicat:i.ons associated with instillation were more frequent in calfactant patients and were similar to the acute responses ofnew-horns to surfactant instillation. (Pedictty-ics. 1997;100:31-38). Hypotension was seen in 9% of calfactaiit instillations compared with 1% of placebo instillations (P=.005). All patients with hypotensio,ri responded to volume infctsion. Transient hypoxia occurred in 12%
of calfactant instillations cotnpared with 3% of placebo instillations (P=.008), but resolved wlzen the calfactant instillation was slowed and/or the positive-pressure ventilation was transiently increased.. No patient was removed froni. the study because of treatment complications. The incidence of air leaks was 13% in the calfactant group and 16% in the placcbo group (P=.65). Nosocomial. pneumonia was seen in 6% of calf'actant patients and 11% of placebo patients (P=.40). No systemic c=onzplications were ascribed to tlio iriter vention in either group. The ORs an.d associated 95% CIs of the treatment effect on mortality adjusted factors identified a priori (fast vs. slow entry, center) or a posteriori (age, immune status, enrollment nun~ber) are shown in TABLE 3. Although treatnient group is not significant in all models, particularly those that adjust for ilnn:runoconipromised status, the OR associated with the treatment was at least 2.1 for all models listed in TABL:E 3.
j00050j Infants, childreti, and adolescents with AL T who received calfactant in this naulticenter study had. decreased mortality, more rapid. improvement in oxygenation index, arrd were moi-e likely to respond to conventional mechanical ventilation. The prirnary outcome variable, ventilator-free days, was not significantly different between groups. Transient hypoxia and hypotension were nlore common with calfactant treatinc;rrt, bul these effects were mil.d and did not necessitate withdrawal from tlae study.
The acute positive effect of calfactant on ventilation in this trial is consistcnt with previous studies of calfactant in ch.i.[dren(Crit C,are Med. 1996;24:1316-1322, Crit Care Med. 1999;27:1. 8 8-195).
[00051] Infant respiratory distress syndrome results from quantitative de~ficiency of surfactant .leading to respiratory failure from progressive atelectasis.
Surfactant is also deficient in ARDS and ALI, but is al.so inhibited by inila.i7umatory mediators, plasma proteins, and cellular debn's that are seeping into the airspace.
Consequently, the chal-lenges for successful surfactant replacement therapy in ARDS and ALi are more complex than for ll2DS (Biotnetrics. 2001;57:282-286). Two surfactants effective in IRDS had disappointing results when tested in large cliilical trials in ARDS
and ALX (N.
Eragl. .T. Mee 1996;334: 1417-1421, flrri. J. Resl.7it: Crit. Care Itileci;
1997; 155:1309-1315).
[000521 `f`lie previously observed acute benefits of calfactant on lun.g function were replicated herein (C'rit Care Med. 1996;24:1316-1322, Crit. Care Med.
1999;27:188-195).
Both doses of calfactant improved oxygenation, demonstrating that it caz.-i fonn a funetioning film in the injured lung. Calfactant did not, however, restore lung fttnction to norrrial nor did all of the patients respond positively. Only 55% of calfactant patients (vs. 33% of placebo patients) had a 25% or greater improvement in oxygenation indcx by 12 hou.rs after the first intervention.

[00053] The duration of respiratoay failure was not irnproved with calfactant as it was in a pilot study(CYit. Care Med. 1999;27:188-195). The average duration of ventilation In calfactant compared with placebo patients was similar (11.3 vs. 10.8 days), as were lengths of stay and hospital chargcs. Thc absence of beneftt in these param.eters may be a consequence of the unexpected clisproportiol-tate survival of calfactant-treated patien.ts. As was observed with the introduction of surfactant therapy in prernature infants, increased survival n-iay actually increase the need for prolonged supportive care (J. Clin. .fnvest. 1991 ;88:1976-1981).
[00054] Severity of initial lung injury was expected to influence stlrvival.
Mortality rate was i-iideed higher in fast (37%) cornpztred with slow entry (20%) subgroups.
Mortality was lower in both strata for calfactant patients (26% calfactant vs.
46%
placebo for fast entry and 14 % vs. 26% for slow entry, respectively).
Unresolved respiratory failure was given as the primazy cause or a niajor contributor i1-1 83% of deaths, and lack of iinproven-ient in oxygenafion after the intervention was strorigly associated witli mortality. In-lprovenlent in lung function offers a plausible mechanislzz whereby calfactant treatment might increase survival. because respiratoiy failure was a significant cause of death in this trial.
[00055] Overall mortality in. this study was higher than in the pilot study (Crit. Care Med. 1999;27:188-195) (14% in pilot stttdy vs. 28% herein), att.ribtitable to the inclusion of the previously excluded imnlunoconzpromised patients whose mortality rate (56%) was four times that of i..mnlunocompctcnt paticnts (13%). Mortality rates were lower for calfactant patients in hoth the i.lnmunocompromised (50% vs. 60%) and iinrn'L1iloi;olTlpetCllt (7% v5. 20%) subgroups. The nunlerically greater izumbe.r. of immunocompromised patients in the placebo group (30 in the placebo group vs.
22 in the calfactant group; P=.17) influenced the observed overall m.ortality difference between the groups. The ORs for mortality with placebo treatinent approached but did not z-each statistical significance (P=.08) after post hoc adjustr.nen.t for inzinune status (TABLE 3). This study was not powered sufficiertltly to detect effects in specific patien.t subgroups.
[00056] There may be naultiple reasons for the failure of ather surfiicLanls in the lhr.ee large ARDS trials (N. Engl. J. Med. 1996; 334: 1417-1421, Am. J. Respir. Crit Care ItIecl.
1997; 155:1309-137.5, N. Engi. J. M,ecl. 2004; 351:884-892), but none of these trials used a lung surfactant preparat:ion contai~iing a sufficient ar.nount of SP-B, which.
is the essential factor for ful.l surfacfar-t activity and resista.r.ice of a. surfactant to inlubiti.on by blood and inflammatory protein rltolecules present in Lhe alveoli in ARDS/ALI (J. Clin.
Invest. 1991;
88:1976-1981, A.m. J. Respir. Crit. Ccire Med. 1996;153:176-184). Congenital absence of SP-B in humans causes lethal neonatal respiratoiy distress syndrome (J. Clin_ Invest.
1994;93:1860-1863), and mice who are bred deficient of SP-B die at birth of respiratory failure (Proc. Natl. Acad. Sci. USA. 1995;92: 7794-7798). The SP-B pivtein by itself confers ftill biophysical. and biological activity on surfactant phospholipids (JLipid.Res.
1996;37:1749-1760) The surfactant used in the study has the higllest level of resistance to inactivation, as deterxnined by in vitro and, in vivo experimental testing, due to its high ratio of SP-B to phospholipids (Expert Opin.. Pharrnacother. 2001;2:1479-7 493, Arrr. Rev Respir. Dis. 1992?145:24-30, Eur. Respir,I. 1993:6:971-977). It has greater stu-face activity a.nd physiological activity in animal lungs than Exosurf or Surva7lta, wl-iich arc two surfactants previousty used to treat ART)S in ad.i.i.l.ts (Gliern.. Phys.
Lipids, 2002; 114:21-34).
Additioaially, th.e aixzount of calfactarxt adrn.inistered in this lrial was more than three tirnes the estimated normal lung surfactant content of 20mg/kg {LuYZg Su~factants.
New York, NY: Marcel Dekker, 2000).
j0a0571 In this multicenter, raaldomized., blinded trial., calfactant adrninistration carly in the course of pediatric acute respiratary fail ure resulted in acute i.mproveinent in oxygeii.atioa.i and unexpectedly produced lower mortality. Adverse effects of the therapy were m.inimal.

Claims (12)

1. A process for treating a patient suffering from lung disease that requires the use of mechanical ventilation to sustain breathing, said process comprising:
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 concentration of phospholipid that is sufficient to produce detectable SP-B
dependent activity.

2. The process of claim 1 wherein the patient is selected from the group of (a) patients suffering from Acute Respiratory Distress (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.

3. The process of claim 1 wherein said surfactant is a lung surfactant.

4. The process of claim 3 wherein said lung surfactant is calfactant.

5. The process of claim 1 wherein said step of administering further comprises the step of administering said surfactant by intratracheal instillation.

6. The process of claim 1 wherein said patient has an age of at least about one week.

7. The process of claim 1 wherein said patient is post-neonatal.

8. The process of claim 1 wherein said therapeutically effective dosage comprises about 10 mg phospholipid/kg body weight to about 200 mg phospholipid /kg body weight.

9. The process of claim 1 wherein the surfactant comprises a saline suspension comprising about 25 mg/ml to about 100 mg/ml of phospholipid, plus SP-B in an amount of about 0,1 wt. % to about 4.0 wt.%, based on the weight of phospholipid.

10. The process of claim 9, wherein the SP-B comprises exogenous SP-B.

11. The process of claim 10, wherein the exogenous SP-B is added such that the total amount of SP-B in the surfactant is at least about 0.7 wt %.

12. A process for treating a patient suffering from lung disease that requires the use of mechanical ventilation to sustain breathing, said process comprising:
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 concentration of phospholipid that is sufficient to produce detectable SP-B
dependent activity;
wherein said surfactant is calfactant, and wherein said SP-B comprises exogenous SP-B added such that the total amount of SP-B in the surfactant is at least about 0.7 wt. %.