Comparison of the efficacy and safety of FP-1201-lyo (intravenously administered recombinant human interferon beta-1a) and placebo in the treatment of patients with moderate or severe acute respiratory distress syndrome: study protocol for a randomized controlled trial

Abstract

Background: Acute respiratory distress syndrome (ARDS) results in vascular leakage, inflammation and respiratory failure. There are currently no approved pharmacological treatments for ARDS and standard of care involves treatment of the underlying cause, and supportive care. The vascular leakage may be related to reduced concentrations of local adenosine, which is involved in maintaining endothelial barrier function. Interferon (IFN) beta-1a up-regulates the cell surface ecto-5'-nucleotidase cluster of differentiation 73 (CD73), which increases adenosine levels, and IFN beta-1 may, therefore, be a potential treatment for ARDS. In a phase I/II, open-label study in 37 patients with acute lung injury (ALI)/ARDS, recombinant human IFN beta-1a was well tolerated and mortality rates were significantly lower in treated than in control patients.

Methods/design: In this phase III, double-blind, randomized, parallel-group trial, the efficacy and safety of recombinant human IFN beta-1a (FP-1201-lyo) will be compared with placebo in adult patients with ARDS. Patients will be randomly assigned to receive 10 μg FP-1201-lyo or placebo administered intravenously once daily for 6 days and will be monitored for 28 days or until discharged from the intensive care unit. Follow-up visits will then take place at days 90, 180 and 360. The primary endpoint is a composite endpoint including any cause of death at 28 days and days free of mechanical ventilation within 28 days among survivors. Secondary endpoints include: all-cause mortality at 28, 90, 180 and 360 days; organ failure-free days; length of hospital stay; pharmacodynamic assessment including measurement of myxovirus resistance protein A concentrations; and measures of quality of life, respiratory and neurological function at 180 and 360 days. The estimated sample size to demonstrate a reduction in the primary outcome between groups from 30% to 15% is 300 patients, and the study will be conducted in 70-80 centers in nine countries across Europe.

Discussion: There are no effective specific treatments for patients with ARDS and mortality rates remain high. The results from this study will provide evidence regarding the efficacy of a potential new therapeutic agent, FP-1201-lyo, in improving the clinical course and outcome for patients with moderate/severe ARDS.

Trial registration: European Union Clinical Trials Register, no: 2014-005260-15 . Registered on 15 July 2017.

Keywords: ARDS; CD73; Interferon; Vascular leakage.

Fig. 1

Study design. ^aNot more than 48 h may elapse between confirmation of moderate or severe acute respiratory distress syndrome (ARDS) during screening and administration of the first dose of study drug on day 1. Once eligibility has been met, randomization can occur during screening or pre-dose on day 1

Fig. 2

Schedule of procedures. ^aNo more than 48 hours may elapse between confirmation of moderate or severe ARDS and administration of the first dose of study drug. ^bThese assessments will be done on the day the patient leaves the ICU, which will either be on D28 or earlier, according to the clinical progress of the patient. If the patient is still in the ICU on D28, the next visit or telephone contact will be at D90. If a patient leaves the ICU before D28, the survival status and other endpoints must be assessed on D28. ^cD28 procedures apply for patients leaving the ICU before D28 and for patients withdrawing from the study before D28. For patients withdrawing from the study before D28 a sample should be taken for neutralizing antibodies on the day they leave the ICU. ^dD90 can either be a visit or telephone contact. ^eReconfirm inclusion/exclusion criteria before dosing, including that patient requires mechanical ventilation and is in the ICU. ^fRandomize after consent obtained and once eligibility criteria confirmed. ^gWithin 24 hours of ICU admission. ^h1 hour pre-dose. ⁱBaseline EQ-5D-3L to be obtained from relatives and checked later with patient. ^jFor APACHE II scoring. ^kSamples should be taken in the morning between 04:00 and 10:00. ^lMedicines and therapies in previous month. ^mAdverse events will be recorded after informed consent is obtained. ⁿDeaths are reported as SAE. ⁰if it is possible to be performed by the investigator. APACHE II Acute Physiology and Chronic Health Evaluation, CD Cluster of differentiation, CT Computerized tomography, D Study day, ECG Electrocardiogram, EQ-5D-3L EuroQol 5-Dimensions 3-Levels questionnaire, FEV1 Forced expiratory volume in 1 second, GCS Glasgow Coma Scale, ICU Intensive care unit, IFN Interferon, MxA Myxovirus resistance protein A, PaO2/FiO2 Partial pressure of oxygen/fraction of inspired oxygen, PIM Potential inflammatory marker, SOFA Sequential Organ Failure Assessment, 6MWT 6-minute walk test