Efficacy and Safety of FP-1201-lyo (Interferon Beta-1a) in Patients Having Acute Respiratory Distress Syndrome (ARDS)

Study Overview
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Brief Summary
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In this study effectiveness and safety of a new drug FP-1201-lyo (recombinant human interferon beta-1a) is compared to placebo. Investigation is conducted with patients who have acute respiratory distress syndrome (ARDS). The new drug is expected to reduce the time which a patient need to be on the ventilator and improve patient's chances of survival. Currently there are no approved drugs for treating moderate or severe ARDS patients.

Detailed Description
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This is a Phase III clinical study to investigate the efficacy and safety of FP-1201-lyo (recombinant human interferon [IFN] beta-1a) compared to placebo in patients diagnosed with moderate or severe acute respiratory distress syndrome (ARDS). Primary objective is to demonstrate the efficacy of FP-1201-lyo in improving the clinical course and outcome based on survival and need for mechanical ventilation. Currently there are no approved drugs for treating moderate or severe ARDS patients. FP-1201-lyo is a lyophilised powder form of recombinant human IFN beta-1a reconstituted in water for injection and is administered intravenously. Recombinant human IFN beta-1a is an approved treatment for patients for other indication and its safety profile in such patients is well characterised.

Official Title
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A Phase III Double-blind, Randomised, Parallel-Group Comparison of the Efficacy and Safety of FP-1201-lyo (Recombinant Human IFN Beta-1a) and Placebo in the Treatment of Patients With Moderate or Severe Acute Respiratory Distress Syndrome

Conditions
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Respiratory Distress Syndrome, Adult

Intervention / Treatment
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* Drug: Interferon beta-1a
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients must be intubated and mechanically ventilated to diagnose ARDS and be eligible for the study Patient has a diagnosis of moderate or severe ARDS according to the Berlin definition of ARDS: Acute onset of respiratory failure within 1 week of a known clinical insult or new or worsening respiratory symptoms Respiratory failure associated with known ARDS risk factors and not fully explained by either cardiac failure or fluid overload (an objective assessment of cardiac failure or fluid overload is needed if no risk factors for ARDS [moderate or severe ARDS] are present) Radiological abnormalities on chest X-ray or on computerised tomography scan, i.e., bilateral opacities that are not fully explained by effusions, nodules, masses or lobar/lung collapse Hypoxaemia: Moderate ARDS: PaO2/FiO2 >100 mmHg (>13.3 kPa) to ≤200 mmHg (≤26.6 kPa) with positive end expiratory pressure (PEEP) ≥5 cmH2O Severe ARDS: PaO2/FiO2 ≤100 mmHg (≤13.3 kPa) with positive end expiratory pressure [PEEP] ≥5 centimeter of water [cmH2O] The radiological and hypoxaemia criteria (1.3 and 1.4) must be met within the same 24-hour period. The time of onset of ARDS is when the last of the two specified ARDS criteria is met Administration of the first dose of study drug must be planned to take place within 48 hours of moderate or severe ARDS diagnosis Patient is intubated and mechanically ventilated A signed informed consent form from the patient or the patient's personal legal representative or a professional legal representative must be available Patient is aged ≥18 years Exclusion Criteria: Woman known to be pregnant, lactating or with a positive (urine or serum test) or indeterminate (serum test) pregnancy test Patient is simultaneously taking part in another pharmacotherapy protocol Patient is not expected to survive for 24 hours Patient has an underlying clinical condition where, in the opinion of the Investigator, it would be extremely unlikely that the patient would come off ventilation, e.g., motor neurone disease, Duchenne muscular dystrophy or rapidly progressive interstitial pulmonary fibrosis Patient has severe chronic obstructive pulmonary disease requiring long-term home oxygen therapy or mechanical ventilation (non-invasive ventilation or via tracheotomy) except for continuous positive airway pressure (CPAP) or bi-level positive airway pressure used solely for sleep-disordered breathing Patient has congestive heart failure, defined as New York Heart Association class IV Patient has acute left ventricular failure Patient has liver failure (Child-Pugh grade C) Patient has received any prior interferon Patient has known hypersensitivity to natural or recombinant IFN beta or to any of the excipients Patient is receiving renal dialysis therapy for chronic renal failure Patient is receiving extra-corporeal membrane oxygenation, high-frequency oscillatory ventilation or any form of extra-corporeal lung support Patient has had any form of mechanical ventilation (invasive or non-invasive, excluding CPAP alone) for longer than 48 hours prior to the diagnosis of ARDS. Non-invasive ventilation has to be continuously applied for at least 12 hours per day in these 48 hours Patient has burns to ≥15% of their total body surface area

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FP-1201-lyo 10 μg<br>FP-1201-lyo 10 μg (Interferon beta-1a) will be administered once daily as an intravenous bolus injection for 6 days. Investigational product is lyophilisate for solution for injection which will be reconstituted in water for injection. | Drug: Interferon beta-1a<br>* Investigational drug<br>* Other names: ATC code L03AB07;|
| Placebo Comparator: FP-1201-lyo Placebo<br>FP-1201-lyo Placebo will be administered once daily as an intravenous bolus injection for 6 days. Investigational placebo product is lyophilisate for solution for injection which will be reconstituted in water for injection. | Drug: Placebo<br>* Placebo for investigational drug<br>* Other names: FP-1201-lyo Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Endpoint (VFDsurv; All-cause Mortality and Number of Days Free of Mechanical Ventilation) at Day 28 | VFDsurv is a composite measure of all-cause mortality and the number of days free of mechanical ventilation (VFDsurv) within 28 days among survivors. Ventilator-free days (VFDs) correspond to those days when unassisted breathing (UAB) was possible for a complete calendar day. UAB was defined as: spontaneously breathing with face mask, nasal prong oxygen or room air, T-piece breathing, tracheostomy mask breathing, CPAP less than or equal to 5 cmH2O without pressure support or intermittent mandatory ventilation assistance, use of CPAP or BIPAP solely for sleep apnoea management. A patient was reported as ventilator-free after 2 consecutive calendar days of unassisted breathing (a VFD value of 0 is assigned to patients who die without initiating UAB or who require more than 28 days of mechanical ventilation. All patients who die before Day28 are assigned a VFDsurv value of -1). | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy Endpoint: All-cause Mortality | Fatalities, mortality all-causes from randomisation up to Day 28 | At Day 28 | 
| Efficacy Endpoint: Mortality in ICU | All-cause mortality for subjects who died in Intensive Care Units up to Day 28. | Up to Day 28 | 
| Efficacy Endpoint: Mortality in Hospital | This is the number of subjects who died in hospital (i.e. outside of Intensive Care Units) up to Day 28. | Up to Day 28 | 
| Other Secondary Efficacy Endpoints: Days Free of Organ Failure | The total number of days free of organ failure by Sequential Organ Failure Assessment (SOFA) methodology. Overall, the median number of days free of organ failure was 0 days in both the treatment groups. | Day 28 or last day in intensive care unit [ICU] if patient has left the ICU earlier than Day 28 | 
| Other Secondary Efficacy Endpoints: Days Free of Renal Support | Days without renal support (any renal support was documented). Overall, the median number of days free of renal support was 28 days in the active group and 27 days in the placebo group. | Day 28 | 
| Other Secondary Efficacy Endpoints: Days Free of Vasoactive Support | Days without vasoactive support. The vasoactive support included catecholamine and non-catecholamine vasopressors, inotropes and vasodilating agents. Overall, the median number of days free of vasoactive support was 20 days in the active group and 21 days in the placebo group. | Day 28 | 
| Other Secondary Efficacy Endpoint: Days Free of Mechanical Ventilation | The total number of days free of mechanical ventilation has been derived from the Patient Status report recorded on each day during the 28-day period. Patients who died during this period have been assigned a value of zero. This variable differs from the calculated Ventilation Free Days (VFD) endpoint, which contribute to the VDFsurv primary efficacy endpoint as it require additional conditions of unassisted breathing (UAB) to be met. | Day 28 | 
| Other Secondary Efficacy Endpoints: Number of ICU-free Days | Number of Intensive Care Unit free days up to Day 28, i.e. the patient is no longer receiving care in ICU. Patients who die during this period have been assigned a value of zero for the number of ICU care free days. | Day 28 | 
| Other Secondary Efficacy Endpoints: Number of Days in Hospital | Hospitalisation days (including the stay at Intensive Care Units). Patients who died during this period have been assigned a value of 28 for the number of days in ICU or in hospital. | Day 28 | 
| Evaluation of Safety: Adverse Events and Deaths | Adverse events (AE) up to Day 28. Per protocol, AEs occurring after Day 28 if the investigator considered a causal relationship with the study drug as well as all deaths up to Day 360 were reported. Treatment-emergent AEs (TEAEs) were defined as AEs that begins or worsens in intensity after at least one dose of study drug has been administered. Serious AEs (SAEs) were defined as any untoward medical occurrence that at any dose resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was an important medical event. | AEs up to Day 28, only related after Day 28 and deaths up to Day 360 | 
| Efficacy Endpoint: Presence of Neutralising Antibodies to IFN Beta-1a | The immunological response to FP-1201-lyo was assessed by monitoring presence of anti-drug binding antibodies (BAbs) and neutralising antibodies (NAbs) to IFN beta-1a on pre-dose Day 1 and at Day 28, the last day in ICU or early termination (if earlier). The BAbs were determined first, and if present, the NAbs were also determined. Presence of BAbs and NAbs were summarised categorically, using positive/negative classification. | Baseline and Day 28 (or last day in intensive care unit [ICU] or at withdrawal, if earlier) | 
| Efficacy Endpoint: Evaluation of Pharmacodynamic (PD) Using Myxovirus Resistance Protein A (MxA) Biomarker | Evaluation of MxA biomarker change from baseline to D14 between treatments arms over time. | From baseline to Day 14 | 
| Long-term Efficacy Endpoint: Change in Quality of Life From Baseline to Day 180 | Quality of Life was assessed through EQ-5D-3L (EuroQol 5-Dimensions 3-Levels questionnaire). An EQ Visual Analogue Scale (VAS) total score (ranging from 0-100) was measured (0= Worst imaginable health state, 100= Best imaginable health state). The EQ-5D-3L VAS scores are numerically summarised as change from pre-dose (Day 1) to long term follow-up (Day 180 visit). | Change from baseline to Day 180 | 
| Long-term Efficacy Endpoints Relating to Respiratory Functioning (FEV1) | Measuring FEV1 (forced expiratory volume in 1 second) assessed pulmonary function (airway obstruction, bronchoconstriction or bronchodilation). FEV1 is the volume exhaled during the first second of a forced expiratory manoeuvre, starting from the level of total lung capacity. | Day 180 | 
| Long-term Efficacy Endpoints Relating to Neurological Functioning (6MWT) | The 6-minute walk test (6MWT) measures the distance that a patient can quickly walk on a flat, hard surface in a period of 6 minutes. According to the ERS/ATS technical standard to which the 6MWT was done, the walk test is done twice and the best result is used. It is an evaluation of the global and integrated responses of all systems involved during exercise, including the pulmonary and cardiovascular systems, systemic circulation, peripheral circulation, blood and neuromuscular units and muscle metabolism. The self-paced 6MWT assesses the sub- maximal level of functional capacity and will better reflect the functional exercise level for daily activities. ANOVA parameters estimates (LS Means and 90 % conf.interval) for the overall treatment difference was analysed. | Day 180 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ARDS, human, Acute Respiratory Distress Syndrome, Respiratory Insufficiency