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

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

Status

Terminated

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02622724

Acronym

INTEREST

Enrollment

301

Registered

2015-12-04

Start date

2015-12-23

Completion date

2018-05-23

Last updated

2020-03-30

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Respiratory Distress Syndrome, Adult

Keywords

ARDS, human, Acute Respiratory Distress Syndrome, Respiratory Insufficiency

Brief summary

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

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.

Interventions

DRUGInterferon beta-1a

Investigational drug

DRUGPlacebo

Placebo for investigational drug

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

All patients must be intubated and mechanically ventilated to diagnose ARDS and be eligible for the study 1. 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 \[cmH2O\] 2. 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 3. Administration of the first dose of study drug must be planned to take place within 48 hours of moderate or severe ARDS diagnosis 4. Patient is intubated and mechanically ventilated 5. A signed informed consent form from the patient or the patient's personal legal representative or a professional legal representative must be available 6. Patient is aged ≥18 years

Exclusion criteria

1. Woman known to be pregnant, lactating or with a positive (urine or serum test) or indeterminate (serum test) pregnancy test 2. Patient is simultaneously taking part in another pharmacotherapy protocol 3. Patient is not expected to survive for 24 hours 4. 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 5. 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 6. Patient has congestive heart failure, defined as New York Heart Association class IV 7. Patient has acute left ventricular failure 8. Patient has liver failure (Child-Pugh grade C) 9. Patient has received any prior interferon 10. Patient has known hypersensitivity to natural or recombinant IFN beta or to any of the excipients 11. Patient is receiving renal dialysis therapy for chronic renal failure 12. Patient is receiving extra-corporeal membrane oxygenation, high-frequency oscillatory ventilation or any form of extra-corporeal lung support 13. 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 14. Patient has burns to ≥15% of their total body surface area

Design outcomes

Primary

Measure	Time frame	Description
Composite Endpoint (VFDsurv; All-cause Mortality and Number of Days Free of Mechanical Ventilation) at Day 28	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).

Secondary

Measure	Time frame	Description
Efficacy Endpoint: Mortality in ICU	Up to Day 28	All-cause mortality for subjects who died in Intensive Care Units up to Day 28.
Efficacy Endpoint: Mortality in Hospital	Up to Day 28	This is the number of subjects who died in hospital (i.e. outside of Intensive Care Units) up to Day 28.
Other Secondary Efficacy Endpoints: Days Free of Organ Failure	Day 28 or last day in intensive care unit [ICU] if patient has left the ICU earlier than Day 28	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.
Other Secondary Efficacy Endpoints: Days Free of Renal Support	Day 28	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.
Other Secondary Efficacy Endpoints: Days Free of Vasoactive Support	Day 28	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.
Other Secondary Efficacy Endpoint: Days Free of Mechanical Ventilation	Day 28	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.
Other Secondary Efficacy Endpoints: Number of ICU-free Days	Day 28	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.
Efficacy Endpoint: All-cause Mortality	At Day 28	Fatalities, mortality all-causes from randomisation up to Day 28
Evaluation of Safety: Adverse Events and Deaths	AEs up to Day 28, only related after Day 28 and deaths up to Day 360	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.
Efficacy Endpoint: Presence of Neutralising Antibodies to IFN Beta-1a	Baseline and Day 28 (or last day in intensive care unit [ICU] or at withdrawal, if earlier)	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.
Efficacy Endpoint: Evaluation of Pharmacodynamic (PD) Using Myxovirus Resistance Protein A (MxA) Biomarker	From baseline to Day 14	Evaluation of MxA biomarker change from baseline to D14 between treatments arms over time.
Long-term Efficacy Endpoint: Change in Quality of Life From Baseline to Day 180	Change 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).
Long-term Efficacy Endpoints Relating to Respiratory Functioning (FEV1)	Day 180	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.
Long-term Efficacy Endpoints Relating to Neurological Functioning (6MWT)	Day 180	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.
Other Secondary Efficacy Endpoints: Number of Days in Hospital	Day 28	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.

Other

Measure	Time frame	Description
Extended Long-term Follow-up Exploratory Endpoint: Change in Quality of Life From Baseline to Day 360	Change from baseline to Day 360	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 extended long term follow-up (Day 360 visit).
Evaluation of Safety: Vital Signs - Heart Rate	From baseline to Last Observation Performed (Day 28 or last day in ICU if patient has left the ICU earlier than Day 28, or at withdrawal)	Vital signs were measured supine pre-dose on Day 1 (baseline) and daily up to Day 28 while the patient was in the ICU. The results at baseline and at last observation performed (LOP) were summarized overall by treatment, variable and time point. No statistical analyses were made for vital signs.
Extended Long-term Follow-up Endpoint: Respiratory Functioning (FEV1) at Day 360	Day 360	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.
Neurological Functioning (6MWT) at Extended Long-term Follow-up	Day 360	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 % confidence intervals) for the overall treatment difference was analysed.
Evaluation of Safety: Vital Signs - Body Temperature	From baseline to Last Observation Performed (Day 28 or last day in ICU if patient has left the ICU earlier than Day 28, or at withdrawal)	Vital signs were measured supine pre-dose on Day 1 (baseline) and daily up to Day 28 while the patient was in the ICU. The results at baseline and at last observation performed (LOP) were summarized overall by treatment, variable and time point. No statistical analyses were made for vital signs.
Evaluation of Safety: Vital Signs - Blood Pressure	From baseline to Last Observation Performed (Day 28 or last day in ICU if patient has left the ICU earlier than Day 28, or at withdrawal)	Vital signs were measured supine pre-dose on Day 1 (baseline) and daily up to Day 28 while the patient was in the ICU. The results at baseline and at last observation performed (LOP) were summarized overall by treatment, variable and time point. No statistical analyses were made for vital signs.
Evaluation of Safety: Physical Examination	From baseline to Last Observation Performed (D28 or last day in ICU if patient has left the ICU earlier than Day 28, or at withdrawal)	Physical examination data (covering the major body systems; general appearance, head \[ear, nose and throat\], cardiovascular, eyes, respiratory, abdomen, urogenital, musculoskeletal, neurological, lymph nodes and skin) were categorized as normal; abnormal, not clinically significant; abnormal, clinically significant or not done. Physical examinations were performed at Screening, then at the Last day in ICU and Day 28 (Out of ICU) or Early Termination, from which the last observation performed is derived. The changes from baseline to the last observations performed are categorized as no change, change clinically significant; change not clinically significant, not done.
Evaluation of Safety: Laboratory Results	From baseline to Day 28 (or last day in ICU if patient has left the ICU earlier than Day 28, or at withdrawal)	Laboratory safety assessments of biochemistry, haematology and urinalysis were performed daily during the stay at ICU. Laboratory data were classified according to normal ranges as out of range (OOR; not clinically significant), OOR (clinically significant), or OOR (clinically significant and an AE). Laboratory test results were summarised by actual results by baseline and last observation period.
Evaluation of Pharmacoeconomics: Days Free of Organ Failure	Day 28 (or last day in ICU if patient has left the ICU earlier than Day 28, or at withdrawal)	Due to the study terminating early, costs items from hospitals were not collected and pharmacoeconomic analyses could not be done.
Evaluation of Pharmacoeconomics: Days Free of Renal Support	Day 28 (or last day in ICU if patient has left the ICU earlier than Day 28, or at withdrawal)	Due to the study terminating early, costs items from hospitals were not collected and pharmacoeconomic analyses could not be done.
Evaluation of Pharmacoeconomics: Days Free of Vasoactive Support	Day 28 (or last day in ICU if patient has left the ICU earlier than Day 28, or at withdrawal)	Due to the study terminating early, costs items from hospitals were not collected and pharmacoeconomic analyses could not be done.
Evaluation of Pharmacoeconomics: Days Free of Mechanical Ventilation	Day 28 (or last day in ICU if patient has left the ICU earlier than Day 28, or at withdrawal)	Due to the study terminating early, costs items from hospitals were not collected and pharmacoeconomic analyses could not be done.
Evaluation of Pharmacoeconomics: Number of ICU-free Days	Day 28 (or last day in ICU if patient has left the ICU earlier than Day 28, or at withdrawal)	Due to the study terminating early, costs items from hospitals were not collected and pharmacoeconomic analyses could not be done.
Evaluation of Pharmacoeconomics: Number of Days in Hospital	Day 28 (or last day in ICU if patient has left the ICU earlier than Day 28, or at withdrawal)	Due to the study terminating early, costs items from hospitals were not collected and pharmacoeconomic analyses could not be done.
Exploratory Variables Relating to Efficacy: Composite Endpoint (Mortality and Days Free of Mechanical Ventilation) at Day 90	Within 90 days	Composite endpoint including mortality and days free of mechanical ventilation (VFDsurv) within 90 days among survivors. Ventilation Free Survival at Day 90 has been classified as Dead, Alive but on a ventilator and Alive and breathing unassisted
Change in the Treatment-specific Exploratory Biomarker Cluster of Differentiation 73 (CD73) Concentration	From baseline to Day 14	Evaluation of Cluster of differentiation 73 (CD73) change from baseline to D14 between treatments arms over time.
Changes in Levels of Potential Inflammatory Markers (PIMs)	From baseline to Day 14	Evaluation of potential inflammatory markers (PIMs) change from baseline to D14 between treatments arms over time. Potential biomarkers included IL-1ra, IL-6, FGF basic, IP-10 and TNF-α.
Pharmacogenetic Analysis	Anytime from baseline to Day 28	An optional genetic sample was analysed for subjects based on a separate consent. A carrier frequency was analysed for a C/T polymorphism (rs9984723) located in the 3'PRIME\_UTR/intron region of IFNAR2-gene, which encodes the beta chain for the IFN-alpha/beta receptor and encompasses a regulatory motif for the glucocorticoid receptor. Biomarker responders were defined by a 3-fold elevation in MxA and a 2-fold in CD73 in comparison to baseline.
Exploratory, Extended Long-term Follow-up: Overall Mortality at Day 360	Day 360 /termination of study	Fatalities; as the study was terminated early, the assessment time point for mortality at Day 360 was not reached. Therefore only the overall mortality at study termination is presented.

Countries

Belgium, Czechia, Finland, France, Germany, Italy, Spain, United Kingdom

Participant flow

Participants by arm

Arm	Count
FP-1201-lyo 10 μg 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. Interferon beta-1a: Investigational drug	144
Placebo 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. Placebo: Placebo for investigational drug	152
Total	296

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Death	51	53
Overall Study	Early termination of study	38	43
Overall Study	Lost to Follow-UP, withdrawal of consent	4	7

Baseline characteristics

Characteristic	FP-1201-lyo 10 μg	Placebo	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	55 Participants	51 Participants	106 Participants
Age, Categorical Between 18 and 65 years	89 Participants	101 Participants	190 Participants
Age, Continuous	58.3 years STANDARD_DEVIATION 17.2	58.4 years STANDARD_DEVIATION 14	58.4 years STANDARD_DEVIATION 15.6
Race/Ethnicity, Customized Race American Indian/Alaskan	1 Participants	1 Participants	2 Participants
Race/Ethnicity, Customized Race Asian-Other	1 Participants	2 Participants	3 Participants
Race/Ethnicity, Customized Race Black	4 Participants	5 Participants	9 Participants
Race/Ethnicity, Customized Race Native Arab	4 Participants	2 Participants	6 Participants
Race/Ethnicity, Customized Race Other or not reported	35 Participants	36 Participants	71 Participants
Race/Ethnicity, Customized Race White	99 Participants	106 Participants	205 Participants
Region of Enrollment Belgium	12 Participants	12 Participants	24 Participants
Region of Enrollment Czechia	1 Participants	1 Participants	2 Participants
Region of Enrollment Finland	15 Participants	15 Participants	30 Participants
Region of Enrollment France	54 Participants	58 Participants	112 Participants
Region of Enrollment Germany	8 Participants	7 Participants	15 Participants
Region of Enrollment Italy	18 Participants	19 Participants	37 Participants
Region of Enrollment Spain	11 Participants	11 Participants	22 Participants
Region of Enrollment United Kingdom	25 Participants	29 Participants	54 Participants
Sex: Female, Male Female	42 Participants	61 Participants	103 Participants
Sex: Female, Male Male	102 Participants	91 Participants	193 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	51 / 144	53 / 152
other Total, other adverse events	109 / 144	110 / 152
serious Total, serious adverse events	77 / 144	77 / 152

Outcome results

Primary

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).

Time frame: Day 28

Population: Full Analysis Set (FAS), 296 subjects.

Arm	Measure	Value (MEDIAN)
FP-1201-lyo 10 μg	Composite Endpoint (VFDsurv; All-cause Mortality and Number of Days Free of Mechanical Ventilation) at Day 28	10 Days
Placebo	Composite Endpoint (VFDsurv; All-cause Mortality and Number of Days Free of Mechanical Ventilation) at Day 28	8.5 Days

Comparison: A non-parametric analysis has been used as the data distribution was skewed. This involved a generalised Wilcoxon rank sum-based stratification test which assigns ranks within strata and compares two treatments within strata (Van Elteren hypothesis test).p-value: 0.8219Van Elteren hypothesis test

Secondary

Efficacy Endpoint: All-cause Mortality

Fatalities, mortality all-causes from randomisation up to Day 28

Time frame: At Day 28

Population: Full Analysis Set (FAS) defined as all randomised subjects that received atleast one dose of study drug.

Arm	Measure	Value (NUMBER)
FP-1201-lyo 10 μg	Efficacy Endpoint: All-cause Mortality	26.4 percentage of subjects
Placebo	Efficacy Endpoint: All-cause Mortality	23 percentage of subjects

Secondary

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.

Time frame: From baseline to Day 14

Population: Subjects from Full Analysis Set population for whom samples were available; analysis of last observation performed.

Arm	Measure	Value (MEAN)	Dispersion
FP-1201-lyo 10 μg	Efficacy Endpoint: Evaluation of Pharmacodynamic (PD) Using Myxovirus Resistance Protein A (MxA) Biomarker	31.8 ng/ml	Standard Deviation 63.3
Placebo	Efficacy Endpoint: Evaluation of Pharmacodynamic (PD) Using Myxovirus Resistance Protein A (MxA) Biomarker	7.8 ng/ml	Standard Deviation 28.8

p-value: <0.05ANCOVA

Secondary

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.

Time frame: Up to Day 28

Population: Full Analysis Set

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
FP-1201-lyo 10 μg	Efficacy Endpoint: Mortality in Hospital	1 Participants
Placebo	Efficacy Endpoint: Mortality in Hospital	0 Participants

Secondary

Efficacy Endpoint: Mortality in ICU

All-cause mortality for subjects who died in Intensive Care Units up to Day 28.

Time frame: Up to Day 28

Population: Full Analysis Set

Arm	Measure	Value (NUMBER)
FP-1201-lyo 10 μg	Efficacy Endpoint: Mortality in ICU	25.7 percentage of subjects
Placebo	Efficacy Endpoint: Mortality in ICU	23.0 percentage of subjects

Secondary

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.

Time frame: Baseline and Day 28 (or last day in intensive care unit [ICU] or at withdrawal, if earlier)

Population: Full Analysis Set, the subjects who had laboratory evaluation done. Subjects were analysed for IFN beta NAbs only if BAbs were present.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
FP-1201-lyo 10 μg	Efficacy Endpoint: Presence of Neutralising Antibodies to IFN Beta-1a	Presence of BAbs to IFN β-1a at baseline	2 Participants
FP-1201-lyo 10 μg	Efficacy Endpoint: Presence of Neutralising Antibodies to IFN Beta-1a	Presence of BAbs to IFN β-1a at Day28	0 Participants
FP-1201-lyo 10 μg	Efficacy Endpoint: Presence of Neutralising Antibodies to IFN Beta-1a	Presence of NAbs to IFN β-1a at baseline	1 Participants
FP-1201-lyo 10 μg	Efficacy Endpoint: Presence of Neutralising Antibodies to IFN Beta-1a	Presence of NAbs to IFN β-1a at Day28	0 Participants
Placebo	Efficacy Endpoint: Presence of Neutralising Antibodies to IFN Beta-1a	Presence of NAbs to IFN β-1a at Day28	0 Participants
Placebo	Efficacy Endpoint: Presence of Neutralising Antibodies to IFN Beta-1a	Presence of BAbs to IFN β-1a at baseline	2 Participants
Placebo	Efficacy Endpoint: Presence of Neutralising Antibodies to IFN Beta-1a	Presence of NAbs to IFN β-1a at baseline	0 Participants
Placebo	Efficacy Endpoint: Presence of Neutralising Antibodies to IFN Beta-1a	Presence of BAbs to IFN β-1a at Day28	1 Participants

Secondary

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.

Time frame: AEs up to Day 28, only related after Day 28 and deaths up to Day 360

Population: The analysis population included all participants who were randomized and received at least 1 dose of study treatment.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
FP-1201-lyo 10 μg	Evaluation of Safety: Adverse Events and Deaths	Subjects with TEAE	130 Participants
FP-1201-lyo 10 μg	Evaluation of Safety: Adverse Events and Deaths	Subjects with AE considered related to study drug	41 Participants
FP-1201-lyo 10 μg	Evaluation of Safety: Adverse Events and Deaths	Subjects with SAE	77 Participants
FP-1201-lyo 10 μg	Evaluation of Safety: Adverse Events and Deaths	Death	51 Participants
Placebo	Evaluation of Safety: Adverse Events and Deaths	Death	53 Participants
Placebo	Evaluation of Safety: Adverse Events and Deaths	Subjects with TEAE	132 Participants
Placebo	Evaluation of Safety: Adverse Events and Deaths	Subjects with SAE	77 Participants
Placebo	Evaluation of Safety: Adverse Events and Deaths	Subjects with AE considered related to study drug	33 Participants

Secondary

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).

Time frame: Change from baseline to Day 180

Population: Subjects from Full Analysis Set population who completed QoL questionnaire at Baseline and Day 180.

Arm	Measure	Value (MEDIAN)
FP-1201-lyo 10 μg	Long-term Efficacy Endpoint: Change in Quality of Life From Baseline to Day 180	-10 change score on a scale
Placebo	Long-term Efficacy Endpoint: Change in Quality of Life From Baseline to Day 180	-5 change score on a scale

Secondary

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.

Time frame: Day 180

Population: All subjects in Full Analysis Set population who performed atleast one 6MWT test at Day 180 visit. Furthest distance walked during the two tests was analysed using an ANOVA model.

Arm	Measure	Value (MEAN)	Dispersion
FP-1201-lyo 10 μg	Long-term Efficacy Endpoints Relating to Neurological Functioning (6MWT)	449 maximum distance walked (meters)	Standard Deviation 174
Placebo	Long-term Efficacy Endpoints Relating to Neurological Functioning (6MWT)	424 maximum distance walked (meters)	Standard Deviation 156

Comparison: Treatment effect was analysed using ANOVA parameter estimates (Least Squares Means and 95% Confidence Intervals) for the overall treatment difference for maximum distance walked on Day 180.p-value: >0.0595% CI: [-37.7, 99.9]ANOVA

Secondary

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.

Time frame: Day 180

Population: Full Analysis Set

Arm	Measure	Value (MEAN)	Dispersion
FP-1201-lyo 10 μg	Long-term Efficacy Endpoints Relating to Respiratory Functioning (FEV1)	81.2 %FEV1	Standard Deviation 21.1
Placebo	Long-term Efficacy Endpoints Relating to Respiratory Functioning (FEV1)	79.5 %FEV1	Standard Deviation 29.6

Secondary

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.

Time frame: Day 28

Population: Full Analysis Set

Arm	Measure	Value (MEDIAN)
FP-1201-lyo 10 μg	Other Secondary Efficacy Endpoint: Days Free of Mechanical Ventilation	10 Days
Placebo	Other Secondary Efficacy Endpoint: Days Free of Mechanical Ventilation	9 Days

Comparison: Van Elteren hypothesis test was used as the distribution was non-normal and negatively skewed by patients who are assigned scores of zero in the event of death.p-value: 0.4678Van Elteren p-values

Secondary

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.

Time frame: Day 28 or last day in intensive care unit [ICU] if patient has left the ICU earlier than Day 28

Population: Full Analysis Set

Arm	Measure	Value (MEDIAN)
FP-1201-lyo 10 μg	Other Secondary Efficacy Endpoints: Days Free of Organ Failure	0 Days
Placebo	Other Secondary Efficacy Endpoints: Days Free of Organ Failure	0 Days

Secondary

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.

Time frame: Day 28

Population: Full Analysis Set

Arm	Measure	Value (MEDIAN)
FP-1201-lyo 10 μg	Other Secondary Efficacy Endpoints: Days Free of Renal Support	28 Days
Placebo	Other Secondary Efficacy Endpoints: Days Free of Renal Support	27 Days

Secondary

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.

Time frame: Day 28

Population: Full Analysis Set

Arm	Measure	Value (MEDIAN)
FP-1201-lyo 10 μg	Other Secondary Efficacy Endpoints: Days Free of Vasoactive Support	20 Days
Placebo	Other Secondary Efficacy Endpoints: Days Free of Vasoactive Support	21 Days

Secondary

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.

Time frame: Day 28

Population: Full Analysis Set

Arm	Measure	Value (MEDIAN)
FP-1201-lyo 10 μg	Other Secondary Efficacy Endpoints: Number of Days in Hospital	28 Days
Placebo	Other Secondary Efficacy Endpoints: Number of Days in Hospital	28 Days

Secondary

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.

Time frame: Day 28

Population: Full Analysis Set

Arm	Measure	Value (MEDIAN)
FP-1201-lyo 10 μg	Other Secondary Efficacy Endpoints: Number of ICU-free Days	6 Days
Placebo	Other Secondary Efficacy Endpoints: Number of ICU-free Days	3.5 Days

Other Pre-specified

Change in the Treatment-specific Exploratory Biomarker Cluster of Differentiation 73 (CD73) Concentration

Evaluation of Cluster of differentiation 73 (CD73) change from baseline to D14 between treatments arms over time.

Time frame: From baseline to Day 14

Population: Subjects from Full Analysis Set population for whom samples were available; analysis of last observation performed.

Arm	Measure	Value (MEAN)	Dispersion
FP-1201-lyo 10 μg	Change in the Treatment-specific Exploratory Biomarker Cluster of Differentiation 73 (CD73) Concentration	6.2 ng/ml	Standard Deviation 8.9
Placebo	Change in the Treatment-specific Exploratory Biomarker Cluster of Differentiation 73 (CD73) Concentration	6.1 ng/ml	Standard Deviation 7.9

Other Pre-specified

Changes in Levels of Potential Inflammatory Markers (PIMs)

Evaluation of potential inflammatory markers (PIMs) change from baseline to D14 between treatments arms over time. Potential biomarkers included IL-1ra, IL-6, FGF basic, IP-10 and TNF-α.

Time frame: From baseline to Day 14

Population: Subjects from Full Analysis Set population for whom samples were available; analysis of last observation performed.

Arm	Measure	Group	Value (MEAN)	Dispersion
FP-1201-lyo 10 μg	Changes in Levels of Potential Inflammatory Markers (PIMs)	IL-6	63 pg/mL	Standard Deviation 298
FP-1201-lyo 10 μg	Changes in Levels of Potential Inflammatory Markers (PIMs)	IP-10	1938 pg/mL	Standard Deviation 3543
FP-1201-lyo 10 μg	Changes in Levels of Potential Inflammatory Markers (PIMs)	FGF basic	37 pg/mL	Standard Deviation 17
FP-1201-lyo 10 μg	Changes in Levels of Potential Inflammatory Markers (PIMs)	TNF-α	68 pg/mL	Standard Deviation 60
FP-1201-lyo 10 μg	Changes in Levels of Potential Inflammatory Markers (PIMs)	IL-1ra	1830 pg/mL	Standard Deviation 5252
Placebo	Changes in Levels of Potential Inflammatory Markers (PIMs)	TNF-α	81 pg/mL	Standard Deviation 148
Placebo	Changes in Levels of Potential Inflammatory Markers (PIMs)	IL-1ra	1699 pg/mL	Standard Deviation 4565
Placebo	Changes in Levels of Potential Inflammatory Markers (PIMs)	IL-6	88 pg/mL	Standard Deviation 584
Placebo	Changes in Levels of Potential Inflammatory Markers (PIMs)	FGF basic	38 pg/mL	Standard Deviation 20
Placebo	Changes in Levels of Potential Inflammatory Markers (PIMs)	IP-10	1762 pg/mL	Standard Deviation 3894

Comparison: IL -1ra - changes in levels from baseline to Day 14p-value: >0.05ANCOVA

Comparison: IL- 6 - changes in levels from baseline to Day 14p-value: >0.05ANCOVA

Comparison: FGF basic - changes in levels from baseline to Day 14p-value: <0.05ANCOVA

Comparison: IP-10 - changes in levels from baseline to Day 14.p-value: <0.05ANCOVA

Comparison: TNF-α - changes in levels from baseline to Day 14p-value: >0.05ANCOVA

Other Pre-specified

Evaluation of Pharmacoeconomics: Days Free of Mechanical Ventilation

Due to the study terminating early, costs items from hospitals were not collected and pharmacoeconomic analyses could not be done.