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

Respiratory Distress Syndrome, Adult Clinical Trial

— INTEREST  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02622724
• Other study ID #: FPCLI002
• Secondary ID: 2014-005260-15
• Status: Terminated
• Phase: Phase 3
• Start date: December 23, 2015
• Est. completion date: May 23, 2018

Study information

• Verified date: March 2020
• Source: Faron Pharmaceuticals Ltd
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 301
• Est. completion date: May 23, 2018
• Est. primary completion date: May 17, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Lung Injury
• Respiratory Distress Syndrome, Adult
• Respiratory Distress Syndrome, Newborn
• Syndrome

Intervention

Drug:
• Interferon beta-1a
Investigational drug
• Placebo
Placebo for investigational drug

Locations

Country	Name	City	State
Belgium	Erasmus Hospital	Brussels
Belgium	UZ Brussel	Brussels
Belgium	UZ Antwerpen	Edegem
Belgium	UZ Gent	Gent
Belgium	CHU Charleroi Site Hôpital Civil Marie Curie	Lodelinsart
Belgium	CHU Dinant Godinne UCL Namur	Yvoir
Czechia	Fakultni nemocnice Hradec Kralove	Hradec Králové
Czechia	Fakultni nemocnice Kralovske Vinohrady	Praha 10
Czechia	Hospital Usti nad Labem	Usti nad Labem
Finland	Helsinki University Hospital	Helsinki
Finland	Kuopio University Hospital	Kuopio
Finland	Tampere University Hospital	Tampere
Finland	Turku University Central Hospital	Turku
France	CHU D'Angers	Angers	Pays-de-la-Loire
France	CHU Cavale Blanche	Brest
France	Centre Hospitalier Universitaire de Bicêtre	Le Kremlin-Bicêtre
France	Centre Hospitalier Le Mans	Le Mans
France	Hôpital de la Croix Rousse	Lyon	Rhône
France	Hôpital Nord AP-HM	Marseille
France	CHRU Nancy	Nancy
France	Centre Hospitalier Régional d'Orléans	Orléans	Loiret
France	Hôpital Cochin, Réanimation Médicale Hospitalisation	Paris	Île-de-France
France	Pitié-Salpêtrière Hospital	Paris
France	CHU De Poitiers	Poitiers	Poitou-Charentes
France	CHU Pontchaillou	Rennes
France	Hôpital Charles-Nicolle	Rouen	Seine-Maritime
France	Nouvel Hôpital Civil	Strasbourg	Alsace
France	CHU Bretonneau	Tours
Germany	Klinikum Augsburg Klinik für Anästhesiologie	Augsburg
Germany	Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum	Berlin
Germany	Universitätsklinikum Bonn Klinik und Poliklinik für Anästhesiologie	Bonn
Germany	Universitätsklinikum Carl Gustav Carus Klinik für Anästhesiologie und Intensivmedizin	Dresden
Germany	Universitätsmedizin Göttingen Klinik für Anästhesiologie	Göttingen
Germany	Universitätsklinikum Hamburg-Eppendorf Klinik für Intesivmedizin	Hamburg
Germany	Kliniken der Stadt Köln Klinikum Merheim	Köln
Germany	Universitätsklinik Leipzig Klinik und Poliklinik für Anäesthesiologie und Intensivtherapie	Leipzig
Italy	Azienda Ospedaliera Universitaria Sant' Anna	Cona
Italy	IRCCS Ca' Granda Ospedale Maggiore Policlinico	Milano
Italy	ASST Monza	Monza
Italy	Fondazione Policlinico Universitario Agostino Gemelli	Roma
Italy	Universita degli Studi di Roma "La Sapienza"	Roma
Italy	AOU Città della Salute e della Scienza di Torino	Torino
Spain	Hospital Universitario Germans Trias i Pujol	Badalona
Spain	Hospital Clínic i Provincial de Barcelona	Barcelona
Spain	Hospital de la Santa Creu I Sant Pau	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Hospital Universitario del Henares	Coslada
Spain	Hospital Universitario de Getafe	Getafe
Spain	Hospital Universitario de Gran Canaria Dr Negrin	Las Palmas de Gran Canaria
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitari Son Espases	Palma De Mallorca
Spain	Corporació Sanitària Parc Taulí	Sabadell
Spain	Hospital Universitari Mútua de Terrassa	Terrassa
Spain	Hospital Universitari i Politecnic La Fe de Valencia	Valencia
Spain	Hospital Universitario Rio Hortega	Valladolid
United Kingdom	Bristol Royal Infirmary University Hospitals, Bristol Foundation Trust	Bristol
United Kingdom	University Hospital of Wales	Cardiff
United Kingdom	Royal Infirmary of Edinburgh	Edinburgh
United Kingdom	Charing Cross Hospital Imperial College Healthcare NHS Trust	London
United Kingdom	Charing Cross Hospital St Mary's Hospital, Imperial College Healthcare NHS Trust	London
United Kingdom	Guy's and St Thomas' NHS Foundation Trust	London
United Kingdom	Hammersmith Hospital Imperial College Healthcre NHS Trust	London
United Kingdom	King's College Hospital NHS Foundation Trust	London
United Kingdom	St George's University Hospitals, NHS Foundation Trust	London
United Kingdom	University College London Hospitals, NHS Foundation Trust	London
United Kingdom	Norfolk and Norwich University Hospitals NHS Foundation Trust	Norwich
United Kingdom	Nottingham University Hospitals NHS Trust	Nottingham
United Kingdom	Lancashire Treaching Hospitals NHS Foundation Trust	Preston
United Kingdom	Southampton General Hospital, University Hospital Southampton NHS Foundation Trust	Southampton

Sponsors (2)

Lead Sponsor	Collaborator
Faron Pharmaceuticals Ltd	Seventh Framework Programme

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Evaluation of Safety: Vital Signs - Heart Rate	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.	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)
Other	Evaluation of Safety: Vital Signs - Body Temperature	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.	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)
Other	Evaluation of Safety: Vital Signs - Blood Pressure	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.	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)
Other	Evaluation of Safety: Physical Examination	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".	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)
Other	Evaluation of Safety: Laboratory Results	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.	From baseline to Day 28 (or last day in ICU if patient has left the ICU earlier than Day 28, or at withdrawal)
Other	Evaluation of Pharmacoeconomics: Days Free of Organ Failure	Due to the study terminating early, costs items from hospitals were not collected and pharmacoeconomic analyses could not be done.	Day 28 (or last day in ICU if patient has left the ICU earlier than Day 28, or at withdrawal)
Other	Evaluation of Pharmacoeconomics: Days Free of Renal Support	Due to the study terminating early, costs items from hospitals were not collected and pharmacoeconomic analyses could not be done.	Day 28 (or last day in ICU if patient has left the ICU earlier than Day 28, or at withdrawal)
Other	Evaluation of Pharmacoeconomics: Days Free of Vasoactive Support	Due to the study terminating early, costs items from hospitals were not collected and pharmacoeconomic analyses could not be done.	Day 28 (or last day in ICU if patient has left the ICU earlier than Day 28, or at withdrawal)
Other	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.	Day 28 (or last day in ICU if patient has left the ICU earlier than Day 28, or at withdrawal)
Other	Evaluation of Pharmacoeconomics: Number of ICU-free Days	Due to the study terminating early, costs items from hospitals were not collected and pharmacoeconomic analyses could not be done.	Day 28 (or last day in ICU if patient has left the ICU earlier than Day 28, or at withdrawal)
Other	Evaluation of Pharmacoeconomics: Number of Days in Hospital	Due to the study terminating early, costs items from hospitals were not collected and pharmacoeconomic analyses could not be done.	Day 28 (or last day in ICU if patient has left the ICU earlier than Day 28, or at withdrawal)
Other	Exploratory Variables Relating to Efficacy: Composite Endpoint (Mortality and Days Free of Mechanical Ventilation) at Day 90	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	Within 90 days
Other	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.	From baseline to Day 14
Other	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-a.	From baseline to Day 14
Other	Pharmacogenetic Analysis	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.	Anytime from baseline to Day 28
Other	Exploratory, Extended Long-term Follow-up: Overall Mortality at Day 360	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.	Day 360 /termination of study
Other	Extended Long-term Follow-up Exploratory Endpoint: Change in Quality of Life 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).	Change from baseline to Day 360
Other	Neurological Functioning (6MWT) at Extended Long-term Follow-up	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.	Day 360
Other	Extended Long-term Follow-up Endpoint: Respiratory Functioning (FEV1) at 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.	Day 360
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).	Day 28
Secondary	Efficacy Endpoint: All-cause Mortality	Fatalities, mortality all-causes from randomisation up to Day 28	At Day 28
Secondary	Efficacy Endpoint: Mortality in ICU	All-cause mortality for subjects who died in Intensive Care Units up to Day 28.	Up to Day 28
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.	Up to Day 28
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.	Day 28 or last day in intensive care unit [ICU] if patient has left the ICU earlier than Day 28
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.	Day 28
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.	Day 28
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.	Day 28
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.	Day 28
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.	Day 28
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.	AEs up to Day 28, only related after Day 28 and deaths up to Day 360
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.	Baseline and Day 28 (or last day in intensive care unit [ICU] or at withdrawal, if earlier)
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.	From baseline to Day 14
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).	Change from baseline to Day 180
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.	Day 180
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.	Day 180