Clinical Trial Results:
A Phase III Double-blind, Randomised, Parallel Group Comparison of the Efficacy and Safety of FP-1201-lyo (Recombinant Human Interferon Beta-1a) and Placebo in the Treatment of Patients with Moderate or Severe Acute Respiratory Distress Syndrome
Summary
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EudraCT number |
2014-005260-15 |
Trial protocol |
DE FI BE ES CZ |
Global end of trial date |
23 May 2018
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Results information
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Results version number |
v1 |
This version publication date |
29 Jun 2019
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First version publication date |
29 Jun 2019
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Other versions |
v2 |
Summary report(s) |
SAE listing Adverse Events (Non-SAE) |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
FPCLI002 INTEREST
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02622724 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Faron Pharmaceuticals Ltd
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Sponsor organisation address |
Joukahaisenkatu 6 , Turku, Finland, 20520
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Public contact |
CMO, Faron Pharmaceuticals Ltd, matti.karvonen@faron.com
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Scientific contact |
CMO, Faron Pharmaceuticals Ltd, matti.karvonen@faron.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
23 May 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
23 May 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
23 May 2018
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The primary objective of this study was to demonstrate the efficacy of FP-1201-lyo in improving the clinical course and outcomes based on survival and need for mechanical ventilation in patients with moderate or severe acute respiratory distress syndrome (ARDS).
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Protection of trial subjects |
The trial was performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with ICH/GCP and applicable regulatory requirements. The informed consent process of unconscious patients was documented and approved by Ethics committee and/or competent authorities before the trial started and patients consented themselves as soon as they were medically able. An Independent Data Monitoring Committee reviewed ongoing safety data in an unblinded manner.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
23 Dec 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Spain: 22
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Country: Number of subjects enrolled |
United Kingdom: 54
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Country: Number of subjects enrolled |
Belgium: 24
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Country: Number of subjects enrolled |
Czech Republic: 2
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Country: Number of subjects enrolled |
Finland: 30
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Country: Number of subjects enrolled |
France: 112
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Country: Number of subjects enrolled |
Germany: 15
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Country: Number of subjects enrolled |
Italy: 37
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Worldwide total number of subjects |
296
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EEA total number of subjects |
296
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
190
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From 65 to 84 years |
98
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85 years and over |
8
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Recruitment
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Recruitment details |
The screening period started in the first country in November 2015 and enrolment was completed in all countries in December 2017. Of the 74 study sites across 8 countries in Europe that pre-screened subjects, 47 sites randomly assigned subjects to treatment. The study was early terminated at the long-term/extended follow-up period in May 2018. | |||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Subjects were randomised in a 1:1 ratio to FP-1201-lyo and placebo, using ARDS severity and country as stratification parameters. A total of 363 subjects passed screening, 301 subjects fulfilled all criteria at randomization and were randomly assigned and finally, 296 subjects received treatment in the study. Five study subjects were not dosed. | |||||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall study (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | |||||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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FP-1201-lyo | |||||||||||||||||||||||||||||||||||||||
Arm description |
144 subjects received atleast 1 dose study drug in this arm, the results for these subjects are shown. 3 subjects randomised to this arm experienced serious adverse events (with fatal outcome) before the first dose of study drug was administered, they are not included in the results shown. | |||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
FP-1201-lyo
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Investigational medicinal product code |
FP-1201-lyo
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Other name |
Recombinant Human Interferon Beta-1a
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Pharmaceutical forms |
Powder for solution for injection
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Routes of administration |
Intravenous bolus use
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Dosage and administration details |
10 microgram FP-1201-lyo / placebo was diluted in sterile water for injection and administered as an intravenous bolus injection once daily for six consecutive days.
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Arm title
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Placebo | |||||||||||||||||||||||||||||||||||||||
Arm description |
- | |||||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for solution for injection
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Routes of administration |
Intravenous bolus use
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Dosage and administration details |
10 microgram FP-1201-lyo / placebo was diluted in sterile water for injection and administered as an intravenous bolus injection once daily for six consecutive days.
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Baseline characteristics reporting groups
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Reporting group title |
FP-1201-lyo
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Reporting group description |
144 subjects received atleast 1 dose study drug in this arm, the results for these subjects are shown. 3 subjects randomised to this arm experienced serious adverse events (with fatal outcome) before the first dose of study drug was administered, they are not included in the results shown. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
FP-1201-lyo
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Reporting group description |
144 subjects received atleast 1 dose study drug in this arm, the results for these subjects are shown. 3 subjects randomised to this arm experienced serious adverse events (with fatal outcome) before the first dose of study drug was administered, they are not included in the results shown. | ||
Reporting group title |
Placebo
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Reporting group description |
- | ||
Subject analysis set title |
All subjects
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Full Analysis Set (FAS); all subjects who recieved at least 1 dose of study treatment
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End point title |
Composite endpoint (VDFsurv) at Day 28 | ||||||||||||
End point description |
Composite endpoint include any-cause death by Day 28 and the number of days free of mechanical ventilation (VFDsurv) within 28 days among survivors. Ventilator-free days (VDFs) correspond to those days when unassisted breathing (UAB) was possible for a complete calendar day. For the initiation of the VFD count at least two consecutive calendar days of UAB were required. UAB was defined as: sponstaneously 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.
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End point type |
Primary
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End point timeframe |
VDFsurv is a composite measure of all-cause mortality and the number of days free of mechanical ventilation (VFD) within 28 days among survivors.
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Statistical analysis title |
Primary Efficacy Analysis VDFsurv | ||||||||||||
Statistical analysis description |
A non-parametric analysis has been performed as the data distribution is non-normal and negatively 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)
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Comparison groups |
Placebo v FP-1201-lyo
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Number of subjects included in analysis |
296
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | ||||||||||||
P-value |
= 0.8219 [2] | ||||||||||||
Method |
Van Elteren hypothesis test | ||||||||||||
Parameter type |
Median difference (net) | ||||||||||||
Confidence interval |
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Notes [1] - Analysis were performed on Full Analysis Set (FAS, n=296), defined as all randomised subjects that received atleast one dose of study drug. Primary endpoint was analysed also for the Per Protocol population (PP, n=285), which consisted of subjects from FAS population but excluded subjects with major protocol deviations and subjects who received less than three doses of study drug. [2] - For the Per Protocol population (PP, n=285) p=0.5032 (the overall median VDFsurv was 11.0 days with FP-1201-lyo and 8.0 days with placebo) |
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End point title |
Mortality (all causes) | ||||||||||||||||||
End point description |
Full Analysis Set (FAS), defined as all randomised subjects that received atleast one dose of study drug. Mortality all-causes and mortality in ICU from randomisation up to day 28.
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End point type |
Secondary
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End point timeframe |
Mortality all-causes from randomisation up to day 28.
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No statistical analyses for this end point |
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End point title |
Days free of Mechanical Ventilation | ||||||||||||
End point description |
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 contributes to the VFDsurv primary efficacy endpoint as it require additional conditions of unassisted breating (UAB) to be met.
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End point type |
Secondary
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End point timeframe |
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.
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Statistical analysis title |
Days free of Mechanical Ventilation | ||||||||||||
Statistical analysis description |
Van Elteren hypothesis test as the distribution was non-normal and negatively skewed by patients who are assigned scores of zero (0) in the event of death.
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Comparison groups |
FP-1201-lyo v Placebo
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Number of subjects included in analysis |
296
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.4678 | ||||||||||||
Method |
Van Elteren p-values | ||||||||||||
Confidence interval |
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End point title |
Days free of Organ Failure | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
The total number of days free of Organ Failure (Sequential Organ Failure Assessment, SOFA) has been derived from the Patient Status report recorded on each day during the 28-day period.
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Statistical analysis title |
Days free of Organ Failure | ||||||||||||
Comparison groups |
FP-1201-lyo v Placebo
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Number of subjects included in analysis |
296
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.1547 | ||||||||||||
Method |
Van Elteren p-values | ||||||||||||
Confidence interval |
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End point title |
Days free of Renal Support | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
The total number of days free of Renal Support has been derived from the Patient Status report recorded on each day during the 28-day period.
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Statistical analysis title |
Days free of Renal Support | ||||||||||||
Comparison groups |
FP-1201-lyo v Placebo
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Number of subjects included in analysis |
296
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.7243 | ||||||||||||
Method |
Van Elteren p-values | ||||||||||||
Confidence interval |
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End point title |
Days free of Vasoactive Support | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
The total number of days free of vasoactive support has been derived from the Patient Status report recorded on each day during the 28-day period.
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Statistical analysis title |
Days free of Vasoactive Support | ||||||||||||
Comparison groups |
FP-1201-lyo v Placebo
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Number of subjects included in analysis |
296
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.939 | ||||||||||||
Method |
Van Elteren p-values | ||||||||||||
Confidence interval |
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End point title |
Number of ICU Care free Days | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
The total number of days free of ICU care has been derived from the Patient Status report recorded on each day during the 28-day period.
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Statistical analysis title |
ICU Care-Free Days | ||||||||||||
Comparison groups |
FP-1201-lyo v Placebo
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Number of subjects included in analysis |
296
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.3392 | ||||||||||||
Method |
Van Elteren p-values | ||||||||||||
Confidence interval |
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End point title |
Number of days in hospital | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
The total number of days in hospital has been derived from the Patient Status report recorded on each day during the 28-day period.
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Statistical analysis title |
Number of days in hospital | ||||||||||||
Comparison groups |
FP-1201-lyo v Placebo
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Number of subjects included in analysis |
296
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.7029 | ||||||||||||
Method |
Van Elteren p-values | ||||||||||||
Confidence interval |
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End point title |
Neutralising Antibodies to IFN Beta-1a | ||||||||||||||||||
End point description |
Neutralizing antibodies can interfere with the biological and clinical response to treatment. The ADAs were determined first and if present, the NAbs were also determined. The last observation performed, whether at Day 28, upon last day in the ICU or upon early termination, was derived. Interferon beta-1a ADA (BAb) and NAb were summarised categorically (using Positive/Negative classification). As a very high proportion of the results in both treatment groups was negative, no formal statistical testing was done. The majority of subjects were not tested for IFN beta NAb; of those tested on pre-dose, 1 (0.3 %) study subject in the FP-1201-lyo group was positive, whilst no positive results were observed on the last day in ICU.
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End point type |
Secondary
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End point timeframe |
The immunological response to FP-1201-lyo was assessed through monitoring of anti-drug antibodies (ADAs) and Neutralising Antibodies to IFN beta 1a (NAbs) on pre-dose Day 1 and at Day 28, the last day in ICU or early termination, if earlier
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No statistical analyses for this end point |
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End point title |
Evaluation of Pharmacodynamics with MxA | ||||||||
End point description |
To evaluate the pharmacodynamics of FP-1201-lyo with Myxovirus resistance protein A (MxA), as one of the best markers for IFN beta bioactivity. This response was measured on Day 1 Pre-dose and daily thereafter until Day 14 in the ICU. The Last observation performed whether Day 14 or earlier has been derived. The change from baseline (Day 1 Pre-dose) has been calculated. The mean (adjusted) difference in blood MxA response was significantly higher (p<0.05) in the active group versus the placebo group by 23.76 (95% CI: 12.77, 34.75). There was substantial variation in individual MxA responses.
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End point type |
Secondary
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End point timeframe |
Evaluation of pharmacodynamics using MxA biomarker from baseline to Day 14
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Notes [3] - MxA LS(adjusted) mean change PF-1201-lyo and Placebo from baseline to Last Observation Performed. |
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No statistical analyses for this end point |
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Adverse events information [1]
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Timeframe for reporting adverse events |
The Adverse Event reporting period extended from signing of informed consent to Day 28. All deaths were reported as SAEs throughout the study, up until Day 360.
See attachments:
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Adverse event reporting additional description |
The Adverse Event reporting period extended from signing of informed consent to Day 28. AEs occuring after Day 28 were to be reported if the investigator considered a causal relationship with the study drug. However, all deaths were reported as SAEs throughout the study, up until day 360.
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Assessment type |
Systematic | ||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||
Dictionary version |
21
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Frequency threshold for reporting non-serious adverse events: 0% | |||
Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: The adverse events are reported in the attachments; FPCLI002 SAE listing contain information on all SAEs and FPCLI002 adverse events listing contain information on all non-serious events. |
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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19 Oct 2015 |
Defining and describing in more detail the study monitoring procedures of IDMC |
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22 Oct 2015 |
The substantial changes included:
- addition of APACHEII scoring to access severity of disease
- prolongation of reporting time for deaths as SAE to the end of study and clarification on collection of AEs.
- clarifying the rigth of the investigator to make an independent decision to break the treatment code in case of an emergency
- Addition of an ECG to the Six-Minute Walk Test as a safety precaution
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29 Aug 2017 |
The main analysis of the study and reporting use Day 28 and Day 90 data instead of Day 180 data. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported | |||
Online references |
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http://www.ncbi.nlm.nih.gov/pubmed/29132404 |