Clinical Trial Results:
What is the effect of intravenous iron supplementation on cardiopulmonary haemodynamics, exercise capacity and quality of life in patients with IPAH and iron deficiency?
Summary
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EudraCT number |
2010-024585-22 |
Trial protocol |
GB DE |
Global end of trial date |
22 Dec 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
09 Oct 2019
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First version publication date |
09 Oct 2019
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Other versions |
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 |
WILK3
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01447628 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Imperial College London
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Sponsor organisation address |
South Kensington Campus, London, United Kingdom,
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Public contact |
Luke Howard, Luke Howard, l.howard@imperial.ac.uk
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Scientific contact |
Luke Howard, Luke Howard, l.howard@imperial.ac.uk
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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 |
12 Jul 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
22 Dec 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
22 Dec 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To assess the clinical value of using intravenous iron (ferric carboxymaltose) infusion in iron deficient patients with idiopathic pulmonary arterial hypertension.
The primary endpoint will be endurance time at the end of endurance bicycle cardiopulmonary exercise testing at 80% peak work rate determined from the baseline incremental exercise test, measured at 12 weeks after study treatment.
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Protection of trial subjects |
All adverse events were monitored and recorded throughout the trial. No other specific protection.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
29 Mar 2011
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
United Kingdom: 34
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Country: Number of subjects enrolled |
Germany: 5
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Worldwide total number of subjects |
39
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EEA total number of subjects |
39
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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) |
34
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From 65 to 84 years |
5
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients participating in this study are adult males and females with symptomatic IPAH as defined by the eligibility criteria specified in the protocol. | |||||||||
Pre-assignment
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Screening details |
Potential participants will be screened using data collected during their routine outpatient appointment at the Pulmonary Hypertension Service or PH Clinic. Any unavailable or missing data will be collected at the screening visit (week 0) once the patient has provided written informed consent. | |||||||||
Pre-assignment period milestones
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Number of subjects started |
39 | |||||||||
Number of subjects completed |
39 | |||||||||
Period 1
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Period 1 title |
Baseline
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | |||||||||
Arms
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Arm title
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All patients | |||||||||
Arm description |
There are no products specified, as this is the baseline period, prior to randomisation. | |||||||||
Arm type |
Baseline: no intervention | |||||||||
Investigational medicinal product name |
Ferinject
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
1000mg Ferinject, intravenous infusion
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Period 2
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Period 2 title |
Treatment
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Is this the baseline period? |
No | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Investigator, Data analyst, Carer, Assessor | |||||||||
Arms
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Are arms mutually exclusive |
No
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Arm title
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Active treatment: Ferinject | |||||||||
Arm description |
1000mg Ferinject infused over 15 minutes | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Ferinject
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
1000mg Ferinject, intravenous infusion
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Arm title
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Placebo: Saline | |||||||||
Arm description |
Saline infused over 15 minutes | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
Saline
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
1000ml saline for intravenous infusion
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Baseline characteristics reporting groups
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Reporting group title |
Baseline
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Total population
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
All participants
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End points reporting groups
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Reporting group title |
All patients
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Reporting group description |
There are no products specified, as this is the baseline period, prior to randomisation. | ||
Reporting group title |
Active treatment: Ferinject
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Reporting group description |
1000mg Ferinject infused over 15 minutes | ||
Reporting group title |
Placebo: Saline
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Reporting group description |
Saline infused over 15 minutes | ||
Subject analysis set title |
Total population
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
All participants
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End point title |
Endurance time from start to finish of Cardio-pulmonary exercise test | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
12 weeks post treatment
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Statistical analysis title |
Linear mixed model | ||||||||||||
Statistical analysis description |
All primary and secondary efficacy endpoints were analysed using linear mixed
models appropriate for a crossover design. The linear models included
administration sequence, period and treatment as fixed effects and subject as a
random effect, and all models included relevant and statistically significant baseline
covariates.
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Comparison groups |
Active treatment: Ferinject v Placebo: Saline
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Number of subjects included in analysis |
78
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.7109 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Confidence interval |
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End point title |
Peak VO2 Level at 12 Weeks After Study Treatment | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
12 weeks post study treatment
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Statistical analysis title |
Linear mixed model | ||||||||||||
Comparison groups |
Active treatment: Ferinject v Placebo: Saline
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Number of subjects included in analysis |
78
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.6583 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Confidence interval |
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End point title |
VO2 at Metabolic Threshold | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
12 weeks post study treatment
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Statistical analysis title |
Linear mixed model | ||||||||||||
Comparison groups |
Active treatment: Ferinject v Placebo: Saline
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Number of subjects included in analysis |
78
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.9773 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Confidence interval |
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End point title |
VE/VCO2 Slope | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
12 weeks
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Statistical analysis title |
Linear mixed model | ||||||||||||
Comparison groups |
Active treatment: Ferinject v Placebo: Saline
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Number of subjects included in analysis |
78
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.1815 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Confidence interval |
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End point title |
VO2 / WR Slope | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
12 weeks
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Statistical analysis title |
Linear mixed model | ||||||||||||
Comparison groups |
Active treatment: Ferinject v Placebo: Saline
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Number of subjects included in analysis |
78
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.8751 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Confidence interval |
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End point title |
Peak O2 Pulse Rate | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
12 weeks
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Statistical analysis title |
Linear mixed model | ||||||||||||
Comparison groups |
Active treatment: Ferinject v Placebo: Saline
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Number of subjects included in analysis |
78
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.4813 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Confidence interval |
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End point title |
VO2 at the End of Endurance Cardio-pulmonary Exercise Test | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
12 weeks
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Statistical analysis title |
Linear mixed model | ||||||||||||
Comparison groups |
Active treatment: Ferinject v Placebo: Saline
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Number of subjects included in analysis |
78
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.2395 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Confidence interval |
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End point title |
VO2 at 3 mins | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
12 weeks
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Statistical analysis title |
Linear mixed model | ||||||||||||
Comparison groups |
Active treatment: Ferinject v Placebo: Saline
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Number of subjects included in analysis |
78
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.4758 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Confidence interval |
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End point title |
Iron Indices: Serum Iron | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
12 weeks
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Statistical analysis title |
Linear mixed model | ||||||||||||
Comparison groups |
Active treatment: Ferinject v Placebo: Saline
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Number of subjects included in analysis |
78
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.2002 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Confidence interval |
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End point title |
Iron Indices: Transferrin Saturations | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
12 weeks
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Statistical analysis title |
Linear mixed model | ||||||||||||
Comparison groups |
Active treatment: Ferinject v Placebo: Saline
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Number of subjects included in analysis |
78
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.0727 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Confidence interval |
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End point title |
Iron Indices: Ferritin | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
12 weeks
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Statistical analysis title |
Linear mixed model | ||||||||||||
Comparison groups |
Active treatment: Ferinject v Placebo: Saline
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Number of subjects included in analysis |
78
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.0003 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Confidence interval |
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End point title |
Iron Indices: sTfR | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
12 weeks
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Statistical analysis title |
Linear mixed method | ||||||||||||
Comparison groups |
Active treatment: Ferinject v Placebo: Saline
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Number of subjects included in analysis |
78
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.0001 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Confidence interval |
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End point title |
6 minute walk test: Distance Walked | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
12 weeks
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Statistical analysis title |
Linear mixed method | ||||||||||||
Comparison groups |
Active treatment: Ferinject v Placebo: Saline
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Number of subjects included in analysis |
78
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.8093 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Confidence interval |
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End point title |
6 minute walk test: Borg dyspnoea score after test | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
12 weeks
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Statistical analysis title |
Linear mixed method | ||||||||||||
Comparison groups |
Placebo: Saline v Active treatment: Ferinject
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Number of subjects included in analysis |
78
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.0862 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Confidence interval |
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End point title |
Iron Indices: NT-pro-BNP | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
12 weeks
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Statistical analysis title |
Linear mixed method | ||||||||||||
Comparison groups |
Active treatment: Ferinject v Placebo: Saline
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Number of subjects included in analysis |
78
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.1041 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Confidence interval |
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End point title |
Quality of Life: CAMPHOR Activity Score | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
12 weeks
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Statistical analysis title |
Linear mixed method | ||||||||||||
Comparison groups |
Active treatment: Ferinject v Placebo: Saline
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Number of subjects included in analysis |
78
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.8948 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Confidence interval |
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End point title |
Quality of Life: CAMPHOR Symptom Score | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
12 weeks
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Statistical analysis title |
Linear mixed method | ||||||||||||
Comparison groups |
Active treatment: Ferinject v Placebo: Saline
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||||||||||||
Number of subjects included in analysis |
78
|
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Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.9559 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Confidence interval |
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End point title |
Quality of Life: CAMPHOR QoL Score | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
12 weeks
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Linear mixed method | ||||||||||||
Comparison groups |
Active treatment: Ferinject v Placebo: Saline
|
||||||||||||
Number of subjects included in analysis |
78
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.2423 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Confidence interval |
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End point title |
Mean Right Atrial Pressure | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
12 weeks
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Statistical analysis title |
Linear mixed method | ||||||||||||
Comparison groups |
Active treatment: Ferinject v Placebo: Saline
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||||||||||||
Number of subjects included in analysis |
78
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.1221 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Confidence interval |
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End point title |
Peak VO2 Level in ml/min/kg | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
12 weeks
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||||||||||||
|
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Statistical analysis title |
Linear mixed model | ||||||||||||
Comparison groups |
Active treatment: Ferinject v Placebo: Saline
|
||||||||||||
Number of subjects included in analysis |
78
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.7625 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Confidence interval |
|
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End point title |
VO2 at Metabolic Threshold measured during incremental CPET | ||||||||||||
End point description |
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End point type |
Secondary
|
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End point timeframe |
12 weeks post study treatment
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Linear mixed model | ||||||||||||
Comparison groups |
Active treatment: Ferinject v Placebo: Saline
|
||||||||||||
Number of subjects included in analysis |
78
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.7711 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Confidence interval |
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Adverse events information
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Timeframe for reporting adverse events |
From consent to 24 weeks
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
10
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Reporting groups
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Reporting group title |
All participants
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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05 Aug 2011 |
Change to eligibility criteria, separate patient documents for participating sites. |
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02 Jul 2012 |
Change inclusion criterion 3, change of PI at one participating site. |
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04 Dec 2012 |
Addition of fasting glucose and insulin measurements. |
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24 Sep 2013 |
Change of PI at participating site |
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20 Mar 2014 |
Changes to eligibility, reduction in number of protocol clinic visits, removal of week 36 visit and addition of activity monitor. |
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25 Jun 2015 |
Changes to cardiac cath, activity monitor and replacement of visits 2 and 4 with telephone calls. |
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14 Dec 2015 |
Addition of German site. |
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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. | |||
Pt 2003, 3004, 4002-05 had endurance CPETs performed at incorrect workloads, so those data were replaced by imputed values. Visit 5 CPETs for 1008, 1018 and 1019 were outside protocol window. 1014 received placebo at both treatment visits in error |