Clinical Trial Results:
Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP 2)
Summary
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EudraCT number |
2010-020763-20 |
Trial protocol |
IE GB |
Global end of trial date |
12 May 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
21 Dec 2017
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First version publication date |
21 Dec 2017
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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 |
10072DMcA-CS
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Additional study identifiers
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ISRCTN number |
ISRCTN88244364 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Belfast Health & Social Care Trust (BHSCT)
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Sponsor organisation address |
King Edward Building, Royal Hospitals, Grosvenor Road, Belfast, United Kingdom, BT12 6BA
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Public contact |
Christine McNally, Northern Ireland Clinical Trials Unit (NICTU), 02890 635794, christine.mcnally@nictu.hscni.net
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Scientific contact |
Prof Daniel McAuley, Queen's University of Belfast, 02890 972671, d.f.mcauley@qub.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 |
23 Sep 2015
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
12 May 2015
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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 test the hypothesis that treatment with enteral simvastatin 80mg once daily for a maximum of 28 days would be of therapeutic value in patients with acute lung injury (ALI). Many patients admitted to ICU need a ventilator to help them breathe and ensure that enough oxygen gets into their blood. For reasons that are unclear, when people are critically ill their lungs often fail; termed acute lung injury. There are no specific drugs to treat patients with ALI. Some small studies that have taken place over the past few years have suggested that giving patients with ALI a drug called simvastatin (usually used to treat patients with high cholesterol), might help patients to recover more quickly. We aimed to determine how long patients needed assistance with a ventilator, how fast they recovered. We measured any residual effects of their illness on their lives after one year and took blood and urine samples to determine how ALI develops and how simvastatin might alleviate this
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Protection of trial subjects |
CK and liver function were closely monitored and an additional blood sample was added at day 21 to measure these. Study drug was stopped if the patient's CK or liver function was found to be out of range. To minimize the risk of causing distress to the relation of a patient who died after leaving the hospital, the Clinical Trials Unit contacted the patient's GP and the Health & Social Care Information Centre to ascertain the patient's survival status prior to sending out any follow up questionnaires.
A Clinical Trials Monitor monitored study site compliance with study and CTU SOPs and provided feedback to the Trial Management Group on any actual or potential problems in relation to safeguarding patients safety and wellbeing.
The HARP-2 DMEC was appointed comprising two clinicians with experience in undertaking clinical trials / caring for critically ill patients and a statistician who was independent of the trial. The DMEC met biannually and meetings were formally minuted. The DMEC’s responsibility was to safeguard the interests of the trial participants, in particular with regard to safety and assist and advise the TSC so as to protect the validity and credibility of the trial. The DMEC monitored recruitment, adverse events and outcome data. Patient experience whilst critically ill was taken into consideration when preparing patient information leaflets and consent forms. The Chairman of CritPaL (Barry Williams) represented the patient’s perspective on the TSC ensuring that the trial remained considerate of the needs of the patients and their families.
Site PIs evaluated all AEs/SAES for expectedness, causality and severity. All AEs assessed by the PI as possibly or probably related to the study drug and all SAEs that occurred during this time were followed until they were resolved or were clearly determined to be due to a patient’s stable or chronic condition or intercurrent illness(es). All AEs and SAEs were reviewed by the CI
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Background therapy |
Not applicable | ||
Evidence for comparator |
Not applicable | ||
Actual start date of recruitment |
06 Dec 2010
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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 |
United Kingdom: 510
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Country: Number of subjects enrolled |
Ireland: 29
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Worldwide total number of subjects |
539
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EEA total number of subjects |
539
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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) |
3
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Adults (18-64 years) |
386
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From 65 to 84 years |
147
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85 years and over |
3
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Recruitment
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Recruitment details |
Patients were recruited between 21st December 2010 and 13th March 2014. During the recruiting period to HARP-2 a total of 40 sites participated in the study: 5 in Ireland, 4 in Northern Ireland, 4 in Scotland and 27 in England. 1 site opened in 2010, 25 in 2011, 9 in 2012, 4 in 2013 and 1 in 2014. | |||||||||
Pre-assignment
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Screening details |
Patients ≥ 16 years, intubated and mechanically ventilated with partial pressure of arterial oxygen to fractional inspired oxygen concentration ratio of 300 mmHg or less, with bilateral pulmonary infiltrates consistent with pulmonary oedema present on chest x-ray, and no evidence of left atrial hypertension. 5926 screened, 540 (9%) randomised. | |||||||||
Pre-assignment period milestones
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Number of subjects started |
540 [1] | |||||||||
Number of subjects completed |
539 | |||||||||
Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Consent withdrawn by subject: 1 | |||||||||
Notes [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: One patient withdrew consent for use of their data. So although they were enrolled in the trial we have no data available. This affects the worldwide total when compared to the age categories, so the worldwide total has been amended to 539 for submission. Likewise this affects the baseline placebo arm as technically 281 started and 280 completed but as this does not tally with the worldwide total of 539 now I have amended to 280 starting and added the justification here. |
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Period 1
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Period 1 title |
Overall Trial (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 | |||||||||
Blinding implementation details |
Simvastatin 40mg or identical placebo (95% lactose) tablets were packaged identically and identified only by the unique trial identifier. A computer-generated randomisation sequence was used. Patients were randomised in a 1:1 ratio using an automated centralised 24-hour telephone or web-based randomisation service (Centre for Healthcare Randomised Trials, University of Aberdeen, UK). Randomisation was by permuted block stratified by site and by vasopressor requirement
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Intervention | |||||||||
Arm description |
once daily simvastatin 80mg (as two 40mg tablets) administered enterally via a feeding tube or orally for up to 28 days. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Simvastatin
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Investigational medicinal product code |
PL08215/0042
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Other name |
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Pharmaceutical forms |
Coated tablet
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Routes of administration |
Enteral use
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Dosage and administration details |
once daily simvastatin 80mg (as two 40mg tablets) administered enterally via a feeding tube or orally for up to 28 days.
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Arm title
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Placebo | |||||||||
Arm description |
once daily 80mg placebo (as two 40mg tablets); identical to the Simvastatin, administered enterally via a feeding tube or orally for up to 28 days. | |||||||||
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 |
Coated tablet
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Routes of administration |
Enteral use
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Dosage and administration details |
once daily placebo 80mg, as two 40mg tablets administered enterally via a feeding tube or orally for up to 28 days.
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Baseline characteristics reporting groups
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Reporting group title |
Intervention
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Reporting group description |
once daily simvastatin 80mg (as two 40mg tablets) administered enterally via a feeding tube or orally for up to 28 days. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
once daily 80mg placebo (as two 40mg tablets); identical to the Simvastatin, administered enterally via a feeding tube or orally for up to 28 days. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Intervention
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Reporting group description |
once daily simvastatin 80mg (as two 40mg tablets) administered enterally via a feeding tube or orally for up to 28 days. | ||
Reporting group title |
Placebo
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Reporting group description |
once daily 80mg placebo (as two 40mg tablets); identical to the Simvastatin, administered enterally via a feeding tube or orally for up to 28 days. |
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End point title |
ventilator-free days | ||||||||||||
End point description |
VFDs to day 28 are defined as the number of days from the time of initiating unassisted breathing to day 28 after randomisation, assuming survival for at least two consecutive calendar days after initiating unassisted breathing and continued unassisted breathing to day 28. If a patient returns to assisted breathing and subsequently achieves unassisted breathing to day 28, VFDs will be counted from the end of the last period of assisted breathing to day 28. A period of assisted breathing lasting less than 24 hours and for the purpose of a surgical procedure will not count against the VFD calculation. If a patient was receiving assisted breathing at day 27 or dies prior to day 28, VFDs will be zero.
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End point type |
Primary
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End point timeframe |
up to 28 days post-randomisation
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Statistical analysis title |
VFD analysis | ||||||||||||
Comparison groups |
Placebo v Intervention
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Number of subjects included in analysis |
537
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.21 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
1.1
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.6 | ||||||||||||
upper limit |
2.8 | ||||||||||||
Statistical analysis title |
VFD analysis - bootstrapped | ||||||||||||
Comparison groups |
Placebo v Intervention
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Number of subjects included in analysis |
537
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.22 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
1.1
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.7 | ||||||||||||
upper limit |
2.8 |
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End point title |
non-pulmonary organ failure free days | ||||||||||||
End point description |
The number of days in the first 28 days after randomisation that the patient has none of: cardiovascular support, renal support, liver support or neurological support).
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End point type |
Secondary
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End point timeframe |
up to 28 days post-randomisation
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Statistical analysis title |
non-pulmonary OFFDs analysis | ||||||||||||
Comparison groups |
Intervention v Placebo
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Number of subjects included in analysis |
536
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.11 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
1.6
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.4 | ||||||||||||
upper limit |
3.5 | ||||||||||||
Statistical analysis title |
non-pulmonary OFFDs - bootstrapped | ||||||||||||
Comparison groups |
Intervention v Placebo
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Number of subjects included in analysis |
536
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.1 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
1.6
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.3 | ||||||||||||
upper limit |
3.5 |
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End point title |
change in oxygenation index from baseline to day 3 | ||||||||||||
End point description |
Change in oxygenation index from baseline to day 3
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End point type |
Secondary
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End point timeframe |
day 3
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Statistical analysis title |
OI day 3 | ||||||||||||
Comparison groups |
Intervention v Placebo
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Number of subjects included in analysis |
329
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.02 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-16.8
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-31.5 | ||||||||||||
upper limit |
-2.1 |
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End point title |
change in oxygenation index from baseline to day 7 | ||||||||||||
End point description |
Change in oxygenation index from baseline to day 7
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End point type |
Secondary
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End point timeframe |
day 7
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Statistical analysis title |
OI day 7 | ||||||||||||
Comparison groups |
Intervention v Placebo
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Number of subjects included in analysis |
204
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.8 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-2.9
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-25.4 | ||||||||||||
upper limit |
19.5 |
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End point title |
change in oxygenation index from baseline to day 14 | ||||||||||||
End point description |
Change in oxygenation index from baseline to day 14
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End point type |
Secondary
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End point timeframe |
day 14
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Statistical analysis title |
OI day 14 | ||||||||||||
Comparison groups |
Intervention v Placebo
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Number of subjects included in analysis |
100
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.46 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-13
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-47.7 | ||||||||||||
upper limit |
21.7 |
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End point title |
change in oxygenation index from baseline to day 28 | ||||||||||||
End point description |
Change in oxygenation index from baseline to day 28
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End point type |
Secondary
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End point timeframe |
day 28
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Statistical analysis title |
OI day 28 | ||||||||||||
Comparison groups |
Intervention v Placebo
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Number of subjects included in analysis |
19
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.06 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
74.7
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-3.5 | ||||||||||||
upper limit |
153 |
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End point title |
change in SOFA from baseline to day 3 | ||||||||||||
End point description |
Change in sequential organ failure assessment (SOFA) score from baselines to day 3
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End point type |
Secondary
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End point timeframe |
day 3
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Statistical analysis title |
SOFA day 3 | ||||||||||||
Comparison groups |
Intervention v Placebo
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Number of subjects included in analysis |
430
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.67 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.1
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.5 | ||||||||||||
upper limit |
0.3 |
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End point title |
change in SOFA from baseline to day 7 | ||||||||||||
End point description |
Change in sequential organ failure assessment (SOFA) score from baselines to day 7
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End point type |
Secondary
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End point timeframe |
day 7
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Statistical analysis title |
SOFA day 7 | ||||||||||||
Comparison groups |
Intervention v Placebo
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Number of subjects included in analysis |
307
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.86 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.1
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.7 | ||||||||||||
upper limit |
0.6 |
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End point title |
change in SOFA from baseline to day 14 | ||||||||||||
End point description |
Change in sequential organ failure assessment (SOFA) score from baselines to day 14
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End point type |
Secondary
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End point timeframe |
day 14
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Statistical analysis title |
SOFA day 14 | ||||||||||||
Comparison groups |
Intervention v Placebo
|
||||||||||||
Number of subjects included in analysis |
151
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.047 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-1.1
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-2.1 | ||||||||||||
upper limit |
-0.01 |
|
|||||||||||||
End point title |
change in SOFA from baseline to day 28 | ||||||||||||
End point description |
Change in sequential organ failure assessment (SOFA) score from baselines to day 28
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
day 28
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
SOFA day 28 | ||||||||||||
Comparison groups |
Intervention v Placebo
|
||||||||||||
Number of subjects included in analysis |
38
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.29 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-1.5
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-4.3 | ||||||||||||
upper limit |
1.3 |
|
||||||||||||||||
End point title |
all cause mortality 28 days post randomisation | |||||||||||||||
End point description |
All cause mortality 28 days post randomisation
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
28 days
|
|||||||||||||||
|
||||||||||||||||
Statistical analysis title |
28 day mortality | |||||||||||||||
Comparison groups |
Intervention v Placebo
|
|||||||||||||||
Number of subjects included in analysis |
539
|
|||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||
Analysis type |
superiority | |||||||||||||||
P-value |
= 0.23 | |||||||||||||||
Method |
Fisher exact | |||||||||||||||
Parameter type |
Risk ratio (RR) | |||||||||||||||
Point estimate |
0.8
|
|||||||||||||||
Confidence interval |
||||||||||||||||
level |
95% | |||||||||||||||
sides |
2-sided
|
|||||||||||||||
lower limit |
0.6 | |||||||||||||||
upper limit |
1.1 |
|
||||||||||||||||
End point title |
death before discharge from critical care | |||||||||||||||
End point description |
Patients who died before discharge from critical care environment
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
to discharge from critical care
|
|||||||||||||||
|
||||||||||||||||
Statistical analysis title |
death before discharge from critical care | |||||||||||||||
Comparison groups |
Intervention v Placebo
|
|||||||||||||||
Number of subjects included in analysis |
539
|
|||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||
Analysis type |
superiority | |||||||||||||||
P-value |
= 0.36 | |||||||||||||||
Method |
Fisher exact | |||||||||||||||
Parameter type |
Risk ratio (RR) | |||||||||||||||
Point estimate |
0.9
|
|||||||||||||||
Confidence interval |
||||||||||||||||
level |
95% | |||||||||||||||
sides |
2-sided
|
|||||||||||||||
lower limit |
0.6 | |||||||||||||||
upper limit |
1.2 |
|
||||||||||||||||
End point title |
death before discharge from hospital | |||||||||||||||
End point description |
Participants who died prior to discharge from hospital
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
to discharge from hospital
|
|||||||||||||||
|
||||||||||||||||
Statistical analysis title |
death before discharge from hospital | |||||||||||||||
Comparison groups |
Intervention v Placebo
|
|||||||||||||||
Number of subjects included in analysis |
539
|
|||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||
Analysis type |
superiority | |||||||||||||||
P-value |
= 0.13 | |||||||||||||||
Method |
Fisher exact | |||||||||||||||
Parameter type |
Risk ratio (RR) | |||||||||||||||
Point estimate |
0.8
|
|||||||||||||||
Confidence interval |
||||||||||||||||
level |
95% | |||||||||||||||
sides |
2-sided
|
|||||||||||||||
lower limit |
0.6 | |||||||||||||||
upper limit |
1.1 |
|
|||||||||||||
End point title |
Quality Adjusted Life Years | ||||||||||||
End point description |
QALYs calculated used baseline, 6 and 12 month EQ5D utilities on patients with complete costs and QALY data.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
12 months
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
QALY analysis | ||||||||||||
Comparison groups |
Intervention v Placebo
|
||||||||||||
Number of subjects included in analysis |
292
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
Method |
|||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.064
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.002 | ||||||||||||
upper limit |
0.127 |
|
|||||||||||||
End point title |
Health Service Use Costs | ||||||||||||
End point description |
Total 12 month health service costs for patients with complete costs and QALY data
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
12 months
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Cost Analysis | ||||||||||||
Comparison groups |
Intervention v Placebo
|
||||||||||||
Number of subjects included in analysis |
292
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
Method |
|||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-3600.91
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-8872.17 | ||||||||||||
upper limit |
722.79 |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
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Timeframe for reporting adverse events |
Up to 30 days following the administration of the study drug
|
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Adverse event reporting additional description |
Due to small numbers a breakdown of term is not provided for serious or non-serious AEs. For non serious adverse events, investigations is broken down into the following terms: ALT>8 times the upper limit of normal and/or AST>8 times the upper limit of normal; CK>10 times the upper limit of normal and; Other.
|
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
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Dictionary name |
CTCAE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
4
|
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Reporting groups
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Simvastatin
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Patients on Simvastatin who experienced an adverse event | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Patients receiving a placebo who experienced an adverse event | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
21 Apr 2011 |
Amendment 1 (main changes):
Protocol v1.0_24.06.10 was submitted to ORECNI in the original application for Ethics approval. ORECNI requested some changes which necessitated amending the protocol to v2.0_01.09.10. The major changes included:
• Amending the exclusion criteria to exclude non−english speaking patients or those who did not adequately understand verbal or written information unless an interpreter was available;
• Amending the exclusion criteria to include the wording “currently” and “sustained” in relation to the use of listed concomitant medications. Amiodarone was added to the list of concomitant medications.
• Clarification was given that the 80 mg dose was given as 2 x 40m tablets.
• Sofa score was added to the schedule of assessments in day 14 and day 28.
|
||
27 Jun 2011 |
Protocol v2.0_01.09.10 was amended to v3.0_16.05.11. ORECNI and MHRA approved the following changes:
• Change of address of the Chief Investigator (CI).
• Non pulmonary organ failure free days added to secondary outcomes
• An additional blood sample was added at day 21 to measure CK and liver function.
• The exclusion criteria were amended to allow for patients receiving erythromycin as a prokinetic to be included in the study.
• Change of address of study drug supplier.
• Other changes: additional sites added.
|
||
19 Sep 2011 |
Amendment 3 (main changes):
Protocol v3.0_16.05.11 was amended to v4.0_18.07.11 and was approved by ORECNI and MHRA to include the following changes:
• The exclusion criteria were amended to remove clarithromycin and erythromycin.
• Clarification was given that domiciliary ventilation used for sleep-disordered breathing would not be included as mechanical ventilation.
• Scheduling for research samples submission was changed to allow that research samples due on bank holidays or weekends could be collected up to 2 days after the due date (with the exception of day 1).
|
||
12 Mar 2012 |
Amendment 5 (main changes):
Protocol v4.0_18.07.11 was amended to v5.0_13.01.12. This amendment was approved by ORECNI and MHRA to include the following changes:
• The exclusion criteria was amended to change the upper limit of normal for ALT and AST from > 5 times upper limit of normal to > 8 times upper limit of normal.
|
||
Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported | |||
Online references |
|||
http://www.ncbi.nlm.nih.gov/pubmed/25268516 http://www.ncbi.nlm.nih.gov/pubmed/22985805 http://www.ncbi.nlm.nih.gov/pubmed/28511660 |