Clinical Trial Results:
Can simvastatin significantly reduce the amount of immunosuppressive medication required by patients with sight threatening uveitis? A phase IIb, single site, randomized, placebo controlled, double blinded trial.
Summary
|
|
EudraCT number |
2014-003119-13 |
Trial protocol |
GB |
Global end of trial date |
20 Jul 2018
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
11 Apr 2019
|
First version publication date |
11 Apr 2019
|
Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
Trial identification
|
|||
Sponsor protocol code |
14/0172
|
||
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT02252328 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
|
|||
Sponsor organisation name |
UCL
|
||
Sponsor organisation address |
Joint Research Office, Gower Street , London , United Kingdom, WC1E 6BT
|
||
Public contact |
Sue Lightman, UCL, +44 20 7566-2266, s.lightman@ucl.ac.uk
|
||
Scientific contact |
Sue Lightman, UCL, +44 20 7566-2266, s.lightman@ucl.ac.uk
|
||
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
15 Oct 2018
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
20 Jul 2018
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
20 Jul 2018
|
||
Was the trial ended prematurely? |
Yes
|
||
General information about the trial
|
|||
Main objective of the trial |
To determine whether the mean reduction in prednisolone dosage achieved at 12 months is greater in the simvastatin group compared to the placebo treated group?
|
||
Protection of trial subjects |
Repeat clinical assessments and assessment of any adverse event. Monitoring of complete blood tests and blood chemistry including lipid and creatinine kinase levels.
|
||
Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Sep 2015
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
No
|
||
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
United Kingdom: 33
|
||
Worldwide total number of subjects |
33
|
||
EEA total number of subjects |
33
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
33
|
||
From 65 to 84 years |
0
|
||
85 years and over |
0
|
|
||||||||||||||||
Recruitment
|
||||||||||||||||
Recruitment details |
The patient’s recruitment process started in Sep 2015.Trial candidates were selected from the pool of patients under the care of one consultant (SL) at Moorfields Eye Hospital. Eligibility for the trial was assessed and patients were offered the trial Participant's information sheet was given before subject's enrolment as per study protocol. | |||||||||||||||
Pre-assignment
|
||||||||||||||||
Screening details |
A detailed medical history including current medications was performed. The information obtained were checked against the study inclusion and exclusion criteria. Finally, a consent form was obtained before subjects enrolment. | |||||||||||||||
Period 1
|
||||||||||||||||
Period 1 title |
Overall trial (overall period)
|
|||||||||||||||
Is this the baseline period? |
Yes | |||||||||||||||
Allocation method |
Randomised - controlled
|
|||||||||||||||
Blinding used |
Double blind | |||||||||||||||
Roles blinded |
Subject, Investigator | |||||||||||||||
Blinding implementation details |
We used an online software application (Sealed envelope) for randomising patients into the trial. A random code was generated after confirming that the patient does meet all the inclusion criteria and dose not meet any exclusion criteria. During the trial subjects received double encapsulated IMPs.
|
|||||||||||||||
Arms
|
||||||||||||||||
Are arms mutually exclusive |
Yes
|
|||||||||||||||
Arm title
|
Placebo | |||||||||||||||
Arm description |
Placebo drug | |||||||||||||||
Arm type |
Placebo | |||||||||||||||
Investigational medicinal product name |
Placebo
|
|||||||||||||||
Investigational medicinal product code |
||||||||||||||||
Other name |
||||||||||||||||
Pharmaceutical forms |
Capsule
|
|||||||||||||||
Routes of administration |
Oral use
|
|||||||||||||||
Dosage and administration details |
Placebo
|
|||||||||||||||
Arm title
|
Simvastatin | |||||||||||||||
Arm description |
Simvastatin 80mg | |||||||||||||||
Arm type |
Active comparator | |||||||||||||||
Investigational medicinal product name |
Simvastatin 80mg
|
|||||||||||||||
Investigational medicinal product code |
||||||||||||||||
Other name |
||||||||||||||||
Pharmaceutical forms |
Capsule
|
|||||||||||||||
Routes of administration |
Oral use
|
|||||||||||||||
Dosage and administration details |
Simvastatin 80mg
|
|||||||||||||||
|
|
|||||||||||||||||||||||||||||||||||||
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
||||||||||||||||||||||||||||||||||||
Reporting group description |
Placebo drug | ||||||||||||||||||||||||||||||||||||
Reporting group title |
Simvastatin
|
||||||||||||||||||||||||||||||||||||
Reporting group description |
Simvastatin 80mg | ||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
Subject analysis sets
|
|||||||||||||||||||||||||||||||||||||
Subject analysis set title |
Analysis
|
||||||||||||||||||||||||||||||||||||
Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The primary outcome is prednisolone dose measured at 12 months. The main statistical analyses will estimate the difference in mean prednisolone dose between patients randomised to simvastatin and placebo by intention to treat at 12 months. Group difference estimates and corresponding confidence intervals will be reported.Initially, prednisolone dose at 12 months will be described for each treatment group using means and standard deviations. In addition, plots will be produced that show dosing over time (every 3 months) for each group and the percentage of patients whose dose is under 10mg (safe dose).
The outcome will be formally compared between treatment groups using a linear regression model (below) that adjusts for baseline dose. All modelling assumptions will be checked.
|
||||||||||||||||||||||||||||||||||||
|
|
|||
End points reporting groups
|
|||
Reporting group title |
Placebo
|
||
Reporting group description |
Placebo drug | ||
Reporting group title |
Simvastatin
|
||
Reporting group description |
Simvastatin 80mg | ||
Subject analysis set title |
Analysis
|
||
Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The primary outcome is prednisolone dose measured at 12 months. The main statistical analyses will estimate the difference in mean prednisolone dose between patients randomised to simvastatin and placebo by intention to treat at 12 months. Group difference estimates and corresponding confidence intervals will be reported.Initially, prednisolone dose at 12 months will be described for each treatment group using means and standard deviations. In addition, plots will be produced that show dosing over time (every 3 months) for each group and the percentage of patients whose dose is under 10mg (safe dose).
The outcome will be formally compared between treatment groups using a linear regression model (below) that adjusts for baseline dose. All modelling assumptions will be checked.
|
|
|||||||||||||||||
End point title |
Prednisolone dose at 1-year | ||||||||||||||||
End point description |
The primary outcome is prednisolone dose measured at 12 months. The main statistical analyses will estimate the difference in mean prednisolone dose between patients randomised to simvastatin and placebo by intention to treat at 12 months. Group difference estimates and corresponding confidence intervals will be reported.
Initially, prednisolone dose at 12 months will be described for each treatment group using means and standard deviations. In addition, plots will be produced that show dosing over time (every 3 months) for each group and the percentage of patients whose dose is under 10mg (safe dose).
The outcome will be formally compared between treatment groups using a linear regression model that adjusts for baseline dose.
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
One year
|
||||||||||||||||
|
|||||||||||||||||
Attachments |
Mean reduction in prednisolone dose at 52 weeks |
||||||||||||||||
Notes [1] - One subject did not complete primary endpoint due to fatal adverse event. |
|||||||||||||||||
Statistical analysis title |
Prednisolone dose at 1 year | ||||||||||||||||
Comparison groups |
Placebo v Simvastatin v Analysis
|
||||||||||||||||
Number of subjects included in analysis |
64
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
equivalence | ||||||||||||||||
P-value |
= 0.54 [2] | ||||||||||||||||
Method |
Regression, Linear | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
3.62
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-8.15 | ||||||||||||||||
upper limit |
15.38 | ||||||||||||||||
Variability estimate |
Standard deviation
|
||||||||||||||||
Notes [2] - The regression analysis adjusted for baseline dose suggests no significant difference at 12 months, i.e. patients in simvastatin group have higher prednisolone dose, and the mean difference is 3.62mg (95% CI: -8.15 to 15.38) with a p-value of 0.54 |
|
|||||||||||||||||
End point title |
Reduction in immunosuppressive agents at 24 months | ||||||||||||||||
End point description |
This will be analysed using a chi-squared test
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Two years
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Reduction in second-line immunosuppressive agent | ||||||||||||||||
Statistical analysis description |
The total number of patients included in the analysis is 12, with 6 from each of the treatment arms. chi-square test suggests a test statistic of 0.34 with a p-value of 0.56.
|
||||||||||||||||
Comparison groups |
Simvastatin v Placebo v Analysis
|
||||||||||||||||
Number of subjects included in analysis |
26
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
equivalence | ||||||||||||||||
P-value |
= 0.56 [3] | ||||||||||||||||
Method |
Chi-squared | ||||||||||||||||
Parameter type |
NA | ||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
- | ||||||||||||||||
upper limit |
- | ||||||||||||||||
Notes [3] - The reduction in second-line immunosuppressive agent does not differ significantly between the two groups at 5% level. |
|
|||||||||||||||||
End point title |
Number of patients with disease relapses at 24 months | ||||||||||||||||
End point description |
Disease relapses at 24 months
The number of patients who had disease relapses at 24 months is shown below. The number of patients included in the analysis are 10 and 11 for placebo and simvastatin group, respectively. The proportion of patients who had disease relapses at 24 months is higher (45.5%) compared to that in the placebo group (10%).
will be analysed using a chi-squared test.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Two years
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Number of patients with disease relapse at 2 years | ||||||||||||||||
Statistical analysis description |
e proportion of patients who had disease relapse by 24 months was higher in the simvastatin group (45.5%) compared to that in the placebo group (10%).
|
||||||||||||||||
Comparison groups |
Placebo v Simvastatin
|
||||||||||||||||
Number of subjects included in analysis |
6
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
equivalence [4] | ||||||||||||||||
P-value |
= 0.072 [5] | ||||||||||||||||
Method |
Chi-squared | ||||||||||||||||
Parameter type |
Na | ||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
- | ||||||||||||||||
upper limit |
- | ||||||||||||||||
Notes [4] - The chi-square test suggests that there is weak evidence of a difference between the two groups in disease relapses [5] - The chi-square test suggests a test statistics of 3.23 with a P-value of 0.072, therefore, the disease relapse rate does not differ significantly at 5% level. |
|
|||||||||||||||||
End point title |
Mean reduction in prednisolone dose at two years | ||||||||||||||||
End point description |
Prednisolone dose at 24 months
The number of patients included in the secondary analysis is 11 and 10 for simvastatin and placebo group, respectively. The results from the regression analysis suggest that there is little difference in mean prednisolone dose between the groups at 24 months (difference: -0.3 (Simvastatin.-Placebo.) 95% CI: -4.7 to 4.0, P = 0.87).
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Two years
|
||||||||||||||||
|
|||||||||||||||||
Notes [6] - 10 in placebo and 11 in simvastatin |
|||||||||||||||||
Statistical analysis title |
Prednisolone dose at 2 years | ||||||||||||||||
Statistical analysis description |
Prednisolone dose at 24 months
The number of patients included in the secondary analysis is 11 and 10 for simvastatin and placebo group, respectively. The results from the regression analysis suggest that there is little difference in mean prednisolone dose between the groups at 24 months (difference: -0.3 (Simvastatin.-Placebo.) 95% CI: -4.7 to 4.0, P = 0.87).
|
||||||||||||||||
Comparison groups |
Simvastatin v Placebo v Analysis
|
||||||||||||||||
Number of subjects included in analysis |
54
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
equivalence | ||||||||||||||||
P-value |
= 0.87 | ||||||||||||||||
Method |
Regression, Linear | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Point estimate |
-0.34
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-4.71 | ||||||||||||||||
upper limit |
4.03 | ||||||||||||||||
Variability estimate |
Standard deviation
|
||||||||||||||||
Dispersion value |
0
|
|
|||||||||||||
End point title |
Cholesterol at 24 months | ||||||||||||
End point description |
|||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Two years
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Jan 2016 to July 2018
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Simvastatin
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? No | |||
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 |