Clinical Trial Results:
A SERIES OF RANDOMISED CONTROLLED N-of 1 TRIALS IN PATIENTS WHO HAVE DISCONTINUED OR WISH TO DISCONTINUE STATIN USE DUE TO MUSCLE-RELATED SYMPTOMS TO ASSESS IF ATORVASTATIN TREATMENT CAUSES MORE MUSCLE SYMPTOMS THAN PLACEBO
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Summary
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EudraCT number |
2016-000141-31 |
Trial protocol |
GB |
Global end of trial date |
08 Aug 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
08 May 2021
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First version publication date |
08 May 2021
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Other versions |
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Summary report(s) |
StatinWISE BMJ Article |
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 |
ISRCTN30952488
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Additional study identifiers
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ISRCTN number |
ISRCTN30952488 | ||
US NCT number |
NCT02781064 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
London School of Hygiene and Tropical Medicine
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Sponsor organisation address |
Keppel Street, London, United Kingdom, WC1e 7HT
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Public contact |
StatinWISE trial team, London School of Hygiene and Tropical Medicine, +44 02072994684, statinwise@lshtm.ac.uk
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Scientific contact |
StatinWISE trial team, London School of Hygiene and Tropical Medicine, +44 02072994684, statinwise@lshtm.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 |
08 Aug 2019
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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 |
08 Aug 2019
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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 |
The primary research objective is to determine whether the muscle symptoms attributed to statin use by patients are caused by statins.
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Protection of trial subjects |
This study was conducted in keeping with the principles of Good Clinical Practice and the ethical and regulatory guidelines and regulations of the Medicines & Healthcare products Regulatory Agency (MHRA) and research ethics committees in the United Kingdom where the trial was committed. Participant safety was monitored by the Clinical Trial Unit, the Sponsor, the participant's GP, the data monitoring committee and the MHRA.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Sep 2016
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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: 200
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Worldwide total number of subjects |
200
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EEA total number of subjects |
0
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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) |
56
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From 65 to 84 years |
138
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85 years and over |
6
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Recruitment
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Recruitment details |
Participants were recruited across 50 GP practices in England and Wales between December 2016 and April 2018. | ||||||||||||||||||||
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Pre-assignment
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Screening details |
Participants recruited were considering stopping their statin (recruited opportunistically when they complained of symptoms during a consultation) or had stopped taking a statin in the last three years because of muscle symptoms. | ||||||||||||||||||||
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Period 1
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Period 1 title |
Baseline assessment
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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 | ||||||||||||||||||||
Blinding implementation details |
All participants and clinical and research staff were blinded during baseline assessment as participants had not yet been randomised to a treatment sequence.
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Arms
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Arm title
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N-of-1 trial | ||||||||||||||||||||
Arm description |
All participants were randomly assigned one of 8 sequences of alternating statin or placebo treatment as an N-of-1 trial. | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
Atorvastatin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
20mg atorvastatin, administered orally once daily
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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, Monitor, Data analyst, Carer, Assessor | ||||||||||||||||||||
Blinding implementation details |
Randomisation codes were generated and held securely and confidentially by an information technology team and sponsor representative at the London School of Hygiene and Tropical Medicine Clinical Trials Unit who were independent of the StatinWISE trial management team and the general practitioner surgery staff. Codes were provided Sharp Clinical Services (UK), a good manufacturing practice certified clinical trial supply company, for treatment packs manufacturing.
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Arms
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Arm title
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N-of-1 trial | ||||||||||||||||||||
Arm description |
Participants were allocated with equal probability to one of eight possible sequences which ensured that all participants received one period of statins and one period of placebo in their first two treatment periods (in random order) and no one was allocated to three sequential periods of the same treatment. | ||||||||||||||||||||
Arm type |
N-of-1 trial | ||||||||||||||||||||
Investigational medicinal product name |
Atorvastatin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
20mg atorvastatin, administered orally once daily
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Baseline characteristics reporting groups
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Reporting group title |
Baseline assessment
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
N-of-1 trial
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Reporting group description |
All participants were randomly assigned one of 8 sequences of alternating statin or placebo treatment as an N-of-1 trial. | ||
Reporting group title |
N-of-1 trial
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Reporting group description |
Participants were allocated with equal probability to one of eight possible sequences which ensured that all participants received one period of statins and one period of placebo in their first two treatment periods (in random order) and no one was allocated to three sequential periods of the same treatment. | ||
Subject analysis set title |
Primary outcome analysis - statin periods
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Of the 200 participants, 151 (76%) provided one or more visual analogue scale measurements in both a statin period and a placebo period and were included in the primary analysis. The 151 participants included in the primary analysis contributed 2638 measurements during 392 statin periods.
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Subject analysis set title |
Primary outcome analysis - placebo periods
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Of the 200 participants, 151 (76%) provided one or more visual analogue scale measurements in both a statin period and a placebo period and were included in the primary analysis. The 151 participants included in the primary analysis contributed 2576 symptom score measurements during 383 placebo periods.
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Subject analysis set title |
Secondary outcome analysis - statin compared to placebo period
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
152 participants contributed at least one secondary outcome measurement in a statin period and one in a placebo period.
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Subject analysis set title |
Secondary outcome - location of muscle symptoms
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
In total, there were 493 reports of muscle symptoms during a treatment period arising from 140 participants. Of these 493 reports, 481 (97.6%) included the location of the muscle symptoms.
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Subject analysis set title |
Secondary outcome - adherence
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Adherence to study medication was self-reported and verified by a drug accountability count of returned treatment packs containing the trial medication.
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End point title |
Mean difference in self-reported muscle symptoms on a visual analogue scale | ||||||||||||
End point description |
The primary outcome is self-reported ‘muscle symptoms’, defined as pain, weakness, tenderness, stiffness or cramp to the body of any intensity, recorded where the participant believes they are associated with the study medication; these are the symptoms most commonly reported by patients and are often the reasons for discontinuation. The primary outcome will be assessed by the mean difference in VAS scores (range 0 to 100) between treatment periods with the trial treatment and treatment periods with placebo, estimated via a linear mixed model.
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End point type |
Primary
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End point timeframe |
The primary outcome was measured each day with a validated visual analogue scale (0-10, score 0=no symptoms, 5=moderate symptoms, and 10=worst possible symptoms) for the last seven days of each two month treatment period for 1 year.
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Statistical analysis title |
Primary analysis | ||||||||||||
Statistical analysis description |
The primary analysis was a linear mixed model for visual analogue scale muscle symptom scores with random effects for participant and treatment. The analysis accounted for correlation between the seven daily measurements by modelling the residual errors with a first order autoregressive error structure within each treatment period, and non-normality of the symptom scores by robust standard errors. For the primary outcome, 95% confidence intervals are presented with a two sided P value.
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Comparison groups |
Primary outcome analysis - placebo periods v Primary outcome analysis - statin periods
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Number of subjects included in analysis |
302
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.4 | ||||||||||||
Method |
Regression, Linear | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.11
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.36 | ||||||||||||
upper limit |
0.14 | ||||||||||||
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End point title |
Whether patients found their own trial result helpful in making the decision about future statin use | ||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Collected three months after the end of the participant's final treatment period
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| No statistical analyses for this end point | |||||||||||
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End point title |
Whether the participant had, or intended to, restart treatment with statins | |||||
End point description |
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End point type |
Secondary
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End point timeframe |
Collected three months after the end of the participant's final treatment period
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| No statistical analyses for this end point | ||||||
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End point title |
Location of reported muscle symptoms | ||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Collected on the last day of each two month treatment period for the entire two month period.
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| Notes [1] - 140 participants reported 481 locations of muscle symptoms |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Among patients reporting muscle symptoms, the difference in mean VAS scores (range 0 to 100) for General activity | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Collected on the last day of each two month treatment period.
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| No statistical analyses for this end point | |||||||||
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End point title |
Among patients reporting muscle symptoms, the difference in mean VAS scores (range 0 to 100) for Mood | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Collected on the last day of each two month treatment period.
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| No statistical analyses for this end point | |||||||||
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End point title |
Among patients reporting muscle symptoms, the difference in mean VAS scores (range 0 to 100) for Walking ability | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Collected on the last day of each two month treatment period.
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| No statistical analyses for this end point | |||||||||
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End point title |
Among patients reporting muscle symptoms, the difference in mean VAS scores (range 0 to 100) for Normal work (includes both work outside the home and housework) | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Collected on the last day of each two month treatment period.
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| No statistical analyses for this end point | |||||||||
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End point title |
Among patients reporting muscle symptoms, the difference in mean VAS scores (range 0 to 100) for Relations with other people | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Collected on the last day of each two month treatment period.
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| No statistical analyses for this end point | |||||||||
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End point title |
Among patients reporting muscle symptoms, the difference in mean VAS scores (range 0 to 100) for Sleep | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Collected on the last day of each two month treatment period.
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| No statistical analyses for this end point | |||||||||
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End point title |
Among patients reporting muscle symptoms, the difference in mean VAS scores (range 0 to 100) for Enjoyment of life | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Collected on the last day of each two month treatment period.
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| No statistical analyses for this end point | |||||||||
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End point title |
Adherence to medication | ||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Collected on the last day of each two month treatment period.
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Attachments |
Adherence to study medication |
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| No statistical analyses for this end point | |||||||
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End point title |
Effect of statins on the occurrence of muscle symptoms overall | ||||||||
End point description |
The proportion of patients with muscle symptoms during each two-month period comparing periods of statin treatment with placebo.
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End point type |
Secondary
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End point timeframe |
Collected on the last day of each two month treatment period.
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| No statistical analyses for this end point | |||||||||
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End point title |
Effect of statins on muscle symptoms that could not be attributed to a cause other than the intervention | ||||||||
End point description |
The proportion of patients with muscle symptoms during each two-month period who report that they believe their symptoms were caused by the study medication, comparing periods of statin treatment with placebo.
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End point type |
Secondary
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End point timeframe |
Collected on the last day of each two month treatment period.
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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 |
From time of recruitment until completion of trial at end of final treatment period.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.1
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Reporting groups
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Reporting group title |
N-of-1 trial
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Reporting group description |
All participants were randomly assigned one of 8 sequences of alternating statin or placebo treatment as an N-of-1 trial. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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: On the basis that patients: (1) have had prior exposure the trial treatment, (2) the trial treatment is clinically indicated for their medical condition, and (3) the known safety profile of the trial treatment, adverse event reporting was limited to Serious Adverse Events. This approach received regulatory and ethical approval. |
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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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08 Aug 2016 |
Added a blood test to be completed prior to consenting patients. The blood test results must be within 3 months of the screening visit. The StatinWISE team will now record the CK and ALT results from this blood test to ensure the patient is eligible.
Additional exclusion criterion to reference the contra-indications listed in the SmPC for atorvastatin 20mg.
Additional sites have been added
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19 Dec 2016 |
Addition of all English CCGs as recruiting sites in the study. |
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23 May 2017 |
Revised Patient Information Leaflet
GP surgery poster & waiting room screen display text
Documents pertaining to recruitment via general advertising. |
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14 Jul 2017 |
The amendment is to seek approval for the materials to be used to support our recruitment plan through general advertising. |
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04 Apr 2018 |
The amendment is for the review and approval for the following documents that is part of our already approved process of providing each patient with their study data at the end of their participation, including revealing their treatment allocation for each treatment period and their study 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. | |||
| n/a | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/33627334 |
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