Clinical Trial Results:
Simvastatin as a neuroprotective treatment for Parkinson's disease: a double-blind, randomised, placebo controlled futility study in patients of moderate severity.
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Summary
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EudraCT number |
2015-000148-40 |
Trial protocol |
GB |
Global end of trial date |
05 Jun 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
03 Jun 2021
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First version publication date |
03 Jun 2021
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Other versions |
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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 |
PDSTAT2015
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Additional study identifiers
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ISRCTN number |
ISRCTN16108482 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
REC Reference: 15/NE/0324, IRAS Number: 172703, UHPNT R&D Reference Number: 14/P/125 | ||
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Sponsors
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Sponsor organisation name |
University Hospitals Plymouth NHS Trust
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Sponsor organisation address |
Research Office, L2 MSCP, Bircham Park Offices, 1 Roscoff Rise, Derriford, Plymouth, United Kingdom, PL6 5FP
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Public contact |
Dr Alison Jeffery, Trial Manager , Peninsula Clinical Trials Unit (PenCTU), Faculty of Medicine and Dentistry, University of Plymouth, 01752 439831, PenCTU@plymouth.ac.uk
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Scientific contact |
Dr Camille Carroll, Associate Professor and Honorary Consultant Neurologist, Peninsula Medical School, Faculty of Medicine and Dentistry University of Plymouth
, 01752 439829, camille.carroll@plymouth.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 |
06 Feb 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
05 Jun 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
05 Jun 2020
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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 determine whether simvastatin is clearly ineffective (futile) in preventing the clinical decline of PD as measured by the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor score.
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Protection of trial subjects |
The study is approved by the MHRA, the North East - Newcastle & North Tyneside 2 Research Ethics Committee (NRES) and the Health Research Authority (HRA). Study monitoring is conducted by the Peninsula Clinical Trials Unit (PenCTU) and an Independent Trial Steering Committee (TSC), Trial Management Group (TMG) and Data Monitoring Committee (DMC) are set up for the study oversight.
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Background therapy |
Levodopa. | ||
Evidence for comparator |
The active investigational medicinal product is simvastatin. Active trial medication will be provided as simvastatin 40mg for the first month then 80mg for the following 23 months with cellulose microcrystalline powder in capsule form, to be taken orally. The comparator is a matched placebo capsule containing cellulose microcrystalline powder only. | ||
Actual start date of recruitment |
01 Oct 2015
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy, Ethical reason, Scientific research | ||
Long term follow-up duration |
26 Months | ||
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: 235
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Worldwide total number of subjects |
235
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EEA total number of subjects |
235
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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) |
105
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From 65 to 84 years |
125
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85 years and over |
5
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Recruitment
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Recruitment details |
Patients will be recruited over 12 months from clinical lists, through research registrars, publicity and word of mouth. | |||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Demographic information and medical history. Concomitant medication and ‘wearing-off’ questionnaire. Provide “Wearing off guide for patients" (for participant to take home). Physical examination (inc. assessment of modified Hoehn & Yahr stage). MoCA. MADRS. Blood samples for: CK, AST, ALT, eGFR, HDL total, TSH, HbA1C, urea and electrolytes. | |||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall study period (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 |
Investigator, Monitor, Data analyst, Subject, Assessor | |||||||||||||||||||||||||||
Blinding implementation details |
Statistical analyses completed blinded before allocation groups were revealed.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | |||||||||||||||||||||||||||
Arm description |
Participants received placebo capsules containing cellulose microcrystalline power, taken orally. | |||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||
Investigational medicinal product name |
cellulose microcrystalline
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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 |
The comparator is a matched placebo capsule containing cellulose microcrystalline powder only.
Medication will be prescribed in two phases: a lower dose phase of 40 mg active drug/equivalent placebo for one month and a higher dose maintenance phase of 80 mg active drug/equivalent placebo for 23 months.
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Investigational medicinal product name |
cellulose microcrystalline
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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 |
Medication will be prescribed in two phases: a lower dose phase of 40 mg active drug/equivalent placebo for one month and a higher dose maintenance phase of 80 mg active drug/equivalent placebo for 23 months.
The comparator is a matched placebo capsule containing cellulose microcrystalline powder only.
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Arm title
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Simvastatin | |||||||||||||||||||||||||||
Arm description |
Participants received simvastatin 40mg with cellulose microcrytalline powder in capsule form, taken orally. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
simvastatin
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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 |
The active investigational medicinal product is simvastatin. Active trial medication will be provided as simvastatin 40mg with cellulose microcrystalline powder in capsule form, to be taken orally.
Medication will be prescribed in two phases: a lower dose phase of 40 mg active drug/equivalent placebo for one month and a higher dose maintenance phase of 80 mg active drug/equivalent placebo for 23 months.
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Participants received placebo capsules containing cellulose microcrystalline power, taken orally. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Simvastatin
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Reporting group description |
Participants received simvastatin 40mg with cellulose microcrytalline powder in capsule form, taken orally. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Participants received placebo capsules containing cellulose microcrystalline power, taken orally. | ||
Reporting group title |
Simvastatin
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Reporting group description |
Participants received simvastatin 40mg with cellulose microcrytalline powder in capsule form, taken orally. | ||
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End point title |
Change in MDS-UPDRS Part III (Off) | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Change from baseline to 24 months
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| Notes [1] - Progressed to the high dose with valid MDS-UPDRS part III (OFF) at baseline and 24 months [2] - Progressed to the high dose with valid MDS-UPDRS part III (OFF) at baseline and 24 months |
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Statistical analysis title |
Mixed effects linear regression model | ||||||||||||
Statistical analysis description |
A mixed effects linear regression model was fitted to the change in MDS-UPDRS part III (OFF) from baseline to 24 months, with adjustments for baseline MDS-UPDRS part III (OFF), age and PD duration at baseline, sex, and Hoehn & Yahr stratification as fixed effects and study centre as a random effect.
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Comparison groups |
Placebo v Simvastatin
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Number of subjects included in analysis |
178
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Analysis specification |
Pre-specified
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Analysis type |
other [3] | ||||||||||||
P-value |
= 0.006 [4] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
1.52
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Confidence interval |
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80% | ||||||||||||
sides |
2-sided
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lower limit |
-0.77 | ||||||||||||
upper limit |
3.8 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
1.78
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| Notes [3] - Futility analysis of the mean between-group difference (placebo - simvastatin) estimated from the mixed effects linear regression model. Rejection of the null hypothesis indicates intervention futility. [4] - Null hypothesis: mean between-group difference (placebo - simvastatin) = -3 Alternate hypothesis: mean between-group difference (placebo - simvastatin) > -3 |
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Adverse events information
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Timeframe for reporting adverse events |
Timeframe for AE
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Adverse event reporting additional description |
AE additional description
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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 |
19.0
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Reporting groups
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Reporting group title |
Placebo and simvastatin combined
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Reporting group description |
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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27 Oct 2015 |
Protocol updated to v2.0 Kings College Hospital, London, added as a participating site and amendment to enable the use of Participant Identification Centres. |
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17 Nov 2015 |
No change to study protocol. Simplified Investigational Medicinal Product Dossier amended to fulfil condition of the CTA application for the study. |
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19 Feb 2016 |
No change to study protocol. Change to Principal Investigator at Musgrove Park Hospital, Taunton. |
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23 Mar 2016 |
Protocol updated to version 3.2 to clarify details of qualitative sub study following confirmation of additional funding. |
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21 Jul 2016 |
Protocol updated to version 3.3 to clarify target population being approached for qualitative sub study and to bring study under HRA approval. |
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20 Jan 2017 |
No change to protocol. Change to Principal Investigator at Clinical Ageing Research Unit, Newcastle. |
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20 Feb 2017 |
No change to protocol. New documents for approval for qualitative sub study and amended documents for genetic sub study. |
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28 Mar 2017 |
Modification of previous amendment following unfavourable opinion from REC. Carer focus group documents removed from the amendment. |
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27 Apr 2017 |
Protocol updated to version 4.1 to electro magnetic sensor measurement sub study and other administrative changes. |
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31 Jul 2017 |
Addition of 3 new study sites: Rotherham Hospital, Royal Stoke University Hospital and Royal Berkshire Hospital. |
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24 Apr 2018 |
Addition of study newsletters to be sent to participants twice a year. |
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27 Jul 2018 |
Change to Principal Investigator at Royal Preston Hospital. |
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21 Nov 2018 |
Change to Principal Investigator at Leeds General Infirmary. |
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26 Nov 2018 |
Update to SmPC, protocol updated to version 4.3, updated study documentation and addition of end of study postcards. |
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30 Jan 2019 |
Protocol updated to version 4.4 to include: GP letter re updated medication recommendations; End of study GP letter; Addition of EMS measurement at 26 weeks; Home visits. |
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22 Apr 2020 |
Protocol updated to version 4.6 to include addition of qualitative sub study comprising survey and semi structured interviews for site staff. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
