To assess the efficacy of add-on high-dose simvastatin on markers for disease progression in MS patients treated with natalizumab or ocrelizumab for at least six months.
ID
Source
Brief title
Condition
- Demyelinating disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The change in whole brain atrophy rate, comparing rates during 6-month run-in
period to 18-month treatment period.
Secondary outcome
Secondary outcome measures include clinical outcome measures (neurological
exam, arm- and walking functions, cognitive functions), biochemical outcome
measures (sNfL, multi-parameter analysis of peripheral blood mononuclear cells
(PBMC) and serum cholesterol), other imaging outcome measures (regional white
and gray matter atrophy rate, functional connectivity on brain MRI, OCT),
patient-reported outcome measures (questionnaires on the impact of MS on arm
function, walking function, neuropsychological status and quality of life) and
safety and tolerability (incidence of (serious) adverse events, CK levels).
Background summary
There are currently no satisfying therapeutic options for disease progression
in multiple sclerosis (MS). The beneficial effects and favorable safety profile
of statins are well established in cardiovascular disease. In the central
nervous system, statins are shown to have cell-protective and anti-inflammatory
properties. Previous studies in secondary progressive MS (SPMS) patients and
relapsing-remitting MS (RRMS) patients with first-line treatment showed that
add-on high-dose statins were well tolerated and reduced atrophy rates and
disability after 2 and 8 years respectively. The effect in a population with
completely suppressed inflammation and on serum neurofilament light (sNfL) as a
biomarker for disease progression remain unclear. The purpose of this
single-center phase II clinical trial is therefore to investigate the efficacy
of simvastatin in MS patients treated with natalizumab (NTZ) or ocrelizumab
(OCR) for at least six months.
Study objective
To assess the efficacy of add-on high-dose simvastatin on markers for disease
progression in MS patients treated with natalizumab or ocrelizumab for at least
six months.
Study design
In this single-center investigator-initiated phase II clinical trial we choose
to treat all subjects with the investigational product for 18 months and
compare results to a run-in period of 6 months without treatment. Through this
design, participants act as both subjects and controls and may all benefit from
treatment. Moreover, the sample sizes that are needed to find differences
between time points and subgroups remain limited. The occurrence of adverse
events and the effect on clinical, biochemical and imaging measures will be
closely monitored. Following informed consent, patients are screened for
eligibility. Patients who meet inclusion criteria without exclusion criteria
will start the 6 month run-in period without simvastatin. In month 7, patients
will start simvastatin at a dosage of 40 mg a day and then escalate to
high-dose treatment with 80 mg a day from month 8 to 24 (17 months). Patients
will undero clinical, biochemical and imaging measures. Compared to our routine
practice for patients treated with OCR or NTZ, the number of additional scans
and measurements is limited.
Intervention
Add-on high-dose simvastatin 80 mg per day for 17 months (40 mg per day in
month 7).
Study burden and risks
Simvastatin can be administered independently and proven safe and well
tolerated for prevention of cardiovascular disease. Careful monitoring with
blood samples every 3 to 6 months, yearly clinical measures, questionnaires and
brain MRI is routine practice for MS patients treated in our center. Additional
measures for this study include BICAMS, 6-MWTEC, functional MRI, OCT and 3
questionnaires. These are performed at baseline, month 6, month 12 and month
24. Routine laboratory tests are continued with additional serum cholesterol
and CK monitoring. Adverse events survey is collected at every study and blood
sample visit. The study schedule is designed in a way to limit the additional
blood samples and visits compared to routine practice.
De Boelelaan 1117
Amsterdam 1081HV
NL
De Boelelaan 1117
Amsterdam 1081HV
NL
Listed location countries
Age
Inclusion criteria
1. Definite diagnosis of multiple sclerosis (MS) according to the revised
McDonald 2017 criteria.
2. Treatment with ocrelizumab or natalizumab for at least 6 months prior to
inclusion.
4. Age 18 to 65 years old.
5. EDSS score 3.0 - 7.0 (inclusive).
Exclusion criteria
1. MS relapse within 6 months of baseline visit, with or without treatment with
steroids.
2. Use of immunomodulation or -suppression other than ocrelizumab or
natalizumab within the previous 6 months.
3. Commencement of treatment with fampridine within 3 months of baseline visit.
4. Concomitant use of lipid lowering drugs or use within 6 months before
baseline visit.
5. Concomitant use of potent CYP3A4 inhibitors.
6. (History of) hypersensitivity, muscular toxicity or other adverse reaction
due to statin or fibrate use.
7. Any predisposing factor to rhabdomyolysis: renal impairment (creatinine
clearance <70 mL/min), uncontrolled hypothyroidism, personal or familial
history of hereditary muscular disorders, alcohol abuse (>14 standard drinks
units per week).
8. Baseline serum creatine kinase (CK) levels of >5 x ULN (confirmed by second
measurement within 5-7 days), or at least 3-fold increase from baseline with
associated muscle symptoms.
9. Active liver disease or unexplained persistent elevations of serum
transaminases 3 x ULN.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-003127-38-NL |
| CCMO | NL71001.029.19 |