| Conditions: |
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Primary Progressive Multiple Sclerosis |
| Purpose: |
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Background:
- Multiple sclerosis (MS) is an inflammatory disorder of the central nervous system that
progressively weakens and destroys the pathways of the nervous system. About 10 percent
to 15 percent of patients develop primary-progressive MS (PP-MS), characterized by
progressive accumulation of disability from the disease onset, without any marked
improvements or relapses. There are currently no effective treatments for PP-MS.
- Idebenone is a manmade drug that is similar to a naturally occurring compound known as
coenzyme Q10, a common dietary supplement. Research data suggest that idebenone may be
able to limit demyelination and death of brain cells and thereby slow or halt the
progression of neurological dysfunction such as that occurring in MS.
Objectives:
- To evaluate the safety and effectiveness of using idebenone to treat primary progressive
MS.
Eligibility:
- Individuals between 18 and 65 years of age who have been diagnosed with primary
progressive multiple sclerosis.
Design:
- The study will last 3 years and will be divided into two parts: a 1-year pretreatment
baseline and 2 years of treatment with either idebenone or a placebo.
- Pre-treatment study: approximately 5 clinic visits over 1 year.
- Visit 1: Comprehensive medical history and neurological examination, with brain scans
and neurological tests.
- Visit 2: Magnetic resonance imaging (MRI) scan of the spine and lymphocytapheresis
(withdrawal of white blood cells for testing).
- Visit 3: Lumbar puncture.
- Visit 4: Skin biopsy.
- Visit 5: Repeat MRI of the brain and spinal cord, as well as neurological tests; these
tests will be scheduled over 2 days.
- After the five pretreatment visits, patients will receive a 6-month supply of study
medication (either idebenone or a placebo) to take three times a day with food
- Patients will continue to have regular followup clinic visits with brain MRI scans,
blood tests, and other evaluations of brain and nervous system function. Randomly
selected participants will have additional MRI scans for further safety precautions.
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| Study Summary: |
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Objective: The goal of this study is to assess the safety, therapeutic efficacy and
mechanism of action of idebenone in primary-progressive multiple sclerosis (PP-MS) patients.
Study Population: Adult, untreated patients with PP-MS with disability ranging from none to
moderately severe will be included in the trial. The upper age limit in this study has been
set at 65; setting an age limit should permit us to focus on the potential neuroprotective
effect of idebenone in PP-MS and limit the confounding factor of the natural aging process
and its known negative influence on neuro-regeneration. Published data indicate that higher
doses (10-50 mg/kg) of idebenone per day are required for beneficial effects on neurological
disability in comparison to the lower doses (5-10mg/kg) that are sufficient for beneficial
effects on cardiac/systemic functions in Friedreich's ataxia (FRDA) patients. Therefore, in
order to target the CNS compartment, we will use a daily dose of 2250mg (750mg 3 times per
day), which will provide target values of 10-50mg/kg for virtually all adult patients.
Design: This is a Phase I/II safety/efficacy trial with an adaptive trial design: one year
of pretreatment baseline period serves the dual purpose of collecting patient-specific
biomarkers of disease progression and collecting longitudinal neuroimaging and clinical data
for selection of primary outcome measures. This baseline period is then followed by a
double-blind, idebenone versus placebo treatment phase for a total of 2 years. Based on
preliminary sample size estimates, current enrollment calls for a total of 66 patients (33
per arm).
Outcome Measures: Quantitative neuroimaging measures of central nervous system (CNS: i.e.
brain and spinal cord) tissue destruction and clinical and functional (i.e.
electrophysiological) measures of neurological disability will be collected every 6-12
months. Additionally, biomarkers focusing on analysis of reactive oxygen species (ROS) and
oxidative stress will be collected every 12 months. The trial is currently powered using
progression of brain atrophy as detected by SIENA methodology as the primary outcome
measure. However, this may not be the most sensitive outcome available. In recognition of
this, the trial has an adaptive design: i.e. it incorporates analysis of progression of CNS
tissue destruction as measured by quantitative MRI markers and clinical/paraclinical markers
defined as secondary outcome measures in the first 30 enrolled patients during the one year
pre-treatment baseline, before randomization. All defined outcome measures collected in the
first 30 enrolled patients will be transformed into z-scores and compared for the robustness
of longitudinal change over the coefficient of variation. This will permit to select the
most sensitive and most accurate outcome measure for detecting progression of CNS tissue
damage. As a result, the primary outcome measure of this trial will be the comparison of
individualized rates of brain atrophy progression between the idebenone and placebo groups
after 2 years of treatment, unless the predetermined analysis of the pre-treatment baseline
period in the first 30 enrolled subjects determines that one of the predefined secondary
outcome measures has a higher z-score than brain atrophy measurement. In this case, the
primary outcome would be the efficacy of idebenone versus placebo in inhibiting
patient-specific slopes of functional or structural deterioration as measured by this more
sensitive biomarker of CNS tissue destruction, yet to be defined by the analysis of the
1-year longitudinal data from pre-treatment baseline.
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| Criteria: |
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- INCLUSION CRITERIA:
1. PP-MS as determined by the 2005 modification of McDonald's diagnostic criteria
2. Age from 18-65 years (inclusive)
3. EDSS measure of neurological disability from 1 (no disability, clinical signs
only) to 7 (ambulatory with bilateral support)
4. Able to provide informed consent
5. Willing to participate in all aspects of trial design and follow-up
6. If able to become pregnant or to father a child, agreeing to commit to the use
of a reliable/accepted method of birth control (i.e. hormonal contraception
(birth control pills, injected hormones, vaginal ring), intrauterine device,
barrier methods with spermicide (diaphragm with spermicide, condom with
spermicide) or surgical sterilization (hysterectomy, tubal ligation, or
vasectomy in a partner)) for the duration of treatment arm of the study
7. Not receiving any immunomodulatory/immunosuppressive therapies for a period of
at least 3 months before enrollment in the study
8. No exposure to idebenone, coenzyme-Q(10) or other dietary supplements (such as
antioxidants, mitochondrial-function promoting supplements or vitamins in excess
of 3 times recommended daily doses) for a period of at least 1 month before
enrollment in the study
A single patient (NIB 334) has been granted an amendment to inclusion criteria #2. NIB
334 meets all remaining inclusion and none of the exclusion criteria for the study. This
patient has no comorbidities. If this patient is completes the baseline and is dosed with
idebenone/placebo, he will be analyzed the same as other patients. The FDA was consulted,
and expressed no objections to this plan.
EXCLUSION CRITERIA:
1. Alternative diagnoses that can explain neurological disability and MRI findings
2. Clinically significant medical disorders that, in the judgment of the investigators,
could cause CNS tissue damage or limit its repair, or might expose the patient to
undue risk of harm or prevent the patient from completing the study
3. History of hypersensitivity reaction to idebenone or coenzyme-Q (10)
4. Pregnant or lactating women. All women of child-bearing potential must have a
negative pregnancy test prior to the medication phase of the study.
5. Abnormal screening/baseline blood tests exceeding any of the limits defined below:
i. Serum alanine transaminase or aspartate transaminase levels greater than 3 times
the upper limit of normal values
ii. Total white blood cell count < 3,000/mm(3)
iii. Platelet count < 85,000/mm(3)
iv. Serum creatinine level > 2.0 mg/dl or eGFR (glomerular filtration rate) < 30
v. Positive pregnancy test
6. Patients who are receiving any immunosuppressive therapies (including cytostatic
agents) due to the concern that these drugs may contribute to neurodegeneration or
limit CNS repair
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| NCT ID: |
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NCT00950248 |
| Primary Contact: |
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Principal Investigator
Bibiana Bielekova, M.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Joan M Ohayon, C.R.N.P.
Phone: (301) 496-0064
Email: ohayonj@ninds.nih.gov
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| Backup Contact: |
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Email: bielekovab@mail.nih.gov
Bibiana Bielekova, M.D.
Phone: (301) 496-1801
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| Location Contact: |
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Bethesda, Maryland 20892
United States
For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)
Phone: 800-411-1222
Email: prpl@mail.cc.nih.gov
Site Status: Recruiting |