Clinical Trial of Idebenone in Primary Progressive Multip... | NCT00950248

NCT00950248

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

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Document Section

Large Document Module

Derived Section

Miscellaneous Info Module

ID	Type	Description	Link
09-I-0197	Other Identifier	NIH
NCT00950248	Registry Identifier	clinicaltrials.gov

Status Module

Description Module

Brief Summary

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.

Detailed Description

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.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Idebenone	Active Comparator	Idebenone (150mg tablets) administered orally as five tablets, three times per day with food.	Drug: Idebenone
Placebo	Placebo Comparator	Placebo tablets administered orally as five tablets, three times per day with food.	Other: placebo

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Idebenone	Drug	idebenone, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium povidone, magnesium stearate, silicon dioxide, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc)

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Change in the Area Under the Curve (AUC) of the Combinatorial Weight-Adjusted Disability Score (CombiWISE) From Baseline to Treatment Phase	The AUCs of the CombiWISE scores during the 2-year treatment period was analyzed using an Analysis of Covariance (ANCOVA) model with the AUC of the pre-treatment CombiWISE scores, Baseline (Month 0) CombiWISE score and Baseline age as covariates. CombiWISE is a composite scale derived from Expanded Disability Status Scale (EDSS) , Scripps Neurological Disability Scale (SNRS), times 25 foot walk (25FW), and non-dominant hand of 9 hole peg test (9HPT) with a minimum value of 0 (no disability) and maximum value of 100 (maximum disability). The AUC values were calculated for both the pre-treatment baseline phase (from Months -12, -6, and 0) and for the double-blind phase (from Months 0, 6, 12, 18, and 24). Because the follow-up times varied from patient to patient, the AUC values were made comparable by scaling them by dividing the AUC value by the square of the actual duration (in years) of each of the phases.	1-year pre-treatment baseline vs 2-year treatment period

Secondary Outcomes

Measure	Description	Time Frame
Change in the AUC of Individualized Rates of Enlargement of Ventricular Volume From Baseline to Treatment Phase	The AUCs of the Ventricular volume scores (individualized rates of enlargement of segmented volume of lateral and 3rd ventricles) during the baseline and the 2-year treatment period were assessed using an ANCOVA model with the AUC of the pre-treatment Volumetric score, Baseline (Month 0) Volumetric score, and group as covariates. The AUC values were calculated for both the pre-treatment baseline phase (from Months -12, -6, and 0) and for the double-blind phase (from Months 0, 6, 12, 18 and 24). Because the follow-up times varied from patient to patient, the AUC values were made comparable by scaling them by dividing the AUC value by the square of the actual duration (in years) of each of the phases.

Eligibility Module

Eligibility Criteria

INCLUSION CRITERIA:
1. PP-MS as determined by the 2005 modification of McDonald s diagnostic criteria
2. Age from 18-65 years (inclusive)
3. Expanded Disability Status Scale (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

EXCLUSION CRITERIA:

Alternative diagnoses that can explain neurological disability and MRI findings
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
History of hypersensitivity reaction to idebenone or coenzyme-Q (10)
Pregnant or lactating women. All women of child-bearing potential must have a negative pregnancy test prior to the medication phase of the study.
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 (estimated glomerular filtration rate) <30

v. Positive pregnancy test
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

Name	Affiliation	Role
Bibiana Bielekova, M.D.	National Institute of Allergy and Infectious Diseases (NIAID)	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
National Institutes of Health Clinical Center, 9000 Rockville Pike		Bethesda	Maryland	20892	United States

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
12368988	Background	Artuch R, Aracil A, Mas A, Colome C, Rissech M, Monros E, Pineda M. Friedreich's ataxia: idebenone treatment in early stage patients. Neuropediatrics. 2002 Aug;33(4):190-3. doi: 10.1055/s-2002-34494.
16585503	Background	Bielekova B, Catalfamo M, Reichert-Scrivner S, Packer A, Cerna M, Waldmann TA, McFarland H, Henkart PA, Martin R. Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis. Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5941-6. doi: 10.1073/pnas.0601335103. Epub 2006 Apr 3.

Arm/Group Information

ID	Title	Description
FG000	Untreated	Patients in their first year baseline prior to study drug phase
FG001	Idebenone	Idebenone (150mg tablets) administered orally as five tablets, three times per day with food. Idebenone: idebenone, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium povidone, magnesium stearate, silicon dioxide, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc)
FG002	Placebo	Placebo tablets administered orally as five tablets, three times per day with food. placebo: lactose monohydrate, microcrystalline cellulose, magnesium stearate, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc)

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Idebenone	Idebenone (150mg tablets) administered orally as five tablets, three times per day with food. Idebenone: idebenone, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium povidone, magnesium stearate, silicon dioxide, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc)

Units	Counts
Participants	BG000

Baseline Measures

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Categorical			Count of Participants

Outcome Measures Module

Outcome Measures

Type	Title	Description	Population Description	Reporting Status	Anticipated Posting Date	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Time Frame	Units Analyzed	Denominator Units Selected	Arm/Group Information	Denominators	Classes	Analyses
Primary	Change in the Area Under the Curve (AUC) of the Combinatorial Weight-Adjusted Disability Score (CombiWISE) From Baseline to Treatment Phase	The AUCs of the CombiWISE scores during the 2-year treatment period was analyzed using an Analysis of Covariance (ANCOVA) model with the AUC of the pre-treatment CombiWISE scores, Baseline (Month 0) CombiWISE score and Baseline age as covariates. CombiWISE is a composite scale derived from Expanded Disability Status Scale (EDSS) , Scripps Neurological Disability Scale (SNRS), times 25 foot walk (25FW), and non-dominant hand of 9 hole peg test (9HPT) with a minimum value of 0 (no disability) and maximum value of 100 (maximum disability). The AUC values were calculated for both the pre-treatment baseline phase (from Months -12, -6, and 0) and for the double-blind phase (from Months 0, 6, 12, 18, and 24). Because the follow-up times varied from patient to patient, the AUC values were made comparable by scaling them by dividing the AUC value by the square of the actual duration (in years) of each of the phases.	The primary outcome was assessed in Intention-to-treat population of patients: all randomized patients who have at least one post-baseline (post Mo 0) efficacy assessment. 38 out of 39 patients randomized to idebenone and 35 out of 38 patients randomized to placebo fulfill this definition.	Posted		Mean	Standard Deviation	units on a scale per year		1-year pre-treatment baseline vs 2-year treatment period

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Untreated	Patients in their first year baseline prior to study drug phase	0

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Jun 14, 2018	Oct 23, 2018	Prot_000.pdf
SAP	No	Yes	No	Statistical Analysis Plan	Feb 14, 2018	Oct 23, 2018	SAP_001.pdf

ID	Term
D020528	Multiple Sclerosis, Chronic Progressive
D009103	Multiple Sclerosis

ID	Term
D020278	Demyelinating Autoimmune Diseases, CNS
D020274	Autoimmune Diseases of the Nervous System
D009422	Nervous System Diseases
D003711	Demyelinating Diseases