Clinical Trial of Idebenone in Primary Progressive Multiple Sclerosis (IPPoMS) (IPPoMS)

Double Blind Placebo-Controlled Phase I/II Clinical Trial of Idebenone in Patients With Primary Progressive Multiple Sclerosis

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.

Study Overview

• Status: Completed
• Conditions: Primary Progressive Multiple Sclerosis
• Intervention / Treatment: Drug: Idebenone; Other: placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 85
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• 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:

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 (estimated 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Idebenone; Idebenone (150mg tablets) administered orally as five tablets, three times per day with food.	Drug: 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); Other Names: SNT-MC17/F02
Placebo Comparator: Placebo; Placebo tablets administered orally as five tablets, three times per day with food.	Other: 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); Other Names: SNT-MC17/F03

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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 Outcome Measures

Outcome Measure	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.	1-year pre-treatment baseline vs 2-year treatment period
Disability Progression Measured by EDSS-plus	Categorical time-to-event endpoints (EDSS-plus) were analyzed using Cox Proportional hazards models, with treatment group as a covariate. The EDSS-plus event was defined as disability progression on at least 1 of 3 components [EDSS, 25FW, and/or non-dominant hand 9HPT]) confirmed 6 months apart and with a ≥ 20% minimum threshold change for 25FW and non-dominant hand 9HPT). The patients who did not have an event during the study were censored at the time of the last assessment of EDSS-plus. The number of months from the date of first dose to date of event or censoring were used as endpoint. The measure is time to disease progression and unit of this measure is months.	2-year treatment period
Change in Slopes of 25FW Time From Baseline to Treatment Phase	Lower extremity disability was measured by an average of two trials of timed 25 foot walk assessed at month -12, -6, and 0 for the baseline phase and at month 0, 6, 12, 18, and 24 for the treatment phase. The progression rate was calculated as a difference between baseline and treatment slopes using a piecewise linear mixed-effect model with breaking point at month 0. The maximum time assigned for a trial is 180s. Patients unable to complete the 25 foot trial within this time limit are coded as "179.9"	1-year pre-treatment baseline vs 2-year treatment period
Change in Slopes of 9HPT Time From Baseline to Treatment Phase	Upper extremity/fine motor movements disability was measured as an average of left and right hand time, with each hand assessed as an average of two trials with upper limit of 5 (300s) per trial. Patients unable to complete the task within this time are coded as "777" The outcome was assessed at month -12, -6, and 0 for the baseline phase and at month 0, 6, 12, 18, and 24 for the treatment phase. The progression rate was calculated as a difference between baseline and treatment slopes using a piecewise linear mixed-effect model with breaking point at month 0.	1-year pre-treatment baseline vs 2-year treatment period
Change in Slopes of SNRS From Baseline to Treatment Phase on	SNRS scale combines various elements of a neurological exam into a single number. The scale ranges from 100 to 0, where 100 marks no disability and 0 marks maximum disability. SNRS was assessed at month -12, -6, and 0 for the baseline phase and at month 0, 6, 12, 18, and 24 for the treatment phase. The progression rate was calculated as a difference between baseline and treatment slopes using a piecewise linear mixed-effect model with breaking point at month 0.	1-year pre-treatment baseline vs 2-year treatment period
Change in Slopes of EDSS From Baseline to Treatment Phase	EDSS scale combines various elements of neurological exam. EDSS is a discrete scale ranging from 0 to 10 with 0.5 point increments. EDSS of 0 means no neurological disability, while EDSS of 10 marks death due to MS. EDSS was assessed at month -12, -6, and 0 for the baseline phase and at month 0, 6, 12, 18, and 24 for the treatment phase.The progression rate was calculated as a difference between baseline and treatment slopes using a piecewise linear mixed-effect model with breaking point at month 0.	1-year pre-treatment baseline vs 2-year treatment period

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Principal Investigator: Bibiana Bielekova, M.D., National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

General Publications

• 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.
• Hartung HP, Aktas O. Bleak prospects for primary progressive multiple sclerosis therapy: downs and downs, but a glimmer of hope. Ann Neurol. 2009 Oct;66(4):429-32. doi: 10.1002/ana.21880. No abstract available.
• 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.
• Bieniek M, Altmann DR, Davies GR, Ingle GT, Rashid W, Sastre-Garriga J, Thompson AJ, Miller DH. Cord atrophy separates early primary progressive and relapsing remitting multiple sclerosis. J Neurol Neurosurg Psychiatry. 2006 Sep;77(9):1036-9. doi: 10.1136/jnnp.2006.094748. Epub 2006 Jun 22.
• Kosa P, Ghazali D, Tanigawa M, Barbour C, Cortese I, Kelley W, Snyder B, Ohayon J, Fenton K, Lehky T, Wu T, Greenwood M, Nair G, Bielekova B. Development of a Sensitive Outcome for Economical Drug Screening for Progressive Multiple Sclerosis Treatment. Front Neurol. 2016 Aug 15;7:131. doi: 10.3389/fneur.2016.00131. eCollection 2016.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2009
• Primary Completion (Actual): April 30, 2018
• Study Completion (Actual): August 6, 2018

Study Registration Dates

• First Submitted: July 30, 2009
• First Submitted That Met QC Criteria: July 30, 2009
• First Posted (Estimate): July 31, 2009

Study Record Updates

• Last Update Posted (Actual): March 19, 2019
• Last Update Submitted That Met QC Criteria: March 6, 2019
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Multiple Sclerosis; MS; Magnetic Resonance Spectroscopy; Magnetic Resonance Imaging (MRI); Primary Progressive Multiple Sclerosis; Idebenone; Mitochondrial Enhancer
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Antioxidants; Idebenone
• Other Study ID Numbers: 090197; 09-I-0197 (Other Identifier: NIH); NCT00950248 (Registry Identifier: clinicaltrials.gov)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: raw data will be shared as supplementary material in publication
• IPD Sharing Time Frame: available at the time of publication
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes