Idebenone for Primary Progressive Multiple Sclerosis

• ClinicalTrials.gov Identifier: NCT01854359
• Recruitment Status: Completed
• First Posted: May 15, 2013
• Results First Posted: May 19, 2021
• Last Update Posted: May 19, 2021
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Tracking Information

• First Submitted Date: May 11, 2013
• First Posted Date: May 15, 2013
• Results First Submitted Date: October 30, 2019
• Results First Posted Date: May 19, 2021
• Last Update Posted Date: May 19, 2021
• Actual Study Start Date: March 12, 2013
• Actual Primary Completion Date: October 31, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 27, 2021)

Area Under the Curve (AUC) of the Combinatorial Weight-Adjusted Disability Score (CombiWISE) [ Time Frame: 1-year pre-treatment baseline vs 2-year randomized double-blind phased vs 1-year treatment period ]

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 study groups (Active treatment group in the 09-I-0197 trial and Placebo group in the 09-I-0197) as follows:

1. pre-treatment baseline during the 09-I-0197 trial (from Months -12, -6, and 0)
2. double-blind phase during the 09-I-0197 trial (from Months 0, 6, 12, 18, and 24)
3. extension phase during the 13-I-0088 trial (from Months 24, 30, and 36)

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.

• Original Primary Outcome Measures (submitted: May 11, 2013): The primary outcome measure that comes out of the pre-determined analysis in the IPPoMS trial will be adopted as primary outcome measure in the IPPoMS-E trial. [ Time Frame: month 30 and 36 ]

Current Secondary Outcome Measures (submitted: April 27, 2021)

• Slopes of 25 Foot Walk (25FW) Time [ Time Frame: 3-years double-blind phase and 1-year extension phase ]
  slopes of measured times of 25FW during the 3-year 09-I-0197 trial (one year of pre-treatment baseline and two years of double-blind randomized treatment) and during one year extension phase of the 13-I-0088 trial. The slopes were measured separately for placebo and active treatment arm as randomized in the the 09-I-0197 trial. Lower extremity disability was measured by an average of two trials of timed 25 foot walk assessed every 6 month. 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"
• Slopes of 9 Hole Peg Test (9HPT) Time [ Time Frame: 3-years double-blind phase and 1-year extension phase ]
  Slopes of measured times of 9HPT during the 3-year 09-I-0197 trial (one year of pre-treatment baseline and two years of double-blind randomized treatment) and during one year extension phase of the 13-I-0088 trial. The slopes were measured separately for placebo and active treatment arm as randomized in the the 09-I-0197 trial. 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 every 6 months.
• Slopes of Expanded Disability Status Scale (EDSS) Score [ Time Frame: 3-years double-blind phase and 1-year extension phase ]
  Slopes of measured EDSS scores during the 3-year 09-I-0197 trial (one year of pre-treatment baseline and two years of double-blind randomized treatment) and during one year extension phase of the 13-I-0088 trial. The slopes were measured separately for placebo and active treatment arm as randomized in the the 09-I-0197 trial. 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 Multiple Sclerosis (MS). EDSS was assessed every 6 months.
• Change in Slopes of Scripps Neurological Rating Scale (SNRS) Score [ Time Frame: 3-years double-blind phase and 1-year extension phase ]
  Slopes of measured SNRS scores during the 3-year 09-I-0197 trial (one year of pre-treatment baseline and two years of double-blind randomized treatment) and during one year extension phase of the 13-I-0088 trial. The slopes were measured separately for placebo and active treatment arm as randomized in the the 09-I-0197 trial. 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 every 6 months.

• Original Secondary Outcome Measures (submitted: May 11, 2013): Neuroimaging, Clinical/functional, and biological/immunological outcomes include: Inhibition of the rates of development of brain atrophy, increased ventricular volume, SC atrophy.; Progression of neuro disability; Analysis of changes in CSF [ Time Frame: month 30 and 36 ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Idebenone for Primary Progressive Multiple Sclerosis
• Official Title: Open Label Extension Trial of Idebenone for Primary Progressive Multiple Sclerosis

Brief Summary

Background:

- The Idebenone in Patients With Primary Progressive Multiple Sclerosis (IPPoMS) trial tested a new drug for multiple sclerosis. In the IPPoMS trial, participants took either idebenone or placebo. Researchers want to give idebenone to all participants for 1 year. It is still not certain whether idebenone can slow the progression of multiple sclerosis, but this study may help answer that question.

Objectives:

• To provide idebenone to all participants on the IPPoMS trial.
• To collect data on the safety and effectiveness of idebenone for primary progressive multiple sclerosis.

Eligibility:

- Individuals at least 18 years of age who have completed 3 years in the IPPoMS trial.

Design:

• The first study visit for this trial will happen on the same day as the last visit for the IPPoMS trial.
• Participants will provide a blood samples and will have a lumbar puncture. They will also receive a new supply of idebenone to take three times a day with food. They will keep a diary to report on any side effects.
• After this first treatment visit, participants will have two follow-up visits to the NIH 6 months apart. These visits may be scheduled over multiple days. Participants will provide blood and urine samples. They will also have imaging studies of the brain and spine.
• Participants will have phone calls with the study researchers to provide updates on their condition and any side effects.

Detailed Description

OBJECTIVE:

A Phase I/II clinical trial is being conducted to investigate the safety, therapeutic efficacy and mechanism of action of idebenone in primary-progressive multiple sclerosis (PP-MS) patients (IPPoMS (Protocol Number 09-N-0197). Patients who have completed the 2-year treatment period of IPPoMS, may enter into this open-label extension study (IPPoMS-E) if they are found to be eligible by the Investigator and desire treatment with idebenone despite remaining blinded as to their allocation to active treatment versus placebo during the IPPoMS trial. The aim of this open-label extension study is gather additional data on safety, efficacy and effects of idebenone on cerebrospinal fluid (CSF) biomarkers in these patients over a period of 1 year. This study will provide open-label idebenone for patients with PP-MS, previously randomized to idebenone or to placebo in the blinded phase of IPPoMS.

STUDY POPULATION:

Patients who were previously enrolled in the IPPoMS (Protocol Number 09-N-0197) will be invited to participate in the trial. The same idebenone dose used in the randomized clinical trial (2250 mg/day) will be used in this study.

DESIGN:

This is a single group, open-label safety and efficacy extension trial with a one year treatment period. Patient-specific biomarkers of disease progression, CSF biomarkers of oxidative stress, longitudinal neuroimaging including quantitative measures of CNS tissue destruction and clinical data will be collected as in the randomized study.

OUTCOME MEASURES:

The measurement and collection of data will be performed as in the randomized trial. Quantitative neuroimaging measures of central nervous system (CNS: i.e. brain and spinal cord) tissue destruction and clinical and functional 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 primary outcome measure defined in the IPPoMS trial will be also utilized in IPPoMS-E. For patients originally randomized to placebo, patient-specific slopes of disease progression during 2 years of placebo therapy (as measured by primary and secondary outcomes) will be compared to patient-specific slopes of disease progression during 1 year of open label idebenone therapy. Combination of IPPoMS and IPPoMS-E trials will significantly expand paired no therapy vs. idebenone therapy CSF samples for biomarker studies. It will also provide (for the subgroup of subjects who were originally randomized to idebenone) longitudinal CSF samples on idebenone therapy (collected 2 years apart). This will allow calculations of intra-individual changes in CSF biomarkers on and off idebenone therapy, which may provide important insight into the mechanism of action of idebenone in PP-MS.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Multiple Sclerosis
• Primary Progressive Multiple Sclerosis

• Intervention: Drug: Idebenone

Study Arms

Active treatment

Idebenone (150mg tablets) administered orally as five tablets, three times per day with food.

Intervention: Drug: Idebenone

Publications *

• Albrecht P, Ringelstein M, Muller AK, Keser N, Dietlein T, Lappas A, Foerster A, Hartung HP, Aktas O, Methner A. Degeneration of retinal layers in multiple sclerosis subtypes quantified by optical coherence tomography. Mult Scler. 2012 Oct;18(10):1422-9. doi: 10.1177/1352458512439237. Epub 2012 Mar 2.
• Andrews HE, Nichols PP, Bates D, Turnbull DM. Mitochondrial dysfunction plays a key role in progressive axonal loss in Multiple Sclerosis. Med Hypotheses. 2005;64(4):669-77. doi: 10.1016/j.mehy.2004.09.001.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 3, 2018): 61
• Original Estimated Enrollment (submitted: May 11, 2013): 80
• Actual Study Completion Date: October 31, 2018
• Actual Primary Completion Date: October 31, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

• INCLUSION CRITERIA:
• Completion of 3 years in study IPPoMS (Protocol Number 09-N-0197)
• Able to provide informed consent
• Adults, at least 18 years of age
• Willing to participate in all aspects of trial design and follow-up
• 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)) for the duration of treatment arm of the study

EXCLUSION CRITERIA:

• Pregnant or lactating women. All women of child-bearing potential must have a negative pregnancy test
• Patients dropping out of IPPoMS due to adverse events (AE) considered related to study medication

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01854359
• Other Study ID Numbers: 130088; 13-I-0088
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes

• IPD Sharing Statement: Not Provided
• Current Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
• Original Responsible Party: National Institute of Neurological Disorders and Stroke (NINDS)
• Current Study Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Original Study Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)
• Collaborators: Not Provided

Investigators

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

• PRS Account: National Institutes of Health Clinical Center (CC)
• Verification Date: October 2018