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| ID | Type | Description | Link |
|---|---|---|---|
| 13-I-0088 |
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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:
Eligibility:
- Individuals at least 18 years of age who have completed 3 years in the IPPoMS trial.
Design:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Active treatment | Other | Idebenone (150mg tablets) administered orally as five tablets, three times per day with food. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Idebenone | Drug |
|
| Measure | Description | Time Frame |
|---|---|---|
| Area Under the Curve (AUC) of the Combinatorial Weight-Adjusted Disability Score (CombiWISE) | 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:
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 randomized double-blind phased vs 1-year treatment period |
| Measure | Description | Time Frame |
|---|---|---|
| Slopes of 25 Foot Walk (25FW) Time | 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" |
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EXCLUSION CRITERIA:
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| 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 |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22389411 | Background | 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. | |
| 15694681 | Background |
| Label | URL |
|---|---|
| NIH Clinical Center Detailed Web Page | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Active Treatment in 09-I-0197 | Idebenone (150mg tablets) administered orally as five tablets, three times per day with food. This group completed a total of 3 years of Idebenone treatment |
| FG001 | Placebo in 09-I-0197 | Idebenone (150mg tablets) administered orally as five tablets, three times per day with food. This group completed a total of 1 year of Idebenone treatment (following 2 years of placebo treatment in the 09-I-0198 trial). |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Active Treatment in 09-I-0197 | Idebenone (150mg tablets) administered orally as five tablets, three times per day with food. This group completed a total of 3 years of Idebenone treatment. |
| BG001 | Placebo in 09-I-0197 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| 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 | Area Under the Curve (AUC) of the Combinatorial Weight-Adjusted Disability Score (CombiWISE) | 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:
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. | 61 subjects that completed three year 09-I-0197 trial enrolled into the one year open-label extension phase of the 13-I-0088. Out of the 61 subjects, 31 were assigned to the active treatment group in the 09-I-0197 trial and 30 received placebo. The 09-I-1097 consisted of one-year pre-treatment baseline and 2 years of double-blind treatment phase. | Posted | Mean | Standard Deviation | units on a scale * year | 1-year pre-treatment baseline vs 2-year randomized double-blind phased vs 1-year treatment period |
1 year
Adverse events are collected on 61 patients enrolled in the 1-year open-label phase
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Active Treatment in 09-I-0197 | Idebenone (150mg tablets) administered orally as five tablets, three times per day with food. Two years of Idebenone treatment during the 09-I-0197 double-blind phase |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Elevated liver enzynes | Blood and lymphatic system disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| back pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Peter Kosa (Staff Scientist) | National Institutes of Allergy and Infectious Diseases | (301) 731-6444 | peter.kosa@nih.gov |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 1, 2018 | Oct 30, 2019 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D009103 | Multiple Sclerosis |
| D020528 | Multiple Sclerosis, Chronic Progressive |
| ID | Term |
|---|---|
| D020278 | Demyelinating Autoimmune Diseases, CNS |
| D020274 | Autoimmune Diseases of the Nervous System |
| D009422 | Nervous System Diseases |
| D003711 | Demyelinating Diseases |
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| ID | Term |
|---|---|
| C036619 | idebenone |
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| 3-years double-blind phase and 1-year extension phase |
| Slopes of 9 Hole Peg Test (9HPT) Time | 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. | 3-years double-blind phase and 1-year extension phase |
| Slopes of Expanded Disability Status Scale (EDSS) Score | 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. | 3-years double-blind phase and 1-year extension phase |
| Change in Slopes of Scripps Neurological Rating Scale (SNRS) Score | 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. | 3-years double-blind phase and 1-year extension phase |
| 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. |
| 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. |
Idebenone (150mg tablets) administered orally as five tablets, three times per day with food.
This group completed a total of 1 year of Idebenone treatment (following 2 years of placebo treatment in the 09-I-0197 trial)
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
|
|
|
| Secondary | Slopes of 25 Foot Walk (25FW) Time | 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" | 61 subjects that completed three year 09-I-0197 trial enrolled into the one year open-label extension phase of the 13-I-0088. Out of the 61 subjects, 31 were assigned to the active treatment group in the 09-I-0197 trial and 30 received placebo. The 09-I-1097 consisted of one-year pre-treatment baseline and 2 years of double-blind treatment phase. | Posted | Mean | Standard Error | seconds per year | 3-years double-blind phase and 1-year extension phase |
|
|
|
| Secondary | Slopes of 9 Hole Peg Test (9HPT) Time | 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. | 61 subjects that completed three year 09-I-0197 trial enrolled into the one year open-label extension phase of the 13-I-0088. Out of the 61 subjects, 31 were assigned to the active treatment group in the 09-I-0197 trial and 30 received placebo. The 09-I-1097 consisted of one-year pre-treatment baseline and 2 years of double-blind treatment phase. | Posted | Mean | Standard Error | seconds per year | 3-years double-blind phase and 1-year extension phase |
|
|
|
| Secondary | Slopes of Expanded Disability Status Scale (EDSS) Score | 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. | 61 subjects that completed three year 09-I-0197 trial enrolled into the one year open-label extension phase of the 13-I-0088. Out of the 61 subjects, 31 were assigned to the active treatment group in the 09-I-0197 trial and 30 received placebo. The 09-I-1097 consisted of one-year pre-treatment baseline and 2 years of double-blind treatment phase. | Posted | Mean | Standard Error | score on a scale per year | 3-years double-blind phase and 1-year extension phase |
|
|
|
| Secondary | Change in Slopes of Scripps Neurological Rating Scale (SNRS) Score | 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. | 61 subjects that completed three year 09-I-0197 trial enrolled into the one year open-label extension phase of the 13-I-0088. Out of the 61 subjects, 31 were assigned to the active treatment group in the 09-I-0197 trial and 30 received placebo. The 09-I-1097 consisted of one-year pre-treatment baseline and 2 years of double-blind treatment phase. | Posted | Mean | Standard Error | score on a scale per year | 3-years double-blind phase and 1-year extension phase |
|
|
|
| 0 |
| 31 |
| 4 |
| 31 |
| 10 |
| 31 |
| EG001 | Placebo in 09-I-0197 | Idebenone (150mg tablets) administered orally as five tablets, three times per day with food. Two years of placebo during the 09-I-0197 double-blind phase | 0 | 30 | 4 | 30 | 14 | 30 |
| Myocardial infarction | Cardiac disorders | Systematic Assessment |
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| decreased ejection fraction | Cardiac disorders | Systematic Assessment |
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| stomach cancer | Gastrointestinal disorders | Systematic Assessment |
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| severe constipation | Gastrointestinal disorders | Systematic Assessment |
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| gallstones | Hepatobiliary disorders | Systematic Assessment |
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| ruptured apendix | Infections and infestations | Systematic Assessment |
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| broken ribs | Injury, poisoning and procedural complications | Systematic Assessment |
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| broken femur | Injury, poisoning and procedural complications | Systematic Assessment |
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| chest tightness | Cardiac disorders | Systematic Assessment |
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| basal cell carcinoma | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| benign thyroid nodule | Endocrine disorders | Systematic Assessment |
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| cellulitis | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| chest pain | Cardiac disorders | Systematic Assessment |
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| dehydration | Metabolism and nutrition disorders | Systematic Assessment |
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| diarrhea | Gastrointestinal disorders | Systematic Assessment |
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| edema | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| fall | Injury, poisoning and procedural complications | Systematic Assessment |
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| fractured bone | Injury, poisoning and procedural complications | Systematic Assessment |
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| H1N1 influenza | Infections and infestations | Systematic Assessment |
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| hair loss | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| hypertension | Cardiac disorders | Systematic Assessment |
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| increased mobility problems | General disorders | Systematic Assessment |
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| injured meniscus | Injury, poisoning and procedural complications | Systematic Assessment |
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| nausea | Gastrointestinal disorders | Systematic Assessment |
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| penumonia | Infections and infestations | Systematic Assessment |
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| radiculopathy | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| retinal detachment | Eye disorders | Systematic Assessment |
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| skin rash | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| transient graying of vision | Eye disorders | Systematic Assessment |
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| urinary tract infection | Infections and infestations | Systematic Assessment |
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| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |