Multiple Sclerosis, Primary Progressive Multiple Sclerosis
Conditions
Keywords
Multiple Sclerosis, Extension Trial
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.
Interventions
DRUGIdebenone
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve (AUC) of the Combinatorial Weight-Adjusted Disability Score (CombiWISE) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Slopes of 25 Foot Walk (25FW) Time | 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 | 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 | 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 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 31 |
| 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-0197 trial) | 30 |
| Total | 61 |
Baseline characteristics
| Characteristic | Placebo in 09-I-0197 | Total | Active Treatment in 09-I-0197 |
|---|---|---|---|
| Age, Continuous | 59.2 years STANDARD_DEVIATION 7.2 | 59.6 years STANDARD_DEVIATION 6.9 | 60.0 years STANDARD_DEVIATION 6.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 6 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 27 Participants | 55 Participants | 28 Participants |
| Sex: Female, Male Female | 17 Participants | 31 Participants | 14 Participants |
| Sex: Female, Male Male | 13 Participants | 30 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 30 |
| other Total, other adverse events | 10 / 31 | 14 / 30 |
| serious Total, serious adverse events | 4 / 31 | 4 / 30 |
Outcome results
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: 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.
Time frame: 1-year pre-treatment baseline vs 2-year randomized double-blind phased vs 1-year treatment period
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pre-treatment Baseline (Placebo Group) | Area Under the Curve (AUC) of the Combinatorial Weight-Adjusted Disability Score (CombiWISE) | 1.55 units on a scale * year | Standard Deviation 2.02 |
| Double-blind Phase (Placebo Group) | Area Under the Curve (AUC) of the Combinatorial Weight-Adjusted Disability Score (CombiWISE) | 0.80 units on a scale * year | Standard Deviation 1.96 |
| Extension Phase (Placebo Group) | Area Under the Curve (AUC) of the Combinatorial Weight-Adjusted Disability Score (CombiWISE) | 0.46 units on a scale * year | Standard Deviation 1.93 |
| Pre-treatment Baseline (Active Treatment Group) | Area Under the Curve (AUC) of the Combinatorial Weight-Adjusted Disability Score (CombiWISE) | 0.89 units on a scale * year | Standard Deviation 1.81 |
| Double-blind Phase (Active Treatment Group) | Area Under the Curve (AUC) of the Combinatorial Weight-Adjusted Disability Score (CombiWISE) | 0.75 units on a scale * year | Standard Deviation 1.82 |
| Extension Phase (Active Treatment Group) | Area Under the Curve (AUC) of the Combinatorial Weight-Adjusted Disability Score (CombiWISE) | 1.30 units on a scale * year | Standard Deviation 2.3 |
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.
Time frame: 3-years double-blind phase and 1-year extension phase
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pre-treatment Baseline (Placebo Group) | Change in Slopes of Scripps Neurological Rating Scale (SNRS) Score | -1.8838 score on a scale per year | Standard Error 0.4829 |
| Double-blind Phase (Placebo Group) | Change in Slopes of Scripps Neurological Rating Scale (SNRS) Score | -2.1655 score on a scale per year | Standard Error 1.0735 |
| Extension Phase (Placebo Group) | Change in Slopes of Scripps Neurological Rating Scale (SNRS) Score | -2.009 score on a scale per year | Standard Error 0.3789 |
| Pre-treatment Baseline (Active Treatment Group) | Change in Slopes of Scripps Neurological Rating Scale (SNRS) Score | -2.7263 score on a scale per year | Standard Error 1.0073 |
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
Time frame: 3-years double-blind phase and 1-year extension phase
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pre-treatment Baseline (Placebo Group) | Slopes of 25 Foot Walk (25FW) Time | 0.04322 seconds per year | Standard Error 0.009617 |
| Double-blind Phase (Placebo Group) | Slopes of 25 Foot Walk (25FW) Time | -0.00531 seconds per year | Standard Error 0.01599 |
| Extension Phase (Placebo Group) | Slopes of 25 Foot Walk (25FW) Time | 0.04031 seconds per year | Standard Error 0.0106 |
| Pre-treatment Baseline (Active Treatment Group) | Slopes of 25 Foot Walk (25FW) Time | 0.03401 seconds per year | Standard Error 0.01286 |
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.
Time frame: 3-years double-blind phase and 1-year extension phase
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pre-treatment Baseline (Placebo Group) | Slopes of 9 Hole Peg Test (9HPT) Time | 0.000665 seconds per year | Standard Error 0.000491 |
| Double-blind Phase (Placebo Group) | Slopes of 9 Hole Peg Test (9HPT) Time | 0.000947 seconds per year | Standard Error 0.001189 |
| Extension Phase (Placebo Group) | Slopes of 9 Hole Peg Test (9HPT) Time | 0.000718 seconds per year | Standard Error 0.000462 |
| Pre-treatment Baseline (Active Treatment Group) | Slopes of 9 Hole Peg Test (9HPT) Time | 0.001086 seconds per year | Standard Error 0.000614 |
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.
Time frame: 3-years double-blind phase and 1-year extension phase
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pre-treatment Baseline (Placebo Group) | Slopes of Expanded Disability Status Scale (EDSS) Score | 0.1447 score on a scale per year | Standard Error 0.05778 |
| Double-blind Phase (Placebo Group) | Slopes of Expanded Disability Status Scale (EDSS) Score | 0.1435 score on a scale per year | Standard Error 0.07625 |
| Extension Phase (Placebo Group) | Slopes of Expanded Disability Status Scale (EDSS) Score | 0.1107 score on a scale per year | Standard Error 0.03651 |
| Pre-treatment Baseline (Active Treatment Group) | Slopes of Expanded Disability Status Scale (EDSS) Score | 0.1584 score on a scale per year | Standard Error 0.09479 |