Amyotrophic Lateral Sclerosis, Lou Gehrig's Disease
Conditions
Keywords
amyotrophic lateral sclerosis, ALS, Lou Gehrig's disease, CoQ10, coenzyme Q10, antioxidants, free radicals, mitochondrial dysfunction
Brief summary
The purpose of this study is to determine the efficacy and preferred dose of CoQ10 in individuals with ALS for a possible future phase III study.
Detailed description
Amyotrophic lateral sclerosis (ALS) is a progressive and devastating neurodegenerative disorder. Available treatment for ALS remains scarce. Oxidative stress and mitochondrial dysfunction have been implicated in the pathophysiology of ALS. Oxidative stress refers to the effects of cell-damaging reactive oxygen species, also known as free radicals. Oxidative stress is thought to contribute to nerve cell loss in ALS. Mitochondria are organelles within each cell that are sometimes called powerhouses of the cell because cellular energy metabolism is located within the mitochondria. Coenzyme Q10 (CoQ10), a mitochondrial cofactor known for its antioxidant properties, has prolonged survival in the mouse model of ALS and has slowed functional decline in another neurodegenerative disorder, Parkinson's disease. The goals of this double-blind, placebo-controlled, two-dose comparison phase II study are to obtain preliminary efficacy data and to select the preferred dose for a larger phase III study. Participants were randomly assigned to CoQ10 (at two different dose levels) or placebo in the first stage, then the 2,700 mg dose was selected in the second stage. Duration of the trial was 9 months with a total of 7 visits.
Interventions
DRUGcoenzyme Q10
antioxidant and mitochondrial cofactor, given in capsules three times daily
DRUGPlacebo
Placebo capsules, indistinguishable from CoQ10 capsules, given three times daily
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Columbia University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Clinical diagnosis of definite, probable, or laboratory-supported probable ALS * Negative pregnancy test for women of childbearing age and adequate birth control measures * Subjects must be able and willing to give informed consent and must be capable of complying with the trial procedures * Forced Vital Capacity (FVC) \>/= 60% of predicted * Age 21 to 85 years, inclusive * Disease duration of less than 5 years * Subjects may take riluzole (without change in dose for more than 30 days before enrollment) * Patients who have taken CoQ10 in the past will be eligible if they stop at least 30 days before enrollment * Patients who have taken vitamin E in the past will be eligible if they stop at least 14 days before enrollment
Exclusion criteria
* Dependency on mechanical ventilation (non-invasive ventilation \> 23 hours) * Severe and unstable concomitant medical or psychiatric illness * Insufficiently controlled diabetes mellitus * Concomitant warfarin therapy * Women who are breast feeding or have a high likelihood of pregnancy * Significant hepatic dysfunction * Forced Vital Capacity (FVC) less than 60% * Exposure to CoQ10 within 30 days of enrollment * Exposure to other experimental medications within 30 days of enrollment * Exposure to vitamin E within 14 days of enrollment * Sensitivity to color additive FD&C Yellow No. 5 * Sensitivity to aspirin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the ALS Functional Rating Scale-revised (ALSFRSr) Score. | 9 months | The ALSFRSr, a questionnaire-based scale assessing daily living function ranging from 48 (best score) to 0 (worst), was administered to the patient, or to a proxy if the patient could not communicate effectively. Decline was defined as ALSFRSr at baseline minus ALSFRSr at month 9. Thus a positive value indicates worsening. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Fatigue Severity Scale | 9 months | The change over 9 months in fatigue severity scale. A 9-item scale measuring the impact of fatigue. Scores range from 7 (strongly disagree)-63 (strongly agree) with higher scores indicating a worse outcome. |
| Change in Forced Vital Capacity | 9 months | The change over 9 months in forced vital capacity is the volume (liters) of gas that can be exhaled by maximum voluntary effort following deep inspiration. The best of three trials will be recorded. The result is recorded as percentage of predicted for age, height and weight. |
| Change in Short Form (SF)-36 Score (Physical) | 9 months | The change over 9 months in SF-36 score, which is a quality of life measure. Scores range from 0-100 with a higher score indicating a better outcome. |
| Change in Short Form (SF)-36 Score (Mental) | 9 months | The change over 9 months in SF-36 score, which is a quality of life measure. Scores range from 0-100 with a higher score indicating a better outcome. |
Countries
United States
Participant flow
Recruitment details
Subjects were randomized between April, 2005 and May, 2007. The last participant completed the trial March 2008.
Pre-assignment details
Exclusion criteria were forced vital capacity (FVC) of less than 60%, severe medical illness, or disease onset more than 5 years before study entry.
Participants by arm
| Arm | Count |
|---|---|
| 2700mg CoQ10 35 subjects from stage 1 + 40 new subjects; all taking 2,700mg CoQ10 - total 75. | 75 |
| Placebo 35 subjects from stage 1 + 40 new subjects; all receiving placebo - total 75. | 75 |
| 1,800 mg CoQ10 35 patients. This dose group was discontinued after stage 1; only the 2,700 mg group was compared with placebo in the efficacy analysis. | 35 |
| Total | 185 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Stage 1: Dose Selection | Lost to Follow-up | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | 1,800 mg CoQ10 | Total | 2700mg CoQ10 |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 13 Participants | 12 Participants | 38 Participants | 13 Participants |
| Age, Categorical Between 18 and 65 years | 62 Participants | 23 Participants | 147 Participants | 62 Participants |
| Age, Continuous | 56.9 years STANDARD_DEVIATION 11 | 58.9 years STANDARD_DEVIATION 12.5 | 56.9 years STANDARD_DEVIATION 11.2 | 56 years STANDARD_DEVIATION 10.8 |
| Region of Enrollment United States | 75 participants | 35 participants | 185 participants | 75 participants |
| Sex: Female, Male Female | 29 Participants | 10 Participants | 74 Participants | 35 Participants |
| Sex: Female, Male Male | 46 Participants | 25 Participants | 111 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 63 / 75 | 64 / 75 | 35 / 35 |
| serious Total, serious adverse events | 18 / 75 | 19 / 75 | 10 / 35 |
Outcome results
Primary
Change in the ALS Functional Rating Scale-revised (ALSFRSr) Score.
The ALSFRSr, a questionnaire-based scale assessing daily living function ranging from 48 (best score) to 0 (worst), was administered to the patient, or to a proxy if the patient could not communicate effectively. Decline was defined as ALSFRSr at baseline minus ALSFRSr at month 9. Thus a positive value indicates worsening.
Time frame: 9 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 2700mg CoQ10 | Change in the ALS Functional Rating Scale-revised (ALSFRSr) Score. | 8.80 units on a scale | Standard Deviation 7.34 |
| Placebo | Change in the ALS Functional Rating Scale-revised (ALSFRSr) Score. | 9.44 units on a scale | Standard Deviation 8.82 |
| 1,800 mg CoQ10 | Change in the ALS Functional Rating Scale-revised (ALSFRSr) Score. | 10.9 units on a scale | Standard Deviation 9.3 |
Comparison: Null hypothesis: 2,700mg CoQ10 is at least 20% superior to placebo.p-value: 0.14futility (non-superiority)
Secondary
Change in Fatigue Severity Scale
The change over 9 months in fatigue severity scale. A 9-item scale measuring the impact of fatigue. Scores range from 7 (strongly disagree)-63 (strongly agree) with higher scores indicating a worse outcome.
Time frame: 9 months
Population: 1,800 mg CoQ10 group was not included in the efficacy analysis because the 1,800 mg dose was discontinued after stage 1.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 2700mg CoQ10 | Change in Fatigue Severity Scale | 0.71 score on a scale | Standard Deviation 1.21 |
| Placebo | Change in Fatigue Severity Scale | 0.88 score on a scale | Standard Deviation 1.51 |
Secondary
Change in Forced Vital Capacity
The change over 9 months in forced vital capacity is the volume (liters) of gas that can be exhaled by maximum voluntary effort following deep inspiration. The best of three trials will be recorded. The result is recorded as percentage of predicted for age, height and weight.
Time frame: 9 months
Population: 1,800 mg CoQ10 group was not included in the efficacy analysis because the 1,800 mg dose was discontinued after stage 1.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 2700mg CoQ10 | Change in Forced Vital Capacity | 0.20 Percent of Predicted | Standard Deviation 0.15 |
| Placebo | Change in Forced Vital Capacity | 0.17 Percent of Predicted | Standard Deviation 0.18 |
Secondary
Change in Short Form (SF)-36 Score (Mental)
The change over 9 months in SF-36 score, which is a quality of life measure. Scores range from 0-100 with a higher score indicating a better outcome.
Time frame: 9 months
Population: 1,800 mg CoQ10 group was not included in the efficacy analysis because the 1,800 mg dose was discontinued after stage 1.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 2700mg CoQ10 | Change in Short Form (SF)-36 Score (Mental) | 2.87 score on a scale | Standard Deviation 11.78 |
| Placebo | Change in Short Form (SF)-36 Score (Mental) | 5.01 score on a scale | Standard Deviation 11.69 |
Secondary
Change in Short Form (SF)-36 Score (Physical)
The change over 9 months in SF-36 score, which is a quality of life measure. Scores range from 0-100 with a higher score indicating a better outcome.
Time frame: 9 months
Population: 1,800 mg CoQ10 group was not included in the efficacy analysis because the 1,800 mg dose was discontinued after stage 1.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 2700mg CoQ10 | Change in Short Form (SF)-36 Score (Physical) | 4.22 score on a scale | Standard Deviation 8.02 |
| Placebo | Change in Short Form (SF)-36 Score (Physical) | 6.04 score on a scale | Standard Deviation 6.85 |