MELAS Syndrome
Conditions
Brief summary
The purpose of this study is to compare the efficacy of two (2) different doses of idebenone with that of a placebo over a one month period on cerebral lactate concentration as measured by magnetic resonance spectroscopy.
Detailed description
MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes), a progressive and often devastating multisystem disorder, is most commonly associated with mitochondrial Deoxyribonucleic acid (mtDNA) point mutation at nucleotide 3243. Seizures, cognitive deterioration, and neurobehavioral abnormalities are frequent features of this disease which typically shortens life expectancy. Idebenone, an ATP production modulator and antioxidant, improves neurological function in Friedreich's ataxia, a disease also associated with mitochondrial dysfunction. Given that there is no effective treatment for MELAS, the investigators propose a Phase II proof of concept trial of idebenone to study its preliminary efficacy in patients with MELAS and the A3243G mtDNA mutation, and to study its safety and tolerability in this patient group. The investigators propose to evaluate 21 patients with the A3243G mitochondrial DNA mutation and MELAS (defined by a history of either seizures or stroke). Patients will receive idebenone (900 mg/day or 2250 mg/day) or matching placebo for one month. The primary outcome measure is cerebral lactate levels measured by Magnetic Resonance Spectroscopy (MRS), a biomarker associated with disease worsening. This study will help the investigators to determine if there is sufficient signal to proceed to efficacy studies. Also it will provide additional information on the safety and tolerability of two different doses of idebenone in MELAS.
Interventions
DRUGIdebenone
900 mg/day for 1 month
OTHERPlacebo
Placebo - No idebenone
Sponsors
Santhera Pharmaceuticals
Michio Hirano
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
8 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of MELAS with confirmed A3243G mtDNA mutation, or evidence of central nervous system involvement (cognitive problems, migraines, memory loss) * Cerebral lactate level equal to or greater than 5.0 i.u. at baseline * Patients at least 8 and \< 65 years of age at baseline * Patients with a body weight \> 37 kg/82 lbs at baseline * Stable co-medication/vitamins/supplements within 1 month prior to baseline * Patients who in the opinion of the investigator are able to comply with the requirements of the study, including swallowing the study medication * Negative urine pregnancy test at screening and baseline (female patients of childbearing potential)
Exclusion criteria
* Contraindication to MRS (e.g. metal implant, claustrophobia) * Stroke like event within 2 months prior to baseline * Treatment with idebenone at any dose, or coenzyme Q10 at doses above 100mg/d within 1 month prior to baseline * Inadequate contraception use * Pregnancy and/or breast-feeding * Clinically significant abnormalities of clinical hematology or biochemistry including, but not limited to, elevations greater than 1.5 times the upper limit of normal of aspartate aminotransferase (AST), alanine aminotransferase (ALT) or creatinine * Current abuse of drugs or alcohol * Participation in a trial of another investigational drug within the last month * Other factor that, in the investigator's opinion, excludes the patient from entering the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Cerebral Lactate Concentration (as Measured by Magnetic Resonance Spectroscopy) | Up to 4 weeks from baseline | To compare the efficacy of 1 month treatment with 2 different doses of idebenone with that of placebo on cerebral lactate concentration as measured by magnetic resonance spectroscopy (MRS) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Venous Lactate Concentration | Up to 4 weeks from baseline | To compare the efficacy of 1 month treatment with 2 different doses of idebenone with that of placebo on venous lactate concentration |
| Mean Change in Score on the Fatigue Severity Scale (FSS) | Baseline and Week 4 | To assess changes following 1 month treatment with 2 different doses of idebenone with that of placebo in fatigue as assessed by the Fatigue Severity Scale (FSS). Scale score minimum is 9 (least fatigue) and maximum is 63 (maximum fatigue). Scores of 36 or less indicate possibility that patient may not be suffering from fatigue, while scores 36 and over suggest suffering from fatigue |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Idebenone 900 mg/Day Idebenone 900 mg/day
Idebenone: 900 mg/day for 1 month | 10 |
| Idebenone 2250 mg/Day Idebenone 2250 mg/day
Idebenone: 2250 mg/day for one month | 9 |
| Placebo Placebo
Placebo: Placebo - No idebenone | 8 |
| Total | 27 |
Baseline characteristics
| Characteristic | Idebenone 900 mg/Day | Idebenone 2250 mg/Day | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 9 Participants | 8 Participants | 26 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 8 Participants | 8 Participants | 23 Participants |
| Region of Enrollment United States | 10 participants | 9 participants | 8 participants | 27 participants |
| Sex: Female, Male Female | 9 Participants | 5 Participants | 6 Participants | 20 Participants |
| Sex: Female, Male Male | 1 Participants | 4 Participants | 2 Participants | 7 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 | 10 / 10 | 9 / 9 | 8 / 8 |
| serious Total, serious adverse events | 0 / 10 | 0 / 9 | 0 / 8 |
Outcome results
Primary
Mean Change in Cerebral Lactate Concentration (as Measured by Magnetic Resonance Spectroscopy)
To compare the efficacy of 1 month treatment with 2 different doses of idebenone with that of placebo on cerebral lactate concentration as measured by magnetic resonance spectroscopy (MRS)
Time frame: Up to 4 weeks from baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Idebenone 900 mg/Day | Mean Change in Cerebral Lactate Concentration (as Measured by Magnetic Resonance Spectroscopy) | -0.09 IU | Standard Deviation 0.95 |
| Idebenone 2250 mg/Day | Mean Change in Cerebral Lactate Concentration (as Measured by Magnetic Resonance Spectroscopy) | 0.16 IU | Standard Deviation 1.49 |
| Placebo | Mean Change in Cerebral Lactate Concentration (as Measured by Magnetic Resonance Spectroscopy) | -0.49 IU | Standard Deviation 1.18 |
Secondary
Mean Change in Score on the Fatigue Severity Scale (FSS)
To assess changes following 1 month treatment with 2 different doses of idebenone with that of placebo in fatigue as assessed by the Fatigue Severity Scale (FSS). Scale score minimum is 9 (least fatigue) and maximum is 63 (maximum fatigue). Scores of 36 or less indicate possibility that patient may not be suffering from fatigue, while scores 36 and over suggest suffering from fatigue
Time frame: Baseline and Week 4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Idebenone 900 mg/Day | Mean Change in Score on the Fatigue Severity Scale (FSS) | -3.8 units on a scale | Standard Deviation 11 |
| Idebenone 2250 mg/Day | Mean Change in Score on the Fatigue Severity Scale (FSS) | -1.3 units on a scale | Standard Deviation 10 |
| Placebo | Mean Change in Score on the Fatigue Severity Scale (FSS) | 4.3 units on a scale | Standard Deviation 4.5 |
Secondary
Mean Change in Venous Lactate Concentration
To compare the efficacy of 1 month treatment with 2 different doses of idebenone with that of placebo on venous lactate concentration
Time frame: Up to 4 weeks from baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Idebenone 900 mg/Day | Mean Change in Venous Lactate Concentration | -0.24 mM/L | Standard Deviation 1.18 |
| Idebenone 2250 mg/Day | Mean Change in Venous Lactate Concentration | 0.7 mM/L | Standard Deviation 1.31 |
| Placebo | Mean Change in Venous Lactate Concentration | -0.46 mM/L | Standard Deviation 1.07 |