MELAS: Study of Idebenone in the Treatment of Mitochondrial Encephalopathy Lactic Acidosis & Stroke-like Episodes

• Sponsor: Michio Hirano (Other)
• Overall Status: Completed
• CT.gov ID: NCT00887562
• Collaborator: Santhera Pharmaceuticals (Industry)
• Enrollment: 27
• Location: 1
• Arms: 3
• Duration (Months): 38
• Patients Per Site Per Month: 0.7

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
MELAS Syndrome	Drug: Idebenone; Drug: Idebenone; Other: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase IIa Double-Blind, Randomized, Placebo-Controlled, Dose-Finding Study of Idebenone in the Treatment of Mitochondrial Encephalopathy Lactic Acidosis and Stroke-like Episodes
• Study Start Date: May 1, 2009
• Actual Primary Completion Date: Jul 1, 2012
• Actual Study Completion Date: Jul 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Idebenone 900 mg/day Idebenone 900 mg/day	Drug: Idebenone; 900 mg/day for 1 month; Other Names: active drug
Experimental: Idebenone 2250 mg/day Idebenone 2250 mg/day	Drug: Idebenone; 2250 mg/day for 1 month; Other Names: active drug
Placebo Comparator: placebo Placebo	Other: Placebo; Placebo - No idebenone; Other Names: No active drug

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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

2. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 8 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Columbia University Medical Center	New York	New York	United States	10032

Sponsors and Collaborators

• Michio Hirano
• Santhera Pharmaceuticals

Investigators

• Principal Investigator: Michio Hirano, MD, Columbia University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Michio Hirano, Professor of Neurology, Columbia University
• ClinicalTrials.gov Identifier: NCT00887562
• Other Study ID Numbers: AAAC9240; SNT-II-007
• First Posted: Apr 24, 2009
• Last Update Posted: Oct 26, 2016
• Last Verified: Sep 1, 2016

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: MELAS Syndrome; Brain Diseases; Acidosis; Acidosis, Lactic; Ubiquinone; Idebenone

Study Results

Participant Flow

Arm/Group Title	Idebenone 900 mg/Day	Idebenone 2250 mg/Day	Placebo
Arm/Group Description	Idebenone 900 mg/day Idebenone: 900 mg/day for 1 month	Idebenone 2250 mg/day Idebenone: 2250 mg/day for one month	Placebo Placebo: Placebo - No idebenone
Period Title: Overall Study
STARTED	10	9	8
COMPLETED	7	7	7
NOT COMPLETED	3	2	1

Baseline Characteristics

Arm/Group Title	Idebenone 900 mg/Day	Idebenone 2250 mg/Day	Placebo	Total
Arm/Group Description	Idebenone 900 mg/day Idebenone: 900 mg/day for 1 month	Idebenone 2250 mg/day Idebenone: 2250 mg/day for one month	Placebo Placebo: Placebo - No idebenone	Total of all reporting groups
Overall Participants	10	9	8	27
Age (Count of Participants)
<=18 years	1 10%	0 0%	0 0%	1 3.7%
Between 18 and 65 years	9 90%	9 100%	8 100%	26 96.3%
>=65 years	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	9 90%	5 55.6%	6 75%	20 74.1%
Male	1 10%	4 44.4%	2 25%	7 25.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	3 30%	0 0%	0 0%	3 11.1%
Asian	0 0%	1 11.1%	0 0%	1 3.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%
White	7 70%	8 88.9%	8 100%	23 85.2%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	10 100%	9 100%	8 100%	27 100%

Outcome Measures

1. Primary Outcome

Title	Mean Change in Cerebral Lactate Concentration (as Measured by Magnetic Resonance Spectroscopy)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Idebenone 900 mg/Day	Idebenone 2250 mg/Day	Placebo
Arm/Group Description	Idebenone 900 mg/day Idebenone: 900 mg/day for 1 month	Idebenone 2250 mg/day Idebenone: 2250 mg/day for one month	Placebo Placebo: Placebo - No idebenone
Measure Participants	7	7	7
Mean (Standard Deviation) [IU]	-0.09 (0.95)	0.16 (1.49)	-0.49 (1.18)

2. Secondary Outcome

Title	Mean Change in Venous Lactate Concentration
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Idebenone 900 mg/Day	Idebenone 2250 mg/Day	Placebo
Arm/Group Description	Idebenone 900 mg/day Idebenone: 900 mg/day for 1 month	Idebenone 2250 mg/day Idebenone: 2250 mg/day for one month	Placebo Placebo: Placebo - No idebenone
Measure Participants	7	7	7
Mean (Standard Deviation) [mM/L]	-0.24 (1.18)	0.7 (1.31)	-0.46 (1.07)

3. Secondary Outcome

Title	Mean Change in Score on the Fatigue Severity Scale (FSS)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	900 mg/Day	2250 mg/Day	Placebo
Arm/Group Description	Idebenone 900 mg/day Idebenone: 900 mg/day for 1 month	Idebenone 2250 mg/day Idebenone: 2250 mg/day for one month	Placebo Placebo: Placebo - No idebenone
Measure Participants	7	7	7
Mean (Standard Deviation) [units on a scale]	-3.8 (11)	-1.3 (10)	4.3 (4.5)

Adverse Events

Time Frame	6 weeks
Arm/Group Title	Idebenone 900 mg/Day		Idebenone 2250 mg/Day		Placebo
Arm/Group Description	Idebenone 900 mg/day Idebenone: 900 mg/day for 1 month		Idebenone 2250 mg/day Idebenone: 2250 mg/day for one month		Placebo Placebo: Placebo - No idebenone
All Cause Mortality
	Idebenone 900 mg/Day		Idebenone 2250 mg/Day		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Idebenone 900 mg/Day		Idebenone 2250 mg/Day		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/9 (0%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Idebenone 900 mg/Day		Idebenone 2250 mg/Day		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/10 (100%)		9/9 (100%)		8/8 (100%)
Blood and lymphatic system disorders
lymphadenopathy	1/10 (10%)	3	0/9 (0%)	0	0/8 (0%)	0
bilirubin decreased	2/10 (20%)	2	1/9 (11.1%)	2	1/8 (12.5%)	1
chloride decreased	0/10 (0%)	0	0/9 (0%)	0	2/8 (25%)	2
creatine phosphokinase increased	1/10 (10%)	1	0/9 (0%)	0	1/8 (12.5%)	1
glucose decreased	2/10 (20%)	3	0/9 (0%)	0	0/8 (0%)	0
glucose increase	0/10 (0%)	0	1/9 (11.1%)	1	1/8 (12.5%)	1
lactic acid increase	3/10 (30%)	4	2/9 (22.2%)	2	2/8 (25%)	2
carbon dioxide decrease	3/10 (30%)	3	0/9 (0%)	0	2/8 (25%)	2
hematocrit decrease	1/10 (10%)	1	0/9 (0%)	0	1/8 (12.5%)	1
hemoglobin decrease	1/10 (10%)	1	1/9 (11.1%)	1	0/8 (0%)	0
high density lipoprotein decrease	1/10 (10%)	1	1/9 (11.1%)	1	0/8 (0%)	0
monocyte increased	0/10 (0%)	0	3/9 (33.3%)	3	0/8 (0%)	0
red blood cell decreased	1/10 (10%)	1	0/9 (0%)	0	2/8 (25%)	2
lymphadenopathy	1/10 (10%)	3	0/9 (0%)	0	0/8 (0%)	0
Cardiac disorders
EKG abnormal	0/10 (0%)	0	2/9 (22.2%)	2	2/8 (25%)	2
Eye disorders
visual impairment	0/10 (0%)	0	0/9 (0%)	0	1/8 (12.5%)	3
Gastrointestinal disorders
abdominal discomfort	0/10 (0%)	0	0/9 (0%)	0	2/8 (25%)	2
abdominal distention	1/10 (10%)	1	2/9 (22.2%)	2	1/8 (12.5%)	2
abdominal pain	1/10 (10%)	2	1/9 (11.1%)	2	0/8 (0%)	0
constipation	1/10 (10%)	1	0/9 (0%)	0	0/8 (0%)	0
diarrhea	2/10 (20%)	2	3/9 (33.3%)	5	1/8 (12.5%)	1
dispepsia	1/10 (10%)	1	0/9 (0%)	0	0/8 (0%)	0
dysphagia	1/10 (10%)	1	0/9 (0%)	0	0/8 (0%)	0
epigastric discomfort	1/10 (10%)	1	0/9 (0%)	0	0/8 (0%)	0
flatulence	0/10 (0%)	0	1/9 (11.1%)	1	1/8 (12.5%)	1
nausea	3/10 (30%)	5	0/9 (0%)	0	0/8 (0%)	0
General disorders
chest pain	0/10 (0%)	0	1/9 (11.1%)	1	1/8 (12.5%)	1
fatigue	5/10 (50%)	8	1/9 (11.1%)	2	3/8 (37.5%)	3
feeling abnormal	1/10 (10%)	1	1/9 (11.1%)	1	1/8 (12.5%)	1
irratibility	0/10 (0%)	0	0/9 (0%)	0	1/8 (12.5%)	2
Infections and infestations
influenza	1/10 (10%)	1	0/9 (0%)	0	1/8 (12.5%)	1
sinusitus	1/10 (10%)	1	1/9 (11.1%)	1	1/8 (12.5%)	1
urinary tract infection	1/10 (10%)	1	0/9 (0%)	0	1/8 (12.5%)	1
Musculoskeletal and connective tissue disorders
arthralgia	1/10 (10%)	1	1/9 (11.1%)	1	0/8 (0%)	0
muscle weakness	1/10 (10%)	2	0/9 (0%)	0	0/8 (0%)	0
myalgia	2/10 (20%)	2	0/9 (0%)	0	1/8 (12.5%)	1
pain in extremity	1/10 (10%)	1	1/9 (11.1%)	1	0/8 (0%)	0
Nervous system disorders
dizziness	1/10 (10%)	2	0/9 (0%)	0	1/8 (12.5%)	2
headache	3/10 (30%)	6	2/9 (22.2%)	2	4/8 (50%)	14
hypoaesthesia	1/10 (10%)	2	1/9 (11.1%)	2	0/8 (0%)	0
migraine	3/10 (30%)	3	0/9 (0%)	0	3/8 (37.5%)	7
petit mal eplipsey	2/10 (20%)	6	0/9 (0%)	0	1/8 (12.5%)	1
somnolence	0/10 (0%)	0	1/9 (11.1%)	1	1/8 (12.5%)	1
Psychiatric disorders
nervousness	1/10 (10%)	2	0/9 (0%)	0	1/8 (12.5%)	1
Renal and urinary disorders
albumin in urine	1/10 (10%)	1	1/9 (11.1%)	1	1/8 (12.5%)	1
glucose in urine increased	1/10 (10%)	1	2/9 (22.2%)	2	0/8 (0%)	0
ketone in urine increased	0/10 (0%)	0	2/9 (22.2%)	2	0/8 (0%)	0
urine leukocyte esterase increase	4/10 (40%)	4	1/9 (11.1%)	1	1/8 (12.5%)	1
pollakiuria	0/10 (0%)	0	2/9 (22.2%)	2	0/8 (0%)	0

Limitations/Caveats

Clinical variability in severity of disease among participants

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.