Mitochondrial Diseases
Conditions
Keywords
mitochondrial diseases, respiratory chain complex I deficiencies, respiratory chain complex II deficiencies, respiratory chain complex III deficiencies, respiratory chain complex IV deficiencies, mutations of a gene coding for a respiratory chain component
Brief summary
To show that oral CoQ10 is a safe and effective treatment for children with inborn errors of mitochondrial energy metabolism due to defects in specific respiratory chain (RC) complexes or mitochondrial DNA (mtDNA) mutations, and that this beneficial action is reflected in improved motor and neurobehavioral function.
Detailed description
In many patients mitochondrial disease leads to progressive nerve and muscle damage that may be associated with problems with thinking, talking, remembering, walking or balancing. Sometimes it may also cause abnormal build up in the blood and spinal fluid of a substance called lactic acid. This problem makes the blood and spinal fluid too acid, which can be life-threatening. There is no known specific or effective treatment for mitochondrial diseases. Sometimes certain diets can improve the condition but seldom prevent the nerve or muscle damage or reduce the chance of developing life-threatening acidity of the blood. CoQ10 is not approved by the Food and Drug Administration (FDA) for the treatment of mitochondrial diseases. It is an investigational drug that we believe may help people with certain mitochondrial diseases, like the one you have, both in terms of reducing the acidity of your blood and preventing or decreasing nerve and muscle damage. Our belief is based on previous studies that have been conducted in children with mitochondrial diseases of various types. Therefore, a 12 month study has been designed to determine the safety and benefit of taking CoQ10 every day. This will be done by comparing the subjects response to taking CoQ10 for 6 months to taking a placebo for 6 months. A placebo looks, smells, and tastes like the drug being tested (in this case, CoQ10) but has no effect. Placebo studies such as this one are very common in evaluating investigational drugs for any disease and are usually required by the FDA before a drug can be approved. CoQ10 or placebo will be given as a liquid once per day in the evening, by mouth or feeding tube. The CoQ10 dose will be 10 mg/kg with a maximum dose of 400 mg a day. Neither the subject nor the health care givers will know exactly when subjects are receiving CoQ10 or when subjects are receiving the placebo. However, subjects will receive CoQ10 for at least 6 months. At each visit the subject will be given a seven month supply of CoQ10, nutritional cocktail, and multivitamins to take home and they will be asked to bring back any unused medications at the next visit. At each visit subjects will be given a medication diary to record the time and date that they take the medications that will be provided. This diary should be returned to the study coordinator at the subject's scheduled visit. During the 12 month period that subjects are on the study, they will be expected to stop taking all medications and other supplements except for those provided by the study and those that the study doctor determines are medically needed. Except in the case of an emergency, the subject must contact the study doctor before taking any new medications or supplements. In the case of an emergency, subjects are required to inform the study doctor of the emergency and treatments as soon as possible. Subjects will be hospitalized on the General Clinical Research Center (GCRC) ward of Shands Hospital for 2-4 days every three to six months. A parent or legal guardian will be expected to stay with the subject. During that hospitalization, physical and intellectual development will be measured by standard tests. The GCRC dietician will ask questions about current diet at each visit and record answers. A general medical history and physical examination (including gross motor function and/or strength tests) will be performed during each visit as well as a six minute walking test. While enrolled in this study, a special nutritional cocktail and a Centrum-like multivitamin supplement will be provided for subjects to take daily. The nutritional cocktail has vitamin C, up to 10 mg/kg/day (max. 400 mg/day), riboflavin, up to 2.5 mg/kg/day (max. 100 mg/day), thiamine, up to 2.5 mg/kg/day (100 mg/day), carnitine, up to 10 mg/kg/day (max. 400 mg/day). The nutritive cocktail is in capsule form and the number of capsules that the subject will take will be based on body weight (for every 4 kg. of body weight subjects will receive 1 capsule daily). Each capsule contains: Vitamin C 40 mg, Riboflavin 10 mg, thiamine 10 mg and carnitine 40 mg. The maximum amount of capsules that will be given daily to anyone in this study is 10 capsules daily. A parent or legal guardian will be asked to complete each of eight questionnaires regarding behavioral and developmental, quality of life (5), and sleep. The behavioral and developmental, four of the quality of life (QOL) questionnaires, and the sleep questionnaire should be completed at the 0, 6 and 12 month visits. One of the QOL questionnaires (46 questions) will need to be completed monthly and mailed back to the study center after completion (self-addressed, stamped envelopes will be provided by the study and given to you by the coordinator). We expect that it will take up to 20 minutes to complete the monthly QOL questionnaire and up to 3 hours at the 0, 6 and 12 month visit to complete the rest of the questionnaires. About 15-20 ml. of blood (3-4 teaspoons) will be obtained during each hospitalization. A urine sample will also be collected during each hospital visit. In females of child-bearing age, urine will also be collected and tested for the presence of HCG (a hormone that determines pregnancy). Within 24 hours of blood and urine collection test results will be assessed by the study physician.
Interventions
DRUGCoenzymeQ10
CoenzymeQ10 will be given in 10 mg/kg daily up to 400 mg. Then a draw of CoQ10 troughs every three months will be performed.
DRUGPlacebo
Placebo will be given in 10 mg/kg daily up to 400 mg. Then a draw of placebo troughs every three months will be performed. This treatment group will be treated as the active group.
Sponsors
FDA Office of Orphan Products Development
Food and Drug Administration (FDA)
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Months to 17 Years
Healthy volunteers
No
Inclusion criteria
* Age 12 m - 17 y * Biochemical proof of a deficiency of complex I, III or IV of the RC or a molecular genetic proof of a mutation in mtDNA, or an nDNA mutation in a gene known to be associated with dysfunction of the electron transport chain (e.g., SURF1) * Willingness to stop all other medication regimens and supplements other than what the Steering and Planning Committee deems medically necessary
Exclusion criteria
* A genetic mitochondrial disease other than those stipulated under inclusion criteria * Intractable epilepsy, defined as grand mal seizures occurring with a frequency \> 4/month, despite treatment with conventional antiepileptic drugs * Primary, defined organic acidurias other than lactic acidosis (e.g., propionic aciduria * Primary disorders of amino acid metabolism * Primary disorders of fatty acid oxidation * Secondary lactic acidosis due to impaired oxygenation or circulation (e.g., due to severe cardiomyopathy or congenital heart defects) * Severe anemia, defined as a hematocrit \<30% * Malabsorption syndromes associated with D-lactic acidosis * Renal insufficiency, defined as (1) a requirement for chronic dialysis or (2) serum creatinine ≥ 1.2 mg/dl or creatinine clearance \<60 ml/min * Primary hepatic disease unrelated to mitochondrial disease * Allergy to CoQ10 or placebo ingredients * Pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| McMaster Gross Motor Function (GMFM 88) | Taken at 6 and 12 Months | The McMaster Gross Motor Function is a validated scale ranging from 0 to 100 (the higher the better). Since there was the possibility of a subject becoming totally disabled our FDA peer reviewed design called for its use as follows: If the subject completed both periods, the score was calculated as the difference in scores between the end of Period 2 (at 12 months) minus that at the end of Period 1 (6 months). If a subject became totally disabled, this difference was considered as plus infinity if it occurred in period 1 (Penalizes period 1), and minus infinity if it occurred in Period 2 (Penalizes period 2). The two treatments were compared via the Wilcoxon test, and the effect size was estimated using Kendall's Tau-B. This is interpreted in a similar manner to correlation with positive values favoring COQenzyme10 and negative values favoring placebo. One of the links in this report is to the the GMFM scale and how it is scored. A link to the instrument is included. |
| Pediatric Quality of Life Scale | At 6 and 12 Months | The Pediatric Quality of Life Scale is a validated scale ranging from 0 to 100 (the higher the better). Since there was the possibility of a subject becoming totally disabled our FDA peer reviewed design called for its use as follows: If the subject completed both periods, the score was calculated as the difference in scores between the end of Period 2 (at 12 months) minus that at the end of Period 1 (6 months). If a subject became totally disabled, this difference was considered as plus infinity if it occurred in period 1 (Penalizes period 1), and minus infinity if it occurred in Period 2 (Penalizes period 2). The two treatments were compared via the Wilcoxon test, and the effect size was estimated using Kendall's Tau-B. This is interpreted in a similar manner to correlation with positive values favoring COQenzyme10 and negative values favoring placebo. Goggle pedsQL and Mapi to browse the copyrighted manual. A link to the instrument is included. |
| Non-parametric Hotelling T-square Bivariate Analysis of GMGF 88 and OPeds QOL. | end of 12 month minus end of 6 month difference. | This is a multivariate analysis of the first two outcomes: Period 2 minus Period 1 GMFM88 and Peds Quality of Life, analyzed as follows: First, to be in the analysis, subjects must contribute at least one of these endpoints. Second, if the subject became totally disabled during period 1, the difference was defined as + infinity, (highest possible evidence favoring period 2), and if the subject became totally disabled in period 2, the subject was scored as - infinity (highest possible evidence favoring period 1). Period 2 minus period 1 differences were ranked form low to high with missing values scores at the mid-rank. The Hotelling T-square was computed on these ranks and the P-value was obtained from 100,000 rerandomizations as the fraction of rerandomizations with T-sq at least as large as that observed. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo First Patients will be randomized to receive Placebo in Period #1 (Months 0-6) and CoenzymeQ10 given in Period #2( Months 7-12.)
Placebo: Placebo will be given in 10 mg/kg daily up to 400 mg. Then a draw of placebo troughs every three months will be performed. This treatment group will be treated as the active group.
CoenzymeQ10: CoenzymeQ10 will be given in 10 mg/kg daily up to 400 mg. Then a draw of CoQ10 troughs every three months will be performed. | 12 |
| CoenzymeQ10 Frist Patients will be randomized to receive CoenzymeQ10 in Period #1 (Months 0-6) and Placebo given in Period #2( Months 7-12.)
CoenzymeQ10: CoenzymeQ10 will be given in 10 mg/kg daily up to 400 mg. Then a draw of CoQ10 troughs every three months will be performed.
Placebo: Placebo will be given in 10 mg/kg daily up to 400 mg. Then a draw of placebo troughs every three months will be performed. This treatment group will be treated as the active group. | 12 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Months 0-6 | Too disabled to score | 1 | 0 |
| Months 0-6 | Withdrawal by Subject | 4 | 4 |
| Months 7 - 12 | Too disabled to score | 0 | 1 |
| Months 7 - 12 | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo First | CoenzymeQ10 Frist | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 12 Participants | 12 Participants | 24 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 9.0 years STANDARD_DEVIATION 6.3 | 7.5 years STANDARD_DEVIATION 4.5 | 8.3 years STANDARD_DEVIATION 5.4 |
| Region of Enrollment Canada | 2 participants | 3 participants | 5 participants |
| Region of Enrollment United States | 10 participants | 9 participants | 19 participants |
| Sex: Female, Male Female | 6 Participants | 8 Participants | 14 Participants |
| Sex: Female, Male Male | 6 Participants | 4 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 19 | 10 / 20 |
| serious Total, serious adverse events | 1 / 19 | 2 / 20 |
Outcome results
Primary
McMaster Gross Motor Function (GMFM 88)
The McMaster Gross Motor Function is a validated scale ranging from 0 to 100 (the higher the better). Since there was the possibility of a subject becoming totally disabled our FDA peer reviewed design called for its use as follows: If the subject completed both periods, the score was calculated as the difference in scores between the end of Period 2 (at 12 months) minus that at the end of Period 1 (6 months). If a subject became totally disabled, this difference was considered as plus infinity if it occurred in period 1 (Penalizes period 1), and minus infinity if it occurred in Period 2 (Penalizes period 2). The two treatments were compared via the Wilcoxon test, and the effect size was estimated using Kendall's Tau-B. This is interpreted in a similar manner to correlation with positive values favoring COQenzyme10 and negative values favoring placebo. One of the links in this report is to the the GMFM scale and how it is scored. A link to the instrument is included.
Time frame: Taken at 6 and 12 Months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo First | McMaster Gross Motor Function (GMFM 88) | -0.002 units on a scale |
| CoenzymeQ10 Frist | McMaster Gross Motor Function (GMFM 88) | -0.12 units on a scale |
Comparison: Study intended to accrue 40 subjects, but only obtained 14 evaluable on this endpoint.p-value: 0.9595% CI: [-0.44, 0.48]Wilcoxon (Mann-Whitney)
Primary
Non-parametric Hotelling T-square Bivariate Analysis of GMGF 88 and OPeds QOL.
This is a multivariate analysis of the first two outcomes: Period 2 minus Period 1 GMFM88 and Peds Quality of Life, analyzed as follows: First, to be in the analysis, subjects must contribute at least one of these endpoints. Second, if the subject became totally disabled during period 1, the difference was defined as + infinity, (highest possible evidence favoring period 2), and if the subject became totally disabled in period 2, the subject was scored as - infinity (highest possible evidence favoring period 1). Period 2 minus period 1 differences were ranked form low to high with missing values scores at the mid-rank. The Hotelling T-square was computed on these ranks and the P-value was obtained from 100,000 rerandomizations as the fraction of rerandomizations with T-sq at least as large as that observed.
Time frame: end of 12 month minus end of 6 month difference.
Population: Subjects contributes at least one difference (either GMFM or Peds QOL). Thirteen contributed both and one each was missing GMFM or Peds QOL.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo First | Non-parametric Hotelling T-square Bivariate Analysis of GMGF 88 and OPeds QOL. | 7 participants |
| CoenzymeQ10 Frist | Non-parametric Hotelling T-square Bivariate Analysis of GMGF 88 and OPeds QOL. | 8 participants |
Comparison: The actual study was powered to have 40 participants but only 24 participated and of these only 15 had outcome data.p-value: 0.42Non-parametric Hotelling T-square
Primary
Pediatric Quality of Life Scale
The Pediatric Quality of Life Scale is a validated scale ranging from 0 to 100 (the higher the better). Since there was the possibility of a subject becoming totally disabled our FDA peer reviewed design called for its use as follows: If the subject completed both periods, the score was calculated as the difference in scores between the end of Period 2 (at 12 months) minus that at the end of Period 1 (6 months). If a subject became totally disabled, this difference was considered as plus infinity if it occurred in period 1 (Penalizes period 1), and minus infinity if it occurred in Period 2 (Penalizes period 2). The two treatments were compared via the Wilcoxon test, and the effect size was estimated using Kendall's Tau-B. This is interpreted in a similar manner to correlation with positive values favoring COQenzyme10 and negative values favoring placebo. Goggle pedsQL and Mapi to browse the copyrighted manual. A link to the instrument is included.
Time frame: At 6 and 12 Months
Population: 7 subjects in each group were evaluable for this endpoint. The two subjects who became disabled are evaluable. One subject did not have period 2 Quality of Life data and is excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo First | Pediatric Quality of Life Scale | -1.1 units on a scale |
| CoenzymeQ10 Frist | Pediatric Quality of Life Scale | -11.9 units on a scale |
Comparison: Study intended to accrue 40 subjects, but only obtained 14 evaluable on this endpoint.p-value: 0.1895% CI: [-0.12, 0.72]Wilcoxon (Mann-Whitney)