Phase III Trial of Coenzyme Q10 in Mitochondrial Disease

NCT00432744 | Completed Phase 3 Results DMC

• 2 other identifiers: 1R01FD003032-01A1R01FD003032-01A1
• Study Type: interventional
• Target: 24
• Locations: 2 countries
• Sites: 3

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.

Conditions

Mitochondrial Diseases

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

Outcome Measures

Primary Outcomes (3)

• 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.

  Taken at 6 and 12 Months

• 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.

  At 6 and 12 Months

• 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.

  end of 12 month minus end of 6 month difference.

Study Arms (2)

CoenzymeQ10

ACTIVE COMPARATOR

CoenzymeQ10: patients will be randomized to receive CoenzymeQ10 in either Period #1 (Months 0-6) or Period #2 (Months 7-12).

Drug: CoenzymeQ10

Placebo

PLACEBO COMPARATOR

Placebo: patients will be randomized to receive placebo either ion Period #1 (months 1-6) or Period #2 (months 7-12).

Drug: Placebo

Interventions

CoenzymeQ10 DRUG

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.

CoenzymeQ10

Placebo DRUG

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.

Placebo

Eligibility Criteria

• Age: 12 Months - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Florida: lead
• FDA Office of Orphan Products Development: collaborator
• Food and Drug Administration (FDA): collaborator

Study Sites (3)

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45267, United States

Location

Case Western Reserve University

Cleveland, Ohio, 44106, United States

Location

Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

Related Publications (26)

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• Geromel V, Darin N, Chretien D, Benit P, DeLonlay P, Rotig A, Munnich A, Rustin P. Coenzyme Q(10) and idebenone in the therapy of respiratory chain diseases: rationale and comparative benefits. Mol Genet Metab. 2002 Sep-Oct;77(1-2):21-30. doi: 10.1016/s1096-7192(02)00145-2.

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Related Links

• University of Florida Clinical Research Center, Clinical and Translational Science Institute
• Describes the 23 item Pediatric Quality of Life

MeSH Terms

Conditions

Mitochondrial Diseases

Condition Hierarchy (Ancestors)

Metabolic Diseases; Nutritional and Metabolic Diseases

Limitations and Caveats

The trial intended to accrual 40 subjects, but accrual was below expectations and the granting agency turned down a request for extended accrual.

Results Point of Contact

• Title: Dr. Peter W Stacpoole
• Organization: University of Florida

pws@ufl.edu

352-273-9023

Study Officials

• Douglas S. Kerr, MD, PhD

  Case Western Reserve University

  PRINCIPAL INVESTIGATOR

• Ton J deGrauw, MD, PhD

  Children's Hospital Medical Center, Cincinnati

  PRINCIPAL INVESTIGATOR

• Annette S. Feigenbaum, MD

  SickKids, Toronto, Canada/University of Toronto

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 6, 2007
• First Posted: February 8, 2007
• Study Start: January 1, 2007
• Primary Completion: May 1, 2013
• Study Completion: May 1, 2013
• Last Updated: September 11, 2017
• Results First Posted: May 1, 2014

Record last verified: 2017-09

Locations

CA (1); US (2)