Phase III Trial of Coenzyme Q10 in Mitochondrial Disease - Full Text View

Purpose

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.

Condition	Intervention	Phase
Mitochondrial Diseases	Drug: CoenzymeQ10 Drug: Placebo	Phase 3


Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Crossover Assignment Masking: Triple (Participant, Care Provider, Investigator) Primary Purpose: Treatment
Official Title:	Phase 3 Trial of Coenzyme Q10 in Mitochondrial Disease

Resource links provided by NLM:

Genetics Home Reference related topics: ataxia neuropathy spectrum childhood myocerebrohepatopathy spectrum deoxyguanosine kinase deficiency mitochondrial neurogastrointestinal encephalopathy disease myoclonic epilepsy myopathy sensory ataxia

MedlinePlus related topics: Mitochondrial Diseases

Drug Information available for: Ubidecarenone

U.S. FDA Resources

Further study details as provided by University of Florida:

Primary Outcome Measures:

McMaster Gross Motor Function (GMFM 88) [ Time Frame: 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 [ Time Frame: 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. [ Time Frame: 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.


Enrollment:	24
Study Start Date:	January 2007
Study Completion Date:	May 2013
Primary Completion Date:	May 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: CoenzymeQ10 CoenzymeQ10: patients will be randomized to receive CoenzymeQ10 in either Period #1 (Months 0-6) or Period #2 (Months 7-12).	Drug: 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 Comparator: Placebo Placebo: patients will be randomized to receive placebo either ion Period #1 (months 1-6) or Period #2 (months 7-12).	Drug: 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.

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Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:	12 Months to 17 Years (Child)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00432744

Locations


United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45267
Case Western Reserve University
Cleveland, Ohio, United States, 44106
Canada, Ontario
Hospital for Sick Children
Toronto, Ontario, Canada, M5G 1X8

Sponsors and Collaborators

University of Florida

FDA Office of Orphan Products Development

Food and Drug Administration

Investigators


Principal Investigator:	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

More Information

Additional Information:

University of Florida Clinical Research Center, Clinical and Translational Science Institute This link exits the ClinicalTrials.gov site

Describes the 23 item Pediatric Quality of Life This link exits the ClinicalTrials.gov site

Publications:

Hanna MG, Nelson IP. Genetics and molecular pathogenesis of mitochondrial respiratory chain diseases. Cell Mol Life Sci. 1999 May;55(5):691-706. Review.

Kerr DS. Treatment of congenital lactic acidosis: a review. Intern Pediatr, 1995;10:75-81.

Abe K, Fujimura H, Nishikawa Y, Yorifuji S, Mezaki T, Hirono N, Nishitani N, Kameyama M. Marked reduction in CSF lactate and pyruvate levels after CoQ therapy in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Acta Neurol Scand. 1991 Jun;83(6):356-9.

Ogasahara S, Nishikawa Y, Yorifuji S, Soga F, Nakamura Y, Takahashi M, Hashimoto S, Kono N, Tarui S. Treatment of Kearns-Sayre syndrome with coenzyme Q10. Neurology. 1986 Jan;36(1):45-53.

Gold R, Seibel P, Reinelt G, Schindler R, Landwehr P, Beck A, Reichmann H. Phosphorus magnetic resonance spectroscopy in the evaluation of mitochondrial myopathies: results of a 6-month therapy study with coenzyme Q. Eur Neurol. 1996;36(4):191-6.

Matthews PM, Ford B, Dandurand RJ, Eidelman DH, O'Connor D, Sherwin A, Karpati G, Andermann F, Arnold DL. Coenzyme Q10 with multiple vitamins is generally ineffective in treatment of mitochondrial disease. Neurology. 1993 May;43(5):884-90.

Bresolin N, Doriguzzi C, Ponzetto C, Angelini C, Moroni I, Castelli E, Cossutta E, Binda A, Gallanti A, Gabellini S, et al. Ubidecarenone in the treatment of mitochondrial myopathies: a multi-center double-blind trial. J Neurol Sci. 1990 Dec;100(1-2):70-8.

Shults CW, Oakes D, Kieburtz K, Beal MF, Haas R, Plumb S, Juncos JL, Nutt J, Shoulson I, Carter J, Kompoliti K, Perlmutter JS, Reich S, Stern M, Watts RL, Kurlan R, Molho E, Harrison M, Lew M; Parkinson Study Group. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol. 2002 Oct;59(10):1541-50.

Ogasahara S, Engel AG, Frens D, Mack D. Muscle coenzyme Q deficiency in familial mitochondrial encephalomyopathy. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2379-82.

Musumeci O, Naini A, Slonim AE, Skavin N, Hadjigeorgiou GL, Krawiecki N, Weissman BM, Tsao CY, Mendell JR, Shanske S, De Vivo DC, Hirano M, DiMauro S. Familial cerebellar ataxia with muscle coenzyme Q10 deficiency. Neurology. 2001 Apr 10;56(7):849-55.

Lamperti C, Naini A, Hirano M, De Vivo DC, Bertini E, Servidei S, Valeriani M, Lynch D, Banwell B, Berg M, Dubrovsky T, Chiriboga C, Angelini C, Pegoraro E, DiMauro S. Cerebellar ataxia and coenzyme Q10 deficiency. Neurology. 2003 Apr 8;60(7):1206-8.

Rahman S, Hargreaves I, Clayton P, Heales S. Neonatal presentation of coenzyme Q10 deficiency. J Pediatr. 2001 Sep;139(3):456-8.

Argov Z, Bank WJ, Maris J, Eleff S, Kennaway NG, Olson RE, Chance B. Treatment of mitochondrial myopathy due to complex III deficiency with vitamins K3 and C: A 31P-NMR follow-up study. Ann Neurol. 1986 Jun;19(6):598-602.

Geromel V, Darin N, Chrétien D, Bénit P, DeLonlay P, Rötig 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. Review.

Beal MF. Mitochondria, oxidative damage, and inflammation in Parkinson's disease. Ann N Y Acad Sci. 2003 Jun;991:120-31. Review.

Turunen M, Olsson J, Dallner G. Metabolism and function of coenzyme Q. Biochim Biophys Acta. 2004 Jan 28;1660(1-2):171-99. Review.

Miles MV, Horn PS, Tang PH, Morrison JA, Miles L, DeGrauw T, Pesce AJ. Age-related changes in plasma coenzyme Q10 concentrations and redox state in apparently healthy children and adults. Clin Chim Acta. 2004 Sep;347(1-2):139-44.

ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002 Jul 1;166(1):111-7.

Cerveri I, Fanfulla F, Zoia MC, Manni R, Tartara A. Sleep disorders in neuromuscular diseases. Monaldi Arch Chest Dis. 1993 Aug;48(4):318-21.

Johnston K, Newth CJ, Sheu KF, Patel MS, Heldt GP, Schmidt KA, Packman S. Central hypoventilation syndrome in pyruvate dehydrogenase complex deficiency. Pediatrics. 1984 Dec;74(6):1034-40.

Kotagal S, Archer CR, Walsh JK, Gomez C. Hypersomnia, bithalamic lesions, and altered sleep architecture in Kearns-Sayre syndrome. Neurology. 1985 Apr;35(4):574-7.

Pronicka E, Piekutowska-Abramczuk DH, Popowska E, Pronicki M, Karczmarewicz E, Sykut-Cegielskâ Y, Taybert J. Compulsory hyperventilation and hypocapnia of patients with Leigh syndrome associated with SURF1 gene mutations as a cause of low serum bicarbonates. J Inherit Metab Dis. 2001 Dec;24(7):707-14.

Sakaue S, Ohmuro J, Mishina T, Miyazaki H, Yamaguchi E, Nishimura M, Fujita M, Nagashima K, Tagami S, Kawakami Y. A case of diabetes, deafness, cardiomyopathy, and central sleep apnea: novel mitochondrial DNA polymorphisms. Tohoku J Exp Med. 2002 Mar;196(3):203-11.

Spranger M, Schwab S, Wiebel M, Becker CM. [Adult Leigh syndrome. A rare differential diagnosis of central respiratory insufficiency]. Nervenarzt. 1995 Feb;66(2):144-9. German.

Yasaki E, Saito Y, Nakano K, Katsumori H, Hayashi K, Nishikawa T, Osawa M. Characteristics of breathing abnormality in Leigh and its overlap syndromes. Neuropediatrics. 2001 Dec;32(6):299-306.

Sembrano E, Barthlen GM, Wallace S, Lamm C. Polysomnographic findings in a patient with the mitochondrial encephalomyopathy NARP. Neurology. 1997 Dec;49(6):1714-7.


Responsible Party:	University of Florida
ClinicalTrials.gov Identifier:	NCT00432744 History of Changes
Other Study ID Numbers:	1R01FD003032-01A1 ( U.S. FDA Grant/Contract ) R01FD003032-01A1 ( U.S. FDA Grant/Contract )
First Submitted:	February 6, 2007
First Posted:	February 8, 2007
Results First Submitted:	April 11, 2014
Results First Posted:	May 1, 2014
Last Update Posted:	September 11, 2017
Last Verified:	September 2017

Keywords provided by University of Florida:


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

Additional relevant MeSH terms:


Mitochondrial Diseases Metabolic Diseases Coenzyme Q10 Ubiquinone	Micronutrients Growth Substances Physiological Effects of Drugs Vitamins