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

Sponsors and Collaborators:	University of Florida FDA Office of Orphan Products Development
Information provided by:	University of Florida
ClinicalTrials.gov Identifier:	NCT00432744

Purpose

Our central hypothesis is 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 and in quality of life.

Condition	Intervention	Phase
Mitochondrial Diseases	Drug: CoenzymeQ10 Drug: Coenzyme Q10 Drug: Placebo	Phase III

Genetics Home Reference related topics: mitochondrial neurogastrointestinal encephalopathy disease

Drug Information available for: Coenzyme Q10

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator), Placebo Control, Crossover Assignment, Safety/Efficacy Study

Further study details as provided by University of Florida:

Primary Outcome Measures:

Gross motor function and [ Time Frame: Every six months ] [ Designated as safety issue: No ]
home quality of life (QOL) [ Time Frame: Monthly ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

diagnostic laboratory data; [ Time Frame: Every three months ] [ Designated as safety issue: Yes ]
H&P: patient demographic information and pertinent physiologic measures; [ Time Frame: Every three months ] [ Designated as safety issue: Yes ]
motor assessments: Gross Motor Function Measure, [ Time Frame: Every six months ] [ Designated as safety issue: No ]
neurobehavioral assessments: NIHM neurobehavioral examination, the Child Development Inventory and the American Association on Mental Retardation Adaptive Behavior Scales; [ Time Frame: Every six months ] [ Designated as safety issue: No ]
QOL assessment; [ Time Frame: Every three months ] [ Designated as safety issue: No ]
sleep questionnaire; [ Time Frame: Every three months ] [ Designated as safety issue: No ]
CoQ10 profile data; [ Time Frame: Once upon entrance into trial ] [ Designated as safety issue: No ]
LiQ-nol parent survey Effects Report and [ Time Frame: Every three months ] [ Designated as safety issue: Yes ]
QOL Validity Studies [ Time Frame: Every three months ] [ Designated as safety issue: No ]

Estimated Enrollment:	50
Study Start Date:	January 2007
Estimated Study Completion Date:	May 2009
Estimated Primary Completion Date:	May 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Active Comparator Draw CoQ10 troughs every three months	Drug: CoenzymeQ10 Draw CoQ10 troughs every three months Drug: Coenzyme Q10 10 mg/k daily up to 400 mg
2: Placebo Comparator Placebo	Drug: Placebo Placebo daily

Detailed Description:

This postulate will be tested by accomplishing the following specific aims:

Specific Aim 1. Conduct a multicenter, prospective, randomized, double-blind, placebo controlled crossover trial of oral CoQ10 in children with biochemically proven deficiencies of complex I, III or IV of the RC or with mutations of a gene coding for an RC component (mtDNA and nDNA). This aim tests the hypothesis that supplementation with CoQ10 (10 mg/kg/d) is safe and more effective in improving outcome than placebo. General Clinical Research Centers (GCRCs) or similar facilities will be the venues for this phase 3 clinical trial.

Specific Aim 2. Determine the effectiveness of CoQ10 in improving the morbidity of affected patients. This aim addresses the postulate that high dose CoQ10 improves quality of life and motor function as determined by a validated questionnaire for this patient population, and by objective, standardized measures of motor function.

Specific Aim 3. Determine the safety of CoQ10 in the target population. This aim tests the postulate that the formulation and dose of CoQ10 employed is well tolerated and the administration of this product is not associated with significantly more numerous or more severe adverse events than is administration of placebo.

Eligibility

Ages Eligible for Study:	12 Months to 17 Years
Genders Eligible for Study:	Both
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

Please refer to this study by its ClinicalTrials.gov identifier: NCT00432744

Contacts

Contact: Peter W Stacpoole, PhD, MD	352/392-2321	peter.stacpoole@medicine.ufl.edu
Contact: Lesa R Gilbert, RN	888/961-9068	lesa.gilbert@medicine.ufl.edu

Locations

United States, Ohio
Case Western Reserve University	Recruiting
Cleveland, Ohio, United States, 44106
Contact: Shawn McCandless, MD 216-844-1612 sxm32@case.edu
Contact: Janice Bartos, RN (216) 844-7124 janice.bartos@uhhs.com
Principal Investigator: Douglas S. Kerr, MD, PhD
Cincinnati Children's Hospital Medical Center	Recruiting
Cincinnati, Ohio, United States, 45267
Contact: Ton J deGrauw, MD, PhD 513-636-8680 t.degrauw@cchmc.org
Contact: Gail Chuck, RN (513) 636-8016 gail.chuck@cchmc.org
Principal Investigator: Ton J deGrauw, MD, PhD
Canada, Ontario
Hospital for Sick Children	Recruiting
Toronto, Ontario, Canada, M5G 1X8
Contact: Annette S. Feigenbaum, MD (416) 813-5340 annette.feigenbaum@sickkids.ca
Contact: Mohammed Hussain (416) 813-7654 ext 2646 mohammed.hussain@sickkids.ca
Principal Investigator: Annette S. Feigenbaum, MD

Sponsors and Collaborators

University of Florida

FDA Office of Orphan Products Development

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

University of Florida General Clinical Research Center 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, 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. 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. No abstract available.

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-Cegielska 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:	UFlorida ( Peter W. Stacpoole, PhD, MD )
Study ID Numbers:	1 R01 FD003032-01A1
Study First Received:	February 6, 2007
Last Updated:	June 4, 2008
ClinicalTrials.gov Identifier:	NCT00432744
Health Authority:	United States: Food and Drug Administration

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

Study placed in the following topic categories:

Metabolic Diseases
Ubiquinone
Metabolic disorder
Mitochondrial Diseases
Coenzyme Q10

Additional relevant MeSH terms:

Vitamins
Growth Substances
Physiological Effects of Drugs
Micronutrients
Pharmacologic Actions

ClinicalTrials.gov processed this record on January 16, 2009