Phase III Trial of Coenzyme Q10 in Mitochondrial Disease

• Gross motor function and
• home quality of life (QOL)

• 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 ]
• neurobehavioral assessments: the American Association on Mental Retardation Adaptive Behavior Scales; [ Time Frame: Every six months ] [ Designated as safety issue: No ]

• diagnostic laboratory data;
• H&P: patient demographic information and pertinent physiologic measures;
• motor assessments: Gross Motor Function Measure,
• neurobehavioral assessments: NIHM neurobehavioral examination, the Child Development Inventory and the American Association on Mental Retardation Adaptive Behavior Scales;
• QOL assessment;
• sleep questionnaire;
• CoQ10 profile data;
• LiQ-nol parent survey Effects Report and
• QOL Validity Studies

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.

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.

• 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.
  Other Name: CoenzymeQ10
• 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.
  Other Name: Placebo

• Active Comparator: CoenzymeQ10
  CoenzymeQ10, patients will be randomized to receive CoenzymeQ10.
  Intervention: Drug: CoenzymeQ10
• Placebo Comparator: Placebo
  Placebo, patients will be randomized to receive placebo.
  Intervention: Drug: Placebo

• 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.

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