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Open-Label, Dose-Escalating Study Assessing Safety, Tolerability, Efficacy, of RP103 in Mitochondrial Disease (MITO-001)

This study has been completed.
ClinicalTrials.gov Identifier:
First Posted: December 30, 2013
Last Update Posted: October 16, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Horizon Pharma USA, Inc.
Patients with mitochondrial diseases, who are ≥ 2 years old and < 18 years, will be included in this study. It is anticipated that approximately one half of subjects will have genetically confirmed Leigh Syndrome. Up to 25 patients will be enrolled if there is no toxicity up to the level of 1.3 g/m2/day of RP103. Interim analyses will occur after 4 and then 12 subjects complete the study through Week 24. If the study is not stopped early, final analysis will occur after 25 subjects have completed through Week 24.

Condition Intervention Phase
Inherited Mitochondrial Disease, Including Leigh Syndrome Drug: Cysteamine Bitartrate Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Open-Label, Dose-Escalating Study to Assess Safety, Tolerability, Efficacy, Pharmacokinetics and Pharmacodynamics of Cysteamine Bitartrate Delayed-release Capsules (RP103) in Children With Inherited Mitochondrial Disease

Resource links provided by NLM:

Further study details as provided by Horizon Pharma USA, Inc.:

Primary Outcome Measures:
  • Change in Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) Sections I-IV to assess Disease Progression [ Time Frame: Baseline through Week 24 ]
    Quality of life

Secondary Outcome Measures:
  • Change over time in Pharmacodynamic Biomarkers [ Time Frame: Baseline and Weeks 4, 8, 12, 16, 20, 24 ]
    Glutathione, glutathione disulfide, and lactate

  • Change over time in two of the most preeminent symptoms [ Time Frame: Baseline and Weeks 4, 8, 12, 16, 20, 24 ]
    Myopathy, Dystonia, Ataxia, Retarded motor development, Reduced activities of daily living, Vision

Enrollment: 36
Actual Study Start Date: June 2014
Study Completion Date: October 2016
Primary Completion Date: October 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cysteamine Bitartrate Delayed-release
RP103 will be administered Cysteamine Bitartrate Delayed-release Capsules following a dose-escalation design with a progressive weekly dose increase over 6 weeks
Drug: Cysteamine Bitartrate
Cysteamine Bitartrate Delayed-release Capsules
Other Name: RP103

Detailed Description:

This is an open-label, dose-escalation study to assess the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of Cysteamine Bitartrate Delayed-release Capsules (RP103) for treatment of children with inherited mitochondrial disease.

Patients with inherited mitochondrial diseases associated with nuclear or mitochondrial DNA mutations that impair the respiratory chain. These include, but are not limited to the following clinical syndromes: Leber's hereditary optic neuropathy; myoclonic epilepsy and ragged-red fibers (MERFF); mitochondrial encephalomyopathy, lactic acidosis, and strokelike syndrome (MELAS); KearnSayre syndrome; subacute necrotizing encephalopathy (Leigh Syndrome); POLGrelated disorders (Alpers-Huttenlocher Syndrome, Autosomal Dominant Progressive External Ophthalmoplegia, Autosomal Recessive Progressive External Ophthalmoplegia, Childhood Myocerebrohepatopathy Spectrum Disorders, Myoclonic Epilepsy Myopathy Sensory Ataxia, POLGRelated Ataxia Neuropathy Spectrum Disorders); Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), also called myoneurogastrointestinal encephalopathy syndrome or POLIP syndrome; others, e.g., mitochondrial cardiomyopathies and other syndromes due to multiple mitochondrial DNA deletions.

Prior to treatment, patients will undergo a Screening Visit. If eligible, each subject will return for the Day 1 study visit and begin RP103 dosing on that day. Every 2 weeks over the subsequent 8 weeks, subjects will alternate between returning to the clinic for detailed assessments (Weeks 4 and 8) and receiving a telephone call from the Investigator team to assess safety and RP103 dose (Weeks 2 and 6) and the potential need for an immediate unscheduled study visit. Thereafter, subjects will continue to return to the clinic every 4 weeks for detailed assessments at Weeks 12, 16, 20 and 24 (the Study Exit visit). The Week 24 visit will be the same as the Study Exit visit (i.e. a single visit rather two separate ones) if a subject elects to continue on to the RP103-MITO-002 (NCT02473445) extension study, and that study has been IRB approved at the site or if the subject does not continue on to the extension study. If the extension study has not yet been IRB approved by the time a subject reaches Week 24, and that subject elects to continue on RP103, then Study Exit visit will take place later and separately from the Week 24 visit.

The extension study will continue until results of the present RP103-MITO-001 study are known.


Information from the National Library of Medicine

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Ages Eligible for Study:   6 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Age ≥ 6 years and < 18 years
  2. Body weight ≥ 5 kgs
  3. Documented (genetically confirmed known mutation, i.e. no variants of uncertain significance) diagnosis of inherited mitochondrial disease other than Friedreich's ataxia (FRDA)
  4. Moderate disease severity based on Newcastle Pediatric Mitochondrial Disease Scale (NPMD) score, with a score between 15 to 45 inclusive [LHON subjects are exempt of this inclusion criteria], if approved by the sponsor.
  5. For patients regularly taking dietary supplements such as creatinine, alpha-lipoic acid, CoQ10, vitamin B, carnitine, etc. they have to have been taking them for at least 3 months pre-study and will agree to keep these the same throughout the study (from the Screening Visit to Study Exit)
  6. With respect to concomitant medications, the subject must:

    1. Be willing to abstain from initiating dietary supplements and non-prescribed medications, except as allowed by the Investigator, throughout the study (from the Screening Visit to Study Exit);
    2. Be on a stable dose of medications prescribed for seizure management and prevention. Stable dose in this context means unchanged for at least 30 days prior to the Screening Visit.
  7. Willing and able to comply with study drug dosing requirements, i.e. ingest the RP103 capsules intact, or sprinkled in liquid or soft food, or using a g-tube
  8. Sexually active female subjects of childbearing potential (i.e., not surgically sterile [tubal ligation, hysterectomy, or bilateral oophorectomy]) must agree to utilize two of the following acceptable forms of contraception throughout the study (from the Screening Visit to Study Exit):

    1. Hormonal contraception: birth control pills, injection, patch, vaginal ring or implant;
    2. Condom or diaphragm, with spermicide;
    3. Intrauterine device (IUD)
    4. Sterile male partner (vasectomy performed at least 6 months prior to the study).
  9. Subjects's legally authorized representative must provide written informed consent; Subject must provide assent, if required by local/institutional requirements
  10. Have mitochondrial myopathy as evidenced by one or more of the following criteria:

    1. Weakness consistent with myopathy (e.g. accompanied by muscle wasting and/or absence of neuropathy) on physical exam
    2. OR documented myopathy on the basis of muscle biopsy consistent with mitochondrial myopathy disease
    3. OR weakness and/or progressive exercise intolerance (in which modest exercise typically provokes heaviness, weakness, aching of active muscles, or tachycardia). Weakness should be due to myopathy and not neuropathy or other causes as deemed by investigator

Exclusion Criteria:

  1. Documented diagnosis of concurrent inborn errors of metabolism
  2. Non-elective hospitalization relative to mitochondrial disease or direct complication of disease within 60 days prior to the Screening Visit.
  3. Platelet count, lymphocyte count or hemoglobin below the lower limit of normal (LLN) at the Screening Visit
  4. Hepatic insufficiency with liver enzyme tests (alkaline phosphatase, AST or ALT) greater than 2.5 times the upper limit of normal (ULN) at the Screening Visit
  5. Bilirubin > 1.2 g/dL at the Screening Visit
  6. Inability to complete the elements of the study, e.g., coma, hemodynamic instability or requiring continuous ventilator support.
  7. Malabsorption requiring TPN, chronic diarrhea, bouts of pseudo obstruction
  8. Severe end-organ hypo-perfusion syndrome secondary to cardiac failure resulting in lactic acidosis
  9. Patients with suspected elevated intracranial pressure, pseudotumor cerebri (PTC) and/or papilledema
  10. Severe gastrointestinal disease including gastroparesis
  11. History of angina, myocardial infarction, or cardiac surgery within 2 years prior to the Screening Visit
  12. Any clinically significant ECG, including dysrhythmia, or clinically significant abnormal laboratory finding not already listed above at the Screening Visit
  13. History of drug or alcohol abuse
  14. History of pancreatitis
  15. Participated in an investigational drug trial within 30 days or, within 90 days for a biologic, device, or surgical treatment, for inherited mitochondrial diseases prior to the Screening Visit
  16. Known or suspected hypersensitivity to cysteamine and penicillamine
  17. Female subjects who are nursing, planning a pregnancy, known or suspected to be pregnant, or with a positive serum pregnancy test at the Screening Visit
  18. Subject's who, in the opinion of the Investigator, are not able or willing to comply with the protocol.
  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): NCT02023866

United States, California
University of California at San Diego (UCSD)
San Diego, California, United States, 92093-0935
Stanford University
Stanford, California, United States, 94305
United States, Ohio
Akron Children's Hospital
Akron, Ohio, United States, 44308
United States, Texas
Baylor College of Medicine
Houston, Texas, United States, 77030
United States, Utah
University of Utah, Division of Medical Genetics
Salt Lake City, Utah, United States, 84132
Sponsors and Collaborators
Horizon Pharma USA, Inc.
Study Director: Evelyn Olson, BS Horizon Pharma USA, Inc.
  More Information

Responsible Party: Horizon Pharma USA, Inc.
ClinicalTrials.gov Identifier: NCT02023866     History of Changes
Other Study ID Numbers: RP103-MITO-001
First Submitted: December 17, 2013
First Posted: December 30, 2013
Last Update Posted: October 16, 2017
Last Verified: April 2017

Keywords provided by Horizon Pharma USA, Inc.:
Leigh Syndrome
Leber's hereditary optic neuropathy
myoclonic epilepsy
mitochondrial encephalomyopathy
Kearn-Sayre syndrome
POLG-related disorders
Neurogastrointestinal encephalopathy

Additional relevant MeSH terms:
Mitochondrial Diseases
Leigh Disease
Pathologic Processes
Metabolic Diseases
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Pyruvate Metabolism, Inborn Errors
Carbohydrate Metabolism, Inborn Errors
Cystine Depleting Agents
Molecular Mechanisms of Pharmacological Action