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Open-Label, Dose-Escalating Study to Assess Safety, Tolerability, Efficacy, PK and PD of RP103 in Children With Inherited Mitochondrial Disease (RP103-MITO-001)

This study is enrolling participants by invitation only.
Information provided by (Responsible Party):
Raptor Pharmaceuticals Inc. Identifier:
First received: December 17, 2013
Last updated: January 28, 2016
Last verified: June 2015

Patients (male or female) with either documented genetically confirmed diagnosis of inherited mitochondrial diseases, who are ≥ 2 years old and < 18 years, and meet other specified inclusion and exclusion criteria, will be included in this study.

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 stroke-like syndrome (MELAS); Kearn-Sayre syndrome; subacute necrotizing encephalopathy (Leigh Syndrome); POLG-related disorders (Alpers-Huttenlocher Syndrome, Autosomal Dominant Progressive External Ophthalmoplegia, Autosomal Recessive Progressive External Ophthalmoplegia, Childhood Myocerebrohepatopathy Spectrum Disorders, Myoclonic Epilepsy Myopathy Sensory Ataxia, POLG-Related 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.

During the pre-screening and screening process, eligibility criteria for each subject will be reviewed by participating Investigators and Raptor's medical officer, in an attempt to ensure all enrolled subjects have a mitochondrial disease with a known genetic mutation (i.e., patients with a clinical presentation and known mitochondrial disease mutations and no variants of uncertain significance). It is anticipated that approximately two-thirds 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. Initial sample size estimate is 25 subjects. Interim analyses will occur after 4 and then 12 subjects complete the study through Week 24. There is a possibility of stopping for efficacy or for futility after either interim analysis. If the study is not stopped early, final analysis will occur after 25 subjects have completed through Week 24.

The rationale for choosing patients with inherited mitochondrial disease who are age 2 and older is based on available clinical data collected in previous and current RP103 studies in other indications, in subjects aged 2 years and older.

Condition Intervention Phase
Inherited Mitochondrial Disease, Including Leigh Syndrome
Drug: Cysteamine Bitartrate Delayed-release Capsules (RP103)
Phase 2
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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 Raptor Pharmaceuticals Inc.:

Primary Outcome Measures:
  • Change in Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) Score [ Time Frame: Baseline vs. Week 24 ] [ Designated as safety issue: No ]
    Quality of life

Secondary Outcome Measures:
  • Change over time in Pharmacodynamic Biomarkers [ Time Frame: Baseline and Weeks 4, 8, 12, 16, 20, 24 ] [ Designated as safety issue: No ]
    glutathione, acetoacetate, beta-hydroxybutyrate, lactate

Estimated Enrollment: 32
Study Start Date: June 2014
Estimated Study Completion Date: June 2016
Estimated Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: RP103 Drug: Cysteamine Bitartrate Delayed-release Capsules (RP103)


Ages Eligible for Study:   2 Years to 17 Years   (Child)
Genders Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Age ≥ 2 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 [NB: This inclusion criterion will not be met if a subject has LHON. A protocol deviation must be pre-approved in writing by the Sponsor before any LHON subject is enrolled.]
  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. Patient's legally authorized representative must provide written informed consent; Patient must provide assent, if required by local/institutional requirements

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 ventilator.
  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. Patients who, in the opinion of the Investigator, are not able or willing to comply with the protocol
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its identifier: 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
Raptor Pharmaceuticals Inc.
Principal Investigator: Bruce H. Cohen, MD Akron Children's Hospital
  More Information

Responsible Party: Raptor Pharmaceuticals Inc. Identifier: NCT02023866     History of Changes
Other Study ID Numbers: RP103-MITO-001 
Study First Received: December 17, 2013
Last Updated: January 28, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by Raptor Pharmaceuticals Inc.:
subacute necrotizing encephalopathy (Leigh Syndrome);
Leber's hereditary optic neuropathy;
myoclonic epilepsy and ragged-red fibers (MERFF);
mitochondrial encephalomyopathy, lactic acidosis, and stroke-like syndrome (MELAS);
Kearn-Sayre syndrome;
POLG-related disorders;
Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE)

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 processed this record on January 17, 2017