Open-Label, Dose-Escalating Study Assessing Safety, Tolerability, Efficacy, of RP103 in Mitochondrial Disease
Condition: Inherited Mitochondrial Disease, Including Leigh Syndrome
MeSH terms: Leigh Disease; Mitochondrial Diseases; Syndrome
Intervention: Cysteamine Bitartrate
Intervention description: Cysteamine Bitartrate Delayed-release capsules
Intervention MeSH terms: Cysteamine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 36.0
Sex: All
Minimum age: 6 Years
Maximum age: 17 Years
Healthy volunteers: No
Keywords: Leigh Syndrome; Leber's hereditary optic neuropathy; myoclonic epilepsy; mitochondrial encephalomyopathy; Kearn-Sayre syndrome; POLG-related disorders; Neurogastrointestinal encephalopathy

Summary:

      To evaluate safety, tolerability and efficacy of cysteamine bitartrate delayed-release
      capsules (RP103) administered up to 1.3 g/m²/day in two divided doses, every 12 hours, for up
      to 6 months in patients with inherited mitochondrial disease.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age ≥ 6 years and < 18 years

          2. Body weight ≥ 5 kg

          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
             (NPMDS) score, with a score between 15 to 45 inclusive [Leber's Hereditary Optic
             Neuropathy (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, coenzyme Q10 (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 related 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, aspartate
             aminotransferase [AST] or alanine aminotransferase [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 total parenteral nutrition (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 electrocardiogram (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.