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

NCT02023866 | Completed Phase 2 Results

• 1 other identifier: RP103-MITO-001
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 5

Brief Summary

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

Conditions

Inherited Mitochondrial Disease, Including Leigh Syndrome

Keywords

Leigh Syndrome; Leber's hereditary optic neuropathy; myoclonic epilepsy; mitochondrial encephalomyopathy; Kearn-Sayre syndrome; POLG-related disorders; Neurogastrointestinal encephalopathy

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) Sections I-IV

  The NPMDS evaluates the progression of mitochondrial disease in pediatric patients in 4 domains: I - Current Function (vision, hearing, communication, feeding, and mobility) with scores ranging from 0 to 21; II -System Specific Involvement (seizures, encephalopathy, bleeding diathesis or coagulation defects, gastrointestinal, endocrine, respiratory, cardiovascular, renal, liver, and blood) with scores ranging from 0 to 30. III - Current Clinical Assessment (growth and development over past 6 months, vision, strabismus and eye movement, myopathy, ataxia, pyramidal, extrapyramidal, and neuropathy) with scores ranging from 0 to 28; and IV - Quality of Life with scores ranging from 0 to 25. For sections I-III, higher scores reflect more severe disease. For Section IV, a higher score reflects a lower quality of life.

  Baseline through Week 24

Secondary Outcomes (9)

• Change From Baseline in Glutathione

  Baseline and Weeks 4, 8, 12, 16, 20, 24

• Change From Baseline in Glutathione Disulfide

  Baseline and Weeks 4, 8, 12, 16, 20, 24

• Change From Baseline in Lactic Acid

  Baseline and Weeks 4, 8, 12, 16, 20, 24

• Change From Baseline in 6 Minute Walk Test

  Baseline and Weeks 4, 8, 12, 16, 20, 24

• Change From Baseline in Jamar Dynamometer Hand Strength

  Baseline and Weeks 4, 8, 12, 16, 20, 24

Study Arms (1)

Cysteamine Bitartrate Delayed-release

EXPERIMENTAL

Cysteamine bitartrate delayed-release capsules were administered twice daily following a dose-escalation design with a progressive weekly dose increase over the first 6 weeks. The starting dose was 0.2 g/m²/day, up to a maximum dose of 1.3 g/m²/day. Participants remained on their highest tolerated dose until Week 24.

Drug: Cysteamine Bitartrate

Interventions

Cysteamine Bitartrate DRUG

Cysteamine Bitartrate Delayed-release capsules

Also known as: RP103

Cysteamine Bitartrate Delayed-release

Eligibility Criteria

• Age: 6 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Age ≥ 6 years and \< 18 years
• Body weight ≥ 5 kg
• Documented (genetically confirmed known mutation, i.e. no variants of uncertain significance) diagnosis of inherited mitochondrial disease other than Friedreich's ataxia (FRDA)
• 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)
• With respect to concomitant medications, the subject must:
• 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);
• 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.
• 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
• 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):
• Hormonal contraception: birth control pills, injection, patch, vaginal ring or implant;
• Condom or diaphragm, with spermicide;
• Intrauterine device (IUD)
• Sterile male partner (vasectomy performed at least 6 months prior to the study).
• Subjects's legally authorized representative must provide written informed consent; Subject must provide assent, if required by local/institutional requirements
• Have mitochondrial myopathy as evidenced by one or more of the following criteria:

You may not qualify if:

• Documented diagnosis of concurrent inborn errors of metabolism
• Non-elective hospitalization related to mitochondrial disease or direct complication of disease within 60 days prior to the Screening Visit.
• Platelet count, lymphocyte count or hemoglobin below the lower limit of normal (LLN) at the Screening Visit
• 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
• Bilirubin \> 1.2 g/dL at the Screening Visit
• Inability to complete the elements of the study, e.g., coma, hemodynamic instability or requiring continuous ventilator support.
• Malabsorption requiring total parenteral nutrition (TPN), chronic diarrhea, bouts of pseudo obstruction
• Severe end-organ hypo-perfusion syndrome secondary to cardiac failure resulting in lactic acidosis
• Patients with suspected elevated intracranial pressure, pseudotumor cerebri (PTC) and/or papilledema
• Severe gastrointestinal disease including gastroparesis
• History of angina, myocardial infarction, or cardiac surgery within 2 years prior to the Screening Visit
• Any clinically significant electrocardiogram (ECG), including dysrhythmia, or clinically significant abnormal laboratory finding not already listed above at the Screening Visit
• History of drug or alcohol abuse
• History of pancreatitis
• 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

Sponsors & Collaborators

• Amgen: lead

Study Sites (5)

University of California at San Diego (UCSD)

San Diego, California, 92093-0935, United States

Location

Stanford University

Stanford, California, 94305, United States

Location

Akron Children's Hospital

Akron, Ohio, 44308, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

University of Utah, Division of Medical Genetics

Salt Lake City, Utah, 84132, United States

Location

Related Publications (4)

• Bousquet M, Gibrat C, Ouellet M, Rouillard C, Calon F, Cicchetti F. Cystamine metabolism and brain transport properties: clinical implications for neurodegenerative diseases. J Neurochem. 2010 Sep;114(6):1651-8. doi: 10.1111/j.1471-4159.2010.06874.x. Epub 2010 Aug 19.

  PMID: 20569301 BACKGROUND

• Salmi H, Leonard JV, Rahman S, Lapatto R. Plasma thiol status is altered in children with mitochondrial diseases. Scand J Clin Lab Invest. 2012 Apr;72(2):152-7. doi: 10.3109/00365513.2011.646299. Epub 2012 Jan 2.

  PMID: 22208644 BACKGROUND

• Maher P, Lewerenz J, Lozano C, Torres JL. A novel approach to enhancing cellular glutathione levels. J Neurochem. 2008 Nov;107(3):690-700. doi: 10.1111/j.1471-4159.2008.05620.x. Epub 2008 Aug 12.

  PMID: 18702664 BACKGROUND

• Mancuso M, Orsucci D, Logerfo A, Rocchi A, Petrozzi L, Nesti C, Galetta F, Santoro G, Murri L, Siciliano G. Oxidative stress biomarkers in mitochondrial myopathies, basally and after cysteine donor supplementation. J Neurol. 2010 May;257(5):774-81. doi: 10.1007/s00415-009-5409-7. Epub 2009 Dec 4.

  PMID: 19960200 BACKGROUND

MeSH Terms

Conditions

Leigh Disease; Optic Atrophy, Hereditary, Leber; Epilepsies, Myoclonic; Mitochondrial Encephalomyopathies; Ophthalmoplegia, Chronic Progressive External

Interventions

Cysteamine

Condition Hierarchy (Ancestors)

Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pyruvate Metabolism, Inborn Errors; Carbohydrate Metabolism, Inborn Errors; Metabolic Diseases; Nutritional and Metabolic Diseases; Mitochondrial Diseases; Optic Atrophies, Hereditary; Optic Atrophy; Optic Nerve Diseases; Cranial Nerve Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Eye Diseases, Hereditary; Eye Diseases; Epilepsy, Generalized; Epilepsy; Epileptic Syndromes; Mitochondrial Myopathies; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Ophthalmoplegia; Ocular Motility Disorders; Paralysis; Neurologic Manifestations; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Mercaptoethylamines; Ethylamines; Amines; Organic Chemicals; Sulfhydryl Compounds; Sulfur Compounds

Results Point of Contact

• Title: Evelyn Olson, Director
• Organization: Horizon Pharma USA, Inc.

clinicaltrials@horizonpharma.com

224- 383-3000

Study Officials

• MD

  Amgen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 17, 2013
• First Posted: December 30, 2013
• Study Start: May 1, 2014
• Primary Completion: October 1, 2016
• Study Completion: October 1, 2016
• Last Updated: December 27, 2024
• Results First Posted: November 13, 2017

Record last verified: 2024-12

Locations

US (5)