Clinical trial NCT02473445: A Long-term Extension of Study RP103-MITO-001 (NCT02023866) to Assess Cysteamine Bitartrate Delayed-release Capsules (RP103) in Children With Inherited Mitochondrial Disease
Official title: A Long-Term Open-Label Extension Study of RP103-MITO-001 to Assess the Safety, Tolerability and Efficacy of Cysteamine Bitartrate Delayed-release Capsules (RP103) for Treatment of Children With Inherited Mitochondrial Disease
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Mitochondrial Diseases
Keywords: Inherited mitochondrial disease
Leigh Syndrome
Leber's Hereditary Optic Neuropathy (LHON)
Myoclonic epilepsy and ragged-red fibers (MERFF)
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like syndrome (MELAS)
Kearn-Sayre syndrome
Polymerase gamma (POLG) -related disorders
Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE)
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2015-06-16
Enrollment: 22
Sex: ALL
Minimum age (years): 6
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Open-label extension study
Primary purpose: TREATMENT

Brief summary: A long-term extension study to assess the safety, tolerability and efficacy of cysteamine bitartrate delayed-release capsules (RP103) in children with inherited mitochondrial diseases who previously enrolled into study RP103-MITO-001 (NCT02023866).

Detailed description: Patients with inherited mitochondrial diseases associated with nuclear or mitochondrial deoxyribonucleic acid (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); polymerase gamma (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 polyneuropathy-ophthalmoplegia-leukoencephalopathy- Intestinal pseudoobstruction (POLIP) syndrome; others, e.g., mitochondrial cardiomyopathies and other syndromes due to multiple mitochondrial DNA deletions.

Patients completing study RP103-MITO-001 (NCT02023866) are eligible for enrollment into the extension study RP103-MITO-002 if all inclusion and exclusion criteria are fulfilled. Subjects continue on the last total daily dose of cysteamine bitartrate delayed-release capsules taken during RP103-MITO-001. Dose-adjustments are permitted.

Study with completed results acquired from Horizon in 2024.

Eligibility criteria: Inclusion Criteria:

1. Completed all visits in Study RP103-MITO-001 (NCT02023866).
2. Body weight ≥ 5 kg.
3. 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 Day 1 to Study Exit).
4. 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.
5. 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 Day 1 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).
6. 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. Platelet count, lymphocyte count or hemoglobin below the lower limit of normal (LLN) at the Baseline visit.
3. 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 Baseline Visit.
4. Bilirubin \> 1.2 g/dL at the Baseline Visit.
5. Inability to complete the elements of the study, e.g., coma, hemodynamic instability or requiring continuous ventilator support.
6. Malabsorption requiring total parenteral nutrition (TPN), chronic diarrhea, bouts of pseudo obstruction.
7. Severe end-organ hypo-perfusion syndrome secondary to cardiac failure resulting in lactic acidosis.
8. Patients with suspected elevated intracranial pressure, pseudotumor cerebri (PTC) and/or papilledema.
9. Severe gastrointestinal disease including gastroparesis.
10. History of drug or alcohol abuse.
11. History of pancreatitis.
12. Participated in an investigational drug trial (except the RP103-MITO-001 study) within 30 days or, within 90 days for a biologic, device, or surgical treatment, for inherited mitochondrial diseases prior to the Baseline Visit.
13. Known or suspected hypersensitivity to cysteamine and penicillamine.
14. Female subjects who are nursing, planning a pregnancy, known or suspected to be pregnant, or with a positive serum pregnancy test at the Baseline visit.
15. Patients who, in the opinion of the Investigator, are not able or willing to comply with the protocol.

Primary outcomes:
measure: Change in Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) Score
timeFrame: Baseline, every 3 months and Study Exit (up to 24 Months)
Secondary outcomes:
measure: Change Over Time in Two of the Most Pre-eminent Symptoms
timeFrame: Baseline, every 3 months and Study Exit (up to 24 Months)
measure: Change Over Time in Pharmacodynamic Biomarkers
timeFrame: Baseline, every 3 months and Study Exit (up to 24 Months)
Other outcomes:
Locations:
city: San Diego
country: United States
facility: University of California at San Diego (UCSD)
state: California
city: Stanford
country: United States
facility: Stanford University School of Medicine
state: California
city: Akron
country: United States
facility: Akron Children's Hospital
state: Ohio
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.