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

NCT ID: NCT02023866

Last Updated: 2024-12-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 36 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-05-31
• Study Completion Date: 2016-10-31

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.

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.

Prior to treatment, patients will undergo a Screening Visit. If eligible, each participant will return for the Day 1 study visit and begin dosing. Every 2 weeks over the subsequent 8 weeks, participants 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, participants 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 Study Exit visit will occur at Week 24, and participants will be offered the opportunity to continue on to an extension study (RP103-MITO-002 [NCT02473445]) until results of the present study are known.

Study with completed results acquired from Horizon in 2024.

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cysteamine Bitartrate Delayed-release

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.

Group Type: EXPERIMENTAL

Cysteamine Bitartrate

Intervention Type: DRUG

Cysteamine Bitartrate Delayed-release capsules

Interventions

Cysteamine Bitartrate

Cysteamine Bitartrate Delayed-release capsules

Intervention Type: DRUG

Other Intervention Names

RP103

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)

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.

• Minimum Eligible Age: 6 Years
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Amgen

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

MD

Role: STUDY_DIRECTOR

Amgen

Locations

University of California at San Diego (UCSD)

San Diego, California, United States

Stanford University

Stanford, California, United States

Akron Children's Hospital

Akron, Ohio, United States

Baylor College of Medicine

Houston, Texas, United States

University of Utah, Division of Medical Genetics

Salt Lake City, Utah, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 20569301 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22208644 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 18702664 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19960200 (View on PubMed)

Other Identifiers

RP103-MITO-001

Identifier Type: -

Identifier Source: org_study_id