Mitochondrial Diseases
Conditions
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)
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.
Interventions
Cysteamine Bitartrate Delayed-release capsules
Sponsors
Amgen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-label extension study
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) Score | Baseline, every 3 months and Study Exit (up to 24 Months) | 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; 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change Over Time in Two of the Most Pre-eminent Symptoms | Baseline, every 3 months and Study Exit (up to 24 Months) | The two pre-eminent symptoms previously identified in study RP103-MITO-001 were to be continued to be assessed during the extension study. Symptoms included myopathy, dystonia, ataxia, retarded motor development, reduced activities of daily living, and vision. |
| Change Over Time in Pharmacodynamic Biomarkers | Baseline, every 3 months and Study Exit (up to 24 Months) | Change from baseline in glutathione, glutathione disulfide, and lactate analyses were not performed as the study was prematurely terminated. |
Countries
United States
Participant flow
Recruitment details
Participants who completed study RP103-MITO-001 (NCT02023866) study were eligible for enrollment into this extension study. The study was conducted at 5 sites in the United States.
Participants by arm
| Arm | Count |
|---|---|
| Cysteamine Bitartrate Delayed-release Participants received cysteamine bitartrate delayed-release capsules (RP103) twice daily for up to 2 years. The starting dose was the same as the last dose received in study RP103-MITO-001, the maximum dose was 1.3 g/m²/day. | 22 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Sponsor Decision | 20 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Cysteamine Bitartrate Delayed-release |
|---|---|
| Age, Continuous | 10.8 years STANDARD_DEVIATION 4.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants |
| Race/Ethnicity, Customized Black of African American | 0 Participants |
| Race/Ethnicity, Customized Multiple | 2 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants |
| Race/Ethnicity, Customized White | 18 Participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 22 |
| other Total, other adverse events | 18 / 22 |
| serious Total, serious adverse events | 9 / 22 |
Outcome results
Primary
Change in Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) Score
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; 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.
Time frame: Baseline, every 3 months and Study Exit (up to 24 Months)
Population: The study was closed prematurely due to lack of efficacy demonstrated in base study RP103-MITO-001. As a result, only a limited amount of data was collected for patients that were enrolled prior to termination. The decision was made that the data were not complete enough, and no analyses were conducted.
Secondary
Change Over Time in Pharmacodynamic Biomarkers
Change from baseline in glutathione, glutathione disulfide, and lactate analyses were not performed as the study was prematurely terminated.
Time frame: Baseline, every 3 months and Study Exit (up to 24 Months)
Population: The study was closed prematurely due to lack of efficacy demonstrated in base study RP103-MITO-001. As a result, only a limited amount of data was collected for patients that were enrolled prior to termination. The decision was made that the data were not complete enough, and no analyses were conducted.
Secondary
Change Over Time in Two of the Most Pre-eminent Symptoms
The two pre-eminent symptoms previously identified in study RP103-MITO-001 were to be continued to be assessed during the extension study. Symptoms included myopathy, dystonia, ataxia, retarded motor development, reduced activities of daily living, and vision.
Time frame: Baseline, every 3 months and Study Exit (up to 24 Months)
Population: The study was closed prematurely due to lack of efficacy demonstrated in base study RP103-MITO-001. As a result, only a limited amount of data was collected for patients that were enrolled prior to termination. The decision was made that the data were not complete enough, and no analyses were conducted.