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

An Open-Label, Dose-Escalating 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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02023866

Acronym

MITO-001

Enrollment

Registered

2013-12-30

Start date

2014-05-31

Completion date

2016-10-31

Last updated

2024-12-27

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

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

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.

Interventions

DRUGCysteamine Bitartrate

Cysteamine Bitartrate Delayed-release capsules

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

6 Years to 17 Years

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Change From Baseline in Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) Sections I-IV	Baseline through Week 24	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.

Secondary

Measure	Time frame	Description
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	The investigator selected the two most preeminent symptoms for each participant during the screening visit from the following: Myopathy, dystonia, ataxia, retarded motor development, reduced activities of daily living, and vision. The 2 symptoms selected for each participant were then assessed at each subsequent study visit. Myopathy was assessed using the 6 minute walk test, which measures the distance walked in a 6 minute walk test.
Change From Baseline in Jamar Dynamometer Hand Strength	Baseline and Weeks 4, 8, 12, 16, 20, 24	The investigator selected the two most preeminent symptoms for each participant during the screening visit from the following: myopathy, dystonia, ataxia, retarded motor development, reduced activities of daily living, and vision. The 2 symptoms selected for each participant were then assessed at each subsequent study visit. Myopathy was assessed using standard grip strength evaluation, which measures hand strength in both hands using a Jamar dynamometer.
Change From Baseline in Glutathione	Baseline and Weeks 4, 8, 12, 16, 20, 24	—
Change From Baseline in Friedreich Ataxia Rating Scale	Baseline and Weeks 4, 8, 12, 16, 20, 24	The investigator selected the two most preeminent symptoms for each participant during the screening visit from the following: myopathy, dystonia, ataxia, retarded motor development, reduced activities of daily living, and vision. The 2 symptoms selected for each participant were then assessed at each subsequent study visit. Ataxia was assessed using the Friedreich Ataxia Rating Scale (FARS). FARS comprises a functional ataxia staging score of overall mobility (score 0 to 6), an assessment of the activities of daily living (ADL) (score 0 to 36) and a neurological assessment (score from 0 to 117) which is composed of bulbar (score 0-11), upper limb (score 0- 36) and lower limb (score 0-16), peripheral nerve (score 0-26) and upright stability/gait (score 0-28). The scores were summed to calculate the total score which ranges from 0 to 159. A higher score indicates a greater level of disability.
Change From Baseline in Gross Motor Function	Baseline and Weeks 4, 8, 12, 16, 20, 24	The investigator selected the two most preeminent symptoms for each participant during the screening visit from the following: myopathy, dystonia, ataxia, retarded motor development, reduced activities of daily living, and vision. The 2 symptoms selected for each participant were then assessed at each subsequent study visit. Retarded motor development was assessed using the Gross Motor Function Measure (GMFM)-88 which consists of 88 items scored on a scale of 0 to 3: 0: Does not initiate the task; 1. Initiates the task (completes \< 10%); 2. Partially completes the task (10 to 99%); 3. Completes the task (100%). The 88 items are grouped into five dimensions: 1) lying and rolling, 2) sitting, 3) crawling and kneeling, 4) standing, and 5) walking, running and jumping. Scores are expressed as a percentage of the maximum score for that dimension. The total score is the average of the 5 the percentage scores where higher scores indicate better performance.
Change From Baseline in Modified Lansky Play Performance Scale	Baseline and Weeks 4, 8, 12, 16, 20, 24	The investigator selected the 2 most preeminent symptoms for each participant during the screening visit from the following: myopathy, dystonia, ataxia, retarded motor development, reduced activities of daily living, and vision. The 2 symptoms were assessed at each subsequent study visit. Reduced activities of daily living was assessed using the modified Lansky Play Performance Scale, completed by parents based on their child's activity in the past week, where 100=fully active; 90=minor restrictions in strenuous physical activity; 80=active, gets tired more quickly; 70=greater restriction of play, less time spent in play activity; 60=up and around, active play minimal; quieter activities; 50=lying around much of the day; no active playing, all quiet play and activities; 40=mainly in bed; quiet activities; 30=bedbound; needs assistance even for quiet play; 20=sleeps often; play limited to very passive activities; 10=doesn't play or get out of bed; 5=unresponsive 0=dead
Change From Baseline in Barry-Albright Dystonia Scale Total Score	Baseline and Weeks 4, 8, 12, 16, 20, 24	The investigator selected the two most preeminent symptoms for each participant during the screening visit from the following: myopathy, dystonia, ataxia, retarded motor development, reduced activities of daily living, and vision. The 2 symptoms selected for each participant were then assessed at each subsequent study visit. Dystonia symptoms were assessed using the Barry-Albright Dystonia Scale for Dystonia. Participants were assessed for dystonia in each of the following regions: eyes, mouth, neck, trunk, and each upper and lower extremity (8 body regions) on a scale from 0 (absent) to 4 (severe symptoms). The individual scores were summed to calculate the total score which ranges from 0 (dystonia absent) to 32 (severe dystonia).

Countries

United States

Participant flow

Participants by arm

Arm	Count
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.	36
Total	36

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	3
Overall Study	Non-compliance	2
Overall Study	Withdrawal by Subject	1

Baseline characteristics

Characteristic	Cysteamine Bitartrate Delayed-release
Age, Continuous	9.3 years STANDARD_DEVIATION 4.8
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	31 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Mitochondrial Disease Subtype Kearns-Sayre syndrome	1 Participants
Mitochondrial Disease Subtype Leigh Syndrome	9 Participants
Mitochondrial Disease Subtype LHON	3 Participants
Mitochondrial Disease Subtype MELAS	6 Participants
Mitochondrial Disease Subtype MERFF	4 Participants
Mitochondrial Disease Subtype NUBPL Related Encephalopathy	2 Participants
Mitochondrial Disease Subtype Others	4 Participants
Mitochondrial Disease Subtype POLG-related disorders	7 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	3 Participants
Race/Ethnicity, Customized Asian	0 Participants
Race/Ethnicity, Customized Black of African American	0 Participants
Race/Ethnicity, Customized Multiple	3 Participants
Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander	0 Participants
Race/Ethnicity, Customized Other	2 Participants
Race/Ethnicity, Customized White	28 Participants
Sex: Female, Male Female	17 Participants
Sex: Female, Male Male	19 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	1 / 36
other Total, other adverse events	35 / 36
serious Total, serious adverse events	11 / 36

Outcome results

Primary

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.

Time frame: Baseline through Week 24

Population: Completers Analysis Set included all participants who received at least one dose of study drug (RP103) with at least one post-baseline NPMDS assessment and an evaluable Week 24 NPMDS assessment within the protocol specified window.

Arm	Measure	Group	Value (MEAN)	Dispersion
Cysteamine Bitartrate Delayed-release	Change From Baseline in Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) Sections I-IV	Section I	-0.3 units on a scale	Standard Deviation 0.7
Cysteamine Bitartrate Delayed-release	Change From Baseline in Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) Sections I-IV	Section II	0.1 units on a scale	Standard Deviation 1.1
Cysteamine Bitartrate Delayed-release	Change From Baseline in Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) Sections I-IV	Section III	-0.6 units on a scale	Standard Deviation 1.2
Cysteamine Bitartrate Delayed-release	Change From Baseline in Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) Sections I-IV	Section IV	0.0 units on a scale	Standard Deviation 4

Comparison: Section I - Current Function Null hypothesis = change from baseline is 0.p-value: 0.1875Wilcoxon Signed Rank

Comparison: Section II - System Specific Involvement Null hypothesis = change from baseline is 0.p-value: 1Wilcoxin Signed Rank

Comparison: Section III - Current Clinical Assessment Null hypothesis = change from baseline is 0.p-value: 0.0781Wilcoxin Signed Rank

Comparison: Section IV - Quality of Life Null hypothesis = change from baseline is 0.p-value: 0.2941t-test, 2 sided

Secondary

Change From Baseline in 6 Minute Walk Test

The investigator selected the two most preeminent symptoms for each participant during the screening visit from the following: Myopathy, dystonia, ataxia, retarded motor development, reduced activities of daily living, and vision. The 2 symptoms selected for each participant were then assessed at each subsequent study visit. Myopathy was assessed using the 6 minute walk test, which measures the distance walked in a 6 minute walk test.