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Open-Label, Dose-Escalating Study Assessing Safety, Tolerability, Efficacy, of RP103 in Mitochondrial Disease (MITO-001)

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ClinicalTrials.gov Identifier: NCT02023866
Recruitment Status : Completed
First Posted : December 30, 2013
Results First Posted : November 13, 2017
Last Update Posted : November 13, 2017
Sponsor:
Information provided by (Responsible Party):
Horizon Pharma USA, Inc.

Tracking Information
First Submitted Date  ICMJE December 17, 2013
First Posted Date  ICMJE December 30, 2013
Results First Submitted Date  ICMJE October 13, 2017
Results First Posted Date  ICMJE November 13, 2017
Last Update Posted Date November 13, 2017
Actual Study Start Date  ICMJE May 2014
Actual Primary Completion Date October 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 13, 2017)
Change From Baseline in Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) Sections I-IV [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: December 24, 2013)
Change in Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) Score [ Time Frame: Baseline vs. Week 24 ]
Quality of life
Change History Complete list of historical versions of study NCT02023866 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 13, 2017)
  • Change From Baseline in Glutathione [ Time Frame: Baseline and Weeks 4, 8, 12, 16, 20, 24 ]
  • Change From Baseline in Glutathione Disulfide [ Time Frame: Baseline and Weeks 4, 8, 12, 16, 20, 24 ]
  • Change From Baseline in Lactic Acid [ Time Frame: Baseline and Weeks 4, 8, 12, 16, 20, 24 ]
  • Change From Baseline in 6 Minute Walk Test [ Time Frame: 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 [ Time Frame: 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 Barry-Albright Dystonia Scale Total Score [ Time Frame: 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).
  • Change From Baseline in Friedreich Ataxia Rating Scale [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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
Original Secondary Outcome Measures  ICMJE
 (submitted: December 24, 2013)
Change over time in Pharmacodynamic Biomarkers [ Time Frame: Baseline and Weeks 4, 8, 12, 16, 20, 24 ]
glutathione, acetoacetate, beta-hydroxybutyrate, lactate
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Open-Label, Dose-Escalating Study Assessing Safety, Tolerability, Efficacy, of RP103 in Mitochondrial Disease
Official Title  ICMJE 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
Brief Summary To evaluate safety, tolerability and efficacy of cysteamine bitartrate delayed-release capsules (RP103) administered up to 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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Inherited Mitochondrial Disease, Including Leigh Syndrome
Intervention  ICMJE Drug: Cysteamine Bitartrate
Cysteamine Bitartrate Delayed-release capsules
Other Name: RP103
Study Arms  ICMJE Experimental: 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.
Intervention: Drug: Cysteamine Bitartrate
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 15, 2017)
36
Original Estimated Enrollment  ICMJE
 (submitted: December 24, 2013)
32
Actual Study Completion Date  ICMJE October 2016
Actual Primary Completion Date October 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 6 Years to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02023866
Other Study ID Numbers  ICMJE RP103-MITO-001
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Horizon Pharma USA, Inc.
Study Sponsor  ICMJE Horizon Pharma USA, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Evelyn Olson, BS Horizon Pharma USA, Inc.
PRS Account Horizon Pharma USA, Inc.
Verification Date October 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP