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A Study to Evaluate ASP0367 in Participants With Primary Mitochondrial Myopathy (MOUNTAINSIDE)

Primary Purpose

Primary Mitochondrial Myopathy

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Bocidelpar
Placebo
Sponsored by
Astellas Pharma Inc
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Primary Mitochondrial Myopathy focused on measuring ASP0367, fatigue, exercise intolerance, muscle weakness, Primary Mitochondrial Myopathy

Eligibility Criteria

18 Years - 54 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Participant agrees and is able to adhere to the study requirements for the length of the study, including performing 6MWT, as well as the use of digital applications and video recordings.
  • Diagnosed with primary mitochondrial myopathy (PMM), consisting of the following:

    • Molecular genetic abnormality (i.e., nuclear or mitochondrial) known to be associated with causing mitochondrial dysfunction (such as, but not limited to, mitochondrial DNA (mtDNA) single, variable deletions in chronic progressive external ophthalmoplegia (CPEO) and Kearns-Sayre syndrome (KSS); mtDNA m.3243 A > G common mutation in mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS); pathogenic nuclear or mitochondrial genome variants demonstrated to cause primary mitochondrial disease), and
    • Participant reported symptoms (i.e., muscle weakness, fatigue and exercise intolerance) or physical examination findings of myopathy that are the predominant symptoms of the participant's mitochondrial disorder.
  • Participant has been on stable dose regimen of coenzyme Q10 (CoQ10), carnitine, creatine or other mitochondrial disease-focused vitamins or supplemental therapies for 3 months prior to randomization and intends to stay on a stable dose for duration of study period (for participants who take any above-mentioned medications or supplements).
  • Participant has been on stable exercise regimen within 4 weeks prior to randomization and intends to stay on a stable regimen for duration of study period (for participants who participate in a regular exercise regimen).
  • Female participant is not pregnant and at least one of the following conditions apply:

    • Not a woman of childbearing potential (WOCBP).
    • WOCBP who agrees to follow the contraceptive guidance from the time of informed consent through at least 30 days after final study treatment administration.
  • Female participant must agree not to breastfeed starting at screening and throughout the study period and for 30 days after final study treatment administration.
  • Female participant must not donate ova starting at first dose of IP and throughout the study period and for 30 days after final study treatment administration.
  • Male participant with female partner(s) of childbearing potential (including breastfeeding partner) must agree to use contraception throughout the treatment period and for 30 days after final study treatment administration.
  • Male participant must not donate sperm during the treatment period and for 30 days after final study treatment administration.
  • Male participant with pregnant partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy throughout the study period and for 30 days after final study treatment administration.
  • Participant agrees not to participate in another interventional study while participating in the present study.

Open-label Extension Continuation Criteria:

  • Participant must meet all of the following OLE criteria at the week 52 study visit in the treatment period to be eligible for OLE:

    • Participant must continue to be able and willing to adhere to the study requirements.
    • Participant who is eligible to continue in OLE.

Exclusion Criteria:

  • Participant has additional signs and/or symptoms due to non-myopathic process (e.g., cerebellar dysfunctions, movement disorder, peripheral neuropathy, stroke or other) or a gait problem not attributed to the myopathy that would interfere/may in addition to the myopathy affect the participant's performance during 6MWT or 5 times sit to stand (5XSTS).
  • Participant has received any investigational therapy within 28 days or 5 half-lives, whichever is longer, prior to screening.
  • Participant has any condition, which makes the participant unsuitable for study participation.
  • Participant has cardiac troponin I (cTnI) > upper limit of normal (ULN) at screening and is assessed as clinically significant.
  • Participant has estimated glomerular filtration rate (eGFR) calculated by the chronic kidney disease epidemiology collaboration equation < 60 milliliter per minute per 1.73 meter square at screening.
  • Participant has at screening: total bilirubin (TBL) > ULN or transaminase(s) (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) > ULN in the absence of elevations in creatine kinase (CK). Participants who have a slightly elevated TBL and/or ALT and/or AST and are suitable candidates for the study, can be enrolled in the study as long as the investigator can rule out any underlying liver dysfunction by running additional tests and after discussing the case with the medical monitor.
  • Participant has psychiatric conditions such as schizophrenia, bipolar disorder or major depressive disorder that has not been under control within 3 months prior to screening.
  • Participant has a history of suicide attempt, suicidal behavior or has any suicidal ideation within 1 year prior to screening that meets criteria at a level of 4 or 5 by using the Columbia-Suicide Severity Rating Scale (C-SSRS) or who is at significant risk to commit suicide.
  • Participant has severe behavioral or cognitive problems that preclude participation in the study.
  • Participant has undergone an in-patient hospitalization that precludes participation in the study, within the 30 days prior to the randomization.
  • Participant has a planned hospitalization or a surgical procedure during the study, which may affect the study assessments.
  • Participant has clinically significant and unstable respiratory disease and/or cardiac disease (medical history or current clinical findings), or prior interventional cardiac procedure (e.g., cardiac catheterization, angioplasty/percutaneous coronary intervention, balloon valvuloplasty, etc.) within 3 months prior to randomization. Participants with pacemakers are allowed in the study per investigator's discretion and after discussion with the medical monitor, and as long as it is used for prevention and there is no underlying cardiac dysfunction.
  • Participant has a corrected mean QT interval using Fridericia's correction (QTcF) > 450 msec for male participants and > 480 msec for female participants at screening or randomization. If QTcF exceeds these limits, one additional triplicate ECG can be repeated on the same day in order to determine the participant's eligibility.
  • ECG evidence of acute ischemia, atrial fibrillation or active conduction system abnormalities with the exception of any of the following:

    • First degree atrioventricular (AV)-block
    • Second degree AV-block Type 1 (Mobitz Type 1/Wenckebach type)
    • Right bundle branch block
    • Left fascicular block
    • Bi-fascicular block
  • Participant requires any ventilator support.
  • Participant has severe vision impairment that may interfere with their ability to complete all study requirements.
  • Participant has an intractable seizure disorder that may interfere with their ability to complete all study requirements.
  • Active malignancy or any other cancer from which the participant has been disease-free for < 5 years, except for curative treated localized non-melanoma skin cancer (e.g., basal cell or squamous cell carcinoma).
  • Participant has a solid organ transplant and/or is currently receiving treatment with therapy for immunosuppression.
  • Participant has severe scoliosis or kyphoscoliosis that significantly impair respiratory capacity and pulmonary function tests or limit positioning due to pain who would be likely to require orthopedic surgical intervention within a year after study randomization.
  • Participant has a positive for human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection at screening.
  • Participant has previously received ASP0367.
  • Participant has a history of active substance abuse within 1 year prior to randomization.
  • Participant has used any peroxisome proliferator-activated receptor (PPAR) ligands such as fibrates and thiazolidinediones within 4 weeks prior to randomization.
  • Participant has initiated the use of CoQ10, carnitine, creatine or other mitochondrial disease-focused supplements within 3 months prior to study randomization.
  • Participant has a known or suspected hypersensitivity to ASP0367 or any components of the formulation used.
  • Participant has symptomatic coronavirus disease 2019 (COVID-19) infection within 3 months prior to study randomization that required treatment (Monoclonal antibodies, ventilator support, hospitalization) and/or led to long-term sequelae or lingering symptoms.
  • Participant has BMI below 18.5 kilogram per meter square (kg/m^2) or above 35 kg/m^2 at screening
  • Participant has bulbar weakness due to either neuropathy or myopathy

Sites / Locations

  • Mayo Clinic ArizonaRecruiting
  • University of California, San DiegoRecruiting
  • Stanford University Medical CenterRecruiting
  • Children's Hospital ColoradoRecruiting
  • Mayo Clinic FloridaRecruiting
  • Massachusetts General HospitalRecruiting
  • Mayo ClinicRecruiting
  • Columbia University Irving Medical CenterRecruiting
  • Akron Children's HospitalRecruiting
  • Cleveland ClinicRecruiting
  • Children's Hospital of PhiladelphiaRecruiting
  • Baylor College of MedicineRecruiting
  • University of Texas Health Science Center at HosutonRecruiting
  • Seattle Children's HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Experimental

Placebo Comparator

Experimental

Placebo Comparator

Experimental

Arm Label

Phase 2: low dose ASP0367

Phase 2: high dose ASP0367

Phase 2: Placebo

Phase 3: ASP0367

Phase 3: Placebo

Open Label Extension: ASP0367

Arm Description

Participants will receive ASP0367 once daily in the morning for 2 weeks.

Participants will receive ASP0367 once daily in the morning for 2 weeks.

Participants will receive placebo once daily in the morning for 2 weeks.

Participants will receive ASP0367 once daily in the morning for up to 52 weeks.

Participants will receive placebo once daily in the morning for up to 52 weeks.

Participants will receive ASP0367 once daily in the morning for 24 weeks.

Outcomes

Primary Outcome Measures

Phase 2 portion: Pharmacokinetics (PK) of ASP0367 in plasma: AUCtau
AUCtau: AUC from the time of dosing to the start of the next dosing interval at multiple dose conditions. AUCtau will be recorded from the PK plasma samples collected.
Phase 2 portion: PK of ASP0367 in plasma: Cmax
Cmax: maximum concentration. Cmax will be recorded from the PK plasma samples collected.
Phase 2 portion: Percent change from baseline peroxisome proliferator-activated receptor (PPAR) delta target gene expression levels in blood
Whole blood cell samples will be collected to measure percent change in target gene expressions.
Phase 2 and Phase 3 portions: Safety and tolerability assessed by nature, frequency and severity of treatment emergent adverse events (TEAEs)
Treatment emergent adverse events will be coded using medical dictionary for regulatory activities (MedDRA). A TEAE is defined as an adverse event (AE) observed after starting administration of the investigational product (IP) to 28 days after last dose of IP or moving to the OLE, whichever comes first. An AE is any untoward medical occurrence in a participant, temporally associated with the use of IP, whether or not considered related to the IP. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of IP. This includes events related to the comparator and events related to the study procedures.
Phase 2 and Phase 3 portions: Number of participants with body weight change abnormalities and/ or AEs
Number of participants with potentially clinically significant body weight changes.
Phase 2 and Phase 3 portions: Number of participants with 12-lead electrocardiogram (ECG) abnormalities and/ or AEs
Number of participants with potentially clinically significant 12-lead ECG values.
Phase 2 and Phase 3 portions: Number of participants with laboratory value abnormalities and/ or AEs
Number of participants with potentially clinically significant laboratory values.
Phase 2 and Phase 3 portions: Number of participants with vital sign abnormalities and/ or AEs
Number of participants with potentially clinically significant vital sign values.
Phase 2 and Phase 3 portions: Number of participants with suicidal ideation and/ or behavior as assessed Columbia-Suicide Severity Rating Scale (C-SSRS)
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a clinician administered assessment tool that evaluates suicidal ideation and behavior. Number of participants that have an affirmative response provided to the 5 items for suicidal ideation (1. Wish to be dead, 2. Nonspecific active suicidal thoughts, 3. Active suicidal ideation with any methods (not plan) without intent to act, 4. Active suicidal ideation with some intent to act, without specific plan, 5. Active suicidal ideation with specific plan and intent) and/or to the 6 items for suicidal behavior (1. Actual attempt, 2. Interrupted attempt, 3. Aborted attempt, 4. Preparatory acts or behavior, 5. Suicidal Behavior 6. Completed suicide).
Phase 3 portion: Safety and tolerability assessed by nature, frequency and severity of treatment emergent adverse events (TEAEs)
Treatment emergent adverse events will be coded using medical dictionary for regulatory activities (MedDRA). A TEAE is defined as an adverse event (AE) observed after starting administration of the investigational product (IP) to 28 days after last dose of IP or moving to the OLE, whichever comes first. An AE is any untoward medical occurrence in a participant, temporally associated with the use of IP, whether or not considered related to the IP. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of IP. This includes events related to the comparator and events related to the study procedures.
Phase 3 portion: Number of participants with body weight change abnormalities and/ or AEs
Number of participants with potentially clinically significant body weight changes.
Phase 3 portion: Number of participants with 12-lead electrocardiogram (ECG) abnormalities and/ or AEs
Number of participants with potentially clinically significant 12-lead ECG values.
Phase 3 portion: Number of participants with laboratory value abnormalities and/ or AEs
Number of participants with potentially clinically significant laboratory values.
Phase 3 portion: Number of participants with vital sign abnormalities and/ or AEs
Number of participants with potentially clinically significant vital sign values.
Phase 3 portion: Number of participants with suicidal ideation and/ or behavior as assessed Columbia-Suicide Severity Rating Scale (C-SSRS)
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a clinician administered assessment tool that evaluates suicidal ideation and behavior. Number of participants that have an affirmative response provided to the 5 items for suicidal ideation (1. Wish to be dead, 2. Nonspecific active suicidal thoughts, 3. Active suicidal ideation with any methods (not plan) without intent to act, 4. Active suicidal ideation with some intent to act, without specific plan, 5. Active suicidal ideation with specific plan and intent) and/or to the 6 items for suicidal behavior (1. Actual attempt, 2. Interrupted attempt, 3. Aborted attempt, 4. Preparatory acts or behavior, 5. Suicidal Behavior 6. Completed suicide).
Phase 3 portion: Change from baseline in distance walked in 6 minutes assessed in meters
The 6-minute walk test (6MWT) is a measurement of endurance that assesses walking distance over 6 minutes.

Secondary Outcome Measures

Phase 3 portion: Change from baseline in quality of life in neurological disorders (Neuro-QoL) Short Form Fatigue score
The Neuro-QoL Short Form Fatigue score is an 8-item self- assessment questionnaire evaluating the perception of fatigue and its impact in daily life activities. Participants have five response options for each item: 1=Never, 2=Rarely, 3=Sometimes, 4=Often, 5=Always. The questionnaire is scored by adding the response to each of the items. Higher scores indicate a greater level of fatigue.
Phase 3 portion: Change from baseline in time spent on the 5 Times Sit to Stand (5XSTS) test
Change from baseline in time spent on the 5XSTS test. The test requires participants to sit with arms folded across chest and back against the chair and stand up and sit down 5 times in a row, as quickly as he/she can.
Phase 3 portion: Change from baseline in Modified Fatigue Impact Scale (MFIS)
MFIS is a modified form of the Fatigue Impact Scale questionnaire specific to measuring how fatigue impacts the lives of those affected by fatigue-like symptoms. The 21 items in the scale measure three domains of fatigue including physical, cognitive and psychosocial functioning. Participants have five response options for each item: 0=Never, 1=Rarely, 2=Sometimes, 3=Often, and 4=Almost always. The scale is scored by adding the response to each of the items. Higher scores indicate a greater level of fatigue.
Phase 3 portion: Change from baseline in Neuro-QoL Short Form Lower Extremity Function (Mobility) score
The Neuro-QoL Short Form Lower Extremity Function (Mobility) score is an 8-item self-assessment questionnaire evaluating one's ability to carry out various activities involving the trunk region and increasing degrees of bodily movement, ambulation, balance or endurance. Participants have five response options for each item: 1=Unable to do, 2=With much difficulty, 3=With some difficulty, 4=With a little difficulty, 5=Without any difficulty. The questionnaire is scored by adding the response to each of the items. Higher scores indicate a greater level of lower extremity function (Mobility).
Phase 3 portion: Score on Patient Global Impression of Change (PGIC)
The Patient Global Impression of Change evaluates participant's most bothersome symptom and assesses if there has been an improvement or decline in clinical status. Ratings range from (1) very much improved to (7) very much worse.
Phase 3 portion: Change from baseline in Patient Global Impression of Severity (PGIS)
The Patient Global Impression of Severity questionnaire assesses patient's impression of disease severity. The questionnaire asks the participant to best describe the severity of the participant's most bothersome pre-defined symptom over the past week scored from (1) None to (4) Severe.

Full Information

First Posted
November 19, 2020
Last Updated
August 21, 2023
Sponsor
Astellas Pharma Inc
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1. Study Identification

Unique Protocol Identification Number
NCT04641962
Brief Title
A Study to Evaluate ASP0367 in Participants With Primary Mitochondrial Myopathy
Acronym
MOUNTAINSIDE
Official Title
A Randomized, Double-blind, Placebo-controlled Adaptive Phase 2/3 Study With Open-label Extension to Assess the Efficacy, Safety and Tolerability of ASP0367 in Participants With Primary Mitochondrial Myopathy
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 17, 2021 (Actual)
Primary Completion Date
October 31, 2023 (Anticipated)
Study Completion Date
May 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Astellas Pharma Inc

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of the phase 2 portion of this study is to select a biologically-active ASP0367 dose level by pharmacokinetic (PK) and pharmacodynamic (PD) evaluation. The phase 2 portion of this study will also assess the safety and tolerability of ASP0367. The purpose of the phase 3 portion of this study is to assess the effect of ASP0367 on functional improvement relative to placebo and will also assess the safety and tolerability of ASP0367 relative to placebo. The phase 3 portion of this study will also assess the effect of ASP0367 on functional improvement and fatigue relative to placebo and will assess the effect of ASP0367 in overall participant functioning relative to placebo.
Detailed Description
Efficacy (i.e., functional improvement) will be assessed by a functional motor test, 6-minute walk test (6MWT). The study consists of the following portions: screening (4 weeks); phase 2 dose selection portion with 2 doses of ASP0367 versus matching placebo (2 weeks); phase 3 portion with selected, single dose treatment versus placebo (up to 52 weeks); open-label extension (OLE) (24 weeks); and follow-up (4 weeks). During the phase 2 portion of the study, participants will be randomly placed into 1 of 3 arms (low dose ASP0367, high dose ASP0367 or placebo). The relevant dose level will be selected based on the pharmacokinetics/pharmacodynamics and overall safety. Participants will maintain their original Phase 2 dose level and no new participants will be enrolled in the study until phase 3 dose selection is made. After the phase 3 dose is selected, all participants except the placebo group will switch to the selected dose level of ASP0367 for the remainder of the phase 3 portion of the study (up to a total 52 weeks including the phase 2 portion). Participants who were originally assigned to placebo will remain on placebo for up to 52 weeks. The remaining enrollment of participants will be randomized to either ASP0367 or matching placebo at a ratio of 1:1. All participants who have completed the phase 3 portion of the study and are eligible for the OLE will be offered the opportunity to take ASP0367 for an additional 24 weeks.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Primary Mitochondrial Myopathy
Keywords
ASP0367, fatigue, exercise intolerance, muscle weakness, Primary Mitochondrial Myopathy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Masking Description
Phase 2/3 masking: Subject, Caregiver, Investigator Open-label extension: No masking
Allocation
Randomized
Enrollment
195 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Phase 2: low dose ASP0367
Arm Type
Experimental
Arm Description
Participants will receive ASP0367 once daily in the morning for 2 weeks.
Arm Title
Phase 2: high dose ASP0367
Arm Type
Experimental
Arm Description
Participants will receive ASP0367 once daily in the morning for 2 weeks.
Arm Title
Phase 2: Placebo
Arm Type
Placebo Comparator
Arm Description
Participants will receive placebo once daily in the morning for 2 weeks.
Arm Title
Phase 3: ASP0367
Arm Type
Experimental
Arm Description
Participants will receive ASP0367 once daily in the morning for up to 52 weeks.
Arm Title
Phase 3: Placebo
Arm Type
Placebo Comparator
Arm Description
Participants will receive placebo once daily in the morning for up to 52 weeks.
Arm Title
Open Label Extension: ASP0367
Arm Type
Experimental
Arm Description
Participants will receive ASP0367 once daily in the morning for 24 weeks.
Intervention Type
Drug
Intervention Name(s)
Bocidelpar
Other Intervention Name(s)
MA-0211, ASP0367
Intervention Description
Oral
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Oral
Primary Outcome Measure Information:
Title
Phase 2 portion: Pharmacokinetics (PK) of ASP0367 in plasma: AUCtau
Description
AUCtau: AUC from the time of dosing to the start of the next dosing interval at multiple dose conditions. AUCtau will be recorded from the PK plasma samples collected.
Time Frame
Day 14
Title
Phase 2 portion: PK of ASP0367 in plasma: Cmax
Description
Cmax: maximum concentration. Cmax will be recorded from the PK plasma samples collected.
Time Frame
Day 14
Title
Phase 2 portion: Percent change from baseline peroxisome proliferator-activated receptor (PPAR) delta target gene expression levels in blood
Description
Whole blood cell samples will be collected to measure percent change in target gene expressions.
Time Frame
Baseline and Day 14
Title
Phase 2 and Phase 3 portions: Safety and tolerability assessed by nature, frequency and severity of treatment emergent adverse events (TEAEs)
Description
Treatment emergent adverse events will be coded using medical dictionary for regulatory activities (MedDRA). A TEAE is defined as an adverse event (AE) observed after starting administration of the investigational product (IP) to 28 days after last dose of IP or moving to the OLE, whichever comes first. An AE is any untoward medical occurrence in a participant, temporally associated with the use of IP, whether or not considered related to the IP. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of IP. This includes events related to the comparator and events related to the study procedures.
Time Frame
Through Week 52
Title
Phase 2 and Phase 3 portions: Number of participants with body weight change abnormalities and/ or AEs
Description
Number of participants with potentially clinically significant body weight changes.
Time Frame
Through Week 52
Title
Phase 2 and Phase 3 portions: Number of participants with 12-lead electrocardiogram (ECG) abnormalities and/ or AEs
Description
Number of participants with potentially clinically significant 12-lead ECG values.
Time Frame
Through Week 52
Title
Phase 2 and Phase 3 portions: Number of participants with laboratory value abnormalities and/ or AEs
Description
Number of participants with potentially clinically significant laboratory values.
Time Frame
Through Week 52
Title
Phase 2 and Phase 3 portions: Number of participants with vital sign abnormalities and/ or AEs
Description
Number of participants with potentially clinically significant vital sign values.
Time Frame
Through Week 52
Title
Phase 2 and Phase 3 portions: Number of participants with suicidal ideation and/ or behavior as assessed Columbia-Suicide Severity Rating Scale (C-SSRS)
Description
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a clinician administered assessment tool that evaluates suicidal ideation and behavior. Number of participants that have an affirmative response provided to the 5 items for suicidal ideation (1. Wish to be dead, 2. Nonspecific active suicidal thoughts, 3. Active suicidal ideation with any methods (not plan) without intent to act, 4. Active suicidal ideation with some intent to act, without specific plan, 5. Active suicidal ideation with specific plan and intent) and/or to the 6 items for suicidal behavior (1. Actual attempt, 2. Interrupted attempt, 3. Aborted attempt, 4. Preparatory acts or behavior, 5. Suicidal Behavior 6. Completed suicide).
Time Frame
Through Week 52
Title
Phase 3 portion: Safety and tolerability assessed by nature, frequency and severity of treatment emergent adverse events (TEAEs)
Description
Treatment emergent adverse events will be coded using medical dictionary for regulatory activities (MedDRA). A TEAE is defined as an adverse event (AE) observed after starting administration of the investigational product (IP) to 28 days after last dose of IP or moving to the OLE, whichever comes first. An AE is any untoward medical occurrence in a participant, temporally associated with the use of IP, whether or not considered related to the IP. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of IP. This includes events related to the comparator and events related to the study procedures.
Time Frame
Through Week 80
Title
Phase 3 portion: Number of participants with body weight change abnormalities and/ or AEs
Description
Number of participants with potentially clinically significant body weight changes.
Time Frame
Through Week 80
Title
Phase 3 portion: Number of participants with 12-lead electrocardiogram (ECG) abnormalities and/ or AEs
Description
Number of participants with potentially clinically significant 12-lead ECG values.
Time Frame
Through Week 80
Title
Phase 3 portion: Number of participants with laboratory value abnormalities and/ or AEs
Description
Number of participants with potentially clinically significant laboratory values.
Time Frame
Through Week 80
Title
Phase 3 portion: Number of participants with vital sign abnormalities and/ or AEs
Description
Number of participants with potentially clinically significant vital sign values.
Time Frame
Through Week 80
Title
Phase 3 portion: Number of participants with suicidal ideation and/ or behavior as assessed Columbia-Suicide Severity Rating Scale (C-SSRS)
Description
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a clinician administered assessment tool that evaluates suicidal ideation and behavior. Number of participants that have an affirmative response provided to the 5 items for suicidal ideation (1. Wish to be dead, 2. Nonspecific active suicidal thoughts, 3. Active suicidal ideation with any methods (not plan) without intent to act, 4. Active suicidal ideation with some intent to act, without specific plan, 5. Active suicidal ideation with specific plan and intent) and/or to the 6 items for suicidal behavior (1. Actual attempt, 2. Interrupted attempt, 3. Aborted attempt, 4. Preparatory acts or behavior, 5. Suicidal Behavior 6. Completed suicide).
Time Frame
Through Week 80
Title
Phase 3 portion: Change from baseline in distance walked in 6 minutes assessed in meters
Description
The 6-minute walk test (6MWT) is a measurement of endurance that assesses walking distance over 6 minutes.
Time Frame
Baseline and Week 52
Secondary Outcome Measure Information:
Title
Phase 3 portion: Change from baseline in quality of life in neurological disorders (Neuro-QoL) Short Form Fatigue score
Description
The Neuro-QoL Short Form Fatigue score is an 8-item self- assessment questionnaire evaluating the perception of fatigue and its impact in daily life activities. Participants have five response options for each item: 1=Never, 2=Rarely, 3=Sometimes, 4=Often, 5=Always. The questionnaire is scored by adding the response to each of the items. Higher scores indicate a greater level of fatigue.
Time Frame
Baseline and Week 52
Title
Phase 3 portion: Change from baseline in time spent on the 5 Times Sit to Stand (5XSTS) test
Description
Change from baseline in time spent on the 5XSTS test. The test requires participants to sit with arms folded across chest and back against the chair and stand up and sit down 5 times in a row, as quickly as he/she can.
Time Frame
Baseline and Week 52
Title
Phase 3 portion: Change from baseline in Modified Fatigue Impact Scale (MFIS)
Description
MFIS is a modified form of the Fatigue Impact Scale questionnaire specific to measuring how fatigue impacts the lives of those affected by fatigue-like symptoms. The 21 items in the scale measure three domains of fatigue including physical, cognitive and psychosocial functioning. Participants have five response options for each item: 0=Never, 1=Rarely, 2=Sometimes, 3=Often, and 4=Almost always. The scale is scored by adding the response to each of the items. Higher scores indicate a greater level of fatigue.
Time Frame
Baseline and Week 52
Title
Phase 3 portion: Change from baseline in Neuro-QoL Short Form Lower Extremity Function (Mobility) score
Description
The Neuro-QoL Short Form Lower Extremity Function (Mobility) score is an 8-item self-assessment questionnaire evaluating one's ability to carry out various activities involving the trunk region and increasing degrees of bodily movement, ambulation, balance or endurance. Participants have five response options for each item: 1=Unable to do, 2=With much difficulty, 3=With some difficulty, 4=With a little difficulty, 5=Without any difficulty. The questionnaire is scored by adding the response to each of the items. Higher scores indicate a greater level of lower extremity function (Mobility).
Time Frame
Baseline and Week 52
Title
Phase 3 portion: Score on Patient Global Impression of Change (PGIC)
Description
The Patient Global Impression of Change evaluates participant's most bothersome symptom and assesses if there has been an improvement or decline in clinical status. Ratings range from (1) very much improved to (7) very much worse.
Time Frame
Week 52
Title
Phase 3 portion: Change from baseline in Patient Global Impression of Severity (PGIS)
Description
The Patient Global Impression of Severity questionnaire assesses patient's impression of disease severity. The questionnaire asks the participant to best describe the severity of the participant's most bothersome pre-defined symptom over the past week scored from (1) None to (4) Severe.
Time Frame
Baseline and Week 52

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
54 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Participant agrees and is able to adhere to the study requirements for the length of the study, including performing 6MWT, as well as the use of digital applications and video recordings. Diagnosed with primary mitochondrial myopathy (PMM), consisting of the following: Molecular genetic abnormality (i.e., nuclear or mitochondrial) known to be associated with causing mitochondrial dysfunction (such as, but not limited to, mitochondrial DNA (mtDNA) single, variable deletions in chronic progressive external ophthalmoplegia (CPEO) and Kearns-Sayre syndrome (KSS); mtDNA m.3243 A > G common mutation in mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS); pathogenic nuclear or mitochondrial genome variants demonstrated to cause primary mitochondrial disease), and Participant reported symptoms (i.e., muscle weakness, fatigue and exercise intolerance) or physical examination findings of myopathy that are the predominant symptoms of the participant's mitochondrial disorder. Participant has been on stable dose regimen of coenzyme Q10 (CoQ10), carnitine, creatine or other mitochondrial disease-focused vitamins or supplemental therapies for 3 months prior to randomization and intends to stay on a stable dose for duration of study period (for participants who take any above-mentioned medications or supplements). Participant has been on stable exercise regimen within 4 weeks prior to randomization and intends to stay on a stable regimen for duration of study period (for participants who participate in a regular exercise regimen). Female participant is not pregnant and at least one of the following conditions apply: Not a woman of childbearing potential (WOCBP). WOCBP who agrees to follow the contraceptive guidance from the time of informed consent through at least 30 days after final study treatment administration. Female participant must agree not to breastfeed starting at screening and throughout the study period and for 30 days after final study treatment administration. Female participant must not donate ova starting at first dose of IP and throughout the study period and for 30 days after final study treatment administration. Male participant with female partner(s) of childbearing potential (including breastfeeding partner) must agree to use contraception throughout the treatment period and for 30 days after final study treatment administration. Male participant must not donate sperm during the treatment period and for 30 days after final study treatment administration. Male participant with pregnant partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy throughout the study period and for 30 days after final study treatment administration. Participant agrees not to participate in another interventional study while participating in the present study. Open-label Extension Continuation Criteria: • Participant must meet all of the following OLE criteria at the week 52 study visit in the treatment period to be eligible for OLE: Participant must continue to be able and willing to adhere to the study requirements. Participant who is eligible to continue in OLE. Exclusion Criteria: Participant has additional signs and/or symptoms due to non-myopathic process (e.g., cerebellar dysfunctions, movement disorder, peripheral neuropathy, stroke or other) or a gait problem not attributed to the myopathy that would interfere/may in addition to the myopathy affect the participant's performance during 6MWT or 5 times sit to stand (5XSTS). Participant has received any investigational therapy within 28 days or 5 half-lives, whichever is longer, prior to screening. Participant has any condition, which makes the participant unsuitable for study participation. Participant has cardiac troponin I (cTnI) > upper limit of normal (ULN) at screening and is assessed as clinically significant. Participant has estimated glomerular filtration rate (eGFR) calculated by the chronic kidney disease epidemiology collaboration equation < 60 milliliter per minute per 1.73 meter square at screening. Participant has at screening: total bilirubin (TBL) > ULN or transaminase(s) (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) > ULN in the absence of elevations in creatine kinase (CK). Participants who have a slightly elevated TBL and/or ALT and/or AST and are suitable candidates for the study, can be enrolled in the study as long as the investigator can rule out any underlying liver dysfunction by running additional tests and after discussing the case with the medical monitor. Participant has psychiatric conditions such as schizophrenia, bipolar disorder or major depressive disorder that has not been under control within 3 months prior to screening. Participant has a history of suicide attempt, suicidal behavior or has any suicidal ideation within 1 year prior to screening that meets criteria at a level of 4 or 5 by using the Columbia-Suicide Severity Rating Scale (C-SSRS) or who is at significant risk to commit suicide. Participant has severe behavioral or cognitive problems that preclude participation in the study. Participant has undergone an in-patient hospitalization that precludes participation in the study, within the 30 days prior to the randomization. Participant has a planned hospitalization or a surgical procedure during the study, which may affect the study assessments. Participant has clinically significant and unstable respiratory disease and/or cardiac disease (medical history or current clinical findings), or prior interventional cardiac procedure (e.g., cardiac catheterization, angioplasty/percutaneous coronary intervention, balloon valvuloplasty, etc.) within 3 months prior to randomization. Participants with pacemakers are allowed in the study per investigator's discretion and after discussion with the medical monitor, and as long as it is used for prevention and there is no underlying cardiac dysfunction. Participant has a corrected mean QT interval using Fridericia's correction (QTcF) > 450 msec for male participants and > 480 msec for female participants at screening or randomization. If QTcF exceeds these limits, one additional triplicate ECG can be repeated on the same day in order to determine the participant's eligibility. ECG evidence of acute ischemia, atrial fibrillation or active conduction system abnormalities with the exception of any of the following: First degree atrioventricular (AV)-block Second degree AV-block Type 1 (Mobitz Type 1/Wenckebach type) Right bundle branch block Left fascicular block Bi-fascicular block Participant requires any ventilator support. Participant has severe vision impairment that may interfere with their ability to complete all study requirements. Participant has an intractable seizure disorder that may interfere with their ability to complete all study requirem ents. Active malignancy or any other cancer from which the participant has been disease-free for < 5 years, except for curative treated localized non-melanoma skin cancer (e.g., basal cell or squamous cell carcinoma). Participant has a solid organ transplant and/or is currently receiving treatment with therapy for immunosuppression. Participant has severe scoliosis or kyphoscoliosis that significantly impair respiratory capacity and pulmonary function tests or limit positioning due to pain who would be likely to require orthopedic surgical intervention within a year after study randomization. Participant has a positive for human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection at screening. Participant has previously received ASP0367. Participant has a history of active substance abuse within 1 year prior to randomization. Participant has used any peroxisome proliferator-activated receptor (PPAR) ligands such as fibrates and thiazolidinediones within 4 weeks prior to randomization. Participant has initiated the use of CoQ10, carnitine, creatine or other mitochondrial disease-focused supplements within 3 months prior to study randomization. Participant has a known or suspected hypersensitivity to ASP0367 or any components of the formulation used. Participant has symptomatic coronavirus disease 2019 (COVID-19) infection within 3 months prior to study randomization that required treatment (Monoclonal antibodies, ventilator support, hospitalization) and/or led to long-term sequelae or lingering symptoms. Participant has BMI below 18.5 kilogram per meter square (kg/m^2) or above 35 kg/m^2 at screening Participant has bulbar weakness due to either neuropathy or myopathy
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Astellas Pharma Inc.
Phone
800-888-7704
Email
Astellas.registration@astellas.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Senior Medical Director
Organizational Affiliation
Astellas Pharma Inc
Official's Role
Study Director
Facility Information:
Facility Name
Mayo Clinic Arizona
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85054
Country
United States
Individual Site Status
Recruiting
Facility Name
University of California, San Diego
City
La Jolla
State/Province
California
ZIP/Postal Code
92093
Country
United States
Individual Site Status
Recruiting
Facility Name
Stanford University Medical Center
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Individual Site Status
Recruiting
Facility Name
Children's Hospital Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Individual Site Status
Recruiting
Facility Name
Mayo Clinic Florida
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32224
Country
United States
Individual Site Status
Recruiting
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Individual Site Status
Recruiting
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Individual Site Status
Recruiting
Facility Name
Columbia University Irving Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Individual Site Status
Recruiting
Facility Name
Akron Children's Hospital
City
Akron
State/Province
Ohio
ZIP/Postal Code
44308
Country
United States
Individual Site Status
Recruiting
Facility Name
Cleveland Clinic
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Individual Site Status
Recruiting
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Individual Site Status
Recruiting
Facility Name
Baylor College of Medicine
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Individual Site Status
Recruiting
Facility Name
University of Texas Health Science Center at Hosuton
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Individual Site Status
Recruiting
Facility Name
Seattle Children's Hospital
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States
Individual Site Status
Recruiting

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as compounds terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.
IPD Sharing Time Frame
Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
IPD Sharing Access Criteria
Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
IPD Sharing URL
https://www.clinicalstudydatarequest.com/

Learn more about this trial

A Study to Evaluate ASP0367 in Participants With Primary Mitochondrial Myopathy

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