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Evaluation of Safety, Tolerability, and Changes in Biomarker and Clinical Outcome Assessments of Losmapimod for FSHD1 (FSHD)

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ClinicalTrials.gov Identifier: NCT04004000
Recruitment Status : Active, not recruiting
First Posted : July 1, 2019
Last Update Posted : February 7, 2020
Sponsor:
Information provided by (Responsible Party):
Fulcrum Therapeutics

Tracking Information
First Submitted Date  ICMJE June 25, 2019
First Posted Date  ICMJE July 1, 2019
Last Update Posted Date February 7, 2020
Actual Study Start Date  ICMJE August 23, 2019
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 28, 2019)
Treatment-Emergent Adverse Events [ Time Frame: Week 56 ]
Incidence of treatment-emergent adverse events assessed by clinically significant laboratory test results, ECGs, and vital signs.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 2, 2019)
  • Target Engagement in Blood [ Time Frame: Week 52 ]
    Change from baseline in phospho-HSP27 and ratio of pHSP27/total HSP27 will be measured in peripheral whole blood.
  • Target Engagement in Skeletal Muscle [ Time Frame: Week 40 ]
    Change from baseline in phospho-HSP27 and ratio of pHSP27/total HSP27 will be measured in muscle.
  • Plasma Concentration of Losmapimod [ Time Frame: Week 52 ]
    Blood samples will be collected to measure the plasma concentration of losmapimod at specified timepoints.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 28, 2019)
  • Target Engagement in Blood [ Time Frame: Week 52 ]
    Change from baseline in phospho-HSP27 and ratio of pHSP27/total HSP27 will be measured in peripheral whole blood.
  • Target Engagement in Skeletal Muscle [ Time Frame: Week 40 ]
    Change from baseline in phospho-HSP27 and ratio of pHSP27/total HSP27 will be measured in muscle.
  • Plasma Concentration of Losmapimod [ Time Frame: Week 52 ]
    Blood samples will be collected to measure the plasma concentration of losmapidod at specified timepoints.
Current Other Pre-specified Outcome Measures
 (submitted: July 2, 2019)
  • Muscle Disease Transcripts [ Time Frame: Week 40 ]
    To evaluate the change from baseline in inflammatory, immune, apoptotic, and muscle disease transcripts in muscle biopsy and circulating proteins in plasma and serum.
  • DUX4 Activity [ Time Frame: Week 40 ]
    Change from baseline in DUX4 activity will be measured by quantitative polymerase chain reaction (qPCR) of skeletal muscle using a subset of DUX4‑regulated gene transcripts.
  • Muscle Lean Tissue Volume [ Time Frame: Week 52 ]
    Change from baseline in skeletal muscle lean tissue volume as measured by whole body magnetic resonance imaging (MRI).
  • Muscle Tissue Replacement by Fat [ Time Frame: Week 52 ]
    Change from baseline in skeletal muscle tissue replacement by fat as measured by whole body magnetic resonance imaging (MRI).
  • Muscle Ultrasound [ Time Frame: Week 52 ]
    Ultrasound will be used to evaluate the echogenicity of specified muscles.
  • Reachable Work Space (RWS) [ Time Frame: Week 52 ]
    Subjects are seated in front of a 3D camera and asked to perform a standardized upper extremity movement protocol under the supervision of a study clinical evaluator with and without weights.
  • Timed Up and Go (TUG) [ Time Frame: Week 52 ]
    Subjects are timed as they start from a seated or laying position, rise to a standing position, walk a total of 6 meters and then return to either a seated or laying position.
  • Motor Function Measure (MFM) Domain 1 [ Time Frame: Week 52 ]
    The MFM domain 1 is a validated evaluator administered functional measure for neuromuscular disorders, with 13 items related to standing and transfers.
  • Muscle Strength [ Time Frame: Week 52 ]
    Muscle strength will be assessed by Hand-Held Quantitative Dynamometry.
  • FSHD Rasch-built Overall Disability Scale (RODS) [ Time Frame: Week 52 ]
    The FSHD-RODS is a patient-reported, linearly weighted scale that precisely measures activities of daily living (ADLs) and participation in subjects with FSHD using 50 items based on the Rasch model.
  • FSHD Health Index (FSHD-HI) [ Time Frame: Week 52 ]
    The HI is a 15 domain questionnaire designed and based on patient interviews to measure total FSHD health-related quality-of-life, including both motor impairment and the social and emotional impact of FSHD. 116 questions are combined into a total score, the score is transformed onto a percentage scale, with 100 representing maximal disability, and lower scores representing decreasing disability.
  • Patients' Global Impression of Change (PGIC) [ Time Frame: Week 52 ]
    The PGIC is a single question that assesses on a scale of 1-7 if there has been an improvement, decline or no change in clinical status.
  • Real World Mobility Assessments [ Time Frame: Week 52 ]
    Each subject's activity will be monitored in the outpatient setting intermittently from the signing of the informed consent form (ICF) to the end of the study. Wearable activity monitoring devices will be provided to each subject at the start of the study. One device is placed on 1 arm, and 1 device goes on 1 leg.
  • Respiratory Function [ Time Frame: Week 52 ]
    Forced vital capacity and forced expiratory volume in 1 second using bedside spirometry.
  • Quantitative Dynamometry [ Time Frame: Week 52 ]
    Force will be measured on digital myometer, in KG-force.
Original Other Pre-specified Outcome Measures
 (submitted: June 28, 2019)
  • Muscle Disease Transcripts [ Time Frame: Week 40 ]
    Change from baseline muscle disease transcripts related to immune function in muscle biopsy and in plasma and serum.
  • DUX4 Activity [ Time Frame: Week 40 ]
    Change from baseline in DUX4 activity will be measured by quantitative polymerase chain reaction (qPCR) of skeletal muscle using a subset of DUX4‑regulated gene transcripts.
  • Muscle Lean Tissue Volume [ Time Frame: Week 52 ]
    Change from baseline in skeletal muscle lean tissue volume as measured by whole body magnetic resonance imaging (MRI).
  • Muscle Tissue Replacement by Fat [ Time Frame: Week 52 ]
    Change from baseline in skeletal muscle tissue replacement by fat as measured by whole body magnetic resonance imaging (MRI).
  • Muscle Ultrasound [ Time Frame: Week 52 ]
    Ultasound will be used to evaluate the echogenicity of specified muscles.
  • Reachable Work Space (RWS) [ Time Frame: Week 52 ]
    Subjects are seated in front of a 3D camera and asked to perform a standardized upper extremity movement protocol under the supervision of a study clinical evaluator with and without weights.
  • Timed Up and Go (TUG) [ Time Frame: Week 52 ]
    Subjects are timed as they start from a seated or laying position, rise to a standing position, walk a total of 6 meters and then return to either a seated or laying position.
  • Motor Function Measure (MFM) Domain 1 [ Time Frame: Week 52 ]
    The MFM domain 1 is a validated evaluator administered functional measure for neuromuscular disorders, with 13 items related to standing and transfers.
  • Muscle Strength [ Time Frame: Week 52 ]
    Muscle strength will be assessed by Hand-Held Quantitative Dynamometry.
  • FSHD Rasch-built Overall Disability Scale (RODS) [ Time Frame: Week 52 ]
    The FSHD-RODS is a patient-reported, linearly weighted scale that precisely measures activities of daily living (ADLs) and participation in subjects with FSHD using 50 items based on the Rasch model.
  • FSHD Health Index (FSHD-HI) [ Time Frame: Week 52 ]
    The HI is a 15 domain questionnaire designed and based on patient interviews to measure total FSHD health-related quality-of-life, including both motor impairment and the social and emotional impact of FSHD. 116 questions are combined into a total score, the score is transformed onto a percentage scale, with 100 representing maximal disability, and lower scores representing decreasing disability.
  • Patients' Global Impression of Change (PGIC) [ Time Frame: Week 52 ]
    The PGIC is a single question that assesses on a scale of 1-7 if there has been an improvement, decline or no change in clinical status.
  • Real World Mobility Assessments [ Time Frame: Week 52 ]
    Each subject's activity will be monitored in the outpatient setting intermittently from the signing of the informed consent form (ICF) to the end of the study. Wearable activity monitoring devices will be provided to each subject at the start of the study. One device is placed on 1 arm, and 1 device goes on 1 leg.
  • Respiratory Function [ Time Frame: Week 52 ]
    Forced vital capacity and forced expiratory volume in 1 second using bedside spirometry.
  • Quantitative Dynamometry [ Time Frame: Week 52 ]
    Force will be measured on digital myometer, in KG-force.
 
Descriptive Information
Brief Title  ICMJE Evaluation of Safety, Tolerability, and Changes in Biomarker and Clinical Outcome Assessments of Losmapimod for FSHD1
Official Title  ICMJE An Open-Label Pilot Study of Losmapimod to Evaluate the Safety, Tolerability, and Changes in Biomarker and Clinical Outcome Assessments in Subjects With Facioscapulohumeral Muscular Dystrophy 1 (FSHD1)
Brief Summary This clinical trial is a study to evaluate the safety, tolerability, and changes in biomarker and clinical outcome assessments of Losmapimod for patients with Facioscapulohumeral Muscular Dystrophy 1 (FSHD1).
Detailed Description

This study is a Phase 2, single-centre, open-label pilot study that will investigate the safety, tolerability, pharmacokinetics (PK), and target engagement during long-term dosing with losmapimod tablets in adult subjects with Facioscapulohumeral Muscular Dystrophy 1 (FSHD1). Patients will participate in this for approximately 68 weeks. The total treatment duration will be approximately 52 weeks. Subjects will be evaluated during an 8-week pre-treatment period (Visits 1 through 3) to establish pre-treatment baseline assessments. Subjects will then be treated with losmapimod for approximately 52 weeks (Visits 4 through 9) and assessed at relatively regular intervals for change from pre-treatment in various assessments. Patients must have a confirmed diagnosis of FSHD1 and genetic confirmation must be obtained prior to the screening MRI and baseline muscle biopsy. Patients will receive 15 mg of losmapimod twice daily given as two 7.5 mg tablets per dose by mouth; for a total of 4 pills or 30 mg daily for 52 weeks. All patients will be asked to visit the study clinic for each scheduled visit.

The primary endpoint of the study is to evaluate the safety and tolerability of long-term dosing of losmapimod tablets in subjects with FSHD1. Secondary endpoints include assessment of target engagement of losmapimod in blood and skeletal muscle and repeated dose pharmacokinetics in subjects with FSHD1 over long-term dosing.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Intervention Model Description:
This is a single-centre, open-label pilot study.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Facioscapulohumeral Muscular Dystrophy 1
Intervention  ICMJE Drug: Losmapimod
This study includes up to a 52 week treatment period. Patients will receive 15 mg of losmapimod twice daily given as two 7.5 mg tablets per dose by mouth; for a total of 4 pills or 30 mg daily. The study drug should be taken with food and the date and time of each dose taken recorded in the subject diary.
Study Arms  ICMJE Experimental: Treatment
FSHD1 patients with genetic confirmation with receive 15 mg of losmapimod twice daily given as two 7.5 mg tablets per dose by mouth; for a total of 4 pills or 30 mg daily for for up to approximately 52 weeks.
Intervention: Drug: Losmapimod
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 Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: February 6, 2020)
14
Original Estimated Enrollment  ICMJE
 (submitted: June 28, 2019)
16
Estimated Study Completion Date  ICMJE January 2021
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • FSHD1 subjects age 18-65 years.
  • Subject will sign and date an informed consent form (ICF).
  • Confirmed diagnosis of FSHD1 with 1 to 9 repeats via assessment of the size of the D4Z4 array on chromosome 4. Genetic confirmation must be obtained prior to the screening MRI and baseline muscle biopsy; genetic confirmation can come from previous testing if verified with appropriate documentation.
  • Must be willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, scheduled needle muscle biopsies, and other study procedures.
  • Both male and female subjects must be willing to practice an approved method of birth control.
  • Clinical Severity Score between 2 and 4 on Ricci's Scale (scale range is from 0 to 5).
  • Commitment to complete the 2 visits for skeletal muscle needle biopsy and all visits for whole-body MRI.
  • Able to complete the RWS, TUG, and FSHD PROs (FSHD-RODS and FSHD-HI) at the screening visit.
  • Must have an MRI-eligible muscle for biopsy

Exclusion Criteria:

  • Subject has a history of any illness or any clinical condition that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject. This may include, but is not limited to, history of relevant drug or food allergies; history of cardiovascular or central nervous system disease; history or presence of clinically significant pathology; clinically significant history of mental disease; and history of cancer, except for squamous cell skin cancer, basal cell skin cancer, and Stage 0 cervical carcinoma in situ (all 3 with no recurrence for the last 5 years).
  • Subject has a known or clinically suspected infection with human immunodeficiency virus or hepatitis B or C viruses.
  • Subject has current clinically significant liver or kidney dysfunction.
  • Subject screens positive for hepatitis B surface antigen, hepatitis C virus (HCV) antibody, or antibodies against human immunodeficiency viruses 1 and 2 (HIV 1/HIV 2 antibodies).
  • Subject has any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy, or other gastrointestinal tract surgery, except appendectomy).
  • Male subject has a female partner who is planning to become pregnant during the study or within 90 days after the last study drug dose.
  • Subject has participated in a clinical trial in which they have received an investigational product within the following time period prior to enrolment in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever was longer).
  • For subjects that are on drug(s) or supplements that may affect muscle function as determined by the treating physician or included in the list of drugs presented in Section 15: subjects must be on a stable dose of that drug(s) or supplement for at least 3 months prior to enrollment in the study and remain on that stable dose for the duration of the study (list of drugs presented in Section 15). Changes to the dose or treatment discontinuation during the study can only be done for strict medical reasons by the treating physician with clear documentation and notification to the sponsor.
  • Subject has a history of sensitivity to any of the study medications or components thereof, or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicated their participation.
  • Subject is unwilling or unable to follow the procedures outlined in the protocol.
  • Subject has any contraindication for MRI (including severe claustrophobia and any shrapnel or metal implants in the body that are not MRI compatible).
  • Subject was mentally or legally incapacitated up to 2 years prior to enrollment.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04004000
Other Study ID Numbers  ICMJE FIS-001-2019
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Fulcrum Therapeutics
Study Sponsor  ICMJE Fulcrum Therapeutics
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Michelle Mellion, MD Fulcrum Therapeutics
PRS Account Fulcrum Therapeutics
Verification Date February 2020

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