Evaluation of Safety, Tolerability, and Changes in Biomarker and Clinical Outcome Assessments of Losmapimod for FSHD1 With Extension (FSHD)
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|ClinicalTrials.gov Identifier: NCT04004000|
Recruitment Status : Active, not recruiting
First Posted : July 1, 2019
Last Update Posted : April 19, 2021
|Condition or disease||Intervention/treatment||Phase|
|Facioscapulohumeral Muscular Dystrophy 1||Drug: Losmapimod||Phase 2|
This study is a 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 FSHD1. 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 1 year (Visits 4 through 9) and assessed at relatively regular intervals for change from pre-treatment assessments. All subjects will undergo two muscle biopsies; one at baseline, pre-treatment (Visit 4, Week 8 ± 1 week) and the second on-treatment muscle biopsy approximately 4 or 8 weeks later (Visit 5, Week 14 ± 2 weeks). Up to 8 subjects will have an on-treatment biopsy at 4 weeks and up to 8 subjects will have the on-treatment biopsy at 8 weeks.
Only subjects who participated in and competed all study procedures in the OLS Study treatment period (Week 60) will be eligible to participate in the open-label extension study.
The extension of this study will enable continued investigation of the efficacy of long-term dosing with losmapimod tablets in adult subjects with FSHD1. During the extension study, subjects will receive 15 mg of losmapimod by mouth twice daily for a total of 30 mg by mouth daily. All subjects will attend clinic visits approximately every 12 weeks and 7 days after the last dose of study drug for safety follow-up assessment. Participation in the open-label extension study will continue until losmapimod is approved, the patient withdraws from the study, or the Sponsor terminates the study.
The primary endpoint of the main 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.
The extension will continue investigation of efficacy with assessment of skeletal muscle by ultrasound as well as the safety, tolerability, pharmacokinetics (PK), and exploration of efficacy measures including whole body skeletal muscle MRI and selected clinical outcome assessments during long- term dosing with losmapimod tablets in adult subjects with FSHD1. Secondary endpoints include assessment of efficacy as evaluated by whole body skeletal muscle MRI parameters, safety and tolerability of long-term dosing, target engagement of losmapimod in blood and skeletal muscle and repeated dose pharmacokinetics in subjects with FSHD1 over long-term dosing.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||14 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||This is a single-centre, open-label pilot study with open-label extension|
|Masking:||None (Open Label)|
|Official Title:||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) With Extension|
|Actual Study Start Date :||August 23, 2019|
|Estimated Primary Completion Date :||January 2024|
|Estimated Study Completion Date :||January 2024|
FSHD1 subjects 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 1 year.
This main study includes a treatment period of approximately one year. Subjects 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.
Only subjects who participated in and completed all procedures for the main study (Week 60) will be eligible to participate in the extension.
For the extension, subjects will receive 15 mg of losmapimod by mouth twice daily for a total of 30 mg by mouth daily. Participation will continue until losmapimod is approved, the subject withdraws from the study, or the Sponsor terminates the study.
- Main Study - Treatment-Emergent Adverse Events [ Time Frame: Week 56 ]To evaluate the safety and tolerability of losmapimod based on the frequency of adverse events and clinically significant laboratory test results, electrocardiograms (ECGs), and vital signs.
- Extension Study - Efficacy of Treatment with Losmapimod [ Time Frame: Week 204 ]Change in skeletal muscle echogenicity will be evaluated by ultrasound of selected muscles.
- 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: Weeks 40 ]Change from baseline in phospho-HSP27 and ratio of pHSP27/total HSP27 will be measured in muscle during the dosing period.
- Plasma Concentration of Losmapimod [ Time Frame: Week 52 ]Blood samples will be collected to measure the plasma concentration of losmapimod at specified timepoints.
- Muscle Concentration of Losmapimod [ Time Frame: Week 52 ]Muscle biopsies will be collected to measure the concentration of losmapimod at specified timepoints.
- 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 in Skeletal Muscle [ Time Frame: Week 40 ]Change from baseline in DUX4 activity by quantitative polymerase chain reaction (qPCR) of skeletal muscle using a subset of DUX4 regulated gene transcripts.
- Muscle Lean Tissue Volume [ Time Frame: Week 204 ]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 204 ]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 Workspace (RWS) [ Time Frame: Week 204 ]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 to detect an individual's range of motion that reflects individual shoulder and proximal arm upper extremity function.
- Timed Up and Go (TUG) [ Time Frame: Week 204 ]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 to determine ambulatory function.
- Motor Function Measure (MFM) Domain 1 [ Time Frame: Week 204 ]The MFM domain 1 is a validated evaluator administered functional measure for neuromuscular disorders, with 13 items related to standing and transfers and assesses the severity of the motor deficit.
- Quantitative Manual Dynamometry [ Time Frame: Week 204 ]Muscle strength will be assessed by quantitative dynamometry with hand-held devices (manual). Force will be measured on digital myometer, in KG-force.
- FSHD Rasch-built Overall Disability Scale (RODS) [ Time Frame: Week 204 ]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.
- Real World Mobility Assessments [ Time Frame: Week 204 ]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.
- FSHD Health Index (FSHD-HI) [ Time Frame: Week 204 ]The FSHD-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 204 ]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.
- 6 Minute Walk Test (6-MWT) [ Time Frame: Week 204 ]Change from the pre-treatment period in the distance a subject is able to walk will be measured in time.
- Spirometry - Respiratory Function [ Time Frame: Week 204 ]Change in lung ventilatory function as measured by forced vital capacity and forced expiratory volume in 1 second using bedside spirometry.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04004000
|Radboud University Medical Center|
|Nijmegen, Netherlands, 9101|
|Study Director:||Michelle Mellion, MD||Fulcrum Therapeutics|