Losmapimod Safety and Efficacy in COVID-19

Study Overview
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Brief Summary
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The therapeutic hypothesis for the use of losmapimod in COVID-19 disease is that increased mortality and severe disease is caused by p38 mitogen-activated protein kinase (MAPK)-mediated exaggerated acute inflammatory response resulting from SARS-CoV-2 infection. The study Sponsor hypothesize's that the early initiation of p38α/β inhibitor therapy in patients hospitalized with moderate COVID-19 who are at increased risk of a poor prognosis based on older age and elevated systemic inflammation will reduce clinical deterioration including progression to respiratory failure and death. To address this hypothesis, Fulcrum Therapeutics is conducting a Phase 3, multicenter, randomized, double-blind, placebo-controlled study that will evaluate the safety and efficacy of losmapimod versus placebo in subjects 50 and older who are hospitalized with moderate COVID-19 disease.

Detailed Description
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The therapeutic hypothesis for the use of losmapimod in COVID-19 disease is that increased disease severity and consequent increased mortality is caused by p38 mitogen-activated protein kinase (MAPK)-mediated exaggerated acute inflammatory response resulting from SARS-CoV-2 infection. It is anticipated that the early initiation of p38α/β inhibitor therapy in patients with moderate COVID-19 will prevent further clinical deterioration and reduce the need for both increased respiratory support as well as mortality. This is the main hypothesis for this study. To address this hypothesis, Fulcrum Therapeutics is conducting a Phase 3, multicenter, randomized, double-blind, placebo-controlled study that will evaluate the safety and efficacy of losmapimod versus placebo in subjects with COVID-19 disease. Losmapimod is currently in Phase 2 clinical trials for the treatment of facioscapulohumeral dystrophy (FSHD) and has previously been administered to more than 3600 adult healthy volunteers and subjects including participants in a large Phase 3 trial which looked at clinical outcomes and safety after major cardiovascular events. Patients will participate in this study for approximately 34 days. The total treatment duration will be 14 days. Subjects will be evaluated during a 3 day pre-treatment period (Screening and Baseline Visits) to establish pre-treatment baseline assessments and eligibility. Subjects will then be randomized to treatment with losmapimod or placebo for 14 days and assessed frequently for changes from pre-treatment in various clinical outcome assessments. Patients must have a confirmed diagnosis of COVID-19 by viral PCR prior to randomization and first dosing. Patients will receive 15 mg of losmapimod, or placebo twice daily given as two 7.5 mg tablets per dose by mouth: for a total of 4 pills or 30 mg daily for 14 consecutive days. All study visits during the first week of treatment are anticipated to be conducted in the inpatient setting while later visits are anticipated to be conducted as outpatient. The primary endpoint of the study is to assess the efficacy of losmapimod tablets compared with placebo for the treatment of COVID-19 when administered concurrently with the local standard of care. Secondary endpoints include evaluating the effect of losmapimod compared with placebo on clinical outcomes, clinical status, effect on survival, safety, and tolerability and to characterize changes in the levels of SARS-CoV-2 infection.

Official Title
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A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of Losmapimod in Adult Subjects With COVID-19 (LOSVID STUDY)

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Losmapimod oral tablet
* Drug: Placebo oral tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able and willing to provide written informed consent Willing and able to comply with all study procedures Age ≥50 years at time of screening Confirmed infection with SARS-CoV-2 virus at or before the baseline visit by polymerase chain reaction (PCR) testing ≤7 days to the time of randomization from the time of collection of the specimen that tested positive for the SARS-CoV-2 virus Hospitalization at the time of the baseline visit ≥90% oxygen saturation on room air and/or ≥94% oxygen saturation on oxygen administration at 2 L/min by nasal cannula at the baseline visit Radiographic (X-ray or computed tomography scan, per local standard of care) and/or clinical evidence of pulmonary involvement consistent with COVID-19 at screening or baseline, per the judgment of the investigator Clinical syndrome consistent with COVID-19 at screening, per the judgment of the investigator (CDC 2020) CRP at screening >15 mg/L (i.e., >1.5 mg/dL) on local laboratory testing Agrees to practice an approved method of birth control Exclusion Criteria: Inability to take oral medication at screening or baseline visit Evidence at screening or baseline of critical COVID-19 disease (e.g., cardiac failure, septic shock) or severe pulmonary involvement) Positive pregnancy test at screening for women of childbearing potential Lactating female at baseline for women of childbearing potential Note: A female will be considered eligible who is lactating at screening if she agrees to discontinue breastfeeding for the duration of the trial plus 14 days post last dose ≥5 × upper limit of normal (ULN) for alanine or aspartate aminotransferases or total bilirubin >1.5 × ULN at screening or known history of Child-Pugh Class C, hepatitis B or C, or HIV infection Glomerular filtration rate <30 mL/min/1.73 m2 at screening QTcF >450 msec for male or >470 msec for females or evidence of cardiac dysrhythmia at screening Significant history or evidence of clinically significant disorder, condition, current illness, illicit drug or other addiction, or disease that, in the opinion of the Investigator, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion Has been treated with immunomodulators or immunosuppressants including, but not limited to, interleukin (IL)-6 inhibitors, tumor necrosis factor (TNF) inhibitors, anti-IL-1 agents, and Janus kinase inhibitors, within 5 half-lives or 30 days, whichever is longer, prior to randomization, or plan to receive these agents any time during the study period Treatment with hydroxychloroquine/ chloroquine in the past 30 days or plan to receive these agents as part of investigational clinical trials or SOC any time during the study period Recent (within 30 days) or current participation in other COVID-19 therapeutic trials or expanded access programs Prior or current participation in COVID-19 vaccine trials

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This study is a randomized, double-blind, placebo-controlled study.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Losmapimod<br>COVID-19 patients with PCR confirmation will receive Losmapimod 15 mg twice daily given as two 7.5 mg tablets per dose by mouth; for a total of 4 pills or 30 mg daily for 14 days. | Drug: Losmapimod oral tablet<br>* This study includes a 14-day treatment period. Patients will receive losmapimod 15 mg 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 when possible.<br>|
| Placebo Comparator: Placebo<br>COVID-19 patients with PCR confirmation will receive Placebo twice daily given as two tablets per dose by mouth; for a total of 4 tablets daily for 14 days. | Drug: Placebo oral tablet<br>* This study includes a 14-day treatment period. Patients will receive Placebo twice daily given as two tablets per dose by mouth: for a total of 4 tablets daily. The study drug should be taken with food when possible.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Day 28 Mortality | The efficacy of Losmapimod will be assessed by the development of progression to critical disease as evidence of mortality or development of respiratory failure by Day 28. | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Status Assessment | The change from baseline in clinical disease status will be evaluated using the 9-point World Health Organization (WHO) ordinal scale: 0 indicating, no clinical evidence of SARS-CoV-2 infection and 8 indicating death. | Day 7 and Day 14 | 
| Respiratory Failure Assessment | The response to treatment with Losmapimod in COVID-19 patients will be assessed by the total number of study days not requiring oxygen supplementation. | Day 28 | 
| Treatment Survival | To assess the effect on survival following treatment with Losmapimod, mortality will be evaluated by the number of days alive by Day 28. | Day 28 | 
| Treatment-Emergent Adverse Events | To evaluate the safety and tolerability of Losmapimod, the incidence of treatment-emergent adverse events will be assessed by clinically significant changes in laboratory test results and vital signs. | Screening, Date of enrollment and Days 2-14 and 7 and 14 days after the last dose of study drug | 
| Treatment-Emergent Adverse Events | To characterize changes in SARS-CoV-2 infection following treatment with losmapimod versus placebo. | Day 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19 pandemic, COVID-19 virus disease, COVID-19 virus infection, SARS-CoV-2 infection, coronavirus disease 2019, 2019 novel coronavirus disease, 2019 novel coronavirus infection