LOSVID: Losmapimod Safety and Efficacy in COVID-19

Sponsor

Fulcrum Therapeutics (Industry)

Overall Status

Terminated

CT.gov ID

NCT04511819

Collaborator

(none)

Enrollment

Locations

Arms

7.1

Actual Duration (Months)

3.3

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
COVID-19	Drug: Losmapimod oral tablet Drug: Placebo oral tablet	Phase 3

Detailed Description

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.

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

52 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

This study is a randomized, double-blind, placebo-controlled study.This study is a randomized, double-blind, placebo-controlled study.

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

This study will be performed in a double-blind fashion. The investigator, study staff, subjects, Sponsor, and monitor will remain blinded to the treatment until study closure.

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Aug 28, 2020

Actual Primary Completion Date :

Mar 31, 2021

Actual Study Completion Date :

Mar 31, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Losmapimod 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 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.
Placebo Comparator: Placebo 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 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.

Arm

Intervention/Treatment

Experimental: Losmapimod

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

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.

Placebo Comparator: Placebo

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

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.

Outcome Measures

Primary Outcome Measures

Day 28 Mortality [Day 28]
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.

Secondary Outcome Measures

Clinical Status Assessment [Day 7 and Day 14]
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.
Respiratory Failure Assessment [Day 28]
The response to treatment with Losmapimod in COVID-19 patients will be assessed by the total number of study days not requiring oxygen supplementation.
Treatment Survival [Day 28]
To assess the effect on survival following treatment with Losmapimod, mortality will be evaluated by the number of days alive by Day 28.
Treatment-Emergent Adverse Events [Screening, Date of enrollment and Days 2-14 and 7 and 14 days after the last dose of study drug]
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.
Treatment-Emergent Adverse Events [Day 7]
To characterize changes in SARS-CoV-2 infection following treatment with losmapimod versus placebo.

Other Outcome Measures

Changes in C-Reactive Protein [Days 1, 4, 7 and 14]
The change from baseline in levels of C-reactive protein (CRP), a biomarker of systemic inflammatory response to infection with the SARS-CoV-2 virus will be evaluated in serum by immunoturbidimetric assay.
Changes in Levels of Cytokines [Days 1, 4, 7 and 14]
The change from baseline in the levels of cytokines (IFNγ, IL-2, IL-10 in normalized protein expression (NPX)) in response to the SARS-CoV-2 virus in serum will be evaluated using the Olink immunoassay panel.
Changes in Levels of Chemokines [Days 1, 4, 7 and 14]
The change from baseline in the levels of chemokines (CXCL10, CXCL9 in normalized protein expression (NPX)) in response to the SARS-CoV-2 virus in serum will be evaluated using the Olink immunoassay panel.

Eligibility Criteria

Criteria

Ages Eligible for Study:

50 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California Irvine - Irvine Medical Center	Irvine	California	United States	92697
2	University of Miami	Miami	Florida	United States	33136
3	University of South Florida	Tampa	Florida	United States	33606
4	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
5	Memorial Hermann Hospital South West	Houston	Texas	United States	77030
6	University of Texas Health Science Center at Houston	Houston	Texas	United States	77030
7	United Medical Memorial Hospital	Houston	Texas	United States	77091
8	Hospital Universitario Cassiano Antonio de Moraes-HUCAM/Hospital das Clinicas	Vitória	ES	Brazil	29043260
9	Santa Casa de Misericordia de Belo Horizonte	Belo Horizonte	MG	Brazil	30150221
10	Irmandade de Santa Casa de Misericordia de Porto Alegre	Porto Alegre	SC	Brazil	90035-075
11	Hospital Santa Paula	San Paolo	SP	Brazil	04550-000
12	Hospital Civil Fray Antonio Alcalde	Guadalajara	Jalisco	Mexico	44280
13	Nuevo Hospital Civil de Guadalajara	Guadalajara	JC	Mexico	44340
14	JM Research Cuernavaca	Cuernavaca	Morelos	Mexico	662284
15	Centro para el Desarrollo de la Medicina y de Asistencia Médica Especializada, S.C.	Culiacán	Sinaloa	Mexico	80230
16	Hospital Nacional Carlos Alberto Seguín Escobedo - EsSalud Arequipa	Arequipa	AR	Peru	04001