Losmapimod Safety and Efficacy in COVID-19 (LOSVID)

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

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 hypothesizes 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 40 and older who are hospitalized with moderate COVID-19 disease.

Study Overview

• Status: Terminated
• Conditions: COVID-19
• Intervention / Treatment: Drug: Losmapimod oral tablet; Drug: Placebo oral tablet

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.

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 evaluated 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 Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 48 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Able and willing to provide written informed consent
• Willing and able to comply with all study procedures.
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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; Losmapimod will be administered 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; Placebo will be administered with food when possible.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Progressed to Death or Respiratory Failure by Day 28	Respiratory failure was defined as either need for mechanical ventilation (invasive or non-invasive) or high flow oxygen (defined by greater than 15 liters per minute [LPM] flow of oxygen to maintain oxygen saturation between 90% and 95%), sustained for at least 48 hours, at any time during the study. The fitted logistic regression model was used to predict the response rate for every participant in the study who had received the treatment or the control intervention. The efficacy of Losmapimod was assessed by the development of progression to critical disease as evidence of mortality or development of respiratory failure by Day 28. Percentage of participants who progressed to death or respiratory failure by Day 28 has been presented.	Up to Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Clinical Status at Days 7 and 14 Assessed on the 9-point World Health Organization (WHO) Ordinal Scale	Change in clinical status between Baseline and at Days 7 and 14 was modeled using ordinal logistic regression models, adjusting for stratification factors, sex and baseline C-reactive protein (CRP). WHO 9-point ordinal scale included score ranges as: 0:No clinical evidence of the disease, 1: Discharged from the hospital and without any limitation, 2: Discharged from the hospital but with limitation of activities, 3: Hospitalized but not requiring oxygen therapy, 4: Oxygen therapy but not requiring high-flow or non-invasive ventilation, 5: Noninvasive ventilation or high-flow oxygen therapy, 6: Intubation and mechanical ventilation, 7: Ventilation plus additional organ support and 8: Death. Higher scores indicated worse clinical status. Baseline was defined as the last measurement prior to the first dose of study drug. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.	Baseline and at Day 7 and Day 14
Total Number of Study Days Free of Oxygen Supplementation	A Poisson regression model or a negative binomial model was used to assess the relationship with treatment, adjusting for stratification factors, sex, baseline CRP and number of days on study (as applicable). Total number of study days free of oxygen supplementation has been presented.	Up to Day 28
Percentage of Participants Reporting All-cause Mortality at Day 28	Percentage of participants who reported death have been presented.	At Day 28
Number of Study Days Alive	A Poisson regression model or a negative binomial model was used to assess the relationship with treatment, adjusting for stratification factors, sex, baseline CRP and number of days on study (as applicable). Number of study days alive has been presented.	Up to Day 28
Number of Participants Reporting Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgment. Number of participants with non-serious AEs and SAEs has been presented.	Up to Day 28

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in C-Reactive Protein	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.	Days 1, 4, 7 and 14
Changes in Levels of Cytokines	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.	Days 1, 4, 7 and 14
Changes in Levels of Chemokines	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.	Days 1, 4, 7 and 14

Collaborators and Investigators

• Sponsor: Fulcrum Therapeutics
• Investigators: Study Director: John Ziegler, MD, FASA, Fulcrum Therapeutics

Publications and helpful links

General Publications

• Grimes JM, Grimes KV. p38 MAPK inhibition: A promising therapeutic approach for COVID-19. J Mol Cell Cardiol. 2020 Jul;144:63-65. doi: 10.1016/j.yjmcc.2020.05.007. Epub 2020 May 16.
• Jimenez-Guardeno JM, Nieto-Torres JL, DeDiego ML, Regla-Nava JA, Fernandez-Delgado R, Castano-Rodriguez C, Enjuanes L. The PDZ-binding motif of severe acute respiratory syndrome coronavirus envelope protein is a determinant of viral pathogenesis. PLoS Pathog. 2014 Aug 14;10(8):e1004320. doi: 10.1371/journal.ppat.1004320. eCollection 2014 Aug.
• Vukmanovic-Stejic M, Chambers ES, Suarez-Farinas M, Sandhu D, Fuentes-Duculan J, Patel N, Agius E, Lacy KE, Turner CT, Larbi A, Birault V, Noursadeghi M, Mabbott NA, Rustin MHA, Krueger JG, Akbar AN. Enhancement of cutaneous immunity during aging by blocking p38 mitogen-activated protein (MAP) kinase-induced inflammation. J Allergy Clin Immunol. 2018 Sep;142(3):844-856. doi: 10.1016/j.jaci.2017.10.032. Epub 2017 Nov 17.
• Watz H, Barnacle H, Hartley BF, Chan R. Efficacy and safety of the p38 MAPK inhibitor losmapimod for patients with chronic obstructive pulmonary disease: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2014 Jan;2(1):63-72. doi: 10.1016/S2213-2600(13)70200-5. Epub 2013 Dec 5.
• World Health Organization (WHO). WHO R&D blueprint novel coronavirus COVID-19 therapeutic trial synopsis. Draft Feb 18, 2020.

Study record dates

Study Major Dates

• Study Start (Actual): August 28, 2020
• Primary Completion (Actual): March 31, 2021
• Study Completion (Actual): March 31, 2021

Study Registration Dates

• First Submitted: August 8, 2020
• First Submitted That Met QC Criteria: August 11, 2020
• First Posted (Actual): August 13, 2020

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: February 16, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: SARS-CoV-2 infection; COVID-19 pandemic; coronavirus disease 2019; COVID-19 virus disease; COVID-19 virus infection; 2019 novel coronavirus disease; 2019 novel coronavirus infection
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: FIS-001-2020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No