Losmapimod Safety and Efficacy in COVID-19

NCT04511819 | Terminated Phase 3 Results DMC FDA Drug

• 1 other identifier: FIS-001-2020
• Study Type: interventional
• Target: 52
• Locations: 4 countries
• Sites: 16

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 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.

Conditions

COVID-19

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• Change From Baseline in Clinical Status at Days 7 and 14 Assessed on the 9-point World Health Organization (WHO) Ordinal Scale

  Baseline and at Day 7 and Day 14

• Total Number of Study Days Free of Oxygen Supplementation

  Up to Day 28

• Percentage of Participants Reporting All-cause Mortality at Day 28

  At Day 28

• Number of Study Days Alive

  Up to Day 28

• Number of Participants Reporting Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs)

  Up to Day 28

Study Arms (2)

Losmapimod

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

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

Interventions

Losmapimod oral tablet DRUG

Losmapimod will be administered with food when possible.

Losmapimod

Placebo oral tablet DRUG

Placebo will be administered with food when possible.

Placebo

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Fulcrum Therapeutics: lead

Study Sites (16)

University of California Irvine - Irvine Medical Center

Irvine, California, 92697, United States

Location

University of Miami

Miami, Florida, 33136, United States

Location

University of South Florida

Tampa, Florida, 33606, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Memorial Hermann Hospital South West

Houston, Texas, 77030, United States

Location

University of Texas Health Science Center at Houston

Houston, Texas, 77030, United States

Location

United Medical Memorial Hospital

Houston, Texas, 77091, United States

Location

Hospital Universitario Cassiano Antonio de Moraes-HUCAM/Hospital das Clinicas

Vitória, Espírito Santo, 29043260, Brazil

Location

Santa Casa de Misericordia de Belo Horizonte

Belo Horizonte, Minas Gerais, 30150221, Brazil

Location

Irmandade de Santa Casa de Misericordia de Porto Alegre

Porto Alegre, Santa Catarina, 90035-075, Brazil

Location

Hospital Santa Paula

São Paulo, São Paulo, 04550-000, Brazil

Location

Hospital Civil Fray Antonio Alcalde

Guadalajara, Jalisco, 44280, Mexico

Location

Nuevo Hospital Civil de Guadalajara

Guadalajara, JC, 44340, Mexico

Location

JM Research Cuernavaca

Cuernavaca, Morelos, 662284, Mexico

Location

Centro para el Desarrollo de la Medicina y de Asistencia Médica Especializada, S.C.

Culiacán, Sinaloa, 80230, Mexico

Location

Hospital Nacional Carlos Alberto Seguín Escobedo - EsSalud Arequipa

Arequipa, AR, 04001, Peru

Location

Related Publications (5)

• 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.

  PMID: 32422320 BACKGROUND

• 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.

  PMID: 25122212 BACKGROUND

• 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.

  PMID: 29155150 BACKGROUND

• 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.

  PMID: 24461903 BACKGROUND

• World Health Organization (WHO). WHO R&D blueprint novel coronavirus COVID-19 therapeutic trial synopsis. Draft Feb 18, 2020.

  BACKGROUND

MeSH Terms

Conditions

COVID-19

Interventions

6-(5-((cyclopropylamino)carbonyl)-3-fluoro-2-methylphenyl)-N-(2,2-dimethylprpyl)-3-pyridinecarboxamide

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Results Point of Contact

• Title: Call Center
• Organization: Fulcrum Therapeutics

clinicaltrials@fulcrumtx.com

617-651-8853

Study Officials

• John Ziegler, MD, FASA

  Fulcrum Therapeutics

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

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

Study Record Dates

• First Submitted: August 8, 2020
• First Posted: August 13, 2020
• Study Start: August 28, 2020
• Primary Completion: March 31, 2021
• Study Completion: March 31, 2021
• Last Updated: March 13, 2024
• Results First Posted: March 13, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (7); BR (4); ME (4); PE (1)