Losmapimod Safety and Efficacy in COVID-19 (LOSVID)

• ClinicalTrials.gov Identifier: NCT04511819
• Recruitment Status: Terminated
• First Posted: August 13, 2020
• Last Update Posted: April 4, 2022
• Sponsor: Fulcrum Therapeutics
• Information provided by (Responsible Party): Fulcrum Therapeutics

Tracking Information

• First Submitted Date: August 8, 2020
• First Posted Date: August 13, 2020
• Last Update Posted Date: April 4, 2022
• Actual Study Start Date: August 28, 2020
• Actual Primary Completion Date: March 31, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 11, 2020)

Day 28 Mortality [ Time Frame: 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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 12, 2020)

• Clinical Status Assessment [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Day 7 ]
  To characterize changes in SARS-CoV-2 infection following treatment with losmapimod versus placebo.

Original Secondary Outcome Measures (submitted: August 11, 2020)

• Clinical Status Assessment [ Time Frame: 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 and Survival Assessment [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Day 7 ]
  To characterize changes in SARS-CoV-2 infection following treatment with losmapimod versus placebo.

Current Other Pre-specified Outcome Measures (submitted: August 13, 2020)

• Changes in C-Reactive Protein [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.

Original Other Pre-specified Outcome Measures (submitted: August 11, 2020)

• Changes in C-Reactive Protein [ Time Frame: 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 Circulating Proteins [ Time Frame: Days 1, 4, 7 and 14 ]
  The change from baseline in the levels of cytokines and chemokines in response to the SARS-CoV-2 virus in serum will be evaluated by multiplex ELISA assays.

Descriptive Information

• Brief Title: Losmapimod Safety and Efficacy in COVID-19
• 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)

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.

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 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 Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

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

• Condition: COVID-19

Intervention

• 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.
• 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.

Study Arms

• 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.
  Intervention: Drug: Losmapimod oral tablet
• 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.
  Intervention: Drug: Placebo oral tablet

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.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: August 3, 2021): 52
• Original Estimated Enrollment (submitted: August 11, 2020): 410
• Actual Study Completion Date: March 31, 2021
• Actual Primary Completion Date: March 31, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 50 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Brazil, Mexico, Peru, United States

Administrative Information

• NCT Number: NCT04511819
• Other Study ID Numbers: FIS-001-2020
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Fulcrum Therapeutics
• Original Responsible Party: Same as current
• Current Study Sponsor: Fulcrum Therapeutics
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: John Ziegler, MD, FASA; Fulcrum Therapeutics

• PRS Account: Fulcrum Therapeutics
• Verification Date: March 2022