Clinical trial NCT04511819: 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
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
Lead sponsor: Fulcrum Therapeutics
Sponsor class: INDUSTRY
First posted: 2020-08-13
Enrollment: 52
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This study is a randomized, double-blind, placebo-controlled study.
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Percentage of Participants Who Progressed to Death or Respiratory Failure by Day 28
timeFrame: Up to Day 28
Secondary outcomes:
measure: Change From Baseline in Clinical Status at Days 7 and 14 Assessed on the 9-point World Health Organization (WHO) Ordinal Scale
timeFrame: Baseline and at Day 7 and Day 14
measure: Total Number of Study Days Free of Oxygen Supplementation
timeFrame: Up to Day 28
measure: Percentage of Participants Reporting All-cause Mortality at Day 28
timeFrame: At Day 28
measure: Number of Study Days Alive
timeFrame: Up to Day 28
measure: Number of Participants Reporting Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to Day 28
Other outcomes:
Locations:
city: Irvine
country: United States
facility: University of California Irvine - Irvine Medical Center
state: California
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Houston
country: United States
facility: Memorial Hermann Hospital South West
state: Texas
city: Houston
country: United States
facility: University of Texas Health Science Center at Houston
state: Texas
city: Houston
country: United States
facility: United Medical Memorial Hospital
state: Texas
city: Vitória
country: Brazil
facility: Hospital Universitario Cassiano Antonio de Moraes-HUCAM/Hospital das Clinicas
state: ES
city: Belo Horizonte
country: Brazil
facility: Santa Casa de Misericordia de Belo Horizonte
state: MG
city: Porto Alegre
country: Brazil
facility: Irmandade de Santa Casa de Misericordia de Porto Alegre
state: SC
city: San Paolo
country: Brazil
facility: Hospital Santa Paula
state: SP
city: Guadalajara
country: Mexico
facility: Hospital Civil Fray Antonio Alcalde
state: Jalisco
city: Guadalajara
country: Mexico
facility: Nuevo Hospital Civil de Guadalajara
state: JC
city: Cuernavaca
country: Mexico
facility: JM Research Cuernavaca
state: Morelos
city: Culiacán
country: Mexico
facility: Centro para el Desarrollo de la Medicina y de Asistencia Médica Especializada, S.C.
state: Sinaloa
city: Arequipa
country: Peru
facility: Hospital Nacional Carlos Alberto Seguín Escobedo - EsSalud Arequipa
state: AR
Study officials:
affiliation: Fulcrum Therapeutics
name: John Ziegler, MD, FASA
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: World Health Organization (WHO). WHO R&D blueprint novel coronavirus COVID-19 therapeutic trial synopsis. Draft Feb 18, 2020.