COVID-19
Conditions
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
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.
Interventions
Losmapimod will be administered with food when possible.
DRUGPlacebo oral tablet
Placebo will be administered with food when possible.
Sponsors
Fulcrum Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, 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.
Intervention model description
This study is a randomized, double-blind, placebo-controlled study.
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Progressed to Death or Respiratory Failure by Day 28 | Up to 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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. |
| Total Number of Study Days Free of Oxygen Supplementation | Up to Day 28 | 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. |
| Percentage of Participants Reporting All-cause Mortality at Day 28 | At Day 28 | Percentage of participants who reported death have been presented. |
| Number of Study Days Alive | Up to Day 28 | 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. |
| Number of Participants Reporting Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) | Up to Day 28 | 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. |
Countries
Brazil, Mexico, Peru, United States
Participant flow
Recruitment details
The study was conducted across 5 sites in the United States and 3 sites in Brazil.
Pre-assignment details
This was a Phase 3, multicenter, randomized, double-blind, placebo-controlled study which evaluated the safety and efficacy of losmapimod versus placebo on a background of standard of care in participants with Coronavirus disease-2019 (COVID-19) disease (LOSVID Study)
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants were randomized to receive matching placebo tablets orally (PO) twice per day (BID) with food whenever possible and with 240 milliliters (mL) of room temperature water for 14 days. | 26 |
| Losmapimod 15 Milligrams (mg) Participants were randomized to receive losmapimod tablets 15 mg (2×7.5 mg tablets/dose) PO BID with food whenever possible and with 240 mL of room temperature water for 14 days. | 22 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Non-compliance with study drug | 5 | 1 |
| Overall Study | Protocol deviation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 3 |
Baseline characteristics
| Characteristic | Losmapimod 15 Milligrams (mg) | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 60.8 Years STANDARD_DEVIATION 10 | 59.1 Years STANDARD_DEVIATION 11.21 | 57.7 Years STANDARD_DEVIATION 12.15 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants | 38 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 9 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 9 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 5 Participants | 8 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 31 Participants | 19 Participants |
| Sex: Female, Male Female | 9 Participants | 20 Participants | 11 Participants |
| Sex: Female, Male Male | 13 Participants | 28 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 22 |
| other Total, other adverse events | 15 / 26 | 12 / 22 |
| serious Total, serious adverse events | 0 / 26 | 4 / 22 |
Outcome results
Primary
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.
Time frame: Up to Day 28
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Who Progressed to Death or Respiratory Failure by Day 28 | 61.5 Percentage of participants |
| Losmapimod 15 Milligrams (mg) | Percentage of Participants Who Progressed to Death or Respiratory Failure by Day 28 | 75.0 Percentage of participants |
p-value: 0.876295% CI: [-0.347, 0.174]Regression, Logistic
Secondary
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.
Time frame: Baseline and at Day 7 and Day 14
Population: Full Analysis Set. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Clinical Status at Days 7 and 14 Assessed on the 9-point World Health Organization (WHO) Ordinal Scale | Day 14 | -2.2 Scores on a scale | Standard Deviation 0.83 |
| Placebo | Change From Baseline in Clinical Status at Days 7 and 14 Assessed on the 9-point World Health Organization (WHO) Ordinal Scale | Day 7 | -1.6 Scores on a scale | Standard Deviation 1.14 |
| Losmapimod 15 Milligrams (mg) | Change From Baseline in Clinical Status at Days 7 and 14 Assessed on the 9-point World Health Organization (WHO) Ordinal Scale | Day 14 | -2.0 Scores on a scale | Standard Deviation 1.31 |
| Losmapimod 15 Milligrams (mg) | Change From Baseline in Clinical Status at Days 7 and 14 Assessed on the 9-point World Health Organization (WHO) Ordinal Scale | Day 7 | -1.4 Scores on a scale | Standard Deviation 1.58 |
Secondary
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.
Time frame: Up to Day 28
Population: Safety Analysis Set: included all participants who received any study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants Reporting Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| Placebo | Number of Participants Reporting Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) | Non-serious AEs | 15 Participants |
| Losmapimod 15 Milligrams (mg) | Number of Participants Reporting Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) | Non-serious AEs | 12 Participants |
| Losmapimod 15 Milligrams (mg) | Number of Participants Reporting Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 4 Participants |
Secondary
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.
Time frame: Up to Day 28
Population: Full Analysis Set. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Number of Study Days Alive | 27.9 Days | Standard Deviation 0.27 |
| Losmapimod 15 Milligrams (mg) | Number of Study Days Alive | 27.8 Days | Standard Deviation 0.51 |
Secondary
Percentage of Participants Reporting All-cause Mortality at Day 28
Percentage of participants who reported death have been presented.
Time frame: At Day 28
Population: Full Analysis Set. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Reporting All-cause Mortality at Day 28 | 0.0 Percentage of participants |
| Losmapimod 15 Milligrams (mg) | Percentage of Participants Reporting All-cause Mortality at Day 28 | 0.0 Percentage of participants |
Secondary
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.
Time frame: Up to Day 28
Population: Full Analysis Set. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Total Number of Study Days Free of Oxygen Supplementation | 24.0 Days | Standard Deviation 3.52 |
| Losmapimod 15 Milligrams (mg) | Total Number of Study Days Free of Oxygen Supplementation | 20.6 Days | Standard Deviation 8.8 |