Clinical trial NCT04511819
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
Sponsor: Fulcrum Therapeutics
Start date: 2020-08-28; Completion date: 2021-03-31
Enrollment: 52 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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. arm 2: 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.
Interventions: intervention 1: Losmapimod oral tablet intervention 2: Placebo oral tablet
Intervention descriptions: intervention 1: Losmapimod will be administered with food when possible. intervention 2: Placebo will be administered with food when possible.

Protocol documents:
Prot_000.pdf: 
 
 
 
16. 
APPENDICES 
APPENDIX 16.1: 
STUDY INFORMATION 
APPENDIX 16.1.1: PROTOCOL AND PROTOCOL AMENDMENTS 
Administrative Letter, 25 January 2021 .......................................................................................... 2 
Protocol Clarification Memo #2, 05 January 2021 ......................................................................... 3 
Summary of Changes for All Protocol Versions, 21 October 2020 ............................................... 4 
Protocol Version 3.0, 21 October 2020 .......................................................................................... 7 
Protocol Clarification Memo #1, 18 September 2020 .................................................................. 69 
Protocol Version 2.1, 10 July 2020 ............................................................................................... 70 
Protocol Version 2.0, 29 June 2020 ............................................................................................ 133 
Original Protocol, Version 1.0, 29 May 2020 ............................................................................. 194 
 
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FIS-001-2020: Administrative Letter (25JAN2021) 
 
Page 1 of 1 
 
 
Protocol FIS-001-2020 
                                   Administrative Letter – CRP addition to safety labs on D1, D2, and D4 
Date: 25 January 2021 
 
 
It is well recognized that C-reactive protein (CRP) and interleukin-6 (IL-6) are biomarkers that are 
important in the evaluation of the inflammatory response to the Sars-CoV-2 virus. Fulcrum therefore 
requests that these two biomarkers be added to the chemistry safety labs that are already being drawn on 
treatment Days 1, 2, and 4 (seen in the table below as D1, D2, and D4).  As chemistry safety laboratory 
assessments are already being collected on these days per the protocol table below, no additional blood 
draws would be required for the study subjects. Please note that all other assessments remain as written 
in the protocol and that it is extremely important that all lab draws for safety labs (performed at the local 
lab) and biomarkers (performed at the central lab) be done on time as listed in the protocol.  
 
These changes to the Schedule of Assessment will be reflected in the next protocol amendment. 
 
               
MD 
Medical Director, LOSVID Trial 
Fulcrum Therapeutics, Inc. 
 
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FIS-001-2020: Administrative Amendment (05JAN2020)  
Page 1 of 1 
 
 
 
Protocol FIS-001-2020 
Clarification Memo – Eligibility Screening Labs 
Date: 05 January 2021 
 
 
The labs used to determine eligibility at screening should ideally be drawn after the informed consent 
form (ICF) has been signed and within 3 days of baseline on D1. This is to assure that the patient’s 
current clinical status is known at screening. However, if patients are hospitalized and have had labs 
drawn prior to formal screening and the signing of the ICF and the Principal Investigator believes that 
they are representative of the patient’s current clinical status, those labs can be used for screening 
purposes as long as they were obtained no more than 72 hours prior to D1. The labs need to have been 
drawn at the facility where the patient has been hospitalized continuously since the labs were drawn.   
This accommodation is intended to avoid unnecessary procedures on vulnerable patients while also 
minimizing interactions with hospital staff in an attempt to avoid the spread of infection. 
 
 
 
 
 
 
 
 
___
, MD 
Medical Director, LOSVID Trial 
Fulcrum Therapeutics, Inc. 
 
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Fulcrum Therapeutics 
                  Losmapimod 
Protocol FIS-001-2020 – Summary of changes 
 
Protocol v3.0 Summary of Changes / 
21-Oct-2020  
Fulcrum Therapeutics 
Confidential  
Page 1 of 3 
 
Summary of Changes to the Protocol 
Protocol 
History 
 
Version and 
Date of 
Protocol 
Comments 
Version 3.0, 
21 October 
2020 
Inclusion criteria were updated as follows: 
• 
The age in inclusion criterion 3 was changed from ≥50 years old to 
≥40 years old based on clinical site feedback regarding recruitment 
challenges, while maintaining older age as an important risk factor for 
progression of COVID-19. 
• 
Baseline oxygen requirements in inclusion criterion 7 were changed 
based on clinical site feedback to oxygen saturation ≥ 92%, which 
can be either on room air or on oxygen supplementation if using 
≤10L/min by nasal canula or close-fitting face mask. 
• 
The “note” for inclusion criterion 8 was combined into the main 
criterion 8 for optimal readability. 
Exclusion criteria were updated as follows: 
• 
The definition of critical disease in exclusion criterion 2 was updated 
to remove “anticipated need for intubation” and “severe pulmonary 
involvement” based on clinical site feedback; ARDS and immediate 
need for intubation or mechanical ventilation were retained in the 
definition of critical COVID-19 disease. Evidence of pulmonary 
involvement remains in inclusion criterion 8. 
• 
Exclusion criterion 5 was updated to note that the exclusion is for 
poorly controlled HIV and to allow for the inclusion of subjects with 
HIV if their CD4 counts are normal and they have been on a stable 
antiviral regimen and are anticipated to remain on that regimen for 
the duration of the study. 
The changes above were also applied where applicable in the descriptions 
of the study design and procedures. 
 
Minor administrative/operational and typographical clarifications were made. 
Version 2.1, 
10 July 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minor administrative/operational and typographical clarifications were made, 
including the following: 
• 
IND number was removed on title page to be more broadly applicable 
to worldwide sites 
• 
Clarification made to secondary endpoints that these are measured 
“by Day 28” for alignment with other secondary objective wording and 
clarity 
• 
Note was added to inclusion criterion 1 to clarify that patient’s LAR 
may give consent, in alignment with LAR language in Section 9.1.3 of 
version 2.0 of the protocol.  
o It was further clarified in inclusion 1 and Section 9.1.3 that the 
patient should provide assent in this scenario. 
o In addition, it was clarified in Section 7.1.1 that the LAR may 
report AEs when appropriate 
• 
Inclusion criterion 10 units of measurements were clarified for ease of 
site determination of eligibility 
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                  Losmapimod 
Protocol FIS-001-2020 – Summary of changes 
 
Protocol v3.0 Summary of Changes / 
21-Oct-2020  
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Page 2 of 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
It was clarified that the methods of birth control should follow 
local/country guidelines and regulations as applicable for sites out the 
US, for more broad applicability to worldwide sites 
• 
Exclusion 9 wording was clarified for ease of site determination of 
eligibility  
• 
Wording in statistical analyses sections was clarified to note that the 
adjustment for CRP is for baseline CRP. 
• 
For change in clinical status endpoint, it was clarified that the model 
using regression analyses would be adjusted for stratification factors, 
sex, and baseline CRP, similarly to the primary analysis 
• 
For total number of study days free of oxygen supplementation/in 
ICU/ of hospitalization/ free of respiratory failure / alive, it was 
clarified that the model using regression analyses would be adjusted 
for stratification factors, sex, baseline CRP and number of days on 
study. 
• 
Sample collection language for confirmation of diagnosis was 
clarified, including clarification that saliva or sputum collection may be 
used in addition to swab 
• 
Sample collection language for viral load/viral presence testing in 
sentinel subjects was clarified for alignment with vendor procedures 
and with viral load assessments during the rest of the trial (changed 
to central testing, not local) 
• 
Oxygenation and FiO2 at Days 21 and 28 were added to the 
Schedule of Assessments to align with methodology and analyses as 
specified in version 2.0 of the protocol 
• 
It was clarified that PK assessments in patients with renal 
insufficiency should be measured weekly for 2 weeks at Cmax, when 
possible (overall duration of this weekly assessment added) 
• 
Benefit-risk section was added to consolidate benefit-risk information 
found in protocol version 2.0 into a single location in the protocol for 
convenience 
• 
Reporting of pregnancy section 7.2.2 was updated to clarify that the 
Sponsor’s designee, 
 will collect this information; the name 
of the form was updated to match the designee’s procedures 
• 
Other general editorial/typographical updates 
Version 2.0, 
29 June 2020 
• 
Updated statistical methods based on feedback from the United 
States Food and Drug Administration (FDA): 
• 
Comparisons for primary and secondary endpoints (clinical 
status, percentage of subjects discharged from hospital, all-
cause mortality, clearance of quantifiable viral RNA) will use 
adjusted risk difference obtained from a regression model (with 
sex, CRP, and stratification factors as covariates) rather than 
stratified Cochran-Mantel-Haenszel testing 
• 
A section was added to specify type I error control for selected 
key study endpoints 
• 
Operational clarification was made in Visit and Assessment Schedule 
to align with COVID history will being a separate CRF page from 
medical history (both were to be collected per the main text in the 
original protocol) 
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Protocol v3.0 Summary of Changes / 
21-Oct-2020  
Fulcrum Therapeutics 
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Page 3 of 3 
 
• 
The reasons for study treatment discontinuation were clarified based 
on feedback from the FDA 
• 
The reasons for study discontinuation were clarified based on 
feedback from the FDA 
• 
Subjects may only discontinue from the study due to withdrawal 
of consent or loss to follow-up; subjects should be encouraged to 
complete all follow-up visits if they discontinue study drug 
• 
Operational clarification was made that some of the laboratory 
assessments are done at a central laboratory and some at a local 
laboratory (details are available in the Study Manual) 
• 
For optimal clarity, Section 7.1.1, Recording of adverse events, was 
added to incorporate timing of AE/SAE recording that was in the Visit 
and Assessment schedule in the original protocol 
• 
The name of the CRO was updated to 
, and contact 
information was updated in Reporting of serious adverse events 
section 
• 
Other general editorial/typographical updates 
Version 1.0, 
29 May 2020 
• 
Original Version 
 
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Protocol Version 3.0 / 21-Oct-2020  
Confidential 
Page 1 of 62 
 
 
CLINICAL STUDY PROTOCOL 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled 
Study of the Safety and Efficacy of Losmapimod in Adult 
Subjects with COVID-19 (LOSVID STUDY) 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 
 
 
Short Title: 
Losmapimod safety and efficacy in COVID-19 (LOSVID Study) 
Version: 
3.0. 
Date: 
21-Oct-2020 
Study number: 
FIS-001-2020 
Sponsor: 
Fulcrum Therapeutics 
26 Landsdowne St., 5th floor 
Cambridge, MA 02139 
USA 
Sponsor signatory: 
, MD 
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Losmapimod 
Protocol FIS-001-2020 
 
 
Protocol Version 3.0 / 21-Oct-2020  
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CONTACT DETAILS 
SPONSOR 
  
Fulcrum Therapeutics 
26 Landsdowne Street, 5th floor 
Cambridge, Massachusetts 02139 
USA 
Clinical Trial Leader 
 
 
 MD 
Telephone:
e-mail: 
Drug Safety Physician 
 
 MD 
Telephone: 
e-mail:
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SIGNATURE PAGE - INVESTIGATOR 
 
Study 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) 
 
I have read the protocol and agree to conduct the study as described herein. 
 
 
 
Investigator Name 
Title 
 
 
 
 
Signature 
Date (dd Mmm yyyy) 
 
 
10/22/2020
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Protocol Version 3.0 / 21-Oct-2020  
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SIGNATURE PAGE - SPONSOR 
Fulcrum Therapeutics 
Study 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) 
 
I approve this protocol on behalf of the sponsor. 
 
 
Chief Scientific Officer 
 
 
 
Signature 
Date (dd Mmm yyyy) 
 
 
, MD 
Senior Vice President 
Head, Clinical Development 
 
 
 
 
 
Signature 
Date (dd Mmm yyyy) 
 
10/21/2020
10/22/2020
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TABLE OF CONTENTS 
CONTACT DETAILS ........................................................................................................................................... 2 
SIGNATURE PAGE - INVESTIGATOR .............................................................................................................. 3 
SIGNATURE PAGE - SPONSOR ....................................................................................................................... 4 
TABLE OF CONTENTS ...................................................................................................................................... 5 
LIST OF ABBREVIATIONS ................................................................................................................................ 9 
PROTOCOL SYNOPSIS ................................................................................................................................... 11 
1 
BACKGROUND AND RATIONALE ......................................................................................................... 21 
1.1 
Scientific rationale for investigation of losmapimod in COVID-19 ..................................................... 21 
1.2 
Benefit-risk considerations................................................................................................................. 25 
2 
STUDY OBJECTIVES AND ENDPOINTS ................................................................................................ 26 
3 
STUDY IMPLEMENTATION ..................................................................................................................... 28 
3.1 
Overall study design and plan ........................................................................................................... 28 
3.2 
Start of study and end of study definitions......................................................................................... 28 
3.3 
Selection of doses in the study .......................................................................................................... 28 
3.4 
Study drug modifications and withdrawal .......................................................................................... 29 
3.4.1 
Dose modifications .................................................................................................................... 29 
3.4.2 
Subject withdrawal ..................................................................................................................... 31 
3.4.3 
Replacement policy ................................................................................................................... 31 
3.4.4 
Stopping criteria ......................................................................................................................... 31 
4 
STUDY POPULATION .............................................................................................................................. 32 
4.1 
Inclusion criteria ................................................................................................................................. 32 
4.2 
Exclusion criteria ................................................................................................................................ 33 
4.3 
Concomitant medications .................................................................................................................. 33 
4.4 
Lifestyle restrictions ........................................................................................................................... 34 
4.4.1 
Contraception requirements ...................................................................................................... 34 
5 
INVESTIGATIONAL MEDICINAL PRODUCT .......................................................................................... 35 
5.1 
Investigational drug and matching placebo ....................................................................................... 35 
5.2 
Study drug packaging and labelling ................................................................................................... 35 
5.3 
Drug accountability ............................................................................................................................ 35 
5.4 
Treatment assignment and blinding .................................................................................................. 35 
5.4.1 
Randomization and treatment assignment ................................................................................ 35 
5.4.2 
Blinding ...................................................................................................................................... 36 
5.4.3 
Treatment compliance ............................................................................................................... 36 
6 
STUDY ASSESSMENTS .......................................................................................................................... 37 
6.1 
Medical history and confirmation of COVID diagnosis ...................................................................... 37 
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6.2 
Pharmacokinetic and pharmacodynamic assessments .................................................................... 37 
6.3 
Clinical status and symptoms ............................................................................................................ 38 
6.3.1 
Respiratory failure and survival assessment ............................................................................. 38 
6.3.2 
Clinical status assessment ........................................................................................................ 38 
6.4 
Extended vital signs ........................................................................................................................... 38 
6.5 
Safety and tolerability assessments .................................................................................................. 38 
6.5.1 
Vital signs................................................................................................................................... 39 
6.5.2 
Weight and height ...................................................................................................................... 39 
6.5.3 
Physical examination ................................................................................................................. 39 
6.5.4 
Electrocardiography ................................................................................................................... 39 
6.5.5 
Laboratory assessments ............................................................................................................ 39 
6.6 
Unscheduled visit ............................................................................................................................... 40 
6.6.1 
Early termination visit ................................................................................................................. 40 
6.7 
Alternative follow-up methods to site visits ........................................................................................ 40 
7 
SAFETY REPORTING .............................................................................................................................. 42 
7.1 
Definitions of adverse events ............................................................................................................ 42 
7.1.1 
Recording of adverse events ..................................................................................................... 42 
7.1.2 
Intensity of adverse events ........................................................................................................ 42 
7.1.3 
Relationship to study drug ......................................................................................................... 42 
7.1.4 
Serious adverse events ............................................................................................................. 42 
7.1.5 
Suspected unexpected serious adverse reactions .................................................................... 43 
7.1.6 
Reporting of serious adverse events ......................................................................................... 43 
7.1.7 
Follow-up of adverse events ...................................................................................................... 43 
7.1.8 
Adverse events of special interest ............................................................................................. 43 
7.2 
Pregnancy .......................................................................................................................................... 44 
7.2.1 
Teratogenicity ............................................................................................................................ 44 
7.2.2 
Reporting of pregnancy ............................................................................................................. 44 
8 
STATISTICAL METHODOLOGY AND ANALYSES ................................................................................ 45 
8.1 
Statistical analysis plan...................................................................................................................... 45 
8.1.1 
Determination of sample size .................................................................................................... 45 
8.1.2 
Analysis methods ....................................................................................................................... 45 
8.1.3 
Analysis sets .............................................................................................................................. 45 
8.2 
Protocol violations/deviations ............................................................................................................ 45 
8.3 
Missing, unused and spurious data ................................................................................................... 46 
8.4 
Subject disposition ............................................................................................................................. 46 
8.5 
Baseline parameters and concomitant medications .......................................................................... 46 
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8.5.1 
Demographics and baseline variables ....................................................................................... 46 
8.5.2 
Medical history ........................................................................................................................... 46 
8.5.3 
Prior and concomitant medications ........................................................................................... 46 
8.5.4 
Treatment compliance/exposure ............................................................................................... 46 
8.5.5 
Safety and tolerability endpoints ................................................................................................ 46 
8.5.6 
Adverse events .......................................................................................................................... 46 
8.5.7 
Vital signs................................................................................................................................... 47 
8.5.8 
ECG ........................................................................................................................................... 47 
8.5.9 
Clinical laboratory tests .............................................................................................................. 47 
8.6 
Primary endpoints .............................................................................................................................. 47 
8.7 
Secondary endpoints ......................................................................................................................... 48 
 
 
8.9 
Interim analysis for futility and sample size re-estimation ................................................................. 49 
8.9.1 
Futility Testing ............................................................................................................................ 52 
8.9.2 
Sample Size Re-estimation ....................................................................................................... 52 
8.9.3 
Possible Recommendations by the DMC .................................................................................. 53 
8.10 
Data monitoring committee ................................................................................................................ 53 
8.11 
Type I error for testing key study endpoints ...................................................................................... 54 
9 
GOOD CLINICAL PRACTICE, ETHICS AND ADMINISTRATIVE PROCEDURES ................................ 55 
9.1 
Good clinical practice ......................................................................................................................... 55 
9.1.1 
Ethics and good clinical practice ............................................................................................... 55 
9.1.2 
Ethics committee / institutional review board ............................................................................. 55 
9.1.3 
Informed consent ....................................................................................................................... 55 
9.2 
Data handling and record keeping ..................................................................................................... 56 
9.3 
Access to source data and documents .............................................................................................. 56 
9.4 
Investigator’s obligations ................................................................................................................... 56 
9.5 
Confidentiality .................................................................................................................................... 57 
9.6 
Financial disclosure and obligations .................................................................................................. 57 
9.7 
Investigator documentation ............................................................................................................... 57 
9.8 
Study conduct .................................................................................................................................... 57 
9.9 
Adherence to protocol ........................................................................................................................ 58 
9.10 
Adverse events and study report requirements ................................................................................. 58 
9.11 
Investigator’s final report.................................................................................................................... 58 
9.12 
Records retention .............................................................................................................................. 58 
9.13 
Publications ....................................................................................................................................... 58 
10 
STUDY MANAGEMENT ....................................................................................................................... 59 
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10.1 
Monitoring .......................................................................................................................................... 59 
10.2 
Inspection of records ......................................................................................................................... 59 
10.3 
Management of protocol amendments and deviations ...................................................................... 59 
10.3.1 
Modification of the protocol ........................................................................................................ 59 
10.3.2 
Protocol deviations .................................................................................................................... 59 
10.4 
Study termination ............................................................................................................................... 59 
10.5 
Final report ......................................................................................................................................... 60 
11 
REFERENCES ...................................................................................................................................... 61 
 
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LIST OF ABBREVIATIONS 
ACE2 
angiotensin-converting enzyme 2 
ACS 
acute coronary syndrome 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase/serum glutamic pyruvic transaminase (SGPT) 
 
 
ARDS 
acute respiratory distress syndrome 
AST 
aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
(SGOT) 
BID 
bis in diem / twice per day 
BMI 
body mass index 
BP 
blood pressure 
CI 
confidence interval 
Cmax 
Maximum concentration 
COPD 
chronic obstructive pulmonary disease 
CoV 
coronavirus 
COVID-19 
disease caused by novel coronavirus 
CRP 
C-reactive protein 
CXCL13 
chemokine ligand 13 
DILI 
drug-induced liver injury 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
ECMO 
extracorporeal membrane oxygenation 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
ET 
early termination 
ET-1 
endothelin 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FiO2 
fraction of inspired oxygen 
FSGS 
focal segmental glomerulosclerosis 
FSHD 
facioscapulohumeral muscular dystrophy 
GCP 
Good Clinical Practice 
 
 
GSK 
GlaxoSmithKline 
H5N1 
highly pathogenic Asian avian influenza A, subtype H5N1 
HIV 
human immunodeficiency virus 
HMGB-1 
high mobility group box protein-1 
hsCRP 
high-sensitivity C-reactive protein 
HSV-1 
herpes simplex virus-1 
IA 
interim analysis 
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ICAM-1 
intercellular adhesion molecule-1 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
ICU 
intensive care unit 
IEC 
independent ethics committee 
IL-6 
interleukin-6 
IND 
investigational new drug application 
IRB 
institutional review board 
IxRS 
JAK 
interactive/web voice response system 
Janus kinase 
 
 
LLQ 
lower limit of quantitation 
LS 
least square 
MAPK 
MATE 
mitogen-activated protein kinase 
multidrug and toxin extrusions 
MCAR 
missing-completely-at-random 
MedDRA 
OAT 
Medical Dictionary for Regulatory Activities 
organic anion transporter 
PAO2 
partial pressure of oxygen 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic(s) 
PH 
proportional hazards 
PK 
pharmacokinetics 
PO 
per os / orally 
PPS 
per protocol set 
QTcB 
QT corrected interval using Bazett’s formula 
QTcF 
QT corrected interval using Fridericia’s formula 
RA 
rheumatoid arthritis 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-1 
severe acute respiratory syndrome coronavirus 1 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SAS 
Statistical Analysis Software 
SE 
standard error 
SOC 
standard of care 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
ULN 
US 
upper limit of normal 
United States 
WHO 
World Health Organization 
 
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PROTOCOL SYNOPSIS 
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)  
Short Title 
Losmapimod safety and efficacy in COVID-19 (LOSVID Study) 
Background & Rationale 
Poor prognosis for many COVID-19 patients has been attributed to an exaggerated inflammatory 
response following SARS-CoV-2 infection. This hyperactivated immune response is associated with 
pulmonary edema, acute respiratory distress syndrome (ARDS), and cardiomyopathy that may lead 
to increased mortality in the sickest patients.  
p38 mitogen-activated protein kinase (MAPK) is an important mediator of inflammation, and 
extensive nonclinical data have linked p38 to the hyper-inflammatory response to viral infections.  
Losmapimod is a potent and selective p38α/β MAPK inhibitor that is currently in Phase 2 clinical 
trials for the treatment of facioscapulohumeral dystrophy and has previously been administered to 
more than 3600 adult healthy volunteers and subjects including participants in a Phase 3 trial. Many 
of these trials were for chronic inflammatory indications for which the compound exhibited a 
favorable safety profile not significantly different from placebo. These trials have also indicated that 
losmapimod has good exposure after oral dosing, robust target engagement, and acutely reduces 
inflammatory biomarkers that have been associated with poor prognosis in COVID-19, including 
C-reactive protein (CRP) and interleukin-6 (IL-6). Additionally, a clinical study recently concluded 
that losmapimod restored the normal immune response of older subjects (median 69 years, range: 
65, 77 years) following a viral challenge. Further information is available in the losmapimod 
Investigator Brochure.  
Losmapimod is attractive as a potential therapeutic option for COVID-19: 
• 
p38 inhibition improves survival in mouse SARS-CoV-1 models and other nonclinical viral 
models, suppressing the exaggerated immune response to acute infection. 
• 
Losmapimod acutely has reduced exaggerated inflammatory responses in human trials for 
multiple inflammatory diseases, including IL-6 and CRP, and has normalized immune 
response to viral or other acute inflammatory challenges in older subjects. 
• 
Losmapimod is a clinical-stage, potent, and selective p38 inhibitor with extensive human 
experience and extensive evidence of safety and tolerability, including in a Phase 3 clinical 
trial in acute myocardial infarction. 
• 
p38 inhibition has the potential to reduce hypothesized deleterious effects of increased 
angiotensin II in COVID-19, such as vasoconstriction, increased inflammation, cardiac 
arrhythmias, and organ failure. 
 
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Objectives and Endpoints: 
All study objectives will be evaluated in subjects diagnosed with COVID-19: 
Objectives 
Endpoints 
Primary 
To assess the efficacy of losmapimod 
compared with placebo for treatment of 
COVID-19 when administered concurrently 
with standard of care 
Proportion of progressors to death or respiratory 
failure by Day 28 
Secondary 
To evaluate the effect of losmapimod 
compared with placebo on clinical 
outcomes 
Clinical status by Days 7 and 14 as measured on 
the 9-point WHO ordinal scale: 
• 
(8) death 
• 
(7) ventilation plus additional organ support 
(vasopressors, renal replacement therapy, 
ECMO) 
• 
(6) Intubation and mechanical ventilation 
• 
(5) noninvasive ventilation or high-flow oxygen 
therapy 
• 
(4) oxygen therapy but not requiring high-flow 
or non-invasive ventilation 
• 
(3) hospitalized but not requiring oxygen 
therapy 
• 
(2) Discharged from the hospital but with 
limitation of activities 
• 
(1) Discharged from the hospital and without 
any limitation 
• 
(0) No clinical evidence of the disease 
To assess the effect on clinical status of 
treatment with losmapimod compared with 
placebo 
Total number of study days free of oxygen 
supplementation by Day 28 
Total number of study days in ICU by Day 28 
Total number of study days hospitalized by Day 28 
Total number of respiratory failure-free study days 
by Day 28 
Percentage of subjects discharged from the 
hospital by Day 28 
To assess the effect on survival following 
treatment with losmapimod compared with 
placebo 
All-cause mortality at Day 28 
Number of study days alive by Day 28 
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Objectives 
Endpoints 
To assess the safety and tolerability of 
losmapimod compared with placebo 
Incidence of AEs and SAEs 
Incidence of clinically significant changes in 
laboratory parameters and vital sign measurements 
To characterize changes in SARS-CoV-2 
infection following treatment with 
losmapimod compared with placebo 
Quantifiable viral RNA on Day 7 
Abbreviations: AE = adverse event; 
; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; COVID-19 = disease caused by novel coronavirus; CRP = C-reactive protein; ECG = 
electrocardiogram; ECMO = extracorporeal membrane oxygenation; 
; ICU = intensive care 
unit; IL-6 = interleukin-6; 
; PD = pharmacodynamics; RNA = ribonucleic acid; SAE = serious 
adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; WHO = World Health Organization.  
Design 
This Phase 3 multicenter, randomized, double-blind, placebo-controlled study will evaluate the 
safety and efficacy of losmapimod versus placebo on a background of standard of care in subjects 
with COVID-19 disease. 
This study will be performed in hospitalized subjects ≥40 years old who have a C-reactive protein 
(CRP) >15 mg/L, who have been diagnosed with COVID-19, and who can undergo randomization 
within 7 days of collection of the sample found positive for the SARS-CoV-2 virus and before 
progressing into critical disease. Critical disease is defined as cardiac failure, septic shock, or ARDS 
or immediate need for intubation or mechanical ventilation per the judgment of the investigator. 
Subjects who sign informed consent and meet all entry criteria (listed below) may be enrolled. 
 
Up to 410 subjects will participate for a maximum of 34 days, divided as follows: 
o Screening: Day -3 until Day -1 before the first study drug administration. 
o Treatment period of 14 days: 
o Subjects randomized (1:1) to either:  
▪ 
losmapimod tablets 15 mg orally (PO) twice daily (BID); OR  
▪ 
matching placebo tablets PO BID 
o Randomization will be stratified by age (<65 or ≥65) and requirement for oxygen at 
randomization (yes/no) 
o Follow-up: 7 (± 3) days after last dose and 14 (± 3) days after last dose. 
 
The first 10 enrolled subjects (approximately 5 placebo and 5 losmapimod) will be dosed and 
followed for at least 72 hours after their first dose for an interim “sentinel” safety review before any 
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additional subjects are dosed. Dosing of additional subjects will continue if there are no drug-related 
safety concerns from the initial subjects dosed as assessed by an independent Data Monitoring 
Committee (DMC). The DMC will review safety data for the sentinel subjects and all subjects at 
regular intervals throughout the study as outlined in the charter. 
The Sponsor will monitor individual adverse events (AEs) and toxicities on an ongoing basis 
throughout the study.  
See Table 1 for the time points of the assessments. 
All study visits during the first week of treatment are anticipated to be conducted in the inpatient 
setting. If the clinical status of the subject improves such that the clinician discharges the subject 
from the hospital before the end of the study, the follow-up assessments will be conducted on an 
outpatient basis by alternative methods, including the use of local laboratories/facilities or home 
visits for blood draws, telemedicine, and/or outpatient follow-up clinic visits as deemed clinically 
appropriate per COVID-19 follow-up standard of care (SOC) at each site. 
Investigational drug 
Losmapimod will be provided in tablets of 7.5 mg for oral administration. 
Comparative drug 
Matching placebo tablets will be provided for oral administration. 
Inclusion criteria 
1. Able and willing to provide written informed consent. 
a. Note: Subject’s legally authorized representative may provide informed consent as 
applicable based on local guidelines and regulations. If consent is obtained from a 
legally authorized representative, then assent should be obtained from the subject. 
2. Willing and able to comply with all study procedures. 
3. Age ≥40 years at time of screening. 
4. Confirmed infection with SARS-CoV-2 virus at or before the baseline visit (by polymerase 
chain reaction [PCR] testing). 
a. Note: Refer to the Study Manual for details on PCR SARS-Cov-2 testing procedures. 
5. ≤7 days to the time of randomization from the time of collection of the specimen that tested 
positive for SARS-CoV-2 virus. 
6. Hospitalization at the time of the baseline visit. 
7. Oxygen saturation ≥92% at the baseline visit, which can be either on room air or on oxygen 
supplementation if using ≤ 10LPM by nasal prong or close-fitting mask. 
8. Evidence of pulmonary involvement consistent with COVID-19 by either clinical examination 
or radiographic examination (whichever is per local standard of care), per the judgment of 
the investigator. Evidence of pulmonary involvement obtained by clinical examination should 
be documented in the eCRF. 
9. Clinical syndrome consistent with COVID-19 at screening, per the judgment of the 
investigator 
10. CRP at screening >15 mg/L (which is equivalent to >1.5 mg/dL) on local laboratory testing. 
 
 
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11. Agrees to practice an approved method of birth control as follows (as applicable to local 
[country] guidelines and regulations for sites outside the United States): 
a. Females of childbearing potential: Using 1 of the following acceptable methods of 
contraception: surgical sterilization (eg, bilateral tubal ligation), intrauterine 
contraception/device, hormonal contraception, or any 2 barrier methods (a 
combination of male or female condom with diaphragm, sponge, or cervical cap). 
This criterion must be followed from the time of the first dose of study medication until 
90 days after last dose 
b. Males: Effective male contraception includes a vasectomy with negative semen 
analysis at follow-up, or the use of condoms. This criterion must be followed from the 
time of the first dose of study medication until 90 days after last dose. 
Note: Abstinence can be considered an acceptable method of contraception at the 
discretion of the investigator. Periodic abstinence (eg, calendar, ovulation, 
symptothermal, post ovulation methods) and withdrawal are not considered 
acceptable methods of contraception.  
Exclusion criteria 
1. Inability to take oral medication at screening or baseline visit. 
2. Evidence at screening or baseline of critical COVID-19 disease (eg, cardiac failure, septic 
shock, or ARDS) or immediate need for intubation or mechanical ventilation per the 
judgment of the investigator. 
3. Positive pregnancy test at screening for women of childbearing potential. 
4. Lactating female at baseline for women of childbearing potential. 
a. 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. ≥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 poorly 
controlled HIV infection. (Subjects with HIV infection  who have normal CD4 counts may 
participate if they have been on a stable antiviral regimen for the 30 days prior to screening 
and are anticipated to remain on the regimen throughout the duration of the study.) 
6. Glomerular filtration rate <30 mL/min/1.73 m2 at screening. 
7. QTcF >450 msec for male or >470 msec for females or evidence of cardiac dysrhythmia at 
screening. 
8. 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. 
9. 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. 
10. 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. 
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11. Recent (within 30 days) or current participation in other COVID-19 therapeutic trials or 
expanded access programs. 
12. Prior or current participation in COVID-19 vaccine trials. 
Sample size justification 
The primary efficacy endpoint of this study is the proportion of subjects who progress to death or 
respiratory failure by the end of study (Day 28). It is estimated that approximately 30% of enrolled 
subjects receiving SOC plus placebo will attain this endpoint. It is assumed that losmapimod will 
improve the primary endpoint by 40% over placebo. On the basis of these assumptions, a total of 
410 subjects randomized to the losmapimod arm or the placebo arm in a 1:1 ratio (205 subjects in 
the losmapimod arm and 205 subjects in the placebo arm) will yield approximately 80% power in a 
1-sided test at the 2.5% significance level. The sample size estimate assumes an interim analysis 
(IA) will be conducted after approximately 206 subjects (103 in each of the losmapimod and placebo 
arms) have completed the Day 28 visit, to assess futility.   
Statistical methodology 
A statistical analysis plan (SAP) will be generated and approved prior to database snapshot for the 
IA. The SAP will detail the implementation of all planned statistical analysis. Any deviations from the 
planned analysis will be described and justified in the final clinical study report. 
In general, all study endpoints will be summarized using descriptive statistics. Descriptive statistics 
for continuous data will include number of subjects (n), mean, standard deviation, median, 
minimum, and maximum. Descriptive statistics for categorical data will include frequency and 
percentage.  
 
Where appropriate, descriptive statistics may be presented with 95% confidence intervals. 
Analysis sets 
Full Analysis Set (FAS): The FAS will consist of all subjects who are randomly assigned to receive 
double-blind study drug. All analyses using the FAS will group subjects according to randomized 
treatment. The primary endpoint, clinical outcomes/status, survival, and pharmacodynamic 
endpoints will be analyzed using the FAS. 
Per Protocol Set (PPS): The PPS will consist of all FAS subjects who fulfill all inclusion/exclusion 
criteria and do not have any significant protocol deviations. All analyses using the PPS will group 
subjects according to randomized treatment. 
Safety Analysis Set: The safety analysis set is defined as all subjects who are randomized and 
receive study drug. All analyses using the Safety Analysis Set will group subjects according to 
treatment actually received. The safety analysis set will be used for all safety and tolerability 
analyses. 
Primary endpoint 
For the final analysis, the proportion of subjects achieving the primary endpoint in the treatment 
arms will be compared using an adjusted risk difference obtained from a regression model, adjusted 
for stratification factors, sex, and baseline CRP. Full details of the regression model will be provided 
in the SAP. An interim analysis to assess futility analysis—and potential sample size re estimation—
will be conducted. All results will be summarized descriptively by treatment arm and expressed as 
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proportions, along with corresponding unadjusted/adjusted 95% CI of the difference between 
response rates, and p values. 
Secondary endpoints 
Clinical status at Day 7 and Day 14:  
Change in clinical status between baseline and post-baseline will be modelled using regression 
models appropriate for ordinal data, adjusting for stratification factors, sex, and baseline CRP. 
Details will be provided in the SAP. 
Percentages for each category of the ranking scale will be tabulated by treatment arm, along with 
differences between treatment arms at each time point. The proportion of subjects for each of the 
items in the scale will be compared using an adjusted risk difference obtained from a regression 
model, adjusting for stratification factors, sex, and baseline CRP. Full details of the regression 
model will be provided in the SAP.  
Total number of study days by Day 28: (a) free of oxygen supplementation; (b) in ICU; (c) of 
hospitalization; (d) free of respiratory failure; (e) alive: For each endpoint (a) - (e), a Poisson 
regression model or a negative binomial model will be used to assess the relationship with 
treatment, adjusting for stratification factors, sex, baseline CRP and number of days on study (as 
applicable). Details of the model, including censoring rules, if any, will be provided in the SAP. 
Percentage of subjects discharged from the hospital by Day 28: percentages of subjects discharged 
from the hospital will be tabulated by treatment arm, along with differences between treatment arms. 
The proportion of subjects will be compared using an adjusted risk difference obtained from a 
regression model, adjusting for stratification factors, sex, and baseline CRP. Full details of the 
regression model will be provided in the SAP. 
All-cause mortality at Day 28: percentages of subjects will be tabulated by treatment arm, along with 
differences between treatment arms, at each time point. The proportion of subjects will be compared 
using an adjusted risk difference obtained from a regression model, adjusting for stratification 
factors, sex, and baseline CRP. Full details of the regression model will be provided in the SAP. 
Incidence of AEs/SAEs: will be summarized by system organ class and preferred term and by 
treatment arm using percentages. 
Incidence of clinically significant changes: Percentage of subjects with clinically significant changes 
in laboratory parameters, ECG, and vital sign measurements will be computed for each treatment 
arm along with associated 2-sided 95% Clopper-Pearson CI.  
Clearance of quantifiable viral RNA by Day 7: percentages of subjects with clearance of quantifiable 
viral RNA will be tabulated by treatment arm, along with differences between treatment arms, at 
each time point. The proportion of subjects will be compared using an adjusted risk difference 
obtained from a regression model, adjusting for stratification factors, sex, and baseline CRP. Full 
details of the regression model will be provided in the SAP.
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 Table 1: Visit and Assessment Schedule 
 
SCR 
Treatment Period 
FU14 
ET 
Time point 
Assessment1 
-3d to 
-1d  
D1 
(base-
line) 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D10 
D12 
D14 
D21  
(± 
3d) 
D28  
(± 
3d) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 history and clinical 
diagnosis2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray/CT scan 
X3 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug administration: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Losmapimod or placebo PO BID 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Pharmacodynamics: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug levels/PK4 
 
P, 4-5h 
4-5h 
4-5h 
4-5h 
4-
5h 
4-
5h 
4-
5h 
 
 
 
4-
5h 
 
 
X 
Clinical status and symptoms: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Respiratory failure and survival 
assessment6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical status assessment per WHO 
9-point scale6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Viral presence and viral load by 
central testing 7 
 
X 
X 
(sentinel 
only)7 
X  
(sentinel 
only)7 
X  
(sentinel 
only)7 
 
 
X 
 
 
 
 
 
 
X 
Confirmation of COVID-19 diagnosis 
by PCR 
X2 
X (PR)2 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SCR 
Treatment Period 
FU14 
ET 
Time point 
Assessment1 
-3d to 
-1d  
D1 
(base-
line) 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D10 
D12 
D14 
D21  
(± 
3d) 
D28  
(± 
3d) 
 
 
Oxygenation and FiO28 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety assessments:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Weight/height9 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Hematology, chemistry safety labs6 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
CRP6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis10 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Urine or serum β-hCG (female 
subjects only) 
X11 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
ECG12 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
HR, BP, RR, temperature8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
(S)AEs13 
X 
X 
Concomitant medications (including 
SOC) 
X 
X 
AE = adverse event; BP = blood pressure; COVID-19 = novel coronavirus; HR = heart rate; P = pre dose; PAO2 = partial pressure of oxygen; PR – pre-randomization; RR = respiratory rate; sent = sentinel; 
SOC = standard of care; SCR = screening. 
Note: All screening assessments are to be performed before dosing. If procedures required at any time point have already been performed as part of routine clinical care, these assessments do not need to 
be repeated, and information will be collected and entered on the eCRF from the subject’s medical records. Unscheduled visits can take place at any time at the discretion of the site to check for new 
AEs/SAEs or to repeat key missed assessments or for other reasons. 
1 The order of assessments can be performed at the discretion of the investigator once informed consent is obtained. 
2 COVID-19 diagnosis to be confirmed by local testing (PCR) before randomization and first dosing. Saliva, swab, or sputum testing may be used based on local standard of care. 
3 To be performed while hospitalized based on standard-of-care local assessment. Evidence of pulmonary involvement consistent with COVID-19 may also be obtained from clinical 
examination, per the judgment of the investigator. Evidence of pulmonary involvement obtained by clinical examination should be documented in the eCRF. 
4 PK assessments will be performed as a substudy in all sentinel subjects. For those subjects requiring dialysis, a single pre- and post-dialysis PK should be obtained for review by the 
DMC to decide if dose adjustment is needed. PK should be measured weekly for 2 weeks at Cmax (4-5 hours post dose) for subjects with renal insufficiency when possible. 
6 Assessments for clinical/respiratory status, progression, and safety serum chemistry and hematology tests to be performed and samples to be collected while hospitalized based on 
standard-of-care local laboratory assessments and after discharge from the hospital by home visit or outpatient clinic visit or telemedicine call. For subjects who are discharged to 
home or other outpatient setting after initial hospitalization, the assessments and laboratory samples can be obtained less often but not less than at least once weekly. CRP result 
required to determine eligibility are based on local laboratory results at screening. 
7 Viral load testing will be collected daily for the first 4 days using central testing in the first 10 enrolled subjects as part of the sentinel safety assessment at select sites. For all 
subjects, including the sentinel subjects, swabs, saliva, or other sample collection (as specified in the Study Manual) for central viral load testing will be collected on D1 pretreatment 
and on D7 or earlier if being discharged from the hospital prior to D7.  
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8 Vital signs will be performed after subjects have been supine for at least 5 minutes when possible. Vital signs to include oxygen saturation; PaO2 should be recorded if available from 
blood gases obtained as part of SOC; oxygen administration should also be recorded (eg, room air or oxygen flow by nasal canula or facial mask or endotracheal tube). For subjects 
who are discharged to home or other outpatient setting after initial hospitalization, assessments may be obtained less often but at least once per week in the outpatient clinic or at 
home. 
9 Height assessed at screening only; can be by self-report or from medical records. Weight is an actual recording. 
10 Urinalysis will be performed during the study period only on Day 7 and on any other day only if clinically indicated. 
11 Pregnancy testing to be conducted within 72 hours of the first dose of study treatment. 
12 Standard 12-lead ECGs will be performed after the subject has been supine for at least 5 minutes if possible. ECGs will be performed at Day 7 in all subjects and at any other time 
during the study if clinically indicated. 
13 Adverse events and SAEs will be assessed from the time the subject signs the ICF through the D28 follow-up visit. 
14 Outpatient assessments to be conducted via telemedicine or outpatient clinic. Outpatient laboratory assessments to be completed at outside local laboratory or home or outpatient 
visit.
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1 
BACKGROUND AND RATIONALE 
1.1 
Scientific rationale for investigation of losmapimod in COVID-19 
COVID-19 is a severe pandemic disease with high mortality particularly in older individuals, due to 
infection with the SARS-CoV-2 coronavirus. 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 older population is especially at risk of severe disease 
and death upon infection with SARS-CoV-2. The hyperactivated immune response in COVID-19 
shares features of the cytokine storm syndrome and appears to be responsible for the severe 
pulmonary edema, ARDS, and cardiac and renal disease responsible for most of the severe 
morbidity and mortality.  
The proposal to develop losmapimod, a potent, specific, and bioavailable p38α/β inhibitor, for 
treatment of COVID-19 is based on the following rationale:  
(1) Nonclinical work has shown that older mice infected with SARS-CoV-1 develop much 
more severe disease than younger ones, and that treatment with a p38 MAPK small 
molecule inhibitor greatly reduced their mortality when given after viral inoculation; 
similar survival benefit of p38 MAPK inhibition has been seen in animal models of severe 
H5N1 influenza and HSV-1.  
(2) Nonclinical work has shown that p38 MAPK inhibition reduces viral load in several 
experimental models with coronaviruses, including mouse hepatitis virus, human 
CoV-229E, transmissible gastroenteritis virus, and Middle East respiratory syndrome 
virus.  
(3) p38 MAPK is proposed to play a critical role in the development of ARDS, including 
regulating the expression and activity of inflammatory mediators such as ICAM-1, 
HMGB1, and ET-1, neutrophil chemotaxis and apoptosis, the balance of Treg/Th17 cells, 
and pulmonary endothelial cell apoptosis.  
(4) Clinical investigation showing that excessive acute inflammation in response to external 
stressors in older individuals, including viral antigen challenges, hinders the specific 
immune response to infection; many of the excessive inflammatory mediators associated 
with this aberrant immune response in older individuals are associated with activation of 
the p38 MAPK pathway.  
(5) Treatment with losmapimod in older subjects restored the normal immune response to 
viral antigen challenge and improved the resolution of acute inflammation.  
(6) Treatment of various inflammatory diseases with losmapimod, including active 
rheumatoid arthritis (RA), acute myocardial infarction, and chronic obstructive pulmonary 
disease (COPD) resulted in significant reduction in markers of acute inflammation, 
including interleukin-6 (IL-6), C-reactive protein (CRP), chemokines such as CXCL13, 
and other markers (see Table 5 for further details). 
(7) Losmapimod may be beneficial in COVID-19 treatment via reduction of the damaging 
effects of angiotensin II (Ang II). Angiotensin-converting enzyme 2 (ACE2) is the cellular 
receptor for SARS-CoV viruses and is expressed in the lung and the heart. Upon 
infection with SARS-CoV-2, there is internalization of and depletion of ACE2. ACE2 
converts Ang II into angiotensin 1-7 (Ang 1-7), which counterbalances the 
vasoconstrictive and pro-inflammatory effects of Ang II. Ang II is significantly elevated in 
COVID-19, and the levels are positively correlated with viral load and acute lung injury 
(Liu Y et al, 2020). Blocking the p38 MAPK pathway in nonclinical models has been 
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shown to reduce many of the adverse effects of elevated Ang II, resulting in lower 
frequency of cardiac arrhythmias, renal failure, and hypertension. 
p38 inhibitors have been explored extensively in clinical trials for numerous chronic inflammatory 
indications, as summarized in the Investigator Brochure. Losmapimod has been extensively tested 
in humans and found to be generally well tolerated, including in over 3600 adult healthy volunteers 
and subjects in 11 different indications. The 15 mg oral (PO) twice per day (BID) dose proposed for 
the COVID-19 Phase 3 study has been shown to provide robust and sustained inhibition of the p38 
MAPK pathway systemically and in tissues, specifically in skeletal muscle needle biopsies of 
subjects with facioscapulohumeral muscular dystrophy (FSHD). This dose of losmapimod was 
shown experimentally in older (median 69 years, range: 65, 77 years) human volunteers to restore 
the normal immune response to viral challenge and improve the resolution of acute inflammation. 
Furthermore, losmapimod has been shown to significantly reduce markers of hyperactive acute 
innate immune inflammation in the context of acute myocardial infection, RA, and COPD in clinical 
trials as listed below:  
1- Single-dose study in 50 subjects with RA (RA 3103730). Treatment with losmapimod (N=38) 
reduced levels of IL-6 compared with placebo (N=12). Losmapimod was dosed as follows: 
7.5 mg: 13 subjects; 20 mg: 12 subjects; 60 mg: 13 subjects. Analysis of serum IL-6 at 
3 hours post dose showed significantly lower levels with losmapimod than with placebo 
(Table 2). 
Table 2:  
Change from Baseline in IL-6 Serum Levels with Increasing Single Doses of 
Losmapimod in Subjects with Rheumatoid Arthritis 
Treatment group 
Adjusted ratio to baseline 
95% CI 
Adjusted ratio to placebo 
95% CI 
Placebo 
0.92 
0.60, 1.41 
 
 
Losmapimod 7.5 mg 
0.41 
0.26, 0.63 
0.45 
0.24, 0.82 
Losmapimod 20 mg 
0.43 
0.27, 0.68 
0.47 
0.25, 0.88 
Losmapimod 60 mg 
0.38 
0.25, 0.57 
0.41 
0.23, 0.75 
Abbreviations: CI = confidence interval. 
2- Repeated-dose study in subjects with acute coronary syndrome (ACS; PM1111810). A total 
of 535 subjects with non-ST elevation myocardial infarction were randomized to an initial 
dose of 7.5 or 15 mg of losmapimod followed by 7.5 mg PO BID (N= 388) or matching 
placebo (N=138) for 12 weeks. Results showed that relative to placebo, losmapimod 
significantly suppressed CRP and IL-6 acutely at the 24- to 36-hour assessments (Table 3). 
Table 3: 
Change from Baseline in hsCRP and IL-6 with 7.5mg PO BID Losmapimod Over 
Placebo in Subjects with Acute Coronary Syndrome 
Parameter 
Placebo (N=138) 
All losmapimod 
(N=388) 
P value 
hsCRP at 72 hours or 
discharge (nmol/L) 
110.8 (83.1-147.7) 
64.1 (53.0-77.6) 
<0.05 
IL-6 at 24 hours (ng/L) 
10.6 (8.6-13.1) 
6.6 (5.8-7.4) 
<0.05 
Abbreviations: hsCRP = high-sensitivity C-reactive protein; IL-6 = interleukin-6. 
3- Repeated-dose study in subjects with COPD (MKI113006). In this study, subjects with 
COPD were dosed with losmapimod 2.5 mg BID (N=149), losmapimod 7.5 mg BID (N=151), 
or placebo BID (N=154) for 24 weeks; or losmapimod 7.5 mg BID for 4 weeks followed by 
losmapimod 15 mg BID (N=150) for 20 weeks. Over the first 12 weeks of treatment, 
statistically significant reductions in serum high-sensitivity CRP (hsCRP) levels were 
observed in the losmapimod 7.5 mg and 15 mg groups compared with placebo. For hsCRP, 
Week 12, 7.5 mg dose versus placebo: ratio 0.73; 95% confidence interval [CI] 0.57, 0.93; 
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p=0.011; 15 mg dose versus placebo: ratio 0.64; 95% CI 0.50, 0.82; p<0.001. Table 4 shows 
the results for the subgroup with higher CRP at baseline. 
Table 4: 
Change from Baseline in CRP Over 12 Weeks of Treatment with Different 
Doses of Losmapimod Compared with Placebo in Subjects with COPD and 
High Baseline CRP Levels (>6.4 mg/L) 
Week 12  
Baseline hsCRP 
>6.40 mg/L 
Placebo BID 
(N=42) 
Losmapimod 
2.5 mg BID (N=33) 
Losmapimod 
7.5 mg BID (N=31) 
Losmapimod 
15 mg BID (N=31) 
Geometric LS 
mean (SE of logs) 
6.75 (0.153) 
8.08 (0.180) 
5.16 (0.180) 
3.54 (0.186) 
Geometric LS 
mean ratio to 
baseline (SE of 
logs) 
0.49 (0.153) 
0.59 (0.180) 
0.38 (0.180) 
0.26 (0.186) 
Column vs placebo 
 
 
 
 
Ratio 
 
1.20 
0.77 
0.53 
95% CI 
 
0.75, 1.92 
0.48, 1.22 
0.33, 0.85 
Abbreviations: CI = confidence interval; hsCRP = high-sensitivity C-reactive protein; LS = least square; SE = standard 
error. 
Fulcrum Therapeutics is planning to conduct the initial clinical trial for the investigation of 
losmapimod for the treatment of COVID-19 in these high-risk subjects. Losmapimod is currently in 
Phase 2 clinical development for the treatment of the root cause of FSHD under an open IND in the 
United States (US) and open clinical trial applications in Canada, Spain, France, and The 
Netherlands.  
A summary of published literature supporting the therapeutic hypothesis for the clinical development 
of losmapimod for the treatment of COVID-19 is provided in Table 5.  
Table 5: 
Listing of Evidence Supporting the Development of the p38 Inhibitor 
Losmapimod for Treatment of COVID-19 
Evidence 
References 
Pneumonitis, acute respiratory distress syndrome, 
pulmonary edema, and cardiomyopathy drive COVID-19 
mortality 
• 
Siddiqi HK et al. J Heart Lung 
Transplant. 2020 
• 
Ruan Q et al. Intensive Care 
Med. 2020 Mar 3 
Older patients are at greatest risk of COVID-19 mortality 
• 
Ruan Q et al. Intensive Care 
Med. 2020 Mar 3 
Human SARS-CoV-2 pathology is recapitulated in SARS-
CoV-1 mice 
• 
Zhou F et al. Lancet. 2020 
• 
Nagata N et al. Am J Pathol. 
2008 
Exaggerated acute inflammatory response and lymphopenia 
correlate with mortality in human with COVID-19 and older 
mice infected with SARS-CoV-1 
• 
Nagata N et al. Am J Pathol. 
2008 
• 
Zhou F et al. Lancet. 2020 
SARS-CoV-1 activates the p38 MAPK pathway in peripheral 
blood early in the infection 
• 
Lee CH et al. J Immunol. 2004. 
SARS-CoV envelope protein (E) activates the host’s 
inflammatory response via p38 signaling 
• 
Jimenez-Guardeño JM et al. 
PLOS Pathog. 2014 
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Evidence 
References 
Several nonclinical studies have shown evidence of p38 
inhibition reducing viral replication including with coronavirus 
• 
Kono M et al. Antiviral Res. 
2008  
• 
Dong Y et al. Antiviral Res. 
2020 
• 
Kindrachuk D et al. Anti Microb 
Agents & Chem. 2015 
p38 inhibition reduces mortality in older mice infected with 
SARS-CoV-1 
• 
Jimenez-Guardeño J et al. 
PLOS Pathog. 2014 
Nonclinical efficacy of p38 inhibition also observed in other 
models of severe acute viral pneumonitis and other severe 
acute viral infections 
• 
Shapiro L et al. PNAS. 1998 
• 
Iordanov MS et al. Mol Cell 
Bio. 2000 
• 
Salomon R et al. PNAS. 2007 
• 
Griego SD et al. J Immunol. 
2000 
• 
Banerjee S et al. J Virology. 
2002 
• 
Börgeling Y et al. J Biol Chem. 
2014 
• 
Chen Y et al. J Exp Med. 2017 
• 
He F et al. J Transl Med. 2019 
p38 inhibition reduces lung mucous production in mice 
models of toxic airway injury  
• 
Liu et al. Int 
Immunopharmacol. 2009 
Losmapimod and other p38 inhibitors acutely reduce 
inflammatory markers in humans 
• 
GSK data in Fulcrum Original 
IND 138739, Module 4 
• 
Genovese M et al. J 
Rheumatol. 2011 
• 
Christie J et al. Crit Care Med. 
2015  
Losmapimod reduces inflammatory markers associated with 
COVID-19 severity at currently utilized doses 
• 
Fulcrum clinical data on file 
• 
GSK clinical data  
• 
Newby L et al. Lancet. 2014 
 
Inhibition of p38 with 15 mg losmapimod BID dose in older 
subjects restored the adaptive immune response to viral 
challenge 
• 
Vukmanovic-Stejic M et al. J 
Allergy Clin Immunol. 2018 
Exaggerated acute inflammatory response in older subjects 
is driven to a large extent by p38 activation 
• 
Vukmanovic-Stejic M et al. J 
Allergy Clin Immunol. 2018 
In vivo data in Ferrets indicate SARS-Cov-2 induces 
profoundly lower immune response vs other virus 
• 
Blanco-Melo D et al. bioRxiv. 
2020 
Evidence that p38 inhibition may treat the deleterious effects 
of elevated Ang II in COVID-19 
• 
Grimes JM et al. J Mol Cell 
Cardiol. 2020 
Losmapimod is a highly selective p38 inhibitor at advanced 
stage of clinical development with excellent safety data 
profile 
• 
Losmapimod Investigator 
Brochure Fulcrum 2020 
• 
Cadavid D et al. FSHD IRC 
Poster. 2019 
Abbreviations: BID = twice daily; COVID-19 = disease caused by novel coronavirus; IND = investigational new drug 
application; SARS-CoV-1 = severe acute respiratory syndrome coronavirus 1; SARS-CoV-2 = severe acute respiratory 
syndrome coronavirus 2.  
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1.2 Benefit-risk considerations 
This is the first-in-human clinical trial with losmapimod for the treatment of a novel virus (COVID-19) 
and, therefore, the risk-benefit considerations are based on nonclinical data in conditions related to 
COVID-19 (e.g., SARS-CoV-1) as well as extensive clinical data in other inflammatory conditions 
and conditions involving the p38 MAPK pathway (e.g., FSHD, RA, COPD) including in older healthy 
volunteers; refer to Section 1.1 for further details.   
Losmapimod has been found to be generally well tolerated in clinical trials, including in over 3600 
adult healthy volunteers and subjects in 11 different indications. The 15 mg PO BID dose proposed 
for this study has been shown to provide robust and sustained inhibition of the p38 MAPK pathway 
systemically and in tissues, specifically in skeletal muscle needle biopsies of subjects with FSHD.  
Complete clinical safety data and nonclinical data for losmapimod can be found in the Investigator’s 
Brochure. Additional adverse events not previously observed in animals or in humans may also 
occur in this trial. Subjects in this clinical trial will be monitored closely for the development of 
adverse effects that may result from study drug administration. In addition, a Data Monitoring 
Committee (DMC) will monitor the safety of subjects throughout the study on an ongoing basis. 
COVID-19 is a severe and rapidly progressive infection, especially in the high-risk population (ie, 
older, with comorbidities) selected for this trial. Given the extensive clinical experience with 
losmapimod, the potential benefit of losmapimod treatment in this indication outweighs the risks.  
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2 
STUDY OBJECTIVES AND ENDPOINTS 
All study objectives will be evaluated in subjects diagnosed with COVID-19. 
Objectives 
Endpoints 
Primary 
To assess the efficacy of losmapimod compared 
with placebo for treatment of COVID-19 when 
administered concurrently with standard of care 
Proportion of progressors to death or 
respiratory failure by Day 28 
Secondary 
To evaluate the effect of losmapimod compared 
with placebo on clinical outcomes 
Clinical status by Days 7 and 14 as 
measured on the 9-point WHO ordinal scale 
(WHO 2020): 
• 
(8) death 
• 
(7) ventilation plus additional organ 
support (vasopressors, renal 
replacement therapy, ECMO) 
• 
(6) Intubation and mechanical 
ventilation 
• 
(5) noninvasive ventilation or high-flow 
oxygen therapy 
• 
(4) oxygen therapy but not requiring 
high-flow or non-invasive ventilation 
• 
(3) hospitalized but not requiring oxygen 
therapy 
• 
(2) Discharged from the hospital but 
with limitation of activities 
• 
(1) Discharged from the hospital and 
without any limitation 
• 
(0) No clinical evidence of the disease 
To assess the effect on clinical status of treatment 
with losmapimod compared with placebo 
Total number of study days free of oxygen 
supplementation by Day 28 
Total number of study days in ICU by 
Day 28 
Total number of study days hospitalized by 
Day 28 
Total number of respiratory failure-free 
study days by Day 28 
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Objectives 
Endpoints 
Percentage of subjects discharged from the 
hospital by Day 28 
To assess the effect on survival following treatment 
with losmapimod compared with placebo 
All-cause mortality at Day 28 
Number of study days alive by Day 28 
To assess the safety and tolerability of losmapimod 
compared with placebo 
Incidence of AEs and SAEs 
Incidence of clinically significant changes in 
laboratory parameters and vital sign 
measurements 
To characterize changes in SARS-CoV-2 infection 
following treatment with losmapimod compared 
with placebo 
Quantifiable viral RNA on Day 7 
Abbreviations: AE = adverse event; 
; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; COVID-19 = disease caused by novel coronavirus; CRP = C-reactive protein; ECG = 
electrocardiogram; ECMO = extracorporeal membrane oxygenation; 
; ICU = intensive care 
unit; IL-6 = interleukin-6; 
; PD = pharmacodynamics; RNA = ribonucleic acid; SAE = serious 
adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; WHO = World Health Organization.  
 
 
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3 
STUDY IMPLEMENTATION 
3.1 Overall study design and plan 
This Phase 3 multicenter, randomized, double-blind, placebo-controlled study will evaluate the 
safety and efficacy of losmapimod versus placebo on a background of standard of care in subjects 
with COVID-19 disease. 
This study will be performed in hospitalized subjects ≥40 years old, who have a C-reactive protein 
(CRP) >15 mg/L, who have been diagnosed with COVID-19, and who can undergo randomization 
within 7 days of collection of the sample found positive for the SARS-CoV-2 virus and before 
progressing into critical disease. Critical disease is defined as cardiac failure, septic shock, or ARDS 
or immediate need for intubation or mechanical ventilation per the judgment of the investigator. 
Subjects who sign informed consent (refer to Section 9.1.3) and meet all entry criteria (see 
Section 4) may be enrolled. 
 
Up to 410 subjects will participate for a maximum of 34 days, divided as follows: 
o Screening: Day -3 until Day -1 before the first study drug administration. 
o Treatment period of 14 days: 
o Subjects randomized (1:1) to either:  
▪ 
losmapimod tablets 15 mg PO BID; OR  
▪ 
matching placebo tablets PO BID 
o Randomization will be stratified by age (<65 or ≥65) and requirement for oxygen at 
randomization (yes/no) 
o Follow-up: 7 (± 3) days after last dose and 14 (± 3) days after last dose. 
The first 10 enrolled subjects (approximately 5 placebo and 5 losmapimod) will be dosed and 
followed for at least 72 hours after their first dose for an interim “sentinel” safety review before any 
additional subjects are dosed. Dosing of additional subjects will continue if there are no drug-related 
safety concerns from the initial subjects dosed as assessed by an independent DMC. The DMC will 
review safety data for the sentinel subjects and all subjects at regular intervals throughout the study 
as outlined in the charter (see Section 8.10).  
The Sponsor will monitor individual adverse events (AEs) and toxicities on an ongoing basis 
throughout the study. 
See Table 1 for the time points of the assessments. 
All study visits during the first week of treatment are anticipated to be conducted in the inpatient 
setting. If the clinical status of the subject improves such that the clinician discharges the subject 
from the hospital before the end of the study, the follow-up assessments will be conducted on an 
outpatient basis by alternative methods, including the use of local laboratories/facilities or home 
visits for blood draws, telemedicine, and/or outpatient follow-up clinic visits as deemed clinically 
appropriate per COVID-19 follow-up standard of care (SOC) at each site (refer to Section 6.7). 
3.2 Start of study and end of study definitions 
The start of the study is defined as the date the first enrolled subject signs an informed consent form 
(ICF). The end of the study is defined as the date of the last subject’s last assessment (scheduled or 
unscheduled). 
3.3 Selection of doses in the study 
In the Phase 1 study in healthy volunteers and FSHD subjects (Study FIS-001-2018), the dose 
levels of 7.5 mg and 15 mg given by mouth BID with food were based on predictive nonclinical 
efficacy and published clinical target engagement and safety data for losmapimod previously 
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generated by GSK. This Phase 1 study was recently completed and demonstrated that the 15 mg 
PO BID dose gives higher plasma levels and greater and more sustained target engagement in 
blood and tissues than the 7.5 mg PO BID dose, while resulting in similar safety and tolerability. The 
15 mg BID dose is used in the ongoing Phase 2 studies in FSHD (Study FIS-001-2019 and Study 
FIS-002-2019). Prior results indicated the favorable safety and tolerability of losmapimod for chronic 
administration in the clinic, including in the context of severe acute diseases, such as acute 
myocardial infarction, in older people. 
Prior studies of biodistribution of radiolabeled losmapimod by GSK showed ample distribution to all 
tissues including the lungs and the heart. Our recent target engagement data in the FSHD Phase 1 
Study FIS-001-2018 indicates that pHSP27 inhibition in blood, an assessment of p38 target 
engagement, is nearing a plateau at a losmapimod dose of 15 mg BID (see Investigator Brochure 
[Fulcrum Therapeutics 2020]), so doses of losmapimod higher than 15 mg PO BID are not 
warranted. 
Additionally, at the proposed dose level of 15 mg PO BID, exposures are not expected to exceed 
those previously demonstrated to be safe in humans in multiple previous studies by GSK in healthy 
volunteers and various patient populations including older subjects (Cheriyan et al 2011; Barbour et 
al 2013; Watz et al 2014; Pascoe et al 2017). 
In previous clinical studies performed by GSK, it was shown that losmapimod significantly reduced 
markers of acute inflammation, including IL-6, CRP, and the CXCL13 chemokine after a single 
dose. Additionally, losmapimod reduced IL-6 after 15 days of treatment (GSK study RA3103718) 
and CRP acutely in subjects with acute myocardial infarction treated with 7.5 mg PO BID 
(O’Donoghue et al 2016). In subjects with COPD, losmapimod at 15 mg PO BID significantly 
reduced CRP over 12 weeks compared with placebo (GSK Study MKI 113006). In one study in 
healthy older adult volunteers, it was shown that a 15 mg PO BID dose of losmapimod for 4 days 
restored the normal immune response to varicella-zoster virus antigen challenge (Vukmanovic-
Stejic et al 2018). The same formulation used in these previous clinical studies is the one proposed 
for use in the present clinical study. 
The rationale for the proposed study duration of up to 28 days is that in most cases of COVID-19 
the disease has resolved or resulted in severe outcomes over the first month from onset of 
symptoms. COVID-19 is a severe and rapidly progressive infection, especially in the high-risk 
population selected for the proposed Phase 3 trial. Therefore, treatment for longer than 14 days and 
study duration for longer than 28 days is not justified. 
3.4 Study drug modifications and withdrawal 
3.4.1 
Dose modifications 
Before trial medication is administered, changes in the subject's health status, including laboratory 
results if applicable, since the previous visit or previous dose should be checked.  
Study drug interruptions and reductions are not permitted; subjects who are on dialysis may require 
a dose adjustment. 
Study treatment dose adjustment for subjects on dialysis  
The elimination of losmapimod is almost exclusively by metabolism, with only 2% of the 
administered dose recovered as unchanged drug in urine and feces. The metabolite is clinically 
inactive and does not exert any toxic effects. 
Losmapimod has not been studied in renal insufficiency or renal failure. There has been 1 study of 
losmapimod in 17 subjects with focal segmental glomerulosclerosis (FSGS; FSG117283). In this 
study, subjects were given losmapimod 7.5 mg BID for 2 weeks followed by losmapimod 15 mg BID 
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for 22 weeks. The mean duration of exposure to investigational product in subjects with FSGS was 
approximately 21 weeks (range: 3.7, 25 weeks).  
Creatine and GFR for the population enrolled is in the table below.  
Parameter 
Mean (SD) 
Range 
eGFR (mL/min/1.73m2) 
79.4 (34.9) 
36, 155 
Creatine (µmol/L) 
1.1 (0.5) 
0.48, 2.07 
eGFR = estimated glomerular filtration rate. 
 
Losmapimod plasma concentration data in subjects with FSGS were compared with historical data 
obtained in the Phase 3 clinical trial in subjects with ACS. In general, exposure in subjects with 
FSGS was similar to subjects with ACS over the 24-week treatment period. 
Consistent with the safety database of over 3500 subjects, the 2 most frequently reported AEs in the 
FSGS trial were headache (5/17; 29%) and fatigue (4/17; 24%). Seven AEs (by preferred term: 
vomiting, dizziness, oropharyngeal pain, nausea, blood creatinine increased, muscle spasms, and 
rash) were reported in 3 subjects (18%) each. All other AEs (by preferred term) were reported in 
≤2 subjects each. Four subjects had at least 1 AE that led to withdrawal from the study or from 
treatment. The AEs that led to discontinuation were increase in blood urea nitrogen (related), 
increase in creatinine (not related), increase in cystatin C (related), and joint stiffness (related). 
None of the AEs was serious or severe; 3 of the AEs in 2 subjects were reported as related to study 
treatment. 
Based on the current safety and exposure information, dosing adjustment is likely not needed for 
subjects with renal insufficiency. However, close monitoring of pharmacokinetics (PK) for such 
cases will be implemented to ensure that therapeutic concentrations are maintained (refer to 
Section 6.2). For those subjects requiring dialysis, dose adjustment may be needed and will be 
determined by pre- and post-dialysis PK by the DMC. Adjustments may be recommended by the 
DMC also for subjects on placebo who develop acute renal failure to prevent unblinding at the sites. 
Study treatment discontinuation 
Discontinuation of study treatment should be considered if:  
• 
ALT or AST >8 x the upper limit of normal (ULN)  
• 
ALT or AST >5 x ULN for more than 2 weeks  
• 
ALT or AST >3 x ULN and (total bilirubin >2 x ULN or international normalized ratio >1.5) in 
the absence of reasonable alternative etiology 
• 
ALT or AST >3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
• 
QTcF prolongation with QTcF >500 msec or an increase in QTcF of >60 msec over baseline 
(confirmed by 2 successive repeat measurements) 
In addition, the investigator must permanently discontinue the study drug if continued administration 
of the study drug is believed to be contrary to the best interests of the subject. The premature 
discontinuation of study drug might be triggered by an adverse event (AE), a diagnostic or 
therapeutic procedure, an abnormal assessment (eg, ECG or laboratory abnormalities), pregnancy, 
or for administrative reasons, in particular noncompliance with the protocol or withdrawal of the 
subject’s consent. The reason for study drug interruption or premature discontinuation must be 
clearly documented in the eCRF. 
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3.4.2 
Subject withdrawal 
Subjects may withdraw from the study at any time and for any reason without prejudice to their 
future medical care by the investigator or at the study site. In all cases of impending consent 
withdrawal, investigators will be given instructions to meet and discuss with the participant their 
options of continuing in the study. The investigator should ensure understanding and documentation 
of the reasons for the participant’s desire to withdraw consent. Every effort should be made to keep 
subjects in the study, including if a subject and/or their treating physician decides to prematurely 
discontinue study treatment. Unless the participant provides their written withdrawal of consent or 
there is other written documentation by the investigator confirming the participant’s verbal intent to 
completely withdraw from the trial, participants should be followed for all protocol-specified 
evaluations and assessments. The reasons for subjects not completing the study will be recorded.  
A subject may be withdrawn from the study if he or she is lost to follow-up. For subjects to be 
considered as lost to follow-up, 2 attempts should be made to contact the subject to return for the 
scheduled study visit. After 2 attempts, a certified letter should be sent to the subject’s address 
requesting the subject to contact the investigator to schedule a follow-up assessment. If no reply is 
provided by the subject within 30 days of receipt of the certified letter, the subject can then be 
considered lost to follow-up. 
3.4.3 
Replacement policy 
Subjects who withdraw from the study will not be replaced. 
 
3.4.4 
Stopping criteria 
Dosing will be stopped in case of an unacceptable tolerability profile based on the nature, 
frequency, and intensity of observed AEs judged jointly by the investigator and the sponsor or as 
recommended by the DMC. 
 
In the event of a study hold due to unacceptable tolerability, the sponsor will conduct an extensive 
safety and PK analysis and will communicate to stakeholders, including the Investigators, 
institutional review boards (IRBs)/independent ethics committees (IEC), and health authorities any 
potentially emergent safety information as well as the timing of planned resumption of dosing. 
Dosing and enrollment will not resume unless it is considered safe to do so after consultation with 
Investigators and health authorities and approval by IRBs/IECs. 
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4 
STUDY POPULATION 
4.1 Inclusion criteria 
Eligible subjects must meet all of the following inclusion criteria at screening. 
1. Able and willing to provide written informed consent. 
a. Note: Subject’s legally authorized representative may provide informed consent as 
applicable based on local guidelines and regulations (see Section 9.1.3). If consent is 
obtained from a legally authorized representative, then assent should be obtained 
from the subject. 
2. Willing and able to comply with all study procedures. 
3. Age ≥40 years at time of screening. 
4. Confirmed infection with SARS-CoV-2 virus at or before the baseline visit (by polymerase 
chain reaction [PCR] testing). 
a. Note: Refer to the Study Manual for details on PCR SARS-Cov-2 testing procedures. 
5. ≤7 days to the time of randomization from the time of collection of the specimen that tested 
positive for the SARS-CoV-2 virus. 
6. Hospitalization at the time of the baseline visit. 
7. Oxygen saturation ≥92% at the baseline visit, which can be either on room air or on oxygen 
supplementation if using ≤ 10LPM by nasal prong or close-fitting mask. 
8. Evidence of pulmonary involvement consistent with COVID-19 by either clinical examination 
or radiographic examination (whichever is per local standard of care), per the judgment of 
the investigator. Evidence of pulmonary involvement obtained by clinical examination should 
be documented in the eCRF. 
9. Clinical syndrome consistent with COVID-19 at screening, per the judgment of the 
investigator (CDC 2020). 
10. CRP at screening >15 mg/L (which is equivalent to >1.5 mg/dL) on local laboratory testing. 
11. Agrees to practice an approved method of birth control as follows (as applicable to local 
[country] guidelines and regulations for sites outside the US): 
a. Females of childbearing potential: Using 1 of the following acceptable methods of 
contraception: surgical sterilization (eg, bilateral tubal ligation), intrauterine 
contraception/device, hormonal contraception, or any 2 barrier methods (a 
combination of male or female condom with diaphragm, sponge, or cervical cap). 
This criterion must be followed from the time of the first dose of study medication until 
90 days after last dose 
b. Males: Effective male contraception includes a vasectomy with negative semen 
analysis at follow-up, or the use of condoms. This criterion must be followed from the 
time of the first dose of study medication until 90 days after last dose. 
Note: Abstinence can be considered an acceptable method of contraception at the 
discretion of the investigator. Periodic abstinence (eg, calendar, ovulation, 
symptothermal, post ovulation methods) and withdrawal are not considered 
acceptable methods of contraception. 
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4.2 Exclusion criteria 
1. Inability to take oral medication at screening or baseline visit. 
2. Evidence at screening or baseline of critical COVID-19 disease (eg, cardiac failure, septic 
shock or ARDS) or immediate need for intubation or mechanical ventilation per the judgment 
of the investigator.  
3. Positive pregnancy test at screening for women of childbearing potential. 
4. Lactating female at baseline for women of childbearing potential. 
a. 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. ≥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 poorly 
controlled HIV infection.  (Subjects with HIV infection who have normal CD4 counts may 
participate if they have been on a stable antiviral regimen for the 30 days prior to screening 
and are anticipated to remain on the regimen throughout the duration of the study.) 
6. Glomerular filtration rate <30 mL/min/1.73 m2 at screening. 
7. QTcF >450 msec for male or >470 msec for females or evidence of cardiac dysrhythmia at 
screening. 
8. 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. 
9. 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. 
10. 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. 
11. Recent (within 30 days) or current participation in other COVID-19 therapeutic trials or 
expanded access programs. 
12. Prior or current participation in COVID-19 vaccine trials. 
4.3 Concomitant medications 
All medications (prescription and over-the-counter) taken at the time of study screening will be 
recorded, with indication, route of administration, daily dose, and start and stop dates of 
administration. All subjects will be questioned about concomitant treatment at each clinic visit. 
 
Subjects are allowed to use paracetamol (up to 3 g/day) and/or contraceptives (oral or parenteral), 
and any medications needed for SOC at the local institution. Use of hydroxychloroquine/ 
chloroquine is not permitted. Use of other experimental treatments for COVID-19 is not permitted 
unless it is part of SOC at the local institution. SOC for COVID-19 will be documented at each site 
during the site activation visit; additionally, it will be documented if any restrictions on standard of 
care treatment administration were encountered due to resource limitations. The use of antiviral 
medications is permitted.  
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Concomitant medications used to treat chronic comorbid conditions per SOC are permitted, 
including but not limited to metered dose inhalers, corticosteroids if on stable doses for at least 
30 days prior to screening, or sedative or anesthetic agents. 
 
Concomitant medications initiated or stopped for an AE will be recorded. 
 
Both losmapimod and its major metabolite, GSK198602, are in vitro inhibitors of human BCRP. 
There is a low risk of interaction of losmapimod with orally administered BCRP substrates with a 
narrow therapeutic index (eg, methotrexate, topotecan, rosuvastatin). Therefore, such co-
administration is indicated only if the medical benefit is considered to outweigh the risk for toxicity, 
and careful monitoring for adverse effects of these agents is advised. 
 
Losmapimod is a relatively potent in vitro inhibitor of the renal transporters MATE1 and MATE2-K, 
and it is possible that a mild inhibition of tubular secretion may contribute to the small rise in (model-
adjusted geometric mean) serum creatinine observed clinically. GSK198602 is a relatively potent in 
vitro inhibitor of OAT3 and co-administration of sensitive OAT3 substrates is indicated only if the 
medical benefit is considered to outweigh the risk for toxicity. Careful monitoring for adverse effects 
of these agents is advised, especially for those with narrow therapeutic margin (eg, methotrexate, 
metformin).  
4.4 Lifestyle restrictions  
Subjects should not donate blood, sperm, or ova from the screening visit through 90 days after the 
last dose of study treatment. 
4.4.1 
Contraception requirements 
Teratogenicity and effects on embryofetal survival were noted in rat and rabbit reproductive 
toxicology studies with losmapimod. Therefore, losmapimod should not be taken by women of 
childbearing potential who are not utilizing adequate contraceptive methods. 
All women of childbearing potential and all males must practice effective contraception during the 
study from the time of the first dose of study medication until 90 days after last dose. 
 
Women of child-bearing potential are defined as all women physiologically capable of becoming 
pregnant, unless they meet one of the following conditions: 
▪ 
Postmenopausal: 12 months of natural (spontaneous) amenorrhea or 6 weeks after surgical 
bilateral oophorectomy/bilateral salpingectomy with or without hysterectomy; 
▪ 
Post hysterectomy. 
For the purposes of the study, effective contraception is defined as follows (as applicable to local 
[country] guidelines and regulations for sites outside the US): 
▪ 
Females of childbearing potential: Using 1 or more of the following acceptable methods of 
contraception: surgical sterilization (eg, bilateral tubal ligation), intrauterine 
contraception/device, hormonal contraception, or any 2 barrier methods (a combination of 
male or female condom with diaphragm, sponge, or cervical cap).  
▪ 
Males: Effective male contraception includes a vasectomy with negative semen analysis at 
follow-up, or the use of condoms.  
Abstinence can be considered an acceptable method of contraception at the discretion of the 
investigator. Periodic abstinence (eg, calendar, ovulation, symptothermal, post ovulation methods) 
and withdrawal are not considered acceptable methods of contraception. 
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5 
INVESTIGATIONAL MEDICINAL PRODUCT 
5.1 Investigational drug and matching placebo 
Losmapimod will be provided in tablets of 7.5 mg for oral administration.  
 
Matching placebo tablets will be provided for oral administration. 
 
The tablets are plain white, round, biconvex, film-coated tablets. The proposed dosing regimen is as 
a twice daily dose of 15 mg (2 × 7.5 mg tablets/dose BID). The proposed duration of treatment is for 
up to 14 days. 
 
Subjects should take their dose of losmapimod or placebo with food whenever possible and with 
240 mL of room temperature water.  
 
5.2 Study drug packaging and labelling 
Losmapimod tablets for oral administration are available as white, round, biconvex, plain, 
film-coated tablets containing 7.5 mg of losmapimod as the micronized base, GW856553X. 
Losmapimod tablets also contain the inactive excipients microcrystalline cellulose, lactose 
monohydrate, sodium starch glycolate, magnesium stearate, povidone K30, hypromellose, titanium 
dioxide (E171), and polyethylene glycol. 
Placebo tablets are identical in appearance to losmapimod and have the same excipient ingredients 
as losmapimod but do not have the active compound. 
All tablets are packed in opaque, white, square, high-density polyethylene bottles with induction 
sealed child-resistant closures. 
Losmapimod must be stored in a secure area (eg, a locked cabinet), protected from moisture, and 
kept at a controlled room temperature not to exceed 30°C. 
5.3 Drug accountability 
The investigator is responsible for ensuring that dosing is administered in compliance with the 
protocol. Delegation of this task must be clearly documented and approved by the investigator. 
The Investigator (or designee) will maintain an accurate record of the study supplies received. In 
addition, an accurate drug disposition record will be kept, specifying the amount dispensed to each 
subject and the date of dispensing. This drug accountability record will be available for inspection at 
any time. At the completion of the study, the original drug accountability record will be available for 
review by the sponsor upon request. 
For each batch of unit doses, the empty used unit dose containers will be discarded upon 
satisfactory completion of the compliance and accountability procedures by the sponsor. Any 
unused assembled unit doses will be retained until completion of the study. 
After completion of the study, all unused supplies will be returned to the sponsor or disposed of by 
the study site, per the sponsor’s written instructions. 
5.4 Treatment assignment and blinding 
5.4.1 
Randomization and treatment assignment 
A total of up to 410 subjects will be recruited into this study and will be randomized in a 1:1 ratio to 
15 mg losmapimod (BID) or placebo using an interactive/web voice response system (IxRS) for 
randomization. The randomization list will be produced by a qualified randomization vendor and will 
be stratified by age (<65 or ≥65) and requirement for oxygen at randomization (yes/no) at 
enrollment. 
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Only subjects who have completed screening assessments and are eligible for participation in the 
study will be randomized to receive study drug. Randomized subjects will be sequentially assigned 
a unique subject number from the randomization list per the IxRS. From the time of randomization 
and throughout the duration of the study, subjects will be identified by their unique randomization 
number.  
The authorized site personnel will prepare the appropriate study drug for each subject based on the 
randomization schedule. Treatment codes should not be broken except in emergency situations, ie, 
when knowledge of the treatment is essential for the immediate further management of the subject.  
5.4.2 
Blinding 
This study will be performed in a double-blind fashion. The investigator, study staff, subjects, 
sponsor, and monitor will remain blinded to subject-level treatment assignment until study closure. 
The investigational drug and its matching placebo are indistinguishable and will be packaged in the 
same way. 
5.4.3 
Treatment compliance 
All doses will be administered either in the hospital (anticipated during the first week of study 
treatment) or taken by the study participants on an outpatient basis. 
The subject will bring the study treatment bottle to each visit (clinic or home assessment) for review 
by the site staff. 
The study treatment bottles will be collected at the Day 14 visit whether in the hospital or outpatient 
or at the ET visit if prior to Day 14. 
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6 
STUDY ASSESSMENTS 
See Table 1 for the time points of the assessments.  
 
If additional visits or blood draws are required beyond the planned visits in any part of the 
study, these visits or samples should be recorded in the eCRF as unscheduled visits prior to the 
subject’s completion of the study.  
 
6.1 Medical history and confirmation of COVID diagnosis 
A complete medical history will be taken at Screening and is to include demographic information, 
prior medical illnesses and conditions, and surgical procedures for at least 3 months prior to 
screening. The medical history may be collected from medical records, if available, or during the 
physical examination. 
The history of SARS-CoV-2 infection and symptoms at screening should be recorded; the details of 
how infection history will be assessed and recorded can be found in the Study Manual. Diagnosis of 
COVID-19 should be confirmed by local PCR testing prior to randomization. Refer to the Study 
Manual for details on procedures and type(s) of diagnostic testing allowed. 
A chest X-ray or CT may  be performed while the patient is hospitalized based on standard-of-care 
local assessment. Evidence of pulmonary involvement consistent with COVID-19 may also be 
obtained from clinical examination, per the judgment of the investigator. Evidence of pulmonary 
involvement obtained by clinical examination should be documented in the eCRF. 
A pre-existing condition is one that is present prior to administration of study drug. Such conditions 
should be recorded as medical history. A pre-existing condition should be recorded as an AE or 
serious adverse event (SAE) only if the frequency, intensity, or nature of the condition worsens 
following administration of study drug. 
6.2 Pharmacokinetic and pharmacodynamic assessments 
Blood samples will be collected as outlined in the Schedule of Assessments (Table 1) to assess PK. 
PK assessments will be performed as a substudy in all sentinel subjects to evaluate the PK of 
losmapimod in the population of subjects with COVID-19. 
Blood samples will be collected as outlined in the Schedule of Assessments (Table 1) to assess 
serum and plasma biomarkers of response to COVID-19, which may include 
 
 
Procedures for collection, processing, and return of blood samples will be detailed in the Study 
Manual. Specifics of the analytical methods will be provided in separate documents. 
Cytokines and chemokines will be evaluated using a multiplex assay. Details of the assay and 
specimen sampling will be provided in the Study Manual. 
Viral load will be assessed by nasopharyngeal (preferred) or oropharyngeal swab, saliva, or other 
appropriate assay as outlined in the Schedule of Assessments (Table 1). Study samples will be 
analyzed by central testing. Refer to the Study Manual for details on procedures and type(s) of 
diagnostic testing allowed.  
PK should be measured weekly for 2 weeks at Cmax (4-5 hours) for subjects with renal insufficiency 
(eGFR ≤45 mL/min/ 1.73 m2). For those subjects requiring dialysis, dose adjustment may be 
needed (see Section 3.4.1) and will be determined by pre- and post-dialysis PK by the DMC to 
prevent site unblinding. 
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6.3 Clinical status and symptoms 
 The investigator may consult with a relevant clinical or other specialist as appropriate per SOC. 
6.3.1 
Respiratory failure and survival assessment 
Total number of study days free of oxygen supplementation and total number of study days free of 
respiratory failure will be evaluated. Refer to Section 6.5.1 for further details of vital sign collection. 
• 
Note: Respiratory failure is defined as either need for mechanical ventilation (invasive or 
non-invasive) or high flow oxygen (defined by greater than 15 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 reason for hospitalization and number of total study days of hospitalization and intensive care 
unit (ICU) utilization will be recorded.  
Details of subject discharge (date of discharge and condition at discharge) from the hospital will be 
recorded. 
Any significant deviation from standard of care due to limited resources will be documented.   
Survival status at the end of the study period will be documented, including cause of death for any 
reason. 
6.3.2 
Clinical status assessment 
Clinical status as outlined in the Schedule of Assessments (Table 1) will be measured on the 
following clinician-reported 9-point ranking scale (WHO): 
• 
(8) death 
• 
(7) ventilation plus additional organ support (vasopressors, renal replacement therapy, 
ECMO) 
• 
(6) intubation and mechanical ventilation 
• 
(5) noninvasive ventilation or high-flow oxygen therapy 
• 
(4) oxygen therapy but not requiring high-flow or non-invasive ventilation 
• 
(3) hospitalized but not requiring oxygen therapy 
• 
(2) discharged from the hospital but with limitation of activities 
• 
(1) discharged from the hospital and without any limitation 
• 
(0) no clinical evidence of the disease 
Instructions for administration will be provided in the Study Manual. 
6.4 Extended vital signs 
Extended vital signs, including oxygen saturation and fraction of inspired oxygen (FiO2) will be 
collected as specified in the schedule of assessments. Refer to Section 6.5.1 for further details of 
measurements. 
6.5 Safety and tolerability assessments 
The definitions, reporting, and follow-up of AEs, SAEs, and potential pregnancies are described in 
Section 7. 
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6.5.1 
Vital signs 
Evaluations of systolic and diastolic blood pressure, respiratory rate, and temperature will be 
performed throughout the study. In addition, oxygen saturation and FiO2 will be assessed 
throughout the study. Oxygen administration (eg, room air or oxygen flow by nasal canula or facial 
mask) will be recorded. Vital signs will be performed after subjects have been supine for at least 
5 minutes when possible.  
 
Arterial blood gases may be performed if clinically indicated in some subjects but are not required 
for this study. If arterial blood gasses are measured, the results for arterial pressure of oxygen 
(PaO2) should be reported at each measurement in the eCRF. 
 
Clinically relevant findings found after study drug initiation and meeting the definition of an AE (new 
AE or worsening of previously existing condition) must be recorded. 
6.5.2 
Weight and height 
Weight (kg) will be recorded at screening and the follow-up assessment (by alternative methods 
including outpatient visit). Height (cm) will be recorded and body mass index (BMI) calculated at 
screening. 
 
BMI (kg/m2) = weight (kg)/(height [cm]/100)2 
6.5.3 
Physical examination 
Physical examination (ie, inspection, percussion, palpation, and auscultation) is performed to 
determine eligibility and as clinically indicated during the study. Clinically relevant findings that are 
present prior to study drug initiation must be recorded with the subject’s medical history. Clinically 
relevant findings found after study drug initiation and meeting the definition of an AE (new AE or 
worsening of previously existing condition) must be recorded.  
6.5.4 
Electrocardiography 
ECGs will be taken singly after 5 minutes in the supine position as specified in the schedule of 
assessments. The investigator will assess the ECG recording as 'normal', 'abnormal - not clinically 
significant', or 'abnormal - clinically significant' and include a description of the abnormality as 
required. The ECG parameters assessed will include heart rate, PR, QRS, QT, and QTcB and QTcF 
(calculated using Bazett’s and Fridericia's method, respectively). ECGs will be performed to 
determine eligibility and during the study period only if clinically indicated. Clinically relevant findings 
found after study drug initiation and meeting the definition of an AE (new AE or worsening of 
previously existing condition) must be recorded. 
6.5.5 
Laboratory assessments 
Laboratory parameters 
Additional clinical laboratory evaluations will be performed at other times if judged to be clinically 
appropriate or if the ongoing review of the data suggests a more detailed assessment of clinical 
laboratory safety evaluations is required. 
An Investigator (or designee) will perform a clinical assessment of all clinical laboratory data. 
Clinically relevant findings found after study drug initiation and meeting the definition of an AE (new 
AE or worsening of previously existing condition) must be recorded. Clinical relevance is defined as: 
• 
Is accompanied by clinical symptoms 
• 
Leads to dose modification of study treatment 
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• 
Requires significant changes, addition of, interruption of, discontinuation of a concomitant 
medication, therapy, or treatment 
• 
Reflects a disease and/or organ toxicity 
This does not apply to any abnormal laboratory result that falls outside the laboratory reference 
range but that does not meet the clinical significance criteria or those that is a result of an AE that 
has already been reported. 
Blood and other biological samples will be collected for the following clinical laboratory tests; refer to 
the Study Manual for details of collection and analysis and information on central and local 
laboratories: 
Lab 
Tests 
Hematology 
 
Hemoglobin [including mean corpuscular volume, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration], hematocrit, red cell 
count, total white cell count, and platelet count. Differential blood count, 
including: basophils, eosinophils, neutrophils, lymphocytes, and monocytes. 
Chemistry and 
electrolytes 
Sodium, potassium, calcium, inorganic phosphate, total protein, albumin, blood 
urea nitrogen, creatinine, uric acid, total bilirubin1, alkaline phosphatase, AST, 
ALT, gamma-glutamyl transferase, and LDH. 
Glucose 
Glucose 
Urinalysis 
Leucocytes, blood, nitrite, protein, urobilinogen, bilirubin, pH, specific gravity, 
ketones, glucose. If there is a clinically significant positive result, urine will be 
sent for microscopy and/or culture. 
Pregnancy2 
hCG (urine or serum). If there is a clinically significant, positive result in urine, 
urine will be sent for confirmation. 
1Conjugated bilirubin may be reported when total bilirubin is outside the reference range. 
2Pregnancy test for women of childbearing potential will be performed within 72 hours of first dose 
and if pregnancy is suspected during the study. 
6.6 Unscheduled visit 
Unscheduled visits may be performed at any time at the subject’s or the investigator’s request and 
may include (but are not limited to) vital signs/focused physical examination, ECG, AE review, 
concomitant medications and procedures review, disease-related constitutional symptoms, and/or 
laboratory and biomarker assessments. The date and reason for the unscheduled visit must be 
recorded in the source documentation. 
6.6.1 
Early termination visit 
When the investigator determines that study treatment will no longer be used, the investigator will 
perform the ET procedures and document the reason for discontinuation from study treatment in the 
eCRF. If routine laboratory tests (eg, hematology, serum chemistry) are completed within 7 days 
before the time of study treatment discontinuation, these tests need not be repeated. Every effort 
should be made to keep subjects in the study, including if a subject and/or their treating physician 
decides to prematurely discontinue study treatment. 
6.7 Alternative follow-up methods to site visits 
Trial participants may not be able to come to the investigational site for protocol-specified or 
unscheduled visits. The sponsor may use alternative methods for safety assessments, including 
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telemedicine visits, telephone visits, and/or an alternative location for visits depending on the local 
or institutional standards. 
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7 
SAFETY REPORTING 
7.1 Definitions of adverse events 
An adverse event (AE) is any untoward medical occurrence in a subject who is participating in a 
clinical study performed. The AE does not necessarily have to follow the administration of a study 
drug, or to have a causal relationship with the study drug. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory or vital sign finding), symptom, or disease 
temporally associated with the study participation whether or not it is related to the study drug. 
7.1.1 
Recording of adverse events 
Adverse events and SAEs will be assessed from the time the subject signs the ICF through the D28 
follow-up visit. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
7.1.2 
Intensity of adverse events 
The intensity of clinical AEs is graded 3-point scale as defined below: 
▪ 
Mild: discomfort noticed but no disruption of normal daily activity; 
▪ 
Moderate: discomfort sufficient to reduce or affect normal daily activity; 
▪ 
Severe: inability to work or perform daily activity. 
7.1.3 
Relationship to study drug 
For each AE, the relationship to drug as judged by the investigator: 
▪ 
Probable; 
▪ 
Possible; 
▪ 
Unlikely; 
▪ 
Unrelated. 
7.1.4 
Serious adverse events 
A serious adverse event (SAE) is defined by the International Conference on Harmonization (ICH) 
guidelines as any AE fulfilling at least one of the following criteria: 
▪ 
results in death; 
▪ 
is life threatening (at the time of the event); 
▪ 
requires hospitalization or prolongation of existing inpatient hospitalization; 
o Note: COVID-19-related hospitalization or ICU admission is excluded from this 
definition, as SARS-CoV-2, COVID-19 infection, or pulmonary conditions attributable 
to COVID-19 infection are efficacy-related endpoints 
▪ 
results in persistent or significant disability or incapacity; 
▪ 
is a congenital anomaly or birth defect; or 
▪ 
any other important medical event that did not result in any of the outcomes listed above due 
to medical or surgical intervention but could have been based upon appropriate judgement 
by the investigator. 
An elective hospital admission will not be considered as a SAE. 
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7.1.5 
Suspected unexpected serious adverse reactions 
A suspected unexpected serious adverse reaction (SUSAR) is an SAE that is unexpected (nature or 
severity of which is not consistent with the applicable product information (eg, the Investigator 
Brochure for losmapimod) and suspected (a reasonable possibility of causal relationship with 
investigational drug, regardless of the administered dose). 
7.1.6 
Reporting of serious adverse events 
The investigator must report any AE that meets the SAE criteria (Section 7.1.4) to 
 
immediately (ie, within 24 hours after the site personnel first learn about the event) via electronic 
data capture (EDC). In the event that EDC entry is not possible (eg, system failure or access 
problems), the study site staff should complete the paper SAE report form and fax the form to 
 Pharmacovigilance within 24 hours of awareness or call the 
 safety hotline to 
report. The study site staff should update the EDC system as soon as it is available.  
A full description of every SAE will need to be provided to 
 Pharmacovigilance. 
7.1.7 
Follow-up of adverse events 
All AEs will be followed until they have abated, returned to baseline status or until a stable situation 
has been reached. Depending on the event, follow up may require additional tests or medical 
procedures as indicated, and/or referral to the general physician or a medical specialist. 
7.1.8 
Adverse events of special interest 
An AESI (serious or non-serious) is one of scientific and medical concern for which ongoing 
monitoring and rapid communication by the investigator to the sponsor can be appropriate. Adverse 
events of special interest for this study include QTc prolongation as well as liver tests that meet the 
criteria for potential drug-induced liver injury (DILI), in accordance with the US Food and Drug 
Administration “Guidance for Industry-Drug-Induced Liver Injury: Premarketing Clinical Evaluation”. 
Adverse event of special interest: QTc prolongation 
A thorough QT study (PM1116628) was conducted in healthy volunteers who received losmapimod 
at 7.5 mg BID or 20 mg daily or with placebo administered for 5 days. At the 20 mg dose of 
losmapimod, the upper bound of the 90% CI of the ΔΔQT interval (change from baseline in QTcF 
compared with that for placebo) exceeded the 10 msec threshold at the 24-hour post-dose time 
point. For the 7.5 mg BID dose, the upper bound of the 90% CI of ΔΔQTcF exceeded the 10 msec 
threshold at multiple time points. No subjects experienced QTcF values >480 msec or QTcF 
changes from baseline ≥60 msec at any time in the study. Although the upper bound of the 90% CI 
exceeded the 10 msec regulatory threshold of concern in the primary pharmacodynamic analysis, it 
was determined by GSK that there was no clinically relevant effect on the QT interval, as there was 
no clinically relevant concentration QTc effect using standard placebo/baseline subtracted 
measured QTc data. Additional information on the QTc interval and its behavior, as demonstrated in 
the large cohort of patients with ACS treated with losmapimod (PM1116197), supported the lack of 
a QT effect. PK/PD modeling using the raw QTcF and plasma concentration data showed that at 
plasma losmapimod concentrations 4 times the exposure at the therapeutic dose (7.5 mg BID) (ie, 
at exposures approximately 2-fold higher than 15 mg BID, the predicted upper bound of the 90% CI 
of ΔΔQTcF) did not exceed 10 msec, and the predicted median ΔΔQTcF was less than 5 msec. 
Further details are presented in the Investigator Brochure. No drug effect on QT prolongation of 
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losmapimod over placebo has been documented in any of the phase 2 or the one phase 3 trial 
completed so far.  
Study drug should be discontinued for subjects who meet the QTc prolongation criteria as a result of 
within-protocol specific testing or unscheduled testing (see Section 3.4.4 stopping criteria). This 
AESI must be reported to the sponsor within 24 hours of awareness per the SAE reporting 
procedures (Section 7.1.6). Further safety steps should be taken to closely observe and follow-up 
the event until resolution and treatment initiated per local standard of care.  
Adverse event of special interest: Drug-induced liver injury 
The following 3 laboratory value criteria must be met for potential DILI, or “Hy’s Law”: 
• 
An elevated alanine transaminase or aspartate transaminase laboratory value that is ≥3 × 
ULN 
• 
An elevated total bilirubin laboratory value that is ≥2 × ULN 
• 
An alkaline phosphatase laboratory value that is <2 × ULN 
Study drug should be discontinued for subjects who meet the laboratory criteria for potential DILI as 
a result of within-protocol specific testing or unscheduled testing (see Section 3.4.4 stopping 
criteria). This AESI must be reported to the sponsor within 24 hours of awareness per the SAE 
reporting procedures (Section 7.1.6). Further safety steps should be taken to closely observe and 
follow-up the event until resolution. These steps include, but are not limited to: 
• 
Making every reasonable attempt to have the subject return to the clinic within 24 hours for 
repeat liver tests 
• 
Obtaining a more detailed history of symptoms and prior or concurrent disease, concomitant 
medication use, alcohol use, recreational drug use, and special diets 
• 
Repeating liver enzyme and serum bilirubin tests twice weekly. Frequency of retesting can 
decrease to once a week or less if abnormalities stabilize and the subject is asymptomatic 
• 
Obtaining viral hepatitis serology 
• 
Considering liver imaging and/or hepatology consultation 
7.2 Pregnancy 
7.2.1 
Teratogenicity 
If a woman becomes pregnant when on study drug, study drug should be permanently discontinued. 
The investigator must counsel the subject and discuss the risks of continuing with the pregnancy 
and the possible effects on the fetus. Monitoring of the subject should continue until the outcome of 
the pregnancy is known. In the event of pregnancy in the partner of a study subject, the Investigator 
should make every reasonable attempt to obtain the woman’s consent for release of protected 
health information. 
7.2.2 
Reporting of pregnancy 
Irrespective of the treatment received by the subject, any pregnancy occurring during study drug 
administration or until follow-up, must be reported within 24 hours of the investigator's knowledge of 
the event to 
 using the Exposure in Utero form. The Investigator must make every effort to 
follow the pregnant partner of a male subject through resolution of the pregnancy (delivery or 
termination) and to report the resolution on the SAE form. 
 
 
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8 
STATISTICAL METHODOLOGY AND ANALYSES 
8.1 Statistical analysis plan 
 
A statistical analysis plan (SAP) will be generated and approved prior to database snapshot for the 
interim analysis (IA). The SAP will detail the implementation of all planned statistical analysis. Any 
deviations from the planned analysis will be described and justified in the final clinical study report. 
All safety and statistical programming will be conducted using SAS 9.4 for Windows or newer (SAS 
Institute Inc., Cary, NC, USA), and other statistical programming/sample size calculation software as 
necessary.  
8.1.1 
Determination of sample size 
The primary efficacy endpoint of this study is the proportion of subjects who progress to death or 
respiratory failure by the end of study (Day 28). It is estimated that approximately 30% of enrolled 
subjects receiving SOC plus placebo will attain this endpoint. It is assumed that losmapimod will 
improve the primary endpoint by 40% over placebo. On the basis of these assumptions, a total of up 
to 410 subjects randomized to the losmapimod arm or the placebo arm in a 1:1 ratio (205 subjects 
in the losmapimod arm and 205 subjects in the placebo arm) will yield approximately 80% power in 
a 1-sided test at the 2.5% significance level. The sample size estimate assumes an IA will be 
conducted after approximately 206 subjects (103 in the losmapimod arm, and 103 in the placebo 
arm) have completed the Day 28 visit, to assess early futility, using the rules specified in 
Section 8.9. 
8.1.2 
Analysis methods 
In general, all study endpoints will be summarized using descriptive statistics. Descriptive statistics 
for continuous data will include number of subjects (n), mean, standard deviation, median, 
minimum, and maximum. Descriptive statistics for categorical data will include frequency and 
percentage.  
Where appropriate, descriptive statistics may be presented with 95% CI. 
8.1.3 
Analysis sets 
Full Analysis Set (FAS): The FAS will consist of all subjects who are randomly assigned to receive 
double-blind study drug. All analyses using the FAS will group subjects according to randomized 
treatment. The primary endpoint, clinical outcomes/status, survival, and pharmacodynamic 
endpoints will be analyzed using the FAS. 
Per Protocol Set (PPS): The PPS will consist of all FAS subjects who fulfill all inclusion/exclusion 
criteria and do not have any significant protocol deviations. All analyses using the PPS will group 
subjects according to randomized treatment. 
Safety Analysis Set: The safety analysis set is defined as all subjects who are randomized and 
receive study drug. All analyses using the Safety Analysis Set will group subjects according to 
treatment actually received. The safety analysis set will be used for all safety and tolerability 
analyses. 
8.2 Protocol violations/deviations 
Protocol deviations will be identified based on conditions related to the categories below: 
▪ 
Protocol entry criteria 
▪ 
Forbidden concomitant medications 
▪ 
Missing evaluations for relevant endpoints 
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▪ 
Other protocol deviations occurring during study conduct. 
Major protocol deviations will be identified before study closure and listed where appropriate. 
8.3 Missing, unused and spurious data 
All missing or incomplete safety and PD data, including dates and times, are treated as such. 
Missing test results or assessments will not be imputed, and as such, are assumed missing-
completely-at-random (MCAR). 
 
For laboratory data, values below the limit of quantitation (recorded as “< LLQ”) will be set to half 
that limit. 
Censoring rules for time-to-event endpoints will be discussed in the SAP. Imputation rules for the 
primary endpoint will be discussed in the SAP. The handling of any missing, unused, and spurious 
data will be documented in the SAP or the clinical study report. 
8.4 Subject disposition 
Subject disposition will be listed by subject. 
The following subject data will be summarized: 
• 
number and percentage of subjects screened, 
• 
number and percentage of subjects enrolled, 
• 
number and percentage of subjects completed, 
• 
number and percentage of subjects included in safety population 
A subject who completed the study is defined as a subject where the last PD assessment was 
completed. 
8.5 Baseline parameters and concomitant medications 
8.5.1 
Demographics and baseline variables 
Demographic and other baseline characteristics will be summarized using descriptive statistics for 
the treatment group and overall. 
8.5.2 
Medical history 
Medical history will be listed. 
8.5.3 
Prior and concomitant medications 
Prior and concomitant medications will be listed by international nonproprietary names, dose, 
regimen, route and for which indication it was prescribed. 
8.5.4 
Treatment compliance/exposure 
Exposure to study treatment is described in terms of duration of treatment. 
8.5.5 
Safety and tolerability endpoints 
The safety data set is used to perform all safety analyses. 
 
Baseline is defined as the last value prior to dosing. Change from baseline will be calculated for all 
continuous safety parameters. 
8.5.6 
Adverse events 
The latest version of Medical Dictionary for Regulatory Activities (MedDRA) will be used for the 
coding of AEs. The overall incidence of AEs will be displayed by MedDRA system organ class, 
preferred term, and treatment group.  
 
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All AEs will be displayed in listings. In addition, SAEs and treatment-emergent AEs (TEAEs) leading 
to discontinuation of study drug will be listed. 
Treatment-emergent AEs will be defined as an event that occurs on or after the first dose of study 
drug or the worsening of a preexisting condition on or after the first dose of study drug. If a subject 
does experience an event both prior to and after starting administration of a treatment, the event will 
be considered a TEAE (of the treatment) only if it has worsened in severity (ie, it is reported with a 
new start date) after starting administration of the specific treatment, and prior to the start of another 
treatment, if any. All TEAEs collected during the investigational period will be summarized.  
The number of TEAEs and the number of subjects with at least 1 TEAE will be summarized by 
treatment group for the following: 
1. 
System organ class and preferred term; 
2. 
System organ class, preferred term, and maximum severity 
3. 
System organ class, preferred term, and maximum drug relatedness. 
8.5.7 
Vital signs 
Reported values and change from baseline values of supine blood pressure and pulse rate and 
temperature will be summarized using descriptive statistics by treatment group and time point. The 
number of available observations and out-of-range values (absolute and in percentage) will be 
presented by treatment group. Vital sign variables will be listed. Values outside the reference range 
will be flagged in the listing. 
Vital sign results and change from baseline values will be summarized using descriptive statistics by 
treatment group and time point. 
8.5.8 
ECG 
ECG values will be listed. 
8.5.9 
Clinical laboratory tests 
Reported values and change from baseline values of clinical laboratory variables will be 
summarized using descriptive statistics by treatment group and time point. The number of available 
observations and out-of-range values (absolute and in percentage) will also be presented by 
treatment group. Clinical laboratory values will be listed. 
Clinical laboratory test results and change from baseline values will be summarized using 
descriptive statistics by treatment group and time point. 
8.6 Primary endpoints 
1) Assuming pt is probability of outcome in the losmapimod arm; pc is the probability of outcome 
in the control arm 
Study hypothesis: H0:  = pt – pc = 0 
                              H1:  = pt – pc < 0 
Assuming pt=0.18, pc=0.30, we can restate the hypothesis as  
  H0: θ = θ0 = 0 
  H1: θ = θ1 = –0.12  
For the final analysis, the proportion of subjects achieving the primary endpoint in the treatment 
arms will be compared using an adjusted risk difference obtained from a regression model, adjusted 
for stratification factors, sex, and baseline CRP. Full details of the regression model will be provided 
in the SAP. An interim analysis to assess futility analysis—and potential sample size re-estimation—
is discussed in Section 8.9. All results will be summarized descriptively by treatment arm and 
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expressed as proportions, along with corresponding unadjusted/adjusted 95% CI of the difference 
between response rates, and p-values. 
8.7 Secondary endpoints 
Clinical status at Day 7 and Day 14:  
Change in clinical status between baseline and post-baseline will be modelled using regression 
models appropriate for ordinal data, adjusting for stratification factors, sex, and baseline CRP. 
Details will be provided in the SAP. 
Percentages for each category of the ranking scale will be tabulated by treatment arm, along with 
differences between treatment arms at each time point. The proportion of subjects for each of the 
items in the scale will be compared using an adjusted risk difference obtained from a regression 
model, adjusting for stratification factors, sex, and baseline CRP. Full details of the regression 
model will be provided in the SAP.  
Total number of study days: (a) free of oxygen supplementation; (b) in ICU; (c) of hospitalization; (d) 
free of respiratory failure; (e) alive: For each endpoint (a) - (e), a Poisson regression model or a 
negative binomial model will be used to assess the relationship with treatment,  adjusting for 
stratification factors, sex, baseline CRP and number of days on study (as applicable). Details of the 
model, including censoring rules, if any, will be provided in the SAP. 
Percentage of subjects discharged from the hospital: percentages of subjects discharged from the 
hospital will be tabulated by treatment arm, along with differences between treatment arms. The 
proportion of subjects will be compared using an adjusted risk difference obtained from a regression 
model, adjusting for stratification factors, sex, and baseline CRP. Full details of the regression 
model will be provided in the SAP. 
All-cause mortality at Day 28: percentages of subjects will be tabulated by treatment arm, along with 
differences between treatment arms, at each time point. The proportion of subjects will be compared 
using an adjusted risk difference obtained from a regression model, adjusting for stratification 
factors, sex, and baseline CRP. Full details of the regression model will be provided in the SAP. 
Incidence of AEs/SAEs: will be summarized by system organ class and preferred term and by 
treatment arm using percentages. 
Incidence of clinically significant changes: Percentage of subjects with clinically significant changes 
in laboratory parameters, ECG, and vital sign measurements will be computed for each treatment 
arm along with associated 2-sided 95% Clopper-Pearson CI.  
Clearance of quantifiable viral RNA by Day 7: percentages of subjects with clearance of quantifiable 
viral RNA will be tabulated by treatment arm, along with differences between treatment arms, at 
each time point. The proportion of subjects will be compared using an adjusted risk difference 
obtained from a regression model, adjusting for stratification factors, sex, and baseline CRP. Full 
details of the regression model will be provided in the SAP. 
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8.9 Interim analysis for futility and sample size re-estimation 
An interim analysis (IA) will be conducted after 206 subjects have been enrolled (approximately 103 
in each of the losmapimod and placebo arms) and have been treated for 14 days with 28 days of 
follow-up. Only futility—and potential sample size-estimation—will be assessed by the DMC at the 
IA. The O’Brien-Fleming group sequential method will be used to adjust beta for interim testing. 
Table 6, Figure 1, Figure 2, and Figure 3 contain sample size requirements, boundary information, 
and stopping probabilities for testing futility on the primary endpoint at both the IA and final analysis. 
P-values are single-sided.  Sample size estimation was done using SAS® (Proc SeqDesign, Version 
4.0). The study will not be stopped for efficacy at the IA. 
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Table 6:  Boundary Values for Interim Analysis Futility Assessment 
 
 
 
Analysis 
Stage 
Sample Size 
 
Beta: Futility 
 
 
Alpha: Efficacy 
 
 
 
Losmapimod 
Control 
Standardized- Z 
(p-value) 
MLE 
Stopping Probability 
(accept null under null 
hypothesis) 
Standardized- Z 
(p-value) 
MLE 
Stopping Probability 
(accept null under 
alternative 
hypothesis) 
Interim 
Analysis 
103 
103 
-0.67873 
 
(0.24865) 
 
 
-0.04017 
0.75135 
 
 
 
 
Not applicable 
-- 
0.08871 
Final 
Analysis 
205 
205 
-1.91358 
 
(0.02784) 
-0.08009 
0.97500 
-- 
-- 
0.20000 
Overall alpha=0.025 (1-sided); overall power=80%. 
Abbreviations: MLE: maximum likelihood estimate. 
 
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Figure 1:  Acceptance Region (Standardized-Z Scale) 
 
 
  
Figure 2:  Acceptance Region (P-value) 
 
 
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Figure 3:  Acceptance Region (Maximum Likelihood Estimate) 
 
 
  
8.9.1 
Futility Testing  
The process is as follows: 
1. Futility at IA: If standardized z-value (MLE: maximum likelihood estimate) of pt – pc is 
≥ -0.67873 (-0.04017), or p-value ≥0.24865, then stop for futility. Probability of stopping for 
futility under null hypothesis is ~0.75. 
2. At Final Analysis: The final p-value is tested at an adjusted alpha of 0.02784. 
8.9.2 
Sample Size Re-estimation 
The Chen-DeMets-Lan method (Chen et al 2004) will be used for unblinded sample size 
re-estimation, with IA futility stopping boundaries created using O’Brien-Fleming method, as 
described above. Wald conditional probabilities will be calculated using the actual observed 
proportion from both treatment arms.  
The maximum sample size allowed is 820 subjects. Sample size will be increased only if the 
observed data at the IA are promising; that is, if the conditional power is ≥50% and <80%. Sample 
size will be increased to ensure a target conditional power of at least 80%.  
There is only one IA, and conditional power at IA must lie between 50% and 80% for sample size re-
estimation to be implemented. These 2 conditions ensure that the target Type I error of 2.5% is not 
exceeded by increasing sample size to meet the original target power (Chen et al 2004). 
Sample size re-estimation will not be done in the following 2 instances: 
• 
If conditional power is <50%, then sample size re-estimation will not be done, and decision 
on futility will be made based on boundary values from the O’Brien-Fleming method.  
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• 
If conditional power is ≥80%, then a sample size re-estimation will not be done, as the study 
will be considered sufficiently powered to detect the effect of interest at the final analysis. 
A Wald Test statistic will be calculated and compared with the boundary value for futility (see Table 
6). If the Wald Test statistic lies in the acceptance region then the study will stop for futility. 
All calculations for the IA and the unblinded sample size re-estimation will be conducted by an 
external, unblinded statistician. The DMC will review the results in a closed session and make 
appropriate recommendations to the Sponsor afterwards.  
8.9.3 
Possible Recommendations by the DMC 
After reviewing the results of the IA, the DMC may select 3 or more possible recommendations, 
based on the test statistics obtained at the IA: 
• 
Stop for Futility - Stop trial early due to strong evidence for futility due to test statistic being in 
the futility region. 
• 
Continue without change - Continue until next look with no changes due to test statistic not 
being in the futility region or the conditional power being <50% or ≥80%.  
• 
Add required additional sample size, n, without exceeding the maximum sample size of 820 
and continue the trial.  
At the final analysis, 2 recommendations can be made: 
• 
Efficacy is demonstrated. 
• 
Efficacy is NOT demonstrated.  
8.10 Data monitoring committee 
An independent DMC composed of experts external to the sponsor and investigators will monitor 
the safety of the trial participants and the conduct of the trial on an ongoing basis and will be 
responsible for the interim analysis and recommendations regarding sample size re-estimation. 
Consistent with US Food and Drug Administration (FDA) recommendations (FDA Guidance for 
Industry, Establishment and Operation of Clinical Trial Data Monitoring Committees, 2006), the 
DMC will include at least 2 external clinicians with expertise relevant to the evaluation of COVID-19, 
such as Critical Care, Pulmonology, or Infectious Disease, as well as at least 1 independent 
biostatistician with expertise in clinical trial design and statistical methods for clinical research and 
analysis of research data including interim analysis. 
Details on the composition of the DMC and the schedule and format of DMC meetings and data 
outputs will be presented in the DMC charter. The DMC will review, at a minimum, data for the 
sentinel subjects prior to continued study drug dosing and cumulative safety data at regular intervals 
based on subject enrollment. 
The safety evaluations will be detailed in the DMC charter and will include review of conventional 
safety variables, such as serious adverse events. Any safety event that requires unblinding will be 
immediately reported to the DMC and to the FDA. The DMC may request and review any additional 
reports outside of the planned analyses at any time if deemed necessary to ensure the safety of 
subjects. The DMC will also review the efficacy data at the IA and make recommendations based on 
the futility criteria and for sample size re-estimation if needed (see Section 8.9). After reviewing 
study data, the DMC will make recommendations regarding continuation, termination, or 
modification of the study. The DMC may also perform ad hoc review PK of subjects who require 
dialysis. 
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8.11 Type I error for testing key study endpoints 
The overall Type I error of the study will be controlled at 0.025 for 1-sided tests of hypotheses for 
the following key study endpoints, using an appropriate alpha control method: 
1. Proportion of progressors to death or respiratory failure by Day 28  
2. Change in clinical status using the 9-point WHO scale at Day 14  
3. Change in clinical status using the 9-point WHO scale at Day 7 
4. Oxygen-free days by Day 28 
Further details on the methodology will be provided in the SAP. 
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9 
GOOD CLINICAL PRACTICE, ETHICS AND ADMINISTRATIVE PROCEDURES 
9.1 Good clinical practice 
9.1.1 
Ethics and good clinical practice 
The study will be performed in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, ICH Good Clinical Practice (GCP), the protocol, and all applicable 
regulations. 
9.1.2 
Ethics committee / institutional review board 
Federal regulations and the ICH guidelines require that approval be obtained from an IRB/IEC 
before participation of human subjects in research studies. Before study onset, the protocol, 
informed consent, advertisements to be used for the recruitment of study subjects, and any other 
written information regarding this study to be provided to the subject or the subject’s legal guardian 
must be approved by the IRB/IEC. Documentation of all IRB/IEC approvals and of the IRB/IEC 
compliance with ICH harmonised tripartite guideline E6(R2): Good Clinical Practice will be 
maintained by the site and will be available for review by the sponsor or its designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must identify the 
IRB/IEC name and address, the clinical protocol by title or protocol number or both, and the date on 
which approval or a favorable opinion was granted. 
The investigator is responsible for providing written summaries of the progress and status of the 
study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The investigator must 
promptly supply the sponsor or its designee, the IRB/IEC, and, where applicable, the institution, with 
written reports on any changes significantly affecting the conduct of the study or increasing the risk 
to subjects. 
9.1.3 
Informed consent 
It is the responsibility of the investigator to obtain written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and potential 
hazards of the study. The investigator must also explain to the subjects that they are completely free 
to refuse to enter the study or to withdraw from it at any time for any reason. 
Subjects will be given an opportunity to ask questions about the study prior to providing consent for 
participation. Following discussion of the study with site staff, subjects or their legally authorized 
representative will be required to provide one of the following:  
1. Sign a statement of informed consent that meets the requirements of local regulations, ICH 
guidelines, and the IRB/EC or study center, where applicable. The subject will be given a 
copy of the signed ICF, and the original will be maintained with the subject’s records; OR 
2. If a subject is in isolation due to COVID-19 and institutional infection control policy would 
prevent removal of a document signed by the subject from their hospital room, then one of 
the following methods will be used to obtain informed consent that meets the requirements 
of local regulations, ICH guidelines, and the IRB/EC or study center, where applicable: 
o Obtain the informed consent electronically; OR 
o Obtain the informed consent by teleconference/video conference in alignment 
with local regulatory guidance. 
How the consent was obtained and reason why it was obtained using that particular method 
should be documented in the eCRF. The trial record at the investigational site should 
document how it was confirmed that the subject signed the consent form (ie, either using 
attestation by the witness and investigator or a photograph of the signed consent).  
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Subjects must be re-consented to the most current version of the ICF(s) during their participation in 
the study. 
If consent is obtained from a legally authorized representative, then assent should be obtained from 
the subject using similar methods as described above. 
9.2 Data handling and record keeping 
This study will be conducted according to ICH E6(R2) risk and quality processes described in the 
applicable procedural documents. The quality management approach to be implemented in this 
study will be documented and will comply with the current ICH guidance on quality and risk 
management. 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the subjects treated as part of the research under this protocol. 
The investigator agrees to maintain accurate eCRFs and source documentation as part of the case 
histories. These source documents may include laboratory reports, ECG strips, etc. 
Study site personnel will enter subject data into the EDC program. The analysis data sets will be a 
combination of these data and data from other sources (eg, laboratory data). 
Clinical data management will be performed in accordance with standard data cleaning procedures 
to ensure the integrity of the data, eg, removing errors and inconsistencies in the data. Adverse 
event terms will be coded using MedDRA, an internal validated medical dictionary, and concomitant 
medications will be coded using the World Health Organization Drug Dictionary. 
After final database lock, each study site will receive a CD-ROM containing all of their site specific 
eCRF data as entered into the EDC system for the study, including full discrepancy and audit 
history. Additionally, a CD-ROM copy of all of the study site’s data from the study will be created 
and sent to the sponsor for storage. 
 will maintain a duplicate CD-ROM copy for their 
records. In all cases, subject initials will not be collected or transmitted to the sponsor. 
9.3 Access to source data and documents 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a manner 
designed to maintain subject confidentiality. All records will be kept in a secure storage area with 
limited access. Clinical information will not be released without the written permission of the subject 
(or the subject’s legal guardian), except as necessary for monitoring and auditing by the sponsor, its 
designee, applicable regulatory authorities, or the IRB/IEC. 
To ensure privacy, directly identifying information of study subjects will not be attached to records or 
samples released to the sponsor and its service providers for research purposes. 
The investigator and all employees and coworkers involved with this study may not disclose or use 
for any purpose other than performance of the study any data, record, or other unpublished, 
confidential information disclosed to those individuals for the purpose of the study. Prior written 
agreement from the sponsor or its designee must be obtained for the disclosure of any said 
confidential information to other parties. Additional confidentiality requirements and obligations will 
be set forth in the clinical trial agreement to be entered into by the sponsor, the principal 
investigator, and the institution. 
9.4 Investigator’s obligations 
The following administrative items are meant to guide the investigator in the conduct of the study but 
may be subject to change based on industry and government standard operating procedures, 
working practice documents, or guidelines. Changes will be reported to the IRB/IEC but will not 
result in protocol amendments. 
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9.5 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a manner 
designed to maintain subject confidentiality. All records will be kept in a secure storage area with 
limited access. Clinical information will not be released without the written permission of the subject 
(or the subject’s legal guardian), except as necessary for monitoring and auditing by the sponsor, its 
designee, applicable regulatory authorities, or the IRB/IEC. 
To ensure privacy, directly identifying information of study subjects will not be attached to records or 
samples released to the sponsor and its service providers for research purposes. 
The investigator and all employees and coworkers involved with this study may not disclose or use 
for any purpose other than performance of the study any data, record, or other unpublished, 
confidential information disclosed to those individuals for the purpose of the study. Prior written 
agreement from the sponsor or its designee must be obtained for the disclosure of any said 
confidential information to other parties. Additional confidentiality requirements and obligations will 
be set forth in the clinical trial agreement to be entered into by the sponsor, the principal 
investigator, and the institution.  
9.6 Financial disclosure and obligations 
Investigators are required to provide financial disclosure information to allow the sponsor to submit 
the complete and accurate certification or disclosure statements required by applicable regulatory 
authorities. In addition, the investigator must provide to the sponsor a commitment to promptly 
update this information if any relevant changes occur during the course of the investigation and for 
1 year following the completion of the study. 
Neither the sponsor nor 
 is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the absence of 
specific arrangements, neither the sponsor nor 
 is financially responsible for further 
treatment of the subject’s disease. 
9.7 Investigator documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH E6(R2) 8.2 and Title 
21 of the Code of Federal Regulations by providing the following essential documents, including but 
not limited to: 
• 
IRB/IEC approval 
• 
Original investigator-signed investigator agreement page of the protocol 
• 
FDA Form 1572, fully executed, and all updates on a new fully executed Form FDA 1572 
• 
A curriculum vitae for the investigator and each subinvestigator listed on Form FDA 1572 
• 
Financial disclosure information to allow the sponsor to submit complete and accurate 
certification or disclosure statements required by applicable regulatory authorities. In 
addition, the investigators must provide to the sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and for 
1 year after the completion of the study. 
• 
IRB/IEC-approved informed consent, samples of site advertisements for recruitment for this 
study, and any other written information regarding this study that is to be provided to the 
subject or legal guardian, and 
• 
Laboratory certifications and normal ranges for any local laboratories used by the site. 
9.8 Study conduct 
The investigator agrees that the study will be conducted according to the principles of ICH E6(R2). 
The investigator will conduct all aspects of this study in accordance with all national, state, and local 
laws or regulations. Study information from this protocol will be posted on publicly available clinical 
trial registers before enrollment of subjects begins. 
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9.9 Adherence to protocol 
The investigator agrees to conduct the study as outlined in this protocol in accordance with ICH 
E6(R2) and all applicable guidelines and regulations. 
9.10 Adverse events and study report requirements 
By participating in this study, the investigator agrees to submit reports of SAEs to the sponsor 
and/or IRB/IEC according to the timeline and method outlined in the protocol. In addition, the 
investigator agrees to submit annual reports to the study site IRB/IEC as appropriate. 
9.11 Investigator’s final report 
Upon completion of the study, the investigator, where applicable, should inform the institution; the 
investigator/institution should provide the IRB/IEC with a summary of the study’s outcome and the 
sponsor and regulatory authority(ies) with any reports required. 
9.12 Records retention 
Essential documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents should be retained for a longer 
period, however, if required by the applicable regulatory requirements or by an agreement with the 
sponsor. It is the responsibility of the sponsor to inform the investigator/institution as to when these 
documents no longer need to be retained. 
9.13 Publications 
After completion of the study, the data will be submitted for reporting at a scientific meeting and for 
publication in a peer-reviewed scientific journal. In these cases, the sponsor will be responsible for 
these activities and will work with the investigators to determine how the manuscript is written and 
edited, the number and order of authors, the publication to which it will be submitted, and other 
related issues. The sponsor has final approval authority over all such issues. 
Data are the property of the sponsor and cannot be published without prior authorization from the 
sponsor, but data and publication thereof will not be unduly withheld. Further terms concerning 
publication will be set forth in the clinical trial agreement entered into by the sponsor, the principal 
investigator, any vendors, and the institution. 
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10 STUDY MANAGEMENT 
The administrative structure will include a DMC (see Section 8.10). 
10.1 Monitoring 
The clinical monitor, as a representative of the sponsor, has the obligation to follow the study 
closely. In doing so, the monitor regularly monitors the trial remotely and will periodically visit the 
investigator based on local restrictions, in addition to maintaining necessary telephone and letter 
contact. The monitor will maintain current personal knowledge of the study through observation, 
review of study records and source documentation remotely, and discussion of the conduct of the 
study with the investigator and personnel.  All relevant source documents will be uploaded into the 
 Site Source Portal system or access to the electronic medical records will be provided for 
remote monitoring purposes. 
All aspects of the study will be carefully monitored, by the sponsor or its designee, for compliance 
with applicable government regulation with respect to current GCP and current standard operating 
procedures. 
10.2 Inspection of records 
Investigators and institutions involved in the study will permit study-related monitoring, audits, 
IRB/IEC review, and regulatory inspections by providing direct access to all study records. In the 
event of an audit, the investigator agrees to allow the sponsor, representatives of the sponsor, or a 
regulatory agency (eg, FDA or other regulatory agency) access to all study records. 
The investigator should promptly notify the sponsor and 
 of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to the sponsor. 
10.3 Management of protocol amendments and deviations 
10.3.1 
Modification of the protocol 
Any changes in this research activity, except those necessary to remove an apparent, immediate 
hazard to the subject, must be reviewed and approved by the sponsor or its designee. Amendments 
to the protocol must be submitted in writing to the investigator’s IRB/IEC for approval before 
subjects can be enrolled into an amended protocol. 
10.3.2 
Protocol deviations 
The investigator or designee must document and explain in the subject’s source documentation any 
deviation from the approved protocol. The investigator may implement a deviation from or a change 
of the protocol to eliminate an immediate hazard to study subjects without prior IRB/IEC approval. 
As soon as possible after such an occurrence, the implemented deviation or change, the reasons 
for it, and any proposed protocol amendments should be submitted to the IRB/IEC for review and 
approval, to the sponsor for agreement, and to the regulatory authorities, if required. 
A deviation from the protocol is an unintended or unanticipated departure from the procedures or 
processes approved by the sponsor and the IRB/IEC and agreed to by the investigator. A significant 
deviation occurs when there is nonadherence to the protocol by the subject or investigator that 
results in a significant, additional risk to the subject. Significant deviations can include 
nonadherence to inclusion or exclusion criteria or nonadherence to FDA regulations or ICH GCP 
guidelines and will lead to the subject being withdrawn from the study. A list of major protocol 
deviations will be compiled prior to the start of the study. 
Protocol deviations will be documented by the clinical monitor throughout the course of monitoring 
visits. Principal investigators will be notified in writing by the monitor of deviations. The IRB/IEC 
should be notified of all protocol deviations in a timely manner. 
10.4 Study termination 
Although Fulcrum Therapeutics has every intention of completing the study, Fulcrum reserves the 
right to discontinue the study at any time for clinical or administrative reasons. Should termination of 
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the study be required, the sponsor will promptly inform the investigator and the IRB/IEC and provide 
them with a detailed written explanation. Fulcrum and the investigator will assure that adequate 
consideration is given to the protection of the subjects’ interests. The sponsor has no plans to 
provide study drug to subjects after study closure or termination. The obligations to provide study 
results for subjects and reports to IRB/IEC shall continue as required by applicable laws and 
regulations. 
At any time, the sponsor, the investigators, or the IRBs/IECs may terminate this study for 
reasonable cause. Conditions that may lead to reasonable cause and warrant termination include, 
but are not limited to the following: 
• 
Subject or investigator noncompliance 
• 
Unsatisfactory subject enrollment 
• 
Lack of adherence to protocol procedures 
• 
Lack of evaluable and/or complete data 
• 
Potentially unacceptable risk to study subjects 
• 
Decision to modify drug development plan 
• 
Decision by the regulatory authority 
Written notification that includes the reason for the clinical study termination is required. 
The end of the study is defined as the date on which the last subject completes the last visit 
(includes the safety follow-up visit).  
10.5 Final report 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the clinical 
study reports are prepared and provided to the regulatory agency(ies) as required by the applicable 
regulatory requirement(s). The sponsor will also ensure that the clinical study reports in marketing 
applications meet the standards of the ICH harmonised tripartite guideline E3: Structure and content 
of clinical study reports.  
Where required by applicable regulatory requirements, an investigator signatory will be identified for 
the approval of the clinical study reports. The investigator will be provided reasonable access to 
statistical tables, figures, and relevant reports and will have the opportunity to review the complete 
study results. 
Upon completion of the clinical study reports, the sponsor will provide the investigator with the full 
summary of the study results. The investigator is encouraged to share the summary results with the 
study subjects, as appropriate. The study results will be posted on publicly available clinical trial 
registers. 
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11 REFERENCES 
 
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Barbour AM, Sarov-Blat L, Cai G, et al. Safety, tolerability, pharmacokinetics and 
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Blanco-Melo D, Nilsson-Payant BE, Liu WC, et al. SARS-CoV-2 launches a unique transcriptional 
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Börgeling Y, Schmolke M, Viemann D, et.al. Inhibition of p38 mitogen-activated protein kinase 
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Cadavid D, Mellion M, Wallace O, et al. Safety and tolerability of losmapimod, a selective p38α/β 
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https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html. Accessed 03 
May 2020. 
Chen Y, Wang L, Jin J, et al. p38 inhibition provides anti–DNA virus immunity by regulation of 
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Chen YH, DeMets DL, Gordon Lan KK. Increasing the sample size when the unblinded interim 
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Cheriyan J, Webb AJ, Sarov-Blat L, et al. Inhibition of p38 mitogen-activated protein kinase 
improves nitric oxide-mediated vasodilatation and reduces inflammation in 
hypercholesterolemia. Circulation. 2011;123(5):515-23. 
Christie J, Vaslef S, Chang PK, et.al, A randomized dose-escalation study of the safety and anti-
inflammatory activity of the p38 mitogen-activated protein kinase inhibitor dilmapimod in 
severe trauma subjects at risk for acute respiratory distress syndrome. Crit Care Med. 
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Dong Y, Xie W, Liu Y, et.al, Receptor tyrosine kinase inhibitors block proliferation of TGEV mainly 
through p38 mitogen-activated protein kinase pathways. Antiviral Res. 2020;173;104651. 
Genovese M, Cohen SB, Wofsy D, et al. A 24-week, randomized, double-blind, placebo-controlled, 
parallel group study of the efficacy of oral SCIO-469, a p38 mitogen-activated protein kinase 
inhibitor, in patients with active rheumatoid arthritis. J Rheumatol. 2011;38(5):846-54. 
Griego SD, Weston CB, Adams JL, et al. Role of p38 mitogen-activated protein kinase in rhinovirus-
induced cytokine production by bronchial epithelial cells. J Immunol. 2000;165(9):5211-20. 
Grimes JM, Grimes KV. p38 MAPK inhibition: A promising therapeutic approach for 
COVID-19. J Mol Cell Cardiol. 2020. 
He F, Xiao Z, Yao H, et al. The protective role of microRNA‑21 against coxsackievirus B3 infection 
through targeting the MAP2K3/P38 MAPK signaling pathway. J Transl Med. 2019;17(1):335. 
Iordanov MS, Paranjape JM, Zhou A, et al. Activation of p38 mitogen-activated protein kinase and c-
Jun NH(2)-terminal kinase by double-stranded RNA and encephalomyocarditis virus: 
involvement of RNase L, protein kinase R, and alternative pathways. Mol Cell Biol. 
2000;20(2):617-27. 
Jimenez-Guardeño JM, Nieto-Torres JL, DeDiego ML, et al. The PDZ-binding motif of severe acute 
respiratory syndrome coronavirus envelope protein is a determinant of viral pathogenesis. 
PLoS Pathog. 2014;10(8):e1004320. 
Kindrachuk J, Ork B, Hart BJ, et al. Antiviral potential of ERK/MAPK and PI3K/AKT/mTOR signaling 
modulation for Middle East respiratory syndrome coronavirus infection as identified by 
temporal kinome analysis. Antimicrob Agents Chemother. 2015;59(2):1088-1099. 
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Kono M, Tatsumi K, Imai AM, et al. Inhibition of human coronavirus 229E infection in human 
epithelial lung cells (L132) by chloroquine: involvement of p38 MAPK and ERK. Antiviral 
Res. 2008;77(2):150-2. 
Lee CH, Chen RF, Liu JW, et al. Altered p38 mitogen kinase expression in different leukocytes with 
increment of immunosuppressive mediators in patients with severe acute respiratory 
syndrome. J Immunol. 2004;172:7841-7847. 
Liu DS, Wang T, Han SX. p38 MAPK and MMP-9 cooperatively regulate mucus overproduction in 
mice exposed to acrolein fog. Internat Immunopharmacol. 2009;9:1228-1235. 
Liu Y, Yang Y, Zhang C, et al. Clinical and biochemical indexes from 2019-nCoV infected patients 
linked to viral loads and lung injury. Sci China Life Sci. 2020;63(3):364-374. 
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med. 1985;4(2):213-226. 
Nagata N, Iwata N, Hasegawa H, et al. Mouse-passaged severe acute respiratory syndrome-
associated coronavirus leads to lethal pulmonary edema and diffuse alveolar damage in 
adult but not young mice. Am J Pathol. 2008;172(6):1625-37. 
Newby L, Marber MS, Melloi C, et al. Losmapimod, a novel p38 mitogen-activated protein kinase 
inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial. 
Lancet. 2014;384(9949):1187-95. 
O’Donoghue ML, Glaser R, Cavender MA, et al. Effect of losmapimod on cardiovascular outcomes 
in patients hospitalized with acute myocardial infarction: a randomized clinical trial. JAMA. 
2016;315(15):1591-9. 
Pascoe S, Costa M, Marks-Konczalik J, et al. Biological effects of p38 MAPK inhibitor losmapimod 
does not translate to clinical benefits in COPD. Respir Med. 2017;130:20-6. 
Ruan Q, Yang K, Wang W, et al. Clinical predictors of mortality due to COVID-19 based on an 
analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020 Mar 3. doi: 
https://doi.org/10.1007/s00134-020-05991-x. [Epub ahead of print] 
Salomon R, Hoffmann E, Webster RG. Inhibition of the cytokine response does not protect against 
lethal H5N1 influenza infection. PNAS. 2007;104(30):12479-12481. 
Shapiro L, Heidenreich KA, Meintzer MK, et al. Role of p38 mitogen-activated protein kinase in HIV 
type 1 production in vitro. Proc Natl Acad Sci USA. 1998;95(13):7422-6. 
Siddiqi HK, Mehra MR. COVID-19 Illness in native and immunosuppressed states: a clinical-
therapeutic staging proposal. J Heart Lung Transplant. Accepted manuscript. Published 
online March 20, 2020. 
Vukmanovic-Stejic M, Chambers ES, Suárez-Farinas M, et al. Enhancement of cutaneous immunity 
during aging by blocking p38 mitogen-activated protein (MAP) kinase-induced inflammation. 
J Allergy Clin Immunol. 2018;142(3):844-56. 
Watz H, Barnacle H, Hartley BF, et al. 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;2(1):63-72. 
World Health Organization (WHO). WHO R&D blueprint novel coronavirus COVID-19 therapeutic 
trial synopsis. Draft Feb 18, 2020.  
Zhou F, Ting Y, Ronghui D, et al. Clinical course and risk factors for mortality of adult inpatients with 
COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-
62. 
 
 
 
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Protocol FIS 001-2020 
LOSVID 
Protocol  Clarification Memo  
Date: 18-September-2020 
 
 
 
This Protocol Clarification memo is to further clarify some items of the protocol FIS 001-2020 LOSVID. 
 
1. Primary Endpoint:  
Please note that the primary endpoint for FIS 001-2020 was defined in agreement with the United 
States FDA, with a focus on reducing a bad outcome.  Fulcrum will ensure that the benefit to 
participants will be made clear in case of positive results. 
 
2. Vaccinations: 
Vaccinations are not to be administered to participants during the study.   
 
3. Exclusion Criterion 8 
 
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.  
 
Clarification: Special attention should be paid to patients with diagnosis of current active tuberculosis 
(TB) or, if known, latent TB treated for less than 4 weeks with appropriate anti-tuberculosis therapy 
according to local guidelines. Those patients should be excluded from the study. 
 
4. Visit and Assessment Schedule:  Electrocardiogram 
 
ECGs should be conducted for eligibility, after 7 days of treatment and at other times of the study, if 
clinically indicated. 
 
 
 
Clinical Operations Lead, Fulcrum Therapeutics 
 
 
 
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CLINICAL STUDY PROTOCOL 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled 
Study of the Safety and Efficacy of Losmapimod in Adult 
Subjects with COVID-19 (LOSVID STUDY) 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor.
Short Title:
Losmapimod safety and efficacy in COVID-19 (LOSVID Study)
Version:
2.1
Date:
10-Jul-2020
Study number:
FIS-001-2020
Sponsor:
Fulcrum Therapeutics
26 Landsdowne St., 5th floor
Cambridge, MA 02139
USA
Sponsor signatory:
MD
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CONTACT DETAILS
SPONSOR
  
Fulcrum Therapeutics
26 Landsdowne Street, 5th floor
Cambridge, Massachusetts 02139
USA
Clinical Trial Leader
MD
Telephone: 
e-mail: 
Drug Safety Physician
 MD
Telephone: 
e-mail:
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SIGNATURE PAGE - INVESTIGATOR
Study 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)
I have read the protocol and agree to conduct the study as described herein.
Investigator Name
Title
Signature
Date (dd Mmm yyyy)
 
 
	

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SIGNATURE PAGE - SPONSOR
Fulcrum Therapeutics
Study 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)
I approve this protocol on behalf of the sponsor.
Chief Scientific Officer
Signature
Date (dd Mmm yyyy)
 MD
Senior Vice President
Head, Clinical Development
Signature
Date (dd Mmm yyyy)


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TABLE OF CONTENTS
CONTACT DETAILS........................................................................................................................................... 2 
SIGNATURE PAGE - INVESTIGATOR.............................................................................................................. 3 
SIGNATURE PAGE - SPONSOR....................................................................................................................... 4 
TABLE OF CONTENTS...................................................................................................................................... 5 
LIST OF ABBREVIATIONS ................................................................................................................................ 9 
PROTOCOL SYNOPSIS................................................................................................................................... 11 
1 
BACKGROUND AND RATIONALE ......................................................................................................... 21 
1.1 
Scientific rationale for investigation of losmapimod in COVID-19 ..................................................... 21 
1.2 
Benefit-risk considerations................................................................................................................. 25 
2 
STUDY OBJECTIVES AND ENDPOINTS................................................................................................ 26 
3 
STUDY IMPLEMENTATION ..................................................................................................................... 28 
3.1 
Overall study design and plan ........................................................................................................... 28 
3.2 
Start of study and end of study definitions......................................................................................... 28 
3.3 
Selection of doses in the study.......................................................................................................... 29 
3.4 
Study drug modifications and withdrawal .......................................................................................... 29 
3.4.1 
Dose modifications .................................................................................................................... 29 
3.4.2 
Subject withdrawal..................................................................................................................... 31 
3.4.3 
Replacement policy ................................................................................................................... 31 
3.4.4 
Stopping criteria......................................................................................................................... 31 
4 
STUDY POPULATION.............................................................................................................................. 32 
4.1 
Inclusion criteria................................................................................................................................. 32 
4.2 
Exclusion criteria................................................................................................................................ 33 
4.3 
Concomitant medications .................................................................................................................. 33 
4.4 
Lifestyle restrictions ........................................................................................................................... 34 
4.4.1 
Contraception requirements ...................................................................................................... 34 
5 
INVESTIGATIONAL MEDICINAL PRODUCT.......................................................................................... 36 
5.1 
Investigational drug and matching placebo ....................................................................................... 36 
5.2 
Study drug packaging and labelling................................................................................................... 36 
5.3 
Drug accountability ............................................................................................................................ 36 
5.4 
Treatment assignment and blinding .................................................................................................. 36 
5.4.1 
Randomization and treatment assignment................................................................................ 36 
5.4.2 
Blinding ...................................................................................................................................... 37 
5.4.3 
Treatment compliance ............................................................................................................... 37 
6 
STUDY ASSESSMENTS .......................................................................................................................... 38 
6.1 
Medical history and confirmation of COVID diagnosis ...................................................................... 38 
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6.2 
Pharmacokinetic and pharmacodynamic assessments .................................................................... 38 
6.3 
Clinical status and symptoms ............................................................................................................ 39 
6.3.1 
Respiratory failure and survival assessment............................................................................. 39 
6.3.2 
Clinical status assessment ........................................................................................................ 39 
6.4 
Extended vital signs........................................................................................................................... 39 
6.5 
Safety and tolerability assessments .................................................................................................. 40 
6.5.1 
Vital signs................................................................................................................................... 40 
6.5.2 
Weight and height...................................................................................................................... 40 
6.5.3 
Physical examination................................................................................................................. 40 
6.5.4 
Electrocardiography................................................................................................................... 40 
6.5.5 
Laboratory assessments............................................................................................................ 40 
6.6 
Unscheduled visit............................................................................................................................... 41 
6.6.1 
Early termination visit................................................................................................................. 41 
6.7 
Alternative follow-up methods to site visits........................................................................................ 42 
7 
SAFETY REPORTING .............................................................................................................................. 43 
7.1 
Definitions of adverse events ............................................................................................................ 43 
7.1.1 
Recording of adverse events..................................................................................................... 43 
7.1.2 
Intensity of adverse events........................................................................................................ 43 
7.1.3 
Relationship to study drug ......................................................................................................... 43 
7.1.4 
Serious adverse events ............................................................................................................. 43 
7.1.5 
Suspected unexpected serious adverse reactions.................................................................... 44 
7.1.6 
Reporting of serious adverse events ......................................................................................... 44 
7.1.7 
Follow-up of adverse events...................................................................................................... 44 
7.1.8 
Adverse events of special interest............................................................................................. 44 
7.2 
Pregnancy.......................................................................................................................................... 45 
7.2.1 
Teratogenicity ............................................................................................................................ 45 
7.2.2 
Reporting of pregnancy ............................................................................................................. 45 
8 
STATISTICAL METHODOLOGY AND ANALYSES ................................................................................ 46 
8.1 
Statistical analysis plan...................................................................................................................... 46 
8.1.1 
Determination of sample size .................................................................................................... 46 
8.1.2 
Analysis methods....................................................................................................................... 46 
8.1.3 
Analysis sets.............................................................................................................................. 46 
8.2 
Protocol violations/deviations ............................................................................................................ 46 
8.3 
Missing, unused and spurious data................................................................................................... 47 
8.4 
Subject disposition............................................................................................................................. 47 
8.5 
Baseline parameters and concomitant medications.......................................................................... 47 
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8.5.1 
Demographics and baseline variables....................................................................................... 47 
8.5.2 
Medical history........................................................................................................................... 47 
8.5.3 
Prior and concomitant medications ........................................................................................... 47 
8.5.4 
Treatment compliance/exposure ............................................................................................... 47 
8.5.5 
Safety and tolerability endpoints................................................................................................ 47 
8.5.6 
Adverse events .......................................................................................................................... 47 
8.5.7 
Vital signs................................................................................................................................... 48 
8.5.8 
ECG ........................................................................................................................................... 48 
8.5.9 
Clinical laboratory tests.............................................................................................................. 48 
8.6 
Primary endpoints.............................................................................................................................. 48 
8.7 
Secondary endpoints......................................................................................................................... 49 
 
 
8.9 
Interim analysis for futility and sample size re-estimation ................................................................. 50 
8.9.1 
Futility Testing............................................................................................................................ 53 
8.9.2 
Sample Size Re-estimation ....................................................................................................... 53 
8.9.3 
Possible Recommendations by the DMC.................................................................................. 54 
8.10 
Data monitoring committee................................................................................................................ 54 
8.11 
Type I error for testing key study endpoints ...................................................................................... 55 
9 
GOOD CLINICAL PRACTICE, ETHICS AND ADMINISTRATIVE PROCEDURES................................ 56 
9.1 
Good clinical practice......................................................................................................................... 56 
9.1.1 
Ethics and good clinical practice ............................................................................................... 56 
9.1.2 
Ethics committee / institutional review board............................................................................. 56 
9.1.3 
Informed consent ....................................................................................................................... 56 
9.2 
Data handling and record keeping..................................................................................................... 57 
9.3 
Access to source data and documents.............................................................................................. 57 
9.4 
Investigator’s obligations ................................................................................................................... 57 
9.5 
Confidentiality .................................................................................................................................... 58 
9.6 
Financial disclosure and obligations.................................................................................................. 58 
9.7 
Investigator documentation ............................................................................................................... 58 
9.8 
Study conduct .................................................................................................................................... 58 
9.9 
Adherence to protocol........................................................................................................................ 59 
9.10 
Adverse events and study report requirements................................................................................. 59 
9.11 
Investigator’s final report.................................................................................................................... 59 
9.12 
Records retention .............................................................................................................................. 59 
9.13 
Publications ....................................................................................................................................... 59 
10 
STUDY MANAGEMENT ....................................................................................................................... 60 
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10.1 
Monitoring .......................................................................................................................................... 60 
10.2 
Inspection of records ......................................................................................................................... 60 
10.3 
Management of protocol amendments and deviations...................................................................... 60 
10.3.1 
Modification of the protocol........................................................................................................ 60 
10.3.2 
Protocol deviations .................................................................................................................... 60 
10.4 
Study termination............................................................................................................................... 60 
10.5 
Final report......................................................................................................................................... 61 
11 
REFERENCES ...................................................................................................................................... 62 
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LIST OF ABBREVIATIONS
ACE2
angiotensin-converting enzyme 2
ACS
acute coronary syndrome
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase/serum glutamic pyruvic transaminase (SGPT)
ARDS
acute respiratory distress syndrome
AST
aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
(SGOT)
BID
bis in diem / twice per day
BMI
body mass index
BP
blood pressure
CI
confidence interval
Cmax
Maximum concentration
COPD
chronic obstructive pulmonary disease
CoV
coronavirus
COVID-19
disease caused by novel coronavirus
CRP
C-reactive protein
CXCL13
chemokine ligand 13
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
ECG
electrocardiogram
ECMO
extracorporeal membrane oxygenation
eCRF
electronic case report form
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
ET
early termination
ET-1
endothelin
FAS
Full Analysis Set
FDA
Food and Drug Administration
FiO2
fraction of inspired oxygen
FSGS
focal segmental glomerulosclerosis
FSHD
facioscapulohumeral muscular dystrophy
GCP
Good Clinical Practice
GSK
GlaxoSmithKline
H5N1
highly pathogenic Asian avian influenza A, subtype H5N1
HIV
human immunodeficiency virus
HMGB-1
high mobility group box protein-1
hsCRP
high-sensitivity C-reactive protein
HSV-1
herpes simplex virus-1
IA
interim analysis
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ICAM-1
intercellular adhesion molecule-1
ICF
informed consent form
ICH
International Conference on Harmonization
ICU
intensive care unit
IEC
independent ethics committee
IL-6
interleukin-6
IND
investigational new drug application
IRB
institutional review board
IxRS
JAK
interactive/web voice response system
Janus kinase
LLQ
lower limit of quantitation
LS
least square
MAPK
MATE
mitogen-activated protein kinase
multidrug and toxin extrusions
MCAR
missing-completely-at-random
MedDRA
OAT
Medical Dictionary for Regulatory Activities
organic anion transporter
PAO2
partial pressure of oxygen
PCR
polymerase chain reaction
PD
pharmacodynamic(s)
PH
proportional hazards
PK
pharmacokinetics
PO
per os / orally
PPS
per protocol set
QTcB
QT corrected interval using Bazett’s formula
QTcF
QT corrected interval using Fridericia’s formula
RA
rheumatoid arthritis
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-1
severe acute respiratory syndrome coronavirus 1
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SAS
Statistical Analysis Software
SE
standard error
SOC
standard of care
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
ULN
US
upper limit of normal
United States
WHO
World Health Organization
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PROTOCOL SYNOPSIS
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) 
Short Title
Losmapimod safety and efficacy in COVID-19 (LOSVID Study)
Background & Rationale
Poor prognosis for many COVID-19 patients has been attributed to an exaggerated inflammatory 
response following SARS-CoV-2 infection. This hyperactivated immune response is associated with 
pulmonary edema, acute respiratory distress syndrome (ARDS), and cardiomyopathy that may lead 
to increased mortality in the sickest patients. 
p38 mitogen-activated protein kinase (MAPK) is an important mediator of inflammation, and
extensive nonclinical data have linked p38 to the hyper-inflammatory response to viral infections. 
Losmapimod LVDSRWHQWDQGVHOHFWLYHSĮȕ0$3.LQKLELWRUWKDWLVFXUUHQWO\LQ3KDVHFOLQLFDO
trials for the treatment of facioscapulohumeral dystrophy and has previously been administered to 
more than 3600 adult healthy volunteers and subjects including participants in a Phase 3 trial. Many 
of these trials were for chronic inflammatory indications for which the compound exhibited a 
favorable safety profile not significantly different from placebo. These trials have also indicated that 
losmapimod has good exposure after oral dosing, robust target engagement, and acutely reduces 
inflammatory biomarkers that have been associated with poor prognosis in COVID-19, including 
C-reactive protein (CRP) and interleukin-6 (IL-6). Additionally, a clinical study recently concluded
that losmapimod restored the normal immune response of older subjects (median 69 years, range: 
65, 77 years) following a viral challenge. Further information is available in the losmapimod 
Investigator Brochure. 
Losmapimod is attractive as a potential therapeutic option for COVID-19:
• 
p38 inhibition improves survival in mouse SARS-CoV-1 models and other nonclinical viral 
models, suppressing the exaggerated immune response to acute infection.
• 
Losmapimod acutely has reduced exaggerated inflammatory responses in human trials for 
multiple inflammatory diseases, including IL-6 and CRP, and has normalized immune 
response to viral or other acute inflammatory challenges in older subjects.
• 
Losmapimod is a clinical-stage, potent, and selective p38 inhibitor with extensive human 
experience and extensive evidence of safety and tolerability, including in a Phase 3 clinical 
trial in acute myocardial infarction.
• 
p38 inhibition has the potential to reduce hypothesized deleterious effects of increased 
angiotensin II in COVID-19, such as vasoconstriction, increased inflammation, cardiac 
arrhythmias, and organ failure.
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Objectives and Endpoints:
All study objectives will be evaluated in subjects diagnosed with COVID-19:
Objectives
Endpoints
Primary
To assess the efficacy of losmapimod 
compared with placebo for treatment of 
COVID-19 when administered concurrently 
with standard of care
Proportion of progressors to death or respiratory 
failure by Day 28
Secondary
To evaluate the effect of losmapimod 
compared with placebo on clinical 
outcomes
Clinical status by Days 7 and 14 as measured on 
the 9-point WHO ordinal scale:
x
(8) death
x
(7) ventilation plus additional organ support 
(vasopressors, renal replacement therapy, 
ECMO)
x
(6) Intubation and mechanical ventilation
x
(5) noninvasive ventilation or high-flow oxygen 
therapy
x
(4) oxygen therapy but not requiring high-flow 
or non-invasive ventilation
x
(3) hospitalized but not requiring oxygen 
therapy
x
(2) Discharged from the hospital but with 
limitation of activities
x
(1) Discharged from the hospital and without 
any limitation
x
(0) No clinical evidence of the disease
To assess the effect on clinical status of 
treatment with losmapimod compared with 
placebo
Total number of study days free of oxygen 
supplementation by Day 28
Total number of study days in ICU by Day 28
Total number of study days hospitalized by Day 28
Total number of respiratory failure-free study days
by Day 28
Percentage of subjects discharged from the 
hospital by Day 28
To assess the effect on survival following 
treatment with losmapimod compared with 
placebo
All-cause mortality at Day 28
Number of study days alive by Day 28
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Objectives
Endpoints
To assess the safety and tolerability of 
losmapimod compared with placebo
Incidence of AEs and SAEs
Incidence of clinically significant changes in 
laboratory parameters and vital sign measurements
To characterize changes in SARS-CoV-2
infection following treatment with 
losmapimod compared with placebo
Quantifiable viral RNA on Day 7
Abbreviations: AE = adverse event; 
 ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; COVID-19 = disease caused by novel coronavirus; CRP = C-reactive protein; ECG = 
electrocardiogram; ECMO = extracorporeal membrane oxygenation; 
; ICU = intensive care 
unit; IL-6 = interleukin-6; 
; PD = pharmacodynamics; RNA = ribonucleic acid; SAE = serious 
adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; WHO = World Health Organization. 
Design
This Phase 3 multicenter, randomized, double-blind, placebo-controlled study will evaluate the 
safety and efficacy of losmapimod versus placebo on a background of standard of care in subjects 
with COVID-19 disease.
This study will be performed in hospitalizeGVXEMHFWV\HDUVROGZKRKDYHD&-reactive protein 
(CRP) >15 mg/L, who have been diagnosed with COVID-19, and who can undergo randomization 
within 7 days of collection of the sample found positive for the SARS-CoV-2 virus and before 
progressing into critical disease. Critical disease is defined as cardiac failure, septic shock, or 
severe pulmonary involvement (eg, bilateral extensive involvement on chest X-ray or chest 
computed tomography, ARDS, immediate need for intubation or mechanical ventilation, anticipated 
need for intubation in the next 48 hours) per the judgment of the investigator.
Subjects who sign informed consent and meet all entry criteria (listed below) may be enrolled.
Up to 410 subjects will participate for a maximum of 34 days, divided as follows:
o
Screening: Day -3 until Day -1 before the first study drug administration.
o
Treatment period of 14 days:
o
Subjects randomized (1:1) to either: 

losmapimod tablets 15 mg orally (PO) twice daily (BID); OR  

matching placebo tablets PO BID
o
RandomizaWLRQZLOOEHVWUDWLILHGE\DJHRUDQGUHTXLUHPHQWIRUR[\JHQDW
randomization (yes/no)
o
Follow-up: 7 (± 3) days after last dose and 14 (± 3) days after last dose. 
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The first 10 enrolled subjects (5 placebo and 5 losmapimod) will be dosed and followed for at least 
72 hours after their first dose for an interim “sentinel” safety review before any additional subjects 
are dosed. Dosing of additional subjects will continue if there are no drug-related safety concerns 
from the initial subjects dosed as assessed by an independent Data Monitoring Committee (DMC). 
The DMC will review safety data for the sentinel subjects and all subjects at regular intervals 
throughout the study as outlined in the charter.
The Sponsor will monitor individual adverse events (AEs) and toxicities on an ongoing basis 
throughout the study. 
See Table 1 for the time points of the assessments.
All study visits during the first week of treatment are anticipated to be conducted in the inpatient
setting. If the clinical status of the subject improves such that the clinician discharges the subject 
from the hospital before the end of the study, the follow-up assessments will be conducted on an 
outpatient basis by alternative methods, including the use of local laboratories/facilities or home 
visits for blood draws, telemedicine, and/or outpatient follow-up clinic visits as deemed clinically 
appropriate per COVID-19 follow-up standard of care (SOC) at each site.
Investigational drug
Losmapimod will be provided in tablets of 7.5 mg for oral administration.
Comparative drug
Matching placebo tablets will be provided for oral administration.
Inclusion criteria
1. Able and willing to provide written informed consent.
a. Note: Subject’s legally authorized representative may provide informed consent as 
applicable based on local guidelines and regulations. If consent is obtained from a 
legally authorized representative, then assent should be obtained from the subject.
2. Willing and able to comply with all study procedures.
3. $JH\HDrs at time of screening.
4. Confirmed infection with SARS-CoV-2 virus at or before the baseline visit (by polymerase 
chain reaction [PCR] testing).
a. Note: Refer to the Study Manual for details on PCR SARS-Cov-2 testing procedures.
5. GD\Vto the time of randomization from the time of collection of the specimen that tested 
positive for SARS-CoV-2 virus.
6. Hospitalization at the time of the baseline visit.
7. R[\JHQVDWXUDWLRQRQURRPDLUDQGRUR[\JHQVDWXUDWLRQRQR[\JHQ
administration at 2 L/min by nasal canula at the baseline visit.
8. Radiographic (X-ray or computed tomography scan, per local standard of care) evidence of 
pulmonary involvement consistent with COVID-19 at screening or baseline, per the judgment 
of the investigator.
a. Note: If radiography is not considered local standard of care for COVID-19 diagnosis, 
evidence of pulmonary involvement consistent with COVID-19 may also be obtained 
from clinical examination, per the judgment of the investigator. Evidence of 
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pulmonary involvement obtained by clinical examination should be documented in 
the eCRF.
9. Clinical syndrome consistent with COVID-19 at screening, per the judgment of the 
investigator
10. CRP at screening >15 mg/L (ie, >1.5 mg/dL) on local laboratory testing.
11. Agrees to practice an approved method of birth control as follows (as applicable to local 
[country] guidelines and regulations for sites outside the United States): 
a. Females of childbearing potential: Using 1 of the following acceptable methods of 
contraception: surgical sterilization (eg, bilateral tubal ligation), intrauterine 
contraception/device, hormonal contraception, or any 2 barrier methods (a 
combination of male or female condom with diaphragm, sponge, or cervical cap). 
This criterion must be followed from the time of the first dose of study medication until 
90 days after last dose
b. Males: Effective male contraception includes a vasectomy with negative semen 
analysis at follow-up, or the use of condoms. This criterion must be followed from the 
time of the first dose of study medication until 90 days after last dose.
Note: Abstinence can be considered an acceptable method of contraception at the 
discretion of the investigator. Periodic abstinence (eg, calendar, ovulation, 
symptothermal, post ovulation methods) and withdrawal are not considered 
acceptable methods of contraception.  
Exclusion criteria
1. Inability to take oral medication at screening or baseline visit.
2. Evidence at screening or baseline of critical COVID-19 disease (eg, cardiac failure, septic 
shock) or severe pulmonary involvement (eg, bilateral extensive involvement on chest X-ray 
or chest computed tomography, ARDS, immediate need for intubation or mechanical 
ventilation, anticipated need for intubation in the next 48 hours) per the judgment of the 
investigator.  
3. Positive pregnancy test at screening for women of childbearing potential.
4. Lactating female at baseline for women of childbearing potential.
a. 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. îXSSHUOLPLWRIQRUPDO8/1IRUDODQLQHor aspartate aminotransferases or total bilirubin 
!î8/1DWVFUHHQLQJRUNQRZQKLVWRU\RI&KLOG-Pugh Class C, hepatitis B or C, or HIV 
infection.
6. Glomerular filtration rate <30 mL/min/1.73 m2 at screening.
7. QTcF >450 msec for male or >470 msec for females or evidence of cardiac dysrhythmia at 
screening.
8. 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.
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9. 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.
10. 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.
11. Recent (within 30 days) or current participation in other COVID-19 therapeutic trials or 
expanded access programs.
12. Prior or current participation in COVID-19 vaccine trials.
Sample size justification
The primary efficacy endpoint of this study is the proportion of subjects who progress to death or 
respiratory failure by the end of study (Day 28). It is estimatHGWKDWDSSUR[LPDWHO\RIHQUROOHG
subjects receiving SOC plus placebo will attain this endpoint. It is assumed that losmapimod will 
LPSURYHWKHSULPDU\HQGSRLQWE\RYHUSODFHER2QWKHEDVLVRIWKese assumptions, a total of 
410 subjects randomized to the losmapimod arm or the placebo arm in a 1:1 ratio (205 subjects in 
the losmapimod arm and 205 VXEMHFWVLQWKHSODFHERDUPZLOO\LHOGDSSUR[LPDWHO\SRZHULQD
1-VLGHGWHVWDWWKHVLJQLILFDQce level. The sample size estimate assumes an interim analysis 
(IA) will be conducted after approximately 206 subjects (103 in each of the losmapimod and placebo 
arms) have completed the Day 28 visit, to assess futility.  
Statistical methodology
A statistical analysis plan (SAP) will be generated and approved prior to database snapshot for the 
IA. The SAP will detail the implementation of all planned statistical analysis. Any deviations from the 
planned analysis will be described and justified in the final clinical study report.
In general, all study endpoints will be summarized using descriptive statistics. Descriptive statistics 
for continuous data will include number of subjects (n), mean, standard deviation, median, 
minimum, and maximum. Descriptive statistics for categorical data will include frequency and
percentage. 
:KHUHDSSURSULDWHGHVFULSWLYHVWDWLVWLFVPD\EHSUHVHQWHGZLWK confidence intervals.
Analysis sets
Full Analysis Set (FAS): The FAS will consist of all subjects who are randomly assigned to receive 
double-blind study drug. All analyses using the FAS will group subjects according to randomized 
treatment. The primary endpoint, clinical outcomes/status, survival, and pharmacodynamic 
endpoints will be analyzed using the FAS.
Per Protocol Set (PPS): The PPS will consist of all FAS subjects who fulfill all inclusion/exclusion 
criteria and do not have any significant protocol deviations. All analyses using the PPS will group 
subjects according to randomized treatment.
Safety Analysis Set: The safety analysis set is defined as all subjects who are randomized and 
receive study drug. All analyses using the Safety Analysis Set will group subjects according to 
treatment actually received. The safety analysis set will be used for all safety and tolerability 
analyses.
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Primary endpoint
For the final analysis, the proportion of subjects achieving the primary endpoint in the treatment 
arms will be compared using an adjusted risk difference obtained from a regression model, adjusted 
for stratification factors, sex, and baseline CRP. Full details of the regression model will be provided 
in the SAP. An interim analysis to assess futility analysis—and potential sample size re estimation—
will be conducted. All results will be summarized descriptively by treatment arm and expressed as 
proportions, alonJZLWKFRUUHVSRQGLQJXQDGMXVWHGDGMXVWHG&,RIWKHGLIIHUHQFHEHWZHHQ
response rates, and p values.
Secondary endpoints
Clinical status at Day 7 and Day 14:  
Change in clinical status between baseline and post-baseline will be modelled using regression
models appropriate for ordinal data, adjusting for stratification factors, sex, and baseline CRP.
Details will be provided in the SAP.
Percentages for each category of the ranking scale will be tabulated by treatment arm, along with 
differences between treatment arms at each time point. The proportion of subjects for each of the 
items in the scale will be compared using an adjusted risk difference obtained from a regression 
model, adjusting for stratification factors, sex, and baseline CRP. Full details of the regression 
model will be provided in the SAP.
Total number of study days by Day 28: (a) free of oxygen supplementation; (b) in ICU; (c) of 
hospitalization; (d) free of respiratory failure; (e) alive: For each endpoint (a) - (e), a Poisson 
regression model or a negative binomial model will be used to assess the relationship with 
treatment, adjusting for stratification factors, sex, baseline CRP and number of days on study (as 
applicable). Details of the model, including censoring rules, if any, will be provided in the SAP.
Percentage of subjects discharged from the hospital by Day 28: percentages of subjects discharged 
from the hospital will be tabulated by treatment arm, along with differences between treatment arms. 
The proportion of subjects will be compared using an adjusted risk difference obtained from a 
regression model, adjusting for stratification factors, sex, and baseline CRP. Full details of the 
regression model will be provided in the SAP. 
All-cause mortality at Day 28: percentages of subjects will be tabulated by treatment arm, along with 
differences between treatment arms, at each time point. The proportion of subjects will be compared 
using an adjusted risk difference obtained from a regression model, adjusting for stratification 
factors, sex, and baseline CRP. Full details of the regression model will be provided in the SAP. 
Incidence of AEs/SAEs: will be summarized by system organ class and preferred term and by 
treatment arm using percentages.
Incidence of clinically significant changes: Percentage of subjects with clinically significant changes 
in laboratory parameters, ECG, and vital sign measurements will be computed for each treatment 
arm along with associated 2-VLGHG&ORSSHU-Pearson CI. 
Clearance of quantifiable viral RNA by Day 7: percentages of subjects with clearance of quantifiable 
viral RNA will be tabulated by treatment arm, along with differences between treatment arms, at 
each time point. The proportion of subjects will be compared using an adjusted risk difference 
obtained from a regression model, adjusting for stratification factors, sex, and baseline CRP. Full 
details of the regression model will be provided in the SAP.
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Table 1: Visit and Assessment Schedule
SCR
Treatment Period
FU14
ET
Time point
Assessment1
-3d to 
-1d 
D1
(base-
line)
D2
D3
D4
D5
D6
D7
D8
D10
D12
D14
D21 
(± 
3d)
D28 
(± 
3d)
Informed consent
X
Demography
X
Inclusion and exclusion criteria
X
X
Medical history 
X
COVID-19 history and clinical 
diagnosis2
X 
Chest X-ray/CT scan
X3
X3
Study drug administration:
Randomization
X
Losmapimod or placebo PO BID
X
X
X
X
X
X
X
X
X
X
X
Pharmacodynamics:
Drug levels/PK4
P, 4-5h
4-5h
4-5h
4-5h
4-
5h
4-
5h
4-
5h
4-
5h
X 
Clinical status and symptoms:
Respiratory failure and survival 
assessment6
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical status assessment per WHO 
9-point scale6
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Viral presence and viral load by 
central testing 7
X
X
(sentinel 
only)7
X
(sentinel 
only)7
X
(sentinel 
only)7
X 
X 
Confirmation of COVID-19 diagnosis
by PCR
X2
X (PR)2
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SCR
Treatment Period
FU14
ET
Time point
Assessment1
-3d to 
-1d 
D1
(base-
line)
D2
D3
D4
D5
D6
D7
D8
D10
D12
D14
D21 
(± 
3d)
D28 
(± 
3d)
Oxygenation and FiO28
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety assessments: 
Physical examination
X
X
Weight/height9
X
X
X
Hematology, chemistry safety labs6
X
X
X
X
X
X
X
X
X
CRP6
X
Urinalysis10
X
X
8ULQHRUVHUXPȕ-hCG (female 
subjects only)
X11 
X 
X 
ECG12
X
X
HR, BP, RR, temperature8
X
X
X
X
X
X
X
X
X
X
X
X
X
(S)AEs13
X
X
Concomitant medications (including 
SOC)
X 
X 
AE = adverse event; BP = blood pressure; COVID-19 = novel coronavirus; HR = heart rate; P = pre dose; PAO2 = partial pressure of oxygen; PR – pre-randomization; RR = respiratory rate; sent = sentinel; 
SOC = standard of care; SCR = screening.
Note: All screening assessments are to be performed before dosing. If procedures required at any time point have already been performed as part of routine clinical care, these assessments do not need to 
be repeated, and information will be collected and entered on the eCRF from the subject’s medical records. Unscheduled visits can take place at any time at the discretion of the site to check for new 
AEs/SAEs or to repeat key missed assessments or for other reasons.
1 The order of assessments can be performed at the discretion of the investigator once informed consent is obtained.
2 COVID-19 diagnosis to be confirmed by local testing (PCR) before randomization and first dosing. Saliva, swab, or sputum testing may be used based on local standard of care.
3 To be performed while hospitalized based on standard-of-care local assessment. Result required for eligibility assessment to confirm radiographic evidence of COVID-19. If
radiography is not considered local standard of care for COVID-19 diagnosis, evidence of pulmonary involvement consistent with COVID-19 may also be obtained from clinical 
examination, per the judgment of the investigator. Evidence of pulmonary involvement obtained by clinical examination should be documented in the eCRF.
4 PK assessments will be performed as a substudy in all sentinel subjects. For those subjects requiring dialysis, a single pre- and post-dialysis PK should be obtained for review by the 
DMC to decide if dose adjustment is needed. PK should be measured weekly for 2 weeks at Cmax (4-5 hours post dose) for subjects with renal insufficiency when possible.
 
. 
6 Assessments for clinical/respiratory status, progression, and safety serum chemistry and hematology tests to be performed and samples to be collected while hospitalized based on 
standard-of-care local laboratory assessments and after discharge from the hospital by home visit or outpatient clinic visit or telemedicine call. For subjects who are discharged to 
home or other outpatient setting after initial hospitalization, the assessments and laboratory samples can be obtained less often but not less than at least once weekly. CRP result 
required to determine eligibility are based on local laboratory results at screening.
7 Viral load testing will be collected daily for the first 4 days using central testing in the first 10 enrolled subjects as part of the sentinel safety assessment at select sites. For all 
subjects, including the sentinel subjects, swabs, saliva, or other sample collection (as specified in the Study Manual) for central viral load testing will be collected on D1 pretreatment 
and on D7 or earlier if being discharged from the hospital prior to D7. 
8 Vital signs will be performed after subjects have been supine for at least 5 minutes when possible. Vital signs to include oxygen saturation; PaO2 should be recorded if available from 
blood gases obtained as part of SOC; oxygen administration should also be recorded (eg, room air or oxygen flow by nasal canula or facial mask or endotracheal tube). For subjects 
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who are discharged to home or other outpatient setting after initial hospitalization, assessments may be obtained less often but at least once per week in the outpatient clinic or at
home.
9 Height assessed at screening only; can be by self-report or from medical records. Weight is an actual recording.
10 Urinalysis will be performed during the study period only on Day 7 and on any other day only if clinically indicated.
11 Pregnancy testing to be conducted within 72 hours of the first dose of study treatment.
12 Standard 12-lead ECGs will be performed after the subject has been supine for at least 5 minutes if possible. ECGs will be performed at Day 7 in all subjects and at any other time 
during the study if clinically indicated.
13 Adverse events and SAEs will be assessed from the time the subject signs the ICF through the D28 follow-up visit.
14 Outpatient assessments to be conducted via telemedicine or outpatient clinic. Outpatient laboratory assessments to be completed at outside local laboratory or home or outpatient 
visit.
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1 
BACKGROUND AND RATIONALE
1.1
Scientific rationale for investigation of losmapimod in COVID-19
COVID-19 is a severe pandemic disease with high mortality particularly in older individuals, due to 
infection with the SARS-CoV-2 coronavirus. 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 older population is especially at risk of severe disease 
and death upon infection with SARS-CoV-2. The hyperactivated immune response in COVID-19 
shares features of the cytokine storm syndrome and appears to be responsible for the severe 
pulmonary edema, ARDS, and cardiac and renal disease responsible for most of the severe 
morbidity and mortality. 
The prRSRVDOWRGHYHORSORVPDSLPRGDSRWHQWVSHFLILFDQGELRDYDLODEOHSĮȕLQKLELWRUIRU
treatment of COVID-19 is based on the following rationale: 
(1) Nonclinical work has shown that older mice infected with SARS-CoV-1 develop much 
more severe disease than younger ones, and that treatment with a p38 MAPK small 
molecule inhibitor greatly reduced their mortality when given after viral inoculation; 
similar survival benefit of p38 MAPK inhibition has been seen in animal models of severe 
H5N1 influenza and HSV-1. 
(2) Nonclinical work has shown that p38 MAPK inhibition reduces viral load in several 
experimental models with coronaviruses, including mouse hepatitis virus, human 
CoV-229E, transmissible gastroenteritis virus, and Middle East respiratory syndrome 
virus.  
(3) p38 MAPK is proposed to play a critical role in the development of ARDS, including 
regulating the expression and activity of inflammatory mediators such as ICAM-1, 
HMGB1, and ET-1, neutrophil chemotaxis and apoptosis, the balance of Treg/Th17 cells, 
and pulmonary endothelial cell apoptosis. 
(4) Clinical investigation showing that excessive acute inflammation in response to external 
stressors in older individuals, including viral antigen challenges, hinders the specific 
immune response to infection; many of the excessive inflammatory mediators associated 
with this aberrant immune response in older individuals are associated with activation of 
the p38 MAPK pathway. 
(5) Treatment with losmapimod in older subjects restored the normal immune response to 
viral antigen challenge and improved the resolution of acute inflammation. 
(6) Treatment of various inflammatory diseases with losmapimod, including active 
rheumatoid arthritis (RA), acute myocardial infarction, and chronic obstructive pulmonary 
disease (COPD) resulted in significant reduction in markers of acute inflammation, 
including interleukin-6 (IL-6), C-reactive protein (CRP), chemokines such as CXCL13, 
and other markers (see Table 5 for further details).
(7) Losmapimod may be beneficial in COVID-19 treatment via reduction of the damaging 
effects of angiotensin II (Ang II). Angiotensin-converting enzyme 2 (ACE2) is the cellular 
receptor for SARS-CoV viruses and is expressed in the lung and the heart. Upon 
infection with SARS-CoV-2, there is internalization of and depletion of ACE2. ACE2 
converts Ang II into angiotensin 1-7 (Ang 1-7), which counterbalances the 
vasoconstrictive and pro-inflammatory effects of Ang II. Ang II is significantly elevated in 
COVID-19, and the levels are positively correlated with viral load and acute lung injury 
(Liu Y et al, 2020). Blocking the p38 MAPK pathway in nonclinical models has been 
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shown to reduce many of the adverse effects of elevated Ang II, resulting in lower 
frequency of cardiac arrhythmias, renal failure, and hypertension.
p38 inhibitors have been explored extensively in clinical trials for numerous chronic inflammatory 
indications, as summarized in the Investigator Brochure. Losmapimod has been extensively tested 
in humans and found to be generally well tolerated, including in over 3600 adult healthy volunteers 
and subjects in 11 different indications. The 15 mg oral (PO) twice per day (BID) dose proposed for 
the COVID-19 Phase 3 study has been shown to provide robust and sustained inhibition of the p38 
MAPK pathway systemically and in tissues, specifically in skeletal muscle needle biopsies of 
subjects with facioscapulohumeral muscular dystrophy (FSHD). This dose of losmapimod was 
shown experimentally in older (median 69 years, range: 65, 77 years) human volunteers to restore 
the normal immune response to viral challenge and improve the resolution of acute inflammation. 
Furthermore, losmapimod has been shown to significantly reduce markers of hyperactive acute 
innate immune inflammation in the context of acute myocardial infection, RA, and COPD in clinical 
trials as listed below: 
1- Single-dose study in 50 subjects with RA (RA 3103730). Treatment with losmapimod (N=38) 
reduced levels of IL-6 compared with placebo (N=12). Losmapimod was dosed as follows: 
7.5 mg: 13 subjects; 20 mg: 12 subjects; 60 mg: 13 subjects. Analysis of serum IL-6 at 
3 hours post dose showed significantly lower levels with losmapimod than with placebo 
(Table 2).
Table 2:
Change from Baseline in IL-6 Serum Levels with Increasing Single Doses of 
Losmapimod in Subjects with Rheumatoid Arthritis
Treatment group
Adjusted ratio to baseline
95% CI
Adjusted ratio to placebo
95% CI
Placebo
0.92
0.60, 1.41
Losmapimod 7.5 mg
0.41
0.26, 0.63
0.45
0.24, 0.82
Losmapimod 20 mg
0.43
0.27, 0.68
0.47
0.25, 0.88
Losmapimod 60 mg
0.38
0.25, 0.57
0.41
0.23, 0.75
Abbreviations: CI = confidence interval.
2- Repeated-dose study in subjects with acute coronary syndrome (ACS; PM1111810). A total 
of 535 subjects with non-ST elevation myocardial infarction were randomized to an initial 
dose of 7.5 or 15 mg of losmapimod followed by 7.5 mg PO BID (N= 388) or matching
placebo (N=138) for 12 weeks. Results showed that relative to placebo, losmapimod 
significantly suppressed CRP and IL-6 acutely at the 24- to 36-hour assessments (Table 3).
Table 3: 
Change from Baseline in hsCRP and IL-6 with 7.5mg PO BID Losmapimod Over 
Placebo in Subjects with Acute Coronary Syndrome
Parameter
Placebo (N=138)
All losmapimod 
(N=388)
P value
hsCRP at 72 hours or 
discharge (nmol/L)
110.8 (83.1-147.7)
64.1 (53.0-77.6)
<0.05
IL-6 at 24 hours (ng/L)
10.6 (8.6-13.1)
6.6 (5.8-7.4)
<0.05
Abbreviations: hsCRP = high-sensitivity C-reactive protein; IL-6 = interleukin-6.
3- Repeated-dose study in subjects with COPD (MKI113006). In this study, subjects with 
COPD were dosed with losmapimod 2.5 mg BID (N=149), losmapimod 7.5 mg BID (N=151), 
or placebo BID (N=154) for 24 weeks; or losmapimod 7.5 mg BID for 4 weeks followed by 
losmapimod 15 mg BID (N=150) for 20 weeks. Over the first 12 weeks of treatment, 
statistically significant reductions in serum high-sensitivity CRP (hsCRP) levels were 
observed in the losmapimod 7.5 mg and 15 mg groups compared with placebo. For hsCRP, 
Week 1PJGRVHYHUVXVSODFHERUDWLRFRQILGHQFHLQWHUYDO>&,@
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S PJGRVHYHUVXVSODFHERUDWLR&,STable 4 shows 
the results for the subgroup with higher CRP at baseline.
Table 4: 
Change from Baseline in CRP Over 12 Weeks of Treatment with Different 
Doses of Losmapimod Compared with Placebo in Subjects with COPD and 
High Baseline CRP Levels (>6.4 mg/L)
Week 12 
Baseline hsCRP 
>6.40 mg/L
Placebo BID 
(N=42)
Losmapimod 
2.5 mg BID (N=33)
Losmapimod 
7.5 mg BID (N=31)
Losmapimod 
15 mg BID (N=31)
Geometric LS 
mean (SE of logs)
6.75 (0.153)
8.08 (0.180)
5.16 (0.180)
3.54 (0.186)
Geometric LS 
mean ratio to 
baseline (SE of 
logs)
0.49 (0.153)
0.59 (0.180)
0.38 (0.180)
0.26 (0.186)
Column vs placebo
Ratio
1.20
0.77
0.53
&,
0.75, 1.92
0.48, 1.22
0.33, 0.85
Abbreviations: CI = confidence interval; hsCRP = high-sensitivity C-reactive protein; LS = least square; SE = standard 
error. 
Fulcrum Therapeutics is planning to conduct the initial clinical trial for the investigation of 
losmapimod for the treatment of COVID-19 in these high-risk subjects. Losmapimod is currently in 
Phase 2 clinical development for the treatment of the root cause of FSHD under an open IND in the 
United States (US) and open clinical trial applications in Canada, Spain, France, and The 
Netherlands. 
A summary of published literature supporting the therapeutic hypothesis for the clinical development 
of losmapimod for the treatment of COVID-19 is provided in Table 5.
Table 5: 
Listing of Evidence Supporting the Development of the p38 Inhibitor 
Losmapimod for Treatment of COVID-19
Evidence
References
Pneumonitis, acute respiratory distress syndrome, 
pulmonary edema, and cardiomyopathy drive COVID-19
mortality
x
Siddiqi HK et al. J Heart Lung 
Transplant. 2020
x
Ruan Q et al. Intensive Care 
Med. 2020 Mar 3
Older patients are at greatest risk of COVID-19 mortality
x
Ruan Q et al. Intensive Care 
Med. 2020 Mar 3
Human SARS-CoV-2 pathology is recapitulated in SARS-
CoV-1 mice
x
Zhou F et al. Lancet. 2020
x
Nagata N et al. Am J Pathol. 
2008
Exaggerated acute inflammatory response and lymphopenia 
correlate with mortality in human with COVID-19 and older 
mice infected with SARS-CoV-1
x
Nagata N et al. Am J Pathol. 
2008
x
Zhou F et al. Lancet. 2020
SARS-CoV-1 activates the p38 MAPK pathway in peripheral 
blood early in the infection
x
Lee CH et al. J Immunol. 2004.
SARS-CoV envelope protein (E) activates the host’s 
inflammatory response via p38 signaling
x
Jimenez-Guardeño JM et al.
PLOS Pathog. 2014
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Evidence
References
Several nonclinical studies have shown evidence of p38 
inhibition reducing viral replication including with coronavirus
x
Kono M et al. Antiviral Res. 
2008
x
Dong Y et al. Antiviral Res. 
2020
x
Kindrachuk D et al. Anti Microb 
Agents & Chem. 2015
p38 inhibition reduces mortality in older mice infected with 
SARS-CoV-1
x
Jimenez-Guardeño J et al. 
PLOS Pathog. 2014
Nonclinical efficacy of p38 inhibition also observed in other 
models of severe acute viral pneumonitis and other severe 
acute viral infections
x
Shapiro L et al. PNAS. 1998
x
Iordanov MS et al. Mol Cell 
Bio. 2000
x
Salomon R et al. PNAS. 2007
x
Griego SD et al. J Immunol. 
2000
x
Banerjee S et al. J Virology. 
2002
x
Börgeling Y et al. J Biol Chem. 
2014
x
Chen Y et al. J Exp Med. 2017
x
He F et al. J Transl Med. 2019
p38 inhibition reduces lung mucous production in mice 
models of toxic airway injury 
x
Liu et al. Int 
Immunopharmacol. 2009
Losmapimod and other p38 inhibitors acutely reduce 
inflammatory markers in humans
x
GSK data in Fulcrum Original 
IND 138739, Module 4
x
Genovese M et al. J
Rheumatol. 2011
x
Christie J et al. Crit Care Med. 
2015
Losmapimod reduces inflammatory markers associated with 
COVID-19 severity at currently utilized doses
x
Fulcrum clinical data on file
x
GSK clinical data 
x
Newby L et al. Lancet. 2014
Inhibition of p38 with 15 mg losmapimod BID dose in older 
subjects restored the adaptive immune response to viral 
challenge
x
Vukmanovic-Stejic M et al. J
Allergy Clin Immunol. 2018
Exaggerated acute inflammatory response in older subjects 
is driven to a large extent by p38 activation
x
Vukmanovic-Stejic M et al. J 
Allergy Clin Immunol. 2018
In vivo data in Ferrets indicate SARS-Cov-2 induces 
profoundly lower immune response vs other virus
x
Blanco-Melo D et al. bioRxiv. 
2020
Evidence that p38 inhibition may treat the deleterious effects 
of elevated Ang II in COVID-19
x
Grimes JM et al. J Mol Cell 
Cardiol. 2020
Losmapimod is a highly selective p38 inhibitor at advanced 
stage of clinical development with excellent safety data 
profile
x
Losmapimod Investigator 
Brochure Fulcrum 2020
x
Cadavid D et al. FSHD IRC 
Poster. 2019
Abbreviations: BID = twice daily; COVID-19 = disease caused by novel coronavirus; IND = investigational new drug 
application; SARS-CoV-1 = severe acute respiratory syndrome coronavirus 1; SARS-CoV-2 = severe acute respiratory 
syndrome coronavirus 2. 
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1.2
Benefit-risk considerations
This is the first-in-human clinical trial with losmapimod for the treatment of a novel virus (COVID-19)
and, therefore, the risk-benefit considerations are based on nonclinical data in conditions related to 
COVID-19 (e.g., SARS-CoV-1) as well as extensive clinical data in other inflammatory conditions
and conditions involving the p38 MAPK pathway (e.g., FSHD, RA, COPD) including in older healthy 
volunteers; refer to Section 1.1 for further details.
Losmapimod has been found to be generally well tolerated in clinical trials, including in over 3600 
adult healthy volunteers and subjects in 11 different indications. The 15 mg PO BID dose proposed 
for this study has been shown to provide robust and sustained inhibition of the p38 MAPK pathway 
systemically and in tissues, specifically in skeletal muscle needle biopsies of subjects with FSHD.  
Complete clinical safety data and nonclinical data for losmapimod can be found in the Investigator’s 
Brochure. Additional adverse events not previously observed in animals or in humans may also 
occur in this trial. Subjects in this clinical trial will be monitored closely for the development of 
adverse effects that may result from study drug administration. In addition, a Data Monitoring 
Committee (DMC) will monitor the safety of subjects throughout the study on an ongoing basis.
COVID-19 is a severe and rapidly progressive infection, especially in the high-risk population (ie, 
older, with comorbidities) selected for this trial. Given the extensive clinical experience with 
losmapimod, the potential benefit of losmapimod treatment in this indication outweighs the risks. 
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2 
STUDY OBJECTIVES AND ENDPOINTS
All study objectives will be evaluated in subjects diagnosed with COVID-19.
Objectives
Endpoints
Primary
To assess the efficacy of losmapimod compared 
with placebo for treatment of COVID-19 when 
administered concurrently with standard of care
Proportion of progressors to death or 
respiratory failure by Day 28
Secondary
To evaluate the effect of losmapimod compared 
with placebo on clinical outcomes
Clinical status by Days 7 and 14 as 
measured on the 9-point WHO ordinal scale 
(WHO 2020):
x
(8) death
x
(7) ventilation plus additional organ 
support (vasopressors, renal 
replacement therapy, ECMO)
x
(6) Intubation and mechanical 
ventilation
x
(5) noninvasive ventilation or high-flow 
oxygen therapy
x
(4) oxygen therapy but not requiring 
high-flow or non-invasive ventilation
x
(3) hospitalized but not requiring oxygen 
therapy
x
(2) Discharged from the hospital but 
with limitation of activities
x
(1) Discharged from the hospital and 
without any limitation
x
(0) No clinical evidence of the disease
To assess the effect on clinical status of treatment 
with losmapimod compared with placebo
Total number of study days free of oxygen 
supplementation by Day 28
Total number of study days in ICU by 
Day 28
Total number of study days hospitalized by 
Day 28
Total number of respiratory failure-free 
study days by Day 28
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Objectives
Endpoints
Percentage of subjects discharged from the 
hospital by Day 28
To assess the effect on survival following treatment 
with losmapimod compared with placebo
All-cause mortality at Day 28
Number of study days alive by Day 28
To assess the safety and tolerability of losmapimod 
compared with placebo
Incidence of AEs and SAEs
Incidence of clinically significant changes in 
laboratory parameters and vital sign 
measurements
To characterize changes in SARS-CoV-2 infection 
following treatment with losmapimod compared 
with placebo
Quantifiable viral RNA on Day 7
Abbreviations: AE = adverse event; 
; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; COVID-19 = disease caused by novel coronavirus; CRP = C-reactive protein; ECG = 
electrocardiogram; ECMO = extracorporeal membrane oxygenation; 
; ICU = intensive care 
unit; IL-6 = interleukin-6; 
; PD = pharmacodynamics; RNA = ribonucleic acid; SAE = serious 
adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; WHO = World Health Organization. 
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3 
STUDY IMPLEMENTATION
3.1
Overall study design and plan
This Phase 3 multicenter, randomized, double-blind, placebo-controlled study will evaluate the 
safety and efficacy of losmapimod versus placebo on a background of standard of care in subjects 
with COVID-19 disease. 
7KLVVWXG\ZLOOEHSHUIRUPHGLQKRVSLWDOL]HGVXEMHFWV\HDUVROGZKRKDYHD&-reactive protein 
(CRP) >15 mg/L, who have been diagnosed with COVID-19, and who can undergo randomization 
within 7 days of collection of the sample found positive for the SARS-CoV-2 virus and before 
progressing into critical disease. Critical disease is defined as cardiac failure, septic shock, or 
severe pulmonary involvement (eg, bilateral extensive involvement on chest X-ray or chest 
computed tomography, ARDS, immediate need for intubation or mechanical ventilation, anticipated 
need for intubation in the next 48 hours) per the judgment of the investigator.
Subjects who sign informed consent (refer to Section 9.1.3) and meet all entry criteria (see 
Section 4) may be enrolled.
Up to 410 subjects will participate for a maximum of 34 days, divided as follows:
o
Screening: Day -3 until Day -1 before the first study drug administration.
o
Treatment period of 14 days: 
o
Subjects randomized (1:1) to either: 

losmapimod tablets 15 mg PO BID; OR  

matching placebo tablets PO BID
o
5DQGRPL]DWLRQZLOOEHVWUDWLILHGE\DJHRUDQGUHTXLUHPHQWIRUR[\JHQDW
randomization (yes/no)
o
Follow-up: 7 (± 3) days after last dose and 14 (± 3) days after last dose.
The first 10 enrolled subjects (5 placebo and 5 losmapimod) will be dosed and followed for at least 
72 hours after their first dose for an interim “sentinel” safety review before any additional subjects 
are dosed. Dosing of additional subjects will continue if there are no drug-related safety concerns 
from the initial subjects dosed as assessed by an independent DMC. The DMC will review safety 
data for the sentinel subjects and all subjects at regular intervals throughout the study as outlined in 
the charter (see Section 8.10). 
The Sponsor will monitor individual adverse events (AEs) and toxicities on an ongoing basis 
throughout the study.
See Table 1 for the time points of the assessments.
All study visits during the first week of treatment are anticipated to be conducted in the inpatient 
setting. If the clinical status of the subject improves such that the clinician discharges the subject 
from the hospital before the end of the study, the follow-up assessments will be conducted on an 
outpatient basis by alternative methods, including the use of local laboratories/facilities or home 
visits for blood draws, telemedicine, and/or outpatient follow-up clinic visits as deemed clinically 
appropriate per COVID-19 follow-up standard of care (SOC) at each site (refer to Section 6.7).
3.2
Start of study and end of study definitions
The start of the study is defined as the date the first enrolled subject signs an informed consent form 
(ICF). The end of the study is defined as the date of the last subject’s last assessment (scheduled or 
unscheduled).
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3.3
Selection of doses in the study
In the Phase 1 study in healthy volunteers and FSHD subjects (Study FIS-001-2018), the dose 
levels of 7.5 mg and 15 mg given by mouth BID with food were based on predictive nonclinical 
efficacy and published clinical target engagement and safety data for losmapimod previously 
generated by GSK. This Phase 1 study was recently completed and demonstrated that the 15 mg 
PO BID dose gives higher plasma levels and greater and more sustained target engagement in 
blood and tissues than the 7.5 mg PO BID dose, while resulting in similar safety and tolerability. The 
15 mg BID dose is used in the ongoing Phase 2 studies in FSHD (Study FIS-001-2019 and Study 
FIS-002-2019). Prior results indicated the favorable safety and tolerability of losmapimod for chronic 
administration in the clinic, including in the context of severe acute diseases, such as acute 
myocardial infarction, in older people.
Prior studies of biodistribution of radiolabeled losmapimod by GSK showed ample distribution to all 
tissues including the lungs and the heart. Our recent target engagement data in the FSHD Phase 1 
Study FIS-001-2018 indicates that pHSP27 inhibition in blood, an assessment of p38 target 
engagement, is nearing a plateau at a losmapimod dose of 15 mg BID (see Investigator Brochure 
[Fulcrum Therapeutics 2020]), so doses of losmapimod higher than 15 mg PO BID are not 
warranted.
Additionally, at the proposed dose level of 15 mg PO BID, exposures are not expected to exceed 
those previously demonstrated to be safe in humans in multiple previous studies by GSK in healthy 
volunteers and various patient populations including older subjects (Cheriyan et al 2011; Barbour et 
al 2013; Watz et al 2014; Pascoe et al 2017).
In previous clinical studies performed by GSK, it was shown that losmapimod significantly reduced 
markers of acute inflammation, including IL-6, CRP, and the CXCL13 chemokine after a single 
dose. Additionally, losmapimod reduced IL-6 after 15 days of treatment (GSK study RA3103718) 
and CRP acutely in subjects with acute myocardial infarction treated with 7.5 mg PO BID 
(O’Donoghue et al 2016). In subjects with COPD, losmapimod at 15 mg PO BID significantly 
reduced CRP over 12 weeks compared with placebo (GSK Study MKI 113006). In one study in 
healthy older adult volunteers, it was shown that a 15 mg PO BID dose of losmapimod for 4 days 
restored the normal immune response to varicella-zoster virus antigen challenge (Vukmanovic-
Stejic et al 2018). The same formulation used in these previous clinical studies is the one proposed 
for use in the present clinical study.
The rationale for the proposed study duration of up to 28 days is that in most cases of COVID-19
the disease has resolved or resulted in severe outcomes over the first month from onset of 
symptoms. COVID-19 is a severe and rapidly progressive infection, especially in the high-risk 
population selected for the proposed Phase 3 trial. Therefore, treatment for longer than 14 days and 
study duration for longer than 28 days is not justified.
3.4
Study drug modifications and withdrawal
3.4.1
Dose modifications
Before trial medication is administered, changes in the subject's health status, including laboratory 
results if applicable, since the previous visit or previous dose should be checked. 
Study drug interruptions and reductions are not permitted; subjects who are on dialysis may require 
a dose adjustment.
Study treatment dose adjustment for subjects on dialysis 
The elimination of losmapimod is almosWH[FOXVLYHO\E\PHWDEROLVPZLWKRQO\RIWKH
administered dose recovered as unchanged drug in urine and feces. The metabolite is clinically 
inactive and does not exert any toxic effects.
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Losmapimod has not been studied in renal insufficiency or renal failure. There has been 1 study of 
losmapimod in 17 subjects with focal segmental glomerulosclerosis (FSGS; FSG117283). In this 
study, subjects were given losmapimod 7.5 mg BID for 2 weeks followed by losmapimod 15 mg BID 
for 22 weeks. The mean duration of exposure to investigational product in subjects with FSGS was 
approximately 21 weeks (range: 3.7, 25 weeks). 
Creatine and GFR for the population enrolled is in the table below. 
Parameter
Mean (SD)
Range
eGFR (mL/min/1.73m2) 
79.4 (34.9)
36, 155
Creatine (μmol/L)
1.1 (0.5)
0.48, 2.07
eGFR = estimated glomerular filtration rate.
Losmapimod plasma concentration data in subjects with FSGS were compared with historical data 
obtained in the Phase 3 clinical trial in subjects with ACS. In general, exposure in subjects with 
FSGS was similar to subjects with ACS over the 24-week treatment period.
Consistent with the safety database of over 3500 subjects, the 2 most frequently reported AEs in the 
)6*6WULDOZHUHKHDGDFKHDQGIDWLJXH6HYHQ AEs (by preferred term: 
vomiting, dizziness, oropharyngeal pain, nausea, blood creatinine increased, muscle spasms, and 
UDVKZHUHUHSRUWHGLQVXEMHFWVHDFK$OORWKHU$(VE\SUHIHUUHGWHUPZHUHUHSRUWHGLQ
 subjects each. Four subjects had at least 1 AE that led to withdrawal from the study or from 
treatment. The AEs that led to discontinuation were increase in blood urea nitrogen (related), 
increase in creatinine (not related), increase in cystatin C (related), and joint stiffness (related). 
None of the AEs was serious or severe; 3 of the AEs in 2 subjects were reported as related to study 
treatment.
Based on the current safety and exposure information, dosing adjustment is likely not needed for 
subjects with renal insufficiency. However, close monitoring of pharmacokinetics (PK) for such 
cases will be implemented to ensure that therapeutic concentrations are maintained (refer to 
Section 6.2). For those subjects requiring dialysis, dose adjustment may be needed and will be 
determined by pre- and post-dialysis PK by the DMC. Adjustments may be recommended by the 
DMC also for subjects on placebo who develop acute renal failure to prevent unblinding at the sites.
Study treatment discontinuation
Discontinuation of study treatment should be considered if: 
• 
ALT or AST >8 x the upper limit of normal (ULN) 
• 
ALT or AST >5 x ULN for more than 2 weeks 
• 
ALT or AST >3 x ULN and (total bilirubin >2 x ULN or international normalized ratio >1.5) in 
the absence of reasonable alternative etiology
• 
ALT or AST >3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
TXDGUDQWSDLQRUWHQGHUQHVVIHYHUUDVKDQGRUHRVLQRSKLOLD!
• 
QTcF prolongation with QTcF >500 msec or an increase in QTcF of >60 msec over baseline 
(confirmed by 2 successive repeat measurements)
In addition, the investigator must permanently discontinue the study drug if continued administration 
of the study drug is believed to be contrary to the best interests of the subject. The premature 
discontinuation of study drug might be triggered by an adverse event (AE), a diagnostic or 
therapeutic procedure, an abnormal assessment (eg, ECG or laboratory abnormalities), pregnancy, 
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or for administrative reasons, in particular noncompliance with the protocol or withdrawal of the 
subject’s consent. The reason for study drug interruption or premature discontinuation must be 
clearly documented in the eCRF. 
3.4.2
Subject withdrawal
Subjects may withdraw from the study at any time and for any reason without prejudice to their 
future medical care by the investigator or at the study site. In all cases of impending consent 
withdrawal, investigators will be given instructions to meet and discuss with the participant their 
options of continuing in the study. The investigator should ensure understanding and documentation 
of the reasons for the participant’s desire to withdraw consent. Every effort should be made to keep 
subjects in the study, including if a subject and/or their treating physician decides to prematurely 
discontinue study treatment. Unless the participant provides their written withdrawal of consent or 
there is other written documentation by the investigator confirming the participant’s verbal intent to 
completely withdraw from the trial, participants should be followed for all protocol-specified 
evaluations and assessments. The reasons for subjects not completing the study will be recorded. 
A subject may be withdrawn from the study if he or she is lost to follow-up. For subjects to be 
considered as lost to follow-up, 2 attempts should be made to contact the subject to return for the 
scheduled study visit. After 2 attempts, a certified letter should be sent to the subject’s address 
requesting the subject to contact the investigator to schedule a follow-up assessment. If no reply is 
provided by the subject within 30 days of receipt of the certified letter, the subject can then be 
considered lost to follow-up.
3.4.3
Replacement policy
Subjects who withdraw from the study will not be replaced.
3.4.4
Stopping criteria
Dosing will be stopped in case of an unacceptable tolerability profile based on the nature, 
frequency, and intensity of observed AEs judged jointly by the investigator and the sponsor or as 
recommended by the DMC.
In the event of a study hold due to unacceptable tolerability, the sponsor will conduct an extensive 
safety and PK analysis and will communicate to stakeholders, including the Investigators, 
institutional review boards (IRBs)/independent ethics committees (IEC), and health authorities any 
potentially emergent safety information as well as the timing of planned resumption of dosing. 
Dosing and enrollment will not resume unless it is considered safe to do so after consultation with 
Investigators and health authorities and approval by IRBs/IECs.
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4 
STUDY POPULATION
4.1
Inclusion criteria
Eligible subjects must meet all of the following inclusion criteria at screening.
1. Able and willing to provide written informed consent.
a. Note: Subject’s legally authorized representative may provide informed consent as 
applicable based on local guidelines and regulations (see Section 9.1.3). If consent is 
obtained from a legally authorized representative, then assent should be obtained 
from the subject.
2. Willing and able to comply with all study procedures.
3. $JH\HDUVDWWLPHRIVFUHHQLQJ
4. Confirmed infection with SARS-CoV-2 virus at or before the baseline visit (by polymerase 
chain reaction [PCR] testing).
a. Note: Refer to the Study Manual for details on PCR SARS-Cov-2 testing procedures.
5. 7 days to the time of randomization from the time of collection of the specimen that tested 
positive for the SARS-CoV-2 virus.
6. Hospitalization at the time of the baseline visit.
7. R[\JHQVDWXUDWLRQRQURRPDLUDQGRUR[\JHQVDWXUDWLRQRQR[\JHQ
administration at 2 L/min by nasal canula at the baseline visit.
8. Radiographic (X-ray or computed tomography scan, per local standard of care) evidence of 
pulmonary involvement consistent with COVID-19 at screening or baseline, per the judgment 
of the investigator.
a. Note: If radiography is not considered local standard of care for COVID-19 diagnosis, 
evidence of pulmonary involvement consistent with COVID-19 may also be obtained 
from clinical examination, per the judgment of the investigator. Evidence of 
pulmonary involvement obtained by clinical examination should be documented in 
the eCRF.
9. Clinical syndrome consistent with COVID-19 at screening, per the judgment of the 
investigator (CDC 2020).
10. CRP at screening >15 mg/L (ie, >1.5 mg/dL) on local laboratory testing.
11. Agrees to practice an approved method of birth control as follows (as applicable to local 
[country] guidelines and regulations for sites outside the US): 
a. Females of childbearing potential: Using 1 of the following acceptable methods of 
contraception: surgical sterilization (eg, bilateral tubal ligation), intrauterine 
contraception/device, hormonal contraception, or any 2 barrier methods (a 
combination of male or female condom with diaphragm, sponge, or cervical cap). 
This criterion must be followed from the time of the first dose of study medication until 
90 days after last dose
b. Males: Effective male contraception includes a vasectomy with negative semen 
analysis at follow-up, or the use of condoms. This criterion must be followed from the 
time of the first dose of study medication until 90 days after last dose.
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Note: Abstinence can be considered an acceptable method of contraception at the 
discretion of the investigator. Periodic abstinence (eg, calendar, ovulation, 
symptothermal, post ovulation methods) and withdrawal are not considered 
acceptable methods of contraception.
4.2
Exclusion criteria
1. Inability to take oral medication at screening or baseline visit.
2. Evidence at screening or baseline of critical COVID-19 disease (eg, cardiac failure, septic 
shock) or severe pulmonary involvement (eg, bilateral extensive involvement on chest X-ray 
or chest computed tomography, ARDS, immediate need for intubation or mechanical 
ventilation, anticipated need for intubation in the next 48 hours) per the judgment of the 
investigator. 
3. Positive pregnancy test at screening for women of childbearing potential.
4. Lactating female at baseline for women of childbearing potential.
a. 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. îXSSHUOLPLWRIQRUPDO8/1IRUDODQLQHRUDVSDUWDWHDPLQRWUDQVIHUDVHVRUWRWDOELOLUXELQ
!î8/1DWVFUHHQLQJRUNQRZQKLVWRU\RI&KLOG-Pugh Class C, hepatitis B or C, or HIV 
infection.
6. Glomerular filtration rate <30 mL/min/1.73 m2 at screening.
7. QTcF >450 msec for male or >470 msec for females or evidence of cardiac dysrhythmia at 
screening.
8. 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.
9. 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.
10. 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.
11. Recent (within 30 days) or current participation in other COVID-19 therapeutic trials or 
expanded access programs.
12. Prior or current participation in COVID-19 vaccine trials.
4.3
Concomitant medications
All medications (prescription and over-the-counter) taken at the time of study screening will be 
recorded, with indication, route of administration, daily dose, and start and stop dates of 
administration. All subjects will be questioned about concomitant treatment at each clinic visit.
Subjects are allowed to use paracetamol (up to 3 g/day) and/or contraceptives (oral or parenteral), 
and any medications needed for SOC at the local institution. Use of hydroxychloroquine/ 
chloroquine is not permitted. Use of other experimental treatments for COVID-19 is not permitted 
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unless it is part of SOC at the local institution. SOC for COVID-19 will be documented at each site 
during the site activation visit; additionally, it will be documented if any restrictions on standard of 
care treatment administration were encountered due to resource limitations. The use of antiviral 
medications is permitted. 
Concomitant medications used to treat chronic comorbid conditions per SOC are permitted, 
including but not limited to metered dose inhalers, corticosteroids if on stable doses for at least 
30 days prior to screening, or sedative or anesthetic agents.
Concomitant medications initiated or stopped for an AE will be recorded.
Both losmapimod and its major metabolite, GSK198602, are in vitro inhibitors of human BCRP. 
There is a low risk of interaction of losmapimod with orally administered BCRP substrates with a 
narrow therapeutic index (eg, methotrexate, topotecan, rosuvastatin). Therefore, such co-
administration is indicated only if the medical benefit is considered to outweigh the risk for toxicity, 
and careful monitoring for adverse effects of these agents is advised.
Losmapimod is a relatively potent in vitro inhibitor of the renal transporters MATE1 and MATE2-K, 
and it is possible that a mild inhibition of tubular secretion may contribute to the small rise in (model-
adjusted geometric mean) serum creatinine observed clinically. GSK198602 is a relatively potent in 
vitro inhibitor of OAT3 and co-administration of sensitive OAT3 substrates is indicated only if the 
medical benefit is considered to outweigh the risk for toxicity. Careful monitoring for adverse effects 
of these agents is advised, especially for those with narrow therapeutic margin (eg, methotrexate, 
metformin). 
4.4
Lifestyle restrictions 
Subjects should not donate blood, sperm, or ova from the screening visit through 90 days after the 
last dose of study treatment.
4.4.1
Contraception requirements
Teratogenicity and effects on embryofetal survival were noted in rat and rabbit reproductive 
toxicology studies with losmapimod. Therefore, losmapimod should not be taken by women of 
childbearing potential who are not utilizing adequate contraceptive methods.
All women of childbearing potential and all males must practice effective contraception during the 
study from the time of the first dose of study medication until 90 days after last dose.
Women of child-bearing potential are defined as all women physiologically capable of becoming 
pregnant, unless they meet one of the following conditions:

Postmenopausal: 12 months of natural (spontaneous) amenorrhea or 6 weeks after surgical 
bilateral oophorectomy/bilateral salpingectomy with or without hysterectomy;

Post hysterectomy.
For the purposes of the study, effective contraception is defined as follows (as applicable to local 
[country] guidelines and regulations for sites outside the US): 
 
Females of childbearing potential: Using 1 or more of the following acceptable methods of 
contraception: surgical sterilization (eg, bilateral tubal ligation), intrauterine 
contraception/device, hormonal contraception, or any 2 barrier methods (a combination of 
male or female condom with diaphragm, sponge, or cervical cap). 
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
Males: Effective male contraception includes a vasectomy with negative semen analysis at 
follow-up, or the use of condoms. 
Abstinence can be considered an acceptable method of contraception at the discretion of the 
investigator. Periodic abstinence (eg, calendar, ovulation, symptothermal, post ovulation methods) 
and withdrawal are not considered acceptable methods of contraception.
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5 
INVESTIGATIONAL MEDICINAL PRODUCT
5.1
Investigational drug and matching placebo
Losmapimod will be provided in tablets of 7.5 mg for oral administration. 
Matching placebo tablets will be provided for oral administration.
The tablets are plain white, round, biconvex, film-coated tablets. The proposed dosing regimen is as 
DWZLFHGDLO\GRVHRIPJîPJWDEOHWV/dose BID). The proposed duration of treatment is for 
up to 14 days.
Subjects should take their dose of losmapimod or placebo with food whenever possible and with 
240 mL of room temperature water. 
5.2
Study drug packaging and labelling
Losmapimod tablets for oral administration are available as white, round, biconvex, plain, 
film-coated tablets containing 7.5 mg of losmapimod as the micronized base, GW856553X.
Losmapimod tablets also contain the inactive excipients microcrystalline cellulose, lactose 
monohydrate, sodium starch glycolate, magnesium stearate, povidone K30, hypromellose, titanium 
dioxide (E171), and polyethylene glycol.
Placebo tablets are identical in appearance to losmapimod and have the same excipient ingredients 
as losmapimod but do not have the active compound.
All tablets are packed in opaque, white, square, high-density polyethylene bottles with induction 
sealed child-resistant closures.
Losmapimod must be stored in a secure area (eg, a locked cabinet), protected from moisture, and 
kept at a controlled room temperature not to exceed 30°C.
5.3
Drug accountability
The investigator is responsible for ensuring that dosing is administered in compliance with the 
protocol. Delegation of this task must be clearly documented and approved by the investigator.
The Investigator (or designee) will maintain an accurate record of the study supplies received. In 
addition, an accurate drug disposition record will be kept, specifying the amount dispensed to each 
subject and the date of dispensing. This drug accountability record will be available for inspection at 
any time. At the completion of the study, the original drug accountability record will be available for 
review by the sponsor upon request.
For each batch of unit doses, the empty used unit dose containers will be discarded upon 
satisfactory completion of the compliance and accountability procedures by the sponsor. Any 
unused assembled unit doses will be retained until completion of the study.
After completion of the study, all unused supplies will be returned to the sponsor or disposed of by 
the study site, per the sponsor’s written instructions.
5.4
Treatment assignment and blinding
5.4.1
Randomization and treatment assignment
A total of up to 410 subjects will be recruited into this study and will be randomized in a 1:1 ratio to 
15 mg losmapimod (BID) or placebo using an interactive/web voice response system (IxRS) for 
randomization. The randomization list will be produced by a qualified randomization vendor and will 
EHVWUDWLILHGE\DJHRUDQGUequirement for oxygen at randomization (yes/no) at 
enrollment.
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Only subjects who have completed screening assessments and are eligible for participation in the 
study will be randomized to receive study drug. Randomized subjects will be sequentially assigned
a unique subject number from the randomization list per the IxRS. From the time of randomization 
and throughout the duration of the study, subjects will be identified by their unique randomization 
number. 
The authorized site personnel will prepare the appropriate study drug for each subject based on the 
randomization schedule. Treatment codes should not be broken except in emergency situations, ie, 
when knowledge of the treatment is essential for the immediate further management of the subject. 
5.4.2
Blinding
This study will be performed in a double-blind fashion. The investigator, study staff, subjects, 
sponsor, and monitor will remain blinded to subject-level treatment assignment until study closure. 
The investigational drug and its matching placebo are indistinguishable and will be packaged in the 
same way.
5.4.3
Treatment compliance
All doses will be administered either in the hospital (anticipated during the first week of study 
treatment) or taken by the study participants on an outpatient basis.
The subject will bring the study treatment bottle to each visit (clinic or home assessment) for review 
by the site staff.
The study treatment bottles will be collected at the Day 14 visit whether in the hospital or outpatient 
or at the ET visit if prior to Day 14.
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6 
STUDY ASSESSMENTS
See Table 1 for the time points of the assessments. 
If additional visits or blood draws are required beyond the planned visits in any part of the
study, these visits or samples should be recorded in the eCRF as unscheduled visits prior to the 
subject’s completion of the study. 
6.1
Medical history and confirmation of COVID diagnosis
A complete medical history will be taken at Screening and is to include demographic information, 
prior medical illnesses and conditions, and surgical procedures for at least 3 months prior to 
screening. The medical history may be collected from medical records, if available, or during the 
physical examination.
The history of SARS-CoV-2 infection and symptoms at screening should be recorded; the details of 
how infection history will be assessed and recorded can be found in the Study Manual. Diagnosis of 
COVID-19 should be confirmed by local PCR testing prior to randomization. Refer to the Study 
Manual for details on procedures and type(s) of diagnostic testing allowed.
A chest X-ray or CT will be performed while the patient is hospitalized based on standard-of-care 
local assessment. The results are required for eligibility assessment to confirm radiographic 
evidence of COVID 19. If radiography is not considered local standard of care for COVID-19
diagnosis, evidence of pulmonary involvement consistent with COVID-19 may also be obtained from 
clinical examination, per the judgment of the investigator. Evidence of pulmonary involvement 
obtained by clinical examination should be documented in the eCRF.
A pre-existing condition is one that is present prior to administration of study drug. Such conditions 
should be recorded as medical history. A pre-existing condition should be recorded as an AE or
serious adverse event (SAE) only if the frequency, intensity, or nature of the condition worsens 
following administration of study drug.
6.2
Pharmacokinetic and pharmacodynamic assessments
Blood samples will be collected as outlined in the Schedule of Assessments (Table 1) to assess PK. 
PK assessments will be performed as a substudy in all sentinel subjects to evaluate the PK of 
losmapimod in the population of subjects with COVID-19. 
Blood samples will be collected as outlined in the Schedule of Assessments (Table 1) to assess 
serum and plasma biomarkers of response to COVID-19, which may include
 
Procedures for collection, processing, and return of blood samples will be detailed in the Study 
Manual. Specifics of the analytical methods will be provided in separate documents.
Cytokines and chemokines will be evaluated using a multiplex assay. Details of the assay and 
specimen sampling will be provided in the Study Manual.
Viral load will be assessed by nasopharyngeal (preferred) or oropharyngeal swab, saliva, or other 
appropriate assay as outlined in the Schedule of Assessments (Table 1). Study samples will be 
analyzed by central testing. Refer to the Study Manual for details on procedures and type(s) of 
diagnostic testing allowed. 
PK should be measured weekly for 2 weeks at Cmax (4-5 hours) for subjects with renal insufficiency 
H*)5 mL/min/ 1.73 m2). For those subjects requiring dialysis, dose adjustment may be 
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needed (see Section 3.4.1) and will be determined by pre- and post-dialysis PK by the DMC to 
prevent site unblinding.
6.3
Clinical status and symptoms
The investigator may consult with a relevant clinical or other specialist as appropriate per SOC.
6.3.1
Respiratory failure and survival assessment
Total number of study days free of oxygen supplementation and total number of study days free of 
respiratory failure will be evaluated. Refer to Section 6.5.1 for further details of vital sign collection.
x
Note: Respiratory failure is defined as either need for mechanical ventilation (invasive or 
non-invasive) or high flow oxygen (defined by greater than 15 LPM flow of oxygen to 
PDLQWDLQR[\JHQVDWXUDWLRQEHWZHHQDQG), sustained for at least 48 hours, at any 
time during the study.
The reason for hospitalization and number of total study days of hospitalization and intensive care 
unit (ICU) utilization will be recorded. 
Details of subject discharge (date of discharge and condition at discharge) from the hospital will be 
recorded.
Any significant deviation from standard of care due to limited resources will be documented.  
Survival status at the end of the study period will be documented, including cause of death for any 
reason.
6.3.2
Clinical status assessment
Clinical status as outlined in the Schedule of Assessments (Table 1) will be measured on the 
following clinician-reported 9-point ranking scale (WHO):
• 
(8) death
• 
(7) ventilation plus additional organ support (vasopressors, renal replacement therapy, 
ECMO)
• 
(6) intubation and mechanical ventilation
• 
(5) noninvasive ventilation or high-flow oxygen therapy
• 
(4) oxygen therapy but not requiring high-flow or non-invasive ventilation
• 
(3) hospitalized but not requiring oxygen therapy
• 
(2) discharged from the hospital but with limitation of activities
• 
(1) discharged from the hospital and without any limitation
• 
(0) no clinical evidence of the disease
Instructions for administration will be provided in the Study Manual.
6.4
Extended vital signs
Extended vital signs, including oxygen saturation and fraction of inspired oxygen (FiO2) will be 
collected as specified in the schedule of assessments. Refer to Section 6.5.1 for further details of 
measurements.
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6.5
Safety and tolerability assessments
The definitions, reporting, and follow-up of AEs, SAEs, and potential pregnancies are described in 
Section 7. 
6.5.1
Vital signs
Evaluations of systolic and diastolic blood pressure, respiratory rate, and temperature will be 
performed throughout the study. In addition, oxygen saturation and FiO2 will be assessed 
throughout the study. Oxygen administration (eg, room air or oxygen flow by nasal canula or facial
mask) will be recorded. Vital signs will be performed after subjects have been supine for at least 
5 minutes when possible. 
Arterial blood gases may be performed if clinically indicated in some subjects but are not required 
for this study. If arterial blood gasses are measured, the results for arterial pressure of oxygen 
(PaO2) should be reported at each measurement in the eCRF.
Clinically relevant findings found after study drug initiation and meeting the definition of an AE (new 
AE or worsening of previously existing condition) must be recorded.
6.5.2
Weight and height
Weight (kg) will be recorded at screening and the follow-up assessment (by alternative methods 
including outpatient visit). Height (cm) will be recorded and body mass index (BMI) calculated at
screening.
BMI (kg/m2) = weight (kg)/(height [cm]/100)2
6.5.3
Physical examination
Physical examination (ie, inspection, percussion, palpation, and auscultation) is performed to 
determine eligibility and as clinically indicated during the study. Clinically relevant findings that are 
present prior to study drug initiation must be recorded with the subject’s medical history. Clinically 
relevant findings found after study drug initiation and meeting the definition of an AE (new AE or 
worsening of previously existing condition) must be recorded. 
6.5.4
Electrocardiography
ECGs will be taken singly after 5 minutes in the supine position as specified in the schedule of 
assessments. The investigator will assess the ECG recording as 'normal', 'abnormal - not clinically 
significant', or 'abnormal - clinically significant' and include a description of the abnormality as 
required. The ECG parameters assessed will include heart rate, PR, QRS, QT, and QTcB and QTcF 
(calculated using Bazett’s and Fridericia's method, respectively). ECGs will be performed to 
determine eligibility and during the study period only if clinically indicated. Clinically relevant findings 
found after study drug initiation and meeting the definition of an AE (new AE or worsening of 
previously existing condition) must be recorded.
6.5.5
Laboratory assessments
Laboratory parameters
Additional clinical laboratory evaluations will be performed at other times if judged to be clinically 
appropriate or if the ongoing review of the data suggests a more detailed assessment of clinical 
laboratory safety evaluations is required.
An Investigator (or designee) will perform a clinical assessment of all clinical laboratory data. 
Clinically relevant findings found after study drug initiation and meeting the definition of an AE (new 
AE or worsening of previously existing condition) must be recorded. Clinical relevance is defined as:
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• 
Is accompanied by clinical symptoms
• 
Leads to dose modification of study treatment
• 
Requires significant changes, addition of, interruption of, discontinuation of a concomitant 
medication, therapy, or treatment 
• 
Reflects a disease and/or organ toxicity
This does not apply to any abnormal laboratory result that falls outside the laboratory reference 
range but that does not meet the clinical significance criteria or those that is a result of an AE that 
has already been reported.
Blood and other biological samples will be collected for the following clinical laboratory tests; refer to 
the Study Manual for details of collection and analysis and information on central and local 
laboratories: 
Lab
Tests
Hematology
Hemoglobin [including mean corpuscular volume, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration], hematocrit, red cell 
count, total white cell count, and platelet count. Differential blood count, 
including: basophils, eosinophils, neutrophils, lymphocytes, and monocytes.
Chemistry and 
electrolytes
Sodium, potassium, calcium, inorganic phosphate, total protein, albumin, blood 
urea nitrogen, creatinine, uric acid, total bilirubin1, alkaline phosphatase, 
 
, gamma-glutamyl transferase, and 
.
Glucose
Glucose
Urinalysis
Leucocytes, blood, nitrite, protein, urobilinogen, bilirubin, pH, specific gravity, 
ketones, glucose. If there is a clinically significant positive result, urine will be 
sent for microscopy and/or culture.
Pregnancy2
hCG (urine or serum). If there is a clinically significant, positive result in urine, 
urine will be sent for confirmation.
1Conjugated bilirubin may be reported when total bilirubin is outside the reference range.
2Pregnancy test for women of childbearing potential will be performed within 72 hours of first dose 
and if pregnancy is suspected during the study.
6.6
Unscheduled visit
Unscheduled visits may be performed at any time at the subject’s or the investigator’s request and 
may include (but are not limited to) vital signs/focused physical examination, ECG, AE review, 
concomitant medications and procedures review, disease-related constitutional symptoms, and/or 
laboratory and biomarker assessments. The date and reason for the unscheduled visit must be
recorded in the source documentation.
6.6.1
Early termination visit
When the investigator determines that study treatment will no longer be used, the investigator will 
perform the ET procedures and document the reason for discontinuation from study treatment in the 
eCRF. If routine laboratory tests (eg, hematology, serum chemistry) are completed within 7 days 
before the time of study treatment discontinuation, these tests need not be repeated. Every effort 
should be made to keep subjects in the study, including if a subject and/or their treating physician 
decides to prematurely discontinue study treatment.
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6.7
Alternative follow-up methods to site visits
Trial participants may not be able to come to the investigational site for protocol-specified or 
unscheduled visits. The sponsor may use alternative methods for safety assessments, including 
telemedicine visits, telephone visits, and/or an alternative location for visits depending on the local 
or institutional standards.
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7 
SAFETY REPORTING
7.1
Definitions of adverse events
An adverse event (AE) is any untoward medical occurrence in a subject who is participating in a 
clinical study performed. The AE does not necessarily have to follow the administration of a study 
drug, or to have a causal relationship with the study drug. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory or vital sign finding), symptom, or disease 
temporally associated with the study participation whether or not it is related to the study drug.
7.1.1
Recording of adverse events
Adverse events and SAEs will be assessed from the time the subject signs the ICF through the D28 
follow-up visit.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative).
7.1.2
Intensity of adverse events
The intensity of clinical AEs is graded 3-point scale as defined below:

Mild: discomfort noticed but no disruption of normal daily activity;

Moderate: discomfort sufficient to reduce or affect normal daily activity;

Severe: inability to work or perform daily activity.
7.1.3
Relationship to study drug
For each AE, the relationship to drug as judged by the investigator:

Probable;

Possible;

Unlikely;

Unrelated.
7.1.4
Serious adverse events
A serious adverse event (SAE) is defined by the International Conference on Harmonization (ICH) 
guidelines as any AE fulfilling at least one of the following criteria:

results in death;

is life threatening (at the time of the event);

requires hospitalization or prolongation of existing inpatient hospitalization;
o
Note: COVID-19-related hospitalization or ICU admission is excluded from this 
definition, as SARS-CoV-2, COVID-19 infection, or pulmonary conditions attributable 
to COVID-19 infection are efficacy-related endpoints

results in persistent or significant disability or incapacity;

is a congenital anomaly or birth defect; or

any other important medical event that did not result in any of the outcomes listed above due 
to medical or surgical intervention but could have been based upon appropriate judgement 
by the investigator.
An elective hospital admission will not be considered as a SAE.
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7.1.5
Suspected unexpected serious adverse reactions
A suspected unexpected serious adverse reaction (SUSAR) is an SAE that is unexpected (nature or 
severity of which is not consistent with the applicable product information (eg, the Investigator 
Brochure for losmapimod) and suspected (a reasonable possibility of causal relationship with 
investigational drug, regardless of the administered dose).
7.1.6
Reporting of serious adverse events
The investigator must report any AE that meets the SAE criteria (Section 7.1.4) to 
immediately (ie, within 24 hours after the site personnel first learn about the event) via electronic 
data capture (EDC). In the event that EDC entry is not possible (eg, system failure or access 
problems), the study site staff should complete the paper SAE report form and fax the form to 
Pharmacovigilance within 24 hours of awareness or call the 
safety hotline to 
report. The study site staff should update the EDC system as soon as it is available. 
A full description of every SAE will need to be provided to
Pharmacovigilance.
7.1.7
Follow-up of adverse events 
All AEs will be followed until they have abated, returned to baseline status or until a stable situation 
has been reached. Depending on the event, follow up may require additional tests or medical 
procedures as indicated, and/or referral to the general physician or a medical specialist.
7.1.8
Adverse events of special interest
An AESI (serious or non-serious) is one of scientific and medical concern for which ongoing 
monitoring and rapid communication by the investigator to the sponsor can be appropriate. Adverse 
events of special interest for this study include QTc prolongation as well as liver tests that meet the 
criteria for potential drug-induced liver injury (DILI), in accordance with the US Food and Drug 
Administration “Guidance for Industry-Drug-Induced Liver Injury: Premarketing Clinical Evaluation”.
Adverse event of special interest: QTc prolongation
A thorough QT study (PM1116628) was conducted in healthy volunteers who received losmapimod 
at 7.5 mg BID or 20 mg daily or with placebo administered for 5 days. At the 20 mg dose of 
losmapimod, the upper bound of thH&,RIWKHǻǻ47Lnterval (change from baseline in QTcF 
compared with that for placebo) exceeded the 10 msec threshold at the 24-hour post-dose time 
point. For the 7.5 mg BID dose, the upper bRXQGRIWKH&,RIǻǻ47F)H[FHHGHGWKHPVHF
threshold at multiple time points. No subjects experienced QTcF values >480 msec or QTcF 
FKDQJHVIURPEDVHOLQHPVHFDWDQ\WLPHLQWKHVWXG\$OWKRXJKWKHXSSHUERXQGRIWKH&,
exceeded the 10 msec regulatory threshold of concern in the primary pharmacodynamic analysis, it 
was determined by GSK that there was no clinically relevant effect on the QT interval, as there was 
no clinically relevant concentration QTc effect using standard placebo/baseline subtracted 
measured QTc data. Additional information on the QTc interval and its behavior, as demonstrated in 
the large cohort of patients with ACS treated with losmapimod (PM1116197), supported the lack of 
a QT effect. PK/PD modeling using the raw QTcF and plasma concentration data showed that at 
plasma losmapimod concentrations 4 times the exposure at the therapeutic dose (7.5 mg BID) (ie, 
at exposures approximately 2-IROGKLJKHUWKDQPJ%,'WKHSUHGLFWHGXSSHUERXQGRIWKH&,
RIǻǻ47F)GLGQRWH[FHHGPVHFDQGWKHSUHGLFWHGPHGLDQǻǻ47F)ZDVOHVVWKDQ 5 msec. 
Further details are presented in the Investigator Brochure. No drug effect on QT prolongation of 
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losmapimod over placebo has been documented in any of the phase 2 or the one phase 3 trial 
completed so far. 
Study drug should be discontinued for subjects who meet the QTc prolongation criteria as a result of 
within-protocol specific testing or unscheduled testing (see Section 3.4.4 stopping criteria). This 
AESI must be reported to the sponsor within 24 hours of awareness per the SAE reporting 
procedures (Section 7.1.6). Further safety steps should be taken to closely observe and follow-up
the event until resolution and treatment initiated per local standard of care. 
Adverse event of special interest: Drug-induced liver injury
The following 3 laboratory value criteria must be met for potential DILI, or “Hy’s Law”:
• 
$QHOHYDWHGDODQLQHWUDQVDPLQDVHRUDVSDUWDWHWUDQVDPLQDVHODERUDWRU\YDOXHWKDWLVî
ULN
• 
$QHOHYDWHGWRWDOELOLUXELQODERUDWRU\YDOXHWKDWLVî8/1
• 
An alkaline phospKDWDVHODERUDWRU\YDOXHWKDWLVî8/1
Study drug should be discontinued for subjects who meet the laboratory criteria for potential DILI as 
a result of within-protocol specific testing or unscheduled testing (see Section 3.4.4 stopping 
criteria). This AESI must be reported to the sponsor within 24 hours of awareness per the SAE 
reporting procedures (Section 7.1.6). Further safety steps should be taken to closely observe and 
follow-up the event until resolution. These steps include, but are not limited to:
• 
Making every reasonable attempt to have the subject return to the clinic within 24 hours for 
repeat liver tests
• 
Obtaining a more detailed history of symptoms and prior or concurrent disease, concomitant 
medication use, alcohol use, recreational drug use, and special diets
• 
Repeating liver enzyme and serum bilirubin tests twice weekly. Frequency of retesting can 
decrease to once a week or less if abnormalities stabilize and the subject is asymptomatic
• 
Obtaining viral hepatitis serology
• 
Considering liver imaging and/or hepatology consultation
7.2
Pregnancy
7.2.1
Teratogenicity
If a woman becomes pregnant when on study drug, study drug should be permanently discontinued. 
The investigator must counsel the subject and discuss the risks of continuing with the pregnancy 
and the possible effects on the fetus. Monitoring of the subject should continue until the outcome of 
the pregnancy is known. In the event of pregnancy in the partner of a study subject, the Investigator 
should make every reasonable attempt to obtain the woman’s consent for release of protected 
health information.
7.2.2
Reporting of pregnancy
Irrespective of the treatment received by the subject, any pregnancy occurring during study drug 
administration or until follow-up, must be reported within 24 hours of the investigator's knowledge of 
the event to 
 using the Exposure in Utero form. The Investigator must make every effort to 
follow the pregnant partner of a male subject through resolution of the pregnancy (delivery or 
termination) and to report the resolution on the SAE form.
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8 
STATISTICAL METHODOLOGY AND ANALYSES
8.1
Statistical analysis plan
A statistical analysis plan (SAP) will be generated and approved prior to database snapshot for the 
interim analysis (IA). The SAP will detail the implementation of all planned statistical analysis. Any 
deviations from the planned analysis will be described and justified in the final clinical study report.
All safety and statistical programming will be conducted using SAS 9.4 for Windows or newer (SAS 
Institute Inc., Cary, NC, USA), and other statistical programming/sample size calculation software as 
necessary. 
8.1.1
Determination of sample size
The primary efficacy endpoint of this study is the proportion of subjects who progress to death or 
respiratory failure by the end of study (Day 28,WLVHVWLPDWHGWKDWDSSUR[LPDWHO\RIHQUROOHG
subjects receiving SOC plus placebo will attain this endpoint. It is assumed that losmapimod will 
LPSURYHWKHSULPDU\HQGSRLQWE\RYHUSODFHER2QWKHEDVLVRIWKHVHDVVXPSWLRQVDWRWDORIXS
to 410 subjects randomized to the losmapimod arm or the placebo arm in a 1:1 ratio (205 subjects 
in the losmapimod arm and 205 subjHFWVLQWKHSODFHERDUPZLOO\LHOGDSSUR[LPDWHO\SRZHULQ
a 1-VLGHGWHVWDWWKHVLJQLILFDQFHOHYHO7KHVDPSOHVL]HHVWLmate assumes an IA will be 
conducted after approximately 206 subjects (103 in the losmapimod arm, and 103 in the placebo 
arm) have completed the Day 28 visit, to assess early futility, using the rules specified in 
Section 8.9. 
8.1.2
Analysis methods
In general, all study endpoints will be summarized using descriptive statistics. Descriptive statistics 
for continuous data will include number of subjects (n), mean, standard deviation, median, 
minimum, and maximum. Descriptive statistics for categorical data will include frequency and 
percentage. 
:KHUHDSSURSULDWHGHVFULSWLYHVWDWLVWLFVPD\EHSUHVHQWHGZLWK&,
8.1.3
Analysis sets
Full Analysis Set (FAS): The FAS will consist of all subjects who are randomly assigned to receive 
double-blind study drug. All analyses using the FAS will group subjects according to randomized 
treatment. The primary endpoint, clinical outcomes/status, survival, and pharmacodynamic 
endpoints will be analyzed using the FAS.
Per Protocol Set (PPS): The PPS will consist of all FAS subjects who fulfill all inclusion/exclusion 
criteria and do not have any significant protocol deviations. All analyses using the PPS will group 
subjects according to randomized treatment.
Safety Analysis Set: The safety analysis set is defined as all subjects who are randomized and 
receive study drug. All analyses using the Safety Analysis Set will group subjects according to 
treatment actually received. The safety analysis set will be used for all safety and tolerability
analyses.
8.2
Protocol violations/deviations
Protocol deviations will be identified based on conditions related to the categories below:

Protocol entry criteria

Forbidden concomitant medications

Missing evaluations for relevant endpoints
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
Other protocol deviations occurring during study conduct.
Major protocol deviations will be identified before study closure and listed where appropriate.
8.3
Missing, unused and spurious data
All missing or incomplete safety and PD data, including dates and times, are treated as such. 
Missing test results or assessments will not be imputed, and as such, are assumed missing-
completely-at-random (MCAR).
For laboratory data, values below the limit of quantitation (recorded as “< LLQ”) will be set to half 
that limit.
Censoring rules for time-to-event endpoints will be discussed in the SAP. Imputation rules for the 
primary endpoint will be discussed in the SAP. The handling of any missing, unused, and spurious 
data will be documented in the SAP or the clinical study report.
8.4
Subject disposition
Subject disposition will be listed by subject.
The following subject data will be summarized:
x
number and percentage of subjects screened,
x
number and percentage of subjects enrolled,
x
number and percentage of subjects completed,
x
number and percentage of subjects included in safety population
A subject who completed the study is defined as a subject where the last PD assessment was 
completed.
8.5
Baseline parameters and concomitant medications
8.5.1
Demographics and baseline variables
Demographic and other baseline characteristics will be summarized using descriptive statistics for 
the treatment group and overall.
8.5.2
Medical history
Medical history will be listed.
8.5.3
Prior and concomitant medications
Prior and concomitant medications will be listed by international nonproprietary names, dose, 
regimen, route and for which indication it was prescribed.
8.5.4
Treatment compliance/exposure
Exposure to study treatment is described in terms of duration of treatment.
8.5.5
Safety and tolerability endpoints
The safety data set is used to perform all safety analyses.
Baseline is defined as the last value prior to dosing. Change from baseline will be calculated for all 
continuous safety parameters.
8.5.6 
Adverse events
The latest version of Medical Dictionary for Regulatory Activities (MedDRA) will be used for the 
coding of AEs. The overall incidence of AEs will be displayed by MedDRA system organ class, 
preferred term, and treatment group. 
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All AEs will be displayed in listings. In addition, SAEs and treatment-emergent AEs (TEAEs) leading 
to discontinuation of study drug will be listed.
Treatment-emergent AEs will be defined as an event that occurs on or after the first dose of study 
drug or the worsening of a preexisting condition on or after the first dose of study drug. If a subject 
does experience an event both prior to and after starting administration of a treatment, the event will 
be considered a TEAE (of the treatment) only if it has worsened in severity (ie, it is reported with a 
new start date) after starting administration of the specific treatment, and prior to the start of another 
treatment, if any. All TEAEs collected during the investigational period will be summarized. 
The number of TEAEs and the number of subjects with at least 1 TEAE will be summarized by 
treatment group for the following:
1.
System organ class and preferred term;
2.
System organ class, preferred term, and maximum severity
3.
System organ class, preferred term, and maximum drug relatedness.
8.5.7
Vital signs
Reported values and change from baseline values of supine blood pressure and pulse rate and 
temperature will be summarized using descriptive statistics by treatment group and time point. The 
number of available observations and out-of-range values (absolute and in percentage) will be 
presented by treatment group. Vital sign variables will be listed. Values outside the reference range 
will be flagged in the listing.
Vital sign results and change from baseline values will be summarized using descriptive statistics by 
treatment group and time point.
8.5.8
ECG
ECG values will be listed.
8.5.9
Clinical laboratory tests
Reported values and change from baseline values of clinical laboratory variables will be 
summarized using descriptive statistics by treatment group and time point. The number of available 
observations and out-of-range values (absolute and in percentage) will also be presented by 
treatment group. Clinical laboratory values will be listed.
Clinical laboratory test results and change from baseline values will be summarized using 
descriptive statistics by treatment group and time point. 
8.6
Primary endpoints
1) Assuming pt is probability of outcome in the losmapimod arm; pc is the probability of outcome 
in the control arm
Study hypothesis: H0:  = pt – pc = 0
                              H1:  = pt – pc < 0 
Assuming pt=0.18, pc=0.30, we can restate the hypothesis as 
H0: ș = ș0 = 0
H1: ș = ș1 = –0.12  
For the final analysis, the proportion of subjects achieving the primary endpoint in the treatment 
arms will be compared using an adjusted risk difference obtained from a regression model, adjusted 
for stratification factors, sex, and baseline CRP. Full details of the regression model will be provided 
in the SAP. An interim analysis to assess futility analysis—and potential sample size re-estimation—
is discussed in Section 8.9. All results will be summarized descriptively by treatment arm and 
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between response rates, and p-values.
8.7
Secondary endpoints
Clinical status at Day 7 and Day 14:  
Change in clinical status between baseline and post-baseline will be modelled using regression 
models appropriate for ordinal data, adjusting for stratification factors, sex, and baseline CRP.
Details will be provided in the SAP.
Percentages for each category of the ranking scale will be tabulated by treatment arm, along with 
differences between treatment arms at each time point. The proportion of subjects for each of the 
items in the scale will be compared using an adjusted risk difference obtained from a regression 
model, adjusting for stratification factors, sex, and baseline CRP. Full details of the regression 
model will be provided in the SAP.
Total number of study days: (a) free of oxygen supplementation; (b) in ICU; (c) of hospitalization; (d) 
free of respiratory failure; (e) alive: For each endpoint (a) - (e), a Poisson regression model or a 
negative binomial model will be used to assess the relationship with treatment, adjusting for 
stratification factors, sex, baseline CRP and number of days on study (as applicable). Details of the
model, including censoring rules, if any, will be provided in the SAP.
Percentage of subjects discharged from the hospital: percentages of subjects discharged from the 
hospital will be tabulated by treatment arm, along with differences between treatment arms. The 
proportion of subjects will be compared using an adjusted risk difference obtained from a regression 
model, adjusting for stratification factors, sex, and baseline CRP. Full details of the regression
model will be provided in the SAP. 
All-cause mortality at Day 28: percentages of subjects will be tabulated by treatment arm, along with 
differences between treatment arms, at each time point. The proportion of subjects will be compared 
using an adjusted risk difference obtained from a regression model, adjusting for stratification 
factors, sex, and baseline CRP. Full details of the regression model will be provided in the SAP. 
Incidence of AEs/SAEs: will be summarized by system organ class and preferred term and by 
treatment arm using percentages.
Incidence of clinically significant changes: Percentage of subjects with clinically significant changes 
in laboratory parameters, ECG, and vital sign measurements will be computed for each treatment 
arm along with associated 2-VLGHG&ORSSHU-Pearson CI. 
Clearance of quantifiable viral RNA by Day 7: percentages of subjects with clearance of quantifiable 
viral RNA will be tabulated by treatment arm, along with differences between treatment arms, at 
each time point. The proportion of subjects will be compared using an adjusted risk difference
obtained from a regression model, adjusting for stratification factors, sex, and baseline CRP. Full 
details of the regression model will be provided in the SAP. 
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8.9
Interim analysis for futility and sample size re-estimation
An interim analysis (IA) will be conducted after 206 subjects have been enrolled (approximately 103 
in each of the losmapimod and placebo arms) and have been treated for 14 days with 28 days of 
follow-up. Only futility—and potential sample size-estimation—will be assessed by the DMC at the 
IA. The O’Brien-Fleming group sequential method will be used to adjust beta for interim testing.
Table 6, Figure 1, Figure 2, and Figure 3 contain sample size requirements, boundary information, 
and stopping probabilities for testing futility on the primary endpoint at both the IA and final analysis. 
P-values are single-sided.  Sample size estimation was done using SAS® (Proc SeqDesign, Version 
4.0). The study will not be stopped for efficacy at the IA.
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Table 6:  Boundary Values for Interim Analysis Futility Assessment
Analysis 
Stage
Sample Size
Beta: Futility
Alpha: Efficacy
Losmapimod
Control
Standardized- Z
(p-value)
MLE
Stopping Probability 
(accept null under null 
hypothesis)
Standardized- Z 
(p-value)
MLE
Stopping Probability
(accept null under 
alternative 
hypothesis)
Interim 
Analysis
103
103
-0.67873
(0.24865)
-0.04017
0.75135
Not applicable
--
0.08871
Final 
Analysis
205
205
-1.91358
(0.02784)
-0.08009
0.97500
--
--
0.20000
Overall alpha=0.025 (1-VLGHGRYHUDOOSRZHU 
Abbreviations: MLE: maximum likelihood estimate. 
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Figure 1:  Acceptance Region (Standardized-Z Scale) 
  
Figure 2:  Acceptance Region (P-value) 
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Figure 3:  Acceptance Region (Maximum Likelihood Estimate)
8.9.1
Futility Testing 
The process is as follows:
1. Futility at IA: If standardized z-value (MLE: maximum likelihood estimate) of pt – pc is 
-0.67873 (-0.04017), or p-YDOXHWKHQVWRSIRUIXWLOLW\3UREDELOLW\RIVWRSSLQJIRU
futility under null hypothesis is ~0.75.
2. At Final Analysis: The final p-value is tested at an adjusted alpha of 0.02784.
8.9.2
Sample Size Re-estimation
The Chen-DeMets-Lan method (Chen et al 2004) will be used for unblinded sample size 
re-estimation, with IA futility stopping boundaries created using O’Brien-Fleming method, as 
described above. Wald conditional probabilities will be calculated using the actual observed 
proportion from both treatment arms. 
The maximum sample size allowed is 820 subjects. Sample size will be increased only if the 
observed data at the IA are promisLQJWKDWLVLIWKHFRQGLWLRQDOSRZHULVDQG6DPSOH
size will be increased tRHQVXUHDWDUJHWFRQGLWLRQDOSRZHURIDWOHDVW
7KHUHLVRQO\RQH,$DQGFRQGLWLRQDOSRZHUDW,$PXVWOLHEHWZHHQDQG for sample size re-
estimation to be implemented. These 2 FRQGLWLRQVHQVXUHWKDWWKHWDUJHW7\SH,HUURURILVQRW
exceeded by increasing sample size to meet the original target power (Chen et al 2004).
Sample size re-estimation will not be done in the following 2 instances:
x
If conditioQDOSRZHULVWKHQVDPSOHVL]HUH-estimation will not be done, and decision 
on futility will be made based on boundary values from the O’Brien-Fleming method. 
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x
,IFRQGLWLRQDOSRZHULVWKHQDVDPSOHVL]HUH-estimation will not be done, as the study 
will be considered sufficiently powered to detect the effect of interest at the final analysis.
A Wald Test statistic will be calculated and compared with the boundary value for futility (see Table 
6). If the Wald Test statistic lies in the acceptance region then the study will stop for futility.
All calculations for the IA and the unblinded sample size re-estimation will be conducted by an
external, unblinded statistician. The DMC will review the results in a closed session and make 
appropriate recommendations to the Sponsor afterwards.
8.9.3
Possible Recommendations by the DMC
After reviewing the results of the IA, the DMC may select 3 or more possible recommendations, 
based on the test statistics obtained at the IA:
x
Stop for Futility - Stop trial early due to strong evidence for futility due to test statistic being in 
the futility region.
x
Continue without change - Continue until next look with no changes due to test statistic not 
EHLQJLQWKHIXWLOLW\UHJLRQRUWKHFRQGLWLRQDOSRZHUEHLQJRU
x
Add required additional sample size, n, without exceeding the maximum sample size of 820 
and continue the trial. 
At the final analysis, 2 recommendations can be made: 
x
Efficacy is demonstrated. 
x
Efficacy is NOT demonstrated.  
8.10 Data monitoring committee
An independent DMC composed of experts external to the sponsor and investigators will monitor 
the safety of the trial participants and the conduct of the trial on an ongoing basis and will be 
responsible for the interim analysis and recommendations regarding sample size re-estimation. 
Consistent with US Food and Drug Administration (FDA) recommendations (FDA Guidance for 
Industry, Establishment and Operation of Clinical Trial Data Monitoring Committees, 2006), the 
DMC will include at least 2 external clinicians with expertise relevant to the evaluation of COVID-19, 
such as Critical Care, Pulmonology, or Infectious Disease, as well as at least 1 independent 
biostatistician with expertise in clinical trial design and statistical methods for clinical research and 
analysis of research data including interim analysis. 
Details on the composition of the DMC and the schedule and format of DMC meetings and data 
outputs will be presented in the DMC charter. The DMC will review, at a minimum, data for the 
sentinel subjects prior to continued study drug dosing and cumulative safety data at regular intervals 
based on subject enrollment.
The safety evaluations will be detailed in the DMC charter and will include review of conventional 
safety variables, such as serious adverse events. Any safety event that requires unblinding will be 
immediately reported to the DMC and to the FDA. The DMC may request and review any additional 
reports outside of the planned analyses at any time if deemed necessary to ensure the safety of 
subjects. The DMC will also review the efficacy data at the IA and make recommendations based on 
the futility criteria and for sample size re-estimation if needed (see Section 8.9). After reviewing 
study data, the DMC will make recommendations regarding continuation, termination, or 
modification of the study. The DMC may also perform ad hoc review PK of subjects who require 
dialysis.
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8.11 Type I error for testing key study endpoints
The overall Type I error of the study will be controlled at 0.025 for 1-sided tests of hypotheses for 
the following key study endpoints, using an appropriate alpha control method: 
1. Proportion of progressors to death or respiratory failure by Day 28 
2. Change in clinical status using the 9-point WHO scale at Day 14 
3. Change in clinical status using the 9-point WHO scale at Day 7
4. Oxygen-free days by Day 28
Further details on the methodology will be provided in the SAP.
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9 
GOOD CLINICAL PRACTICE, ETHICS AND ADMINISTRATIVE PROCEDURES
9.1
Good clinical practice
9.1.1
Ethics and good clinical practice
The study will be performed in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, ICH Good Clinical Practice (GCP), the protocol, and all applicable 
regulations.
9.1.2
Ethics committee / institutional review board
Federal regulations and the ICH guidelines require that approval be obtained from an IRB/IEC 
before participation of human subjects in research studies. Before study onset, the protocol, 
informed consent, advertisements to be used for the recruitment of study subjects, and any other 
written information regarding this study to be provided to the subject or the subject’s legal guardian 
must be approved by the IRB/IEC. Documentation of all IRB/IEC approvals and of the IRB/IEC 
compliance with ICH harmonised tripartite guideline E6(R2): Good Clinical Practice will be 
maintained by the site and will be available for review by the sponsor or its designee.
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must identify the 
IRB/IEC name and address, the clinical protocol by title or protocol number or both, and the date on 
which approval or a favorable opinion was granted.
The investigator is responsible for providing written summaries of the progress and status of the 
study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The investigator must 
promptly supply the sponsor or its designee, the IRB/IEC, and, where applicable, the institution, with 
written reports on any changes significantly affecting the conduct of the study or increasing the risk 
to subjects.
9.1.3
Informed consent
It is the responsibility of the investigator to obtain written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and potential 
hazards of the study. The investigator must also explain to the subjects that they are completely free 
to refuse to enter the study or to withdraw from it at any time for any reason.
Subjects will be given an opportunity to ask questions about the study prior to providing consent for 
participation. Following discussion of the study with site staff, subjects or their legally authorized 
representative will be required to provide one of the following: 
1. Sign a statement of informed consent that meets the requirements of local regulations, ICH 
guidelines, and the IRB/EC or study center, where applicable. The subject will be given a 
copy of the signed ICF, and the original will be maintained with the subject’s records; OR
2. If a subject is in isolation due to COVID-19 and institutional infection control policy would 
prevent removal of a document signed by the subject from their hospital room, then one of 
the following methods will be used to obtain informed consent that meets the requirements 
of local regulations, ICH guidelines, and the IRB/EC or study center, where applicable:
o
Obtain the informed consent electronically; OR
o
Obtain the informed consent by teleconference/video conference in alignment 
with local regulatory guidance.
How the consent was obtained and reason why it was obtained using that particular method 
should be documented in the eCRF. The trial record at the investigational site should 
document how it was confirmed that the subject signed the consent form (ie, either using 
attestation by the witness and investigator or a photograph of the signed consent). 
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Subjects must be re-consented to the most current version of the ICF(s) during their participation in 
the study.
If consent is obtained from a legally authorized representative, then assent should be obtained from 
the subject using VLPLODU methods as described above.
9.2
Data handling and record keeping
This study will be conducted according to ICH E6(R2) risk and quality processes described in the 
applicable procedural documents. The quality management approach to be implemented in this
study will be documented and will comply with the current ICH guidance on quality and risk
management.
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the subjects treated as part of the research under this protocol.
The investigator agrees to maintain accurate eCRFs and source documentation as part of the case 
histories. These source documents may include laboratory reports, ECG strips, etc.
Study site personnel will enter subject data into the EDC program. The analysis data sets will be a 
combination of these data and data from other sources (eg, laboratory data).
Clinical data management will be performed in accordance with standard data cleaning procedures
to ensure the integrity of the data, eg, removing errors and inconsistencies in the data. Adverse 
event terms will be coded using MedDRA, an internal validated medical dictionary, and concomitant
medications will be coded using the World Health Organization Drug Dictionary.
After final database lock, each study site will receive a CD-ROM containing all of their site specific
eCRF data as entered into the EDC system for the study, including full discrepancy and audit
history. Additionally, a CD-ROM copy of all of the study site’s data from the study will be created
and sent to the sponsor for storage.
will maintain a duplicate CD-ROM copy for their
records. In all cases, subject initials will not be collected or transmitted to the sponsor.
9.3
Access to source data and documents
All laboratory specimens, evaluation forms, reports, and other records will be identified in a manner
designed to maintain subject confidentiality. All records will be kept in a secure storage area with
limited access. Clinical information will not be released without the written permission of the subject
(or the subject’s legal guardian), except as necessary for monitoring and auditing by the sponsor, its
designee, applicable regulatory authorities, or the IRB/IEC.
To ensure privacy, directly identifying information of study subjects will not be attached to records or
samples released to the sponsor and its service providers for research purposes.
The investigator and all employees and coworkers involved with this study may not disclose or use
for any purpose other than performance of the study any data, record, or other unpublished,
confidential information disclosed to those individuals for the purpose of the study. Prior written
agreement from the sponsor or its designee must be obtained for the disclosure of any said 
confidential information to other parties. Additional confidentiality requirements and obligations will
be set forth in the clinical trial agreement to be entered into by the sponsor, the principal
investigator, and the institution.
9.4
Investigator’s obligations
The following administrative items are meant to guide the investigator in the conduct of the study but
may be subject to change based on industry and government standard operating procedures,
working practice documents, or guidelines. Changes will be reported to the IRB/IEC but will not
result in protocol amendments.
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9.5
Confidentiality
All laboratory specimens, evaluation forms, reports, and other records will be identified in a manner 
designed to maintain subject confidentiality. All records will be kept in a secure storage area with 
limited access. Clinical information will not be released without the written permission of the subject 
(or the subject’s legal guardian), except as necessary for monitoring and auditing by the sponsor, its 
designee, applicable regulatory authorities, or the IRB/IEC.
To ensure privacy, directly identifying information of study subjects will not be attached to records or 
samples released to the sponsor and its service providers for research purposes.
The investigator and all employees and coworkers involved with this study may not disclose or use 
for any purpose other than performance of the study any data, record, or other unpublished, 
confidential information disclosed to those individuals for the purpose of the study. Prior written 
agreement from the sponsor or its designee must be obtained for the disclosure of any said 
confidential information to other parties. Additional confidentiality requirements and obligations will 
be set forth in the clinical trial agreement to be entered into by the sponsor, the principal 
investigator, and the institution. 
9.6
Financial disclosure and obligations
Investigators are required to provide financial disclosure information to allow the sponsor to submit 
the complete and accurate certification or disclosure statements required by applicable regulatory 
authorities. In addition, the investigator must provide to the sponsor a commitment to promptly 
update this information if any relevant changes occur during the course of the investigation and for 
1 year following the completion of the study.
Neither the sponsor nor 
is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the absence of 
specific arrangements, neither the sponsor nor 
is financially responsible for further 
treatment of the subject’s disease.
9.7
Investigator documentation
Prior to beginning the study, the investigator will be asked to comply with ICH E6(R2) 8.2 and Title 
21 of the Code of Federal Regulations by providing the following essential documents, including but 
not limited to:
• 
IRB/IEC approval
• 
Original investigator-signed investigator agreement page of the protocol
• 
FDA Form 1572, fully executed, and all updates on a new fully executed Form FDA 1572
• 
A curriculum vitae for the investigator and each subinvestigator listed on Form FDA 1572
• 
Financial disclosure information to allow the sponsor to submit complete and accurate 
certification or disclosure statements required by applicable regulatory authorities. In 
addition, the investigators must provide to the sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and for 
1 year after the completion of the study.
• 
IRB/IEC-approved informed consent, samples of site advertisements for recruitment for this 
study, and any other written information regarding this study that is to be provided to the 
subject or legal guardian, and
• 
Laboratory certifications and normal ranges for any local laboratories used by the site.
9.8
Study conduct
The investigator agrees that the study will be conducted according to the principles of ICH E6(R2). 
The investigator will conduct all aspects of this study in accordance with all national, state, and local 
laws or regulations. Study information from this protocol will be posted on publicly available clinical 
trial registers before enrollment of subjects begins.
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9.9
Adherence to protocol
The investigator agrees to conduct the study as outlined in this protocol in accordance with ICH 
E6(R2) and all applicable guidelines and regulations.
9.10 Adverse events and study report requirements
By participating in this study, the investigator agrees to submit reports of SAEs to the sponsor 
and/or IRB/IEC according to the timeline and method outlined in the protocol. In addition, the 
investigator agrees to submit annual reports to the study site IRB/IEC as appropriate.
9.11 Investigator’s final report
Upon completion of the study, the investigator, where applicable, should inform the institution; the 
investigator/institution should provide the IRB/IEC with a summary of the study’s outcome and the 
sponsor and regulatory authority(ies) with any reports required.
9.12 Records retention
Essential documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents should be retained for a longer 
period, however, if required by the applicable regulatory requirements or by an agreement with the 
sponsor. It is the responsibility of the sponsor to inform the investigator/institution as to when these 
documents no longer need to be retained.
9.13 Publications
After completion of the study, the data will be submitted for reporting at a scientific meeting and for 
publication in a peer-reviewed scientific journal. In these cases, the sponsor will be responsible for 
these activities and will work with the investigators to determine how the manuscript is written and 
edited, the number and order of authors, the publication to which it will be submitted, and other 
related issues. The sponsor has final approval authority over all such issues. 
Data are the property of the sponsor and cannot be published without prior authorization from the 
sponsor, but data and publication thereof will not be unduly withheld. Further terms concerning 
publication will be set forth in the clinical trial agreement entered into by the sponsor, the principal 
investigator, any vendors, and the institution.
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10 STUDY MANAGEMENT
The administrative structure will include a DMC (see Section 8.10).
10.1 Monitoring
The clinical monitor, as a representative of the sponsor, has the obligation to follow the study 
closely. In doing so, the monitor regularly monitors the trial remotely and will periodically visit the 
investigator based on local restrictions, in addition to maintaining necessary telephone and letter 
contact. The monitor will maintain current personal knowledge of the study through observation, 
review of study records and source documentation remotely, and discussion of the conduct of the 
study with the investigator and personnel.  All relevant source documents will be uploaded into the 
IBM electronic system or access to the electronic medical records will be provided for remote 
monitoring purposes.
All aspects of the study will be carefully monitored, by the sponsor or its designee, for compliance 
with applicable government regulation with respect to current GCP and current standard operating 
procedures.
10.2 Inspection of records
Investigators and institutions involved in the study will permit study-related monitoring, audits, 
IRB/IEC review, and regulatory inspections by providing direct access to all study records. In the 
event of an audit, the investigator agrees to allow the sponsor, representatives of the sponsor, or a 
regulatory agency (eg, FDA or other regulatory agency) access to all study records.
The investigator should promptly notify the sponsor and 
of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to the sponsor.
10.3 Management of protocol amendments and deviations
10.3.1
Modification of the protocol
Any changes in this research activity, except those necessary to remove an apparent, immediate 
hazard to the subject, must be reviewed and approved by the sponsor or its designee. Amendments 
to the protocol must be submitted in writing to the investigator’s IRB/IEC for approval before 
subjects can be enrolled into an amended protocol.
10.3.2
Protocol deviations
The investigator or designee must document and explain in the subject’s source documentation any 
deviation from the approved protocol. The investigator may implement a deviation from or a change 
of the protocol to eliminate an immediate hazard to study subjects without prior IRB/IEC approval. 
As soon as possible after such an occurrence, the implemented deviation or change, the reasons 
for it, and any proposed protocol amendments should be submitted to the IRB/IEC for review and 
approval, to the sponsor for agreement, and to the regulatory authorities, if required.
A deviation from the protocol is an unintended or unanticipated departure from the procedures or 
processes approved by the sponsor and the IRB/IEC and agreed to by the investigator. A significant 
deviation occurs when there is nonadherence to the protocol by the subject or investigator that 
results in a significant, additional risk to the subject. Significant deviations can include 
nonadherence to inclusion or exclusion criteria or nonadherence to FDA regulations or ICH GCP
guidelines and will lead to the subject being withdrawn from the study. A list of major protocol 
deviations will be compiled prior to the start of the study.
Protocol deviations will be documented by the clinical monitor throughout the course of monitoring 
visits. Principal investigators will be notified in writing by the monitor of deviations. The IRB/IEC 
should be notified of all protocol deviations in a timely manner.
10.4 Study termination
Although Fulcrum Therapeutics has every intention of completing the study, Fulcrum reserves the 
right to discontinue the study at any time for clinical or administrative reasons. Should termination of 
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the study be required, the sponsor will promptly inform the investigator and the IRB/IEC and provide 
them with a detailed written explanation. Fulcrum and the investigator will assure that adequate 
consideration is given to the protection of the subjects’ interests. The sponsor has no plans to 
provide study drug to subjects after study closure or termination. The obligations to provide study 
results for subjects and reports to IRB/IEC shall continue as required by applicable laws and 
regulations.
At any time, the sponsor, the investigators, or the IRBs/IECs may terminate this study for 
reasonable cause. Conditions that may lead to reasonable cause and warrant termination include, 
but are not limited to the following:
• 
Subject or investigator noncompliance
• 
Unsatisfactory subject enrollment
• 
Lack of adherence to protocol procedures
• 
Lack of evaluable and/or complete data
• 
Potentially unacceptable risk to study subjects
• 
Decision to modify drug development plan
• 
Decision by the regulatory authority
Written notification that includes the reason for the clinical study termination is required.
The end of the study is defined as the date on which the last subject completes the last visit 
(includes the safety follow-up visit). 
10.5 Final report
Whether the study is completed or prematurely terminated, the sponsor will ensure that the clinical 
study reports are prepared and provided to the regulatory agency(ies) as required by the applicable 
regulatory requirement(s). The sponsor will also ensure that the clinical study reports in marketing 
applications meet the standards of the ICH harmonised tripartite guideline E3: Structure and content 
of clinical study reports. 
Where required by applicable regulatory requirements, an investigator signatory will be identified for 
the approval of the clinical study reports. The investigator will be provided reasonable access to 
statistical tables, figures, and relevant reports and will have the opportunity to review the complete 
study results.
Upon completion of the clinical study reports, the sponsor will provide the investigator with the full 
summary of the study results. The investigator is encouraged to share the summary results with the 
study subjects, as appropriate. The study results will be posted on publicly available clinical trial 
registers.
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11
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Losmapimod
Protocol FIS-001-2020
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Fulcrum Therapeutics
Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
138


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Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
139
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Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
140


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Clinical Study Report FIS-001-2020
Confidential & Proprietary
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Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
142
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Fulcrum Therapeutics
Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
143


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Confidential & Proprietary
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Confidential & Proprietary
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Clinical Study Report FIS-001-2020
Confidential & Proprietary
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Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
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Fulcrum Therapeutics
Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
148


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Fulcrum Therapeutics
Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
149


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Fulcrum Therapeutics
Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
150
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Fulcrum Therapeutics
Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
151
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Fulcrum Therapeutics
Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
152


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Fulcrum Therapeutics
Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
153


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Fulcrum Therapeutics
Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
154


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Fulcrum Therapeutics
Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
155


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Fulcrum Therapeutics
Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
156


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Fulcrum Therapeutics
Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
157


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Fulcrum Therapeutics
Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
158
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Fulcrum Therapeutics
Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
159


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Fulcrum Therapeutics
Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
160


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Fulcrum Therapeutics
Clinical Study Report FIS-001-2020
Confidential & Proprietary
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Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
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Clinical Study Report FIS-001-2020
Confidential & Proprietary
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Clinical Study Report FIS-001-2020
Confidential & Proprietary
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Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
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Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
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Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
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Clinical Study Report FIS-001-2020
Confidential & Proprietary
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168
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Clinical Study Report FIS-001-2020
Confidential & Proprietary
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Clinical Study Report FIS-001-2020
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Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
174
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Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
175


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Fulcrum Therapeutics
Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
176


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Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
177


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Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
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Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
179
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Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
180
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Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
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Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
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Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
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Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
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Clinical Study Report FIS-001-2020
Confidential & Proprietary
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Clinical Study Report FIS-001-2020
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Clinical Study Report FIS-001-2020
Confidential & Proprietary
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Clinical Study Report FIS-001-2020
Confidential & Proprietary
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Fulcrum Therapeutics
Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
192


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Fulcrum Therapeutics
Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
193


 
 
 
Protocol Version 1 / 29-May-2020  
Confidential 
Page 1 of 60 
CLINICAL STUDY PROTOCOL 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled 
Study of the Safety and Efficacy of Losmapimod in Adult 
Subjects with COVID-19 (LOSVID STUDY) 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 
 
Short Title: 
Losmapimod safety and efficacy in COVID-19 (LOSVID Study) 
Version: 
1 
Date: 
29-May-2020 
Study number: 
FIS-001-2020 
IND number 
149208  
Sponsor: 
Fulcrum Therapeutics 
26 Landsdowne St., 5th floor
Cambridge, MA 02139 
USA 
Sponsor signatory: 
, MD 
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Fulcrum Therapeutics
Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
194
PPD


Fulcrum Therapeutics 
Losmapimod 
Protocol FIS-001-2020 
 
 
Protocol Version 1 / 29-May-2020  
Fulcrum Therapeutics 
Confidential  
Page 2 of 60 
 
CONTACT DETAILS 
SPONSOR 
  
Fulcrum Therapeutics 
26 Landsdowne Street, 5th floor 
Cambridge, Massachusetts 02139 
USA 
Clinical Trial Leader 
 
 
 MD 
Telephone: 
e-mail: 
Drug Safety Physician 
 
 MD 
Teleph
e-mail:
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Fulcrum Therapeutics
Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
195
PPD
PPD
PPD
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PPD
PPD


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Fulcrum Therapeutics
Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
196
PPD


Fulcrum Therapeutics 
Losmapimod 
Protocol FIS-001-2020 
 
 
Protocol Version 1 / 29-May-2020  
Fulcrum Therapeutics 
Confidential  
Page 4 of 60 
 
SIGNATURE PAGE - SPONSOR 
Fulcrum Therapeutics 
Study 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) 
 
I approve this protocol on behalf of the sponsor. 
 
 
Chief Scientific Officer 
 
 
 
Signature 
Date (dd Mmm yyyy) 
 
 
, MD 
Senior Vice President 
Head, Clinical Development 
 
 
 
 
 
Signature 
Date (dd Mmm yyyy) 
 
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Fulcrum Therapeutics
Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
197
PPD
PPD
PPD
PPD


Fulcrum Therapeutics 
Losmapimod 
Protocol FIS-001-2020 
 
 
Protocol Version 1 / 29-May-2020  
Fulcrum Therapeutics 
Confidential  
Page 5 of 60 
 
TABLE OF CONTENTS 
CONTACT DETAILS ........................................................................................................................................... 2 
SIGNATURE PAGE - INVESTIGATOR .............................................................................................................. 3 
SIGNATURE PAGE - SPONSOR ....................................................................................................................... 4 
TABLE OF CONTENTS ...................................................................................................................................... 5 
LIST OF ABBREVIATIONS ................................................................................................................................ 9 
PROTOCOL SYNOPSIS ................................................................................................................................... 11 
1 
BACKGROUND AND RATIONALE ......................................................................................................... 21 
1.1 
Scientific rationale for investigation of losmapimod in COVID-19 ..................................................... 21 
2 
STUDY OBJECTIVES AND ENDPOINTS ................................................................................................ 25 
3 
STUDY IMPLEMENTATION ..................................................................................................................... 27 
3.1 
Overall study design and plan ........................................................................................................... 27 
3.2 
Start of study and end of study definitions......................................................................................... 27 
3.3 
Selection of doses in the study .......................................................................................................... 28 
3.4 
Study drug modifications and withdrawal .......................................................................................... 28 
3.4.1 
Dose modifications .................................................................................................................... 28 
3.4.2 
Subject withdrawal ..................................................................................................................... 30 
3.4.3 
Replacement policy ................................................................................................................... 30 
3.4.4 
Stopping criteria ......................................................................................................................... 30 
4 
STUDY POPULATION .............................................................................................................................. 31 
4.1 
Inclusion criteria ................................................................................................................................. 31 
4.2 
Exclusion criteria ................................................................................................................................ 32 
4.3 
Concomitant medications .................................................................................................................. 32 
4.4 
Lifestyle restrictions ........................................................................................................................... 33 
4.4.1 
Contraception requirements ...................................................................................................... 33 
5 
INVESTIGATIONAL MEDICINAL PRODUCT .......................................................................................... 34 
5.1 
Investigational drug and matching placebo ....................................................................................... 34 
5.2 
Study drug packaging and labelling ................................................................................................... 34 
5.3 
Drug accountability ............................................................................................................................ 34 
5.4 
Treatment assignment and blinding .................................................................................................. 34 
5.4.1 
Randomization and treatment assignment ................................................................................ 34 
5.4.2 
Blinding ...................................................................................................................................... 35 
5.4.3 
Treatment compliance ............................................................................................................... 35 
6 
STUDY ASSESSMENTS .......................................................................................................................... 36 
6.1 
Medical history ................................................................................................................................... 36 
6.2 
Pharmacokinetic and pharmacodynamic assessments .................................................................... 36 
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Fulcrum Therapeutics
Clinical Study Report FIS-001-2020
Confidential & Proprietary
Version 1.0, 30 July 2021
198


Fulcrum Therapeutics 
Losmapimod 
Protocol FIS-001-2020 
 
 
Protocol Version 1 / 29-May-2020  
Fulcrum Therapeutics 
Confidential  
Page 6 of 60 
 
6.3 
Clinical status and symptoms ............................................................................................................ 37 
6.3.1 
Respiratory failure and survival assessment ............................................................................. 37 
6.3.2 
Clinical status assessment ........................................................................................................ 37 
6.4 
Extended vital signs ........................................................................................................................... 37 
6.5 
Safety and tolerability assessments .................................................................................................. 37 
6.5.1 
Vital signs................................................................................................................................... 38 
6.5.2 
Weight and height ...................................................................................................................... 38 
6.5.3 
Physical examination ................................................................................................................. 38 
6.5.4 
Electrocardiography ................................................................................................................... 38 
6.5.5 
Laboratory assessments ............................................................................................................ 38 
6.6 
Unscheduled visit ............................................................................................................................... 39 
6.6.1 
Early termination visit ................................................................................................................. 39 
6.7 
Alternative follow-up methods to site visits ........................................................................................ 39 
7 
SAFETY REPORTING .............................................................................................................................. 41 
7.1 
Definitions of adverse events ............................................................................................................ 41 
7.1.1 
Intensity of adverse events ........................................................................................................ 41 
7.1.2 
Relationship to study drug ......................................................................................................... 41 
7.1.3 
Serious adverse events ............................................................................................................. 41 
7.1.4 
Suspected unexpected serious adverse reactions .................................................................... 41 
7.1.5 
Reporting of serious adverse events ......................................................................................... 42 
7.1.6 
Follow-up of adverse events ...................................................................................................... 42 
7.1.7 
Adverse events of special interest ............................................................................................. 42 
7.2 
Pregnancy .......................................................................................................................................... 43 
7.2.1 
Teratogenicity ............................................................................................................................ 43 
7.2.2 
Reporting of pregnancy ............................................................................................................. 43 
8 
STATISTICAL METHODOLOGY AND ANALYSES ................................................................................ 44 
8.1 
Statistical analysis plan...................................................................................................................... 44 
8.1.1 
Determination of sample size .................................................................................................... 44 
8.1.2 
Analysis methods ....................................................................................................................... 44 
8.1.3 
Analysis sets .............................................................................................................................. 44 
8.2 
Protocol violations/deviations ............................................................................................................ 44 
8.3 
Missing, unused and spurious data ................................................................................................... 45 
8.4 
Subject disposition ............................................................................................................................. 45 
8.5 
Baseline parameters and concomitant medications .......................................................................... 45 
8.5.1 
Demographics and baseline variables ....................................................................................... 45 
8.5.2 
Medical history ........................................................................................................................... 45 
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8.5.3 
Prior and concomitant medications ........................................................................................... 45 
8.5.4 
Treatment compliance/exposure ............................................................................................... 45 
8.5.5 
Safety and tolerability endpoints ................................................................................................ 45 
8.5.6 
Adverse events .......................................................................................................................... 45 
8.5.7 
Vital signs................................................................................................................................... 46 
8.5.8 
ECG ........................................................................................................................................... 46 
8.5.9 
Clinical laboratory tests .............................................................................................................. 46 
8.6 
Primary endpoints .............................................................................................................................. 46 
8.7 
Secondary endpoints ......................................................................................................................... 47 
 
 
8.9 
Interim analysis for futility and sample size re-estimation ................................................................. 48 
8.9.1 
Futility Testing ............................................................................................................................ 51 
8.9.2 
Sample Size Re-estimation ....................................................................................................... 51 
8.9.3 
Possible Recommendations by the DMC .................................................................................. 52 
8.10 
Data monitoring committee ................................................................................................................ 52 
9 
GOOD CLINICAL PRACTICE, ETHICS AND ADMINISTRATIVE PROCEDURES ................................ 53 
9.1 
Good clinical practice ......................................................................................................................... 53 
9.1.1 
Ethics and good clinical practice ............................................................................................... 53 
9.1.2 
Ethics committee / institutional review board ............................................................................. 53 
9.1.3 
Informed consent ....................................................................................................................... 53 
9.2 
Data handling and record keeping ..................................................................................................... 54 
9.3 
Access to source data and documents .............................................................................................. 54 
9.4 
Investigator’s obligations ................................................................................................................... 54 
9.5 
Confidentiality .................................................................................................................................... 54 
9.6 
Financial disclosure and obligations .................................................................................................. 55 
9.7 
Investigator documentation ............................................................................................................... 55 
9.8 
Study conduct .................................................................................................................................... 55 
9.9 
Adherence to protocol ........................................................................................................................ 55 
9.10 
Adverse events and study report requirements ................................................................................. 56 
9.11 
Investigator’s final report.................................................................................................................... 56 
9.12 
Records retention .............................................................................................................................. 56 
9.13 
Publications ....................................................................................................................................... 56 
10 
STUDY MANAGEMENT ....................................................................................................................... 57 
10.1 
Monitoring .......................................................................................................................................... 57 
10.2 
Inspection of records ......................................................................................................................... 57 
10.3 
Management of protocol amendments and deviations ...................................................................... 57 
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10.3.1 
Modification of the protocol ........................................................................................................ 57 
10.3.2 
Protocol deviations .................................................................................................................... 57 
10.4 
Study termination ............................................................................................................................... 57 
10.5 
Final report ......................................................................................................................................... 58 
11 
REFERENCES ...................................................................................................................................... 59 
 
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LIST OF ABBREVIATIONS 
ACE2 
angiotensin-converting enzyme 2 
ACS 
acute coronary syndrome 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase/serum glutamic pyruvic transaminase (SGPT) 
 
 
ARDS 
acute respiratory distress syndrome 
AST 
aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
(SGOT) 
BID 
bis in diem / twice per day 
BMI 
body mass index 
BP 
blood pressure 
CI 
confidence interval 
Cmax 
Maximum concentration 
COPD 
chronic obstructive pulmonary disease 
CoV 
coronavirus 
COVID-19 
disease caused by novel coronavirus 
CRP 
C-reactive protein 
CXCL13 
chemokine ligand 13 
DILI 
drug-induced liver injury 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
ECMO 
extracorporeal membrane oxygenation 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
ET 
early termination 
ET-1 
endothelin 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FiO2 
fraction of inspired oxygen 
FSGS 
focal segmental glomerulosclerosis 
FSHD 
facioscapulohumeral muscular dystrophy 
GCP 
Good Clinical Practice 
 
 
GSK 
GlaxoSmithKline 
H5N1 
highly pathogenic Asian avian influenza A, subtype H5N1 
HIV 
human immunodeficiency virus 
HMGB-1 
high mobility group box protein-1 
hsCRP 
high-sensitivity C-reactive protein 
HSV-1 
herpes simplex virus-1 
IA 
interim analysis 
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ICAM-1 
intercellular adhesion molecule-1 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
ICU 
intensive care unit 
IEC 
independent ethics committee 
IL-6 
interleukin-6 
IND 
investigational new drug application 
IRB 
institutional review board 
IxRS 
JAK 
interactive/web voice response system 
Janus kinase 
 
 
LLQ 
lower limit of quantitation 
LS 
least square 
MAPK 
MATE 
mitogen-activated protein kinase 
multidrug and toxin extrusions 
MCAR 
missing-completely-at-random 
MedDRA 
OAT 
Medical Dictionary for Regulatory Activities 
organic anion transporter 
PAO2 
partial pressure of oxygen 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic(s) 
PH 
proportional hazards 
PK 
pharmacokinetics 
PO 
per os / orally 
PPS 
per protocol set 
QTcB 
QT corrected interval using Bazett’s formula 
QTcF 
QT corrected interval using Fridericia’s formula 
RA 
rheumatoid arthritis 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-1 
severe acute respiratory syndrome coronavirus 1 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SAS 
Statistical Analysis Software 
SE 
standard error 
SOC 
standard of care 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
ULN 
WHO 
upper limit of normal 
World Health Organization 
 
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PROTOCOL SYNOPSIS 
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)  
Short Title 
Losmapimod safety and efficacy in COVID-19 (LOSVID Study) 
Background & Rationale 
Poor prognosis for many COVID-19 patients has been attributed to an exaggerated inflammatory 
response following SARS-CoV-2 infection. This hyperactivated immune response is associated with 
pulmonary edema, acute respiratory distress syndrome (ARDS), and cardiomyopathy that may lead 
to increased mortality in the sickest patients.  
p38 mitogen-activated protein kinase (MAPK) is an important mediator of inflammation, and 
extensive nonclinical data have linked p38 to the hyper-inflammatory response to viral infections.  
/RVPDSLPRGLVDSRWHQWDQGVHOHFWLYHSĮȕ0$3.LQKLELWRUWKDWLVFXUUHQWO\LQ3KDVHFOLQLFDO
trials for the treatment of facioscapulohumeral dystrophy and has previously been administered to 
more than 3600 adult healthy volunteers and subjects including participants in a Phase 3 trial. Many 
of these trials were for chronic inflammatory indications for which the compound exhibited a 
favorable safety profile not significantly different from placebo. These trials have also indicated that 
losmapimod has good exposure after oral dosing, robust target engagement, and acutely reduces 
inflammatory biomarkers that have been associated with poor prognosis in COVID-19, including 
C-reactive protein (CRP) and interleukin-6 (IL-6). Additionally, a clinical study recently concluded 
that losmapimod restored the normal immune response of older subjects (median 69 years, range: 
65, 77 years) following a viral challenge. Further information is available in the losmapimod 
Investigator Brochure.  
Losmapimod is attractive as a potential therapeutic option for COVID-19: 
• 
p38 inhibition improves survival in mouse SARS-CoV-1 models and other nonclinical viral 
models, suppressing the exaggerated immune response to acute infection. 
• 
Losmapimod acutely has reduced exaggerated inflammatory responses in human trials for 
multiple inflammatory diseases, including IL-6 and CRP, and has normalized immune 
response to viral or other acute inflammatory challenges in older subjects. 
• 
Losmapimod is a clinical-stage, potent, and selective p38 inhibitor with extensive human 
experience and extensive evidence of safety and tolerability, including in a Phase 3 clinical 
trial in acute myocardial infarction. 
• 
p38 inhibition has the potential to reduce hypothesized deleterious effects of increased 
angiotensin II in COVID-19, such as vasoconstriction, increased inflammation, cardiac 
arrhythmias, and organ failure. 
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Objectives and Endpoints: 
All study objectives will be evaluated in subjects diagnosed with COVID-19: 
Objectives 
Endpoints 
Primary 
To assess the efficacy of losmapimod 
compared with placebo for treatment of 
COVID-19 when administered concurrently 
with standard of care 
Proportion of progressors to death or respiratory 
failure by Day 28 
Secondary 
To evaluate the effect of losmapimod 
compared with placebo on clinical 
outcomes 
Clinical status by Days 7 and 14 as measured on 
the 9-point WHO ordinal scale: 
x 
(8) death 
x 
(7) ventilation plus additional organ support 
(vasopressors, renal replacement therapy, 
ECMO) 
x 
(6) Intubation and mechanical ventilation 
x 
(5) noninvasive ventilation or high-flow oxygen 
therapy 
x 
(4) oxygen therapy but not requiring high-flow 
or non-invasive ventilation 
x 
(3) hospitalized but not requiring oxygen 
therapy 
x 
(2) Discharged from the hospital but with 
limitation of activities 
x 
(1) Discharged from the hospital and without 
any limitation 
x 
(0) No clinical evidence of the disease 
To assess the effect on clinical status of 
treatment with losmapimod compared with 
placebo 
Total number of study days free of oxygen 
supplementation 
Total number of study days in ICU 
Total number of study days hospitalized 
Total number of respiratory failure-free study days 
Percentage of subjects discharged from the 
hospital  
To assess the effect on survival following 
treatment with losmapimod compared with 
placebo 
All-cause mortality at Day 28 
Number of study days alive 
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Objectives 
Endpoints 
To assess the safety and tolerability of 
losmapimod compared with placebo 
Incidence of AEs and SAEs 
Incidence of clinically significant changes in 
laboratory parameters and vital sign measurements 
To characterize changes in SARS-CoV-2 
infection following treatment with 
losmapimod compared with placebo 
Quantifiable viral RNA on Day 7 
Abbreviations: AE = adverse event; 
; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; COVID-19 = disease caused by novel coronavirus; CRP = C-reactive protein; ECG = 
electrocardiogram; ECMO = extracorporeal membrane oxygenation; 
; ICU = intensive care 
unit; IL-6 = interleukin-6; 
; PD = pharmacodynamics; RNA = ribonucleic acid; SAE = serious 
adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; WHO = World Health Organization.  
Design 
This Phase 3 multicenter, randomized, double-blind, placebo-controlled study will evaluate the 
safety and efficacy of losmapimod versus placebo on a background of standard of care in subjects 
with COVID-19 disease. 
This study will be performed in hospitali]HGVXEMHFWV\HDUVROGZKRKDYHD&-reactive protein 
(CRP) >15 mg/L, who have been diagnosed with COVID-19, and who can undergo randomization 
within 7 days of collection of the sample found positive for the SARS-CoV-2 virus and before 
progressing into critical disease. Critical disease is defined as cardiac failure, septic shock, or 
severe pulmonary involvement (eg, bilateral extensive involvement on chest X-ray or chest 
computed tomography, ARDS, immediate need for intubation or mechanical ventilation, anticipated 
need for intubation in the next 48 hours) per the judgment of the investigator. 
Subjects who sign informed consent and meet all entry criteria (listed below) may be enrolled. 
Up to 410 subjects will participate for a maximum of 34 days, divided as follows: 
o
Screening: Day -3 until Day -1 before the first study drug administration.
o
Treatment period of 14 days:
o
Subjects randomized (1:1) to either:

losmapimod tablets 15 mg orally (PO) twice daily (BID); OR

matching placebo tablets PO BID
o
5DQGRPL]DWLRQZLOOEHVWUDWLILHGE\DJHRUDQGUHTXLUHPHQWIRUR[\JHQDW
randomization (yes/no)
o
Follow-up: 7 (± 3) days after last dose and 14 (± 3) days after last dose.
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The first 10 enrolled subjects (5 placebo and 5 losmapimod) will be dosed and followed for at least 
72 hours after their first dose for an interim “sentinel” safety review before any additional subjects 
are dosed. Dosing of additional subjects will continue if there are no drug-related safety concerns 
from the initial subjects dosed as assessed by an independent Data Monitoring Committee (DMC). 
The DMC will review safety data for the sentinel subjects and all subjects at regular intervals 
throughout the study as outlined in the charter. 
The Sponsor will monitor individual adverse events (AEs) and toxicities on an ongoing basis 
throughout the study.  
See Table 1 for the time points of the assessments. 
All study visits during the first week of treatment are anticipated to be conducted in the inpatient 
setting. If the clinical status of the subject improves such that the clinician discharges the subject 
from the hospital before the end of the study, the follow-up assessments will be conducted on an 
outpatient basis by alternative methods, including the use of local laboratories/facilities or home 
visits for blood draws, telemedicine, and/or outpatient follow-up clinic visits as deemed clinically 
appropriate per COVID-19 follow-up standard of care (SOC) at each site. 
Investigational drug 
Losmapimod will be provided in tablets of 7.5 mg for oral administration. 
Comparative drug 
Matching placebo tablets will be provided for oral administration. 
Inclusion criteria 
1. Able and willing to provide written informed consent. 
2. Willing and able to comply with all study procedures. 
3. $JH\HDUVDWWLPHRIVFUHHQLQJ 
4. Confirmed infection with SARS-CoV-2 virus at or before the baseline visit (by polymerase 
chain reaction [PCR] testing). 
a. Note: Refer to the Study Manual for details on PCR SARS-Cov-2 testing procedures. 
5. GD\Vto the time of randomization from the time of collection of the specimen that tested 
positive for SARS-CoV-2 virus. 
6. Hospitalization at the time of the baseline visit. 
7. R[\JHQ VDWXUDWLRQRQURRPDLUDQGRUR[\JHQVDWXUDWLRQRQR[\JHQ
administration at 2 L/min by nasal canula at the baseline visit. 
8. Radiographic (X-ray or computed tomography scan, per local standard of care) evidence of 
pulmonary involvement consistent with COVID-19 at screening or baseline, per the judgment 
of the investigator. 
a. Note: If radiography is not considered local standard of care for COVID-19 diagnosis, 
evidence of pulmonary involvement consistent with COVID-19 may also be obtained 
from clinical examination, per the judgment of the investigator. Evidence of 
pulmonary involvement obtained by clinical examination should be documented in 
the eCRF. 
9. Clinical syndrome consistent with COVID-19 at screening, per the judgment of the 
investigator 
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10. CRP at screening >15 mg/L on local laboratory testing. 
11. Agrees to practice an approved method of birth control as follows: 
a. Females of childbearing potential: Using 1 of the following acceptable methods of 
contraception: surgical sterilization (eg, bilateral tubal ligation), intrauterine 
contraception/device, hormonal contraception, or any 2 barrier methods (a 
combination of male or female condom with diaphragm, sponge, or cervical cap). 
This criterion must be followed from the time of the first dose of study medication until 
90 days after last dose 
b. Males: Effective male contraception includes a vasectomy with negative semen 
analysis at follow-up, or the use of condoms. This criterion must be followed from the 
time of the first dose of study medication until 90 days after last dose. 
Note: Abstinence can be considered an acceptable method of contraception at the 
discretion of the investigator. Periodic abstinence (eg, calendar, ovulation, 
symptothermal, post ovulation methods) and withdrawal are not considered 
acceptable methods of contraception. 
Exclusion criteria 
1. Inability to take oral medication at screening or baseline visit. 
2. Evidence at screening or baseline of critical COVID-19 disease (eg, cardiac failure, septic 
shock) or severe pulmonary involvement (eg, bilateral extensive involvement on chest X-ray 
or chest computed tomography, ARDS, immediate need for intubation or mechanical 
ventilation, anticipated need for intubation in the next 48 hours) per the judgment of the 
investigator.  
3. Positive pregnancy test at screening for women of childbearing potential. 
4. Lactating female at baseline for women of childbearing potential. 
a. 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. îXSSHUOLPLWRIQRUPDO8/1IRUDODQLQHor aspartate aminotransferases or total bilirubin 
!î8/1DWVFUHHQLQJRUNQRZQKLVWRU\RI&KLOG-Pugh Class C, hepatitis B or C, or HIV 
infection. 
6. Glomerular filtration rate <30 mL/min/1.73 m2 at screening. 
7. QTcF >450 msec for male or >470 msec for females or evidence of cardiac dysrhythmia at 
screening. 
8. 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. 
9. Treatment with anti-IL 6, anti-IL-6R antibodies, Janus kinase (JAK) inhibitors, or other 
immune modulators (unless considered part of local standard of care) in the past 30 days or 
5 half-lives (whichever is longer) or plan to receive these agents as part of investigational 
clinical trials any time during the study period. 
10. 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. 
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11. Recent (within 30 days) or current participation in other COVID-19 therapeutic trials or 
expanded access programs. 
12. Prior or current participation in COVID-19 vaccine trials. 
Sample size justification 
The primary efficacy endpoint of this study is the proportion of subjects who progress to death or 
UHVSLUDWRU\IDLOXUHE\WKHHQGRIVWXG\'D\,WLVHVWLPDWHGWKDWDSSUR[LPDWHO\RIHQUROOHG
subjects receiving SOC plus placebo will attain this endpoint. It is assumed that losmapimod will 
LPSURYHWKHSULPDU\HQGSRLQWE\RYHUSODFHER2QWKHEDVLVRIWKHVHDVVXPSWLRQVDWRWDORI
410 subjects randomized to the losmapimod arm or the placebo arm in a 1:1 ratio (205 subjects in 
the losmapimod arm and 205 VXEMHFWVLQWKHSODFHERDUPZLOO\LHOGDSSUR[LPDWHO\SRZHULQD
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(IA) will be conducted after approximately 206 subjects (103 in each of the losmapimod and placebo 
arms) have completed the Day 28 visit, to assess futility.   
Statistical methodology 
A statistical analysis plan (SAP) will be generated and approved prior to database snapshot for the 
IA. The SAP will detail the implementation of all planned statistical analysis. Any deviations from the 
planned analysis will be described and justified in the final clinical study report. 
In general, all study endpoints will be summarized using descriptive statistics. Descriptive statistics 
for continuous data will include number of subjects (n), mean, standard deviation, median, 
minimum, and maximum. Descriptive statistics for categorical data will include frequency and 
percentage.  
 
Where appropriate, descriptive statistics may be SUHVHQWHGZLWKFRQILGHQFHLQWHUYDOV 
Analysis sets 
Full Analysis Set (FAS): The FAS will consist of all subjects who are randomly assigned to receive 
double-blind study drug. All analyses using the FAS will group subjects according to randomized 
treatment. The primary endpoint, clinical outcomes/status, survival, and pharmacodynamic 
endpoints will be analyzed using the FAS. 
Per Protocol Set (PPS): The PPS will consist of all FAS subjects who fulfill all inclusion/exclusion 
criteria and do not have any significant protocol deviations. All analyses using the PPS will group 
subjects according to randomized treatment. 
Safety Analysis Set: The safety analysis set is defined as all subjects who are randomized and 
receive study drug. All analyses using the Safety Analysis Set will group subjects according to 
treatment actually received. The safety analysis set will be used for all safety and tolerability 
analyses. 
Primary endpoint 
For the final analysis, the proportion of subjects achieving the primary endpoint in the treatment 
arms will be compared using a stratified Cochran-Mantel-Haenszel test, adjusting for randomization 
stratification variables. An interim analysis to assess futility analysis—and potential sample size re 
estimation—will be conducted. All results will be summarized descriptively by treatment arm and 
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between response rates, and p values. 
Secondary endpoints 
Clinical status at Day 7 and Day 14: percentages for each category of the ranking scale will be 
tabulated by treatment arm, along with differences between treatment arms. The proportion of 
subjects for each of the items in the scale will be compared using a stratified Cochran-Mantel-
Haenszel test, adjusting for randomization stratification variable.  
Total number of study days: (a) free of oxygen supplementation; (b) in ICU; (c) of hospitalization; (d) 
free of respiratory failure; (e) alive: For each endpoint (a) - (e), a Poisson regression model or a 
negative binomial model will be used to assess the relationship with treatment, with age group as a 
covariate with stratification factors as covariates. Details of the model, including censoring rules, if 
any, will be provided in the SAP. 
Percentage of subjects discharged from the hospital: percentages of subjects discharged from the 
hospital will be tabulated by treatment arm, along with differences between treatment arms. The 
proportion of subjects will be compared using a stratified Cochran-Mantel-Haenszel test, adjusting 
for randomization stratification variables. 
All-cause mortality at Day 28: percentages of subjects will be tabulated by treatment arm, along with 
differences between treatment arms, at each time point. The proportion of subjects will be compared 
using a stratified Cochran-Mantel-Haenszel test, adjusting for randomization stratification variables. 
Incidence of AEs/SAEs: will be summarized by system organ class and preferred term and by 
treatment arm using percentages. 
Incidence of clinically significant changes: Percentage of subjects with clinically significant changes 
in laboratory parameters, ECG, and vital sign measurements will be computed for each treatment 
arm along with associated 2-VLGHG&ORSSHU-Pearson CI.  
Clearance of quantifiable viral RNA by Day 7: percentages of subjects with clearance of quantifiable 
viral RNA will be tabulated by treatment arm, along with differences between treatment arms, at 
each time point. The proportion of subjects will be compared using a stratified Cochran-Mantel-
Haenszel test, adjusting for randomization stratification variables.
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 Table 1: Visit and Assessment Schedule 
 
SCR 
Treatment Period 
FU14 
ET 
Time point 
Assessment1 
-3d to 
-1d  
D1 
(base-
line) 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D10 
D12 
D14 
D21  
(± 
3d) 
D28  
(± 
3d) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history, including COVID-19 
clinical diagnosis2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray/CT scan 
X3 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug administration: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Losmapimod or placebo PO BID 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Pharmacodynamics: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug levels/PK4 
 
P, 4-5h 
4-5h 
4-5h 
4-5h 
4-
5h 
4-
5h 
4-
5h 
 
 
 
4-
5h 
 
 
X 
X 
X 
Clinical status and symptoms: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Respiratory failure and survival 
assessment6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical status assessment per WHO 9-
point scale6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Viral presence and viral load by central 
testing (nasopharyngeal [preferred] or 
oropharyngeal swab) 7 
 
X 
X 
(sentinel 
only)7 
X (sentinel 
only)7 
X (sentinel 
only)7 
 
 
X 
 
 
 
 
 
 
X 
Confirmation of COVID-19 diagnosis 
(nasopharyngeal [preferred] or 
oropharyngeal swab) 
X2 
X (PR)2 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oxygenation and FiO28 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
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SCR 
Treatment Period 
FU14 
ET 
Time point 
Assessment1 
-3d to 
-1d  
D1 
(base-
line) 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D10 
D12 
D14 
D21  
(± 
3d) 
D28  
(± 
3d) 
Safety assessments:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Weight/height9 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Hematology, chemistry safety labs6 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
CRP6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis10 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
8ULQHRUVHUXPȕ-hCG (female subjects 
only) 
X11 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
ECG12 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
HR, BP, RR, temperature8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
(S)AEs13 
X 
X 
Concomitant medications (including 
SOC) 
X 
X 
AE = adverse event; BP = blood pressure; COVID-19 = novel coronavirus; HR = heart rate; P = pre dose; PAO2 = partial pressure of oxygen; PR – pre-randomization; RR = respiratory rate; sent = sentinel; 
SOC = standard of care; SCR = screening. 
Note: All screening assessments are to be performed before dosing. If procedures required at any time point have already been performed as part of routine clinical care, these assessments do not need to 
be repeated, and information will be collected and entered on the eCRF from the subject’s medical records. Unscheduled visits can take place at any time at the discretion of the site to check for new 
AEs/SAEs or to repeat key missed assessments or for other reasons. 
1 The order of assessments can be performed at the discretion of the investigator once informed consent is obtained. 
2 COVID-19 diagnosis to be confirmed by local testing (PCR) before randomization and first dosing. 
3 To be performed while hospitalized based on standard-of-care local assessment. Result required for eligibility assessment to confirm radiographic evidence of COVID-19. If 
radiography is not considered local standard of care for COVID-19 diagnosis, evidence of pulmonary involvement consistent with COVID-19 may also be obtained from clinical 
examination, per the judgment of the investigator. Evidence of pulmonary involvement obtained by clinical examination should be documented in the eCRF. 
4 PK assessments will be performed as a substudy in all sentinel subjects. For those subjects requiring dialysis, a single pre- and post-dialysis PK should be obtained for review by the 
DMC to decide if dose adjustment is needed. PK should be measured weekly at Cmax (4-5 hours post dose) for subjects with renal insufficiency when possible. 
 
.  
6 Assessments for clinical/respiratory status, progression, and safety serum chemistry and hematology tests to be performed and samples to be collected while hospitalized based on 
standard-of-care local laboratory assessments and after discharge from the hospital by home visit or outpatient clinic visit or telemedicine call. For subjects who are discharged to 
home or other outpatient setting after initial hospitalization, the assessments and laboratory samples can be obtained less often but not less than at least once weekly. CRP result 
required to determine eligibility are based on local laboratory results at screening. 
7 Viral load testing will be collected daily for the first 4 days using local testing in the first 10 enrolled subjects as part of the sentinel safety assessment. For all subjects, including the 
sentinel subjects, swabs or other sample collection for central viral load testing will be collected on D1 pretreatment  and on D7 or earlier if being discharged from the hospital prior to 
D7.  
8 Vital signs will be performed after subjects have been supine for at least 5 minutes when possible. Vital signs to include oxygen saturation; PaO2 should be recorded if available from 
blood gases obtained as part of SOC; oxygen administration should also be recorded (eg, room air or oxygen flow by nasal canula or facial mask or endotracheal tube). For subjects 
who are discharged to home or other outpatient setting after initial hospitalization, assessments may be obtained less often but at least once per week in the outpatient clinic or at 
home. 
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9 Height assessed at screening only; can be by self-report or from medical records. Weight is an actual recording. 
10 Urinalysis will be performed during the study period only on Day 7 and on any other day only if clinically indicated. 
11 Pregnancy testing to be conducted within 72 hours of the first dose of study treatment. 
12 Standard 12-lead ECGs will be performed after the subject has been supine for at least 5 minutes if possible. ECGs will be performed at Day 7 in all subjects and at any other time 
during the study if clinically indicated. 
13 Adverse events and SAEs will be assessed from the time the subject signs the ICF through the D28 follow-up visit. 
14 Outpatient assessments to be conducted via telemedicine or outpatient clinic. Outpatient laboratory assessments to be completed at outside local laboratory or home or outpatient 
visit.
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1 
BACKGROUND AND RATIONALE 
1.1 
Scientific rationale for investigation of losmapimod in COVID-19 
COVID-19 is a severe pandemic disease with high mortality particularly in older individuals, due to 
infection with the SARS-CoV-2 coronavirus. 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 older population is especially at risk of severe disease 
and death upon infection with SARS-CoV-2. The hyperactivated immune response in COVID-19 
shares features of the cytokine storm syndrome and appears to be responsible for the severe 
pulmonary edema, ARDS, and cardiac and renal disease responsible for most of the severe 
morbidity and mortality.  
The proposal to develop losmapimod, a potent, specific, and bioavDLODEOHSĮȕLQKLELWRUIRU
treatment of COVID-19 is based on the following rationale:  
(1) Nonclinical work has shown that older mice infected with SARS-CoV-1 develop much 
more severe disease than younger ones, and that treatment with a p38 MAPK small 
molecule inhibitor greatly reduced their mortality when given after viral inoculation; 
similar survival benefit of p38 MAPK inhibition has been seen in animal models of severe 
H5N1 influenza and HSV-1.  
(2) Nonclinical work has shown that p38 MAPK inhibition reduces viral load in several 
experimental models with coronaviruses, including mouse hepatitis virus, human 
CoV-229E, transmissible gastroenteritis virus, and Middle East respiratory syndrome 
virus.  
(3) p38 MAPK is proposed to play a critical role in the development of ARDS, including 
regulating the expression and activity of inflammatory mediators such as ICAM-1, 
HMGB1, and ET-1, neutrophil chemotaxis and apoptosis, the balance of Treg/Th17 cells, 
and pulmonary endothelial cell apoptosis.  
(4) Clinical investigation showing that excessive acute inflammation in response to external 
stressors in older individuals, including viral antigen challenges, hinders the specific 
immune response to infection; many of the excessive inflammatory mediators associated 
with this aberrant immune response in older individuals are associated with activation of 
the p38 MAPK pathway.  
(5) Treatment with losmapimod in older subjects restored the normal immune response to 
viral antigen challenge and improved the resolution of acute inflammation.  
(6) Treatment of various inflammatory diseases with losmapimod, including active 
rheumatoid arthritis (RA), acute myocardial infarction, and chronic obstructive pulmonary 
disease (COPD) resulted in significant reduction in markers of acute inflammation, 
including interleukin-6 (IL-6), C-reactive protein (CRP), chemokines such as CXCL13, 
and other markers (see Table 5 for further details). 
(7) Losmapimod may be beneficial in COVID-19 treatment via reduction of the damaging 
effects of angiotensin II (Ang II). Angiotensin-converting enzyme 2 (ACE2) is the cellular 
receptor for SARS-CoV viruses and is expressed in the lung and the heart. Upon 
infection with SARS-CoV-2, there is internalization of and depletion of ACE2. ACE2 
converts Ang II into angiotensin 1-7 (Ang 1-7), which counterbalances the 
vasoconstrictive and pro-inflammatory effects of Ang II. Ang II is significantly elevated in 
COVID-19, and the levels are positively correlated with viral load and acute lung injury 
(Liu Y et al, 2020). Blocking the p38 MAPK pathway in nonclinical models has been 
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shown to reduce many of the adverse effects of elevated Ang II, resulting in lower 
frequency of cardiac arrhythmias, renal failure, and hypertension. 
p38 inhibitors have been explored extensively in clinical trials for numerous chronic inflammatory 
indications, as summarized in the Investigator Brochure. Losmapimod has been extensively tested 
in humans and found to be generally well tolerated, including in over 3600 adult healthy volunteers 
and subjects in 11 different indications. The 15 mg oral (PO) twice per day (BID) dose proposed for 
the COVID-19 Phase 3 study has been shown to provide robust and sustained inhibition of the p38 
MAPK pathway systemically and in tissues, specifically in skeletal muscle needle biopsies of 
subjects with facioscapulohumeral muscular dystrophy (FSHD). This dose of losmapimod was 
shown experimentally in older (median 69 years, range: 65, 77 years) human volunteers to restore 
the normal immune response to viral challenge and improve the resolution of acute inflammation. 
Furthermore, losmapimod has been shown to significantly reduce markers of hyperactive acute 
innate immune inflammation in the context of acute myocardial infection, RA, and COPD in clinical 
trials as listed below:  
1- Single-dose study in 50 subjects with RA (RA 3103730). Treatment with losmapimod (N=38) 
reduced levels of IL-6 compared with placebo (N=12). Losmapimod was dosed as follows: 
7.5 mg: 13 subjects; 20 mg: 12 subjects; 60 mg: 13 subjects. Analysis of serum IL-6 at 
3 hours post dose showed significantly lower levels with losmapimod than with placebo 
(Table 2). 
Table 2:  
Change from Baseline in IL-6 Serum Levels with Increasing Single Doses of 
Losmapimod in Subjects with Rheumatoid Arthritis 
Treatment group 
Adjusted ratio to baseline 
95% CI 
Adjusted ratio to placebo 
95% CI 
Placebo 
0.92 
0.60, 1.41 
 
 
Losmapimod 7.5 mg 
0.41 
0.26, 0.63 
0.45 
0.24, 0.82 
Losmapimod 20 mg 
0.43 
0.27, 0.68 
0.47 
0.25, 0.88 
Losmapimod 60 mg 
0.38 
0.25, 0.57 
0.41 
0.23, 0.75 
Abbreviations: CI = confidence interval. 
2- Repeated-dose study in subjects with acute coronary syndrome (ACS; PM1111810). A total 
of 535 subjects with non-ST elevation myocardial infarction were randomized to an initial 
dose of 7.5 or 15 mg of losmapimod followed by 7.5 mg PO BID (N= 388) or matching 
placebo (N=138) for 12 weeks. Results showed that relative to placebo, losmapimod 
significantly suppressed CRP and IL-6 acutely at the 24- to 36-hour assessments (Table 3). 
Table 3: 
Change from Baseline in hsCRP and IL-6 with 7.5mg PO BID Losmapimod Over 
Placebo in Subjects with Acute Coronary Syndrome 
Parameter 
Placebo (N=138) 
All losmapimod 
(N=388) 
P value 
hsCRP at 72 hours or 
discharge (nmol/L) 
110.8 (83.1-147.7) 
64.1 (53.0-77.6) 
<0.05 
IL-6 at 24 hours (ng/L) 
10.6 (8.6-13.1) 
6.6 (5.8-7.4) 
<0.05 
Abbreviations: hsCRP = high-sensitivity C-reactive protein; IL-6 = interleukin-6. 
3- Repeated-dose study in subjects with COPD (MKI113006). In this study, subjects with 
COPD were dosed with losmapimod 2.5 mg BID (N=149), losmapimod 7.5 mg BID (N=151), 
or placebo BID (N=154) for 24 weeks; or losmapimod 7.5 mg BID for 4 weeks followed by 
losmapimod 15 mg BID (N=150) for 20 weeks. Over the first 12 weeks of treatment, 
statistically significant reductions in serum high-sensitivity CRP (hsCRP) levels were 
observed in the losmapimod 7.5 mg and 15 mg groups compared with placebo. For hsCRP, 
:HHNPJGRVHYHUVXVSODFHERUDWLRFRQILGHQFHLQWHUYDO>&,@
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Losmapimod 
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Protocol Version 1 / 29-May-2020  
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S PJGRVHYHUVXVSODFHERUDWLR&,S01. Table 4 shows 
the results for the subgroup with higher CRP at baseline. 
Table 4: 
Change from Baseline in CRP Over 12 Weeks of Treatment with Different 
Doses of Losmapimod Compared with Placebo in Subjects with COPD and 
High Baseline CRP Levels (>6.4 mg/L) 
Week 12  
Baseline hsCRP 
>6.40 mg/L 
Placebo BID 
(N=42) 
Losmapimod 
2.5 mg BID (N=33) 
Losmapimod 
7.5 mg BID (N=31) 
Losmapimod 
15 mg BID (N=31) 
Geometric LS 
mean (SE of logs) 
6.75 (0.153) 
8.08 (0.180) 
5.16 (0.180) 
3.54 (0.186) 
Geometric LS 
mean ratio to 
baseline (SE of 
logs) 
0.49 (0.153) 
0.59 (0.180) 
0.38 (0.180) 
0.26 (0.186) 
Column vs placebo 
 
 
 
 
Ratio 
 
1.20 
0.77 
0.53 
&, 
 
0.75, 1.92 
0.48, 1.22 
0.33, 0.85 
Abbreviations: CI = confidence interval; hsCRP = high-sensitivity C-reactive protein; LS = least square; SE = standard 
error. 
Fulcrum Therapeutics is planning to conduct the initial clinical trial for the investigation of 
losmapimod for the treatment of COVID-19 in these high-risk subjects. Losmapimod is currently in 
Phase 2 clinical development for the treatment of the root cause of FSHD under an open IND in the 
United States and open clinical trial applications in Canada, Spain, France, and The Netherlands.  
A summary of published literature supporting the therapeutic hypothesis for the clinical development 
of losmapimod for the treatment of COVID-19 is provided in Table 5.  
Table 5: 
Listing of Evidence Supporting the Development of the p38 Inhibitor 
Losmapimod for Treatment of COVID-19 
Evidence 
References 
Pneumonitis, acute respiratory distress syndrome, 
pulmonary edema, and cardiomyopathy drive COVID-19 
mortality 
x 
Siddiqi HK et al. J Heart Lung 
Transplant. 2020 
x 
Ruan Q et al. Intensive Care 
Med. 2020 Mar 3 
Older patients are at greatest risk of COVID-19 mortality 
x 
Ruan Q et al. Intensive Care 
Med. 2020 Mar 3 
Human SARS-CoV-2 pathology is recapitulated in SARS-
CoV-1 mice 
x 
Zhou F et al. Lancet. 2020 
x 
Nagata N et al. Am J Pathol. 
2008 
Exaggerated acute inflammatory response and lymphopenia 
correlate with mortality in human with COVID-19 and older 
mice infected with SARS-CoV-1 
x 
Nagata N et al. Am J Pathol. 
2008 
x 
Zhou F et al. Lancet. 2020 
SARS-CoV-1 activates the p38 MAPK pathway in peripheral 
blood early in the infection 
x 
Lee CH et al. J Immunol. 2004. 
SARS-CoV envelope protein (E) activates the host’s 
inflammatory response via p38 signaling 
x 
Jimenez-Guardeño JM et al. 
PLOS Pathog. 2014 
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Evidence 
References 
Several nonclinical studies have shown evidence of p38 
inhibition reducing viral replication including with coronavirus 
x 
Kono M et al. Antiviral Res. 
2008  
x 
Dong Y et al. Antiviral Res. 
2020 
x 
Kindrachuk D et al. Anti Microb 
Agents & Chem. 2015 
p38 inhibition reduces mortality in older mice infected with 
SARS-CoV-1 
x 
Jimenez-Guardeño J et al. 
PLOS Pathog. 2014 
Nonclinical efficacy of p38 inhibition also observed in other 
models of severe acute viral pneumonitis and other severe 
acute viral infections 
x 
Shapiro L et al. PNAS. 1998 
x 
Iordanov MS et al. Mol Cell 
Bio. 2000 
x 
Salomon R et al. PNAS. 2007 
x 
Griego SD et al. J Immunol. 
2000 
x 
Banerjee S et al. J Virology. 
2002 
x 
Börgeling Y et al. J Biol Chem. 
2014 
x 
Chen Y et al. J Exp Med. 2017 
x 
He F et al. J Transl Med. 2019 
p38 inhibition reduces lung mucous production in mice 
models of toxic airway injury  
x 
Liu et al. Int 
Immunopharmacol. 2009 
Losmapimod and other p38 inhibitors acutely reduce 
inflammatory markers in humans 
x 
GSK data in Fulcrum Original 
IND 138739, Module 4 
x 
Genovese M et al. J 
Rheumatol. 2011 
x 
Christie J et al. Crit Care Med. 
2015  
Losmapimod reduces inflammatory markers associated with 
COVID-19 severity at currently utilized doses 
x 
Fulcrum clinical data on file 
x 
GSK clinical data  
x 
Newby L et al. Lancet. 2014 
 
Inhibition of p38 with 15 mg losmapimod BID dose in older 
subjects restored the adaptive immune response to viral 
challenge 
x 
Vukmanovic-Stejic M et al. J 
Allergy Clin Immunol. 2018 
Exaggerated acute inflammatory response in older subjects 
is driven to a large extent by p38 activation 
x 
Vukmanovic-Stejic M et al. J 
Allergy Clin Immunol. 2018 
In vivo data in Ferrets indicate SARS-Cov-2 induces 
profoundly lower immune response vs other virus 
x 
Blanco-Melo D et al. bioRxiv. 
2020 
Evidence that p38 inhibition may treat the deleterious effects 
of elevated Ang II in COVID-19 
x 
Grimes JM et al. J Mol Cell 
Cardiol. 2020 
Losmapimod is a highly selective p38 inhibitor at advanced 
stage of clinical development with excellent safety data 
profile 
x 
Losmapimod Investigator 
Brochure Fulcrum 2020 
x 
Cadavid D et al. FSHD IRC 
Poster. 2019 
Abbreviations: BID = twice daily; COVID-19 = disease caused by novel coronavirus; IND = investigational new drug 
application; SARS-CoV-1 = severe acute respiratory syndrome coronavirus 1; SARS-CoV-2 = severe acute respiratory 
syndrome coronavirus 2.  
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2 
STUDY OBJECTIVES AND ENDPOINTS 
All study objectives will be evaluated in subjects diagnosed with COVID-19. 
Objectives 
Endpoints 
Primary 
To assess the efficacy of losmapimod compared 
with placebo for treatment of COVID-19 when 
administered concurrently with standard of care 
Proportion of progressors to death or 
respiratory failure by Day 28 
Secondary 
To evaluate the effect of losmapimod compared 
with placebo on clinical outcomes 
Clinical status by Days 7 and 14 as 
measured on the 9-point WHO ordinal scale 
(WHO 2020): 
x 
(8) death 
x 
(7) ventilation plus additional organ 
support (vasopressors, renal 
replacement therapy, ECMO) 
x 
(6) Intubation and mechanical 
ventilation 
x 
(5) noninvasive ventilation or high-flow 
oxygen therapy 
x 
(4) oxygen therapy but not requiring 
high-flow or non-invasive ventilation 
x 
(3) hospitalized but not requiring oxygen 
therapy 
x 
(2) Discharged from the hospital but 
with limitation of activities 
x 
(1) Discharged from the hospital and 
without any limitation 
x 
(0) No clinical evidence of the disease 
To assess the effect on clinical status of treatment 
with losmapimod compared with placebo 
Total number of study days free of oxygen 
supplementation 
Total number of study days in ICU 
Total number of study days hospitalized 
Total number of respiratory failure-free 
study days 
Percentage of subjects discharged from the 
hospital  
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Objectives 
Endpoints 
To assess the effect on survival following treatment 
with losmapimod compared with placebo 
All-cause mortality at Day 28 
Number of study days alive 
To assess the safety and tolerability of losmapimod 
compared with placebo 
Incidence of AEs and SAEs 
Incidence of clinically significant changes in 
laboratory parameters and vital sign 
measurements 
To characterize changes in SARS-CoV-2 infection 
following treatment with losmapimod compared 
with placebo 
Quantifiable viral RNA on Day 7 
Abbreviations: AE = adverse event; 
 ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; COVID-19 = disease caused by novel coronavirus; CRP = C-reactive protein; ECG = 
electrocardiogram; ECMO = extracorporeal membrane oxygenation; 
; ICU = intensive care 
unit; IL-6 = interleukin-6; 
; PD = pharmacodynamics; RNA = ribonucleic acid; SAE = serious 
adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; WHO = World Health Organization.  
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3 
STUDY IMPLEMENTATION 
3.1 Overall study design and plan 
This Phase 3 multicenter, randomized, double-blind, placebo-controlled study will evaluate the 
safety and efficacy of losmapimod versus placebo on a background of standard of care in subjects 
with COVID-19 disease. 
7KLVVWXG\ZLOOEHSHUIRUPHGLQKRVSLWDOL]HGVXEMHFWV\HDUVROGZKRKDYHD&-reactive protein 
(CRP) >15 mg/L, who have been diagnosed with COVID-19, and who can undergo randomization 
within 7 days of collection of the sample found positive for the SARS-CoV-2 virus and before 
progressing into critical disease. Critical disease is defined as cardiac failure, septic shock, or 
severe pulmonary involvement (eg, bilateral extensive involvement on chest X-ray or chest 
computed tomography, ARDS, immediate need for intubation or mechanical ventilation, anticipated 
need for intubation in the next 48 hours) per the judgment of the investigator. 
Subjects who sign informed consent (refer to Section 9.1.3) and meet all entry criteria (see 
Section 4) may be enrolled. 
 
Up to 410 subjects will participate for a maximum of 34 days, divided as follows: 
o Screening: Day -3 until Day -1 before the first study drug administration. 
o Treatment period of 14 days: 
o Subjects randomized (1:1) to either:  
 
losmapimod tablets 15 mg PO BID; OR  
 
matching placebo tablets PO BID 
o 5DQGRPL]DWLRQZLOOEHVWUDWLILHGE\DJHRUDQGUHTXLUHPHQWIRUR[\JHQDW
randomization (yes/no) 
o Follow-up: 7 (± 3) days after last dose and 14 (± 3) days after last dose. 
The first 10 enrolled subjects (5 placebo and 5 losmapimod) will be dosed and followed for at least 
72 hours after their first dose for an interim “sentinel” safety review before any additional subjects 
are dosed. Dosing of additional subjects will continue if there are no drug-related safety concerns 
from the initial subjects dosed as assessed by an independent Data Monitoring Committee (DMC). 
The DMC will review safety data for the sentinel subjects and all subjects at regular intervals 
throughout the study as outlined in the charter (see Section 8.10).  
The Sponsor will monitor individual adverse events (AEs) and toxicities on an ongoing basis 
throughout the study. 
See Table 1 for the time points of the assessments. 
All study visits during the first week of treatment are anticipated to be conducted in the inpatient 
setting. If the clinical status of the subject improves such that the clinician discharges the subject 
from the hospital before the end of the study, the follow-up assessments will be conducted on an 
outpatient basis by alternative methods, including the use of local laboratories/facilities or home 
visits for blood draws, telemedicine, and/or outpatient follow-up clinic visits as deemed clinically 
appropriate per COVID-19 follow-up standard of care (SOC) at each site (refer to Section 6.7). 
3.2 Start of study and end of study definitions 
The start of the study is defined as the date the first enrolled subject signs an informed consent form 
(ICF). The end of the study is defined as the date of the last subject’s last assessment (scheduled or 
unscheduled). 
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3.3 Selection of doses in the study 
In the Phase 1 study in healthy volunteers and FSHD subjects (Study FIS-001-2018), the dose 
levels of 7.5 mg and 15 mg given by mouth BID with food were based on predictive nonclinical 
efficacy and published clinical target engagement and safety data for losmapimod previously 
generated by GSK. This Phase 1 study was recently completed and demonstrated that the 15 mg 
PO BID dose gives higher plasma levels and greater and more sustained target engagement in 
blood and tissues than the 7.5 mg PO BID dose, while resulting in similar safety and tolerability. The 
15 mg BID dose is used in the ongoing Phase 2 studies in FSHD (Study FIS-001-2019 and Study 
FIS-002-2019). Prior results indicated the favorable safety and tolerability of losmapimod for chronic 
administration in the clinic, including in the context of severe acute diseases, such as acute 
myocardial infarction, in older people. 
Prior studies of biodistribution of radiolabeled losmapimod by GSK showed ample distribution to all 
tissues including the lungs and the heart. Our recent target engagement data in the FSHD Phase 1 
Study FIS-001-2018 indicates that pHSP27 inhibition in blood, an assessment of p38 target 
engagement, is nearing a plateau at a losmapimod dose of 15 mg BID (see Investigator Brochure 
[Fulcrum Therapeutics 2020]), so doses of losmapimod higher than 15 mg PO BID are not 
warranted. 
Additionally, at the proposed dose level of 15 mg PO BID, exposures are not expected to exceed 
those previously demonstrated to be safe in humans in multiple previous studies by GSK in healthy 
volunteers and various patient populations including older subjects (Cheriyan et al 2011; Barbour et 
al 2013; Watz et al 2014; Pascoe et al 2017). 
In previous clinical studies performed by GSK, it was shown that losmapimod significantly reduced 
markers of acute inflammation, including IL-6, CRP, and the CXCL13 chemokine after a single 
dose. Additionally, losmapimod reduced IL-6 after 15 days of treatment (GSK study RA3103718) 
and CRP acutely in subjects with acute myocardial infarction treated with 7.5 mg PO BID 
(O’Donoghue et al 2016). In subjects with COPD, losmapimod at 15 mg PO BID significantly 
reduced CRP over 12 weeks compared with placebo (GSK Study MKI 113006). In one study in 
healthy older adult volunteers, it was shown that a 15 mg PO BID dose of losmapimod for 4 days 
restored the normal immune response to varicella-zoster virus antigen challenge (Vukmanovic-
Stejic et al 2018). The same formulation used in these previous clinical studies is the one proposed 
for use in the present clinical study. 
The rationale for the proposed study duration of up to 28 days is that in most cases of COVID-19 
the disease has resolved or resulted in severe outcomes over the first month from onset of 
symptoms. COVID-19 is a severe and rapidly progressive infection, especially in the high-risk 
population selected for the proposed Phase 3 trial. Therefore, treatment for longer than 14 days and 
study duration for longer than 28 days is not justified. 
3.4 Study drug modifications and withdrawal 
3.4.1 
Dose modifications 
Before trial medication is administered, changes in the subject's health status, including laboratory 
results if applicable, since the previous visit or previous dose should be checked.  
Study drug interruptions and reductions are not permitted; subjects who are on dialysis may require 
a dose adjustment. 
Study treatment dose adjustment for subjects on dialysis  
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administered dose recovered as unchanged drug in urine and feces. The metabolite is clinically 
inactive and does not exert any toxic effects. 
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Losmapimod has not been studied in renal insufficiency or renal failure. There has been 1 study of 
losmapimod in 17 subjects with focal segmental glomerulosclerosis (FSGS; FSG117283). In this 
study, subjects were given losmapimod 7.5 mg BID for 2 weeks followed by losmapimod 15 mg BID 
for 22 weeks. The mean duration of exposure to investigational product in subjects with FSGS was 
approximately 21 weeks (range: 3.7, 25 weeks).  
Creatine and GFR for the population enrolled is in the table below.  
Parameter 
Mean (SD) 
Range 
eGFR (mL/min/1.73m2) 
79.4 (34.9) 
36, 155 
Creatine (μmol/L) 
1.1 (0.5) 
0.48, 2.07 
eGFR = estimated glomerular filtration rate. 
 
Losmapimod plasma concentration data in subjects with FSGS were compared with historical data 
obtained in the Phase 3 clinical trial in subjects with ACS. In general, exposure in subjects with 
FSGS was similar to that in subjects with ACS over the 24-week treatment period. 
Consistent with the safety database of over 3500 subjects, the 2 most frequently reported AEs in the 
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vomiting, dizziness, oropharyngeal pain, nausea, blood creatinine increased, muscle spasms, and 
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 subjects each. Four subjects had at least 1 AE that led to withdrawal from the study or from 
treatment. The AEs that led to discontinuation were increase in blood urea nitrogen (related), 
increase in creatinine (not related), increase in cystatin C (related), and joint stiffness (related). 
None of the AEs was serious or severe; 3 of the AEs in 2 subjects were reported as related to study 
treatment. 
Based on the current safety and exposure information, dosing adjustment is likely not needed for 
subjects with renal insufficiency. However, close monitoring of pharmacokinetics (PK) for such 
cases will be implemented to ensure that therapeutic concentrations are maintained (refer to 
Section 6.2). For those subjects requiring dialysis, dose adjustment may be needed and will be 
determined by pre- and post-dialysis PK by the DMC. Adjustments may be recommended by the 
DMC also for subjects on placebo who develop acute renal failure to prevent unblinding at the sites. 
Study treatment discontinuation 
Discontinuation of study treatment should be considered if:  
• 
ALT or AST >8 x the upper limit of normal (ULN)  
• 
ALT or AST >5 x ULN for more than 2 weeks  
• 
ALT or AST >3 x ULN and (total bilirubin >2 x ULN or international normalized ratio >1.5) in 
the absence of reasonable alternative etiology 
• 
ALT or AST >3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or WHQGHUQHVVIHYHUUDVKDQGRUHRVLQRSKLOLD! 
• 
QTcF prolongation with QTcF >500 msec or an increase in QTcF of >60 msec over baseline 
(confirmed by 2 successive repeat measurements) 
In addition, the investigator must permanently discontinue the study drug if continued administration 
of the study drug is believed to be contrary to the best interests of the subject. The premature 
discontinuation of study drug might be triggered by an adverse event (AE), a diagnostic or 
therapeutic procedure, an abnormal assessment (eg, ECG or laboratory abnormalities), or for 
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administrative reasons, in particular withdrawal of the subject’s consent. The reason for study drug 
interruption or premature discontinuation must be clearly documented in the eCRF. 
3.4.2 
Subject withdrawal 
Subjects may withdraw from the study at any time and for any reason without prejudice to their 
future medical care by the investigator or at the study site. Every effort should be made to keep 
subjects in the study, including if a subject and/or their treating physician decides to prematurely 
discontinue study treatment. The reasons for subjects not completing the study will be recorded. A 
subject may be withdrawn from the study for any of the following reasons: 
1. The subject is noncompliant with the protocol. 
2. The subject has a serious or intolerable adverse event(s) (AE[s]) that, in the investigator’s 
opinion, require(s) withdrawal from the study. 
3. The subject has laboratory safety results that reveal clinically significant hematological or 
biochemical worsening from the baseline values that could be attributed to the study 
medication. 
4. The subject develops symptoms or an intercurrent illness not consistent with the protocol 
requirements or that justify withdrawal. 
5. The subject is lost to follow-up. 
6. Other reasons (eg, pregnancy, development of contraindications of use of study drug as 
determined by the sponsor or the treating physician). 
7. The study is discontinued by the sponsor or the study site. 
For subjects to be considered as lost to follow-up, 2 attempts should be made to contact the subject 
to return for the scheduled study visit. After 2 attempts, a certified letter should be sent to the 
subject’s address requesting the subject to contact the investigator to schedule a follow-up 
assessment. If no reply is provided by the subject within 30 days of receipt of the certified letter, the 
subject can then be considered lost to follow-up. 
3.4.3 
Replacement policy 
Subjects who withdraw from the study will not be replaced. 
 
3.4.4 
Stopping criteria 
Dosing will be stopped in case of an unacceptable tolerability profile based on the nature, 
frequency, and intensity of observed AEs judged jointly by the investigator and the sponsor or as 
recommended by the DMC. 
 
In the event of a study hold due to unacceptable tolerability, the sponsor will conduct an extensive 
safety and PK analysis and will communicate to stakeholders, including the Investigators, 
institutional review boards (IRBs)/independent ethics committees (IEC), and health authorities any 
potentially emergent safety information as well as the timing of planned resumption of dosing. 
Dosing and enrollment will not resume unless it is considered safe to do so after consultation with 
Investigators and health authorities and approval by IRBs/IECs. 
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4 
STUDY POPULATION 
4.1 Inclusion criteria 
Eligible subjects must meet all of the following inclusion criteria at screening. 
1. Able and willing to provide written informed consent. 
2. Willing and able to comply with all study procedures. 
3. $JH\HDUVDWWLPHRIscreening. 
4. Confirmed infection with SARS-CoV-2 virus at or before the baseline visit (by polymerase 
chain reaction [PCR] testing). 
a. Note: Refer to the Study Manual for details on PCR SARS-Cov-2 testing procedures. 
5. 7 days to the time of randomization from the time of collection of the specimen that tested 
positive for the SARS-CoV-2 virus. 
6. Hospitalization at the time of the baseline visit. 
7. R[\JHQVDWXUDWLRQRQURRPDLUDQGRUR[\JHQVDWXUDWLRQRQR[\JHQ
administration at 2 L/min by nasal canula at the baseline visit. 
8. Radiographic (X-ray or computed tomography scan, per local standard of care) evidence of 
pulmonary involvement consistent with COVID-19 at screening or baseline, per the judgment 
of the investigator. 
a. Note: If radiography is not considered local standard of care for COVID-19 diagnosis, 
evidence of pulmonary involvement consistent with COVID-19 may also be obtained 
from clinical examination, per the judgment of the investigator. Evidence of 
pulmonary involvement obtained by clinical examination should be documented in 
the eCRF. 
9. Clinical syndrome consistent with COVID-19 at screening, per the judgment of the 
investigator (CDC 2020). 
10. CRP at screening >15 mg/L on local laboratory testing. 
11. Agrees to practice an approved method of birth control as follows: 
a. Females of childbearing potential: Using 1 of the following acceptable methods of 
contraception: surgical sterilization (eg, bilateral tubal ligation), intrauterine 
contraception/device, hormonal contraception, or any 2 barrier methods (a 
combination of male or female condom with diaphragm, sponge, or cervical cap). 
This criterion must be followed from the time of the first dose of study medication until 
90 days after last dose 
b. Males: Effective male contraception includes a vasectomy with negative semen 
analysis at follow-up, or the use of condoms. This criterion must be followed from the 
time of the first dose of study medication until 90 days after last dose. 
Note: Abstinence can be considered an acceptable method of contraception at the 
discretion of the investigator. Periodic abstinence (eg, calendar, ovulation, 
symptothermal, post ovulation methods) and withdrawal are not considered 
acceptable methods of contraception. 
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4.2 Exclusion criteria 
1. Inability to take oral medication at screening or baseline visit. 
2. Evidence at screening or baseline of critical COVID-19 disease (eg, cardiac failure, septic 
shock) or severe pulmonary involvement (eg, bilateral extensive involvement on chest X-ray 
or chest computed tomography, ARDS, immediate need for intubation or mechanical 
ventilation, anticipated need for intubation in the next 48 hours) per the judgment of the 
investigator.  
3. Positive pregnancy test at screening for women of childbearing potential. 
4. Lactating female at baseline for women of childbearing potential. 
a. 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. îXSSHUOLPLWRIQRUPDO8/1IRUDODQLQHRUDVSDUWDWHDPLQRWUDQsferases or total bilirubin 
!î8/1DWVFUHHQLQJRUNQRZQKLVWRU\RI&KLOG-Pugh Class C, hepatitis B or C, or HIV 
infection. 
6. Glomerular filtration rate <30 mL/min/1.73 m2 at screening. 
7. QTcF >450 msec for male or >470 msec for females or evidence of cardiac dysrhythmia at 
screening. 
8. 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. 
9. Treatment with anti-IL 6, anti-IL-6R antibodies, Janus kinase (JAK) inhibitors, or other 
immune modulators (unless considered part of local standard of care) in the past 30 days or 
5 half-lives (whichever is longer) or plan to receive these agents as part of investigational 
clinical trials any time during the study period. 
10. 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. 
11. Recent (within 30 days) or current participation in other COVID-19 therapeutic trials or 
expanded access programs. 
12. Prior or current participation in COVID-19 vaccine trials. 
4.3 Concomitant medications 
All medications (prescription and over-the-counter) taken at the time of study screening will be 
recorded, with indication, route of administration, daily dose, and start and stop dates of 
administration. All subjects will be questioned about concomitant treatment at each clinic visit. 
 
Subjects are allowed to use paracetamol (up to 3 g/day) and/or contraceptives (oral or parenteral), 
and any medications needed for SOC at the local institution. Use of hydroxychloroquine/ 
chloroquine is not permitted. Use of other experimental treatments for COVID-19 is not permitted 
unless it is part of SOC at the local institution. SOC for COVID-19 will be documented at each site 
during the site activation visit; additionally, it will be documented if any restrictions on standard of 
care treatment administration were encountered due to resource limitations. The use of antiviral 
medications is permitted.  
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Concomitant medications used to treat chronic comorbid conditions per SOC are permitted, 
including but not limited to metered dose inhalers, corticosteroids if on stable doses for at least 
30 days prior to screening, or sedative or anesthetic agents. 
 
Concomitant medications initiated or stopped for an AE will be recorded. 
 
Both losmapimod and its major metabolite, GSK198602, are in vitro inhibitors of human BCRP. 
There is a low risk of interaction of losmapimod with orally administered BCRP substrates with a 
narrow therapeutic index (eg, methotrexate, topotecan, rosuvastatin). Therefore, such co-
administration is indicated only if the medical benefit is considered to outweigh the risk for toxicity, 
and careful monitoring for adverse effects of these agents is advised. 
 
Losmapimod is a relatively potent in vitro inhibitor of the renal transporters MATE1 and MATE2-K, 
and it is possible that a mild inhibition of tubular secretion may contribute to the small rise in (model-
adjusted geometric mean) serum creatinine observed clinically. GSK198602 is a relatively potent in 
vitro inhibitor of OAT3 and co-administration of sensitive OAT3 substrates is indicated only if the 
medical benefit is considered to outweigh the risk for toxicity. Careful monitoring for adverse effects 
of these agents is advised, especially for those with narrow therapeutic margin (eg, methotrexate, 
metformin).  
4.4 Lifestyle restrictions  
Subjects should not donate blood, sperm, or ova from the screening visit through 90 days after the 
last dose of study treatment. 
4.4.1 
Contraception requirements 
Teratogenicity and effects on embryofetal survival were noted in rat and rabbit reproductive 
toxicology studies with losmapimod. Therefore, losmapimod should not be taken by women of 
childbearing potential who are not utilizing adequate contraceptive methods. 
All women of childbearing potential and all males must practice effective contraception during the 
study from the time of the first dose of study medication until 90 days after last dose. 
 
Women of child-bearing potential are defined as all women physiologically capable of becoming 
pregnant, unless they meet one of the following conditions: 
 
Postmenopausal: 12 months of natural (spontaneous) amenorrhea or 6 weeks after surgical 
bilateral oophorectomy/bilateral salpingectomy with or without hysterectomy; 
 
Post hysterectomy. 
For the purposes of the study, effective contraception is defined as follows: 
 
Females of childbearing potential: Using 1 or more of the following acceptable methods of 
contraception: surgical sterilization (eg, bilateral tubal ligation), intrauterine 
contraception/device, hormonal contraception, or any 2 barrier methods (a combination of 
male or female condom with diaphragm, sponge, or cervical cap).  
 
Males: Effective male contraception includes a vasectomy with negative semen analysis at 
follow-up, or the use of condoms.  
Abstinence can be considered an acceptable method of contraception at the discretion of the 
investigator. Periodic abstinence (eg, calendar, ovulation, symptothermal, post ovulation methods) 
and withdrawal are not considered acceptable methods of contraception. 
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5 
INVESTIGATIONAL MEDICINAL PRODUCT 
5.1 Investigational drug and matching placebo 
Losmapimod will be provided in tablets of 7.5 mg for oral administration.  
 
Matching placebo tablets will be provided for oral administration. 
 
The tablets are plain white, round, biconvex, film-coated tablets. The proposed dosing regimen is as 
DWZLFHGDLO\GRVHRIPJîPJWDEOHWVGRVH%,'7KHSURSRVHGGXUDWLRQRIWUHDWPHQWLVIRU
up to 14 days. 
 
Subjects should take their dose of losmapimod or placebo with food whenever possible and with 
240 mL of room temperature water.  
 
5.2 Study drug packaging and labelling 
Losmapimod tablets for oral administration are available as white, round, biconvex, plain, 
film-coated tablets containing 7.5 mg of losmapimod as the micronized base, GW856553X. 
Losmapimod tablets also contain the inactive excipients microcrystalline cellulose, lactose 
monohydrate, sodium starch glycolate, magnesium stearate, povidone K30, hypromellose, titanium 
dioxide (E171), and polyethylene glycol. 
Placebo tablets are identical in appearance to losmapimod and have the same excipient ingredients 
as losmapimod but do not have the active compound. 
All tablets are packed in opaque, white, square, high-density polyethylene bottles with induction 
sealed child-resistant closures. 
Losmapimod must be stored in a secure area (eg, a locked cabinet), protected from moisture, and 
kept at a controlled room temperature not to exceed 30°C. 
5.3 Drug accountability 
The investigator is responsible for ensuring that dosing is administered in compliance with the 
protocol. Delegation of this task must be clearly documented and approved by the investigator. 
The Investigator (or designee) will maintain an accurate record of the study supplies received. In 
addition, an accurate drug disposition record will be kept, specifying the amount dispensed to each 
subject and the date of dispensing. This drug accountability record will be available for inspection at 
any time. At the completion of the study, the original drug accountability record will be available for 
review by the sponsor upon request. 
For each batch of unit doses, the empty used unit dose containers will be discarded upon 
satisfactory completion of the compliance and accountability procedures by the sponsor. Any 
unused assembled unit doses will be retained until completion of the study. 
After completion of the study, all unused supplies will be returned to the sponsor or disposed of by 
the study site, per the sponsor’s written instructions. 
5.4 Treatment assignment and blinding 
5.4.1 
Randomization and treatment assignment 
A total of up to 410 subjects will be recruited into this study and will be randomized in a 1:1 ratio to 
15 mg losmapimod (BID) or placebo using an interactive/web voice response system (IxRS) for 
randomization. The randomization list will be produced by a qualified randomization vendor and will 
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enrollment. 
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Only subjects who have completed screening assessments and are eligible for participation in the 
study will be randomized to receive study drug. Randomized subjects will be sequentially assigned 
a unique subject number from the randomization list per the IxRS. From the time of randomization 
and throughout the duration of the study, subjects will be identified by their unique randomization 
number.  
The authorized site personnel will prepare the appropriate study drug for each subject based on the 
randomization schedule. Treatment codes should not be broken except in emergency situations, ie, 
when knowledge of the treatment is essential for the immediate further management of the subject.  
5.4.2 
Blinding 
This study will be performed in a double-blind fashion. The investigator, study staff, subjects, 
sponsor, and monitor will remain blinded to subject-level treatment assignment until study closure. 
The investigational drug and its matching placebo are indistinguishable and will be packaged in the 
same way. 
5.4.3 
Treatment compliance 
All doses will be administered either in the hospital (anticipated during the first week of study 
treatment) or taken by the study participants on an outpatient basis. 
The subject will bring the study treatment bottle to each visit (clinic or home assessment) for review 
by the site staff. 
The study treatment bottles will be collected at the Day 14 visit whether in the hospital or outpatient 
or at the ET visit if prior to Day 14. 
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6 
STUDY ASSESSMENTS 
See Table 1 for the time points of the assessments.  
 
If additional visits or blood draws are required beyond the planned visits in any part of the 
study, these visits or samples should be recorded in the eCRF as unscheduled visits prior to the 
subject’s completion of the study.  
 
6.1 Medical history 
A complete medical history will be taken at Screening and is to include demographic information, 
prior medical illnesses and conditions, and surgical procedures for at least 3 months prior to 
screening. The medical history may be collected from medical records, if available, or during the 
physical examination. 
The history of SARS-CoV-2 infection and symptoms at screening should be recorded; the details of 
how infection history will be assessed and recorded can be found in the Study Manual. 
A chest X-ray or CT will be performed while the patient is hospitalized based on standard-of-care 
local assessment. The results are required for eligibility assessment to confirm radiographic 
evidence of COVID 19. If radiography is not considered local standard of care for COVID-19 
diagnosis, evidence of pulmonary involvement consistent with COVID-19 may also be obtained from 
clinical examination, per the judgment of the investigator. Evidence of pulmonary involvement 
obtained by clinical examination should be documented in the eCRF. 
A pre-existing condition is one that is present prior to administration of study drug. Such conditions 
should be recorded as medical history. A pre-existing condition should be recorded as an AE or 
serious adverse event (SAE) only if the frequency, intensity, or nature of the condition worsens 
following administration of study drug. 
6.2 Pharmacokinetic and pharmacodynamic assessments 
Blood samples will be collected as outlined in the Schedule of Assessments (Table 1) to assess PK. 
PK assessments will be performed as a substudy in all sentinel subjects to evaluate the PK of 
losmapimod in the population of subjects with COVID-19. 
Blood samples will be collected as outlined in the Schedule of Assessments (Table 1) to assess 
plasma biomarkers of response to COVID-19, 
 
 
Procedures for collection, processing, and return of blood samples will be detailed in the Study 
Manual. Specifics of the analytical methods will be provided in separate documents. 
Cytokines and chemokines will be evaluated using a multiplex assay. Details of the assay and 
specimen sampling will be provided in the Study Manual. 
Viral load will be assessed by nasopharyngeal (preferred) or oropharyngeal swab or saliva assay as 
outlined in the Schedule of Assessments (Table 1). Diagnosis of COVID-19 should be confirmed by 
local PCR testing prior to randomization. Refer to the Study Manual for details on procedures and 
type(s) of diagnostic testing allowed.  
PK should be measured weekly at Cmax (4-5 hours) for subjects with renal insufficiency (eGFR 
 mL/min/ 1.73 m2). For those subjects requiring dialysis, dose adjustment may be needed (see 
Section 3.4.1) and will be determined by pre- and post-dialysis PK by the DMC to prevent site 
unblinding. 
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6.3 Clinical status and symptoms 
 The investigator may consult with a relevant clinical or other specialist as appropriate per SOC. 
6.3.1 
Respiratory failure and survival assessment 
Total number of study days free of oxygen supplementation and total number of study days free of 
respiratory failure will be evaluated. Refer to Section 6.5.1 for further details of vital sign collection. 
x 
Note: Respiratory failure is defined as either need for mechanical ventilation (invasive or 
non-invasive) or high flow oxygen (defined by greater than 15 LPM flow of oxygen to 
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time during the study. 
The reason for hospitalization and number of total study days of hospitalization and intensive care 
unit (ICU) utilization will be recorded.  
Details of subject discharge (date of discharge and condition at discharge) from the hospital will be 
recorded. 
Any significant deviation from standard of care due to limited resources will be documented.   
Survival status at the end of the study period will be documented, including cause of death for any 
reason. 
6.3.2 
Clinical status assessment 
Clinical status as outlined in the Schedule of Assessments (Table 1) will be measured on the 
following clinician-reported 9-point ranking scale (WHO): 
• 
(8) death 
• 
(7) ventilation plus additional organ support (vasopressors, renal replacement therapy, 
ECMO) 
• 
(6) intubation and mechanical ventilation 
• 
(5) noninvasive ventilation or high-flow oxygen therapy 
• 
(4) oxygen therapy but not requiring high-flow or non-invasive ventilation 
• 
(3) hospitalized but not requiring oxygen therapy 
• 
(2) discharged from the hospital but with limitation of activities 
• 
(1) discharged from the hospital and without any limitation 
• 
(0) no clinical evidence of the disease 
Instructions for administration will be provided in the Study Manual. 
6.4 Extended vital signs 
Extended vital signs, including oxygen saturation and fraction of inspired oxygen (FiO2) will be 
collected as specified in the schedule of assessments. Refer to Section 6.5.1 for further details of 
measurements. 
6.5 Safety and tolerability assessments 
The definitions, reporting, and follow-up of AEs, SAEs, and potential pregnancies are described in 
Section 7. 
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6.5.1 
Vital signs 
Evaluations of systolic and diastolic blood pressure, respiratory rate, and temperature will be 
performed throughout the study. In addition, oxygen saturation and FiO2 will be assessed 
throughout the study. Oxygen administration (eg, room air or oxygen flow by nasal canula or facial 
mask) will be recorded. Vital signs will be performed after subjects have been supine for at least 
5 minutes when possible.  
 
Arterial blood gases may be performed if clinically indicated in some subjects but are not required 
for this study. If arterial blood gasses are measured, the results for arterial pressure of oxygen 
(PaO2) should be reported at each measurement in the eCRF. 
 
Clinically relevant findings found after study drug initiation and meeting the definition of an AE (new 
AE or worsening of previously existing condition) must be recorded. 
6.5.2 
Weight and height 
Weight (kg) will be recorded at screening and the follow-up assessment (by alternative methods 
including outpatient visit). Height (cm) will be recorded and body mass index (BMI) calculated at 
screening. 
 
BMI (kg/m2) = weight (kg)/(height [cm]/100)2 
6.5.3 
Physical examination 
Physical examination (ie, inspection, percussion, palpation, and auscultation) is performed to 
determine eligibility and as clinically indicated during the study. Clinically relevant findings that are 
present prior to study drug initiation must be recorded with the subject’s medical history. Clinically 
relevant findings found after study drug initiation and meeting the definition of an AE (new AE or 
worsening of previously existing condition) must be recorded.  
6.5.4 
Electrocardiography 
ECGs will be taken singly after 5 minutes in the supine position as specified in the schedule of 
assessments. The investigator will assess the ECG recording as 'normal', 'abnormal - not clinically 
significant', or 'abnormal - clinically significant' and include a description of the abnormality as 
required. The ECG parameters assessed will include heart rate, PR, QRS, QT, and QTcB and QTcF 
(calculated using Bazett’s and Fridericia's method, respectively). ECGs will be performed to 
determine eligibility and during the study period only if clinically indicated. Clinically relevant findings 
found after study drug initiation and meeting the definition of an AE (new AE or worsening of 
previously existing condition) must be recorded. 
6.5.5 
Laboratory assessments 
Laboratory parameters 
Additional clinical laboratory evaluations will be performed at other times if judged to be clinically 
appropriate or if the ongoing review of the data suggests a more detailed assessment of clinical 
laboratory safety evaluations is required. 
An Investigator (or designee) will perform a clinical assessment of all clinical laboratory data. 
Clinically relevant findings found after study drug initiation and meeting the definition of an AE (new 
AE or worsening of previously existing condition) must be recorded. Clinical relevance is defined as: 
• 
Is accompanied by clinical symptoms 
• 
Leads to dose modification of study treatment 
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• 
Requires significant changes, addition of, interruption of, discontinuation of a concomitant 
medication, therapy, or treatment 
• 
Reflects a disease and/or organ toxicity 
This does not apply to any abnormal laboratory result that falls outside the laboratory reference 
range but that does not meet the clinical significance criteria or those that is a result of an AE that 
has already been reported. 
Blood and other biological samples will be collected for the following clinical laboratory tests; refer to 
the Study Manual for details of collection and analysis and information on the central clinical 
laboratory: 
Lab 
Tests 
Hematology 
 
Hemoglobin [including mean corpuscular volume, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration], hematocrit, red cell 
count, total white cell count, and platelet count. Differential blood count, 
including: basophils, eosinophils, neutrophils, lymphocytes, and monocytes. 
Chemistry and 
electrolytes 
Sodium, potassium, calcium, inorganic phosphate, total protein, albumin, blood 
urea nitrogen, creatinine, uric acid, total bilirubin1, alkaline phosphatase, AST, 
ALT, gamma-glutamyl transferase, and LDH. 
Glucose 
Glucose 
Urinalysis 
Leucocytes, blood, nitrite, protein, urobilinogen, bilirubin, pH, specific gravity, 
ketones, glucose. If there is a clinically significant positive result, urine will be 
sent to the central laboratory facility for microscopy and/or culture. 
Pregnancy2 
hCG (urine or serum). If there is a clinically significant, positive result in urine, 
urine will be sent to the central laboratory facility for confirmation. 
1Conjugated bilirubin will be reported only when total bilirubin is outside the reference range. 
2Pregnancy test for women of childbearing potential will be performed within 72 hours of first dose 
and if pregnancy is suspected during the study. 
6.6 Unscheduled visit 
Unscheduled visits may be performed at any time at the subject’s or the investigator’s request and 
may include (but are not limited to) vital signs/focused physical examination, ECG, AE review, 
concomitant medications and procedures review, disease-related constitutional symptoms, and/or 
laboratory and biomarker assessments. The date and reason for the unscheduled visit must be 
recorded in the source documentation. 
6.6.1 
Early termination visit 
When the investigator determines that study treatment will no longer be used, the investigator will 
perform the ET procedures and document the reason for discontinuation from study treatment in the 
eCRF. If routine laboratory tests (eg, hematology, serum chemistry) are completed within 7 days 
before the time of study treatment discontinuation, these tests need not be repeated. Every effort 
should be made to keep subjects in the study, including if a subject and/or their treating physician 
decides to prematurely discontinue study treatment. 
6.7 Alternative follow-up methods to site visits 
Trial participants may not be able to come to the investigational site for protocol-specified or 
unscheduled visits. The sponsor may use alternative methods for safety assessments, including 
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telemedicine visits, telephone visits, and/or an alternative location for visits depending on the local 
or institutional standards. 
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7 
SAFETY REPORTING 
7.1 Definitions of adverse events 
An adverse event (AE) is any untoward medical occurrence in a subject who is participating in a 
clinical study performed. The AE does not necessarily have to follow the administration of a study 
drug, or to have a causal relationship with the study drug. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory or vital sign finding), symptom, or disease 
temporally associated with the study participation whether or not it is related to the study drug. 
7.1.1 
Intensity of adverse events 
The intensity of clinical AEs is graded 3-point scale as defined below: 
 
Mild: discomfort noticed but no disruption of normal daily activity; 
 
Moderate: discomfort sufficient to reduce or affect normal daily activity; 
 
Severe: inability to work or perform daily activity. 
7.1.2 
Relationship to study drug 
For each AE, the relationship to drug as judged by the investigator: 
 
Probable; 
 
Possible; 
 
Unlikely; 
 
Unrelated. 
7.1.3 
Serious adverse events 
A serious adverse event (SAE) is defined by the International Conference on Harmonization (ICH) 
guidelines as any AE fulfilling at least one of the following criteria: 
 
results in death; 
 
is life threatening (at the time of the event); 
 
requires hospitalization or prolongation of existing inpatient hospitalization; 
o Note: COVID-19-related hospitalization or ICU admission is excluded from this 
definition, as SARS-CoV-2, COVID-19 infection, or pulmonary conditions attributable 
to COVID-19 infection are efficacy-related endpoints 
 
results in persistent or significant disability or incapacity; 
 
is a congenital anomaly or birth defect; or 
 
any other important medical event that did not result in any of the outcomes listed above due 
to medical or surgical intervention but could have been based upon appropriate judgement 
by the investigator. 
An elective hospital admission will not be considered as a SAE. 
7.1.4 
Suspected unexpected serious adverse reactions 
A suspected unexpected serious adverse reaction (SUSAR) is an SAE that is unexpected (nature or 
severity of which is not consistent with the applicable product information (eg, the Investigator 
Brochure for losmapimod) and suspected (a reasonable possibility of causal relationship with 
investigational drug, regardless of the administered dose). 
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7.1.5 
Reporting of serious adverse events 
The investigator must report any AE that meets the SAE criteria (Section 7.1.3) to PPD immediately 
(ie, within 24 hours after the site personnel first learn about the event) via electronic data capture 
(EDC). In the event that EDC entry is not possible (eg, system failure or access problems), the 
study site staff should complete the paper SAE report form and fax the form to PPD 
Pharmacovigilance within 24 hours of awareness or call the PPD safety hotline to report. The study 
site staff should update the EDC system as soon as it is available.  
A full description of every SAE will need to be provided to PPD Pharmacovigilance. 
7.1.6 
Follow-up of adverse events 
All AEs will be followed until they have abated, returned to baseline status or until a stable situation 
has been reached. Depending on the event, follow up may require additional tests or medical 
procedures as indicated, and/or referral to the general physician or a medical specialist. 
7.1.7 
Adverse events of special interest 
An AESI (serious or non-serious) is one of scientific and medical concern for which ongoing 
monitoring and rapid communication by the investigator to the sponsor can be appropriate. Adverse 
events of special interest for this study include QTc prolongation as well as liver tests that meet the 
criteria for potential drug-induced liver injury (DILI), in accordance with the US Food and Drug 
Administration “Guidance for Industry-Drug-Induced Liver Injury: Premarketing Clinical Evaluation”. 
Adverse event of special interest: QTc prolongation 
A thorough QT study (PM1116628) was conducted in healthy volunteers who received losmapimod 
at 7.5 mg BID or 20 mg daily or with placebo administered for 5 days. At the 20 mg dose of 
ORVPDSLPRGWKHXSSHUERXQGRIWKH&,RIWKHǻǻ47LQWHUYDOFKDQJHIURPEDVHOLQHLQ47F)
compared with that for placebo) exceeded the 10 msec threshold at the 24-hour post-dose time 
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threshold at multiple time points. No subjects experienced QTcF values >480 msec or QTcF 
FKDQJHVIURPEDVHOLQHPVHFDWDQ\WLPHLQWKHVWXG\$OWKRXJKWKHXSSHUERXQGRIWKH&,
exceeded the 10 msec regulatory threshold of concern in the primary pharmacodynamic analysis, it 
was determined by GSK that there was no clinically relevant effect on the QT interval, as there was 
no clinically relevant concentration QTc effect using standard placebo/baseline subtracted 
measured QTc data. Additional information on the QTc interval and its behavior, as demonstrated in 
the large cohort of patients with ACS treated with losmapimod (PM1116197), supported the lack of 
a QT effect. PK/PD modeling using the raw QTcF and plasma concentration data showed that at 
plasma losmapimod concentrations 4 times the exposure at the therapeutic dose (7.5 mg BID) (ie, 
at exposures approximately 2-fold higher than 15 mg BID, the predicted uppHUERXQGRIWKH&,
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Further details are presented in the Investigator Brochure. No drug effect on QT prolongation of 
losmapimod over placebo has been documented in any of the phase 2 or the one phase 3 trial 
completed so far.  
Study drug should be discontinued for subjects who meet the QTc prolongation criteria as a result of 
within-protocol specific testing or unscheduled testing (see Section 3.4.4 stopping criteria). This 
AESI must be reported to the sponsor within 24 hours of awareness per the SAE reporting 
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procedures (Section 7.1.5). Further safety steps should be taken to closely observe and follow-up 
the event until resolution and treatment initiated per local standard of care.  
Adverse event of special interest: Drug-induced liver injury 
The following 3 laboratory value criteria must be met for potential DILI, or “Hy’s Law”: 
• 
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ULN 
• 
An elevated total bilirubin laboratory value that is î8/1 
• 
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Study drug should be discontinued for subjects who meet the laboratory criteria for potential DILI as 
a result of within-protocol specific testing or unscheduled testing (see Section 3.4.4 stopping 
criteria). This AESI must be reported to the sponsor within 24 hours of awareness per the SAE 
reporting procedures (Section 7.1.5). Further safety steps should be taken to closely observe and 
follow-up the event until resolution. These steps include, but are not limited to: 
• 
Making every reasonable attempt to have the subject return to the clinic within 24 hours for 
repeat liver tests 
• 
Obtaining a more detailed history of symptoms and prior or concurrent disease, concomitant 
medication use, alcohol use, recreational drug use, and special diets 
• 
Repeating liver enzyme and serum bilirubin tests twice weekly. Frequency of retesting can 
decrease to once a week or less if abnormalities stabilize and the subject is asymptomatic 
• 
Obtaining viral hepatitis serology 
• 
Considering liver imaging and/or hepatology consultation 
7.2 Pregnancy 
7.2.1 
Teratogenicity 
If a woman becomes pregnant when on study drug, study drug should be permanently discontinued. 
The investigator must counsel the subject and discuss the risks of continuing with the pregnancy 
and the possible effects on the fetus. Monitoring of the subject should continue until the outcome of 
the pregnancy is known. In the event of pregnancy in the partner of a study subject, the Investigator 
should make every reasonable attempt to obtain the woman’s consent for release of protected 
health information. 
7.2.2 
Reporting of pregnancy 
Irrespective of the treatment received by the subject, any pregnancy occurring during study drug 
administration or until follow-up, must be reported within 24 hours of the investigator's knowledge of 
the event to the sponsor. The Investigator must make every effort to follow the pregnant partner of a 
male subject through resolution of the pregnancy (delivery or termination) and to report the 
resolution on the SAE form. 
 
 
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8 
STATISTICAL METHODOLOGY AND ANALYSES 
8.1 Statistical analysis plan 
 
A statistical analysis plan (SAP) will be generated and approved prior to database snapshot for the 
interim analysis (IA). The SAP will detail the implementation of all planned statistical analysis. Any 
deviations from the planned analysis will be described and justified in the final clinical study report. 
All safety and statistical programming will be conducted using SAS 9.4 for Windows or newer (SAS 
Institute Inc., Cary, NC, USA), and other statistical programming/sample size calculation software as 
necessary.  
8.1.1 
Determination of sample size 
The primary efficacy endpoint of this study is the proportion of subjects who progress to death or 
respiratory failure by the end of study (Day 28). It is estimated thDWDSSUR[LPDWHO\RIHQUROOHG
subjects receiving SOC plus placebo will attain this endpoint. It is assumed that losmapimod will 
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to 410 subjects randomized to the losmapimod arm or the placebo arm in a 1:1 ratio (205 subjects 
in the losmapimod arm and 205 VXEMHFWVLQWKHSODFHERDUPZLOO\LHOGDSSUR[LPDWHO\SRZHULQ
a 1-VLGHGWHVWDWWKHVLJQLILFDQFHOHYHO7KHVDPSOHVL]HHVWLPDWHDVVXPHVDQ,$ZLll be 
conducted after approximately 206 subjects (103 in the losmapimod arm, and 103 in the placebo 
arm) have completed the Day 28 visit, to assess early futility, using the rules specified in 
Section 8.9. 
8.1.2 
Analysis methods 
In general, all study endpoints will be summarized using descriptive statistics. Descriptive statistics 
for continuous data will include number of subjects (n), mean, standard deviation, median, 
minimum, and maximum. Descriptive statistics for categorical data will include frequency and 
percentage.  
:KHUHDSSURSULDWHGHVFULSWLYHVWDWLVWLFVPD\EHSUHVHQWHGZLWK&, 
8.1.3 
Analysis sets 
Full Analysis Set (FAS): The FAS will consist of all subjects who are randomly assigned to receive 
double-blind study drug. All analyses using the FAS will group subjects according to randomized 
treatment. The primary endpoint, clinical outcomes/status, survival, and pharmacodynamic 
endpoints will be analyzed using the FAS. 
Per Protocol Set (PPS): The PPS will consist of all FAS subjects who fulfill all inclusion/exclusion 
criteria and do not have any significant protocol deviations. All analyses using the PPS will group 
subjects according to randomized treatment. 
Safety Analysis Set: The safety analysis set is defined as all subjects who are randomized and 
receive study drug. All analyses using the Safety Analysis Set will group subjects according to 
treatment actually received. The safety analysis set will be used for all safety and tolerability 
analyses. 
8.2 Protocol violations/deviations 
Protocol deviations will be identified based on conditions related to the categories below: 
 
Protocol entry criteria 
 
Forbidden concomitant medications 
 
Missing evaluations for relevant endpoints 
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 
Other protocol deviations occurring during study conduct. 
Major protocol deviations will be identified before study closure and listed where appropriate. 
8.3 Missing, unused and spurious data 
All missing or incomplete safety and PD data, including dates and times, are treated as such. 
Missing test results or assessments will not be imputed, and as such, are assumed missing-
completely-at-random (MCAR). 
 
For laboratory data, values below the limit of quantitation (recorded as “< LLQ”) will be set to half 
that limit. 
Censoring rules for time-to-event endpoints will be discussed in the SAP. Imputation rules for the 
primary endpoint will be discussed in the SAP. The handling of any missing, unused, and spurious 
data will be documented in the SAP or the clinical study report. 
8.4 Subject disposition 
Subject disposition will be listed by subject. 
The following subject data will be summarized: 
x 
number and percentage of subjects screened, 
x 
number and percentage of subjects enrolled, 
x 
number and percentage of subjects completed, 
x 
number and percentage of subjects included in safety population 
A subject who completed the study is defined as a subject where the last PD assessment was 
completed. 
8.5 Baseline parameters and concomitant medications 
8.5.1 
Demographics and baseline variables 
Demographic and other baseline characteristics will be summarized using descriptive statistics for 
the treatment group and overall. 
8.5.2 
Medical history 
Medical history will be listed. 
8.5.3 
Prior and concomitant medications 
Prior and concomitant medications will be listed by international nonproprietary names, dose, 
regimen, route and for which indication it was prescribed. 
8.5.4 
Treatment compliance/exposure 
Exposure to study treatment is described in terms of duration of treatment. 
8.5.5 
Safety and tolerability endpoints 
The safety data set is used to perform all safety analyses. 
 
Baseline is defined as the last value prior to dosing. Change from baseline will be calculated for all 
continuous safety parameters. 
8.5.6 
Adverse events 
The latest version of Medical Dictionary for Regulatory Activities (MedDRA) will be used for the 
coding of AEs. The overall incidence of AEs will be displayed by MedDRA system organ class, 
preferred term, and treatment group.  
 
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All AEs will be displayed in listings. In addition, SAEs and treatment-emergent AEs (TEAEs) leading 
to discontinuation of study drug will be listed. 
Treatment-emergent AEs will be defined as an event that occurs on or after the first dose of study 
drug or the worsening of a preexisting condition on or after the first dose of study drug. If a subject 
does experience an event both prior to and after starting administration of a treatment, the event will 
be considered a TEAE (of the treatment) only if it has worsened in severity (ie, it is reported with a 
new start date) after starting administration of the specific treatment, and prior to the start of another 
treatment, if any. All TEAEs collected during the investigational period will be summarized.  
The number of TEAEs and the number of subjects with at least 1 TEAE will be summarized by 
treatment group for the following: 
1. 
System organ class and preferred term; 
2. 
System organ class, preferred term, and maximum severity 
3. 
System organ class, preferred term, and maximum drug relatedness. 
8.5.7 
Vital signs 
Reported values and change from baseline values of supine blood pressure and pulse rate and 
temperature will be summarized using descriptive statistics by treatment group and time point. The 
number of available observations and out-of-range values (absolute and in percentage) will be 
presented by treatment group. Vital sign variables will be listed. Values outside the reference range 
will be flagged in the listing. 
Vital sign results and change from baseline values will be summarized using descriptive statistics by 
treatment group and time point. 
8.5.8 
ECG 
ECG values will be listed. 
8.5.9 
Clinical laboratory tests 
Reported values and change from baseline values of clinical laboratory variables will be 
summarized using descriptive statistics by treatment group and time point. The number of available 
observations and out-of-range values (absolute and in percentage) will also be presented by 
treatment group. Clinical laboratory values will be listed. 
Clinical laboratory test results and change from baseline values will be summarized using 
descriptive statistics by treatment group and time point. 
8.6 Primary endpoints 
1) Assuming pt is probability of outcome in the losmapimod arm; pc is the probability of outcome 
in the control arm 
Study hypothesis: H0:  = pt – pc = 0 
                              H1:  = pt – pc > 0 
Assuming pt=0.18, pc=0.30, we can restate the hypothesis as  
  H0: ș = ș0 = 0 
  H1: ș = ș1 = –0.12  
For the final analysis, the proportion of subjects achieving the primary endpoint in the treatment 
arms will be compared using a stratified Cochran-Mantel-Haenszel test, adjusting for randomization 
stratification variables. An interim analysis to assess futility analysis—and potential sample size 
re-estimation—is discussed in Section 8.9. All results will be summarized descriptively by treatment 
DUPDQGH[SUHVVHGDVSURSRUWLRQVDORQJZLWKFRUUHVSRQGLQJXQDGMXVWHGDGMXVWHG&,RIWKH
difference between response rates, and p-values. 
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8.7 Secondary endpoints 
Clinical status at Day 7 and Day 14: percentages for each category of the ranking scale will be 
tabulated by treatment arm, along with differences between treatment arms. The proportion of 
subjects for each of the items in the scale will be compared using a stratified Cochran-Mantel-
Haenszel test, adjusting for randomization stratification variable.  
Total number of study days: (a) free of oxygen supplementation; (b) in ICU; (c) of hospitalization; (d) 
free of respiratory failure; (e) alive: For each endpoint (a) - (e), a Poisson regression model or a 
negative binomial model will be used to assess the relationship with treatment, with age group as a 
covariate with stratification factors as covariates. Details of the model, including censoring rules, if 
any, will be provided in the SAP. 
Percentage of subjects discharged from the hospital: percentages of subjects discharged from the 
hospital will be tabulated by treatment arm, along with differences between treatment arms. The 
proportion of subjects will be compared using a stratified Cochran-Mantel-Haenszel test, adjusting 
for randomization stratification variables. 
All-cause mortality at Day 28: percentages of subjects will be tabulated by treatment arm, along with 
differences between treatment arms, at each time point. The proportion of subjects will be compared 
using a stratified Cochran-Mantel-Haenszel test, adjusting for randomization stratification variables. 
Incidence of AEs/SAEs: will be summarized by system organ class and preferred term and by 
treatment arm using percentages. 
Incidence of clinically significant changes: Percentage of subjects with clinically significant changes 
in laboratory parameters, ECG, and vital sign measurements will be computed for each treatment 
arm along with associated 2-VLGHG&ORSSHU-Pearson CI.  
Clearance of quantifiable viral RNA by Day 7: percentages of subjects with clearance of quantifiable 
viral RNA will be tabulated by treatment arm, along with differences between treatment arms, at 
each time point. The proportion of subjects will be compared using a stratified Cochran-Mantel-
Haenszel test, adjusting for randomization stratification variables. 
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8.9 Interim analysis for futility and sample size re-estimation 
An interim analysis (IA) will be conducted after 206 subjects have been enrolled (approximately 103 
in each of the losmapimod and placebo arms) and have been treated for 14 days with 28 days of 
follow-up. Only futility—and potential sample size-estimation—will be assessed by the DMC at the 
IA. The O’Brien-Fleming group sequential method will be used to adjust beta for interim testing. 
Table 7, Figure 1, Figure 2, and Figure 3 contain sample size requirements, boundary information, 
and stopping probabilities for testing futility on the primary endpoint at both the IA and final analysis. 
P-values are single-sided. 6DPSOHVL]HHVWLPDWLRQZDVGRQHXVLQJ6$63URF6HT'HVLJQ
9HUVLRQThe study will not be stopped for efficacy at the IA.
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Table 6:  Boundary Values for Interim Analysis Futility Assessment 
Analysis 
Stage 
Sample Size 
Beta: Futility 
Alpha: Efficacy 
Losmapimod 
Control 
Standardized- Z 
(p-value) 
MLE 
Stopping Probability 
(accept null under null 
hypothesis) 
Standardized- Z 
(p-value) 
MLE 
Stopping Probability 
(accept null under 
alternative 
hypothesis) 
Interim 
Analysis 
103 
103 
-0.67873
(0.24865) 
-0.04017
0.75135 
Not applicable 
-- 
0.08871 
Final 
Analysis 
205 
205 
-1.91358
(0.02784) 
-0.08009
0.97500 
-- 
-- 
0.20000 
Overall alpha=0.025 (1-VLGHGRYHUDOOSRZHU  
Abbreviations: MLE: maximum likelihood estimate. 
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Figure 1:  Acceptance Region (Standardized-Z Scale) 
 
 
  
Figure 2:  Acceptance Region (P-value) 
 
 
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Figure 3:  Acceptance Region (Maximum Likelihood Estimate) 
8.9.1 
Futility Testing 
The process is as follows: 
1. Futility at IA: If standardized z-value (MLE: maximum likelihood estimate) of pt – pc is
-0.67873 (-0.04017), or p-YDOXHWKHQVWRSIRUIXWLOLW\3UREDELOLW\RIVWRSSLQJIRU
futility under null hypothesis is ~0.75.
2. At Final Analysis: The final p-value is tested at an adjusted alpha of 0.02784.
8.9.2 
Sample Size Re-estimation 
The Chen-DeMets-Lan method (Chen et al 2004) will be used for unblinded sample size 
re-estimation, with IA futility stopping boundaries created using O’Brien-Fleming method, as 
described above. Wald conditional probabilities will be calculated using the actual observed 
proportion from both treatment arms.  
The maximum sample size allowed is 820 subjects. Sample size will be increased only if the 
REVHUYHGGDWDDWWKH,$DUHSURPLVLQJWKDWLVLIWKHFRQGLWLRQDOSRZHULVDQG6DPSOH
VL]HZLOOEHLQFUHDVHGWRHQVXUHDWDUJHWFRQGLWLRQDOSRZHURIDWOHDVW 
7KHUHLVRQO\RQH,$DQGFRQGLWLRQDOSRZHUDW,$PXVWOLHEHWZHHQDQGIRUVDPSOHVL]H
UHHVWLPDWLRQWREHLPSOHPHQWHG7KHVH2 FRQGLWLRQVHQVXUHWKDWWKHWDUJHW7\SH,HUURURILV
QRWH[FHHGHGE\LQFUHasing sample size to meet the original target power (Chen et al 2004). 
Sample size re-estimation will not be done in the following 2 instances: 
x
,IFRQGLWLRQDOSRZHULVWKHQVDPSOHVL]HUH-estimation will not be done, and decision
on futility will be made based on boundary values from the O’Brien-Fleming method.
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x 
,IFRQGLWLRQDOSRZHULVWKHQDVDPSOHVL]HUH-estimation will not be done, as the study 
will be considered sufficiently powered to detect the effect of interest at the final analysis. 
A Wald Test statistic will be calculated and compared with the boundary value for futility (see 
Table 7). If the Wald Test statistic lies in the acceptance region, then the study will stop for futility. 
All calculations for the IA and the unblinded sample size re-estimation will be conducted by an 
external, unblinded statistician. The DMC will review the results in a closed session and make 
appropriate recommendations to the Sponsor afterwards.  
8.9.3 
Possible Recommendations by the DMC 
After reviewing the results of the IA, the DMC may select 3 or more possible recommendations, 
based on the test statistics obtained at the IA: 
x 
Stop for Futility - Stop trial early due to strong evidence for futility due to test statistic being in 
the futility region. 
x 
Continue without change - Continue until next look with no changes due to test statistic not 
EHLQJLQWKHIXWLOLW\UHJLRQRUWKHFRQGLWLRQDOSRZHUEHLQJRU 
x 
Add required additional sample size, n, without exceeding the maximum sample size of 820 
and continue the trial.  
At the final analysis, 2 recommendations can be made: 
x 
Efficacy is demonstrated. 
x 
Efficacy is NOT demonstrated.  
8.10 Data monitoring committee 
An independent DMC composed of experts external to the sponsor and investigators will monitor 
the safety of the trial participants and the conduct of the trial on an ongoing basis and will be 
responsible for the interim analysis and recommendations regarding sample size re-estimation. 
Consistent with US Food and Drug Administration (FDA) recommendations (FDA Guidance for 
Industry, Establishment and Operation of Clinical Trial Data Monitoring Committees, 2006), the 
DMC will include at least 2 external clinician with expertise relevant to the evaluation of COVID-19, 
such as Critical Care, Pulmonology, or Infectious Disease, as well as at least 1 independent 
biostatistician with expertise in clinical trial design and statistical methods for clinical research and 
analysis of research data including interim analysis. 
Details on the composition of the DMC and the schedule and format of DMC meetings and data 
outputs will be presented in the DMC charter. The DMC will review, at a minimum, data for the 
sentinel subjects prior to continued study drug dosing and cumulative safety data at regular intervals 
based on subject enrollment. 
The safety evaluations will be detailed in the DMC charter and will include review of conventional 
safety variables, such as serious adverse events. Any safety event that requires unblinding will be 
immediately reported to the DMC and to the FDA. The DMC may request and review any additional 
reports outside of the planned analyses at any time if deemed necessary to ensure the safety of 
subjects. The DMC will also review the efficacy data at the IA and make recommendations based on 
the futility criteria and for sample size re-estimation if needed (see Section 8.9). After reviewing 
study data, the DMC will make recommendations regarding continuation, termination, or 
modification of the study. The DMC may also perform ad hoc review PK of subjects who require 
dialysis. 
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9 
GOOD CLINICAL PRACTICE, ETHICS AND ADMINISTRATIVE PROCEDURES 
9.1 Good clinical practice 
9.1.1 
Ethics and good clinical practice 
The study will be performed in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, ICH Good Clinical Practice (GCP), the protocol, and all applicable 
regulations. 
9.1.2 
Ethics committee / institutional review board 
Federal regulations and the ICH guidelines require that approval be obtained from an IRB/IEC 
before participation of human subjects in research studies. Before study onset, the protocol, 
informed consent, advertisements to be used for the recruitment of study subjects, and any other 
written information regarding this study to be provided to the subject or the subject’s legal guardian 
must be approved by the IRB/IEC. Documentation of all IRB/IEC approvals and of the IRB/IEC 
compliance with ICH harmonised tripartite guideline E6(R2): Good Clinical Practice will be 
maintained by the site and will be available for review by the sponsor or its designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must identify the 
IRB/IEC name and address, the clinical protocol by title or protocol number or both, and the date on 
which approval or a favorable opinion was granted. 
The investigator is responsible for providing written summaries of the progress and status of the 
study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The investigator must 
promptly supply the sponsor or its designee, the IRB/IEC, and, where applicable, the institution, with 
written reports on any changes significantly affecting the conduct of the study or increasing the risk 
to subjects. 
9.1.3 
Informed consent 
It is the responsibility of the investigator to obtain written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and potential 
hazards of the study. The investigator must also explain to the subjects that they are completely free 
to refuse to enter the study or to withdraw from it at any time for any reason. 
Subjects will be given an opportunity to ask questions about the study prior to providing consent for 
participation. Following discussion of the study with site staff, subjects or their legally authorized 
representative will be required to provide one of the following:  
1. Sign a statement of informed consent that meets the requirements of local regulations, ICH 
guidelines, and the IRB/EC or study center, where applicable. The subject will be given a 
copy of the signed ICF, and the original will be maintained with the subject’s records; OR 
2. If a subject is in isolation due to COVID-19 and institutional infection control policy would 
prevent removal of a document signed by the subject from their hospital room, then one of 
the following methods will be used to obtain informed consent that meets the requirements 
of local regulations, ICH guidelines, and the IRB/EC or study center, where applicable: 
o Obtain the informed consent electronically; OR 
o Obtain the informed consent by teleconference/video conference in alignment 
with local regulatory guidance. 
How the consent was obtained and reason why it was obtained using that particular method 
should be documented in the eCRF. The trial record at the investigational site should 
document how it was confirmed that the subject signed the consent form (ie, either using 
attestation by the witness and investigator or a photograph of the signed consent).  
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Subjects must be re-consented to the most current version of the ICF(s) during their participation in 
the study. 
9.2 Data handling and record keeping 
This study will be conducted according to ICH E6(R2) risk and quality processes described in the 
applicable procedural documents. The quality management approach to be implemented in this 
study will be documented and will comply with the current ICH guidance on quality and risk 
management. 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the subjects treated as part of the research under this protocol. 
The investigator agrees to maintain accurate eCRFs and source documentation as part of the case 
histories. These source documents may include laboratory reports, ECG strips, etc. 
Study site personnel will enter subject data into the EDC program. The analysis data sets will be a 
combination of these data and data from other sources (eg, laboratory data). 
Clinical data management will be performed in accordance with applicable PPD standards and data 
cleaning procedures to ensure the integrity of the data, eg, removing errors and inconsistencies in 
the data. Adverse event terms will be coded using MedDRA, an internal validated medical 
dictionary, and concomitant medications will be coded using the World Health Organization Drug 
Dictionary. 
After final database lock, each study site will receive a CD-ROM containing all of their site specific 
eCRF data as entered into the EDC system for the study, including full discrepancy and audit 
history. Additionally, a CD-ROM copy of all of the study site’s data from the study will be created 
and sent to the sponsor for storage. PPD will maintain a duplicate CD-ROM copy for their records. 
In all cases, subject initials will not be collected or transmitted to the sponsor. 
9.3 Access to source data and documents 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a manner 
designed to maintain subject confidentiality. All records will be kept in a secure storage area with 
limited access. Clinical information will not be released without the written permission of the subject 
(or the subject’s legal guardian), except as necessary for monitoring and auditing by the sponsor, its 
designee, applicable regulatory authorities, or the IRB/IEC. 
To ensure privacy, directly identifying information of study subjects will not be attached to records or 
samples released to the sponsor and its service providers for research purposes. 
The investigator and all employees and coworkers involved with this study may not disclose or use 
for any purpose other than performance of the study any data, record, or other unpublished, 
confidential information disclosed to those individuals for the purpose of the study. Prior written 
agreement from the sponsor or its designee must be obtained for the disclosure of any said 
confidential information to other parties. Additional confidentiality requirements and obligations will 
be set forth in the clinical trial agreement to be entered into by the sponsor, the principal 
investigator, and the institution. 
9.4 Investigator’s obligations 
The following administrative items are meant to guide the investigator in the conduct of the study but 
may be subject to change based on industry and government standard operating procedures, 
working practice documents, or guidelines. Changes will be reported to the IRB/IEC but will not 
result in protocol amendments. 
9.5 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a manner 
designed to maintain subject confidentiality. All records will be kept in a secure storage area with 
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limited access. Clinical information will not be released without the written permission of the subject 
(or the subject’s legal guardian), except as necessary for monitoring and auditing by the sponsor, its 
designee, applicable regulatory authorities, or the IRB/IEC. 
To ensure privacy, directly identifying information of study subjects will not be attached to records or 
samples released to the sponsor and its service providers for research purposes. 
The investigator and all employees and coworkers involved with this study may not disclose or use 
for any purpose other than performance of the study any data, record, or other unpublished, 
confidential information disclosed to those individuals for the purpose of the study. Prior written 
agreement from the sponsor or its designee must be obtained for the disclosure of any said 
confidential information to other parties. Additional confidentiality requirements and obligations will 
be set forth in the clinical trial agreement to be entered into by the sponsor, the principal 
investigator, and the institution.  
9.6 Financial disclosure and obligations 
Investigators are required to provide financial disclosure information to allow the sponsor to submit 
the complete and accurate certification or disclosure statements required by applicable regulatory 
authorities. In addition, the investigator must provide to the sponsor a commitment to promptly 
update this information if any relevant changes occur during the course of the investigation and for 
1 year following the completion of the study. 
Neither the sponsor nor PPD is financially responsible for further testing or treatment of any medical 
condition that may be detected during the screening process. In addition, in the absence of specific 
arrangements, neither the sponsor nor PPD is financially responsible for further treatment of the 
subject’s disease. 
9.7 Investigator documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH E6(R2) 8.2 and Title 
21 of the Code of Federal Regulations by providing the following essential documents, including but 
not limited to: 
• 
IRB/IEC approval 
• 
Original investigator-signed investigator agreement page of the protocol 
• 
FDA Form 1572, fully executed, and all updates on a new fully executed Form FDA 1572 
• 
A curriculum vitae for the investigator and each subinvestigator listed on Form FDA 1572 
• 
Financial disclosure information to allow the sponsor to submit complete and accurate 
certification or disclosure statements required by applicable regulatory authorities. In 
addition, the investigators must provide to the sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and for 
1 year after the completion of the study. 
• 
IRB/IEC-approved informed consent, samples of site advertisements for recruitment for this 
study, and any other written information regarding this study that is to be provided to the 
subject or legal guardian, and 
• 
Laboratory certifications and normal ranges for any local laboratories used by the site. 
9.8 Study conduct 
The investigator agrees that the study will be conducted according to the principles of ICH E6(R2). 
The investigator will conduct all aspects of this study in accordance with all national, state, and local 
laws or regulations. Study information from this protocol will be posted on publicly available clinical 
trial registers before enrollment of subjects begins. 
9.9 Adherence to protocol 
The investigator agrees to conduct the study as outlined in this protocol in accordance with ICH 
E6(R2) and all applicable guidelines and regulations. 
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9.10 Adverse events and study report requirements 
By participating in this study, the investigator agrees to submit reports of SAEs to the sponsor 
and/or IRB/IEC according to the timeline and method outlined in the protocol. In addition, the 
investigator agrees to submit annual reports to the study site IRB/IEC as appropriate. 
9.11 Investigator’s final report 
Upon completion of the study, the investigator, where applicable, should inform the institution; the 
investigator/institution should provide the IRB/IEC with a summary of the study’s outcome and the 
sponsor and regulatory authority(ies) with any reports required. 
9.12 Records retention 
Essential documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents should be retained for a longer 
period, however, if required by the applicable regulatory requirements or by an agreement with the 
sponsor. It is the responsibility of the sponsor to inform the investigator/institution as to when these 
documents no longer need to be retained. 
9.13 Publications 
After completion of the study, the data will be submitted for reporting at a scientific meeting and for 
publication in a peer-reviewed scientific journal. In these cases, the sponsor will be responsible for 
these activities and will work with the investigators to determine how the manuscript is written and 
edited, the number and order of authors, the publication to which it will be submitted, and other 
related issues. The sponsor has final approval authority over all such issues. 
Data are the property of the sponsor and cannot be published without prior authorization from the 
sponsor, but data and publication thereof will not be unduly withheld. Further terms concerning 
publication will be set forth in the clinical trial agreement entered into by the sponsor, the principal 
investigator, any vendors, and the institution. 
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10 STUDY MANAGEMENT 
The administrative structure will include a DMC (see Section 8.10). 
10.1 Monitoring 
The clinical monitor, as a representative of the sponsor, has the obligation to follow the study 
closely. In doing so, the monitor regularly monitors the trial remotely and will periodically visit the 
investigator based on local restrictions, in addition to maintaining necessary telephone and letter 
contact. The monitor will maintain current personal knowledge of the study through observation, 
review of study records and source documentation remotely, and discussion of the conduct of the 
study with the investigator and personnel.  All relevant source documents will be uploaded into the 
IBM electronic system or access to the electronic medical records will be provided for remote 
monitoring purposes. 
All aspects of the study will be carefully monitored, by the sponsor or its designee, for compliance 
with applicable government regulation with respect to current GCP and current standard operating 
procedures. 
10.2 Inspection of records 
Investigators and institutions involved in the study will permit study-related monitoring, audits, 
IRB/IEC review, and regulatory inspections by providing direct access to all study records. In the 
event of an audit, the investigator agrees to allow the sponsor, representatives of the sponsor, or a 
regulatory agency (eg, FDA or other regulatory agency) access to all study records. 
The investigator should promptly notify the sponsor and PPD of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to the sponsor. 
10.3 Management of protocol amendments and deviations 
10.3.1 
Modification of the protocol 
Any changes in this research activity, except those necessary to remove an apparent, immediate 
hazard to the subject, must be reviewed and approved by the sponsor or its designee. Amendments 
to the protocol must be submitted in writing to the investigator’s IRB/IEC for approval before 
subjects can be enrolled into an amended protocol. 
10.3.2 
Protocol deviations 
The investigator or designee must document and explain in the subject’s source documentation any 
deviation from the approved protocol. The investigator may implement a deviation from or a change 
of the protocol to eliminate an immediate hazard to study subjects without prior IRB/IEC approval. 
As soon as possible after such an occurrence, the implemented deviation or change, the reasons 
for it, and any proposed protocol amendments should be submitted to the IRB/IEC for review and 
approval, to the sponsor for agreement, and to the regulatory authorities, if required. 
A deviation from the protocol is an unintended or unanticipated departure from the procedures or 
processes approved by the sponsor and the IRB/IEC and agreed to by the investigator. A significant 
deviation occurs when there is nonadherence to the protocol by the subject or investigator that 
results in a significant, additional risk to the subject. Significant deviations can include 
nonadherence to inclusion or exclusion criteria or nonadherence to FDA regulations or ICH GCP 
guidelines and will lead to the subject being withdrawn from the study. A list of major protocol 
deviations will be compiled prior to the start of the study. 
Protocol deviations will be documented by the clinical monitor throughout the course of monitoring 
visits. Principal investigators will be notified in writing by the monitor of deviations. The IRB/IEC 
should be notified of all protocol deviations in a timely manner. 
10.4 Study termination 
Although Fulcrum Therapeutics has every intention of completing the study, Fulcrum reserves the 
right to discontinue the study at any time for clinical or administrative reasons. Should termination of 
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the study be required, the sponsor will promptly inform the investigator and the IRB/IEC and provide 
them with a detailed written explanation. Fulcrum and the investigator will assure that adequate 
consideration is given to the protection of the subjects’ interests. The sponsor has no plans to 
provide study drug to subjects after study closure or termination. The obligations to provide study 
results for subjects and reports to IRB/IEC shall continue as required by applicable laws and 
regulations. 
At any time, the sponsor, the investigators, or the IRBs/IECs may terminate this study for 
reasonable cause. Conditions that may lead to reasonable cause and warrant termination include, 
but are not limited to the following: 
• 
Subject or investigator noncompliance 
• 
Unsatisfactory subject enrollment 
• 
Lack of adherence to protocol procedures 
• 
Lack of evaluable and/or complete data 
• 
Potentially unacceptable risk to study subjects 
• 
Decision to modify drug development plan 
• 
Decision by the regulatory authority 
Written notification that includes the reason for the clinical study termination is required. 
The end of the study is defined as the date on which the last subject completes the last visit 
(includes the safety follow-up visit).  
10.5 Final report 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the clinical 
study reports are prepared and provided to the regulatory agency(ies) as required by the applicable 
regulatory requirement(s). The sponsor will also ensure that the clinical study reports in marketing 
applications meet the standards of the ICH harmonised tripartite guideline E3: Structure and content 
of clinical study reports.  
Where required by applicable regulatory requirements, an investigator signatory will be identified for 
the approval of the clinical study reports. The investigator will be provided reasonable access to 
statistical tables, figures, and relevant reports and will have the opportunity to review the complete 
study results. 
Upon completion of the clinical study reports, the sponsor will provide the investigator with the full 
summary of the study results. The investigator is encouraged to share the summary results with the 
study subjects, as appropriate. The study results will be posted on publicly available clinical trial 
registers. 
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11 REFERENCES 
 
Banerjee S, Narayanan K, Mizutani T, Makino S. Murine coronavirus replication-induced p38 
mitogen-activated protein kinase activation promotes interleukin-6 production and virus 
replication in cultured cells. J Virol. 2002;76(12):5937–5948.2. 
Barbour AM, Sarov-Blat L, Cai G, et al. Safety, tolerability, pharmacokinetics and 
pharmacodynamics of losmapimod following a single intravenous or oral dose in healthy 
volunteers. Brit J Clin Pharmacol. 2013;76(1):99-106. 
Blanco-Melo D, Nilsson-Payant BE, Liu WC, et al. SARS-CoV-2 launches a unique transcriptional 
signature from in vitro, ex vivo, and in vivo systems. Preprint. Posted online March 24, 2020. 
bioRxiv. doi: https://doi.org/10.1101/2020.03.24.004655 
Börgeling Y, Schmolke M, Viemann D, et.al. Inhibition of p38 mitogen-activated protein kinase 
impairs influenza virus-induced primary and secondary host gene responses and protects 
mice from lethal H5N1 infection. J Biol Chem. 2014;289(1):13-27. 
&DGDYLG'0HOOLRQ0:DOODFH2HWDO6DIHW\DQGWROHUDELOLW\RIORVPDSLPRGDVHOHFWLYHSĮȕ
MAPK inhibitor, for treatment of FSHD at its root cause. Poster presented at: FSHD 
International Research Congress; June 19-20, 2019; Marseille, France. 
Centers for Disease Control. Symptoms of coronavirus. Available at:  
https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html. Accessed 03 
May 2020. 
Chen Y, Wang L, Jin J, et al. p38 inhibition provides anti–DNA virus immunity by regulation of 
USP21 phosphorylation and STING activation. J Exp Med. 2017;214(4):991-1010. 
Chen YH, DeMets DL, Gordon Lan KK. Increasing the sample size when the unblinded interim 
result is promising. Stat Med. 2004;23(7):1023-38. 
Cheriyan J, Webb AJ, Sarov-Blat L, et al. Inhibition of p38 mitogen-activated protein kinase 
improves nitric oxide-mediated vasodilatation and reduces inflammation in 
hypercholesterolemia. Circulation. 2011;123(5):515-23. 
Christie J, Vaslef S, Chang PK, et.al, A randomized dose-escalation study of the safety and anti-
inflammatory activity of the p38 mitogen-activated protein kinase inhibitor dilmapimod in 
severe trauma subjects at risk for acute respiratory distress syndrome. Crit Care Med. 
2015;43(9):1859-69. 
Dong Y, Xie W, Liu Y, et.al, Receptor tyrosine kinase inhibitors block proliferation of TGEV mainly 
through p38 mitogen-activated protein kinase pathways. Antiviral Res. 2020;173;104651. 
Genovese M, Cohen SB, Wofsy D, et al. A 24-week, randomized, double-blind, placebo-controlled, 
parallel group study of the efficacy of oral SCIO-469, a p38 mitogen-activated protein kinase 
inhibitor, in patients with active rheumatoid arthritis. J Rheumatol. 2011;38(5):846-54. 
Griego SD, Weston CB, Adams JL, et al. Role of p38 mitogen-activated protein kinase in rhinovirus-
induced cytokine production by bronchial epithelial cells. J Immunol. 2000;165(9):5211-20. 
Grimes JM, Grimes KV. p38 MAPK inhibition: A promising therapeutic approach for 
COVID-19. J Mol Cell Cardiol. 2020. 
He F, Xiao Z, Yao H, et al. The protective role of microRNA-21 against coxsackievirus B3 infection 
through targeting the MAP2K3/P38 MAPK signaling pathway. J Transl Med. 2019;17(1):335. 
Iordanov MS, Paranjape JM, Zhou A, et al. Activation of p38 mitogen-activated protein kinase and c-
Jun NH(2)-terminal kinase by double-stranded RNA and encephalomyocarditis virus: 
involvement of RNase L, protein kinase R, and alternative pathways. Mol Cell Biol. 
2000;20(2):617-27. 
Jimenez-Guardeño JM, Nieto-Torres JL, DeDiego ML, et al. The PDZ-binding motif of severe acute 
respiratory syndrome coronavirus envelope protein is a determinant of viral pathogenesis. 
PLoS Pathog. 2014;10(8):e1004320. 
Kindrachuk J, Ork B, Hart BJ, et al. Antiviral potential of ERK/MAPK and PI3K/AKT/mTOR signaling 
modulation for Middle East respiratory syndrome coronavirus infection as identified by 
temporal kinome analysis. Antimicrob Agents Chemother. 2015;59(2):1088-1099. 
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Kono M, Tatsumi K, Imai AM, et al. Inhibition of human coronavirus 229E infection in human 
epithelial lung cells (L132) by chloroquine: involvement of p38 MAPK and ERK. Antiviral 
Res. 2008;77(2):150-2. 
Lee CH, Chen RF, Liu JW, et al. Altered p38 mitogen kinase expression in different leukocytes with 
increment of immunosuppressive mediators in patients with severe acute respiratory 
syndrome. J Immunol. 2004;172:7841-7847. 
Liu DS, Wang T, Han SX. p38 MAPK and MMP-9 cooperatively regulate mucus overproduction in 
mice exposed to acrolein fog. Internat Immunopharmacol. 2009;9:1228-1235. 
Liu Y, Yang Y, Zhang C, et al. Clinical and biochemical indexes from 2019-nCoV infected patients 
linked to viral loads and lung injury. Sci China Life Sci. 2020;63(3):364-374. 
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med. 1985;4(2):213-226. 
Nagata N, Iwata N, Hasegawa H, et al. Mouse-passaged severe acute respiratory syndrome-
associated coronavirus leads to lethal pulmonary edema and diffuse alveolar damage in 
adult but not young mice. Am J Pathol. 2008;172(6):1625-37. 
Newby L, Marber MS, Melloi C, et al. Losmapimod, a novel p38 mitogen-activated protein kinase 
inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial. 
Lancet. 2014;384(9949):1187-95. 
O’Donoghue ML, Glaser R, Cavender MA, et al. Effect of losmapimod on cardiovascular outcomes 
in patients hospitalized with acute myocardial infarction: a randomized clinical trial. JAMA. 
2016;315(15):1591-9. 
Pascoe S, Costa M, Marks-Konczalik J, et al. Biological effects of p38 MAPK inhibitor losmapimod 
does not translate to clinical benefits in COPD. Respir Med. 2017;130:20-6. 
Ruan Q, Yang K, Wang W, et al. Clinical predictors of mortality due to COVID-19 based on an 
analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020 Mar 3. doi: 
https://doi.org/10.1007/s00134-020-05991-x. [Epub ahead of print] 
Salomon R, Hoffmann E, Webster RG. Inhibition of the cytokine response does not protect against 
lethal H5N1 influenza infection. PNAS. 2007;104(30):12479-12481. 
Shapiro L, Heidenreich KA, Meintzer MK, et al. Role of p38 mitogen-activated protein kinase in HIV 
type 1 production in vitro. Proc Natl Acad Sci USA. 1998;95(13):7422-6. 
Siddiqi HK, Mehra MR. COVID-19 Illness in native and immunosuppressed states: a clinical-
therapeutic staging proposal. J Heart Lung Transplant. Accepted manuscript. Published 
online March 20, 2020. 
Vukmanovic-Stejic M, Chambers ES, Suárez-Farinas M, et al. Enhancement of cutaneous immunity 
during aging by blocking p38 mitogen-activated protein (MAP) kinase-induced inflammation. 
J Allergy Clin Immunol. 2018;142(3):844-56. 
Watz H, Barnacle H, Hartley BF, et al. 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;2(1):63-72. 
World Health Organization (WHO). WHO R&D blueprint novel coronavirus COVID-19 therapeutic 
trial synopsis. Draft Feb 18, 2020.  
Zhou F, Ting Y, Ronghui D, et al. Clinical course and risk factors for mortality of adult inpatients with 
COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-
62. 
 
 
 
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SAP_001.pdf: 
Fulcrum Therapeutics 
CONFIDENTIAL 
             Statistical Analysis Plan 
Protocol FIS-001-2020 
 
           Version 1.0, 27APR2021 
Page 1 of 33 
 
 
 
Protocol 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) 
 
Protocol Number: 
FIS-001-2020 
 
Protocol Version/Date: 
Version 1/ 29MAY2020 
Version 2/ 29JUN2020 
Version 2.1/ 10JUL2020 
Version 3.0/ 21Oct2020 
 
Investigational Product: Losmapimod 
 
 
Sponsor: 
Fulcrum Therapeutics 
26 Landsdowne St., 5th floor 
Cambridge, MA 02139, USA  
 
 
SAP Version/Date: 
SAP 1.0/27APR2021 
 
 
 
CONFIDENTIAL 
Information described herein is confidential and may be disclosed only with the express written 
permission of the sponsor. 
 
 
 


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Protocol 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) 
 
Protocol Number: 
FIS-001-2020 
 
SAP Version/Date: 
SAP 1.0/27APR2021 
We, the undersigned, have reviewed and approved this Statistical Analysis Plan: 
Signature 
 Date 
  
  
Director, Biostatistics 
  
 
  
 
  
Biostatistician 
  
  
  
Vice President, Infectious Diseases 
  
  
  
 MD 
Medical Director, LOSVID Trial 
Fulcrum Therapeutics 
  
  
  
Vice President, Biometrics 
Fulcrum Therapeutics 
  
 
 


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VERSION HISTORY 
Version 
Version Date 
Description 
1.0 
27APR2021 
Original signed version 
 
 
 
 
 


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TABLE OF CONTENTS 
1 
Introduction ......................................................................................................................... 7 
2 
Study Overview ................................................................................................................... 7 
2.1 
Objectives and Endpoints ............................................................................................ 7 
2.2 
Study Design ............................................................................................................... 8 
2.2.1 
Overview ............................................................................................................... 8 
2.2.2 
Randomization and Blinding ................................................................................10 
2.2.3 
Study Drug ...........................................................................................................10 
2.2.4 
Sample Size Determination ..................................................................................10 
3 
Statistical Methodology ......................................................................................................11 
3.1 
General Considerations ..............................................................................................11 
3.1.1 
Analysis Day ........................................................................................................11 
3.1.2 
Definition of Baseline ...........................................................................................11 
3.1.3 
Summary Statistics ..............................................................................................11 
3.1.4 
Hypothesis Testing ..............................................................................................11 
3.1.5 
Type I Error for Testing Key Study Endpoints ......................................................11 
3.1.6 
Evaluation of Site Effect .......................................................................................12 
3.1.7 
Adjustment of Covariates .....................................................................................12 
3.1.8 
Handling of Dropouts and Missing Data ...............................................................12 
3.2 
Analysis Populations ...................................................................................................13 
3.2.1 
Full Analysis Set (FAS) ........................................................................................13 
3.2.2 
Safety Analysis Set ..............................................................................................13 
3.2.3 
Pharmacokinetic (PK)/Pharmacodynamic (PD) Analysis Set ...............................13 
3.3 
Subject Data and Study Conduct ................................................................................13 
3.3.1 
Subject Disposition ..............................................................................................13 
3.3.2 
Protocol Deviations ..............................................................................................13 
3.3.3 
Analysis Populations ............................................................................................13 
3.3.4 
Demographic and Baseline Characteristics ..........................................................14 
3.3.5 
Medical History ....................................................................................................14 
3.3.6 
Prior and Concomitant Medications .....................................................................14 
3.3.7 
Concomitant Procedures/Non-Drug Therapies .....................................................14 
3.3.8 
Study Drug Exposure and Compliance ................................................................15 
3.4 
Efficacy Assessment ...................................................................................................15 
3.4.1 
Primary Efficacy Endpoint ....................................................................................15 
3.4.2 
Secondary Efficacy Endpoints .............................................................................16 
 
 
3.4.4 
Subgroups ...........................................................................................................18 
3.5 
Safety Assessment .....................................................................................................19 
3.5.1 
Adverse Events (AEs) ..........................................................................................19 
3.5.2 
Clinical Laboratory Tests .....................................................................................19 


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3.5.3 
Vital Signs ............................................................................................................20 
3.5.4 
ECG .....................................................................................................................20 
3.5.5 
Other Safety Assessments ...................................................................................20 
4 
Data Monitoring Committee ...............................................................................................20 
5 
Analysis Timing ..................................................................................................................21 
5.1 
Interim Analysis ..........................................................................................................21 
5.1.1 
Futility Testing ......................................................................................................21 
5.1.2 
Sample Size Re-estimation ..................................................................................21 
5.1.3 
Possible Recommendations by the DMC .............................................................24 
5.1.4 
Operating Characteristics of the Fixed Sample and Adaptive Designs, Conditional 
on Interim Outcome ...........................................................................................................24 
5.2 
Final Analysis ..............................................................................................................27 
6 
Changes from Protocol-Specified Statistical Analyses .......................................................27 
7 
Programming Specifications ..............................................................................................27 
Appendix C:  References ..........................................................................................................33 
 
 
 




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Abbreviation
Definition
SDTM 
Study Data Tabulation Model 
SOC 
Standard of care 
TEAE 
Treatment-emergent adverse event 
TFL 
Tables Figures and Listings 
WHO 
World Health Organization 
 
1 INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide a description of the statistical 
methods to be implemented for the analysis of data from the study with protocol number FIS-
001-2020.  The SAP will be finalized prior to the planned Interim Analysis (IA).  Any deviations 
from the SAP after IA will be documented in the final Clinical Study Report (CSR). 
2 STUDY OVERVIEW 
2.1 Objectives and Endpoints 
Objectives  
Endpoints  
Primary 
To assess the efficacy of losmapimod 
compared with placebo for treatment of 
COVID-19 when administered concurrently 
with standard of care 
Proportion of progressors to death or 
respiratory failure by Day 28 
Secondary 
To evaluate the effect of losmapimod 
compared with placebo on clinical outcomes 
Clinical status by Days 7 and 14 as 
measured on the 9-point WHO ordinal scale: 
 
(vasopressors, renal replacement therapy, 
ECMO) 
 
-flow 
oxygen therapy 
-
flow or non-invasive ventilation 
therapy 
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This study will be performed in 
40 years old who have a CRP >15 mg/L, 
who have been diagnosed with COVID-19, and who can undergo randomization within 7 days of 
collection of the sample found positive for the SARS-CoV-2 virus and before progressing into 
critical disease. Critical disease is defined as cardiac failure, septic shock, or ARDS or 
immediate need for intubation or mechanical ventilation per the judgment of the investigator.  
Subjects who sign informed consent and meet all entry criteria may be enrolled.  
Up to 410 subjects will participate for a maximum of 34 days, divided as follows:  
 
Screening: Day -3 until Day -1 before the first study drug administration. 
 
Treatment period of 14 days:  
 Subjects randomized (1:1) to either:   
 
losmapimod tablets 15 mg orally (PO) twice daily (BID); OR  
 
matching placebo tablets PO BID  
 
at randomization (yes/no)  
 
Follow-up: 7 (± 3) days after last dose and 14 (± 3) days after last dose.  
The first 10 enrolled subjects will be dosed and followed for at least 72 hours after their first 
dose for a 
subjects will continue if there are no drug-related safety concerns from the initial subjects dosed 
as assessed by an independent Data Monitoring Committee (DMC). The DMC will review safety 
data for the sentinel subjects and all subjects at regular intervals throughout the study as 
outlined in the charter.  
The Sponsor will monitor individual adverse events (AEs) and toxicities on an ongoing basis 
throughout the study.  
All study visits during the first week of treatment are anticipated to be conducted in the inpatient 
setting. If the clinical status of the subject improves such that the clinician discharges the 
subject from the hospital before the end of the study, the follow-up assessments will be 
conducted on an outpatient basis by alternative methods, including the use of local 
laboratories/facilities or home visits for blood draws, telemedicine, and/or outpatient follow-up 
clinic visits as deemed clinically appropriate per COVID-19 follow-up standard of care (SOC) at 
each site.   
 


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2.2.2 Randomization and Blinding 
A total of up to 410 subjects will be recruited into this study and will be randomized in a 1:1 ratio 
to 15 mg losmapimod (BID) or placebo using an interactive/web voice response system (IxRS) 
for randomization. The randomization 
oxygen at randomization (yes/no) at enrollment.  
Only subjects who have completed screening assessments and are eligible for participation in 
the study will be randomized to receive study drug. Randomized subjects will be sequentially 
assigned a unique subject number from the randomization list per the IxRS. From the time of 
randomization and throughout the duration of the study, subjects will be identified by their 
unique randomization number.  
The authorized site personnel will prepare the appropriate study drug for each subject based on 
the randomization schedule. Treatment codes should not be broken except in emergency 
situations, i.e., when knowledge of the treatment is essential for the immediate further 
management of the subject.   
This study will be performed in a double-blind fashion. The investigator, study staff, subjects, 
sponsor, and monitor will remain blinded to subject-level treatment assignment until study 
closure. The investigational drug and its matching placebo are indistinguishable and will be 
packaged in the same way.  
All doses will be administered either in the hospital (anticipated during the first week of study 
treatment) or taken by the study participants on an outpatient basis. The subject will bring the 
study treatment bottle to each visit (clinic or home assessment) for review by the site staff. The 
study treatment bottles will be collected at the Day 14 visit whether in the hospital or outpatient 
or at the ET visit if prior to Day 14.  
2.2.3 Study Drug 
Losmapimod will be provided in tablets of 7.5 mg for oral administration. 
Matching placebo tablets will be provided for oral administration.  
The tablets are plain white, round, biconvex, film-coated tablets. The proposed dosing regimen 
is as a twice daily dose of 15 mg (2 × 7.5 mg tablets/dose BID). The proposed duration of 
treatment is for up to 14 days.  
Subjects should take their dose of losmapimod or placebo with food whenever possible and with 
240 mL of room temperature water.   
2.2.4 Sample Size Determination 
The primary efficacy endpoint of this study is the proportion of subjects who progress to death 
or respiratory failure by the end of study (Day 28). It is estimated that approximately 30% of 
enrolled subjects receiving SOC plus placebo will attain this endpoint. It is assumed that 
losmapimod will improve the primary endpoint by 40% over placebo. On the basis of these 
assumptions, a total of up to 410 subjects randomized to the losmapimod arm or the placebo 
arm in a 1:1 ratio (205 subjects in the losmapimod arm and 205 subjects in the placebo arm) will 
yield approximately 80% power in a 1-sided test at the 2.5% significance level. 


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The sample size estimate assumes an IA will be conducted after approximately 206 subjects 
(103 in the losmapimod arm, and 103 in the placebo arm) have completed the Day 28 visit, to 
assess early futility, using the rules specified in Section 5.1. 
3 STATISTICAL METHODOLOGY 
3.1 General Considerations 
3.1.1 Analysis Day 
Analysis day will be calculated from the date of first dose of study drug.  The day of the first 
dose of study drug will be Day 1, and the day immediately before Day 1 will be Day -1.  There 
will be no Day 0. 
3.1.2 Definition of Baseline  
Baseline is defined as the last measurement prior to the first dose of study drug. 
3.1.3 Summary Statistics 
Categorical data will generally be summarized with counts and percentages of subjects.  The 
denominator used for the percentage calculation will be clearly stated. Continuous data will 
generally be summarized with descriptive statistics including n (number of non-missing values), 
mean (with its standard error), first quartile, median, third quartile, standard deviation, minimum, 
and maximum. 
Where appropriate, descriptive statistics may be presented with 95% CI. 
3.1.4 Hypothesis Testing 
All statistical comparisons will be made using one-
will be of no treatment difference, and all alternative hypotheses will be one-sided. Confidence 
intervals will be 2-
summary statistic (e.g., mean), and standard error will be reported to one additional decimal 
place. P-values will be reported to four decimal places, with p-values less than 0.0001 reported 
. 
3.1.5 Type I Error for Testing Key Study Endpoints 
The overall Type I error of the study will be controlled at 0.025 for 1-sided tests of hypotheses 
for the following key study endpoints, using a closed test procedure. The key endpoints will be 
tested in the fixed sequence procedure as the same sequence they are listed below. Assuming 
the analysis of the prior endpoint yields statistically significant treatment effect, the next key 
endpoint will be tested. 
1. Proportion of progressors to death or respiratory failure by Day 28   
2. Change in clinical status using the 9-point WHO scale at Day 14 
3. Change in clinical status using the 9-point WHO scale at Day 7 
4. Oxygen-free days by Day 28 


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3.1.6 Evaluation of Site Effect 
Low enrolling sites will be pooled for analysis. For sites with less than 10 subjects in total, they 
will be pooled. Pooled sites will be only used for descriptive summary of biomarker endpoints of 
CRP and IL-6. 
3.1.7 Adjustment of Covariates 
In the event that the analysis models do not converge (e.g., due to sparse data), sex will be 
removed from the model, followed by the stratification factors until the model converges. 
For mixed-model-repeated measures (MMRM) model, covariance structure will be updated to 
first-order autoregressive (AR(1)) prior to the removal of any covariate.   
3.1.8 Handling of Dropouts and Missing Data 
All missing or incomplete safety and PD data, including dates and times, will be treated as such. 
Missing test results or assessments will not be imputed, and as such, are assumed missing 
completely-at-random (MCAR).  
For laboratory data, values 
half that limit. 
For the analysis of hospital-free and ICU-free days, subjects who die prior to the analysis time 
point will have post-death days considered to be not hospital-free and not ICU-free.  
Adverse events with missing start dates will be considered as treatment-emergent unless the 
partial date excludes that possibility, e.g., the adverse event month is prior to the first dose of 
study drug. Otherwise, the first day of the month will be used to impute missing start days and 
January will be used to impute missing start months. For example, if the first dose of study drug 
was on January 8, 2021 and an adverse event started in January 2021 with missing day, the 
start date will be imputed as the first dose date (January 8, 2021) and this adverse event will be 
considered as treatment-emergent. In the same example, if another adverse event has start 
month of December 2020 with missing day (before the first dose date of January 8, 2021), its 
start date will be imputed as December 1, 2020 and will not be considered as treatment-
emergent. 
Subjects who terminate the study prior to the analysis time point, not due to death, will be 
considered as missing for the analysis of key efficacy endpoints. Missing data in each treatment 
arm will be imputed using the observed data in their respective arm under the missing at 
random (MAR) assumption. Multiple imputation (MI) will be performed using the fully conditional 
specification (FCS) model. The imputation model will include the stratification factors, sex, and 
baseline CRP. 
The handling of missing data for the key efficacy endpoints are outlined as the following: 
1. Primary endpoint: patients whose status could not be ascertained (lost-to-follow up, etc.) 
will be imputed using multiple imputation approach.  
2. Change in Clinical Status at Days 7 and 14: missing clinical status at the post-baseline 
timepoint will be imputed using multiple imputation approach. 
3. Oxygen-free, ICU, hospitalized, respiratory failure-free days: subjects who die prior to 
the analysis time point will have post-death days considered not event free. For 
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free, ICU, hospitalized, respiratory failure-free days. Subjects who terminate the study 
for other reasons prior to the analysis time point will be  imputed using multiple 
imputation approach. 
3.2 Analysis Populations 
3.2.1 Full Analysis Set (FAS) 
The FAS will consist of all subjects who are randomized and receive any study drug. All 
analyses using the FAS will group subjects according to randomized treatment. The primary 
endpoint, clinical outcomes/status, survival, and pharmacodynamic endpoints will be analyzed 
using the FAS. The IA will be based on FAS. 
3.2.2 Safety Analysis Set 
The Safety Analysis Set is defined as all subjects who receive any study drug. All analyses 
using the Safety Analysis Set will group subjects according to treatment actually received. The 
Safety Analysis Set will be used for all safety and tolerability analyses.   
3.2.3 Pharmacokinetic (PK)/Pharmacodynamic (PD) Analysis Set 
The PK/PD Analysis Set will consist of all the sentinel subjects who receive any study drug. 
3.3 Subject Data and Study Conduct 
3.3.1 Subject Disposition 
Subject disposition will be listed by subject.  
The number and percentage of subjects in each of the following categories will be presented by 
the treatment group and overall for all screened subjects:  
 
screened,  
 
randomized,  
 
treated, 
 
randomized but not treated, 
 
completed the Treatment Period, and 
 
completed the study. 
Primary reasons for discontinuation of study treatment and primary reasons for discontinued 
study will be tabulated. 
3.3.2 Protocol Deviations 
Any major protocol deviation will be documented as described in the protocol deviation plan, 
and its impact on inclusion in each analysis population for any subject will be specified. The final 
list of protocol deviations impacting the analysis populations will be reviewed prior to database 
lock. Counts and percentages of subjects with major protocol deviations by deviation category 
will be summarized for all randomized subjects. 
3.3.3 Analysis Populations  
The numbers and percentages of subjects randomized and included in each analysis population 
will be tabulated. 


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3.3.4 Demographic and Baseline Characteristics 
The following demographic and baseline characteristics will be summarized: 
 
 
 
Sex 
 
Race 
 
Ethnicity 
 
Height (cm) 
 
Weight (kg) 
 
Body mass index (BMI) (kg/m2) and BMI categories (<30 kg/m2
2)  
 
Requirement for oxygen at randomization (yes, no) 
 
Chest imaging 
 
COVID-19 diagnosis 
 
Baseline CRP by central lab (Day 1) and categories 
 
Baseline IL-6 by central lab (Day 1) 
 
Viral load by central lab PCR (Day 1 and Day 7, unless sentinel group or ET) 
 
Region (US, Ex-US) 
Demographic and other baseline characteristics will be summarized using descriptive statistics 
for the treatment group and overall for all randomized subjects. 
3.3.5 Medical History 
Medical history terms will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA, Version 23.0). Medical history will be summarized by treatment group and overall 
using coded system organ class and preferred term. In addition, COVID-19 associated medical 
history which may include diabetes, obesity, chronic kidney disease, hypertension, cancer, 
cardiac disease, immunocompromised state post-transplant, Chronic obstructive pulmonary 
disease, and asthma will be summarized separately. Medical history will also be listed. 
3.3.6 Prior and Concomitant Medications 
Prior medications will include medications which started prior to the first dose of study drug. 
Concomitant medications will include medications or non-medication therapeutic agents 
(convalescent plasma therapy for example) taken on and after the first dose of study drug.  
Medications that started prior to the first dose of study drug but continued into treatment are 
considered as both prior and concomitant.  
All medications will be coded using the World Health Organization Drug Dictionary (WHO Drug 
Global B3, March 2020). A frequency table of the number and percentage of subjects will be 
provided for concomitant medications by therapeutic class and preferred name for the Safety 
Analysis Set. Prior and concomitant medications will be summarized separately.  
Prior and concomitant medications will be also listed by international nonproprietary names, 
dose, regimen, route and for which indication it was prescribed. 
3.3.7 Concomitant Procedures/Non-Drug Therapies 
Concomitant procedures and non-drug therapies will be listed. 


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3.3.8 Study Drug Exposure and Compliance 
Exposure to study treatment will be described in terms of duration of treatment. Exposure in 
days is defined as the date of last dose of study drug minus the date of first dose of study drug 
plus 1. Exposure in days will be summarized. In addition, a contingency table will be provided to 
display the number and percentage of subjects with exposure in the following categories: 
 
<1 week (<7 days), 
 
>=1 - <=2 weeks (7 - 14 days), 
 
>2 weeks (>14 days). 
Treatment compliance will be calculated as (the number of tablets dispensed - the number of 
tablets returned) divided by (the number of tablets expected to be taken during the Treatment 
Period, calculated as four tablets daily times 14 days). Percent compliance will be summarized. 
In addition, the number and percentage of subjects within each treatment group with overall 
compliance in the following categories: <80%, 80% to 120%, and >120%, will be provided for 
the Safety Analysis Set. 
3.4 Efficacy Assessment 
3.4.1 Primary Efficacy Endpoint 
3.4.1.1 
Primary Analysis 
The primary efficacy endpoint is the proportion of subjects who progress to death or respiratory 
failure by Day 28.  
Respiratory failure is defined as either need for mechanical ventilation (invasive or non-invasive) 
or high flow oxygen (defined by greater than 15 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 is used to predict the response rate for every subject in the 
study as if they had received the treatment or the control intervention.  
Assuming pt is probability of outcome in the losmapimod arm; pc is the probability of outcome in 
the control arm 
Study hypothesis: H0:  pt  pc = 0                              
      H1:  pt  pc < 0  
Assuming pt=0.18, pc=0.30, we can restate the hypothesis as 
    H0
0 = 0   
    H1
1 = -0.12  
t  pc. For the final analysis, the proportion of subjects achieving the 
primary endpoint in the treatment arms will be compared using an adjusted risk difference 
obtained from the logistic regression model, adjusted for stratification factors, sex, and baseline 
CRP. Sample SAS codes are provided in Appendix A. More details can be found in Guo et al. 
(2012) and Ge et al. (2011).  
An interim analysis to assess futility analysis
and potential sample size re-estimation
 will be 
conducted, as discussed in Section 5.1.  




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the relationship with treatment, adjusting for stratification factors, sex, baseline CRP and 
number of days on study. The key study endpoint of 
at 1-sided significance level of 0.025 as outlined in Section 3.1.5. 
If a patient died, the number of days of (a)-(e) are considered as having the events on and after 
the patient died. For example, if a patient died on Day 6. The days from Day 6 and after are 
considered not free of oxygen supplementation, hospitalization, ICU, and respiratory failure. 
Percentage of subjects discharged from the hospital by Day 28:  
Percentages of subjects discharged from the hospital will be tabulated by treatment arm, along 
with differences between treatment arms. The proportion of subjects will be compared using an 
adjusted risk difference obtained from a logistic regression model, adjusting for stratification 
factors, sex, and baseline CRP. 
The percentage of subjects discharged from the hospital is defined as the number of subjects 
discharged from the hospital divided by the sum of the number of subjects who completed the 
study and the number of subjects who died during the study period.  
A sensitivity analysis will be performed by excluding the subjects who died after being 
discharged from the hospital from the numerator of the above percentage calculation. 
Missing data will be imputed similarly as primary endpoint for the above endpoints. 
All-cause mortality at Day 28:  
Percentages of subjects will be tabulated by treatment arm, along with differences between 
treatment arms, at each time point. The proportion of subjects will be compared using an 
adjusted risk difference obtained from a logistic regression model, adjusting for stratification 
factors, sex, and baseline CRP.  
Standard survival analysis methods will be used as sensitivity analyses to compare the time to 
each of these clinical events of interest (death and respiratory failure) as well as the composite 
thereof. Specifically, the cumulative incidence rates between two groups at Day 28 will be 
compared, accounting for potential differential follow-up. 
Incidence of AEs/SAEs by Day 28: will be summarized by system organ class and preferred 
term and by treatment arm using percentages. 
Incidence of AEs/SAEs is calculated by the number of subjects who developed AEs/SAEs 
during the study divided by the sum of the number of subjects who completed the study and the 
number of subjects who died during the study period. (see above edit) 
Incidence of clinically significant changes by Day 28: Percentage of subjects with clinically 
significant changes in laboratory parameters, ECG, and vital sign measurements will be 
computed for each treatment arm along with associated 2-sided 95% Clopper-Pearson CI.   
Changes in the assessments will be considered as clinically significant if the Baseline 
assessment is not clinically significantly abnormal and there has been at least one occurrence 
of post-Baseline assessments with a clinically significant abnormal result by Day 28. 
Death is not considered a form of missing data or censoring. The incidence of clinically 
significant changes is calculated by the number of subjects with clinically significant changes 
during the study divided by the sum of the number of subjects who completed the study and the 
number of subjects who died during the study period. 


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Clearance of quantifiable viral RNA by Day 7: percentages of subjects with clearance of 
quantifiable viral RNA will be tabulated by treatment arm, along with differences between 
treatment arms, at each time point. The proportion of subjects will be compared using an 
adjusted risk difference obtained from a logistic regression model, adjusting for stratification 
factors, sex, and baseline CRP.  
Change from baseline in viral RNA will be summarized by treatment arm and also analyzed 
using an analysis of covariance (ANCOVA) model with fixed effects of treatment, and 
stratification factors, sex and baseline CRP as covariates. 
Death is not considered a form of missing data or censoring. The proportion of subjects with 
clearance of quantifiable viral RNA by Day 7 is calculated by the number of subjects with 
clearance of quantifiable viral RNA by Day 7 divided by the sum of the number of subjects who 
is in study by Day 7 and the number of subjects died by Day 7. 
The endpoint of comparing percentage of subjects discharged from the hospital, all-cause 
mortality by Day 28, incidence of AEs/SAEs, incidence of clinically significant changes, and 
percentage of subjects with clearance of quantifiable viral RNA by Day 7 between treatment 
groups will be analyzed similarly as the primary endpoint. 
. 
 
3.4.4 Subgroups 
The key study endpoints will be analyzed over time, including Forest plots, for the following 
subgroups of the FAS: 
 
Age (<65 years, 65 years), 


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Requirement for oxygen (Yes, No), 
 
Region (US, Ex-US), 
 
Baseline CRP (15-49, 50-100, >100 mg/L), 
 
Use of antivirals (Yes, No), 
 
Country. 
3.5 Safety Assessment 
3.5.1 Adverse Events (AEs) 
The latest version of Medical Dictionary for Regulatory Activities (MedDRA) will be used for the 
coding of AEs.  
Treatment-emergent AEs will be defined as an event that occurs on or after the first dose of 
study drug or the worsening of a preexisting condition on or after the first dose of study drug. If a 
subject does experience an event both prior to and after starting administration of a treatment, 
the event will be considered a TEAE (of the treatment) only if it has worsened (i.e., it is reported 
with a new start date and the event is worsened in severity or becomes serious) after starting 
administration of the specific treatment, and prior to the start of another treatment, if any. All 
TEAEs collected during the investigational period will be summarized.  
A summary overview of TEAEs will be provided, which presents the number of events and the 
number and percentage of subjects in each treatment group from the Safety Analysis Set for 
each of the following categories: 
 
TEAEs (overall, by maximum severity, and by maximum drug relatedness) 
 
Study drug-related TEAEs (overall and by maximum severity) 
 
All treatment-emergent adverse events of special interest (AESI) 
 
All treatment-emergent serious AEs (TESAEs) 
 
All study drug-related TESAEs 
 
TEAEs leading to death 
 
TEAEs leading to study drug discontinuation 
 
Study drug-related TEAEs leading to study drug discontinuation  
 
TEAEs leading to study drug interruption 
 
Study drug-related TEAEs leading to study drug interruption 
The number of TEAEs and the number of subjects with at least 1 TEAE will be summarized by 
treatment group for each of the categories in the overview.  
All AEs will be displayed in listings.  In addition, SAEs and TEAEs leading to study drug 
discontinuation will be listed. 
3.5.2 Clinical Laboratory Tests 
Reported values and change from baseline values of clinical laboratory variables will be 
summarized using descriptive statistics by treatment group and time point. The number of 


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available observations and out-of-range values (absolute and in percentage) will also be 
presented by treatment group. For out-of-range values summaries, all post-baseline values, 
including those from unscheduled visits will be evaluated. 
3.5.3 Vital Signs 
Reported values and change from baseline values of supine blood pressure and pulse rate and 
temperature will be summarized using descriptive statistics by treatment group and time point. 
The number of available observations and out-of-range values (absolute and in percentage) will 
be presented by treatment group. Vital sign variables will be listed. Values outside the reference 
range (see Table 1) will be flagged in the listing.  
Table 1: Normal vital sign ranges for the average healthy adult while resting 
Variable 
Normal Range 
Systolic Blood Pressure 
90 to 120 mm Hg 
Diastolic Blood Pressure 
60 to 80 mm Hg 
Breathing 
12 to 19 breaths per minute 
Pulse 
60 to 100 beats per minute 
Temperature 
97.8 to 99.1°F (36.5°C to 37.3°C) 
 
Extended vital signs, including oxygen saturation and fraction of inspired oxygen will also be 
summarized using descriptive statistics and listed in similar manners as other the vital signs. 
3.5.4 ECG 
Other than the summary table of ECG for one of the secondary endpoints, ECG values will be 
listed. 
3.5.5 Other Safety Assessments 
Other safety assessments such as hospitalizations and physical examinations will be listed. 
4 DATA MONITORING COMMITTEE 
An independent DMC composed of experts external to the sponsor and investigators will 
monitor the safety of trial participants and the conduct of the trial on an ongoing basis and will 
be responsible for the IA and recommendations regarding sample size re-estimation. Consistent 
with US Food and Drug Administration (FDA) recommendations (FDA Guidance for Industry, 
Establishment and Operation of Clinical Trial Data Monitoring Committees, 2006), the DMC will 
include at least 2 external clinicians with expertise relevant to the evaluation of COVID-19, such 
as Critical Care, Pulmonology, or Infectious Disease, as well as at least 1 independent 
biostatistician with expertise in clinical trial design and statistical methods for clinical research 
and analysis of research data including interim analysis. Details on the composition of the DMC 
and the schedule and format of DMC meetings and data outputs are provided in the DMC 
charter. The DMC will review, at a minimum, data for the sentinel subjects prior to continued 


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study drug dosing and cumulative safety data at regular intervals based on subject enrollment. 
The safety evaluations will be detailed in the DMC charter and will include review of 
conventional safety variables, such as serious adverse events. Any safety event that requires 
unblinding will be immediately reported to the DMC and to the FDA. The DMC may request and 
review any additional reports outside of the planned analyses at any time if deemed necessary 
to ensure the safety of subjects. The DMC will also review the efficacy data at the IA and make 
recommendations based on the futility criteria and for sample size re-estimation if needed (see 
Section 8.9). After reviewing study data, the DMC will make recommendations regarding 
continuation, termination, or modification of the study. The DMC may also perform ad hoc 
review of PK of subjects who require dialysis.  
5 ANALYSIS TIMING 
5.1 Interim Analysis 
An IA will be conducted after 206 subjects have been enrolled (approximately 103 in each of the 
losmapimod and placebo arms) and have been treated for 14 days with 28 days of follow-up. 
Only futility
and potential sample size-estimation
will be assessed by the DMC at the IA. The 
-Fleming group sequential method will be used to adjust alpha and beta for interim 
testing. Table 2, Figure 1, Figure 2, and Figure 3 contain sample size requirements, boundary 
information, and stopping probabilities for testing futility on the primary endpoint at both the IA 
and final analysis. P -values are single-sided. Sample size estimation was done using SAS® 
(Proc SeqDesign, Version 4.0). The study will not be stopped for efficacy at the IA.   
5.1.1 Futility Testing 
The process is as follows:  
1. Futility at IA: If standardized z-value (MLE: maximum likelihood estimate) of pt  pc is 
-0.67873 (-0.04017), or p-
for futility under null hypothesis is ~0.75.  
2. At Final Analysis: The final p-value is tested at an adjusted alpha of 0.02784.  
5.1.2 Sample Size Re-estimation 
The Chen-DeMets-Lan method (Chen et al 2004) will be used for unblinded sample size re-
-Fleming method, as 
described above. Wald conditional probabilities will be calculated using the actual observed 
proportion from both treatment arms.   
The maximum sample size allowed is 820 subjects. Sample size will be increased only if the 
Sample size will be increased to ensure a target conditional power of at least 80%. See 
appendix A for sample SAS codes for the conditional power calculation. 
There is only one IA, and conditional power at IA must lie between 50% and 80% for sample 
size re-estimation to be implemented. These 2 conditions ensure that the target Type I error of 
2.5% is not exceeded by increasing sample size to meet the original target power (Chen et al 
2004).  
Sample size re-estimation will not be done in the following 2 instances:  


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If conditional power is <50%, then sample size re-estimation will not be done, and 
-Fleming 
method.   
 
-estimation will not be done, as the 
study will be considered sufficiently powered to detect the effect of interest at the final 
analysis.  
A Wald Test statistic will be calculated and compared with the boundary value for futility (see 
Table 2). If the Wald Test statistic lies in the acceptance region then the study will stop for 
futility.  
All calculations for the IA and the unblinded sample size re-estimation will be conducted by an 
external, unblinded statistician. The DMC will review the results in a closed session and make 
appropriate recommendations to the Sponsor afterwards.   
Table 2: Boundary Values for Interim Analysis Futility Assessment 
Analysis 
Stage  
Sample Size 
 
Beta: Futility 
 
 
Alpha: 
Efficacy 
 
 
 
Losmapimod 
Control
Standardized- 
Z 
(p-value) 
MLE 
Stopping 
Probability 
(accept null 
under null 
hypothesis) 
Standardized- 
Z 
(p-value) 
MLE 
Stopping 
Probability 
(accept null 
under 
alternative 
hypothesis) 
Interim 
Analysis 
103 
103 
-0.67873 
(0.24865) 
-0.04017 
0.75135 
Not applicable 
-- 
0.08871 
Final 
Analysis 
205 
205 
-1.91358 
(0.02784) 
-0.08009 
0.97500 
-- 
-- 
0.20000 
Overall alpha=0.025 (1-sided); overall power=80%. 
Abbreviations: MLE: maximum likelihood estimate. 


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Figure 1 Acceptance Region (Standardized-Z Scale) 
 
Figure 2 Acceptance Region (P-value) 
 
 


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Figure 3 Acceptance Region (Maximum Likelihood Estimate) 
 
 
5.1.3 Possible Recommendations by the DMC 
After reviewing the results of the IA, the DMC may select 3 or more possible recommendations, 
based on the test statistics obtained at the IA:  
1. Stop for Futility - Stop trial early due to strong evidence for futility due to test statistic 
being in the futility region.  
2. Continue without change - Continue until next look with no changes due to test statistic 
 
3. Add required additional sample size, n, without exceeding the maximum sample size of 
820 and continue the trial.   
At the final analysis, 2 recommendations can be made:  
1. Efficacy is demonstrated.  
2. Efficacy is NOT demonstrated. 
5.1.4 Operating Characteristics of the Fixed Sample and Adaptive Designs, 
Conditional on Interim Outcome 
The additional sample size resources are requested only if the interim results are promising, 
which means conditional power at IA lie between 50% and 80%. If the interim results are either 
unfavorable or favorable, there is no sample size adjustment. Table 3 shows the simulation 
results for the operating characteristics of the fixed sample and adaptive designs, conditional on 
interim outcome based on 10000 replications. The adaptive sample size was determined by 
ensuring a target conditional power of at least 80%. Under different simulation scenarios, the 


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gain in conditional power is substantial when there is an increase in sample size. The expected 
sample sizes after sample size adjustment are between 528 and 548. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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5.2 Final Analysis 
Topline TFLs (Tables Figures and Listings) will be provided approximately 1 week after the 
study database is declared final. Final TFLs will be provided approximately 3 weeks after the 
study database is declared final. In addition to TFLs, SDTM (Study Data Tabulation Model) data 
and ADaM (Analysis Data Model) data along with associated files will be provided. Associated 
files may include annotated case report forms (CRFs), SDTM specifications, SDTM programs, 
ADaM specifications, ADaM programs, TFL programs, and Clinical Data Interchange Standards 
Consortium (CDISC) Define packages for both SDTM and ADaM data.   
6 CHANGES FROM PROTOCOL-SPECIFIED STATISTICAL 
ANALYSES 
The statistical analysis plan introduced the following modifications to the analyses planned in 
the protocol: 
1. Per Protocol, the FAS will consist of all subjects who are randomly assigned to receive 
double-blind study drug. Due to limited data, the FAS is updated to consist of all subjects 
who are randomized and receive any study drug. 
2. Due to limited data, considerations on adjusting the model covariates have been added 
in the SAP. 
7 PROGRAMMING SPECIFICATIONS 
Analyses will be performed using SAS® version 9.4 or higher.  All available data will be 
presented in subject data listings which will be sorted by subject and visit date as applicable.  
Detailed Programming Specifications will be provided in a separate document. 
 
 


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APPENDIX C:  REFERENCES 
Chen YH, DeMets DL, Gordon Lan KK. Increasing the sample size when the unblinded interim result is 
promising. Stat Med. 2004;23(7):1023-38. 
Guo, Y., Wu, V., Li, X., Xu, X., & Cheng, C. An Illustration of Rate Difference Estimation with SAS in 
Logistic Regression. 
Ge, M., Durham, L. K., Meyer, R. D., Xie, W., & Thomas, N. (2011). Covariate-adjusted difference in 
proportions from clinical trials using logistic regression and weighted risk differences. Drug information 
journal: DIJ/Drug Information Association, 45(4), 481-493.