Clinical trial NCT04334460
Conditions: Sars-CoV-2 Covid19
Sponsor: Blade Therapeutics
Start date: 2020-05-04; Completion date: 2021-06-21
Enrollment: 120 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
BLD-2660 is a novel, synthetic, orally active, small molecule inhibitor of calpain (CAPN) 1, 2, and 9 that is selective over the cathepsins as well as other protease families, displays good metabolic stability and permeability, oral bioavailability and low cytochrome P450 (CYP) inhibition. It is under development for the treatment of coronavirus disease-19 (COVID-19) resulting from infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV2), where there is significant unmet medical need.

Detailed description:
Interleukin 6 (IL-6), a proinflammatory cytokine, is a key driver of a cytokine storm that plays a significant role in clinical complications and acute lung injury. Emerging data indicate that serum levels of IL-6 are elevated in COVID-19 patients and are predictive of respiratory failure and mortality. IL-6 has been shown to contribute to lung damage during SARS-CoV infection and the virus itself is capable of directly inducing its expression. Suppression of pro-inflammatory IL-6 have been shown to have a therapeutic effect in many inflammatory diseases, including viral infections.

In a mouse model of lung injury employing bleomycin, BLD-2660, at therapeutic doses of 30 and 100 mg/kg twice per day (BID), reduced IL-6 levels in bronchoalveolar lavage (BAL) fluid. BLD-2660 also attenuated fibrosis damage as measured by significant reductions in the alpha smooth muscle actin and collagen 1 in lung tissue. BLD-2660 also demonstrated target engagement by inhibiting cleavage of one of its substrates, spectrin, in bronchoalveolar cells.

BLD-2660 was also evaluated in a mouse model of NASH fibrosis, demonstrating an anti-fibrotic effect. A significant decrease in IL-6 transcription was also observed. This suggests that the effect of BLD-2660 on IL-6 is independent of the injury, or the affected organ.

It has been shown that the receptor for SARS-CoV-1 and -2 entry into the cell is angiotensin-converting enzyme 2 (ACE-2). ACE-2 and the dimeric calpains (data on file) are co-expressed in respiratory epithelial cells, the site of both viral entry and predominant early lung injury in COVID-19. Inhibition of dimeric calpain activity has not been associated with impairment of normal immune function. The safety and tolerability of BLD-2660 has been demonstrated in the recently completed Phase 1 single ascending dose (SAD)/multiple ascending dose (MAD) B-2660-101 study.

As BLD-2660 has been demonstrated to (1) reduce tissue IL-6 levels and (2) attenuate lung fibrosis damage, it could therefore, potentially reduce the nonproductive IL-6 mediated host-response to infection, which contribute to morbidity and mortality in COVID-19. In addition, data suggest that survivors of SARS-CoV-2 infection are at risk for chronic impairment of pulmonary function, likely attributable to pulmonary fibrosis secondary to lung injury and inflammation. Although there is not yet available data documenting numbers of patients infected with SARS CoV2 pneumonia who progress to pulmonary fibrosis, epidemiology, viral immunology, and current clinical evidence support that pulmonary fibrosis may become one of the serious long-term complications of survivors of COVID-19 related pneumonia.

Thus, BLD-2660 could not only potentially downregulate the nonproductive host-response to infection, which contributes to morbidity and mortality in COVID-19 but also could reduce potential long-term fibrosis and loss of pulmonary function resulting from SARS-CoV pneumonia. This study will evaluate BLD-2660 as an add-on therapy to standard of care (SOC) in hospitalized subjects with recent diagnosis of COVID-19.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: BLD-2660
Intervention descriptions: intervention 1: BLD-2660 is a novel, synthetic, orally active, small molecule inhibitor of calpain (CAPN) 1, 2, and 9.

Protocol documents:
Prot_000.pdf: 
 
Study drug: BLD-2660 
Protocol Number: B-2660-204 
 
Confidential 
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Version 3.0, Amendment 2.0 
 
 
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CLINICAL STUDY PROTOCOL 
TITLE PAGE 
Protocol Title:  
A Phase 2, Randomized, Double-blind, Placebo-controlled 
Study to Evaluate Safety and Antiviral Activity of 
BLD-2660 in Hospitalized Subjects with Recently 
Diagnosed COVID-19 Compared to Standard of Care 
Treatment 
Protocol Number:  
B-2660-204 
Study Drug:  
BLD-2660 
Study Indications 
Coronavirus disease 2019 (COVID-19) 
Study Phase:  
2 
Study Sites 
Multiple US sites 
Sponsor Name: 
Blade Therapeutics, Inc. 
Legal Registered Address: 
442 Littlefield Avenue,  
South San Francisco, CA 94080, United States 
Sponsor Representative: 
Gary Patou, MD 
Chief Medical Officer 
Regulatory Agency Identifier 
Number(s): 
IND: 149130 
Approval Date: 
08 May 2020 
Version: 
3.0 
Amendment 
2.0 
Confidentiality Notice 
This document contains confidential information of Blade Therapeutics, Inc. the contents of which must not be 
disclosed to anyone other than the study staff and members of the respective Institutional Review Board/Ethics 
Committee. 
The information in this document cannot be used for any purpose other than the evaluation or conduct of the 
clinical investigation without the prior written consent of Blade Therapeutics, Inc. 
 
E 
THERAPEUTICS 


DE 
THERAPEUTICS 
Gary Patou, MD 
Chief Medical Offi er 
gpatou@blademed.com 
SPONSOR SIGNATORY 
Study drug: BLD-2660 
Protocol Number: B-2660-204 
Date 
Sponsor's Designated Medical Monitor contact details will be provided separately in the study 
reference manual. 
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THERAPEUTICS 
Study drug: BLD-2660 
Protocol Number: B-2660-204 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
Protocol Number: 
Version and Date: 
Amendment No. 
IND Number: 
A Phase 2, Randomized, Double-blind, Placebo-controlled 
Study to Evaluate the Safety and Antiviral Activity of 
BLD-2660 in Huspilalizt:<l Subjt:cls wilh Rt:ct:nlly Diagnust:<l 
COVID-19 Compared to Standard of Care Treatment 
B-2660-204
3.0, 08 May 2020 
2.0 
149130 
I, the undersigned, have read this protocol and agree to personally supervise conduct of this protocol in 
accordance with ethical principles as outlined in the International Council for Harmonisation (ICH) 
guidelines on Good Clinical Practice, any applicable laws and requirements (including Part 54: Financial 
Disclosure by Clinical Investigators) and any additional conditions mandated by a regulatory authority 
and/or Institutional Review Board/Independent Ethics Committee (IRB/IEC). 
I acknowledge that I am responsible for the overall study conduct; I approve of and will comply with all 
conditions, instructions and restrictions described in this protocol. I am aware that my adherence to the 
above protocol is mandatory and that any changes in the protocol or consent form, except those 
necessary to eliminate apparent immediate hazards to human subjects, must first be approved in writing 
by <company> and the respective IRB/IEC. 
I also agree that all information provided to me by the Sponsor, including this document, Investigator's 
Brochure, case report form, and verbal and written information, will be kept strictly confidential and 
confined to the clinical personnel involved in conducting the study. It is recognized that this information 
may be related in confidence to the IRB/IEC. I also understand that reports of information about the 
study or its progress will not be provided to anyone not involved in the study other than to the Principal 
Investigator, or in confidence to the IRB/IEC or to the FDA or other legally constituted authority. 
Confidential 
Date 
1/4.M/r: //4M '1..£1Jk J)4j&il6.w ✓54-
Institution City, Cou try 
I 
Page 3 of75 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Protocol V3.0, Amendment 2 
08 May 2020 
Protocol V2.0, Amendment 1 
23April 2020 
Original Protocol V1 
05 April 2020 
Amendment 2, 08 May 2020 
Overall Rationale for the Amendment: 
Blade has introduced the following modifications to protocol V3.0, these changes are 
presented in order of appearance:  
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
2.1 Study rationale 
• 
Update rationale  
• 
To reflect emerging data 
1.1 Synopsis 
3.0 Objectives and Endpoints 
• 
Revise primary endpoints and add 
new co-primary endpoint (time to 
recovery) 
• 
Add an endpoint regarding 
remdesivir use 
• 
Move anti-viral endpoints to 
exploratory endpoints 
• 
To reflect emerging data 
1.2 Schedule of Activities 
• 
Update per changes in the protocol 
• 
Add D-dimer assessment on Day 5 
• 
To ensure accuracy and 
consistency 
2.2 Background 
2.3.2 Benefit 
• 
Update text regarding approved EUA 
medications 
• 
To reflect emerging data 
5.1.1 Inclusion criteria 
• 
Delete SARS-CoV-2 infection 
confirmation by PCR 
• 
Update oxygenation requirements to 
match remdesivir (SpO2≤94%) 
• 
Temperature clarification  
• 
To reflect emerging data 
and change in COVID 
treatment management 
• 
Typo correction 
5.1.2 Exclusion criteria 
• 
Correct exclusion criterion no. 5 to 
≥0.75 FiO2 
• 
Delete exclusion of antiviral agents 
(e.g. remdesivir) 
• 
Typo correction 
• 
To reflect change in 
COVID treatment 
management 


 
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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
4.1 Overall design 
6.4 Measure to minimize 
bias: randomization and 
blinding 
• 
Change stratification to remdesivir 
use at study entry 
• 
To reflect change in 
COVID treatment 
management 
6.6 Concomitant therapy 
• 
Allow remdesivir as concomitant 
medication 
• 
Move anti-IL, IL-6 receptor 
antagonist or use of JAKi from 
restricted to prohibited medication 
during the study 
• 
Add EUA agent or compassionate 
use as restricted medication 
• 
To reflect change in 
COVID treatment 
management 
• 
To reflect change in 
primary endpoint 
8.1 Efficacy Assessments 
• 
Reorganize subsections to match 
endpoint order. 
• 
For consistency across 
the protocol 
8.3 AEs and SAEs 
• 
Add that SAEs will also be collected 
for remdesivir 
 
• 
Per FDA request 
9 Statistical consideration 
• 
Update to reflect changes to 
objectives/endpoints 
• 
For consistency across 
the protocol 
General 
• 
Corrected typos, formatting, style 
• 
Aligned changes across protocol 
• 
Updated Abbreviation (Appendix 6) 
• 
For clarity and 
readability 
 


 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE .................................. 4 
1. 
PROTOCOL SUMMARY ................................................................................ 10 
1.1. 
Synopsis ............................................................................................................ 10 
1.2. 
Schedule of Activities (SoA) ............................................................................ 16 
2. 
INTRODUCTION ............................................................................................ 21 
2.1. 
Study Rationale ................................................................................................. 21 
2.2. 
Background ....................................................................................................... 22 
2.3. 
Benefit/Risk Assessment .................................................................................. 23 
2.3.1. 
Risk Assessment ............................................................................................... 23 
2.3.2. 
Benefit Assessment ........................................................................................... 23 
2.3.3. 
Overall Benefit: Risk Conclusion ..................................................................... 23 
3. 
OBJECTIVES AND ENDPOINTS .................................................................. 24 
4. 
STUDY DESIGN ............................................................................................. 27 
4.1. 
Overall Design .................................................................................................. 27 
4.2. 
Scientific Rationale for Study Design .............................................................. 27 
4.3. 
Justification for Dose ........................................................................................ 27 
4.4. 
Study Duration .................................................................................................. 28 
4.5. 
End of Study Definition .................................................................................... 28 
5. 
STUDY POPULATION ................................................................................... 29 
5.1. 
Eligibility Criteria ............................................................................................. 29 
5.1.1. 
Inclusion Criteria .............................................................................................. 29 
5.1.2. 
Exclusion Criteria ............................................................................................. 30 
5.2. 
Screen Failures .................................................................................................. 31 
6. 
STUDY DRUG ................................................................................................. 32 
6.1. 
Study Drugs Administered ............................................................................... 32 
6.2. 
Standard of Care ............................................................................................... 33 
6.3. 
Preparation/Handling/Storage/Accountability .................................................. 33 
6.4. 
Measures to Minimize Bias: Randomization and Blinding .............................. 33 
6.5. 
Study Drug Compliance ................................................................................... 34 
6.6. 
Concomitant Therapy ....................................................................................... 34 


 
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6.6.1. 
Prohibited Medications and Herbal Supplements: ........................................... 34 
6.6.2. 
Restricted Medications ..................................................................................... 34 
6.7. 
Dose Modification ............................................................................................ 37 
6.8. 
Treatment of Overdose ..................................................................................... 37 
6.9. 
Intervention after the End of the Study ............................................................. 37 
7. 
DISCONTINUATION OF STUDY DRUG AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ........................................................ 38 
7.1. 
Stopping Rules .................................................................................................. 38 
7.1.1. 
Pregnancy ......................................................................................................... 38 
7.2. 
Discontinuation of Study Drug ......................................................................... 38 
7.3. 
Withdrawal from the Study .............................................................................. 39 
7.4. 
Lost to Follow up .............................................................................................. 39 
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................ 40 
8.1. 
Efficacy Assessments ....................................................................................... 40 
8.1.1. 
Oxygenation Measures ..................................................................................... 40 
8.1.2. 
Measure of Clinical Support ............................................................................. 40 
8.1.3. 
Clinical Status Ordinal Score ............................................................................ 41 
8.1.4. 
National Early Warning Score (NEWS) ........................................................... 41 
8.1.5. 
Hospital Discharge Readiness Criteria ............................................................. 42 
8.1.6. 
Antiviral Activity .............................................................................................. 42 
8.2. 
Safety Assessments ........................................................................................... 43 
8.2.1. 
Physical Examinations ...................................................................................... 43 
8.2.2. 
Vital Signs ........................................................................................................ 43 
8.2.3. 
Electrocardiograms ........................................................................................... 43 
8.2.4. 
Clinical Safety Laboratory Assessments .......................................................... 43 
8.3. 
Adverse Events and Serious Adverse Events ................................................... 44 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information ............. 44 
8.3.2. 
Method of Detecting AEs and SAEs ................................................................ 45 
8.3.3. 
Follow-up of AEs and SAEs ............................................................................. 45 
8.3.4. 
Regulatory Reporting Requirements for SAEs ................................................. 45 
8.3.5. 
Pregnancy ......................................................................................................... 45 
8.3.6. 
Deaths ............................................................................................................... 46 


 
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8.4. 
Pharmacokinetics .............................................................................................. 46 
8.5. 
Pharmacodynamics and Biomarker Assessments ............................................. 46 
9. 
STATISTICAL CONSIDERATIONS ............................................................. 47 
9.1. 
Statistical Hypothesis ........................................................................................ 47 
9.2. 
Sample Size Determination .............................................................................. 47 
9.3. 
Population Analysis Set .................................................................................... 48 
9.4. 
Statistical Methods ............................................................................................ 48 
9.4.1. 
General .............................................................................................................. 48 
9.4.2. 
Efficacy Analyses ............................................................................................. 48 
9.4.3. 
Safety and Tolerability Analyses ...................................................................... 49 
9.4.4. 
Other Analyses .................................................................................................. 50 
9.5. 
Interim Analysis ................................................................................................ 50 
9.5.1. 
Data Monitoring Committee ............................................................................. 51 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ........................................................................................ 52 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .......... 52 
10.1.1. 
Regulatory and Ethical Considerations ............................................................ 52 
10.1.2. 
Financial Disclosure ......................................................................................... 52 
10.1.3. 
Informed Consent Process ................................................................................ 53 
10.1.4. 
Data Protection ................................................................................................. 53 
10.1.5. 
Dissemination of Clinical Study Data .............................................................. 53 
10.1.6. 
Data Quality Assurance .................................................................................... 54 
10.1.7. 
Source Documents ............................................................................................ 54 
10.1.8. 
Study and Site Start and Closure ...................................................................... 55 
10.1.9. 
Publication Policy ............................................................................................. 55 
10.2. 
Appendix 2: Clinical Laboratory Tests ............................................................. 56 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting .............................................................. 57 
10.3.1. 
Definition of AE ............................................................................................... 57 
10.3.2. 
Definition of SAE ............................................................................................. 58 
10.3.3. 
Recording and Follow-Up of AE and/or SAE .................................................. 59 
10.3.4. 
Reporting of SAEs ............................................................................................ 62 


 
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10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information
 .......................................................................................................................... 63 
10.4.1. 
Definitions ........................................................................................................ 63 
10.4.2. 
Contraception Guidance ................................................................................... 64 
10.4.3. 
Collection of Pregnancy Information ............................................................... 65 
10.5. 
Appendix 5: Cardiac Monitoring Protocol ....................................................... 66 
10.6. 
Appendix 6: Abbreviations ............................................................................... 67 
10.7. 
Appendix 7: Protocol Amendment History ...................................................... 70 
11. 
REFERENCES ................................................................................................. 72 
 
LIST OF TABLES 
Table 1: 
Treatment Groups ............................................................................................. 15 
Table 2: 
Schedule of Activities ....................................................................................... 16 
Table 3: 
Study Drug Administered ................................................................................. 32 
Table 4: 
A 4-Point Oxygen Ordinal Scale for Severity Categories by SpO2/FiO2 Ratio 40 
Table 5: 
A 6-Point Ordinal Score for Assessing Clinical Status .................................... 41 
Table 6: 
NEW Score ....................................................................................................... 42 
Table 7: 
Adverse Event Reporting Periods ..................................................................... 44 
Table 8: 
Protocol-Required Laboratory Assessments..................................................... 56 
 
LIST OF FIGURES 
Figure 1 
Comparison of IL-6 levels among mild, severe and critical patients with 
COVID-19 Pneumonia ..................................................................................... 10 
Figure 2 
A Mouse Bleomycin (bleo) Pulmonary Fibrosis Model Assessing IL-6 in 
Bronchoalveolar Lavage (BAL) Fluid .............................................................. 11 
Figure 3: 
BLD-2660 Attenuates Fibrosis Damage in a Mouse Bleomycin (bleo) 
Pulmonary Fibrosis Model ............................................................................... 12 
 
 


 
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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title 
A Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and 
Antiviral Activity of BLD-2660 in Hospitalized Subjects with Recently Diagnosed 
COVID-19 Compared to Standard of Care Treatment 
Rationale 
BLD-2660 is a novel, synthetic, orally active, small molecule inhibitor of calpain (CAPN) 1, 
2, and 9 that is selective over the cathepsins as well as other protease families, displays good 
metabolic stability and permeability, oral bioavailability and low cytochrome P450 (CYP) 
inhibition. It is under development for the treatment of coronavirus disease-19 (COVID-19) 
resulting from infection with Severe Acute Respiratory Syndrome Coronavirus 2 
(SARS-CoV-2), where there is significant unmet medical need. 
Interleukin 6 (IL-6), a proinflammatory cytokine, is a key driver of a cytokine storm that 
plays a significant role in clinical complications and acute lung injury (Dinarello, 2000). 
Emerging data indicate that serum levels of IL-6 are elevated in COVID-19 patients and are 
predictive of respiratory failure (Coomes, 2020; Herold, 2020; McGonagle, 2020) and 
mortality (Gong, 2020) (Figure 1). IL-6 has been shown to contribute to lung damage during 
SARS-CoV infection and the virus itself is capable of directly inducing its expression 
(Bozym, 2011; Yoon, 2008). Suppression of pro-inflammatory IL-6 have been shown to have 
a therapeutic effect in many inflammatory diseases, including viral infections (Conti, 2020).  
Figure 1 
Comparison of IL-6 levels among mild, severe and critical patients with 
COVID-19 Pneumonia 
 
Source: (Gong, 2020) 


 
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In a mouse model of lung injury employing bleomycin, BLD-2660, at therapeutic doses of 30 
and 100 mg/kg twice per day (BID),  reduced IL-6 levels in bronchoalveolar lavage (BAL) 
fluid (Figure 2). BLD-2660 also attenuated fibrosis damage as measured by significant 
reductions in the alpha smooth muscle actin and collagen 1 in lung tissue (Figure 3). 
BLD-2660 also demonstrated target engagement by inhibiting cleavage of one of its 
substrates, spectrin, in bronchoalveolar cells. 
Figure 2 
A Mouse Bleomycin (bleo) Pulmonary Fibrosis Model Assessing IL-6 in 
Bronchoalveolar Lavage (BAL) Fluid 
 
 


 
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Figure 3: 
BLD-2660 Attenuates Fibrosis Damage in a Mouse Bleomycin (bleo) 
Pulmonary Fibrosis Model 
 
 
BLD-2660 was also evaluated in a mouse model of NASH fibrosis, demonstrating an anti-
fibrotic effect. A significant decrease in IL-6 transcription was also observed. This suggests 
that the effect of BLD-2660 on IL-6 is independent of the injury, or the affected organ. 
It has been shown that the receptor for SARS-CoV-1 and -2 entry into the cell is angiotensin-
converting enzyme 2 (ACE-2) (Kuba, 2010). ACE-2 and the dimeric calpains (data on file) 
are co-expressed in respiratory epithelial cells, the site of both viral entry and predominant 
early lung injury in COVID-19. Inhibition of dimeric calpain activity has not been associated 
with impairment of normal immune function. The safety and tolerability of BLD-2660 has 
been demonstrated in the recently completed Phase 1 single ascending dose (SAD)/multiple 
ascending dose (MAD) B-2660-101 study. 
As BLD-2660 has been demonstrated to (1) reduce tissue IL-6 levels and (2) attenuate lung 
fibrosis damage, it could therefore, potentially reduce the nonproductive IL-6 mediated host-
response to infection, which contribute to morbidity and mortality in COVID-19. In addition, 
data suggest that survivors of SARS-CoV-2 infection are at risk for chronic impairment of 
pulmonary function, likely attributable to pulmonary fibrosis secondary to lung injury and 
inflammation. Although there is not yet available data documenting numbers of patients 
infected with SARS CoV2 pneumonia who progress to pulmonary fibrosis, epidemiology, 
viral immunology, and current clinical evidence support that pulmonary fibrosis may become 


 
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one of the serious long-term complications of survivors of COVID-19 related pneumonia 
(Wang, 2020b). 
Thus, BLD-2660 could not only potentially downregulate the nonproductive host-response to 
infection, which contributes to morbidity and mortality in COVID-19 but also could reduce 
potential long-term fibrosis and loss of pulmonary function resulting from SARS-CoV 
pneumonia (Wang, 2020a, Ong, 2005). This study will evaluate BLD-2660 as an add-on 
therapy to standard of care (SOC) in hospitalized subjects with recent diagnosis of COVID-
19. 
Objectives and Endpoints (Primary and Secondary) 
Objectives 
Endpoints 
Primary 
• To evaluate clinical benefit of BLD-2660 
in hospitalized adults with recently 
diagnosed SARS-CoV-2 infection 
• Time to recovery as defined by no longer 
requiring oxygen support or hospital 
discharge, whichever occurs first 
 
• To evaluate improvement in oxygenation 
in hospitalized adults with COVID-19 
treated with BLD-2660 
• Change from baseline to Day 10 or 
hospital discharge, if sooner, in the ratio 
of peripheral hemoglobin oxygen 
saturation to fraction of inspired oxygen 
(SpO2/FiO2) 
Secondary 
• To evaluate the safety and tolerability of 
BLD-2660 in the same population 
• Incidence of TEAEs and serious adverse 
events (SAEs) 
• To evaluate improvement in oxygenation 
• Improvement from baseline to Days 10, 
14, 21 and 28 as measured by the ratio of 
hemoglobin oxygen saturation to inspired 
oxygen fraction (SpO2/FiO2), categorized 
on the 4--point ordinal scale (Table 4) 
• Time to discontinuation of oxygen 
supplementation requirement 
• Mean SpO2 for subjects not requiring 
oxygen supplementation at Days 5, 10, 
21 and 28 
• Number of O2 supplementation free days 
during hospitalization 


 
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Objectives 
Endpoints 
• Proportion of subjects who do not require 
oxygen supplementation (sustained for at 
least 24 hours) during hospitalization  
Note, criteria for removal of oxygen 
supplementation is defined as resting (5 
minutes of rest) room air saturation >90% 
• Additional efficacy outcomes 
• Mortality rate during the 28-day study 
period following enrollment 
• Time to hospital discharge readiness 
• Proportion of subjects ready to be 
discharged from the hospital during the 
28-day study period following enrollment 
• Proportion of subjects with resolution of 
fever below entry criteria for 24 hours (as 
defined in Section 5.1.1) by Day 10 in 
subjects with fever at baseline 
• Time to resolution of fever below entry 
criteria for 24 hours (as defined in 
Section 5.1.1) in subjects with fever at 
baseline 
• Duration (in days) of remdesivir use in 
subjects starting remdesivir within 24 
hours of first dose of BLD-2660 
• Change from baseline to Days 10, 14, 21 
and 28 in clinical status outcome using a 
6-point ordinal scale (Section 8.1.3) 
• Proportion of subjects reporting each 
6--point ordinal scale of the clinical status 
outcome assessment 
• Change from baseline to Days 5, 10, 14, 
21 and 28 in NEWS score  
• Change from baseline to Days 10, 14, 21 
and 28 in IL-6 and D-dimer 


 
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Overall Design 
This is a Phase 2 randomized, double-blind, placebo-controlled multicenter study designed to 
evaluate BLD-2660 as add-on to standard of care (SOC) therapy in hospitalized subjects with 
recently diagnosed COVID-19 compared to SOC treatment. 
The study will include a Screening period, a Treatment period, and a Follow-up period. 
After signing informed consent form (ICF), potential candidates who are hospitalized for 
confirmed infection with SARS-CoV-2 will undergo additional screening procedures. 
On Day 1, eligible subjects will be randomized in 2:1 ratio to one of 2 treatment groups, as 
shown in Table 1. Randomization will be stratified by remdesivir use at study entry. All 
subjects will receive study drug in combination with SOC over 10 days (through Day 10/end 
of treatment) or until hospital discharge, if sooner. Subjects will be followed for at least 18 
days after the last dose of study drug on Days 14, 21 and 28. Subjects will be contacted 60 
days post-study to collect information on mortality and forced vital capacity (FVC). 
Subjects will be evaluated as specified in the Schedule of Activities (SoA; Section 1.2). 
Number of Subjects, Intervention Groups and Duration 
Intervention Groups 
Table 1: 
Treatment Groups 
Treatment 
Group 
Dose Level, Schedule and Route of 
administration 
Number of 
subjects 
Active 
BLD-2660 900 mg twice per day (BID), oral + SOC 
80 
Control 
Matching placebo, BID, oral + SOC 
40 
 
Duration 
For each subject the study is expected to last as follows: 
Study Period 
Duration  
Screening period  
Up to 3 days 
Treatment period  
10 days  
Follow-up period 
18 days 
Post study follow-up 
60 days 
Data Monitoring Committee: Yes 


 
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1.2. 
Schedule of Activities (SoA) 
Table 2: 
Schedule of Activities 
General Notes: 
• 
In case of natural disasters or pandemics, some visits/study procedures can be done via virtual visits (e.g., telemedicine or telephone) or at 
home visits after hospital discharge. Refer to study reference manual for more details. 
• 
Assessments completed as part of standard of care within the protocol defined windows, will not need to be repeated specifically for the 
protocol. 
Procedure 
Screening 
Treatment Period 
 
Follow-up 
Post-
study 
visit 
Notes 
 
 
BL 
Daily 
visits‡ 
EOT/ET* 
 
 
EOS 
Baseline (BL); End of Treatment 
(EOT), Early termination (ET); End 
of study (EOS) 
‡ If a subject is discharged prior to 
Day 10, they will complete Day 5 
and Day 10 visits assessments 
* This visit will be conducted at 
hospital discharge, if subject is 
discharged prior to Day 10 
Study Day 
-3 to -1 
1 
2-9 
10 
14 
21 
28 
+60 
days 
from 
EOS 
Visit window (days) 
 
 
 
±1 
±2 
±2 
±2 
±10 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Current medical 
conditions 
X 
X 
 
 
 
 
 
 
Including time from onset of 
symptoms (fever, cough, etc.) to 
study entry, COVID-19 severity for 
each subject 
Comprehensive 
physical exam 
X 
 
 
X 
 
 
 
 
 
Height and weight  
X 
 
 
X* 
 
 
 
 
*Weight only 


 
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Procedure 
Screening 
Treatment Period 
 
Follow-up 
Post-
study 
visit 
Notes 
 
 
BL 
Daily 
visits‡ 
EOT/ET* 
 
 
EOS 
Baseline (BL); End of Treatment 
(EOT), Early termination (ET); End 
of study (EOS) 
‡ If a subject is discharged prior to 
Day 10, they will complete Day 5 
and Day 10 visits assessments 
* This visit will be conducted at 
hospital discharge, if subject is 
discharged prior to Day 10 
Study Day 
-3 to -1 
1 
2-9 
10 
14 
21 
28 
+60 
days 
from 
EOS 
Visit window (days) 
 
 
 
±1 
±2 
±2 
±2 
±10 
 
Limited physical exam 
 
X 
Day 5 
 
X 
X 
X 
 
Physical exam will be symptom-
directed exam 
Hematology 
X 
X 
Day 5 
X 
X 
X 
X 
 
Refer to Section 10.2 
Clinical chemistries 
X 
X 
Day 5 
X 
X 
X 
X 
 
Refer to Section 10.2 
INR  
X 
 
 
 
 
 
X 
 
International normal ratio (INR) 
Urinalysis 
X 
 
 
 
 
 
X 
 
Refer to Section 10.2 
Sputum samples and 
nasopharyngeal swab 
for SARS-CoV-2 PCR 
 
X 
Day 5 
X 
X 
X 
X 
 
Samples to be frozen as specified in 
the laboratory manual for viral 
quantification. 
Serum hsCRP and 
ferritin 
 
X 
Day 5 
X 
X 
X 
X 
 
High sensitivity c-reactive protein 
(CRP) 
Reserve blood sample 
for biomarker analyses 
 
X 
Day 5 
X 
X 
X 
X 
 
Date and times to be recorded when 
samples were collected. 
IL-6 
 
X 
X 
X 
X 
X 
X 
 
Interleukin 6 (IL-6) 
Serum troponin 
 
X 
X 
X 
X 
X 
X 
 
 
D-dimer 
 
X 
Day 5 
X 
X 
X 
X 
 
 
Pharmacokinetics 
plasma* 
 
 
Day 5 
 
 
 
 
 
Predose and 1-2 hours postdose 
*if naso-gastic tube (NGT) is 
inserted, PK samples will also be 
collected 2 hours postdose after the 
first NGT use. 


 
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Procedure 
Screening 
Treatment Period 
 
Follow-up 
Post-
study 
visit 
Notes 
 
 
BL 
Daily 
visits‡ 
EOT/ET* 
 
 
EOS 
Baseline (BL); End of Treatment 
(EOT), Early termination (ET); End 
of study (EOS) 
‡ If a subject is discharged prior to 
Day 10, they will complete Day 5 
and Day 10 visits assessments 
* This visit will be conducted at 
hospital discharge, if subject is 
discharged prior to Day 10 
Study Day 
-3 to -1 
1 
2-9 
10 
14 
21 
28 
+60 
days 
from 
EOS 
Visit window (days) 
 
 
 
±1 
±2 
±2 
±2 
±10 
 
Serum Pregnancy test 
(WOCBP only) 
X 
 
 
 
 
 
 
 
Women of childbearing potential 
(WOCBP) 
12-lead ECG 
X 
X 
Day 5 
X 
 
 
X 
 
Electrocardiogram (ECG) 
Can be done more frequently if 
clinically indicated (e.g., elevated 
troponin post baseline level) per 
safety cardiac monitoring 
(Section 10.5) 
X 
 
 
 
 
 
 
 
If subjects are on telemetry, ECG is 
only required at screening. 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
 
Temperature should be collected 
twice per day (morning and night) 
while hospitalized; same method 
for temperature measurement 
should be used throughout the study 
Chest x-ray or CT scan 
of lungs (if conducted 
as SOC) 
X 
 
 
 
 
 
X 
 
Computed tomography (CT), 
standard of care (SOC) 
Same modality to be used 
throughout the study, where 
possible  


 
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Procedure 
Screening 
Treatment Period 
 
Follow-up 
Post-
study 
visit 
Notes 
 
 
BL 
Daily 
visits‡ 
EOT/ET* 
 
 
EOS 
Baseline (BL); End of Treatment 
(EOT), Early termination (ET); End 
of study (EOS) 
‡ If a subject is discharged prior to 
Day 10, they will complete Day 5 
and Day 10 visits assessments 
* This visit will be conducted at 
hospital discharge, if subject is 
discharged prior to Day 10 
Study Day 
-3 to -1 
1 
2-9 
10 
14 
21 
28 
+60 
days 
from 
EOS 
Visit window (days) 
 
 
 
±1 
±2 
±2 
±2 
±10 
 
SpO2% 
X 
X 
X 
X 
X 
X 
X 
 
Peripheral capillary oxygen 
saturation (SpO2) is to be recorded 
morning and night while 
hospitalized (coinciding with body 
temperature) 
Record FiO2 
X 
X 
X 
X 
X 
X 
X 
 
Fraction of inspired oxygen (FiO2) 
at each SpO2 assessment (morning 
and night while hospitalized) 
FVC  
 
 
 
 
 
 
* 
X* 
Forced vital capacity (FVC) 
*Subjects will be requested to 
conduct FVC post study, 
approximately 50 to 70 days after 
last follow-up visit 
APACHE II score 
 
X 
 
 
 
 
 
 
APACHE (acute physiology and 
chronic health evaluation) 
Hospital discharge 
readiness assessment 
 
X 
X 
X 
X 
X 
X 
 
Refer to Section 8.1.5 
Clinical status 6-point 
ordinal scale 
X 
X 
X 
X 
X 
X 
X 
 
Refer to Section 8.1.2 
State of consciousness 
X 
X 
X 
X 
X 
X 
X 
 
Level of consciousness: alert (A), 
arousable only to voice (V), or pain 
(P) and unresponsive (U) 


 
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Procedure 
Screening 
Treatment Period 
 
Follow-up 
Post-
study 
visit 
Notes 
 
 
BL 
Daily 
visits‡ 
EOT/ET* 
 
 
EOS 
Baseline (BL); End of Treatment 
(EOT), Early termination (ET); End 
of study (EOS) 
‡ If a subject is discharged prior to 
Day 10, they will complete Day 5 
and Day 10 visits assessments 
* This visit will be conducted at 
hospital discharge, if subject is 
discharged prior to Day 10 
Study Day 
-3 to -1 
1 
2-9 
10 
14 
21 
28 
+60 
days 
from 
EOS 
Visit window (days) 
 
 
 
±1 
±2 
±2 
±2 
±10 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Study drug 
administration 
 
X 
X 
X 
 
 
 
 
Treatment to be administered 
during hospitalization only 
Study drug 
accountability 
 
 
X 
X 
 
 
 
 
 
AE and SAE review 
 
X 
X 
X 
X 
X 
X 
 
Adverse event (AEs), Serious AE 
(SAEs) 
Prior and concomitant 
medication  
X 
X 
X 
X 
X 
X 
X 
 
 
Survival status 
 
 
 
 
X 
X 
X 
X 
 
 


 
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2. 
INTRODUCTION 
2.1. 
Study Rationale 
BLD-2660 is a novel, synthetic, orally active, small molecule inhibitor of calpain (CAPN) 1, 2, 
and 9 that is selective over the cathepsins as well as other protease families, displays good 
metabolic stability and permeability, oral bioavailability and low cytochrome P450 (CYP) 
inhibition. It is under development for the treatment of coronavirus disease-19 (COVID-19) 
resulting from infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV2), 
where there is significant unmet medical need. 
Interleukin 6 (IL-6), a proinflammatory cytokine, is a key driver of a cytokine storm that plays a 
significant role in clinical complications and acute lung injury (Dinarello, 2000). Emerging data 
indicate that serum levels of IL-6 are elevated in COVID-19 patients and are predictive of 
respiratory failure (Coomes, 2020; Herold, 2020; McGonagle, 2020) and mortality (Gong, 2020) 
(Figure 1). IL-6 has been shown to contribute to lung damage during SARS-CoV infection and 
the virus itself is capable of directly inducing its expression (Bozym, 2011; Yoon, 2008). 
Suppression of pro-inflammatory IL-6 have been shown to have a therapeutic effect in many 
inflammatory diseases, including viral infections (Conti, 2020). 
In a mouse model of lung injury employing bleomycin, BLD-2660, at therapeutic doses of 30 
and 100 mg/kg twice per day (BID),  reduced IL-6 levels in bronchoalveolar lavage (BAL) fluid 
(Figure 2). BLD-2660 also attenuated fibrosis damage as measured by significant reductions in 
the alpha smooth muscle actin and collagen 1 in lung tissue (Figure 3). BLD-2660 also 
demonstrated target engagement by inhibiting cleavage of one of its substrates, spectrin, in 
bronchoalveolar cells. 
BLD-2660 was also evaluated in a mouse model of NASH fibrosis, demonstrating an anti-
fibrotic effect. A significant decrease in IL-6 transcription was also observed. This suggests that 
the effect of BLD-2660 on IL-6 is independent of the injury, or the affected organ. 
It has been shown that the receptor for SARS-CoV-1 and -2 entry into the cell is angiotensin-
converting enzyme 2 (ACE-2) (Kuba, 2010). ACE-2 and the dimeric calpains (data on file) are 
co-expressed in respiratory epithelial cells, the site of both viral entry and predominant early 
lung injury in COVID-19. Inhibition of dimeric calpain activity has not been associated with 
impairment of normal immune function. The safety and tolerability of BLD-2660 has been 
demonstrated in the recently completed Phase 1 single ascending dose (SAD)/multiple ascending 
dose (MAD) B2660-101 study. 
As BLD-2660 has been demonstrated to (1) reduce tissue IL-6 levels and (2) attenuate lung 
fibrosis damage, it could therefore, potentially reduce the nonproductive IL-6 mediated host-
response to infection, which contribute to morbidity and mortality in COVID-19. In addition, 
data suggest that survivors of SARS-CoV-2 infection are at risk for chronic impairment of 
pulmonary function, likely attributable to pulmonary fibrosis secondary to lung injury and 
inflammation. Although there is not yet available data documenting numbers of patients infected 
with SARS CoV2 pneumonia who progress to pulmonary fibrosis, epidemiology, viral 


 
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immunology, and current clinical evidence support that pulmonary fibrosis may become one of 
the serious long-term complications of survivors of COVID-19 related pneumonia (Wang, 
2020b). 
Thus, BLD-2660 could not only potentially downregulate the nonproductive host-response to 
infection, which contributes to morbidity and mortality in COVID-19 but also could reduce 
potential long-term fibrosis and loss of pulmonary function resulting from SARS-CoV 
pneumonia (Wang, 2020a, Ong, 2005). This study will evaluate BLD-2660 as an add-on therapy 
to standard of care (SOC) in hospitalized subjects with recent diagnosis of COVID-19. 
2.2. 
Background 
SARS-CoV-2, a positive-sense single-stranded RNA virus of zoonotic origin, is highly 
contagious in humans and is the cause of the ongoing worldwide pandemic of COVID-19. As of 
April 4, 2020, the SARS-CoV-2 has been responsible for more than 1.2 million infections and 
70,000 deaths worldwide (data from https://coronavirus.jhu.edu/). 
SARS-CoV-2 is transmitted via respiratory droplets (fomites infectious particles) within a range 
of about 2 meters and direct contact with contaminated surfaces. The median incubation period 
was estimated to be 4-5 days, and the majority (97.5%) developed symptoms within 11.5 days 
(CI, 8.2 to 15.6 days) of infection (Guan, 2020; Lauer, 2020). Higher viral loads are detected 
soon after symptom onset, with higher viral loads detected in the nose than in the throat (Zou, 
2020). The mean viral load of severe cases was around 60 times higher than that of mild cases, 
suggesting that higher viral loads might be associated with severe clinical outcomes (Liu, 2020). 
Clinical symptoms of COVID-19 include fever, cough, and dyspnea (Guan, 2020; Jiang, 2020; 
Rodriguez-Morales, 2020; Rothan, 2020); a small population of patients also may suffer from 
gastrointestinal symptoms (Guan, 2020; Guo, 2020). Radiologic features in the lungs include 
bilateral ground glass opacities on chest x-ray or computed tomography (CT) (Guan, 2020). 
COVID-19 appears to be more prevalent in males than females (Adhikari, 2020). The population 
most at risk are immune-compromised patients such as the elderly, and subjects with co-morbid 
diseases (e.g., diabetes, cardiovascular, cancer). This population is prone to serious outcomes, 
which may be associated with acute respiratory distress syndrome (ARDS) and cytokine storm 
(Adhikari, 2020; Guo, 2020). Approximately 14% (95%CI 6.2–21.5%) of hospitalized patients 
had fatal outcomes (case fatality rate, CFR) (Rodriguez-Morales, 2020). 
Initially, the SARS-CoV-2 predominantly infects lower airways and binds to ACE-2 on alveolar 
epithelial cells (Guo, 2020; Kuba, 2010). It is a potent inducer of inflammatory cytokines. The 
“cytokine storm” or “cytokine cascade” is the postulated mechanism for organ damage. The 
virus activates immune cells and induces the secretion of inflammatory cytokines and 
chemokines into pulmonary vascular endothelial cells (Jiang, 2020). 
The FDA has recently approved an emergency use authorization (EUA) for remdesivir to treat 
patients with severe COVID-19. There are no other approved treatments for COVID-19, or 
vaccines against SARS-CoV-2. Treatment management is mainly focused on symptomatic and 
respiratory support. There are few specific antiviral strategies, but several potent candidates of 
antivirals and repurposed drugs are under urgent investigation (Guo, 2020). Chloroquine 
phosphate, a drug for treatment of malaria, was shown to have apparent efficacy against COVID-


 
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19 associated pneumonia in multicenter clinical trials conducted in China (Gao, 2020), however, 
these studies were not well controlled. A recent French study showed no benefit with 
hydroxychloroquine in hospitalized patients with COVID-19 infections requiring oxygen 
(Mahevas, 2020), and another retrospective study in US veterans hospitalized with COVID-19 
showed that hydroxychloroquine increased mortality rate (Magagnoli, 2020). In addition, IL-6 or 
IL-6-receptor blocking antibodies like tocilizumab (Actemra, Roche-Genentech), sarilumab 
(Kevzara, Regeneron), and siltuximab (Sylvant, EUSA Pharma) which are FDA-approved for 
various conditions, including cytokine release syndrome (CRS), are being investigated in 
critically ill patients with COVID-19-induced hypoxia (Ascierto, 2020; Conti, 2020). Other 
treatments and therapies include antibiotics, corticosteroids, mechanical ventilation, 
extracorporeal membrane oxygenation (ECMO), oxygen therapy, and continuous renal 
replacement techniques (CRRT) (Jiang, 2020). 
A detailed description of the chemistry, pharmacology, efficacy, and safety of BLD-2660 is 
provided in the Investigator’s Brochure (IB). 
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of BLD-2660 may be found in the IB. 
2.3.1. 
Risk Assessment 
Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for Potential Risk for Study 
Drug BLD-2660 
Mitigation 
Strategy 
Elevated troponin 
Transient, asymptomatic mild troponin elevation was observed 
in 2 healthy volunteers in Phase 1; there were no associated 
clinical, electrocardiographic or imaging findings and these 
changes resolved without sequalae despite continued dosing. 
Biologically, calpain inhibition has not been associated with 
cardiac toxicity in animal models, and there was no evidence of 
cardiac toxicity in acute and chronic toxicology studies. 
Safety 
cardiac 
monitoring 
protocol (see 
Section 10.5) 
2.3.2. 
Benefit Assessment 
The FDA has recently approved an emergency use authorization (EUA) for remdesivir to treat 
patients with severe COVID-19. There are no other approved medical therapies for COVID-19. 
BLD-2660 is a candidate for treating COVID-19 due to the potential protection from lung damage 
which occurs during SARS-CoV-2 infection by reducing IL-6 levels. 
2.3.3. 
Overall Benefit: Risk Conclusion 
By implementing measures to minimize risk to subjects participating in this study, the potential 
risks identified in association with BLD-2660 are justified by the anticipated benefits that may be 
afforded to subjects with COVID-19. 


 
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3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
• To evaluate clinical benefit of 
BLD-2660 in hospitalized adults with 
recently diagnosed SARS-CoV-2 
infection 
• Time to recovery as defined by no longer 
requiring oxygen support or hospital 
discharge, whichever occurs first 
 
• To evaluate improvement in 
oxygenation in hospitalized adults with 
COVID-19 treated with BLD-2660 
• Change from baseline to Day 10 or hospital 
discharge, if sooner, in the ratio of 
peripheral hemoglobin oxygen saturation to 
fraction of inspired oxygen (SpO2/FiO2) 
Secondary 
• To evaluate the safety and tolerability of 
BLD-2660 in the same population 
• Incidence of TEAEs and serious adverse 
events (SAEs) 
• To evaluate improvement in 
oxygenation 
• Improvement from baseline to Days 10, 14, 
21 and 28 as measured by the ratio of 
hemoglobin oxygen saturation to inspired 
oxygen fraction (SpO2/FiO2), categorized on 
the 4-point ordinal scale (Table 4) 
• Time to discontinuation of oxygen 
supplementation requirement 
• Mean SpO2 for subjects not requiring 
oxygen supplementation at Days 5, 10, 21 
and 28 
• Number of O2 supplementation free days 
during hospitalization  
• Proportion of subjects who do not require 
oxygen supplementation (sustained for at 
least 24 hours) during hospitalization  
Note, criteria for removal of oxygen 
supplementation is defined as resting (5 
minutes of rest) room air saturation >90% 


 
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Objectives 
Endpoints 
• Additional efficacy outcomes 
• Mortality rate during the 28-day study 
period following enrollment 
• Time to hospital discharge readiness 
• Proportion of subjects ready to be 
discharged from the hospital during the 
28-day study period following enrollment 
• Proportion of subjects with resolution of 
fever below entry criteria for 24 hours (as 
defined in Section 5.1.1) by Day 10 in 
subjects with fever at baseline 
• Time to resolution of fever below entry 
criteria for 24 hours (as defined in 
Section 5.1.1) in subjects with fever at 
baseline 
• Duration (in days) of remdesivir use in 
subjects starting remdesivir within 24 hours 
of first dose of BLD-2660 
• Change from baseline to Days 10, 14, 21 
and 28 in clinical status outcome using a 
6-point ordinal scale (Section 8.1.3) 
• Proportion of subjects reporting each 6-
point ordinal scale of the clinical status 
outcome assessment 
• Change from baseline to Days 5, 10, 14, 21 
and 28 in NEWS score 
• Change from baseline to Days 10, 14, 21 
and 28 in IL-6 and D-dimer 
Exploratory 
• Other efficacy outcomes 
• Proportion of subjects who require 
mechanical ventilation after study entry 
• Number of ventilator-free days to Day 21 
• Proportion of subjects with ICU transfer 
and/or ventilator dependence during the 28-
day study period following enrollment 


 
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Objectives 
Endpoints 
• The time to a NEWS of ≤ 2 and maintained 
for 24 hours 
• Change in NEWS from baseline to Days 3, 
5, 8, 10, 14, 21 and 28 in NEWS 
• To evaluate antiviral activity of 
BLD-2660 in the same population 
• Proportion of subjects who are 
SARS--CoV-2 virus free by Day 10/EOT 
or hospital discharge, whichever is sooner 
• Time to eradication of SARS-CoV-2 
• Change from baseline in SARS-CoV-2 
viral load at Days 5, 10, 14, and 28 
• Other safety outcomes 
• Clinically relevant changes from baseline 
in electrocardiogram (ECG), and clinical 
laboratory values at each post baseline 
timepoint 
• Proportion of subjects with clinically 
significant drug-related troponin elevations 
that have repeat elevation upon 
confirmatory testing as adjudicated by the 
DMC while continuing on study drug 
during the 10-day treatment period 
• To assess population pharmacokinetics 
(PK) characteristics of BLD-2660 
• BLD-2660 plasma concentrations 


 
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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 2 randomized, double-blind, placebo-controlled multicenter study designed to 
evaluate BLD-2660 as add-on to standard of care (SOC) therapy in hospitalized subjects with 
recently diagnosed COVID-19 compared to SOC treatment. 
The study will include a Screening period, a Treatment period, and a Follow-up period. 
After signing informed consent form (ICF), potential candidates who are hospitalized  for 
confirmed infection with SARS-CoV-2 will undergo additional screening procedures. 
On Day 1, eligible subjects will be randomized in 2:1 ratio to one of 2 treatment groups, active or 
control, as shown in Table 1. Randomization will be stratified by remdesivir at study entry. All 
subjects will receive study drug in combination with SOC over 10 days (through Day 10/end of 
treatment) or until hospital discharge, if sooner. Subjects will be followed for at least 18 days 
after the last dose of study drug on Days 14, 21 and 28. Subjects will be contacted 60 days 
post-study to collect information on mortality and forced vital capacity (FVC). 
Subjects will be evaluated as specified in the Schedule of Activities (SoA; Section 1.2). 
4.2. 
Scientific Rationale for Study Design 
This Phase 2, randomized, double-blind, placebo-controlled study compares 2 treatment groups, 
active and control. The study drug will be administered as add-on therapy to SOC as currently 
there are no approved treatments for this potentially lethal disease. 
4.3. 
Justification for Dose 
The BLD-2660 dose selected for this study is 900 mg BID is based on nonclinical and clinical 
studies as follows: 
• No maximum tolerated dose has been established due to saturation of absorption at 
doses above 900 mg. After a single 900 mg dose or 900 mg BID for 2 weeks, BLD-
2660 was well-tolerated. 
• A threshold plasma concentration ≥ 400 ng/mL was associated with efficacy in the 
mouse bleomycin model of idiopathic pulmonary fibrosis (IPF). Based upon the 
similarity of the IC50 of BLD-2660 in mice and humans (474 nM and 170 nM, 
respectively) and similar pharmacokinetics (PK) curves, the anticipated threshold 
exposure in humans for target engagement is likely to be similar to that seen in the 
mouse. The 900mg dose demonstrated plasma exposure (Cmax) at or above the 400 
ng/ml for up to 60 minutes on Day 1 and exposures were lower at Day 7 and 14. 
• BID dosing is also proposed to maximize the time above the plasma concentration 
associated with efficacy in the animal models. 
• The 900 mg BID dosing has a wide safety margin with respect to the no observed 
adverse effects level (NOAEL) doses administered in the rat and dog with a 10-fold 


 
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safety profile when comparing Cmax and AUC values from the two chronic Good 
Laboratory Practice (GLP) repeated dose toxicology studies. 
For additional details, refer to the Investigator Brochure. 
4.4. 
Study Duration 
For each subject the study is expected to last as follows: 
Study Period 
Duration  
Screening period  
Up to 3 days 
Treatment period  
10 days  
Follow-up period 
11 days 
Post study follow-up 
60 days 
 
4.5. 
End of Study Definition 
A subject is considered to have completed the study if he/she has completed all phases of the 
study including the last visit on Day 28. The end of the study is defined as the date of the last 
visit of the last subject in the study. 


 
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5. 
STUDY POPULATION 
5.1. 
Eligibility Criteria 
5.1.1. 
Inclusion Criteria 
To be eligible for participation in this study, subjects must meet all the following: 
Age 
1. At least 18 years of age at the time of signing the ICF. 
Type of Subject and Disease Characteristics 
2. Hospitalized for COVID-19. 
3. Diagnosed with COVID-19 as defined by having at least 2 of the following signs or 
symptoms within the past 2 days: 
a. Fever defined as a body temperature of ≥ 38.0 °C oral, or ≥ 38.3 °C rectal, ≥37.7 °C 
forehead or ≥38.7°C aural (axillary temperatures are not allowable); 
b. Cough; 
c. Fatigue; 
d. Shortness of breath. 
4. Radiographic evidence (chest x-ray or CT scan) of one the following: 
a. Ground-glass opacities, or 
b. Local or bilateral patchy infiltrates, or 
c. Interstitial pulmonary infiltrates. 
5. Oxygen requirements: 
a. SpO2 ≤ 94% on ambient air 
OR 
b. Requires supplemental oxygen administration by nasal cannula, simple face mask, 
or other similar oxygen delivery device. 
Sex 
6. Male and/or female subjects. 
Contraception use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
7. All subjects (male or female) who are of childbearing potential must agree to use highly 
effective contraception during the study. Female subjects and male partners of female 
subjects must continue to use highly effective contraception for 30 days after the last dose 
of study drug. Female subjects should not donate oocytes during this time. Male subjects 
and female partners of male subjects must continue to use highly effective contraception 
for 90 days. Male subjects must agree not to donate sperm during this time. 


 
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Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject. 
Note: Ethinyl estradiol is the primary estrogen used in hormonal contraceptives. The 
progestin component consists of norethindrone, levonorgestrel, norgestrel, 
norethindrone acetate, ethynodiol diacetate, norgestimate, desogestrel, and 
drospirenone. As BLD-2660 is a weak CYP3A4 inducer, exposure to both the 
estrogen and progestin components in hormonal contraceptives may be decreased, 
resulting in an increased risk of pregnancy. As such, it is recommended that subjects 
who are on hormonal contraceptives for birth control should use an alternate means 
of contraception (condoms, diaphragms, intrauterine device (IUD), other barrier 
methods, sexual abstinence, etc.) during participation in the study. 
8. Women of childbearing potential must have a negative serum pregnancy test at Screening 
within 72 hours prior to first administration of study drug. 
9. Women not of childbearing potential must be postmenopausal (defined as cessation of 
regular menstrual periods for at least 1 year 
Informed Consent 
10. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol. 
5.1.2. 
Exclusion Criteria 
Subjects will be excluded from study participation if they meet any of the following: 
Medical Conditions 
1. Active bacterial pneumonia infection 
2. Known active tuberculosis (TB). 
3. History of Child-Pugh B or C cirrhosis. 
4. History of ischemic heart disease or myocardial infarction or acute coronary syndrome. 
5. Subjects requiring supplemental oxygen ≥0.75 FiO2. 
6. It is not in the best interest of the subjects to participate, in the opinion of the treating 
Investigator. 
7. Female subjects who are pregnant or breastfeeding or expecting to conceive within the 
projected duration of the study, starting with the screening visit through 90 days after the 
last dose of study drug. 
Diagnostic Assessments 
8. The following laboratory parameters are excluded: 
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 x upper 
limit of normal (ULN); 


 
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• Creatinine clearance < 50 mL/min. 
Prior Therapy (refer to Section 6.6 for allowed, prohibited and restricted therapy during 
the study) 
9. Requiring, or expected to require mechanical ventilation at screening. 
10. Treatment with chloroquine or hydroxychloroquine at study entry.  
11. Treatment with anti-IL-6, anti-IL-6 receptor antagonists, or with Janus kinase inhibitors 
(JAKi) in the past 30 days or plans to receive during the study period. 
Prior/Concurrent Clinical Study Experience 
12. Participation in any other clinical study of an experimental drug treatment for COVID-19 
within 6 half-lives of the experimental treatment. 
13. Current participation or have participated in a study of an investigational agent or has 
used an investigational device within 4 weeks prior to the first dose of study drug. 
Note: Subjects participating in an observational study are an exception to this criterion and 
may qualify for the study with Sponsor approval. 
Note:  Subjects who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous investigational 
agent. 
Other Exclusions 
14. Unable to swallow solid oral medication or known malabsorption disorder. 
15. Subjects who have allergy to BLD-2660 or inactive components of BLD-2660. 
5.2. 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure subjects to meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes screening number, demography, reason for screen 
failure and eligibility criteria. 
Rescreening requests will be on a case-by-case basis and will require Medical Monitor approval. 


 
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6. 
STUDY DRUG 
6.1. 
Study Drugs Administered 
For more details on specific indications refer to the BLD-2660 Investigator Brochure (IB). 
Table 3: 
Study Drug Administered 
 
Active 
Control  
Drug Name 
BLD-2660 
Placebo 
Type  
Drug (small molecule) 
Drug 
Dose Formulation 
Capsules, Hard gelatin size ‘00’ 
Capsules, Hard gelatin size 
‘00’ 
Unit Dose Strength(s) 
150 mg 
NA 
Dosage Level(s) 
900 mg BID (6 capsules BID) for 
a total of 1800 mg per day 
NA 
Route of Administration 
Oral (PO); naso-gastric tube (NGT) may be used in special 
cases as detailed in Administration instruction below. 
Administration 
instruction 
Study drug to be taken orally BID: 
• Morning dose to be taken at least one hour before food 
• Evening dose to be taken at least 2 hours after food 
In the case where a subject needs mechanical ventilation, study 
drug can be administered via an NGT by opening the study 
drug capsules and suspending the contents in the required 
amount of water as described in the Pharmacy Manual, then 
administering through the tube. Lavage with additional 20-30 
mL of water to ensure study drug does not stick to the tubing. 
Do not attempt to administer through a feeding tube. 
Sourcing 
Study drug will be provided to the site centrally by the Sponsor 
or designated representative. 
Packaging and Labeling 
Drug product, both active and placebo, will be supplied in bulk 
packaging (40 capsules/bottle). Label text will at a minimum 
include the protocol number, lot number, storage conditions, 
and Sponsor name and address. Labels comply with regulatory 
requirements for study drugs. 
 


 
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6.2. 
Standard of Care 
In both study groups, subjects should receive appropriate supportive care measures as deemed 
necessary by the treating Investigator. 
6.3. 
Preparation/Handling/Storage/Accountability 
• Drug product will be shipped refrigerated at 2-8°C with a temperature monitor. The 
Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study drug received and any discrepancies are 
reported and resolved before use of the study drug. 
• Only subjects enrolled in the study may receive study drug and only authorized site 
staff may supply or administer study drug. All study drugs must be stored in a secure, 
refrigerated (2-8°C), and monitored (manual or automated) area in accordance with 
the labeled storage conditions with access limited to the Investigator and authorized 
site staff. 
• The Investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study drug accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records). Clinical supplies including 
study drug and inventory records must be made available upon inspection by 
Sponsor/FDA upon request. The site monitors will review the records along with 
other study records during monitoring visits. 
• Further guidance and information for the final disposition of unused study drug is 
provided within the Pharmacy Manual. 
6.4. 
Measures to Minimize Bias: Randomization and Blinding 
All subjects will be centrally assigned to randomized study drug using an Interactive Response 
Technology (IRT). Before the study is initiated, the log in information & directions for the IRT 
will be provided to each site. 
Randomization will be stratified by remdesivir use at study entry (yes/no)  
Study drug will be dispensed by the unblinded pharmacy staff to the study staff/research nurse in 
a blinded manner per the schedule summarized in the SoA (Section 1.2). 
The IRT will be programmed with blind-breaking instructions. Subject safety must always be the 
first consideration in making such a determination. If the Investigator decides that unblinding is 
warranted, the Investigator should make every effort to contact the Sponsor prior to unblinding a 
subject’s drug assignment unless this could delay emergency treatment of the subject. If a 
subject’s drug assignment is unblinded, the Sponsor must be notified within 24 hours after 
breaking the blind. The date and reason that the blind was broken must be recorded in the source 
documentation and case report form, as applicable. 


 
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6.5. 
Study Drug Compliance 
Compliance with study drug will be assessed by the study staff by documenting that at all 6 
capsules per dose are administered. Unused capsules that have been dispensed to the subject but 
not administered should be documented as such in the source documents and CRF. Deviation(s) 
from the prescribed dosage regimen should be recorded in the eCRF. 
A record of the number of BLD-2660 capsules dispensed to and taken by each subject must be 
maintained and reconciled with study drug and compliance records. Drug start and stop dates, 
including dates for drug delays will also be recorded in the eCRF. 
6.6. 
Concomitant Therapy 
All medications including over -the -counter medications and herbal supplements taken during 
the 30 days prior to the first study drug administration will be recorded and reviewed by the 
Investigator (or designee) to determine whether the subject is eligible for inclusion. 
Treatment with another study drug, investigational device, or approved therapy for 
investigational use within 30 days (or five half-lives, whichever is longer) before anticipated 
dosing is prohibited. 
Allowed medications during the study: 
• Remdesivir 
Note, for subjects receiving remdesivir therapy, BLD-2660 is to be administered at least an hour 
before remdesivir administration. 
6.6.1. 
Prohibited Medications and Herbal Supplements: 
Below is a list of medications that are prohibited during the study. 
• Anti-IL-6, IL-6 receptor antagonists, or JAKi 
 
6.6.2. 
Restricted Medications 
Restricted medications are defined as medications which should be avoided, if possible; 
however, they are not necessarily prohibited during this study. If such medications are 
required, consider switching to another medication in the class that is not restricted. If a 
restricted medication is required, seek approval of the Medical Monitor and use with caution per 
approved product label. 
• FDA EUA or compassionate use agent(s) (to be discussed with Medical Monitor) 
• Chloroquine, hydroxychloroquine, azithromycin (Note: prior to prescribing these 
medications, must seek approval of the Sponsor’s Medical Monitor) 
• HIV anti-viral drugs 
• H2 blockers and antacids will be allowed as long as they are administered 2 hours 
before or after administration of study drug. 


 
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BLD-2660 as a Perpetrator  
CYP3A4  
The following are examples of some CYP3A4 substrates whose exposure could be reduced due 
to induction of that enzyme; however, it is not all inclusive and subjects should be monitored for 
adverse effects of these and CYP3A4 substrates in general. 
• HMG CoA reductase inhibitors:  atorvastatin, cervistatin, lovastatin, and simvastatin. 
Note: Subjects taking the above statins can be switched to any of the following 
medications: pravastatin (Pravachol), rosuvastatin (Crestor), pitavastatin (Livalo), 
and fluvastatin (Lescol). If subject is unable to switch statin medications for any 
reason, the investigator to consult with Sponsor’s Medical Monitor. 
• Benzodiazepines 
• Immune modulators 
• Cyclosporine 
• Tacrolimus 
• Calcium channel blockers 
• Hormonal contraceptives (refer to Section 10.4.2) 
CYP1A2 
The following are examples of some CYP1A2 substrates whose exposure could be reduced due 
to induction of that enzyme; however, it is not all inclusive and subjects should be monitored for 
adverse effects of these and CYP1A2 substrates in general. 
• Non-steroidal anti-inflammatory drugs (NSAIDs):  Acetaminophen, phenacetin, 
naproxen 
• Anticoagulants:  Warfarin 
• Antiemetics:  Ondansetron 
• Tricyclic antidepressants:  Clomipramine, doxepin, imipramine 
• Selective serotonin and norepinephrine reuptake inhibitors (SSNRIs):  Duloxetine, 
fluvoxamine 
• Antipsychotics:  Olanzapine 
• Bronchodilators:  Theophylline 
• Calcium channel blockers:  Verapamil 
CYP2B6 
The following are examples of some CYP2B6 substrates whose exposure could be altered due to 
inhibition or induction of that enzyme; however, it is not all inclusive and subjects should be 
monitored for adverse effects of these and CYP2B6 substrates in general. 


 
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• Antidepressants:  Bupropion, selegiline 
• Anesthetics and analgesics:  Ketamine, meperidine, propofol, tramadol 
BLD-2660 as a Victim 
BLD-2660 has been shown in vitro to be a substrate of CYP3A4. Consequently, drugs that 
inhibit or induce CYP3A4 have the potential to increase or decrease exposure to BLD-2660. 
The following are examples of some CYP3A4 inhibitors; however, it is not all inclusive and 
subjects should be monitored for adverse effects when any CYP3A4 inhibitor is coadministered 
with BLD-2660. 
• Azole antifungals:  Fluconazole, itraconazole, ketoconazole 
• Macrolide antibiotics:  clarithromycin, erythromycin, 
• Quinoline antibiotics:  ciprofloxacin, norfloxacin 
• Proton pump inhibitors:  esomeprazole, omeprazole, pantoprazole 
• Calcium channel blockers:  Verapamil 
• Others:  Grapefruit juice, starfruit 
The following are examples of some CYP3A4 inducers; however, it is not all inclusive and 
subjects should be monitored for adverse effects when any CYP3A4 inducer is coadministered 
with BLD-2660. 
• Barbiturates 
• Anticonvulsants:  Carbamazepine, oxcarbazepine, phenytoin 
• Rifabutin and rifampin 
• Glucocorticoids 
• St. John’s Wort 
Transporter Interactants 
The following are examples of some P-glycoprotein inhibitors; however, it is not all inclusive 
and subjects should be monitored for adverse effects when any P-glycoprotein inhibitor is 
coadministered with BLD-2660. 
• amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, lapatinib, 
lopinavir and ritonavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir and 
ritonavir, telaprevir, tipranavir and ritonavir, verapamil 
The following are examples of some breast cancer resistance protein (BCRP) inhibitors; 
however, it is not all inclusive and subjects should be monitored for adverse effects when any 
BCRP inhibitor is coadministered with BLD-2660. 
• curcumin, cyclosporine A, elthrombopag  
 


 
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6.7. 
Dose Modification 
Dose modifications are not planned in this study. 
6.8. 
Treatment of Overdose 
For this study, any dose of study drug greater than the prescribed daily dose will be considered 
an overdose. There is no specific treatment recommended to treat an overdose of study drug and 
the subject should receive treatment directed towards any symptoms manifested. 
In the event of an overdose, the Investigator should: 
1. Contact the Medical Monitor as soon as possible. 
2. Closely monitor the subject for any AE/SAE and laboratory abnormalities. 
3. Document the quantity of the excess dose as well as the duration of the 
overdose. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the subject 
6.9. 
Intervention after the End of the Study 
No additional intervention is planned beyond the end of the study. 


 
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7. 
DISCONTINUATION OF STUDY DRUG AND SUBJECT 
DISCONTINUATION/WITHDRAWAL 
7.1. 
Stopping Rules 
Given severity of illness in COVID-19, there are no pre-specified stopping rules for this study as 
a whole. Instead there will be close oversight by the Sponsor and DMC reviews for safety as 
specified in Section 9.5.1. 
7.1.1. 
Pregnancy 
A subject must permanently discontinue study drug if she becomes pregnant. See Appendix 4 
(Section 10.4) and Section 8.3.5 for additional details. 
See the SoA (Section 1.2) for data to be collected at the time of study drug discontinuation and 
follow-up, and for any further evaluations that need to be completed. 
7.2. 
Discontinuation of Study Drug 
In some instances, it may be necessary for a subject to permanently discontinue study drug. 
Please also refer to stopping rules described in Section 7.1. 
Permanent discontinuation of study drug does not mean withdrawal from the study, and the 
subject will be encouraged to remain in the study and continue to complete all study visits. See 
the SoA (Section 1.2) for data to be collected at the time of drug discontinuation and follow-up 
and for any further evaluations that need to be completed. 
Subjects may discontinue or be discontinued from study drug at any time. A subject may 
discontinue study drug for reasons including but not limited to: 
• Adverse event 
• Death 
• Lost to follow-up 
• Non-compliance with study drug 
• Physician decision 
• Pregnancy 
• Lack of efficacy 
• Protocol deviation 
• Study terminated by Sponsor 
• Withdrawal by subject* (*only for discontinuing study drug, but will remain in study) 
The reason for subject discontinuation from study drug will be recorded in the eCRF. At the time 
of treatment completion or study drug discontinuation, the EOT/ET visit should be completed as 
shown in the SoA (Section 1.2). Subjects should continue to be followed for safety even if they 
discontinue study drug prematurely unless they withdraw consent. 


 
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Pregnancy is a mandatory criterion for permanent discontinuation of study drug (see 
Section 7.1.1). 
7.3. 
Withdrawal from the Study 
Subjects have the right to withdraw from the study at any time and for any reason without 
prejudice to their future medical care by the Investigator or at the institution. A subject may 
withdraw from the study for reasons including but not limited to: 
• Death 
• Withdrawal by subject 
• Lost to follow-up 
• Study terminated by Sponsor 
The reason for subject withdrawal from the study will be recorded in the eCRF. 
At the time of withdrawal from the study, the end of study visit should be completed, as shown 
in the SoA (Section 1.2). 
If the subject withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 
If a subject withdraws from the study, he/she may request destruction of any samples taken and 
not tested, and the Investigator must document this in the site study records. 
7.4. 
Lost to Follow up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return to the study 
site or be contacted remotely for scheduled outpatient visits post hospital discharge. 
The following actions must be taken if a subject fails to return to the clinic and/or be available 
for remote contact for a required study visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 
• Before a subject is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, 
if necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
medical record. 
• Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1.8). 


 
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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA (Section 1.2). Protocol 
waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue 
study drug. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The Investigator will maintain screening 
information including details of all subjects screened and to confirm eligibility or 
record reasons for screening failure, as applicable. 
• Missed visits should be avoided if at all possible; if a visit is missed and cannot be 
rescheduled, the subject should resume their original visit schedule at the next 
scheduled visit. In case of natural disasters or pandemics, some visits/study 
procedures can be done via virtual visits or at home visits when discharged. Refer to 
study reference manual for more details. 
8.1. 
Efficacy Assessments 
8.1.1. 
Oxygenation Measures 
Peripheral capillary oxygen saturation (SpO2) with pulse oximeter will be used as surrogate for 
arterial blood oxygen saturation. While hospitalized, the SpO2 will be measured twice a day 
(morning and night). Measurement is to be done with the subject laying supine or with the head 
of the bed inclined, unless indicated otherwise; the same position should be used throughout the 
study and the subject’s position will be captured in the eCRF. The FiO2 at the time of each SpO2 
measurement (morning and night while hospitalized) must also be recorded in the eCRF. 
Peripheral hemoglobin oxygen saturation to inspired oxygen fraction (SpO2/FiO2) will also be 
measured. Oxygenation will be assessed using the categories in Table 4. 
Table 4: 
A 4-Point Oxygen Ordinal Scale for Severity Categories by SpO2/FiO2 Ratio 
Score 
Severity 
SpO2/FiO2 (mmHg) 
0 
None 
> 315 
1 
Mild 
> 235 to 315 
2 
Moderate 
> 150 to 235 
3 
Severe 
≤ 150 
8.1.2. 
Measure of Clinical Support 
At each study day while hospitalized, the following measure of clinical support should be 
assessed: 


 
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• Oxygen requirement 
• Non-invasive mechanical ventilation (via mask) 
• Mechanical ventilator requirement (via endotracheal tube or tracheostomy tube) or 
Extracorporeal membrane oxygenation (ECMO) requirement 
• Level of consciousness: alert vs. (arousable only to voice or pain or unresponsive) 
In addition, date of hospital discharge readiness or date of hospital discharge (if different) will be 
collected. 
8.1.3. 
Clinical Status Ordinal Score 
Clinical status will be assessed using the 6-point ordinal score (Table 5). The ordinal scale is an 
assessment of the clinical status at the first assessment of a given study day. Each day, the worse 
score for the previous day will be recorded. i.e. on day 3, day 2 score is obtained and recorded as 
day 2. This scale has been used successfully as an endpoint for evaluation of treatments for 
severe influenza requiring hospitalization (Peterson, 2017). 
Table 5: 
A 6-Point Ordinal Score for Assessing Clinical Status 
Score 
Description 
1 
Not hospitalized 
2 
Hospitalized, not requiring supplemental oxygen 
3 
Hospitalized, requiring supplemental oxygen 
4 
Hospitalized, on non-invasive ventilation or high flow oxygen devices 
5 
Hospitalized, on invasive mechanical ventilation or ECMO 
6 
Death 
8.1.4. 
National Early Warning Score (NEWS) 
The NEWS has demonstrated an ability to discriminate subjects at risk of poor outcomes. (Smith, 
2016; Williams, 2019). This score is based on 7 clinical parameters, vital signs (respiratory rate, 
temperature, blood pressure, and heart rate), SpO2, breathing room air or supplemental oxygen, 
and consciousness (Table 6). The NEWS is being used as an efficacy measure. 
NEWS will be derived from other parameters to be collected during the study as specified in 
SoA (Section 1.2). 


 
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Table 6: 
NEW Score 
 
Level of consciousness: alert (A), arousable only to voice (V), or pain (P) and unresponsive (U) 
8.1.5. 
Hospital Discharge Readiness Criteria 
The subject’s readiness for hospital discharge will be evaluated based on the following criteria 
(must meet all): 
• Normal O2 saturation on room air or a return to pre-morbid status 
• Afebrile 
• Able to ambulate (or use commode) without assistance or a return to pre-morbid 
mobility (for non-ambulatory subjects) 
• Able to dress self or a return to pre-morbid status 
• Eating pre-morbid full diet or a return to pre-morbid status 
Date of actual hospital discharge and date of any readmission during the study period should be 
captured. Subjects’ oxygen supplementation status at hospital discharge will also be captured 
(with vs. without oxygen supplementation). 
8.1.6. 
Antiviral Activity 
Quantitative viral load using nasopharyngeal swab/sputum SARS-CoV-2 PCR will be used to 
monitor disease status during the study. For more details refer to the laboratory manual. 
 


 
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8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.2). 
8.2.1. 
Physical Examinations 
• Physical examinations will be performed by the principal investigator, a designated 
sub-investigator or a qualified hospital care staff member. 
• A complete physical examination will include, at a minimum, assessments of the 
skin, cardiovascular system, respiratory system, abdomen (gastrointestinal, liver and 
spleen) and neurological system. Height and weight will also be measured and 
recorded. 
• A symptom-directed physical examination will include, at a minimum, assessments of 
the skin, respiratory system, cardiovascular system, and abdomen (liver and spleen). 
8.2.2. 
Vital Signs 
• Blood pressure, heart rate, and respiratory rate will be measured after the subject has 
been resting for 5 minutes. 
• Temperature will be recorded twice daily while hospitalized (morning and evening) 
• Vital signs will be measured prior to any blood draw that occurs at the same 
timepoint 
8.2.3. 
Electrocardiograms 
12-lead ECG will be obtained while subject is in supine position using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, and QT (QTcF), intervals. Subject 
to be resting for at least 2 minutes prior to ECG. 
8.2.4. 
Clinical Safety Laboratory Assessments 
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed 
and to the SoA for the timing and frequency. 
• The Investigator must review the laboratory report, document this review, and record 
any clinically significant adverse changes occurring during the study in the AE 
section of the eCRF. The laboratory reports must be filed with the source documents. 
• All laboratory tests with values considered clinically significantly during participation 
in the study or within 11 days after the last dose of study drug should be repeated 
until the values return to normal or baseline or are no longer considered clinically 
significant by the Investigator or Sponsor’s Medical Monitor/designee. 
− If such clinically significant values do not return to normal/baseline within a 
period of time judged reasonable by the Investigator, the etiology should be 
identified, and the Sponsor notified. 


 
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− All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA. 
− If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in subject 
management or are considered clinically significant by the Investigator (e.g., SAE 
or AE or dose modification), then the results must be recorded in the eCRF. 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of an AE and SAE can be found in Appendix 3 (Section 10.3). 
All AEs will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject's legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of AE, SAE. 
All AEs will be classified for severity using the common terminology criteria for AEs (CTCAE) 
V.5. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
Table 7 below summarizes the different reporting periods for AEs and SAEs. 
Table 7: 
Adverse Event Reporting Periods 
Type of Event 
Adverse Event 
Serious Adverse Event 
Reporting period 
From consent until Day 28 visit (at 
least 18 days after last dose of study 
drug). 
From consent until Day 28 visit (at least 
18 days after the last dose of study drug). 
SAEs will be recorded for study drug 
and for remdesivir. 
Reporting Timelines 
to the Sponsor  
Entered into the clinical database 
on an ongoing basis   
Within 24 hours of site awareness 
Medical occurrences that begin before the start of study drug but after obtaining informed 
consent will be recorded on the Adverse Events section of the case report form (CRF) and will 
be identified in the analysis as non-treatment-emergent adverse events (non-TEAEs). 
All SAEs (for study drug and for remdesivir) will be recorded and reported to the Sponsor or 
designee immediately and under no circumstance should this exceed 24 hours from site 
awareness, as indicated in Appendix 3 (Section 10.3). The Investigator will submit any updated 
SAE data to the Sponsor or designee within 24 hours of it being available. 
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a subject has been discharged from the study, and he/she considers the event to be related to the 
study drug or study participation, the Investigator must promptly notify the Sponsor or designee. 


 
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8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 10.3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences. 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs, will be followed until resolution, stabilization, the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 7.4). Further 
information on follow-up procedures is provided in Appendix 10.3. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the Investigator to the Sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and the 
safety of a study drug under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study drug under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• For all studies must be prepared for suspected unexpected serious adverse reactions 
(SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
8.3.5. 
Pregnancy 
• Details of all pregnancies in female subjects and of female partners of male subjects 
will be collected as outlined in Section 10.4 (Appendix 4). 
• If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in 
Appendix 4. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 


 
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8.3.6. 
Deaths 
All deaths will be recorded in the eCRF. As deaths are always considered SAEs, they should be 
reported to the Sponsor within 24 hours of site awareness. 
8.4. 
Pharmacokinetics 
PK assessment of BLD-2660 will be analyzed using a population PK approach based upon 
sparse sampling to be obtain at designated timepoints as specified in the SoA (Section 1.2). Note, 
if NGT is inserted, PK samples will also be collected 2 hours postdose after the first NGT use. 
• Instructions for the collection and handling of biological samples will be provided by 
the Sponsor. The actual date and time (24-hour clock time) of each sample will be 
recorded. 
• Samples will be used to evaluate the PK of BLD-2660. Samples collected for 
analyses of BLD-2660 serum concentration may also be used to evaluate safety, 
efficacy and/or pharmacodynamic aspects related to concerns or questions arising 
during or after the study. 
• Subject confidentiality will be maintained. At visits during which blood samples for 
the determination of PK, and PD related to BLD-2660 will be taken, 1 sample of 
sufficient volume can be used. 
• Any changes in the timing or addition of time points for any planned study 
assessments must be documented and approved by the relevant study team member 
and then archived in the Sponsor and site study files but will not constitute a protocol 
amendment. The IRB/IEC will be informed of any safety issues that require alteration 
of the safety monitoring scheme or amendment of the ICF. 
8.5. 
Pharmacodynamics and Biomarker Assessments 
Blood samples will be collected and analyzed for biomarker analysis as specified in the SoA 
(Section 1.2) including IL-6 and D-dimers. Additional blood sample for future biomarker 
analyses will also be collected and stored. 
The Sponsor or designee will supply complete written instructions for handling, processing, 
storage, and shipping of biomarker samples in the Laboratory Manual. 
Samples may be stored for a maximum of 15 years after the last subject’s last visit for the study, 
at a facility selected by the Sponsor, to enable further analysis of biomarker responses to 
BLD2660. 


 
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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypothesis 
Two primary hypotheses will be tested. The study will be declared a success if either of the 
hypotheses are statistically significant. 
Hypothesis 1: Will evaluate clinical benefit in hospitalized adult subjects with recent SARS-
CoV-2 infection. The primary endpoint is time to recovery as defined by no longer requiring 
oxygen support or hospital discharge, whichever occurs first. The null hypothesis is the hazard 
ratio is = 1 and the alternative hypothesis is the hazard ratio does not equal 1. 
Hypothesis 2: Will evaluate improvement in oxygenation in hospitalized adult subjects with 
recent SARS-CoV-2 infection at the time of discharge, or Day 10, if they are still hospitalized. 
The primary endpoint is the change from baseline to Day 10 or hospital discharge if sooner in the 
ratio of hemoglobin oxygen saturation to inspired oxygen fraction (SpO2/FiO2). The null 
hypothesis is the mean treatment difference equals 0 and the alternative hypothesis is the mean 
treatment difference does not equal 0. 
9.2. 
Sample Size Determination 
Time to clinical improvement 
A randomized, double-blind, placebo-control study evaluating remdesivir in 1063 hospitalized 
patients with COVID-19 reported 606 recoveries, with a median time to recovery of 11 days and 
15 days in the remdesivir and placebo groups, respectively (remdesivir package insert).  
Recovery was defined as the first day on which the subject satisfies one of the following 3 
categories from the ordinal scale: 1) Hospitalized, not requiring supplemental oxygen - no longer 
requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home 
oxygen; 3) Not hospitalized, no limitations on activities 
(https://clinicaltrials.gov/ct2/show/NCT04280705). 
Assuming the median time to clinical improvement, defined as no longer requiring oxygen 
support or hospital discharge whichever occurs first, will be 12-15 days in the placebo group, 
and that at least 75 of the planned 120 subjects enrolled meet the clinically improved criteria, the 
study will have at least 80% power to detect a 50% reduction in the time to clinical 
improvement, (i.e., hazard ratio of 0.5).  
Change from baseline to Day 10 or hospital discharge if sooner in the ratio of hemoglobin 
oxygen saturation to inspired oxygen fraction (SpO2/FiO2). 
A prospective observational cohort study of non-intubated moderate to severe ARDS patients 
(Ding, 2020) reported the partial pressure of oxygen (PaO2)/FiO2 ratio for 10 patients, which 
gave a mean and standard deviation of 147 ± 46 mm Hg. Converting to a Sp02/FiO2 ratio gives a 
mean and standard deviation of 192 ± 39 using the equation reported by Rice et al. (2007) (Rice, 
2007). 
Assuming a standard deviation of 40 in the SpO2/FiO2 ratio, a sample size of 120 subjects (80 
active, vs 40 control) will provide approximately 90% power to detect a treatment difference in 


 
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the SpO2/FiO2 ratio of 25 or greater, based on a two-sample t-test with a two-sided 5% 
significance level 
9.3. 
Population Analysis Set 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Full Analysis 
Set (FAS) 
All randomized subjects who receive at least one dose of study drug. This 
population will be used for all efficacy analyses 
Modified Intent 
to Treat  (MITT) 
All randomized subjects who receive at least one dose of study drug and 
one post baseline assessment of the SpO2/FiO2 ratio. This population will 
be used for the primary and secondary endpoints related to improvement 
in SpO2/FiO2 ratio. 
Per Protocol 
Analysis Set 
All randomized subjects who receive at least one dose of study drug 
without any major protocol violations that would impact the assessment 
of the primary efficacy endpoints. This population will be used for 
efficacy analyses of the primary efficacy endpoints 
Safety Analysis 
Set 
All enrolled subjects who receive any study drug 
PK Analysis Set 
All enrolled subjects who receive any study drug and have plasma 
concentration data 
9.4. 
Statistical Methods 
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a statistical analysis plan (SAP), which will be maintained by the Sponsor. The 
SAP may modify the plans outlined in the protocol; however, any major modifications will also 
be reflected in a protocol amendment. This section is a summary of the planned statistical 
analyses of the primary and secondary endpoints. 
9.4.1. 
General 
In general, summary tabulations will be presented that display the number of observations, mean, 
standard deviation, median, minimum, and maximum for continuous variables, and the number 
and percent (of non-missing values) per category for categorical data. 
9.4.2. 
Efficacy Analyses 
The primary efficacy endpoint of time to clinical improvement will be presented using the 
Kaplan-Meier estimator. Subjects will be censored at Day 28 or earlier, if they discontinue the 
study prior to observing the event.  A Cox proportional hazards model with treatment, remdesivir 
use (yes/no) and age as covariates will be used to estimate the hazard ratio and compare 
treatment groups. 


 
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The primary efficacy endpoint of change from baseline to Day 10 or hospital discharge if sooner, 
in the ratio of hemoglobin oxygen saturation to inspired oxygen fraction (SpO2/FiO2) will be 
analyzed a mixed measures repeated model (MMRM). The Kenward-Roger method will be used 
to calculate the denominator degrees of freedom for the test of fixed effects and adjusted 
standard errors. The model will contain treatment, time and the treatment by time interaction as 
fixed effects and baseline score, age, and remdesivir drug use (yes vs no) as covariates. An 
unstructured covariance matrix will be assumed to model the within-participant errors.  
Sub-group analyses for the two primary endpoints will also be conducted for the following sub-
groups: Chloroquine or hydroxychloroquine use (yes vs no), HIV anti-viral drug use (yes vs no) 
and azithromycin use (yes vs no). If warranted, these effects may be included in the primary 
model. 
No adjustment for multiplicity among the two primary endpoints will be made, as this is a 
Phase 2 study. Secondary endpoints will be analyzed without adjustment for multiplicity. All 
efficacy analyses will use the FAS analysis set, and MITT analysis set if applicable. 
Secondary endpoints that are defined as time to event endpoints will be analyzed using survival 
analysis methods. Data will be presented using the Kaplan-Meier. Subjects will be censored at 
Day 28 or earlier, if they discontinue the study prior to observing the event. A Cox proportional 
hazards model with treatment, remdesivir use (yes/no), and age as covariates will be used to 
estimate the hazard ratio and compare treatment groups. 
Secondary endpoints that are defined as proportions will be summarized using frequency counts 
and proportions. Treatment groups will be compared using a Cochran–Mantel–Haenszel (CMH) 
test stratified by remdesivir use (yes vs no). Additional covariates may be included if warranted.  
Change from baseline in SARS-CoV-2 viral load at Day 10/EOT (or hospital discharge, 
whichever is sooner and end of study (Day 28) will be analyzed using an MMRM model. 
The proportion of patients reporting each of the categories using the 6-point ordinal scale will be 
compared between treatment groups using the CMH test. 
The change from baseline in the NEWS score will be summarized at each time point. A 
comparison between treatment groups will be made using an MMRM model.  
The following secondary endpoints: number of O2 supplementation free days, change from 
baseline in clinical status using 6-point ordinal scale (Table 5), and improvement (i.e., change) 
from baseline as measured by the ratio of hemoglobin oxygen saturation to inspired oxygen 
fraction (SpO2/FiO2) using the 4-point ordinal scale (Table 4) will be summarized using 
descriptive statistics and comparisons between treatment groups made using appropriate 
statistical methods. 
The mean SpO2 for subjects not requiring oxygen supplementation at Days 5, 10, 21 and 28 will 
be summarized using descriptive statistics. 
9.4.3. 
Safety and Tolerability Analyses 
All safety analyses will be performed on the Safety Analysis Set. AEs will be coded using the 
most current Medical Dictionary for Regulatory Activities (MedDRA®). The number of subjects 


 
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experiencing TEAEs) and number of individual TEAEs will be summarized by treatment, system 
organ class and preferred term. TEAEs will also be summarized by severity and by relationship 
to study drug. Serious TEAEs (SAEs) and TEAEs leading to discontinuation of study drug will 
be summarized by treatment, system organ class and preferred term. 
Laboratory evaluations, vital signs assessments and ECG parameters will be summarized by 
treatment and protocol specified collection time point. 
9.4.4. 
Other Analyses 
BLD-2660 plasma concentrations will be summarized using descriptive statistics. 
Pharmacokinetic parameters will be estimated using a population PK approach. 
Change from baseline in IL6 and D-dimer will be analyzed using a repeated measure mixed 
effects model. Missing data will be assumed to be missing at random. The model will include 
fixed effects for treatment group, and remdesivir use (yes vs no). Additional covariates may be 
included if warranted. Subjects will be treated as random, with an unstructured covariance 
structure. The least square (LS) means, and 95% confidence intervals within treatment and for 
the treatment difference will be reported at each timepoint. 
9.5. 
Interim Analysis 
Interim analyses are planned when approximately 25%, 50% and 75% of subjects have 
completed the study for the purpose of early stopping for efficacy or futility. The timing of these 
interim analyses may change based on the rate of recruitment. If recruitment is extremely quick 
these interim analyses may not be conducted. 
The Lan-DeMets spending function analog of the O’Brien-Fleming boundaries will be used to 
monitor each of the primary endpoints as a guide for the DMC for an overall two-sided type-I 
error rate of 5%, for each endpoint. 
Conditional power will be used as an additional guide to the DMC to assess futility. Conditional 
power allows computation of the probability of obtaining a statistically significant result by the 
end of the study given the data accumulated thus far. If the conditional power is less than 20% 
under the original study assumptions, consideration should be given to stopping the study. 
At the interim analysis when approximately 50% of the subjects have completed the study, a 
sample size re-estimation step will occur using the promising zone approach and method of 
Chen, DeMets and Lan, based on the observed effect size at this interim analysis. The promising 
zone is defined as a conditional power of between 50% and 90%. If the conditional power falls into 
this region the sample size may be increased. Further statistical details surrounding the interim 
analysis, including the stopping boundaries, will be included in the statistical analysis plan. 
The study will not stop enrolment awaiting these DMC reviews, though the DMC may 
recommend temporary or permanent cessation of enrolment based on their safety reviews. 
A separate unblinded statistical team will prepare the above information for the DMC to review 
and make recommendations to the Sponsor. 


 
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9.5.1. 
Data Monitoring Committee 
The DMC, a specific independent committee for the study with external representation, will meet 
when approximately 25%, 50% and 75% of subjects have been recruited and on an ad hoc basis 
to review safety results. The DMC may recommend stopping the study if at any time during the 
study there are unacceptable AEs or safety concerns. The members of the DMC will be listed in 
a separate DMC Charter, the governing document that will supersede this section of the protocol. 


 
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
− Applicable ICH Good Clinical Practice (GCP) Guidelines 
− Applicable laws and regulations 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the 
Investigator and reviewed and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study subjects. 
• The Investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
− Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 


 
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10.1.3. 
Informed Consent Process 
• The Investigator or his/her representative will explain the nature of the study to the 
subject or his/her legally authorized representative and answer all questions regarding 
the study. 
• Subjects must be informed that their participation is voluntary. Subjects will be 
required to sign a statement of informed consent that meets the requirements of 21 
CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or 
study center. 
• The medical record must include a statement that written informed consent was 
obtained before any study-specific procedures were performed and the date the 
written consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF. 
• Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• A copy of the signed ICF(s) must be provided to the subject or the subject’s legally 
authorized representative. 
•  Subjects who are rescreened are required to sign a new ICF. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research. The investigator or authorized designee will explain to each 
subject the objectives of the exploratory research. Subjects will be told that they are free to 
refuse to participate and may withdraw their consent at any time and for any reason during the 
storage period. A separate signature will be required to document a subject's agreement to allow 
any remaining specimens to be used for exploratory research. Subjects who decline to participate 
in this optional research will not provide this separate signature. 
10.1.4. 
Data Protection 
• Subjects will be assigned a unique identifier by the Sponsor. Any subject records or 
datasets that are transferred to the Sponsor will contain the identifier only; subject 
names or any information which would make the subject identifiable will not be 
transferred. 
• The subject must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
10.1.5. 
Dissemination of Clinical Study Data 
A clinical study report will be developed by the Sponsor at completion of data analysis. This 
report will be a clinical and statistical integrated report, according to the ICH E3 guidelines. 


 
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Sponsor will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations. 
10.1.6. 
Data Quality Assurance 
• All subject data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (e.g., laboratory data). 
The Investigator is responsible for verifying that data entries are accurate and correct 
by physically or electronically signing the CRF. 
• The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-
Based Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Clinical Monitoring Plan. Due to the infectious nature 
of COVID-19, the Sponsor (or designees) will work with clinical sites to implement 
remote monitoring procedures with a focus on review and source data verification 
(SDV) of safety data. 
• The Sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator per ICH-GCP and local regulations or 
institutional policies. No records may be destroyed during the retention period 
without the written approval of the Sponsor. No records may be transferred to another 
location or party without written notification to the Sponsor. 
10.1.7. 
Source Documents 
• Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s 
site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• Source documents are original documents, data, and records from which the subject’s 
eCRF data are obtained. These include but are not limited to hospital records, clinical 


 
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and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. 
10.1.8. 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
subjects. 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of subjects by the Investigator 
• Discontinuation of further study drug development 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the subject and 
should assure appropriate subject therapy and/or follow-up. 
10.1.9. 
Publication Policy 
• The results of this study may be published or presented at scientific meetings. If this 
is foreseen, the Investigator agrees to submit all manuscripts or abstracts to the 
Sponsor before submission. This allows the Sponsor to protect proprietary 
information and to provide comments. 
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating Investigator will be designated by mutual 
agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
 
 


 
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10.2. 
Appendix 2: Clinical Laboratory Tests 
• The clinical laboratory tests detailed in Table 8 will be performed by a local 
laboratory, except where specified below, at the timing/frequency detailed in the SoA. 
• Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations 
• Investigators must document their review of each laboratory safety report. 
Table 8: 
Protocol-Required Laboratory Assessments 
Hematology 
 
White blood cell count (WBC) with absolute 
differential (Neutrophils, Lymphocytes, 
Monocytes, Eosinophils, Basophils) 
Red blood cell (RBC) with indices (mean 
corpuscular volume [MCV] and mean corpuscular 
hemoglobin [MCH]) 
Hemoglobin 
Hematocrit 
Platelet count 
 
Clinical Chemistries 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Alkaline phosphatase 
Gamma-glutamyl transferase (GGT) 
Total and direct bilirubin (fractionated) 
Blood urea nitrogen (BUN) 
Albumin 
L-lactate dehydrogenase (LDH) 
Calcium 
Creatinine 
Sodium 
Potassium 
Glucose 
Total protein 
Chloride 
Bicarbonate 
Urinalysis 
Basic Urinalysis (dipstick, including macroscopic appearance, bilirubin, blood, color, glucose, 
ketones, leukocyte esterase, nitrite, pH, protein, specific gravity, urobilinogen) 
Other Laboratory Assessments 
• 
Troponin (serum) 
• 
IL-6 (to be analyzed at central laboratory) 
• 
D-dimer 
• 
Coagulation panel: International normalized ratio (INR) 
• 
Serum ferritin 
• 
Serum high sensitivity C-reactive protein (hsCRP) 
• 
Serum pregnancy test 
• 
SARS-COV-2 (COVID-19) test (RT-PCR via nasopharyngeal swab) 
 
 


 
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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a patient or clinical study subject, 
temporally associated with the use of study drug, whether or not considered related 
to the study drug. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study drug. 
 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline (see bullet below), 
considered clinically significant in the medical and scientific judgment of the 
Investigator (i.e., not related to progression of underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study drug administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
drug or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
 
Events NOT Meeting the AE Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the subject’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
subject’s condition. 


 
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• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
10.3.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
Results in death 
Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject 
was at risk of death at the time of the event. It does not refer to an event which hypothetically 
might have caused death, if it were more severe. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 


 
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Other situations: 
• Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the subject or may require medical or surgical drug to prevent one 
of the other outcomes listed in the above definition. These events should usually be 
considered serious. 
• Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. 
 
10.3.3. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• The Investigator will then record all relevant AE/SAE information in the CRF. 
• It is not acceptable for the Investigator to send photocopies of the subject’s medical 
records to the Sponsor or designee in lieu of completion of the AE/SAE CRF page. 
• There may be instances when copies of medical records for certain cases are 
requested by the Sponsor or designee. In this case, all subject identifiers, with the 
exception of the subject number, will be redacted on the copies of the medical 
records before submission to the Sponsor or designee. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
 


 
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Assessment of Severity 
AE severity will be evaluated by the Investigator in accordance with the NCI CTCAE v5. 0 1. 
For AEs that are not adequately addressed in the NCI CTCAE, the Investigator should classify 
the intensity of the AE using the following guidelines: 
Grade 1:  Mild:  Aware of sign or symptom, but easily tolerated; no intervention needed 
Grade 2:  Moderate:  Discomfort enough to cause interference with usual activity, minimal 
non-invasive intervention indicated (e.g., short course of antibiotics) 
Grade 3:  Severe:  Medically significant but not immediately life-threatening; 
incapacitation with inability to work or do usual activity 
Grade 4:  Life-threatening:  Refers to an event in which the subject was at risk of death at 
the time of the event, as judged by the Investigator; urgent/emergent drug indicated. 
This category should not be used for an event that hypothetically might have caused 
death if it were more severe. 
Grade 5:  Fatal outcome. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality  
• The investigator is obligated to assess the relationship between study intervention 
(investigational drug and/or study procedures) each occurrence of each AE/SAE 
according to the categories below. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• The investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
 
1 Please refer to the CTCAE v5 at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference
_5x7.pdf.  
Accessed April 19, 2019 


 
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• For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality in terms of 
whether the AE/SAE may be related to study intervention and/or study procedures. 
• There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it is 
very important that the investigator always assess causality for every event 
before the initial transmission of the SAE data to the Sponsor 
• The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality 
assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Causality Categories: 
Related: The AE follows a reasonable temporal sequence from the time of study drug 
administration and/or follows a known response to the study drug and cannot be reasonably 
explained by other factors such as the subject's clinical state or other therapeutic interventions, 
or concomitant drugs administered to the subject. 
Not related: The AE is clearly related to other factors such as the subject’s clinical state, 
therapeutic interventions or concomitant drugs administered to the subject. There is no 
temporal relationship between the study drug and event onset. This is especially so when an 
event occurs prior to the commencement of treatment with the study drug. 
 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
Sponsor or designee to elucidate the nature and/or causality of the AE or SAE as 
fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care 
professionals. 
• If a subject dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor with a copy of any postmortem 
findings including histopathology, if available. 
• New or updated information will be recorded in the originally completed CRF. 
• The Investigator will submit any updated SAE data to the Sponsor or designee 
within 24 hours of receipt of the information. 


 
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10.3.4. 
Reporting of SAEs 
SAE Reporting to Medical Monitor via an Electronic Data Collection Tool 
• The primary mechanism for initial reporting of an SAE to Sponsor or designee will 
be the electronic case report form (eCRF). 
• If the eCRF is unavailable, then the site will use the paper SAE data collection tool 
(see next section) in order to report the event within 24 hours. 
• The site will enter the SAE data into the eCRF as soon as it becomes available. 
• After the study is completed at a given site, the eCRF will be taken off-line to 
prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study subject or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the Medical Monitor by telephone. 
• Contacts for SAE reporting can be found in the relevant site manual. 
 
 


 
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10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
10.4.1. 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study drug, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
− Documented hysterectomy 
− Documented bilateral salpingectomy 
− Documented bilateral oophorectomy 
For individuals with permanent infertility due to a medical cause other than the above, (e.g., 
Mullerian agenesis, androgen insensitivity), Investigator discretion should be applied to 
determining study entry. 
Note: Documentation can come from the site personnel’s review of the subject’s medical 
records, medical examination, or medical history interview. 
Postmenopausal female 
• A postmenopausal state is defined as having had no menses for 1 year without an 
alternative medical cause. 
− A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 1 year of amenorrhea, confirmation with more than one FSH measurement is 
required. 
• Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 


 
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10.4.2. 
Contraception Guidance 
Male Subjects: 
Male subjects are eligible to participate if they agree to the following from informed consent, 
during the treatment period and for 90 days after the last dose of study drug: 
• Refrain from donating sperm 
PLUS, either: 
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
OR 
• Must agree to use contraception/barrier as detailed below 
− Agree to use a male condom 
Female Subjects: 
• A female subject is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
− Is not a woman of childbearing potential (WOCBP) 
OR 
− Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of < 1% per year), preferably with low user dependency (see table 
below), at least 28 days prior to Screening, during the intervention period, and for 
30 days after the last dose of study drug, and agrees not to donate eggs (ova, 
oocytes) for the purpose of reproduction during this period. The investigator 
should evaluate the effectiveness of the contraceptive method in relationship to the 
first dose of study drug. 
− A WOCBP must have negative serum pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 72 
hours prior to receiving the first administration of study drug. 
− If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum 
pregnancy test is required, and results must be negative. In such cases, the subject 
must be excluded from participation if the serum pregnancy result is positive. 
Contraceptive use by men or women should be consistent with local regulations regarding the 
use of contraceptive methods for those participating in clinical studies. 
Note: Ethinyl estradiol is the primary estrogen used in hormonal contraceptives. The progestin 
component consists of norethindrone, levonorgestrel, norgestrel, norethindrone acetate, 
ethynodiol diacetate, norgestimate, desogestrel, and drospirenone. As BLD-2660 is a weak 
CYP3A4 inducer, exposure to both the estrogen and progestin components in hormonal 
contraceptives may be decreased, resulting in an increased risk of pregnancy. As such, it is 
recommended that subjects who are on hormonal contraceptives for birth control should use an 


 
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alternate means of contraception (condoms, diaphragms, IUD, other barrier methods, sexual 
abstinence, etc.) during participation in the study. 
 
10.4.3. 
Collection of Pregnancy Information 
• In the event of a pregnancy, the female subject or partner of a male study subject 
should be referred to an obstetrician/gynecologist experienced in reproductive 
toxicity for further evaluation and counseling. 
• The Investigator will follow the female subject or partner of a male study subject until 
completion of the pregnancy 
• The Investigator must notify the Sponsor’s Medical Monitor of the outcome within 5 
days. 
• The Investigator will provide this information as a follow-up to the initial report. 
• If the outcome of the pregnancy meets the criteria for immediate classification as an 
SAE (e.g., spontaneous abortion [any congenital anomaly detected in an aborted fetus 
is to be documented], stillbirth, neonatal death, or congenital anomaly), then the 
Investigator should report it as such. 
• All neonatal deaths that occur within 30 days of birth are to be reported, without 
regard to causality, as SAEs. In addition, any infant death after 30 days that the 
Investigator suspects is related to the in-utero exposure to the study drug should also 
be reported. 
 


 
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10.5. 
Appendix 5: Cardiac Monitoring Protocol 
All troponin elevations and cardiac AEs and SAEs will be reviewed by the DMC. 
Subjects with elevated troponins will be questioned regarding occurrence of any cardiac 
symptoms. The symptoms will be evaluated by a study investigator and a consulting physician 
independent of the investigator team who will recommend whether any additional studies should 
be performed. In addition, during the evaluation period: 
1. Study drug could be withheld, at the discretion of the investigator 
2. Serum troponin, Creatine Kinase-Myocardial Band (CK-MB), myoglobin, 
comprehensive metabolic panel (including AST) will be obtained and 
echocardiogram and ECG performed and interpreted 
3. Detailed history of potential causes of troponin elevation should be obtained 
4. Additional work up will be initiated per the Investigator’s discretion and 
cardiology consultant 
If work up is negative, as determined by Investigator and/or Medical Monitor, no further action 
is required and, if the study drug had been stopped, it may be restarted. 
If work up is positive for a cardiac source, the DMC will review and determine whether the study 
drug should be permanently discontinued and advise on any next steps, if any. 
 


 
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10.6. 
Appendix 6: Abbreviations 
Abbreviation Term 
Description 
ACE-2 
Angiotensin-converting enzyme 2 
AE 
Adverse event 
ALT 
Alanine aminotransferase  
APACHE 
Acute physiology and chronic health evaluation 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate aminotransferase  
BCRP 
Breast cancer resistance protein 
BID 
Twice per day  
BUN 
Blood urea nitrogen  
CAPN 
Small molecule inhibitor of calpain  
CFR 
Case fatality rate 
CIOMS 
Council for International Organizations of Medical Sciences 
CMH 
Cochran–Mantel–Haenszel 
COVID-19 
Coronavirus disease 2019 
CRP 
C-reactive protein 
CRRT 
Continuous rental replacement technique 
CRS 
Cytokine release syndrome 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events  
CYP 
Cytochrome P450  
ECG 
Electrocardiogram  
ECMO 
Extracorporeal membrane oxygenation  
eCRF 
Electronic case report form 
EOS 
End of Study 
EOT 
End of Treatment  
ET 
Early termination  
EUA 
Emergency use authorization 
FAS 
Full analysis set 


 
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Abbreviation Term 
Description 
FiO2 
Fraction of inspired oxygen 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase  
GLP 
Good Laboratory Practice  
HC 
Hormonal contraceptives 
Hgb 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act  
HIV 
Human Immunodeficiency Virus  
hsCRP 
high sensitivity C-reactive protein  
IB 
Investigator’s brochure 
ICF 
Informed consent form  
IEC 
Independent Ethics Committees  
INR 
International normalized ratio  
IPF 
Idiopathic pulmonary fibrosis  
IRT 
Interactive Response Technology  
ITT 
Intent-treat Set 
IUD 
Intrauterine device 
JAKi 
Janus kinase inhibitor 
LAM 
Lactational amenorrhoea method  
LDH 
Lactate dehydrogenase  
LS 
Least square 
MAD 
Multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified intent-to-treat sect 
MMRM 
Mixed measures repeated model 
NEWS 
National Early Warning Score 
NGT 
Naso-gastric tube 
NOAEL 
No observed adverse effects level  


 
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Abbreviation Term 
Description 
NSAID 
Non-steroidal anti-inflammatory drug 
PaO2 
Partial pressure of oxygen 
PCR 
Polymerase chain reaction 
PK 
Pharmacokinetics  
PO 
Oral 
PP 
Per protocol 
PPAR 
peroxisome proliferator-activated receptor  
RBC 
Red blood cell 
SAD 
Single ascending dose 
SAE 
Serious adverse events  
SAP 
Statistical analysis plan  
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
siRNA 
Small interfering RNA 
SoA 
Schedule of Activities 
SOC 
Standard of care  
SpO2 
Peripheral capillary oxygen saturation 
SSNRI 
Selective serotonin and norepinephrine reuptake inhibitor 
SUSAR 
Suspected unexpected serious adverse reactions  
TB 
Tuberculosis 
TEAE 
Treatment emergent adverse event 
ULN 
Upper limit of normal  
WBC 
White blood cell count  
WOCBP 
Women of childbearing potential  


 
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10.7. 
Appendix 7: Protocol Amendment History 
Prior Amendments 
Blade has introduced the following modifications to Protocol Version 2.0. These changes are 
presented in order of appearance:  
Amendment 1, 23 April 2020 
Overall Rationale for the Amendment: 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
3.0 Objectives and endpoints 
• 
Reorganize objectives and endpoints 
• 
For oxygenation endpoints, added 
definition for medically fit for removal 
of oxygen 
• 
Changed mortality rate to be a secondary 
endpoint 
• 
Added Day 28 to relevant endpoints 
• 
Per FDA request 
 
1.1 Synopsis 
1.2 Schedule of Activities 
4.0 Study Design 
8.3.1 Time Period and 
Frequency of Collection of 
AEs 
• 
Extended the study follow-up to Day 28 
• 
Added 60 days post-study to collect 
mortality, safety data and forced vital 
capacity 
• 
Per FDA request 
 
5.1.1 Inclusion Criteria 
• 
Added oxygen requirements inclusion 
criteria 
• 
Per FDA request 
 
5.1.2 Exclusion Criteria 
• 
Modified supplement oxygen exclusion 
criteria 
• 
Added cross reference to the 
Concomitant Medication section of the 
protocol 
• 
Clarified excluded COVID therapies 
prior to study entry 
• 
Based on 
Investigator’s 
input 
• 
For clarity and 
safety measure 
 
6.6 Concomitant Therapy 
• 
Updated restricted medications section to 
include azithromycin 
• 
Clarified to consult with Sponsor’s 
Medical Monitor prior to prescribing 
chloroquine, hydroxychloroquine and 
azithromycin 
• 
Expanded section to include medications 
affected by potential interactions with 
BLD-2660 
• 
Per FDA request 
• 
Safety precaution 


 
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Section # and Name 
Description of Change 
Brief Rationale 
1.2 Schedule of Activities 
8.1.2 Oxygenation Measures 
• 
Clarified procedures for collecting 
oxygen saturation 
• 
Per Investigator 
feedback 
1.2 Schedule of Activities 
8.1.4 Clinical Status Ordinal 
Score 
• 
Changed to 6-point ordinal scale by 
collapsing ‘not hospitalized’ into 1 
category 
• 
Per FDA request 
8.1.6 Hospital Discharge 
Readiness Criteria 
• 
Clarified normal oxygen saturation 
criteria 
• 
Clarified oxygen supplementation status 
will be captured in the database 
• 
Per FDA request 
8.2.1 Physical examinations 
• 
Clarified text 
• 
For clarity 
1.2 Schedule of Activities 
8.4 Pharmacokinetics (PK) 
• 
Clarified that PK samples will also be 
collected after first naso-gastric tube 
(NGT) is inserted 
• 
To allow 
characterization 
of BLD-2660 
using NGT route 
of administration 
1.2 Schedule of Activities 
• 
Update visit window 
• 
Remove biomarker blood sampling at 
screening as well as INR, urinalysis and 
chest x-ray/CT on Day 21 
• 
Add overall survival check 
• 
Other updates as reflected above (e.g., 
adding Day 28) 
• 
To update per 
changes to 
protocol and to 
ensure 
consistency 
throughout 
protocol 
9 Statistical Consideration 
• 
Added azithromycin use to efficacy 
analyses 
• 
Updated to 6-point ordinal scale 
• 
Updated to reflect Day 28 as EOS 
• 
Revised interim analysis to include 
efficacy boundaries and sample size re-
estimation when 50% of subjects 
completed the study 
• 
Per FDA request 
General 
• 
Corrected typos, formatting, style 
• 
Aligned changes across protocol 
• 
Updated Abbreviation (Appendix 6) 
• 
For clarity and 
readability 
 
 
 
 


 
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11. 
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Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N 
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Ong KC, Ng AW, Lee LS, et al. 1-year pulmonary function and health status in survivors of 
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SAP_001.pdf: 
CONFIDENTIAL 
Statistical Analysis Plan [Version 3.0]
1
Statistical Analysis Plan  
Title Page 
Protocol Title: 
A Phase 2, Randomized, Double-blind, Placebo-controlled Study 
to Evaluate the Safety and Antiviral Activity of BLD-2660 in 
Hospitalized Participants with Recently Diagnosed COVID-19 
Compared to Standard of Care Treatment 
Protocol Number:  
B-2660-204 
Study Drug:  
BLD-2660 
Study Indications
Coronavirus disease 2019 (COVID-19) 
Sponsor Name: 
Blade Therapeutics, Inc.
Legal Registered 
Address: 
442 Littlefield Avenue,  
South San Francisco, CA 94080, United States 
Regulatory Agency 
Identifier Number(s): 
IND: 149130
Approval Date: 
 22 October 2020 
Version: 
3.0 
Confidentiality Notice 
This document contains confidential information of Blade Therapeutics, Inc. the contents of which must 
not be disclosed to anyone other than the study staff and members of the respective Institutional Review 
Board/Ethics Committee. 
The information in this document cannot be used for any purpose other than the evaluation or conduct of 
the clinical investigation without the prior written consent of Blade Therapeutics, Inc. 
 


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Statistical Analysis Plan [Version 3.0]
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Signature Page
Approvals:
Prepared by: Sponsor
 
 
Name Statistician: 
 
 
 
Brian Mangal, MSc.
Date: (dd/mmm/yyyy) 
Statistical Consultant
Approved by: Sponsor 
 
 
Name: 
Masoud Mokhtarani, MD
Date: (dd/mmm/yyyy) 
Title: 
Cheif Medical Officer
 


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Table of Contents
Statistical Analysis Plan ................................................................................................................1
Title Page ........................................................................................................................................1
Table of Contents...........................................................................................................................3
Version History ..............................................................................................................................5
1.
Introduction .....................................................................................................................7
1.1.
Objectives and Endpoints .................................................................................................7
1.2.
Study Design .....................................................................................................................8
2.
Statistical Hypotheses...................................................................................................10
3.
Sample Size Determination..........................................................................................11
4.
Analysis Sets..................................................................................................................13
5.
Statistical Analyses .......................................................................................................14
5.1.
General Considerations ...................................................................................................14
5.2.
Visit Windows ................................................................................................................14
5.3.
Missing Data, Outliers, and Pooling...............................................................................15
5.3.1. 
Missing Data...................................................................................................................15
5.3.2. 
Outliers ............................................................................................................................15
5.3.3. 
Pooling............................................................................................................................15
5.4.
Participant Disposition ....................................................................................................15
5.5.
Primary Endpoint(s) Analysis.........................................................................................16
5.5.1. 
Definition of Endpoint(s)................................................................................................16
5.5.2. 
Main Analytical Approach ..............................................................................................17
5.5.3. 
Sensitivity Analysis ........................................................................................................18
5.5.4. 
Supplementary Analyses .................................................................................................19
5.6.
Secondary Endpoint(s) Analysis.....................................................................................19
5.6.1. 
Key/Confirmatory Secondary Endpoint(s) .....................................................................19
5.6.2. 
Supportive Secondary Endpoint(s) .................................................................................19
5.7.
Tertiary/Exploratory Endpoint(s) Analysis ....................................................................20
5.8.
Safety Analyses...............................................................................................................21
5.8.1.
Extent of Exposure..........................................................................................................21
5.8.2. 
Adverse Events ...............................................................................................................21
5.8.3. 
Safety Labs......................................................................................................................22
5.8.4. 
Vital Sigs.........................................................................................................................22
5.8.5. 
12-Lead ECG ..................................................................................................................23
5.8.6. 
Physical Exam .................................................................................................................23
5.9.
Other Analyses ................................................................................................................23
5.9.1. 
Pharmacokinetic Analyses ..............................................................................................23
5.9.2. 
Pharmacodynamic Analyses ...........................................................................................23
5.9.3. 
Subgroup Analyses .........................................................................................................24
5.9.4. 
Demographics and Baseline Characteristics ...................................................................24
5.9.5. 
Medical History ..............................................................................................................24


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5.9.6.
Concomitant Medications...............................................................................................25
5.9.7. 
Compliance .....................................................................................................................25
5.10.
Interim Analyses .............................................................................................................25
6.
References......................................................................................................................29
 


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Version History 
This Statistical Analysis Plan (SAP) for study B-2660-204 is based on the protocol version 3.0 
amendment 2.0, dated May 8th, 2020.  
SAP Version 
Approval Date 
Change 
Rationale 
1.0 
30 August 2020 
Not Applicable 
Original version 
2.0
 
08 October 
2020 
 
Subjects who die or withdraw 
prior to observing clinical 
improvement should be 
censored at Day 28 instead of 
date of death or withdrawal 
Implemented change at the 
request of FDA.  FDA reviewed 
version 1.0 and provided 
comments on 22 September, 
2020 
All modeling was clarified to 
indicate that all covariates would 
be entered into the model at the 
beginning and the stepwise 
selection procedure would be 
used to assess inclusion of these 
covariates. 
For all models, corticosteroid use 
(yes vs no) was added as a 
potential covariate to include in 
the stepwise model selection 
process. 
In the analysis of the exploratory 
endpoint of proportion of 
subjects who are SARS-CoV-2 
virus free at Day 10/EOT or 
hospital discharge, whichever is 
sooner, subjects who 
die/withdraw from the study prior 
to Day 10/discharge will be 
classified as a non-responder 
instead of using their last known 
value. 


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For Poisson Regression models, 
if overdispersion exists, a 
negative binomial model will be 
used and a model where the 
option to adjust the standard 
errors using the scale parameter 
will not be run. 
Removed a number of 
secondary and exploratory 
efficacy analyses 
Based on the DSMB 
recommendation to not expand 
the study, a number of efficacy 
analyses were removed to 
preserve capital 
3.0 
22 October 
2020 
Added additional details on how 
to derive Fi02 values based on 
oxygen flow rates. 
 
 
Changed IL-6 sub-group analysis 
from > ULN to > median,  
eCRFs collected flow rate or 
Fi02.  Additional details on how 
to derive Fi02 were needed for 
programming. 
 
IL-6 values do not have normal 
ranges 


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1. 
Introduction 
This Statistical Analysis Plan (SAP) contains a more technical and detailed elaboration of the 
principal features of the analysis described in the protocol and includes detailed procedures for 
executing the statistical analysis. This SAP should be used in conjunction with the protocol.  If 
there are any discrepancies between the protocol and SAP, this SAP will prevail. Any deviations 
from this SAP that are implemented in the final analysis will be documented with sound clinical 
and statistical rationale in the Clinical Study Report (CSR). In the event of any changes to the 
primary endpoints or analyses, these changes will be documented through a protocol amendment, 
consistent with ICH E9. 
A separate document contains the table, figure and listing specifications and any example 
programming codes. 
 
1.1. 
Objectives and Endpoints 
Objectives
Endpoints 
Primary 
 To evaluate clinical benefit of 
BLD-2660 in hospitalized adults with 
recently diagnosed SARS-CoV-2 
infection
Time to recovery as defined by no longer 
requiring oxygen support or hospital 
discharge, whichever occurs first
 
 To evaluate improvement in 
oxygenation in hospitalized adults with 
COVID-19 treated with BLD-2660
 Change from baseline to Day 10 or hospital 
discharge, if sooner, in the ratio of 
peripheral hemoglobin oxygen saturation to 
fraction of inspired oxygen (SpO2/FiO2)
Secondary
To evaluate the safety and tolerability of 
BLD-2660 in the same population
Incidence of TEAEs and serious adverse 
events (SAEs)
 To evaluate improvement in Biomarkers 
 Change from baseline to Days 10/EOT, 14, 
21 and 28 in serum calprotectin 
 Additional efficacy outcomes 
 Time to hospital discharge readiness
 Proportion of participants reporting each 6-
point ordinal scale of the clinical status 
outcome assessment
Change from baseline to Days 10/EOT, 14, 
21 and 28 in IL-6 and D-dimer 


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Objectives
Endpoints 
Exploratory
Other efficacy outcomes
Proportion of participants who require 
mechanical ventilation after study entry
 
 To evaluate antiviral activity of 
BLD-2660 in the same population 
 Change from baseline in SARS-CoV-2 
viral load at Days 5, 10/EOT, 14, and 28
Other safety outcomes
Clinically relevant changes from baseline 
in electrocardiogram (ECG), and clinical 
laboratory values at each post baseline time 
point 
 Proportion of participants with clinically 
significant drug-related troponin elevations 
that have repeat elevation upon 
confirmatory testing as adjudicated by the 
DMC while continuing study drug during 
the 10-day treatment period
 To assess population pharmacokinetics 
(PK) characteristics of BLD-2660
 BLD-2660 plasma concentrations
1.2. 
Study Design 
This is a Phase 2 randomized, double-blind, placebo-controlled multicenter study designed to 
evaluate BLD-2660 as add-on to standard of care (SOC) therapy in hospitalized participants with 
recently diagnosed COVID-19 compared to SOC treatment.
The study will include a Screening period, a Treatment period, and a Follow-up period. 
After signing informed consent form (ICF), potential candidates who are hospitalized for
confirmed infection with SARS-CoV-2 will undergo additional screening procedures. 
On Day 1, eligible participants will be randomized in 2:1 ratio to one of 2 treatment groups, 
active or control, as shown in Table 1. Randomization will be stratified by remdesivir at study 
entry. All participants will receive study drug in combination with SOC over 10 days (through 
Day 10/end of treatment) or until hospital discharge, if sooner. Participants will be followed for 
at least 18 days after the last dose of study drug on Days 14, 21 and 28. Participants will be 
contacted 60 days post-study to collect information on mortality and forced vital capacity (FVC). 
 


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Table 1: 
Treatment Groups 
Treatment 
Group
Dose Level, Schedule and Route of 
administration 
Number of 
participants 
Active
BLD-2660 900 mg twice per day (BID), oral + SOC
80
Control
Matching placebo, BID, oral + SOC 
40
 
For each participant, the study duration for each study period is expected to last as follows:
Study Period
Duration 
Screening period  
Up to 3 days
Treatment period 
10 days 
Treatment Follow-up period 
18 days
Post study follow-up period 
32 days
Interim analyses are planned when approximately 25%, 50% and 75% of participants have 
completed the study for the purpose of reviewing safety data and for the purpose of early 
stopping for efficacy or futility.  At the 50% interim analyses, the sample size may be increased. 
The final analysis will occur once the last participant enrolled completes the end of study follow-
up visit.  Data from the post study follow-up visit regarding FVC will be included in the final 
databased after the final analysis has been completed.  
 


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2. 
Statistical Hypotheses 
Two primary statistical hypotheses will be tested. The study will be declared a success if either
of the hypotheses are statistically significant. As this is a phase 2 study, no adjustment for 
multiplicity will be made for having two co-primary hypotheses. 
Hypothesis 1: Will evaluate clinical benefit in hospitalized adult participants with recent SARS-
CoV-2 infection. The primary endpoint is time to recovery as defined by no longer requiring 
oxygen support or hospital discharge, whichever occurs first. The null and alternative hypotheses 
are:
H0 (null): Hazard Ratio (BLD2660/Placebo) 1, indicating that treatment does not
reduce the time to recovery compared to placebo control
 
H1 (alternative): Hazard Ratio (BLD2660/Placebo) < 1, indicating that treatment does 
reduce the time to recovery compared to placebo control
 
Hypothesis 2: Will evaluate improvement in oxygenation in hospitalized adult participants with 
recent SARS-CoV-2 infection at the time of discharge, or Day 10, if they are still hospitalized. 
The primary endpoint is the change from baseline to Day 10 or hospital discharge if sooner in the 
ratio of hemoglobin oxygen saturation to inspired oxygen fraction (SpO2/FiO2). The null and 
alternative hypotheses are: 
 H0 (null): Mean Treatment Difference (BLD2660 minus Placebo)  0, indicating that 
treatment does not improve the ratio of hemoglobin oxygen saturation to inspired oxygen 
fraction (SpO2/FiO2) at the time of discharge or Day 10 if they are still hospitalized,
compared to placebo control 
 
 H1 (alternative): Mean Treatment Difference (BLD2660 minus Placebo) > 0, 
indicating that treatment does improve the ratio of hemoglobin oxygen saturation to 
inspired oxygen fraction (SpO2/FiO2) at the time of discharge or Day 10 if they are still 
hospitalized, compared to placebo control
 


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3. 
Sample Size Determination 
Time to clinical improvement
A randomized, double-blind, placebo-control study evaluating remdesivir in 1063 hospitalized 
participants with COVID-19 reported 606 recoveries, with a median time to recovery of 11 days 
and 15 days in the remdesivir and placebo groups, respectively (remdesivir package insert).  
Recovery was defined as the first day on which the participant satisfies one of the following 3 
categories from the ordinal scale: 1) Hospitalized, not requiring supplemental oxygen - no longer 
requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home 
oxygen; 3) Not hospitalized, no limitations on activities
(https://clinicaltrials.gov/ct2/show/NCT04280705).
Assuming the median time to clinical improvement, defined as no longer requiring oxygen 
support or hospital discharge whichever occurs first, will be 12-15 days in the placebo group, 
and that at least 75 of the planned 120 participants enrolled meet the clinically improved criteria, 
the study will have at least 80% power to detect a 50% reduction in the time to clinical 
improvement, (i.e., hazard ratio[BLD2660/Placebo] of 0.5) with a two-sided 5% significance 
level.  
 
The total number of events (d) is estimated based on the following formula 
=
(
/ +
)
(1
)
where 
/ and 
 are the value from a standard normal distribution,  is the proportion of 
participants randomized to control, 1
 is the proportion of participants randomized to active 
and  is the inverse of the log hazard ratio, as we are modeling improvement.    The total number 
of participants is then calculated as the number of events divided by the probability of observing 
the event during the study.  For this study 
 
1/log(0.5) and the 
probability of observing an event is 0.60.
Change from baseline to Day 10 or hospital discharge if sooner in the ratio of hemoglobin 
oxygen saturation to inspired oxygen fraction (SpO2/FiO2). 
A prospective observational cohort study of non-intubated moderate to severe ARDS participants 
(Ding, 2020) reported the partial pressure of oxygen (PaO2)/FiO2 ratio for 10 participants, which 
gave a mean and standard deviation of 147 ± 46 mm Hg. Converting to a Sp02/FiO2 ratio gives a 
mean and standard deviation of 192 ± 39 using the equation reported by Rice et al. (2007) (Rice, 
2007). 
Assuming a standard deviation of 40 in the SpO2/FiO2 ratio, a sample size of 120 participants (80 
active, vs 40 control) will provide approximately 90% power to detect a treatment difference in 
the SpO2/FiO2 ratio of 25 or greater, based on a two-sample t-test with a two-sided 5% 
significance level. 


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The total number of participants (N) is estimated based on the following formula 
= (
/ +
)
(1
)
where 
/ and 
are the value from a standard normal distribution, 
is the proportion of 
participants randomized to control, 1
 is the proportion of participants randomized to active 
and  is the standardized effect size we wish to detect
1
0.625 (i.e., 25/40). 
 
 


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4. 
Analysis Sets 
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All randomized participants 
Full Analysis 
Set (FAS)
All randomized participants who receive at least one dose of study drug. 
This population will be used for all efficacy analyses 
Modified Intent 
to Treat (MITT)
All randomized participants who receive at least one dose of study drug 
and one post baseline assessment of the SpO2/FiO2 ratio. This population 
will be used for the primary and secondary endpoints related to 
improvement in SpO2/FiO2 ratio.
Per Protocol 
Analysis Set 
(PP) 
All randomized participants who receive at least 6 doses of study drug 
without any major protocol violations that would impact the assessment 
of the primary efficacy endpoints. This population will be used for 
efficacy analyses of the primary efficacy endpoints 
Safety Analysis 
Set
All enrolled participants who receive any study drug 
PK Analysis Set
All enrolled participants who receive any study drug and have plasma 
concentration data 


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5. 
Statistical Analyses 
5.1.
General Considerations
The following is a list of general reporting conventions: 
 
Percentages will be based on the number of participants in the analysis set unless otherwise 
indicated. 
 
Categorical variables will be summarized using counts (n) and percentages (%) and will be 
presented in the form of n (%). 
 
Percentages will be reported to 1 decimal place.   
 
Continuous data will be summarized using the mean, standard deviation (SD), median, minimum, 
25th and 75th percentiles, maximum, and number of participants with data.  
 
Means and medians will be reported at 1 more significant digit than the precision of the data.  
Standard deviations and confidence intervals will be reported at 2 more significant digits than the 
precision of the data.  Quartiles, minima and maxima will be reported to the same level of 
precision as the original observations.  
 
The median will be reported as the average of the 2 middle numbers if the dataset contains even 
numbers. 
 
No preliminary rounding should be performed; rounding should only occur after analysis.  To 
up. 
 
All p-values will be 1-sided and reported to 3 decimal places (e.g., 0.XXX).  Values < 0.001 will 
be reported as < 0.001. 
 
If departures from these general conventions are present in the specific evaluations sections of this SAP, 
then those conventions will take precedence over these general conventions.  
5.2. 
Visit Windows 
The following table outlines the analysis visits that data will be mapped to for analysis of 
efficacy, safety and pharmacodynamics data collected during the study. If after mapping, 
multiple data points share the same analysis visit, the data point closest to the expected study 
visit will be used.  If there is a tie, the earlier of the visits will be used.
Study Visit
Analysis Visit 
Analysis Window
Screening
Screening  
0 
Baseline 
Baseline 
0
Days 1 – 9
Days 1 – 9 
0 


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Day 10 
Day 10
± 1 day 
Day 14 
Day 14
± 2 day 
Day 21
Day 21
± 3 day
Day 28/EOS
Day 28
± 3 day 
Post Study Visit
Day 88
± 10 day 
If Baseline is missing then screening data should be mapped to baseline for analysis purposes.
5.3. 
Missing Data, Outliers, and Pooling  
5.3.1. 
Missing Data 
As the rules for imputation of missing data will differ by endpoint, details on imputation rules for 
missing data are provided with the description of the endpoint and analytical methods for 
analysis.  
5.3.2. 
Outliers
All reported values will be included in the analyses.   
5.3.3. 
Pooling
Based on the total sample size of the study, and the anticipated number of sites, participants will be 
pooled across all sites, for all analyses. 
5.4. 
Participant Disposition 
A clear accounting of disposition, including the numbers and percentages of participants 
screened, randomized, completed treatment and completed post treatment follow-up and 
completed post study follow-up, will be reported overall and by treatment group.  In addition, the 
primary reasons for early discontinuation of study intervention during the treatment period and 
early study discontinuation will be reported overall and by treatment group.  A graphical 
representation of participant disposition, by treatment group, will be produced using a
CONSORT flow diagram. 
A summary of the number of participants included in each analysis set (i.e., FAS, MITT, PP, 
Safety, PK) will be provided overall and by treatment group.   Participants could be excluded 
from an analysis set for more than one reason.  All participants excluded from an analysis set 
will be listed with the reason(s) for exclusion. 


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A tabular summary of all major protocol violations will be provided by treatment group and 
overall.  Major protocol violations will be classified as follows: 
Violations of inclusion and exclusion criteria 
 
Receiving the wrong study intervention  
 
Non-compliance with study intervention. A participant is defined as non-compliant if the 
participant took < 80% of the study intervention. 
 
Taking a prohibited medication  
 
Other 
As participants can report multiple protocol violations, they will be included for each observed 
violation (i.e., these categories will not be mutually exclusive).
5.5. 
Primary Endpoint(s) Analysis 
5.5.1. 
Definition of Endpoint(s)
Time to Clinical Improvement
Time to clinical improvement will be derived as the earliest date of either not requiring oxygen 
support or hospital discharge, minus the date of randomization.  Participants who die or 
withdraw from the study prior to observing clinical improvement will be censored on day 28.  
Participants will be censored on day 28, if clinical improvement has not been observed by this 
time point.  If a participant discontinues study drug early, they will still be assessed for this 
endpoint until one of the above criteria (i.e., clinical improvement, death/withdrawal, day 28 visit 
without clinical improvement) is met.
Change from baseline to Day 10 or hospital discharge if sooner, in the ratio of hemoglobin 
oxygen saturation to inspired oxygen fraction (SpO2/FiO2) 
SpO2 and FiO2 will be collected twice daily while a participant is in hospital. The average of the 
twice daily SpO2/FiO2 ratio will be used for all derivations. If only a single ratio is collected, 
that single ratio for that day will be used.  Once discharged, only a single ratio will be used in the 
derivations. Participants who are discharged prior to day 10, will have their end of treatment 
assessment, mapped to day 10. 
The SpO2 value will be recorded on the eCRF. To derive the FiO2 value, oxygen flow rate as 
collected on the eCRF will be converted to FiO2 using the following table. 


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Method
O2 Flow rate (l/min)
Estimated FiO2 (%)
Nasal cannula
1
24
2
28
3
32
  
4 
36
  
5 
40
  
6 
44
Nasopharyngeal catheter 
4 
40
  
5 
50
6
60
Face mask (Simple Mask)
5
40
6-7
50
  
7-8 
60
Face mask with reservoir (non-
rebreather face mask)
<6
Follow nasal cannula
6 
60
  
7 
70
  
8 
80
  
9 
90
  
10
95
  
>10 
100
Venturi Mask
4 
28
 
6 
31
 
8 
40
 
10
50
The change from baseline to Day 10 or hospital discharge if sooner, in the ratio of hemoglobin 
oxygen saturation to inspired oxygen fraction (SpO2/FiO2) will be derived by taking the
SpO2/FiO2 ratio at the earlier of day 10 or hospital discharge and subtracting the baseline 
SpO2/FiO2 ratio. Missing data will be assumed to be missing at random and this endpoint will 
be analyzed using likelihood-based methods, therefore missing data will be maintained as 
missing.  
5.5.2.
Main Analytical Approach
Time to Clinical Improvement
Time to clinical improvement will be presented by treatment group, using the Kaplan-Meier 
estimator.  A Cox proportional hazards model with treatment, remdesivir strata (yes/no) and age
(years) as covariates will be used to estimate the hazard ratio and compare treatment groups.
Additional covariate’s (i.e., Country (USA, Brazil), Chloroquine or hydroxychloroquine use (yes 
vs no), HIV anti-viral drug use (yes vs no), corticosteroid use (yes vs no) and azithromycin use 
(yes vs no)) may also be included if these are found to influence the treatment effect, based on 
observing p-value of < 0.05 for the covariate, after adjusting for the others in the model. The 


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stepwise selection procedure will be used to assess the additional covariates. In addition, the log 
rank test and stratified log rank test, with remdesivir as the strata, will be provided. The primary 
analysis will be conducted using the FAS.   
 
Change from baseline to Day 10 or hospital discharge if sooner, in the ratio of hemoglobin 
oxygen saturation to inspired oxygen fraction (SpO2/FiO2)
The primary efficacy endpoint of change from baseline to Day 10 or hospital discharge if sooner, 
in the ratio of hemoglobin oxygen saturation to inspired oxygen fraction (SpO2/FiO2) will be 
analyzed using a mixed model for repeated measures (MMRM).  The Kenward-Roger method 
will be used to calculate the denominator degrees of freedom for the test of fixed effects and 
adjusted standard errors. The model will contain treatment, time and the treatment by time 
interaction as fixed effects and baseline score, age (years), corticosteroid use (yes vs no)   and 
remdesivir strata as covariates. If age and/or corticosteroid use are not significant at the 5% level, 
they will be removed from the model. As the follow-up visit schedule for each participant will be 
variable, the following timepoints will be used; Day 1, Day 2, Day 3, Day 4, Day 5 and Day 
10/Discharge.  Additional time points (e.g., Days 6-9) may be included if most participants are 
not discharged prior to Day 10.. An unstructured covariance matrix will be assumed to model the 
within-participant errors. This variance-covariance matrix will be estimated across treatment 
groups. However, if there is a convergence problem with the unstructured covariance matrix, 
then alternative covariance structures will be examined (heterogeneous Toeplitz structure, 
Compound Symmetry) and the one with the best fit as determined by the Akaike information 
criteria (AIC) (i.e., smallest AIC value) will be used. The least squares means (LS-means) for 
each treatment, LS-means treatment difference and corresponding confidence interval (CI) for 
the LS-means difference and p-value for the treatment difference, will be reported at the 
Day10/Discharge timepoint.  
The primary analysis will be conducted using the FAS. 
 
5.5.3.
Sensitivity Analysis
Time to Clinical Improvement
The following sensitivity analyses will be conducted: 
1) The primary analysis will be repeated for the PP analysis set.   
Change from baseline to Day 10 or hospital discharge if sooner, in the ratio of hemoglobin 
oxygen saturation to inspired oxygen fraction (SpO2/FiO2) 
The following sensitivity analyses will be conducted: 
1) The primary analysis will be repeated for the MITT analysis set.   
2) The primary analysis will be repeated for the PP analysis set.   


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Depending on the amount of missing data, additional sensitivity analyses may be needed.  If 
these are needed, they will be documented in the CSR.
5.5.4. 
Supplementary Analyses
None.
5.6. 
Secondary Endpoint(s) Analysis 
5.6.1.
Key/Confirmatory Secondary Endpoint(s)
Change from baseline in serum calprotectin 
Both the observed value and the change from baseline value will be summarized. Participants 
who are discharged prior to day 10, will have their end of treatment assessment, mapped to day 
10.
To compare the change from baseline over time a MMRM model will be used. Missing data will 
be assumed to be missing at random and maintained as missing. The Kenward-Roger method 
will be used to calculate the denominator degrees of freedom for the test of fixed effects and 
adjusted standard errors. The model will include baseline value as a covariate, treatment, visit
and visit-by-treatment interaction terms as categorical fixed effects, and participant as a random 
effect. An unstructured covariance matrix will be assumed to model the within-participant errors.
This variance-covariance matrix will be estimated across treatment groups. However, if there is a 
convergence problem with the unstructured covariance matrix, then alternative covariance 
structures will be examined (heterogeneous Toeplitz structure, Compound Symmetry) and the 
one with the best fit as determined by the Akaike information criteria (AIC) (i.e., smallest AIC 
value) will be used. The least squares means (LS-means) for each treatment, LS-means treatment 
difference and corresponding confidence interval (CI) for the LS-means difference and p-value 
for the treatment difference, will be reported at each visit. For each parameter, a plot of the LS-
means (and 95% CI), over time and by treatment group, will be produced. 
5.6.1.1. 
Sensitivity Analysis 
None
5.6.1.2. 
Supplementary Analyses
None
5.6.2. 
Supportive Secondary Endpoint(s) 
 
Time to hospital discharge readiness


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Time to hospital discharge readiness will be derived as the date of discharge readiness minus the 
date of randomization.  Participants who die/withdraw from the study, prior to discharge, will be 
censored at day 28.  Participants still not ready for hospital discharge at day 28 will be censored 
at day 28.  This endpoint will be analyzed using the same approach as the primary endpoint of 
time to clinical improvement. 
 
 
Proportion of participants reporting each 6-point ordinal scale of the clinical status outcome 
assessment at Days 10/EOT, 14, 21 and 28
The frequency and proportion of participants reporting each score will be reported by treatment 
group.  Participants who are discharged prior to day 10, will have their end of treatment 
assessment, mapped to day 10.  The difference in distributions will be compared between 
treatment groups using a Cochran-Mantel-Haenszel (CMH) test with Modified ridit scores and 
stratified by Country (USA, Brazil), age 
, corticosteroid use (yes vs no)  and 
remdesivir use (yes vs no). 
  
 
 
5.7. 
Tertiary/Exploratory Endpoint(s) Analysis 
The following exploratory endpoints will be analyzed using the FAS without adjustment for 
multiplicity.
Proportion of participants requiring mechanical ventilation after study entry 
The frequency and proportion of participants will be reported by treatment group.  The 
difference between treatment groups will be compared using a Cochran-Mantel-Haenszel (CMH) 
test stratified by Country (USA, Brazil), age
, corticosteroid use (yes vs no) and 
remdesivir strata (yes, no). The common risk difference and two-sided 95% stratified Newcombe 
confidence interval will be reported.  The strata will be weighted using Mantel-Haenszel 
weights. 
 
Change from baseline in SARS-CoV-2 viral load at Days 10/EOT, 14, 21 and 28
The change from baseline to each of days 5, 10, 14, 21 and 28 in the SARS-CoV-2 viral load will 
be derived by taking the SARS-CoV-2 viral load at the post baseline timepoint (i.e., Days 10, 14, 
21 and 28) and subtracting the baseline SARS-CoV-2 viral load.  Participants who are 
discharged prior to day 10, will have their end of treatment assessment, mapped to day 10.  
Missing data will be assumed to be missing at random and this endpoint will be analyzed using 
likelihood-based methods, therefore missing data will be maintained as missing.  The change 
from baseline to each of days 5, 10, 14, 21 and 28 in the SARS-CoV-2 viral load will be 


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analyzed using a mixed model for repeated measures (MMRM) approach as outlined for the co-
primary endpoint of change from baseline in SpO2/FiO2 ratio. The data may be log transformed 
prior to analysis if the assumptions of normality are violated.  For values below the limit of 
quantification, half the value between 0 and the limit of quantification will be used.  This 
analysis will only be conducted for patients who are positive at baseline based on PCR testing. 
 
 
5.8. 
Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set. Missing data will be 
maintained as missing, unless otherwise specified.  All safety analyses will be descriptive in 
nature. 
5.8.1. 
Extent of Exposure
Duration of study drug exposure, defined as the number of days between the date of first dose 
following randomization and the date of the last dose, will be summarized by treatment group.  
Duration will be calculated as date of last dose – date of first dose + 1.   
In addition, the number and proportion of participants with study drug exposure of 0-3, 4, 5, 6, 7 
and 8-10 days will be summarized by treatment group 
5.8.2. 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  All AEs that occur on or after the date of first dose of study intervention will be 
considered Treatment Emergent Adverse Events (TEAEs), and will be summarized using 
frequency counts and percentages, with the number of participants in the safety set used as the 
denominator. 
Summaries of TEAEs will be presented by treatment group, and overall, using the MedDRA 
level hierarchy (system organ class and preferred term) as follows:
Overall TEAEs (i.e., regardless of intensity or relationship to treatment)
TEAEs by NCI CTCAE intensity grade (Grade 1, 2, 3, 4, 5)
TEAEs by relationship to study medication (related, not related)
TEAEs leading to permanent discontinuation of study medication (i.e., action taken is drug 
withdrawn)
TEAEs leading to permanent discontinuation of study medication (i.e., action taken is drug 
withdrawn) by relationship to study medication
Serious TEAEs (SAEs)
SAEs by relationship to study medication (related, not related)


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Unless otherwise specified, at each level of summarization a participant will be counted once if 
they reported one or more events at that level of summarization.  If more than one occurrence of 
an event is reported, the event of the worst intensity or the worst-case relationship assessment 
will be summarized.
In the case of an incomplete AE start date, determining if an AE is treatment emergent will be 
based on the following rules. If the day is missing and the month and year of an onset date are
provided and on or after the date of randomization, the following rules will be applied. 
 If month/year of the onset date is on or after the month/year of randomization, the AE 
will be considered treatment emergent. 
 If month/year of the onset date is equal to the month/year of randomization, and the end 
date is present, the end date will be used to determine when the AE started. If the end 
date is on or after randomization, the AE will be considered treatment emergent; 
otherwise, if the AE stopped before randomization, then it will not be considered 
treatment emergent. 
 If month/year of the onset date is equal to the month/year of randomization, and the end 
date is a partial date, the AE will be considered treatment emergent. 
 If, despite implementing the above conventions, the onset date of the AE cannot be 
placed before, on, or after randomization, then the event will be considered treatment 
emergent.
5.8.3. 
Safety Labs 
This study will be using local labs instead of central labs.  Descriptive summary statistics of the 
observed values and change from baseline values for hematology, chemistry and urinalysis data 
at screening, baseline and each post-baseline visit (i.e., Day 5/Discharge, Day 10/Discharge, 14, 
21 and 28) will be presented by treatment group.  Boxplots will be used to display the
distribution of the observed values over time, by treatment group.  
Participants with clinically significant values for any safety labs are to be reported as an AE and 
therefore clinically significant laboratory findings will be interpreted from the AE summaries. 
A listing of participants with clinically significant drug-related troponin elevations that have repeat 
elevation upon confirmatory testing as adjudicated by the DMC while continuing study drug during 
the 10-day treatment period will be provided.
5.8.4. 
Vital Sigs 
Descriptive summary statistics of the observed values for blood pressure (systolic and diastolic), 
heart rate, temperature and respiratory rate data collected at screening, baseline and post-baseline 
visits will be presented by treatment group. As temperature is collected twice daily while a 
participant is hospitalized, the average of the daily measurements will be used. Boxplots will be 


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used to display the distribution of the observed values over time, using all post baseline 
assessments, by treatment group.  
Participants with clinically significant values for any vital signs are to be reported as an AE and 
therefore clinically significant vital sign findings will be interpreted from the AE summaries.
 
5.8.5. 
12-Lead ECG 
Descriptive summary statistics of the observed values for 12-lead ECG data at screening, 
baseline and each post-baseline visit (i.e., Day 5/Discharge, Day 10/Discharge, 14, 21 and 28) 
will be presented by treatment group.  Boxplots will be used to display the distribution of the 
observed values over time, by treatment group.  
Participants with clinically significant values for any 12-lead ECG findings are to be reported as 
an AE and therefore clinically significant 12-lead ECG findings will be interpreted from the AE 
summaries. 
 
5.8.6. 
Physical Exam 
A complete physical exam is planned for screening and day 10.  A limited physical exam is 
planned for baseline, day 5, 14, 21 and 28.  
At each time point, findings that are both abnormal and clinically significant will be summarized 
using frequency counts and percentages, with the number of participants in the safety set used as 
the denominator.  
5.9. 
Other Analyses 
5.9.1. 
Pharmacokinetic Analyses
BLD-2660 plasma concentrations collected on Day 5 pre-dose and 1-2 hours post dose will be 
summarized using descriptive statistics, by time point.  
Pharmacokinetic parameters may be estimated using a population PK approach.  Details of this 
analysis will be provided in a separate analysis plan. 
5.9.2. 
Pharmacodynamic Analyses 
The following pharmacodynamic parameters will be summarized using descriptive statistics, by 
time point and treatment group: 
 IL-6 
 D-Dimer 


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Both the observed value and the change from baseline value will be summarized. Participants 
who are discharged prior to day 10, will have their end of treatment assessment, mapped to day 
10. 
To compare the change in these parameters over time a MMRM model will be used. Missing 
data will be assumed to be missing at random and maintained as missing. The Kenward-Roger 
method will be used to calculate the denominator degrees of freedom for the test of fixed effects
and adjusted standard errors. The model will include baseline value as a covariate, treatment, 
visit and visit-by-treatment interaction terms as categorical fixed effects, and participant as a 
random effect. An unstructured covariance matrix will be assumed to model the within-
participant errors. This variance-covariance matrix will be estimated across treatment groups. 
However, if there is a convergence problem with the unstructured covariance matrix, then 
alternative covariance structures will be examined (heterogeneous Toeplitz structure, Compound 
Symmetry) and the one with the best fit as determined by the Akaike information criteria (AIC) 
(i.e., smallest AIC value) will be used. The least squares means (LS-means) for each treatment, 
LS-means treatment difference and corresponding confidence interval (CI) for the LS-means 
difference and p-value for the treatment difference, will be reported at each visit. For each 
parameter, a plot of the LS-means (and 95% CI), over time and by treatment group, will be 
produced. 
5.9.3. 
Subgroup Analyses 
The following sub-groups will be examined for the primary endpoints.  Results will be displayed 
in both tabular form and graphical form using a forest plot. 
 
 
 Gender (male vs female) 
 Remdesivir Use within 24 hours of Randomization (yes vs no) 
 Country (USA, Brazil) 
 Corticosteroid Use (e.g., Dexamethasone) (yes vs no) 
 Patients with a positive PCR test at baseline vs not positive. 
 Patients with IL-
median at baselin
median 
5.9.4. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment group for the FAS 
set, by treatment group and overall, using descriptive statistics.  No statistical hypothesis tests 
will be performed.   
5.9.5. 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
and summarized by system organ class (SOC) and preferred term for each treatment group, and 
overall. At each level of summarization, a participant is counted once if he/she reported one or 
more medical history terms at that level. No statistical hypothesis tests will be performed.   


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5.9.6. 
Concomitant Medications 
Concomitant medications are those that are taken at any time after the first dose of study 
medication. 
If the start day of a medication is missing, then if the month and year of the start date are on or 
after the date of randomization, the following rules will be applied:
 If month/year of the stat date is equal or after the month/year of the date of 
randomization, the medication will be considered concomitant; 
 If month/year of the start date is equal to the month/year of the date of randomization, 
and the end date is present, the end date will be used to determine if the medication 
stopped prior to randomization or after. If the end date is after, the medication will be 
considered concomitant; otherwise, if the medication stopped prior, then it will be 
considered to be prior; 
 If month/year of the start date is equal to the month/year of the date of randomization, 
and the end date is a partial date, the medication will be considered concomitant; 
 If, despite implementing the above conventions, the start date of the medication cannot be 
placed before, on, or after randomization, then the medication will be considered 
concomitant. 
 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary and summarized by drug class (ATC Level 3) and preferred term for each treatment 
group.  The summaries will present the number and percentage of participants using each 
medication by treatment group and overall. Participants may have more than one medication per 
drug class or preferred term. At each level of summarization, a participant is counted once if 
he/she reported one or more medications at that level. No statistical hypothesis tests will be 
performed.   
 
5.9.7. 
Compliance 
Compliance will be calculated and summarized by treatment group. Compliance will be 
calculated as 100× (total number of capsules taken / total number of capsules expected to be 
taken).  The total number of capsules taken is recorded on the eCRF. The number of expected 
capsules taken will be calculated as the duration of dosing (last dose date minus first dose date, 
plus 1) multiplied by 12.  For example, if a participant is dosed for 10 days the expected number 
of capsules taken is 120. 
5.10. 
Interim Analyses  
The study originally planned interim analyses at approximately 25%, 50% and 75% of 
participants completing the trial.  Due to rapid enrollment, only a single interim analysis was 
conducted, at the time when enrollment had completed (and ~50% of the patients had completed 
the trial).  This interim analysis was not used to stop the trial early for efficacy or futility, as 
enrollment had already completed, and occurred at a scheduled safety review by the independent 


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DMC.  This interim was for the purpose of ensuring safety and included efficacy data to assess 
the risk/benefit.
After the last patient has completed their Day 10 assessment, but prior to final data base lock, an 
interim analysis will be conducted for the purpose of BLADE to begin Phase 3 planning.  Blade 
plans to amend the current protocol to include a second part that would be a Phase 3 trial.  As 
this is a COVID-19 study and there is an immediate public need for effective therapies, BLADE
feels amending the protocol to adopt this second Phase 3 part of the study will significantly 
reduce the start-up time required to initiate the independent phase 3 (part 2 of the study) study by 
4-6 months.   This approach was communicated to FDA on 11-September 2020, and the sponsor 
did not receive any objections to this approach.   The Phase 3 portion will be analyzed separately 
from the Phase 2 portion.   
 
The original interim analysis plans for the Phase 2 portion of the study were as follows.  An 
interim analysis is planned when approximately 25%, 50% and 75% of participants have 
completed the study for the purpose of early stopping for efficacy or futility.  Based on the 
enrollment rates, one or more of these planned interim analyses may occur earlier in time or may 
not occur at all.   
The Lan-DeMets spending function analog of the O’Brien-Fleming boundaries will be used to 
monitor each of the primary endpoints as a guide for the DMC for an overall one-sided type-I 
error rate of 2.5%, for each endpoint.   At the time of the planned interim analyses (when 
approximately 25%, 50% and 75% of participants have completed the study), the amount of 
information (i.e., information rate) for each primary endpoint will be different, and therefore 
each endpoint will have a different critical value to determine if the study should be stopped 
early for efficacy. For the primary endpoint of change from baseline in SpO2/FiO2 ratio the 
interim analyses will occur when approximately, 30, 60, and 90 participants (information rate 
.25, .5 and .75) complete the study. For the primary endpoint of time to clinical improvement the 
amount of information is based on the observed number of events 
 and the 
information rate at the time of the interim analyses will depend on the observed number of events 
at that time (example if there are only 15 events observed at the first planned interim, the 
information rate 
.  The following plot provides the critical 
value boundaries based on the O’Brien-Fleming Lan-DeMets spending function. 
 


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Conditional power will be used as an additional guide to the DMC to assess futility. Conditional 
power allows computation of the probability of obtaining a statistically significant result by the 
end of the study given the data accumulated thus far. If the conditional power is less than 20% 
based on the observed effect size, for both primary endpoints, consideration will be given to 
stopping the study.
The conditional power for each primary endpoint will be calculated as,
where z1 is the observed Wald test statistic at the interim, n2 -tilde is the planned sample size for 
stage 2, n1 is the sample size for stage 1, and n2 is the cumulative planned sample size (i.e., n2
n1 + n2 -tilde) and z is the value from the inverse normal
At the interim analysis when approximately 50% of the participants have completed the study, a 
sample size re-estimation step will occur using the promising zone approach (Mehta and Pocock, 
2011) and method of Chen, DeMets and Lan, based on the observed effect size at this interim 
analysis. The promising zone is defined as a conditional power of between 50% and 80%. If the 
conditional power falls into this region the sample size may be increased to raise the conditional 
power to 80%.


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The study will not stop enrolment awaiting these DMC reviews, though the DMC may 
recommend temporary or permanent cessation of enrolment based on their safety reviews. 
A separate unblinded statistical team will prepare the above information for the DMC to review 
and make recommendations to the Sponsor.  The following efficacy endpoints will be 
summarized at each interim analysis using the FAS: 
 
Objectives
Endpoints 
Primary
To evaluate clinical benefit of 
BLD-2660 in hospitalized adults with 
recently diagnosed SARS-CoV-2 
infection 
 Time to recovery as defined by no longer 
requiring oxygen support or hospital 
discharge, whichever occurs first 
 
 To evaluate improvement in 
oxygenation in hospitalized adults with 
COVID-19 treated with BLD-2660
Change from baseline to Day 10 or hospital 
discharge, if sooner, in the ratio of 
peripheral hemoglobin oxygen saturation to 
fraction of inspired oxygen (SpO2/FiO2)
Secondary
  
 Additional efficacy outcomes 
 Time to hospital discharge readiness
Exploratory
 Other efficacy outcomes 
 Proportion of participants who require 
mechanical ventilation after study entry


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6. 
References 
Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with 
Severe Covid-19. New England Journal of Medicine. 2020. doi:10.1056/NEJMoa2001282.
Ding L, Wang L, Ma W, He H. Efficacy and safety of early prone positioning combined with 
HFNC or NIV in moderate to severe ARDS: a multi-center prospective cohort study. Crit Care. 
2020;24(1):28. doi:10.1186/s13054-020-2738-5. 
Mehta, Cyrus & Pocock, Stuart. (2011). Adaptive Increase in Sample Size When Interim Results 
are Promising: A Practical Guide with Examples. Statistics in medicine. 30. 3267-84. 
doi.org/10.1002/sim.4102. 
Rice TW, Wheeler AP, Bernard GR, et al. Comparison of the SpO2/FIO2 ratio and the 
PaO2/FIO2 ratio in participants with acute lung injury or ARDS. Chest. 2007;132(2):410-417. 
doi:10.1378/chest.07-0617.