Clinical trial NCT04498273
Conditions: COVID-19
Sponsor: Frank C Sciurba
Start date: 2020-09-07; Completion date: 2021-08-05
Enrollment: 657 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A multi-center adaptive randomized placebo-controlled platform trial evaluating the efficacy and safety of anti-thrombotic strategies in COVID-19 adults not requiring hospitalization at time of diagnosis

Detailed description:
The COVID-19 Outpatient Thrombosis Prevention Trial is a multi-center adaptive randomized double-blind placebo-controlled platform trial to compare the effectiveness of anti-coagulation with anti-platelet agents and with placebo to prevent thrombotic events in patients diagnosed with COVID-19 who have evidence of increased inflammation based on elevated D-dimer and hsCRP levels, yet are not admitted to hospital as COVID-19 related symptoms are currently stable. Participants will all be adults between 40 and 79 years who will be enrolled from approximately 100 facilities, such as emergency rooms and other settings where a physician is present to evaluate the patient for inclusion and exclusion criteria.

Arms: arm 1: Anticoagulation: prophylactic dose Apixaban 2.5mg po bid arm 2: Anticoagulation: therapeutic dose Apixaban 5.0mg po bid arm 3: Antiplatelet agent: low dose aspirin 81mg po qd arm 4: Placebo
Interventions: intervention 1: Apixaban 2.5 MG intervention 2: Apixaban 5MG intervention 3: Aspirin intervention 4: Placebo
Intervention descriptions: intervention 1: Subjects will be contacted either electronically or by telephone within 24 hours of randomization to confirm receipt of the study treatment. Study drug will be shipped to subjects home. Subjects will take Apixaban 2.5 MG twice a day; once in the morning and once in the evening for 45 days. Subjects will be contacted (electronic or telephone) minimally weekly after initial start of study medication and contact will continue up to day 75 after starting study treatment. Follow up electronic contact will be dependent on initial patient response, compliance with response, and medication adherence, for the trial duration using electronic contacts and through telephone contacts. Participants will be queried for any clinically relevant endpoints, especially major bleeding, or need to seek healthcare attention for any reason. Follow-up will occur from the time of study drug receipt and through the 30 day safety period. intervention 2: Subjects will be contacted either electronically or by telephone within 24 hours of randomization to confirm receipt of the study treatment. Study drug will be shipped to subjects home. Subjects will take Apixaban 5 MG twice a day; once in the morning and once in the evening for 45 days. Subjects will be contacted (electronic or telephone) minimally weekly after initial start of study medication and contact will continue up to day 75 after starting study treatment. Follow up electronic contact will be dependent on initial patient response, compliance with response, and medication adherence, for the trial duration using electronic contacts and through telephone contacts. Participants will be queried for any clinically relevant endpoints, especially major bleeding, or need to seek healthcare attention for any reason. Follow-up will occur from the time of study drug receipt and through the 30 day safety period. intervention 3: Subjects will be contacted either electronically or by telephone within 24 hours of randomization to confirm receipt of the study treatment. Study drug will be shipped to subjects home. Subjects will take Aspirin twice a day; once in the morning and once in the evening for 45 days. Subjects will be contacted (electronic or telephone) minimally weekly after initial start of study medication and contact will continue up to day 75 after starting study treatment. Follow up electronic contact will be dependent on initial patient response, compliance with response, and medication adherence, for the trial duration using electronic contacts and through telephone contacts. Participants will be queried for any clinically relevant endpoints, especially major bleeding, or need to seek healthcare attention for any reason. Follow-up will occur from the time of study drug receipt and through the 30 day safety period. intervention 4: Subjects will be contacted either electronically or by telephone within 24 hours of randomization to confirm receipt of the study treatment. Study placebo will be shipped to subjects home. Subjects will take placebo twice a day; once in the morning and once in the evening for 45 days. Subjects will be contacted (electronic or telephone) minimally weekly after initial start of study medication and contact will continue up to day 75 after starting study treatment. Follow up electronic contact will be dependent on initial patient response, compliance with response, and medication adherence, for the trial duration using electronic contacts and through telephone contacts. Participants will be queried for any clinically relevant endpoints, especially major bleeding, or need to seek healthcare attention for any reason. Follow-up will occur from the time of study drug receipt and through the 30 day safety period.

Protocol documents:
SAP_002.pdf: 
 
 
May 31, 2021 
Page 1 of 14 
 
 
STATISTICAL ANALYSIS PLAN 
 
for 
 
ACTIV-4B: COVID-19 Outpatient Thrombosis Prevention Trial 
 
A multicenter adaptive randomized placebo-controlled platform trial evaluating the 
efficacy and safety of antithrombotic strategies in COVID-19 adults not requiring 
hospitalization at time of diagnosis 
 
 
May 31, 2021 
 
 


 
 
May 31, 2021 
Page 2 of 14 
1 
PRIMARY AND SECONDARY AIMS OF THE TRIAL 
 
The primary aim of the trial is to compare the effects of treatment with (i) anticoagulation at 
prophylactic doses; (ii) anticoagulation at therapeutic doses; (iii) antiplatelet therapy; and (iv) 
placebo relative to each other on the primary composite endpoint of symptomatic deep venous 
thrombosis, pulmonary embolism, arterial thromboembolism, myocardial infarction, ischemic 
stroke, need for hospitalization for cardiovascular/pulmonary events, and all-cause mortality for 
up to 45 days after initiation of assigned treatment among COVID-19 patients not requiring 
hospitalization at time of diagnosis who are aged > 40 years and < 80 years. 
 
The secondary aims of the trial are: 
 
1. to compare the effects of treatment with (i) anticoagulation at prophylactic doses; (ii) 
anticoagulation at therapeutic doses; (iii) antiplatelet therapy; and (iv) placebo relative to 
each other on the following secondary endpoints up to 45 days after initiation of 
assigned treatment among COVID-19 patients not requiring hospitalization at time of 
diagnosis who are aged > 40 years and < 80 years: 
• 
need for hospitalization for cardiovascular/pulmonary events 
• 
venous thromboembolism including symptomatic DVT and PE. 
• 
arterial thrombotic events including MI, ischemic stroke, and arterial 
thromboembolism. 
• 
all-cause mortality. 
• 
mortality without antecedent hospitalization.  
• 
the time-to-event for the primary composite endpoint of symptomatic deep venous 
thrombosis, pulmonary embolism, arterial thromboembolism, myocardial infarction, 
ischemic stroke, need for hospitalization for cardiovascular/pulmonary events, and 
all-cause mortality  
• 
a clinical rank-based score. 
 
2. to compare the effects of treatment with (i) combined prophylactic and therapeutic doses 
of apixaban with (ii) placebo for the primary endpoints for efficacy and for safety. 
 
3. to test whether D-dimer and/or hsCRP modify the treatment effect of assigned treatment 
on the trial primary and secondary outcomes.   
 
The safety aims of the trial are to compare the effects of treatment with (i) anticoagulation at 
prophylactic doses; (ii) anticoagulation at therapeutic doses; (iii) antiplatelet therapy; and (iv) 
placebo relative to each other on bleeding outcomes for up to 45 days after initiation of assigned 
treatment and after an additional 30 days of safety follow up (day 75) among COVID-19 patients 
not requiring hospitalization at time of diagnosis who are aged > 40 years and < 80 years. 
• 
ISTH major bleeding 
• 
ISTH clinically relevant non-major bleeding (CRNMB).   
• 
development of disseminated intravascular coagulation (DIC)  
 
 


 
 
May 31, 2021 
Page 3 of 14 
2. STUDY DESIGN 
 
2.1 POPULATION 
 
The trial eligibility criteria for randomization are listed below.   
 
Inclusion Criteria 
• 
Age between 40 and 80 years inclusive 
• 
Documentation of PCR or antigen test positive symptomatic COVID-19 infection in the 
past 14 days 
• 
Ability to be contacted by telephone or other electronic methods of communication  
• 
Negative pregnancy test for women of child bearing potential 
 
Exclusion Criteria 
• 
Indication for therapeutic anticoagulation (mechanical heart valve, AF, APS) 
• 
Indication for single or dual antiplatelet therapy  
• 
Lactating 
• 
Primary brain tumor or acute leukemia 
• 
Bleeding risk defined as hospitalization in the past 2 months for: 
o bleeding due to ulcer or GI tract disease 
o major surgery 
o stroke 
o intracranial hemorrhage 
• 
Platelet count < 100,000 per microliter (can be obtained after randomization) 
• 
Calculated creatinine clearance < 30 ml/min (can be obtained after randomization) 
• 
Ever hospitalized after diagnosis of COVID-19  
• 
Concomitant need for strong inducers/inhibitors of p-gp and CYP3A4  
• 
SARS-CoV-2 PCR or antigen test more than 14 days prior to randomization 
• 
Unable to give written informed consent 
 
 
2.2 INTERVENTIONS 
 
Assigned Intervention Groups: Participants will be randomized at a 1:1:1:1 ratio to the four 
treatment groups using a permuted block design.   
 
Group 
Treatment 
Dose AM 
Dose PM 
Duration 
1.  
Apixaban 
2.5 mg  
2.5 mg 
45 days 
2. 
Apixaban 
5.0 mg  
5.0 mg 
45 days 
3. 
Aspirin 
81 mg  
Placebo 
45 days 
4. 
Placebo 
Placebo 
Placebo 
45 days 
 
For randomized participants, treatment duration will be 45 days unless a primary, secondary, or 
safety outcome occurs before 45 days in which case treatment may be stopped for clinical 
reasons. 


 
 
May 31, 2021 
Page 4 of 14 
 
2.3 OUTCOMES AND TIMING 
 
The primary endpoint is the binary (yes/no) composite efficacy endpoint indicating that any of 
the following events occurred: symptomatic deep venous thrombosis, pulmonary embolism, 
arterial thromboembolism, myocardial infarction, ischemic stroke, need for hospitalization for 
cardiovascular/pulmonary events, and all-cause mortality.  
 
Primary treatment comparisons will be conducted in the sample of randomized participants 
who initiate treatment and have at least one follow-up contact.  A follow-up visit includes a 
contact where patient-reported outcomes or site-reported outcomes about patient status are 
collected.  In this modified intention to treat (mITT) sample of patients, endpoint events will be 
tabulated from initiation of assigned therapy through 45 days after treatment initiation.   
Additional analyses will be conducted in the sample of all randomized participants.  In the 
complete randomized sample, follow-up will begin at the time of randomization.  
 
A key secondary endpoint is the Kaplan Meier time-to-event estimate of the cumulative risk of 
the primary composite endpoint.  For treatment comparisons among randomized participants 
who initiate treatment, the cumulative risk 45-days after initiation of assigned therapy will be 
estimated, and for analyses among all randomized participants, the cumulative risk 45-days 
after randomization will be estimated.    
 
The secondary endpoints are: 
• 
Hospitalization for cardiovascular/pulmonary events 
• 
Venous thromboembolism, a composite of symptomatic DVT and PE. 
• 
Symptomatic DVT 
• 
Pulmonary embolism 
• 
Arterial thrombotic events, a composite of MI, ischemic stroke and arterial embolism 
• 
Myocardial infarction 
• 
Ischemic stroke 
• 
Arterial thromboembolism 
• 
All-cause mortality 
• 
Mortality without antecedent hospitalization 
 
Timing for the secondary endpoints is the same as what is described for the primary composite 
efficacy endpoint.   
 
An exploratory tertiary endpoint is a clinical rank-based score.  This clinical rank-based score 
is defined as the worst category accomplished during the 45-day treatment period (i.e. starting 
at treatment initiation) using the numeric rankings from best (score=1) to worst (score=9): 
1. No clinical event (i.e. no study endpoint, safety endpoint or urgent/emergent health care 
encounter).  A minor bleed that does not involve seeking medical attention is not a trial 
safety endpoint and hence is counted in this category. 
2. Non-fatal bleeding that requires medical attention but not a hospital admission 


 
 
May 31, 2021 
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3. Non-fatal event that is one of the composite primary events that requires an urgent care 
center visit or emergency room visit but not a hospital admission (e.g. this includes a 
DVT or pulmonary embolism that do not result in a hospital admission) 
4. Non-fatal hospitalization for bleeding event or cardiovascular/pulmonary event not 
including stroke, MI, pulmonary embolism or DVT. 
5. Non-fatal hospitalization for DVT 
6. Non-fatal hospitalization for PE 
7. Non-fatal hospitalization for MI 
8. Non-fatal hospitalization for stroke 
9. Death 
 
The safety endpoints are: 
• 
Major bleeding (ISTH major bleeding) 
o Drop in hemoglobin of 2 gm/dl attributed to bleeding and 
o Requiring transfusion of 2 or more units 
o Bleeding in a critical site which includes hemorrhagic stroke and intracranial 
hemorrhage 
o Fatal bleeding 
• 
Mild bleeding (ISTH CRNMB): Non-major clinically relevant bleeding is defined as 
overt bleeding not meeting the criteria for major bleeding but associated with medical 
intervention, unscheduled contact (visit or telephone call) with a physician, 
(temporary) cessation of study intervention, or associated with discomfort for the 
participant such as pain or impairment of activities of daily life. 
• 
Development of disseminated intravascular coagulation (DIC) 
 
For the treatment comparisons among randomized participants who initiate treatment and have 
at least one follow-up contact, safety endpoints will be tabulated from initiation of assigned 
therapy through 45 days after treatment initiation and through 75 days after treatment initiation. 
For analyses involving all randomized participants, safety outcomes will be tabulated from time 
of randomization through 45 days after randomization and up to 75 days after randomization.   
 
2.4 POWER AND SAMPLE SIZE 
 
We determined the samples sizes required to provide 80% and 90% power to detect a relative 
reduction of 33% in the 45-day primary outcome event rates between two assigned treatment 
groups using chi-square statistic with one-sided test with alpha=0.025. Based on these 
estimates, we proposed a total sample of N=7000 patients with N=1750 patients assigned to 
each of the four treatment arms. Assuming a placebo event rate of 8.0%, a trial with N=1750 
patients in each arm will have 80% power to detect superiority of apixaban 5.0 mg to placebo 
when there is a 30% relative reduction in risk (i.e. 8.0% vs. 5.62%) and 90% power with a 34% 
relative reduction (i.e. 8.0% vs. 5.28%).  Assuming an event rate of 6.0% with aspirin, a trial with 
N=1750 patients in each arm will have 80% power to detect superiority of apixaban 5.0 mg to 
aspirin when there is a 34% relative reduction in risk (i.e. 6.0% vs. 3.94%) and 90% power with 
a 39% relative reduction (i.e. 6.0% vs. 3.65%).   
 


 
 
May 31, 2021 
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Since we hypothesize that the active treatments will be beneficial, we estimated that the overall 
primary composite efficacy endpoint event risk in the trial (i.e. all treatment groups combined) 
will be this population is approximately 7.0%.  We also estimated the overall bleeding event rate 
will be approximately 1.0%. With a total of N=7000 patients, we therefore assumed that we will 
observe approximately 490 patients with primary endpoint events and 70 with bleeding events. 
 
2.5 ENDPOINT ADJUDICATION 
 
All events suggestive of the primary composite endpoint will be adjudicated by a central 
independent Clinical Endpoints Committee (CEC).  All of the suspected endpoint events will be 
classified by the CEC so that each of the defined secondary endpoint events will be adjudicated.  
All suspected bleeding events deemed to be clinically relevant non-major bleeding (CRNMB), 
major bleeding or DIC will be adjudicated by the CEC.  The specific endpoints are each defined 
in the ACTIV-4B Clinical Endpoints Committee Charter. 
 
The options available to the adjudicators include the ability to confirm an event (if there is 
sufficient clinical information to support the endpoint), disconfirm the event (if there is sufficient 
clinical information to disconfirm the endpoint), or mark the event as having “insufficient 
evidence” for confirmation (or for disconfirmation).   
 
2.6 BLINDING 
 
The ACTIV-4B Outpatient trial is double blinded.  All study participants, clinical investigators, 
staff who collect data, medical monitors who classify adverse events, and Clinical Endpoints 
Committee members who adjudicate study endpoints are blinded to treatment assignment. Only 
the central data management and the unblinded statistical team have access to the treatment 
assignments.   Protocols have been developed so that treatment assignment may be revealed 
in cases of clinical emergencies.   
 
2.7 ANALYSIS POPULATIONS 
 
Modified Intention to Treat (mITT) Population:  The primary treatment comparisons will be 
based on the modified intention to treat (mITT) principle.  The mITT analyses will include only 
randomized participants who initiate their assigned treatment regimen and for whom 
there is at least one follow-up visit.  A follow-up visit includes a contact where patient-
reported outcomes or site-reported outcomes about patient status are collected.  Analyses in 
this sample will be conducted based on the randomly assigned treatment starting at the time of 
treatment initiation.     
 
All Randomized Patients:  The population of all randomized participants will be evaluated from 
time of randomization onward.  The combined population will be used to estimate the overall 
risk of events in this patient cohort. Secondary treatment comparisons will be conducted using 
the intention to treat (ITT) principle based on the randomly assigned treatment group starting at 
the time of randomization.   
 
Per Protocol Population:  The group of randomized participants who report taking ≥70% of 
their pills per week for ≥5 weeks or until the time of a primary outcome or safety event occurred 


 
 
May 31, 2021 
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will be considered adherent to the trial treatment regimen and will be included in the per protocol 
sample.  Analysis of this per protocol group will begin at the time of treatment initiation.  mITT 
participants who adhered to their assigned treatment and have complete 45-day follow-up or 
complete follow-up up to the time of a hospitalization or a death will be included in the analysis 
of the per protocol group.   
 
2.8 HANDLING MISSING DATA 
 
Missing Outcome Data:  The primary endpoint for the ACTIV-4B Outpatient trial is a binary 
(yes/no) outcome indicating whether any of the listed events occurred within 45 days of 
treatment initiation.  Hence, our primary analysis will be conducted in the sample for whom 45-
day outcome data is available (45 day follow-up completed or a death).  We expect that the 
percentage of participants with missing 45-day outcome data due to withdrawal or loss to follow-
up will be small (<5%) and that the probability of missing data will be similar across the four 
treatment arms and will be weakly associated with the missing endpoint.  
 
We will compare those participants with and without missing endpoint data by treatment group 
and by baseline demographic features. We will also present the likelihood that missing data 
would change the conclusions about the treatment effects using a tipping point analyses.  By 
systematically and comprehensively varying assumptions about the missing outcomes in the 
four treatment arms, we will explore the whether the conclusions change.  We will allow 
assumptions about the missing outcomes in the four treatment arms to vary independently, 
including scenarios where dropouts on active drugs tend to have worse outcomes than dropouts 
on control. This approach is consistent with recent FDA guidelines (E9(R1)-Statistical-
Principles-for-Clinical-Trials attached).   
 
The secondary endpoint, the Kaplan-Meier estimate of the cumulative risk of a primary endpoint 
at 45 days, appropriately accounts for variable follow-up time under the assumption of non-
informative censoring.  Analysis of this time to event outcome among all randomized or mITT 
participants (i.e. those with and without missing 45-day data) will provide further insight about 
the robustness of the trial conclusions based on the primary composite efficacy endpoint.   
 
Missing Adjudication Data:  Each suspected specified efficacy and bleeding event is 
adjudicated by the CEC based on medical records.  In the rare case when medical records 
cannot be obtained, the adjudicators will review all available information including narratives 
from the local principal investigator or members of the study team who reported the event.  The 
adjudicators will use all available information to classify the event as confirmed, disconfirmed or 
insufficient evidence.  The primary analyses will be based on confirmed events.  A secondary 
sensitivity analysis will be based on events that are confirmed and those that have insufficient 
evidence. 
 
Missing Covariate Data:  Data will not be removed from the primary analyses due to missing 
covariate data.  Variables that have <10% missing data will be imputed using single imputation.  
Categorical variables that have > 10% missing data will include a category for missing data.  
Continuous variables that have > 10% missing data will be imputed using single imputation and 
a missing indicator variable will be added to the model.   
 


 
 
May 31, 2021 
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3. STATISTICAL ANALYSIS PLAN  
 
3.1 BASELINE DESCRIPTIVE STATISTICS 
 
The distribution of demographic, clinical history, medications and biomarker variables will be 
examined and transformations will be applied as needed.  Baseline characteristics will be 
examined for all randomized participants, for the entire mITT sample, and by assigned 
treatment group within the mITT group. Variables will be summarized using mean, standard 
deviation or median (first and third quartile) for continuous variables and frequency (percentage) 
for categorical variables.  No test of significance levels will be reported for baseline variables.    
 
3.2 RETENTION ANALYSES 
 
The proportion of mITT participants who withdraw or are lost to follow-up before 45-days of 
follow-up will be tabulated overall and by treatment group. Baseline characteristics of patients 
with missing primary outcome data will be compared to those with complete data.   
 
3.3 ADHERENCE ANALYSES 
 
The proportion of mITT participants overall and in each assigned treatment group who have 
interrupted treatment permanently or temporarily and the reason for interruption will be 
described. We will present the proportion of participants who took ≥70% of their pills as 
prescribed for ≥5 weeks or until a clinical event occurred in the overall mITT sample and 
stratified by assigned treatment group.  
 
3.4 PRIMARY OUTCOME ANALYSIS 
 
The primary analyses will be conducted in the mITT sample based on the randomly assigned 
treatment starting at the time of treatment initiation.  Participants who complete at least one 
follow-up visit after starting their assigned drug treatment will be included in the analysis. 
 
The odds of the primary composite efficacy endpoint in the mITT sample will be modeled using 
a logistic regression model defined as: 
 
Log (p/1-p) = β0 + β1Apixiban5.0 +β2Apixiban2.5 + β3Asipirin + β4Non-US + β5age + β6female  
+ β7BlackNH + β8Hispanic + β9OtherRE +β10D-Dimer+ β11HsCRP + β12Weight  
+ β13CrClearance   
 
Race/ethnicity will be defined as white non-Hispanic, black non-Hispanic, Hispanic, and 
Other/unknown race/ethnicity. White non-Hispanic race/ethnicity will serve as the references 
group.   
 
The placebo treatment group will serve as the “reference” treatment group in this model, and we 
will test whether the coefficient for each active treatment group relative to the reference placebo 
group is equal to 0 using a two-sided test with alpha=0.05.  Other pairwise treatment 


 
 
May 31, 2021 
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comparisons (apixaban 5.0 versus apixaban 2.5, apixaban 5.0 versus aspirin, apixaban 2.5 
versus aspirin) will be conducted, and the effect of treatment with apixaban (i.e. the combined 
group including both apixaban 5.0 and apixaban 2.5) will be compared with placebo.   
 
If the number of mITT participants with a primary composite efficacy endpoint event in the 45-
days after treatment initiation is low, a logistic regression model with a reduced number of 
covariates must be used in order to have adequate degrees of freedom for valid estimation. 
Below are the planned models to be used for the primary treatment comparison under the 
scenarios that the number of patients with primary endpoint events is <30, 30-49, and ≥50.  The 
same treatment contrasts will be computed in the reduced models as described for the full 
model. 
 
If the number of mITT participants with a primary endpoint event is <30, an unadjusted 
logistic regression model will be used as the primary model to assess the effect of assigned 
treatment.   
 
Log (p/1-p) = β0 + β1Apixiban5.0 +β2Apixiban2.5 + β3Asipirin  
 
If the number of mITT participants with a primary endpoint event is 30-49, a logistic 
regression model adjusting only for age and D-dimer level will be used as the primary model to 
assess the effect of assigned treatment.   
 
Log (p/1-p) = β0 + β1Apixiban5.0 +β2Apixiban2.5 + β3Asipirin + β4age + β5D-Dimer 
 
If the number of mITT participants with a primary endpoint event is ≥50, the full logistic 
regression model will be used as the primary model to assess the effect of assigned treatment.   
 
Log (p/1-p) = β0 + β1Apixiban5.0 +β2Apixiban2.5 + β3Asipirin + β4Non-US + β5age + β6female  
+ β7BlackNH + β8Hispanic + β9OtherRE +β10D-Dimer+ β11HsCRP + β12Weight  
+ β13CrClearance  
 
In addition to the primary logistic regression analysis, the unadjusted estimated risk of the 
primary composite efficacy endpoint in each treatment group (i.e. # of participants with an event 
/ # of participants in the group), and the pairwise relative risks and absolute risk differences with 
95% confidence intervals will be calculated and presented.  
 
An ITT and a per protocol analysis will be conducted by running the multivariable adjusted 
logistic regression model and the unadjusted risk estimates using the corresponding sample 
and relevant exposure time.  
 
3.5 KEY SECONDARY OUTCOME ANALYSES 
 
Kaplan-Meier cumulative incidence curves will be created for the primary composite efficacy 
endpoint up to 45 days after treatment initiation stratified by assigned treatment group in the 
mITT sample.  Log-rank statistics will be computed to compare the time to event estimates over 
time among the four treatment groups.  The estimated cumulative risk at 45-days and the 95% 
confidence interval for the estimated cumulative risk at 45-days will be determined for each 


 
 
May 31, 2021 
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treatment group. Pairwise differences and 95% confidence intervals for differences will be 
computed.  The combined group of prophylactic and therapeutic doses of apixaban will be 
compared with placebo. 
 
Kaplan-Meier cumulative incidence curves will be created for the primary composite efficacy 
endpoint up to 45 days after randomization for the complete randomized sample overall and 
stratified by assigned treatment group (ITT).  Log-rank statistics will be computed to compare 
the time to event estimates over time among the four assigned treatment groups.  The 
estimated cumulative risk at 45-days and the 95% confidence interval for the estimated 
cumulative risk at 45-days will be determined for the overall group and for each treatment group.    
 
3.6 SECONDARY OUTCOME ANALYSES 
 
For each defined secondary outcome event, the unadjusted risk of the endpoint in each 
treatment group (i.e. # of participants with the specified event / # of participants in the group) 
and pairwise relative risks and the absolute risk difference between treatment groups will be 
calculated with their 95% confidence intervals.  In addition, the effect of treatment with apixaban 
(i.e. prophylactic and therapeutic groups combined) will be compared with placebo. 
 
3.6 EXPLORATORY TERTIARY OUTCOME ANALYSES 
 
The distribution across the 9 categories of the clinical rank-based score and the median and 
25th and 75th percentile will be present each treatment group in the mITT sample.  Kruskal-
Wallace tests will be used to compare the distribution of the clinical rank-based score among 
the assigned treatment groups in the mITT sample.  Pairwise comparisons with Wilcoxon rank 
sum statistics will be conducted to determine if one treatment has a “better” outcome relative to 
another.   
  
3.7 SAFETY ANALYSES 
 
The risk and 95% CI of each defined safety endpoint event and the composite of any defined 
safety endpoint event (major bleeding, CRNMB or DIC) at 45 and at 75 days will be computed 
for each treatment group in the mITT.  Pairwise relative risks and absolute risk differences 
between treatment groups will be calculated with their 95% confidence intervals.   
 
3.8 SUBGROUP ANALYSES AND EFFECT MODIFICATION 
 
A select number of subgroup variables have been specified a priori: 
• 
D-dimer (<1.0 ULN, [1.0-2.0 ULN), [2.0-3.0 ULN), ≥ 3.0 ULN, or by quartiles if needed) 
• 
CRP by quartiles based on the data 
• 
Age (<60 years, ≥60 years) 
• 
Sex 
• 
Race/ethnicity (White non-Hispanic, Black non-Hispanic, Hispanic, other)  
• 
Renal function (creatinine clearance 30-49 ml/min, 50-90 ml/min, >91 ml/min) 
 


 
 
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The risk of the primary composite efficacy endpoint outcome and the 45-day risk of major 
bleeding with 95% confidence intervals will be estimated in each treatment group within each 
subgroup for the mITT sample.  Evidence of effect modification of the treatment effectiveness by 
subgroup will be tested by creating a logistic regression model including the subgroup variable, 
treatment assignment, and the interaction between the subgroup variable and treatment 
assignment.  If a subgroup variable is inherently continuous (i.e. D-dimer, CRP and age), these 
variables will be appropriately transformed as needed to approximate a normal distribution, and 
included in the model as a continuous variable.  The significance of the interaction term will be 
presented. Additional subgroups may be examined in exploratory analyses based on observed 
results from the trial or information from external sources.   
 
We will examine the distribution of baseline D-dimer in the entire mITT and in the randomized 
sample, and we will analyze the odds of the primary composite efficacy endpoint and major 
bleeding, irrespective of assigned treatment group by D-Dimer subgroup.  Logistic regression 
models and associated ROC curves will be created for the primary efficacy endpoint and for 
major bleeding by continuous D-dimer level.   LOESS curves for the logit of the primary efficacy 
endpoint and for major bleeding by continuous D-dimer level will also be examined. 
 
3.9 ANALYSIS OF DURATION OF TREATMENT 
 
Kaplan-Meier cumulative incidence curves will be created to assess the time to the first primary 
endpoint event and the time to the first safety event, irrespective of treatment assignment.  
Assuming that bleeding events occur at a fairly constant rate over time, we suggest that if ≥ 
90% of the primary endpoint events occur in the first 21 days, then the DSMB will consider 
modifying the treatment arms such that the duration of therapy is shortened to 21 days. Curves 
stratified by treatment group will be examined before finalizing a recommendation.   
   
 
4. INTERIM MONITORING PLAN FOR EFFICACY, FUTILITY AND SAFETY  
 
4.1 OVERVIEW OF PLANNED INTERIM ANALYSIS 
 
An independent data safety and monitoring board (DSMB) will review all interim analyses 
prepared by an unblinded statistician.  The number of patients randomized, the number of 
randomized participants who initiated treatment and the primary, secondary and safety 
endpoints for the entire randomized and the entire mITT samples will be presented.  Unadjusted 
risk of the defined primary, secondary and safety endpoints by assigned treatment group in the 
mITT sample will be examined on a monthly basis.  For DSMB presentation, two versions of the 
primary, secondary and safety endpoint tables will be presented: one table will include the best 
information available which will include the adjudicated endpoints for events that have been 
classified by the CEC and self-reported endpoints for events that have not been classified by 
the CEC, and a second table that will include adjudicated endpoints only.  A complete interim 
analysis of efficacy, futility, and safety will be conducted for each full DSMB review meeting 
which will occur approximately every 3 months. 
 
A Bayesian analytic approach is proposed for the interim monitoring plan in order to utilize prior 
information when estimating the posterior probabilities in the sequential interim analyses.  


 
 
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Initially, the placebo group will serve as the “control group”; however, if the placebo arm is 
dropped and the trial continues, the aspirin arm will be designated as the control group for future 
treatment comparisons. 
 
Decision rules have been established for efficacy based on the posterior probability that the 
active treatment regimen is beneficial as compared to placebo with respect to the primary 
composite efficacy endpoint.  Decision rules were created such that the overall type I error 
approximates the pre-specified alpha=0.025 for a one-sided test.  Assuming a non-informative 
prior distribution for each odds ratio at the first interim analysis, we will calculate the posterior 
probability that an active treatment is superior to placebo.  We will update these posterior 
probabilities with new data at each subsequent interim analysis.  If the posterior probability 
exceeds the pre-specified threshold for superiority at any of the interim analyses, the superior 
treatment will be declared efficacious and the other treatment may be dropped.   
  
Decision rules have been developed for assessing futility of the active treatments.  The posterior 
probability that each of the active treatments is inferior or equivalent to placebo with respect to 
the primary composite efficacy endpoint will be calculated assuming non-informative priors at 
the outset of the trial.  When the posterior probability exceeds a specified threshold, futility will 
be established and the respective active therapy may be dropped from the trial.   
 
Safety data will be presented and analyzed at each meeting, but no formal decision rules will be 
established a priori for the bleeding safety endpoints.  Data will be presented so that the DSMB 
can evaluate the net risk benefit ratio for each treatment. 
 
At each meeting, the DSMB will examine the rate of enrollment (and treatment initiation) in the 
trial as well as the overall risk of the primary endpoint.  Based on this information, they may 
request a traditional futility analysis of conditional power to detect superiority.  This involves a 
determination of the detectable risk ratio (or relative risk reduction) conditional on the observed 
data at that time under various assumptions regarding the future risk of endpoint events and the 
underlying treatment risk ratios.     
 
4.2 FORMAL MONITORING OF SUPERIORITY BASED ON PRIMARY ENDPOINT 
 
A logistic regression model will be created for the primary composite efficacy endpoint such that 
the effect of each active treatment group (relative to the placebo reference group) will be 
estimated adjusting for covariates (age, sex, race/ethnicity, D-dimer, and hsCRP, weight and 
calculated creatinine clearance) as specified in Section 3.4 based on the observed number of 
participants with events.  The primary analyses for efficacy will be based on the odds ratios, 
comparing one treatment to another, derived from this model.  One treatment is beneficial 
compared to another if the [ Odds Ratio < 1.00 ] for the primary composite outcome.  Assuming 
non-informative priors at the first look, we will calculate the posterior probabilities that the [ Odds 
Ratio < 1.00 ] for each active treatment compared to placebo.  If at any analysis time-point, the 
upper bound of the lower 99% credible interval for the odds ratio is less than 1.00, the active 
treatment arm will be considered superior.   
 
The decision rule for declaring superiority based on the primary composite outcome is: 
≥ 0.99 Posterior Probability that the OR (active vs placebo) < 1.00 


 
 
May 31, 2021 
Page 13 of 14 
 
The DSMB will use this information to make a recommendation to the NHLBI.  The DSMB can 
recommend that the Outpatient COVID-19 trial should continue as proposed, that the control 
treatment arm should be dropped from the trial, that the trial protocol should be modified, or that 
the Outpatient COVID-19 trial should be terminated early. The final decision to stop trial rests 
with the NHLBI. 
 
4.3 FORMAL MONITORING OF FUTILITY BASED ON PRIMARY ENDPOINT 
 
Using the same logistic regression model that will be used for the primary analyses, we will 
determine the posterior probability that the active arm is equivalent or inferior to placebo 
adjusting for covariates (age, sex, race/ethnicity, D-dimer, and hsCRP, weight and calculated 
creatinine clearance) as specified in Section 3.4 based on the observed number of participants 
with events.  Given that the trial was designed to have powered to detect a relative risk 
reduction of 33% with active treatment, futility will be defined for an active arm if the lower 
bound of the upper 95% credible interval for the odds ratio comparing the active arm to placebo 
is greater than 0.75. 
 
The decision rule for declaring futility based on the primary composite outcome is: 
≥ 0.95 Posterior Probability that the  OR (active vs placebo) > 0.75   
 
This roughly corresponds to the having an estimated Odds Ratio that is 1.00 (or greater) and 
the two-sided 90% confidence interval extends from 0.75 to 1.33 (or greater). 
 
The DSMB will use this information to determine its recommendation to NHLBI. The DSMB can 
recommend that the Outpatient COVID-19 trial should continue as proposed, that the futile 
active treatment arm should be dropped from the trial, that the trial protocol should be modified, 
or that the Outpatient COVID-19 trial should be terminated early. The NHLBI will make the final 
decision.  
 
4.4 MONITORING SAFETY 
 
A logistic regression model will be created for the major bleeding endpoint and for the 
composite safety endpoint (major bleeding, CRNMB and DIC) such that the effect of each active 
treatment group (relative to the placebo reference group) will be estimated and the odds ratios, 
comparing one treatment to another, will be derived from this model.   We will not create explicit 
decision rules based on the bleeding posterior probability.   
 
If safety issues arise, the DSMB will use their clinical judgement to assess the potential risks 
relative to the potential benefits for each active drug compared to control.  The DSMB may also 
examine the safety and efficacy data in subgroups known to be high risk for bleeding such as 
those with older age and/or higher BMI.  The DSMB will use the monitoring information to 
determine its recommendation to NHLBI.  The DSMB can recommend that the Outpatient 
COVID-19 trial should continue as proposed, that one treatment arm may be dropped, that the 
trial protocol should be modified, or that the Outpatient COVID-19 trial should be terminated 
early for safety reasons.  
 


 
 
May 31, 2021 
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4.5 STUDY STAGES AND INTERVENTIONS 
 
The first Stage of this study has been determined and is outlined above. In Stage 1, there will be 
four intervention arms: (1) prophylactic anticoagulation with apixaban 2.5mg po bid; (2) 
therapeutic anticoagulation with apixaban 5.0mg op bid; (3) antiplatelet therapy with low dose 
aspirin 81mg po qd and (4) placebo. Subsequent Stages will incorporate recommendations from 
the DSMB. 
  
The overarching plan for adaptive changes are as follows: 
   
1. If an active drug is found to be futile relative to placebo (i.e. results indicate that an 
active arm is associated with a slightly reduced risk, no effect, or a greater risk of the 
primary outcome as compared with placebo): The futile active arm will be dropped, no new 
treatment arm will be added, and the trial will continue with the remaining treatment arms.  
The randomization scheme will be adjusted to include the 3 remaining arms with equal 
probabilities (i.e. 1:1:1), and the treatment comparisons among these arms will continue as 
designed.   
 
2. If an active drug is found to be superior to placebo: We will declare a winner, and we will 
announce this finding. The placebo arm will be dropped.  If the observed differences 
between the superior active arm and all of the other active arms are sizable (e.g. >20% 
relative reduction) but do not yet cross the decision boundary, the trial may be terminated 
based on a risk/benefit analysis by the DSMB.  If the observed differences between the 
superior active arm and at least one of the other active arms is small, this would be 
announced, and the trial may continue with the “competitive arms” based on a risk/benefit 
analysis by the DSMB.  The randomization scheme will be modified to assign each of the 
remaining treatment arms with an equal probability. The aspirin arm will become the 
reference arm for future statistical models. 
 
3. If a promising new drug is identified from external studies: At the outset of this trial, we 
do not plan on adding any new treatment arms. However, if a promising candidate drug 
were to be identified in the next 6 months, we will consider adding an arm to the trial based 
on time and other pragmatic considerations.  The randomization scheme and analytic 
approach would be modified to include an extra treatment arm.   
 
 

Prot_001.pdf: 
 
 
May 31, 2021 
Page 1 of 14 
 
 
STATISTICAL ANALYSIS PLAN 
 
for 
 
ACTIV-4B: COVID-19 Outpatient Thrombosis Prevention Trial 
 
A multicenter adaptive randomized placebo-controlled platform trial evaluating the 
efficacy and safety of antithrombotic strategies in COVID-19 adults not requiring 
hospitalization at time of diagnosis 
 
 
May 31, 2021 
 
 


 
 
May 31, 2021 
Page 2 of 14 
1 
PRIMARY AND SECONDARY AIMS OF THE TRIAL 
 
The primary aim of the trial is to compare the effects of treatment with (i) anticoagulation at 
prophylactic doses; (ii) anticoagulation at therapeutic doses; (iii) antiplatelet therapy; and (iv) 
placebo relative to each other on the primary composite endpoint of symptomatic deep venous 
thrombosis, pulmonary embolism, arterial thromboembolism, myocardial infarction, ischemic 
stroke, need for hospitalization for cardiovascular/pulmonary events, and all-cause mortality for 
up to 45 days after initiation of assigned treatment among COVID-19 patients not requiring 
hospitalization at time of diagnosis who are aged > 40 years and < 80 years. 
 
The secondary aims of the trial are: 
 
1. to compare the effects of treatment with (i) anticoagulation at prophylactic doses; (ii) 
anticoagulation at therapeutic doses; (iii) antiplatelet therapy; and (iv) placebo relative to 
each other on the following secondary endpoints up to 45 days after initiation of 
assigned treatment among COVID-19 patients not requiring hospitalization at time of 
diagnosis who are aged > 40 years and < 80 years: 
• 
need for hospitalization for cardiovascular/pulmonary events 
• 
venous thromboembolism including symptomatic DVT and PE. 
• 
arterial thrombotic events including MI, ischemic stroke, and arterial 
thromboembolism. 
• 
all-cause mortality. 
• 
mortality without antecedent hospitalization.  
• 
the time-to-event for the primary composite endpoint of symptomatic deep venous 
thrombosis, pulmonary embolism, arterial thromboembolism, myocardial infarction, 
ischemic stroke, need for hospitalization for cardiovascular/pulmonary events, and 
all-cause mortality  
• 
a clinical rank-based score. 
 
2. to compare the effects of treatment with (i) combined prophylactic and therapeutic doses 
of apixaban with (ii) placebo for the primary endpoints for efficacy and for safety. 
 
3. to test whether D-dimer and/or hsCRP modify the treatment effect of assigned treatment 
on the trial primary and secondary outcomes.   
 
The safety aims of the trial are to compare the effects of treatment with (i) anticoagulation at 
prophylactic doses; (ii) anticoagulation at therapeutic doses; (iii) antiplatelet therapy; and (iv) 
placebo relative to each other on bleeding outcomes for up to 45 days after initiation of assigned 
treatment and after an additional 30 days of safety follow up (day 75) among COVID-19 patients 
not requiring hospitalization at time of diagnosis who are aged > 40 years and < 80 years. 
• 
ISTH major bleeding 
• 
ISTH clinically relevant non-major bleeding (CRNMB).   
• 
development of disseminated intravascular coagulation (DIC)  
 
 


 
 
May 31, 2021 
Page 3 of 14 
2. STUDY DESIGN 
 
2.1 POPULATION 
 
The trial eligibility criteria for randomization are listed below.   
 
Inclusion Criteria 
• 
Age between 40 and 80 years inclusive 
• 
Documentation of PCR or antigen test positive symptomatic COVID-19 infection in the 
past 14 days 
• 
Ability to be contacted by telephone or other electronic methods of communication  
• 
Negative pregnancy test for women of child bearing potential 
 
Exclusion Criteria 
• 
Indication for therapeutic anticoagulation (mechanical heart valve, AF, APS) 
• 
Indication for single or dual antiplatelet therapy  
• 
Lactating 
• 
Primary brain tumor or acute leukemia 
• 
Bleeding risk defined as hospitalization in the past 2 months for: 
o bleeding due to ulcer or GI tract disease 
o major surgery 
o stroke 
o intracranial hemorrhage 
• 
Platelet count < 100,000 per microliter (can be obtained after randomization) 
• 
Calculated creatinine clearance < 30 ml/min (can be obtained after randomization) 
• 
Ever hospitalized after diagnosis of COVID-19  
• 
Concomitant need for strong inducers/inhibitors of p-gp and CYP3A4  
• 
SARS-CoV-2 PCR or antigen test more than 14 days prior to randomization 
• 
Unable to give written informed consent 
 
 
2.2 INTERVENTIONS 
 
Assigned Intervention Groups: Participants will be randomized at a 1:1:1:1 ratio to the four 
treatment groups using a permuted block design.   
 
Group 
Treatment 
Dose AM 
Dose PM 
Duration 
1.  
Apixaban 
2.5 mg  
2.5 mg 
45 days 
2. 
Apixaban 
5.0 mg  
5.0 mg 
45 days 
3. 
Aspirin 
81 mg  
Placebo 
45 days 
4. 
Placebo 
Placebo 
Placebo 
45 days 
 
For randomized participants, treatment duration will be 45 days unless a primary, secondary, or 
safety outcome occurs before 45 days in which case treatment may be stopped for clinical 
reasons. 


 
 
May 31, 2021 
Page 4 of 14 
 
2.3 OUTCOMES AND TIMING 
 
The primary endpoint is the binary (yes/no) composite efficacy endpoint indicating that any of 
the following events occurred: symptomatic deep venous thrombosis, pulmonary embolism, 
arterial thromboembolism, myocardial infarction, ischemic stroke, need for hospitalization for 
cardiovascular/pulmonary events, and all-cause mortality.  
 
Primary treatment comparisons will be conducted in the sample of randomized participants 
who initiate treatment and have at least one follow-up contact.  A follow-up visit includes a 
contact where patient-reported outcomes or site-reported outcomes about patient status are 
collected.  In this modified intention to treat (mITT) sample of patients, endpoint events will be 
tabulated from initiation of assigned therapy through 45 days after treatment initiation.   
Additional analyses will be conducted in the sample of all randomized participants.  In the 
complete randomized sample, follow-up will begin at the time of randomization.  
 
A key secondary endpoint is the Kaplan Meier time-to-event estimate of the cumulative risk of 
the primary composite endpoint.  For treatment comparisons among randomized participants 
who initiate treatment, the cumulative risk 45-days after initiation of assigned therapy will be 
estimated, and for analyses among all randomized participants, the cumulative risk 45-days 
after randomization will be estimated.    
 
The secondary endpoints are: 
• 
Hospitalization for cardiovascular/pulmonary events 
• 
Venous thromboembolism, a composite of symptomatic DVT and PE. 
• 
Symptomatic DVT 
• 
Pulmonary embolism 
• 
Arterial thrombotic events, a composite of MI, ischemic stroke and arterial embolism 
• 
Myocardial infarction 
• 
Ischemic stroke 
• 
Arterial thromboembolism 
• 
All-cause mortality 
• 
Mortality without antecedent hospitalization 
 
Timing for the secondary endpoints is the same as what is described for the primary composite 
efficacy endpoint.   
 
An exploratory tertiary endpoint is a clinical rank-based score.  This clinical rank-based score 
is defined as the worst category accomplished during the 45-day treatment period (i.e. starting 
at treatment initiation) using the numeric rankings from best (score=1) to worst (score=9): 
1. No clinical event (i.e. no study endpoint, safety endpoint or urgent/emergent health care 
encounter).  A minor bleed that does not involve seeking medical attention is not a trial 
safety endpoint and hence is counted in this category. 
2. Non-fatal bleeding that requires medical attention but not a hospital admission 


 
 
May 31, 2021 
Page 5 of 14 
3. Non-fatal event that is one of the composite primary events that requires an urgent care 
center visit or emergency room visit but not a hospital admission (e.g. this includes a 
DVT or pulmonary embolism that do not result in a hospital admission) 
4. Non-fatal hospitalization for bleeding event or cardiovascular/pulmonary event not 
including stroke, MI, pulmonary embolism or DVT. 
5. Non-fatal hospitalization for DVT 
6. Non-fatal hospitalization for PE 
7. Non-fatal hospitalization for MI 
8. Non-fatal hospitalization for stroke 
9. Death 
 
The safety endpoints are: 
• 
Major bleeding (ISTH major bleeding) 
o Drop in hemoglobin of 2 gm/dl attributed to bleeding and 
o Requiring transfusion of 2 or more units 
o Bleeding in a critical site which includes hemorrhagic stroke and intracranial 
hemorrhage 
o Fatal bleeding 
• 
Mild bleeding (ISTH CRNMB): Non-major clinically relevant bleeding is defined as 
overt bleeding not meeting the criteria for major bleeding but associated with medical 
intervention, unscheduled contact (visit or telephone call) with a physician, 
(temporary) cessation of study intervention, or associated with discomfort for the 
participant such as pain or impairment of activities of daily life. 
• 
Development of disseminated intravascular coagulation (DIC) 
 
For the treatment comparisons among randomized participants who initiate treatment and have 
at least one follow-up contact, safety endpoints will be tabulated from initiation of assigned 
therapy through 45 days after treatment initiation and through 75 days after treatment initiation. 
For analyses involving all randomized participants, safety outcomes will be tabulated from time 
of randomization through 45 days after randomization and up to 75 days after randomization.   
 
2.4 POWER AND SAMPLE SIZE 
 
We determined the samples sizes required to provide 80% and 90% power to detect a relative 
reduction of 33% in the 45-day primary outcome event rates between two assigned treatment 
groups using chi-square statistic with one-sided test with alpha=0.025. Based on these 
estimates, we proposed a total sample of N=7000 patients with N=1750 patients assigned to 
each of the four treatment arms. Assuming a placebo event rate of 8.0%, a trial with N=1750 
patients in each arm will have 80% power to detect superiority of apixaban 5.0 mg to placebo 
when there is a 30% relative reduction in risk (i.e. 8.0% vs. 5.62%) and 90% power with a 34% 
relative reduction (i.e. 8.0% vs. 5.28%).  Assuming an event rate of 6.0% with aspirin, a trial with 
N=1750 patients in each arm will have 80% power to detect superiority of apixaban 5.0 mg to 
aspirin when there is a 34% relative reduction in risk (i.e. 6.0% vs. 3.94%) and 90% power with 
a 39% relative reduction (i.e. 6.0% vs. 3.65%).   
 


 
 
May 31, 2021 
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Since we hypothesize that the active treatments will be beneficial, we estimated that the overall 
primary composite efficacy endpoint event risk in the trial (i.e. all treatment groups combined) 
will be this population is approximately 7.0%.  We also estimated the overall bleeding event rate 
will be approximately 1.0%. With a total of N=7000 patients, we therefore assumed that we will 
observe approximately 490 patients with primary endpoint events and 70 with bleeding events. 
 
2.5 ENDPOINT ADJUDICATION 
 
All events suggestive of the primary composite endpoint will be adjudicated by a central 
independent Clinical Endpoints Committee (CEC).  All of the suspected endpoint events will be 
classified by the CEC so that each of the defined secondary endpoint events will be adjudicated.  
All suspected bleeding events deemed to be clinically relevant non-major bleeding (CRNMB), 
major bleeding or DIC will be adjudicated by the CEC.  The specific endpoints are each defined 
in the ACTIV-4B Clinical Endpoints Committee Charter. 
 
The options available to the adjudicators include the ability to confirm an event (if there is 
sufficient clinical information to support the endpoint), disconfirm the event (if there is sufficient 
clinical information to disconfirm the endpoint), or mark the event as having “insufficient 
evidence” for confirmation (or for disconfirmation).   
 
2.6 BLINDING 
 
The ACTIV-4B Outpatient trial is double blinded.  All study participants, clinical investigators, 
staff who collect data, medical monitors who classify adverse events, and Clinical Endpoints 
Committee members who adjudicate study endpoints are blinded to treatment assignment. Only 
the central data management and the unblinded statistical team have access to the treatment 
assignments.   Protocols have been developed so that treatment assignment may be revealed 
in cases of clinical emergencies.   
 
2.7 ANALYSIS POPULATIONS 
 
Modified Intention to Treat (mITT) Population:  The primary treatment comparisons will be 
based on the modified intention to treat (mITT) principle.  The mITT analyses will include only 
randomized participants who initiate their assigned treatment regimen and for whom 
there is at least one follow-up visit.  A follow-up visit includes a contact where patient-
reported outcomes or site-reported outcomes about patient status are collected.  Analyses in 
this sample will be conducted based on the randomly assigned treatment starting at the time of 
treatment initiation.     
 
All Randomized Patients:  The population of all randomized participants will be evaluated from 
time of randomization onward.  The combined population will be used to estimate the overall 
risk of events in this patient cohort. Secondary treatment comparisons will be conducted using 
the intention to treat (ITT) principle based on the randomly assigned treatment group starting at 
the time of randomization.   
 
Per Protocol Population:  The group of randomized participants who report taking ≥70% of 
their pills per week for ≥5 weeks or until the time of a primary outcome or safety event occurred 


 
 
May 31, 2021 
Page 7 of 14 
will be considered adherent to the trial treatment regimen and will be included in the per protocol 
sample.  Analysis of this per protocol group will begin at the time of treatment initiation.  mITT 
participants who adhered to their assigned treatment and have complete 45-day follow-up or 
complete follow-up up to the time of a hospitalization or a death will be included in the analysis 
of the per protocol group.   
 
2.8 HANDLING MISSING DATA 
 
Missing Outcome Data:  The primary endpoint for the ACTIV-4B Outpatient trial is a binary 
(yes/no) outcome indicating whether any of the listed events occurred within 45 days of 
treatment initiation.  Hence, our primary analysis will be conducted in the sample for whom 45-
day outcome data is available (45 day follow-up completed or a death).  We expect that the 
percentage of participants with missing 45-day outcome data due to withdrawal or loss to follow-
up will be small (<5%) and that the probability of missing data will be similar across the four 
treatment arms and will be weakly associated with the missing endpoint.  
 
We will compare those participants with and without missing endpoint data by treatment group 
and by baseline demographic features. We will also present the likelihood that missing data 
would change the conclusions about the treatment effects using a tipping point analyses.  By 
systematically and comprehensively varying assumptions about the missing outcomes in the 
four treatment arms, we will explore the whether the conclusions change.  We will allow 
assumptions about the missing outcomes in the four treatment arms to vary independently, 
including scenarios where dropouts on active drugs tend to have worse outcomes than dropouts 
on control. This approach is consistent with recent FDA guidelines (E9(R1)-Statistical-
Principles-for-Clinical-Trials attached).   
 
The secondary endpoint, the Kaplan-Meier estimate of the cumulative risk of a primary endpoint 
at 45 days, appropriately accounts for variable follow-up time under the assumption of non-
informative censoring.  Analysis of this time to event outcome among all randomized or mITT 
participants (i.e. those with and without missing 45-day data) will provide further insight about 
the robustness of the trial conclusions based on the primary composite efficacy endpoint.   
 
Missing Adjudication Data:  Each suspected specified efficacy and bleeding event is 
adjudicated by the CEC based on medical records.  In the rare case when medical records 
cannot be obtained, the adjudicators will review all available information including narratives 
from the local principal investigator or members of the study team who reported the event.  The 
adjudicators will use all available information to classify the event as confirmed, disconfirmed or 
insufficient evidence.  The primary analyses will be based on confirmed events.  A secondary 
sensitivity analysis will be based on events that are confirmed and those that have insufficient 
evidence. 
 
Missing Covariate Data:  Data will not be removed from the primary analyses due to missing 
covariate data.  Variables that have <10% missing data will be imputed using single imputation.  
Categorical variables that have > 10% missing data will include a category for missing data.  
Continuous variables that have > 10% missing data will be imputed using single imputation and 
a missing indicator variable will be added to the model.   
 


 
 
May 31, 2021 
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3. STATISTICAL ANALYSIS PLAN  
 
3.1 BASELINE DESCRIPTIVE STATISTICS 
 
The distribution of demographic, clinical history, medications and biomarker variables will be 
examined and transformations will be applied as needed.  Baseline characteristics will be 
examined for all randomized participants, for the entire mITT sample, and by assigned 
treatment group within the mITT group. Variables will be summarized using mean, standard 
deviation or median (first and third quartile) for continuous variables and frequency (percentage) 
for categorical variables.  No test of significance levels will be reported for baseline variables.    
 
3.2 RETENTION ANALYSES 
 
The proportion of mITT participants who withdraw or are lost to follow-up before 45-days of 
follow-up will be tabulated overall and by treatment group. Baseline characteristics of patients 
with missing primary outcome data will be compared to those with complete data.   
 
3.3 ADHERENCE ANALYSES 
 
The proportion of mITT participants overall and in each assigned treatment group who have 
interrupted treatment permanently or temporarily and the reason for interruption will be 
described. We will present the proportion of participants who took ≥70% of their pills as 
prescribed for ≥5 weeks or until a clinical event occurred in the overall mITT sample and 
stratified by assigned treatment group.  
 
3.4 PRIMARY OUTCOME ANALYSIS 
 
The primary analyses will be conducted in the mITT sample based on the randomly assigned 
treatment starting at the time of treatment initiation.  Participants who complete at least one 
follow-up visit after starting their assigned drug treatment will be included in the analysis. 
 
The odds of the primary composite efficacy endpoint in the mITT sample will be modeled using 
a logistic regression model defined as: 
 
Log (p/1-p) = β0 + β1Apixiban5.0 +β2Apixiban2.5 + β3Asipirin + β4Non-US + β5age + β6female  
+ β7BlackNH + β8Hispanic + β9OtherRE +β10D-Dimer+ β11HsCRP + β12Weight  
+ β13CrClearance   
 
Race/ethnicity will be defined as white non-Hispanic, black non-Hispanic, Hispanic, and 
Other/unknown race/ethnicity. White non-Hispanic race/ethnicity will serve as the references 
group.   
 
The placebo treatment group will serve as the “reference” treatment group in this model, and we 
will test whether the coefficient for each active treatment group relative to the reference placebo 
group is equal to 0 using a two-sided test with alpha=0.05.  Other pairwise treatment 


 
 
May 31, 2021 
Page 9 of 14 
comparisons (apixaban 5.0 versus apixaban 2.5, apixaban 5.0 versus aspirin, apixaban 2.5 
versus aspirin) will be conducted, and the effect of treatment with apixaban (i.e. the combined 
group including both apixaban 5.0 and apixaban 2.5) will be compared with placebo.   
 
If the number of mITT participants with a primary composite efficacy endpoint event in the 45-
days after treatment initiation is low, a logistic regression model with a reduced number of 
covariates must be used in order to have adequate degrees of freedom for valid estimation. 
Below are the planned models to be used for the primary treatment comparison under the 
scenarios that the number of patients with primary endpoint events is <30, 30-49, and ≥50.  The 
same treatment contrasts will be computed in the reduced models as described for the full 
model. 
 
If the number of mITT participants with a primary endpoint event is <30, an unadjusted 
logistic regression model will be used as the primary model to assess the effect of assigned 
treatment.   
 
Log (p/1-p) = β0 + β1Apixiban5.0 +β2Apixiban2.5 + β3Asipirin  
 
If the number of mITT participants with a primary endpoint event is 30-49, a logistic 
regression model adjusting only for age and D-dimer level will be used as the primary model to 
assess the effect of assigned treatment.   
 
Log (p/1-p) = β0 + β1Apixiban5.0 +β2Apixiban2.5 + β3Asipirin + β4age + β5D-Dimer 
 
If the number of mITT participants with a primary endpoint event is ≥50, the full logistic 
regression model will be used as the primary model to assess the effect of assigned treatment.   
 
Log (p/1-p) = β0 + β1Apixiban5.0 +β2Apixiban2.5 + β3Asipirin + β4Non-US + β5age + β6female  
+ β7BlackNH + β8Hispanic + β9OtherRE +β10D-Dimer+ β11HsCRP + β12Weight  
+ β13CrClearance  
 
In addition to the primary logistic regression analysis, the unadjusted estimated risk of the 
primary composite efficacy endpoint in each treatment group (i.e. # of participants with an event 
/ # of participants in the group), and the pairwise relative risks and absolute risk differences with 
95% confidence intervals will be calculated and presented.  
 
An ITT and a per protocol analysis will be conducted by running the multivariable adjusted 
logistic regression model and the unadjusted risk estimates using the corresponding sample 
and relevant exposure time.  
 
3.5 KEY SECONDARY OUTCOME ANALYSES 
 
Kaplan-Meier cumulative incidence curves will be created for the primary composite efficacy 
endpoint up to 45 days after treatment initiation stratified by assigned treatment group in the 
mITT sample.  Log-rank statistics will be computed to compare the time to event estimates over 
time among the four treatment groups.  The estimated cumulative risk at 45-days and the 95% 
confidence interval for the estimated cumulative risk at 45-days will be determined for each 


 
 
May 31, 2021 
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treatment group. Pairwise differences and 95% confidence intervals for differences will be 
computed.  The combined group of prophylactic and therapeutic doses of apixaban will be 
compared with placebo. 
 
Kaplan-Meier cumulative incidence curves will be created for the primary composite efficacy 
endpoint up to 45 days after randomization for the complete randomized sample overall and 
stratified by assigned treatment group (ITT).  Log-rank statistics will be computed to compare 
the time to event estimates over time among the four assigned treatment groups.  The 
estimated cumulative risk at 45-days and the 95% confidence interval for the estimated 
cumulative risk at 45-days will be determined for the overall group and for each treatment group.    
 
3.6 SECONDARY OUTCOME ANALYSES 
 
For each defined secondary outcome event, the unadjusted risk of the endpoint in each 
treatment group (i.e. # of participants with the specified event / # of participants in the group) 
and pairwise relative risks and the absolute risk difference between treatment groups will be 
calculated with their 95% confidence intervals.  In addition, the effect of treatment with apixaban 
(i.e. prophylactic and therapeutic groups combined) will be compared with placebo. 
 
3.6 EXPLORATORY TERTIARY OUTCOME ANALYSES 
 
The distribution across the 9 categories of the clinical rank-based score and the median and 
25th and 75th percentile will be present each treatment group in the mITT sample.  Kruskal-
Wallace tests will be used to compare the distribution of the clinical rank-based score among 
the assigned treatment groups in the mITT sample.  Pairwise comparisons with Wilcoxon rank 
sum statistics will be conducted to determine if one treatment has a “better” outcome relative to 
another.   
  
3.7 SAFETY ANALYSES 
 
The risk and 95% CI of each defined safety endpoint event and the composite of any defined 
safety endpoint event (major bleeding, CRNMB or DIC) at 45 and at 75 days will be computed 
for each treatment group in the mITT.  Pairwise relative risks and absolute risk differences 
between treatment groups will be calculated with their 95% confidence intervals.   
 
3.8 SUBGROUP ANALYSES AND EFFECT MODIFICATION 
 
A select number of subgroup variables have been specified a priori: 
• 
D-dimer (<1.0 ULN, [1.0-2.0 ULN), [2.0-3.0 ULN), ≥ 3.0 ULN, or by quartiles if needed) 
• 
CRP by quartiles based on the data 
• 
Age (<60 years, ≥60 years) 
• 
Sex 
• 
Race/ethnicity (White non-Hispanic, Black non-Hispanic, Hispanic, other)  
• 
Renal function (creatinine clearance 30-49 ml/min, 50-90 ml/min, >91 ml/min) 
 


 
 
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The risk of the primary composite efficacy endpoint outcome and the 45-day risk of major 
bleeding with 95% confidence intervals will be estimated in each treatment group within each 
subgroup for the mITT sample.  Evidence of effect modification of the treatment effectiveness by 
subgroup will be tested by creating a logistic regression model including the subgroup variable, 
treatment assignment, and the interaction between the subgroup variable and treatment 
assignment.  If a subgroup variable is inherently continuous (i.e. D-dimer, CRP and age), these 
variables will be appropriately transformed as needed to approximate a normal distribution, and 
included in the model as a continuous variable.  The significance of the interaction term will be 
presented. Additional subgroups may be examined in exploratory analyses based on observed 
results from the trial or information from external sources.   
 
We will examine the distribution of baseline D-dimer in the entire mITT and in the randomized 
sample, and we will analyze the odds of the primary composite efficacy endpoint and major 
bleeding, irrespective of assigned treatment group by D-Dimer subgroup.  Logistic regression 
models and associated ROC curves will be created for the primary efficacy endpoint and for 
major bleeding by continuous D-dimer level.   LOESS curves for the logit of the primary efficacy 
endpoint and for major bleeding by continuous D-dimer level will also be examined. 
 
3.9 ANALYSIS OF DURATION OF TREATMENT 
 
Kaplan-Meier cumulative incidence curves will be created to assess the time to the first primary 
endpoint event and the time to the first safety event, irrespective of treatment assignment.  
Assuming that bleeding events occur at a fairly constant rate over time, we suggest that if ≥ 
90% of the primary endpoint events occur in the first 21 days, then the DSMB will consider 
modifying the treatment arms such that the duration of therapy is shortened to 21 days. Curves 
stratified by treatment group will be examined before finalizing a recommendation.   
   
 
4. INTERIM MONITORING PLAN FOR EFFICACY, FUTILITY AND SAFETY  
 
4.1 OVERVIEW OF PLANNED INTERIM ANALYSIS 
 
An independent data safety and monitoring board (DSMB) will review all interim analyses 
prepared by an unblinded statistician.  The number of patients randomized, the number of 
randomized participants who initiated treatment and the primary, secondary and safety 
endpoints for the entire randomized and the entire mITT samples will be presented.  Unadjusted 
risk of the defined primary, secondary and safety endpoints by assigned treatment group in the 
mITT sample will be examined on a monthly basis.  For DSMB presentation, two versions of the 
primary, secondary and safety endpoint tables will be presented: one table will include the best 
information available which will include the adjudicated endpoints for events that have been 
classified by the CEC and self-reported endpoints for events that have not been classified by 
the CEC, and a second table that will include adjudicated endpoints only.  A complete interim 
analysis of efficacy, futility, and safety will be conducted for each full DSMB review meeting 
which will occur approximately every 3 months. 
 
A Bayesian analytic approach is proposed for the interim monitoring plan in order to utilize prior 
information when estimating the posterior probabilities in the sequential interim analyses.  


 
 
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Initially, the placebo group will serve as the “control group”; however, if the placebo arm is 
dropped and the trial continues, the aspirin arm will be designated as the control group for future 
treatment comparisons. 
 
Decision rules have been established for efficacy based on the posterior probability that the 
active treatment regimen is beneficial as compared to placebo with respect to the primary 
composite efficacy endpoint.  Decision rules were created such that the overall type I error 
approximates the pre-specified alpha=0.025 for a one-sided test.  Assuming a non-informative 
prior distribution for each odds ratio at the first interim analysis, we will calculate the posterior 
probability that an active treatment is superior to placebo.  We will update these posterior 
probabilities with new data at each subsequent interim analysis.  If the posterior probability 
exceeds the pre-specified threshold for superiority at any of the interim analyses, the superior 
treatment will be declared efficacious and the other treatment may be dropped.   
  
Decision rules have been developed for assessing futility of the active treatments.  The posterior 
probability that each of the active treatments is inferior or equivalent to placebo with respect to 
the primary composite efficacy endpoint will be calculated assuming non-informative priors at 
the outset of the trial.  When the posterior probability exceeds a specified threshold, futility will 
be established and the respective active therapy may be dropped from the trial.   
 
Safety data will be presented and analyzed at each meeting, but no formal decision rules will be 
established a priori for the bleeding safety endpoints.  Data will be presented so that the DSMB 
can evaluate the net risk benefit ratio for each treatment. 
 
At each meeting, the DSMB will examine the rate of enrollment (and treatment initiation) in the 
trial as well as the overall risk of the primary endpoint.  Based on this information, they may 
request a traditional futility analysis of conditional power to detect superiority.  This involves a 
determination of the detectable risk ratio (or relative risk reduction) conditional on the observed 
data at that time under various assumptions regarding the future risk of endpoint events and the 
underlying treatment risk ratios.     
 
4.2 FORMAL MONITORING OF SUPERIORITY BASED ON PRIMARY ENDPOINT 
 
A logistic regression model will be created for the primary composite efficacy endpoint such that 
the effect of each active treatment group (relative to the placebo reference group) will be 
estimated adjusting for covariates (age, sex, race/ethnicity, D-dimer, and hsCRP, weight and 
calculated creatinine clearance) as specified in Section 3.4 based on the observed number of 
participants with events.  The primary analyses for efficacy will be based on the odds ratios, 
comparing one treatment to another, derived from this model.  One treatment is beneficial 
compared to another if the [ Odds Ratio < 1.00 ] for the primary composite outcome.  Assuming 
non-informative priors at the first look, we will calculate the posterior probabilities that the [ Odds 
Ratio < 1.00 ] for each active treatment compared to placebo.  If at any analysis time-point, the 
upper bound of the lower 99% credible interval for the odds ratio is less than 1.00, the active 
treatment arm will be considered superior.   
 
The decision rule for declaring superiority based on the primary composite outcome is: 
≥ 0.99 Posterior Probability that the OR (active vs placebo) < 1.00 


 
 
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The DSMB will use this information to make a recommendation to the NHLBI.  The DSMB can 
recommend that the Outpatient COVID-19 trial should continue as proposed, that the control 
treatment arm should be dropped from the trial, that the trial protocol should be modified, or that 
the Outpatient COVID-19 trial should be terminated early. The final decision to stop trial rests 
with the NHLBI. 
 
4.3 FORMAL MONITORING OF FUTILITY BASED ON PRIMARY ENDPOINT 
 
Using the same logistic regression model that will be used for the primary analyses, we will 
determine the posterior probability that the active arm is equivalent or inferior to placebo 
adjusting for covariates (age, sex, race/ethnicity, D-dimer, and hsCRP, weight and calculated 
creatinine clearance) as specified in Section 3.4 based on the observed number of participants 
with events.  Given that the trial was designed to have powered to detect a relative risk 
reduction of 33% with active treatment, futility will be defined for an active arm if the lower 
bound of the upper 95% credible interval for the odds ratio comparing the active arm to placebo 
is greater than 0.75. 
 
The decision rule for declaring futility based on the primary composite outcome is: 
≥ 0.95 Posterior Probability that the  OR (active vs placebo) > 0.75   
 
This roughly corresponds to the having an estimated Odds Ratio that is 1.00 (or greater) and 
the two-sided 90% confidence interval extends from 0.75 to 1.33 (or greater). 
 
The DSMB will use this information to determine its recommendation to NHLBI. The DSMB can 
recommend that the Outpatient COVID-19 trial should continue as proposed, that the futile 
active treatment arm should be dropped from the trial, that the trial protocol should be modified, 
or that the Outpatient COVID-19 trial should be terminated early. The NHLBI will make the final 
decision.  
 
4.4 MONITORING SAFETY 
 
A logistic regression model will be created for the major bleeding endpoint and for the 
composite safety endpoint (major bleeding, CRNMB and DIC) such that the effect of each active 
treatment group (relative to the placebo reference group) will be estimated and the odds ratios, 
comparing one treatment to another, will be derived from this model.   We will not create explicit 
decision rules based on the bleeding posterior probability.   
 
If safety issues arise, the DSMB will use their clinical judgement to assess the potential risks 
relative to the potential benefits for each active drug compared to control.  The DSMB may also 
examine the safety and efficacy data in subgroups known to be high risk for bleeding such as 
those with older age and/or higher BMI.  The DSMB will use the monitoring information to 
determine its recommendation to NHLBI.  The DSMB can recommend that the Outpatient 
COVID-19 trial should continue as proposed, that one treatment arm may be dropped, that the 
trial protocol should be modified, or that the Outpatient COVID-19 trial should be terminated 
early for safety reasons.  
 


 
 
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4.5 STUDY STAGES AND INTERVENTIONS 
 
The first Stage of this study has been determined and is outlined above. In Stage 1, there will be 
four intervention arms: (1) prophylactic anticoagulation with apixaban 2.5mg po bid; (2) 
therapeutic anticoagulation with apixaban 5.0mg op bid; (3) antiplatelet therapy with low dose 
aspirin 81mg po qd and (4) placebo. Subsequent Stages will incorporate recommendations from 
the DSMB. 
  
The overarching plan for adaptive changes are as follows: 
   
1. If an active drug is found to be futile relative to placebo (i.e. results indicate that an 
active arm is associated with a slightly reduced risk, no effect, or a greater risk of the 
primary outcome as compared with placebo): The futile active arm will be dropped, no new 
treatment arm will be added, and the trial will continue with the remaining treatment arms.  
The randomization scheme will be adjusted to include the 3 remaining arms with equal 
probabilities (i.e. 1:1:1), and the treatment comparisons among these arms will continue as 
designed.   
 
2. If an active drug is found to be superior to placebo: We will declare a winner, and we will 
announce this finding. The placebo arm will be dropped.  If the observed differences 
between the superior active arm and all of the other active arms are sizable (e.g. >20% 
relative reduction) but do not yet cross the decision boundary, the trial may be terminated 
based on a risk/benefit analysis by the DSMB.  If the observed differences between the 
superior active arm and at least one of the other active arms is small, this would be 
announced, and the trial may continue with the “competitive arms” based on a risk/benefit 
analysis by the DSMB.  The randomization scheme will be modified to assign each of the 
remaining treatment arms with an equal probability. The aspirin arm will become the 
reference arm for future statistical models. 
 
3. If a promising new drug is identified from external studies: At the outset of this trial, we 
do not plan on adding any new treatment arms. However, if a promising candidate drug 
were to be identified in the next 6 months, we will consider adding an arm to the trial based 
on time and other pragmatic considerations.  The randomization scheme and analytic 
approach would be modified to include an extra treatment arm.