Clinical trial NCT05592418
Conditions: Post COVID-19 Condition Long COVID
Sponsor: AIM ImmunoTech Inc.
Start date: 2023-06-30; Completion date: 2023-11-30
Enrollment: 80 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the efficacy and safety of Ampligen® administered twice weekly by intravenous (IV) infusions in subjects experiencing the Post-COVID Condition of fatigue.

Detailed description:
This is a Phase 2, two-arm, randomized, double blind, placebo controlled multicenter study to evaluate the efficacy and safety of Ampligen® in patients experiencing the Post-COVID Condition of fatigue. Patients will be randomized 1:1 to receive twice weekly IV infusions of Ampligen® or placebo.

Arms: arm 1: Subjects will receive rintatolimod (intravenous \[IV\]), up to 400 mg twice weekly for 12 weeks. arm 2: Subjects will receive placebo / normal saline (intravenous \[IV\]), up to 160 mL twice weekly for 12 weeks.
Interventions: intervention 1: Rintatolimod intervention 2: Placebo / Normal Saline
Intervention descriptions: intervention 1: 100 to 400 mg twice weekly intervention 2: 40 to 160 mL twice weekly

Protocol documents:
Prot_000.pdf: 
 
A Randomized, Double Blind, Placebo Controlled Study to Evaluate the 
Efficacy and Safety of Ampligen® in Patients with Post-COVID Conditions  
Protocol Number: 
AMP-518 
Version: 
Version 4.0 
Date: 
23-Aug-2023 
 
 
 
Sponsor: 
AIM ImmunoTech Inc.  
2117 SW Highway 484 
Ocala, FL 34473, USA 
 
 
 
 
Clinical Trials.gov Identifier: NCT05592418 
 
 
Confidentiality Statement 
 
This document is a confidential communication of AIM ImmunoTech Inc. It is provided for the 
conduct of a clinical research study. The information contained in this document is confidential 
and, except to the extent necessary to obtain informed consent or IEC/IRB approval, cannot be 
disclosed unless required by governmental regulation. Persons to whom any portion of the contents 
of this document is disclosed must be informed that the information is confidential and may not 
be further disclosed by them. 


 
 
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PROTOCOL APPROVAL PAGE 
 
 
 
 
 
Protocol Number:  
AMP-518 
 
Version: 
 
Version 4.0 
 
Date: 
 
 23-Aug-2023 
 
We, the undersigned, have reviewed this protocol and agree that it contains all relevant information 
required to meet FDA, GCP and all applicable regulatory guidelines and statutes. 
PROTOCOL APPROVAL FOR USE 
 
 
 
 
 
 
 
Program Director; Amarex Clinical Research, LLC  
Signature 
 
Date 
 
 
 
 
 
 
Pharmacovigilance; Amarex Clinical Research, 
LLC.  
 
 
Signature 
 
Date 
 
 
 
 
 
 
Biostatistics; Amarex Clinical Research, LLC.  
 
 
Signature 
 
Date 
 
 
 
 
 
 
Medical Writing; Amarex Clinical Research, LLC. 
 
 
Signature 
 
Date 
 
 
 
 
 
 
Chief Scientific and Medical Officer; AIM 
ImmunoTech Inc. 
 
 
Signature 
 
 Date 


 
 
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INVESTIGATOR’S SIGNATURE PAGE 
 
 
 
 
Protocol Number:  
AMP-518 
 
Version: 
 
Version 4.0 
 
Date: 
 
23-Aug-2023 
 
I have read the protocol specified above and agree to participate in and comply with the procedures, 
as outlined herein for the conduct of this clinical trial. I also agree to comply with US Food and 
Drug Administration (FDA) regulations and Investigational Review Board/Institutional Ethics 
(IRB/IEC) requirements for testing on human subjects. I agree to ensure that the requirements for 
obtaining informed consent are met.  
 
 
 
 
 
Principal Investigator’s Signature 
 
 
 
 
Date 
Print Name 
 
 
 
 
 
 
Site Number 
 
 
 


 
 
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SPONSOR INFORMATION 
 
 
Sponsor Office: 
 
AIM ImmunoTech Inc.  
 
 
 
 
 
 
2117 SW Highway 484 
 
 
 
 
 
 
Ocala, FL 34473, USA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONTRACT RESEARCH ORGANIZATION INFORMATION 
Amarex Clinical Research, LLC  
Amarex Office: 
Amarex Clinical Research, LLC 
 
20201 Century Boulevard, Suite 450 
 
Germantown, MD 20874  
                                               USA 
 
Project Manager: 
   
Telephone number: 
 
Fax number: 
 
E-mail: 
 
 
 
Safety/Pharmacovigilance  
Contact: 
 
 
 
Telephone number:   
 
Fax number:  
 
 
E-mail: 
 
 
  
 
 
 
 
 
 


















 
 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ..............................................................................................................5 
TABLE OF CONTENTS ............................................................................................................13 
List of Tables .................................................................................................................................18 
List of Figures ...............................................................................................................................19 
List of Abbreviations .....................................................................................................................20 
1 INTRODUCTION AND BACKGROUND .........................................................................23 
 Statement of Intent ..............................................................................................................23 
 Background of the COVID-19 Disease ...............................................................................23 
1.2.1. 
Post-COVID Conditions....................................................................................24 
 Name and Description of the Investigational Product .........................................................25 
 Summary of Prior Pre-Clinical and Clinical Studies ...........................................................26 
 
 
 
 
 
 
 
 
 
 
2. STUDY OBJECTIVES AND OUTCOME MEASURES ...................................................39 
 Study Objectives ..................................................................................................................39 
2.1.1. 
Primary Objective..............................................................................................39 
 Study Outcome Measures ....................................................................................................39 
2.2.1. 
Primary Outcome Measure ................................................................................39 
2.2.2. 
Secondary Outcome Measures ..........................................................................39 
2.2.3. 
Exploratory Endpoints .......................................................................................39 
2.2.4. 
Safety Outcome Measures .................................................................................40 
3. STUDY DESIGN ....................................................................................................................41 
 Study Center ........................................................................................................................41 
 Study Population .................................................................................................................41 
 Eligibility Criteria ................................................................................................................41 
3.3.1. 
Inclusion Criteria ...............................................................................................41 
3.3.2. 
Exclusion Criteria ..............................................................................................42 


 
 
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4. STUDY SCHEDULE .............................................................................................................45 
 Screening Phase ...................................................................................................................52 
4.1.1. 
Screening Visit (V1) ..........................................................................................52 
 Treatment Phase ..................................................................................................................53 
4.2.1. 
Randomization (V2) ..........................................................................................53 
4.2.2. 
Subsequent Treatment Visits (V3-V25) ............................................................54 
 Follow-Up Phase .................................................................................................................55 
4.3.1. 
Follow-Up visit 1 (V26) ....................................................................................55 
4.3.2. 
Follow-Up visit 2 (V27) ....................................................................................56 
 Unscheduled Visits ..............................................................................................................57 
5. SUBJECT COMPLETION, WITHDRAWAL AND CRITERIA FOR STOPPING THE 
STUDY ....................................................................................................................................58 
 Subject Completion .............................................................................................................58 
 Subject Treatment Discontinuation .....................................................................................58 
 Subject Withdrawal From Study .........................................................................................58 
 Data Collected from Treatment Discontinued/Withdrawn Study Subjects .........................58 
6. STUDY TREATMENT .........................................................................................................60 
 Description of the Investigational Product ..........................................................................60 
6.1.1. 
Packaging and Labeling ....................................................................................60 
6.1.2. 
Storage and Handling ........................................................................................60 
 Administration .....................................................................................................................60 
6.2.1. 
Study Personnel .................................................................................................62 
 Drug Compliance ................................................................................................................63 
 Concomitant Medications ....................................................................................................63 
 
 
7. DESCRIPTION OF PROTOCOL ASSESSMENTS AND PROCEDURES ...................64 
 Informed Consent ................................................................................................................64 
 Assessment of Eligibility .....................................................................................................64 
7.2.1. 
Re-screening ......................................................................................................64 
 Demographic Information ...................................................................................................65 
 Medical History ...................................................................................................................65 


 
 
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 Physical Examination ..........................................................................................................65 
 Vital Signs, Height and Weight ...........................................................................................66 
 30 Minute Site Check ..........................................................................................................67 
 Concomitant Medication .....................................................................................................67 
 Clinical Laboratory Assessments ........................................................................................67 
 
 
 
 
 
 Pulse oxygen saturation (SpO2) ..........................................................................................69 
 
 
 
 
 
 Viral Testing for SARS-CoV-2 ...........................................................................................69 
 Electrocardiogram ...............................................................................................................70 
 PHQ-9 Patient Depression Questionnaire ...........................................................................70 
 6-Minute Walk Test .............................................................................................................70 
 Montreal Cognitive Assessment ..........................................................................................70 
8. STATISTICAL ANALYSIS .................................................................................................71 
 Treatment Groups ................................................................................................................71 
 Description Of Study Outcomes and Estimand ...................................................................71 
 Sample Size Determination and Rationale ..........................................................................72 
 Randomization and Stratification ........................................................................................72 
 Blinding ...............................................................................................................................72 
 Time to Unblinding .............................................................................................................73 
8.6.1. 
Emergency Unblinding......................................................................................73 
8.6.2. 
Final Analysis ....................................................................................................73 
 Interim Analysis ..................................................................................................................73 
 General Statistical Considerations .......................................................................................73 
8.8.1. 
Analysis Populations .........................................................................................73 
8.8.2. 
Covariates ..........................................................................................................74 
8.8.3. 
Missing Data......................................................................................................74 


 
 
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8.8.4. 
Multiplicity ........................................................................................................74 
 Analysis Methods ................................................................................................................74 
8.9.1. 
Subject Disposition............................................................................................75 
8.9.2. 
Demographic and Baseline Characteristics .......................................................75 
8.9.3. 
Concomitant Medications/Therapies .................................................................75 
8.9.4. 
Efficacy Analyses ..............................................................................................75 
8.9.5. 
Safety Analyses .................................................................................................76 
9. SAFETY REPORTING.........................................................................................................78 
 Adverse event (AE) Definition ............................................................................................78 
 Reporting of Adverse Events ..............................................................................................78 
9.2.1. 
Impact on Study Treatment ...............................................................................78 
9.2.2. 
CTCAE Grade (Intensity) Assessment..............................................................78 
9.2.3. 
Causality Assessment ........................................................................................79 
9.2.4. 
Treatment Given as a Result of the Event .........................................................80 
9.2.5. 
Outcome Assessment ........................................................................................80 
 Serious Adverse Event (SAE) Definition ............................................................................80 
 Reporting of Serious Adverse Events .................................................................................81 
9.4.1. 
SAE Follow-Up .................................................................................................81 
 Expected/anticipated events ................................................................................................81 
 Pregnancy Reporting ...........................................................................................................81 
9.6.1. 
AE and SAE Reporting .....................................................................................82 
9.6.2. 
Informed Consent ..............................................................................................82 
9.6.3. 
Pregnancy Follow-Up........................................................................................82 
10. DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION ......................................83 
11. QUALITY CONTROL AND QUALITY ASSURANCE ...................................................84 
 Monitoring Requirements ....................................................................................................84 
 Acceptability of Case Report Forms (CRFs) ......................................................................84 
 Modification of Protocol .....................................................................................................84 
 Reporting Protocol Deviations ............................................................................................85 
11.4.1. 
Major Protocol Deviation or Violation .............................................................85 
11.4.2. 
Minor Protocol Deviation or Violation .............................................................85 
12. ETHICS AND REGULATORY REQUIREMENTS .........................................................87 


 
 
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 Institutional Review Board/Independent Ethics Committee (IRB/IEC) .............................87 
 Investigator’s Responsibilities ............................................................................................87 
 Subject Informed Consent Requirements ............................................................................88 
13. DATA HANDLING AND RECORD KEEPING ................................................................89 
 Recording and Collection of Data .......................................................................................89 
 Clinical Data Management ..................................................................................................89 
 Archiving .............................................................................................................................90 
14. PUBLICATION PLAN .........................................................................................................91 
15. REFERENCES .......................................................................................................................92 
16. APPENDIX .............................................................................................................................95 
 Appendix 1: Common Terminology Criteria for Adverse Events v5.03 ............................95 
 Appendix 2: PROMIS® Sleep Disturbance – Short Form 4a ..............................................95 
 Appendix 3: PROMIS® Cognitive Function- Abilities short form 8a .................................95 
 Appendix 4: PROMIS® Fatigue Scale.................................................................................95 
 Appendix 5: Symptom Burden Questionnaire for Long COVID (SBQ-LC) ......................95 
 Appendix 6: PHQ-9 Patient Depression Questionnaire ......................................................95 
 Appendix 7: 6-Minute Walk Test ........................................................................................95 
 Appendix 8: Montreal Cognitive Assessment (MoCA) ......................................................95 
 Appendix 9: Holiday/Vacation Week Visit Scheduling Guidance Document ....................96 




 
 
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LIST OF FIGURES 
 
 
 
 
 
 
 
 
 
 
 


 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
ANA 
Antinuclear Antibodies 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
BSL 
Baseline 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CDC 
Centers for Disease Control 
CFR 
Code of Federal Regulations 
CFS 
Chronic Fatigue Syndrome 
CHF 
Congestive Heart Failure 
CNS 
Central Nervous System 
COPD 
Chronic Obstructive Pulmonary Disease 
COVID 
Coronavirus Disease 2019 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRS 
Cytokine Release Syndrome 
CS 
Clinically Significant 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMS 
Clinical Trial Management System 
DIS 
Diagnostic Interview Schedule 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EOT 
End of Treatment 
ETT 
Exercise Tolerance Testing 


 
 
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Abbreviation 
Term 
FDA 
U.S. Food and Drug Administration 
FUV 
Follow-up Visit 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GMP 
Good Manufacturing Practice 
HCT 
Hematocrit 
HEENT 
Head, Ears, Eyes, Nose, and Throat 
HIPAA 
Health Insurance Portability Accountability Act 
HPF 
High Power Field 
IA 
Interim Analysis 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intention to Treat 
IWRS 
Interactive Web Based Response System 
IV 
Intravenous 
KPS 
Karnofsky Performance Score 
LAR 
Legally Authorized Representative 
LDH 
Lactate dehydrogenase 
MoCA 
Montreal Cognitive Assessment 
MCID 
Minimal Clinically Important Difference 
ME 
Myalgic Encephalomyelitis 
ORF 
Open-Reading Frames 
PEM 
Post Exertional Malaise 
PCR 
Polymerase Chain Reaction 
PHQ 
Patient Health Questionnaire 
PI 
Principal Investigator 
RBC 
Red Blood Cells 
RNA 
Ribonucleic Acid 


 
 
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Abbreviation 
Term 
SAE 
Serious Adverse Event 
SARS 
Severe Acute Respiratory Syndrome 
SAS 
Statistical Analysis System 
SBQ-LC 
Symptom Burden Questionnaire for Long COVID 
SLE 
Systemic Lupus Erythematosus 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SV 
Screening Visit 
TEAE 
Treatment Emergent Adverse Event 
TLR3 
Toll like receptor 3 
TRS 
Transcription-Regulating Sequences 
TV 
Treatment Visit 
ULN 
Upper Limit of Normal 
USA 
United States of America 
WBC 
White Blood Cells 


 
 
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1 INTRODUCTION AND BACKGROUND 
 
STATEMENT OF INTENT 
The design, conduct and reporting of this study shall be conducted in compliance with the protocol, 
International Conference on Harmonization/Good Clinical Practice (ICH/GCP), and all 
appropriate regulatory requirements. Investigator(s) participating in this study will have 
documented training in GCP. Independent monitoring of the trial will be accomplished utilizing a 
Contract Research Organization (CRO). 
 
BACKGROUND OF THE COVID-19 DISEASE 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the viral cause of coronavirus 
disease 2019 (COVID-19) was first identified in late 2019 in Wuhan, Hubei province, China. On 
11 March 2020, the World Health Organization declared the disease a global pandemic. The global 
burden of SARS CoV-2 infection continues to increase with estimates of more than 200 million 
people infected and over four million deaths as of September 2021. 
While some individuals infected with SARS-CoV-2 may be asymptomatic, many people display 
symptomatic disease varying from mild to critical in severity. Severe-to-critical illness is typically 
marked by hypoxemic respiratory failure requiring ventilatory support. Morbidity and mortality 
rates are elevated among patients with pre-existing co-morbidities such as cardiovascular disease, 
diabetes mellitus, chronic respiratory disease, hypertension and cancer. The observed case fatality 
ratio (CFR) varies considerably from country to country and over time. However, the CFR in the 
USA has been estimated at 2.8%. While public discourse on COVID-19 has largely centered 
around patients with severe or fatal illness, it has become apparent that a growing number of 
patients experience mild to moderate symptoms for a prolonged period of time. 
Patients and survivors of COVID-19 from the Body Politic COVID-19 Support Group created and 
analyzed a survey targeted at patients experiencing symptoms for over two weeks. Responses from 
640 
patients 
were 
collected 
between 
April 
21 
and 
May 
2, 
2020 
(https://patientresearchcovid19.com/research/report-1/). 
Key findings were symptoms are not limited to cough, fever, and shortness of breath. Other widely 
reported symptoms span neurological, gastrointestinal, cardiovascular, and other systems and 
include fatigue (reported by 81.3% of respondents), chills/sweats (75.9%), body aches (73.9%), 
headache (72.2%), brain fog and concentration issues (68.6%), gastrointestinal issues (66.9%), 
trouble sleeping (66.1%), and dizziness (60.6%). An elevated temperature under 100.1°F was 
reported by 72.2% of respondents while a fever over 100.1°F was reported by only 47.8% of 
respondents. The other key finding was recovery is volatile, includes relapses, and can take six or 
more weeks. At the time respondents took the survey, 90.6% reported not being recovered and 
were, on average, on day 40 of experiencing symptoms. 89% of respondents said that their 
symptoms fluctuated in intensity and frequency, and 70% reported new symptoms appearing at 


 
 
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different stages of their illness. Based on textual responses and anecdotes from the support group, 
patients may feel better for days or weeks only to relapse into old or new symptoms soon after. 
1.2.1. Post-COVID Conditions 
The abundance of symptoms described above have now been narrowed and characterized by the 
CDC as nineteen Post-COVID Conditions [Post-COVID Conditions CDC].  Although most people 
with COVID-19 get better within weeks of illness, some people continue to experience these post-
COVID conditions. Post-COVID conditions are a wide range of new, returning, or ongoing health 
problems people can experience four or more weeks after first being infected with the virus that 
causes COVID-19. Even people who did not experience COVID-19 symptoms in the days or 
weeks after they were infected can have post-COVID conditions.  
These conditions can present as various types and combinations of health problems for different 
lengths of time. Unlike some of the other types of post-COVID conditions that tend only to occur 
in people who have had severe illness, these symptoms can happen to anyone who has had COVID-
19, even if the illness was mild, or if they had no initial symptoms. People commonly report 
experiencing different combinations of the following symptoms: 
• Difficulty breathing or shortness of breath 
• Tiredness or fatigue that interferes with daily life 
• Symptoms that get worse after physical or mental activities (also known as post-exertional 
malaise) 
• Difficulty thinking or concentrating (sometimes referred to as “brain fog”) 
• Cough 
• Chest pain  
• Stomach pain 
• Headache 
• Fast-beating or pounding heart (also known as heart palpitations) 
• Joint or muscle pain 
• Pins-and-needles feeling 
• Diarrhea 
• Sleep problems 
• Fever 
• Dizziness on standing (lightheadedness) 
• Rash 
• Depression or anxiety 
• Change in smell or taste 










 
 
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2. 
STUDY OBJECTIVES AND OUTCOME MEASURES 
 
STUDY OBJECTIVES 
2.1.1. Primary Objective 
The purpose of this study is to assess the efficacy and safety of Ampligen® administered twice 
weekly by IV infusions in subjects experiencing the Post-COVID Condition of fatigue. 
 
STUDY OUTCOME MEASURES 
2.2.1. Primary Outcome Measure 
• Change from baseline to week 13 in PROMIS® Fatigue Score (T-Score). 
2.2.2. Secondary Outcome Measures 
• Change from baseline to week 6 in PROMIS® Fatigue Score (T-Score). 
Note: Additional PROMIS® Fatigue Score analysis (change from baseline) at week 6 and 
13 will be performed excluding response to item, “How often did you have enough energy 
to exercise strenuously?” 
• Change from baseline to week 6 and 13 in distance traveled during a 6-minute walk test. 
• Proportion of subjects with minimal clinically important difference (MCID), defined as at 
least 54 m, in the Six-Minute Walk Test (6MWT) at the end of 12-week treatment phase. 
• Change from baseline to week 6 and 13 in PROMIS® Cognitive Function Score (T-Score).  
• Change from baseline to week 6 and 13 in PROMIS® Sleep Disturbance Score (T-Score). 
2.2.3. Exploratory Endpoints 
• Changes from baseline in COVID-19-related symptoms using Symptom Burden 
Questionnaire for Long COVID (SBQ-LC) during the course of the treatment phase. 
Note: A set of common COVID-19-related symptoms (see Symptom Burden Questionnaire 
for Long COVID (SBQ-LC)) will be evaluated at each scheduled study visit by the patient 
regardless of which symptoms a subject had at baseline, as new symptoms may appear 
following the baseline assessment.  
• Change from baseline in cognitive function as measured by Montreal Cognitive 
Assessment (MoCA) at week 4, 8, and 13 during the treatment phase. 
• Incidence of hospitalization during the treatment phase. 
• Duration (days) of hospitalization during the treatment phase. 
• Evaluation of lymphocyte profile by flow cytometry in patients with post-COVID-19 
conditions. 


 
 
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• Identification and evaluation of plasma protein biomarkers in patients with post-COVID-
19 conditions.  
2.2.4. Safety Outcome Measures 
• Incidence of treatment-related adverse events. 
• Incidence and severity of treatment-emergent adverse events (TEAEs). 
• Incidence of serious adverse events (SAEs). 
• Incidence of TEAEs and SAEs leading to discontinuation of study medication. 
• Changes in blood chemistry, hematology, and coagulation parameter results. 
• Changes in vital signs including temperature, pulse, respiratory rate, systolic and diastolic 
blood pressure. 
• Changes in physical examination results. 
• Change in electrocardiogram (ECG) results. 
 
 


 
 
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3. 
STUDY DESIGN  
This is a Phase 2, two-arm, randomized, double blind, placebo controlled multicenter study to 
evaluate the efficacy and safety of Ampligen® in patients experiencing the Post-COVID Condition 
of fatigue. Patients will be randomized 1:1 to receive twice weekly IV infusions of Ampligen® or 
placebo.  
 
STUDY CENTER 
Up to 10 centers in the United States. Centers must have the capability of implementing appropriate 
infection-control measures to prevent infection of study staff and others who share the clinical site 
space. The facility should be adequately staffed by medical personnel and equipped with a “crash 
cart” in the event of acute allergic reaction or requirement for advanced cardiac life support. 
 
STUDY POPULATION 
The study population for the study will be adult patients with the Post-COVID Condition of 
fatigue. 
 
ELIGIBILITY CRITERIA 
3.3.1. Inclusion Criteria 
Potential subjects are required to meet all of the following criteria for enrollment into the study: 
1. Male or female adult between 18 to 60 (inclusive) years of age at time of enrollment. 
2. Prior confirmed COVID-19 diagnosis by standard RT-PCR assay or equivalent testing at 
least 12 weeks prior to baseline. 
Note: For subjects with COVID-19 symptoms who were not tested for the presence of 
SARS-CoV-2, a positive serum antibody test for SARS-CoV-2 will be sufficient in subjects 
not vaccinated for COVID-19 or it can be shown that the positive antibody cannot be 
associated with the COVID-19 vaccination. 
3. Laboratory confirmed negative SARS-CoV-2 (COVID-19) infection by a government 
approved test / kit at time of enrollment. 
4. Subject meets for the criteria of fatigue per the 1994 CDC Case Definition for Chronic 
Fatigue Syndrome (CFS):  Unexplained persistent or relapsing chronic fatigue that is of new 
or definite onset (i.e., not lifelong), is not the result of ongoing exertion, is not substantially 
alleviated by rest, and results in substantial reduction in previous levels of occupational, 
educational, social, or personal activities.  The fatigue must have persisted or recurred during 
3 or more consecutive months of illness and must not have preceded the onset of the 
COVID-19 symptoms. 


 
 
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5. PROMIS® Fatigue- Short Form 7a response total raw score of ≥21 at screening and 
baseline.  
6. Electrocardiogram (ECG) with no clinically significant findings as assessed by the 
Investigator. 
 
 
Note: Below are the examples of clinically significant ECG abnormalities: 
− Previous documented evidence of myocardial infarction or recent significant change 
in the resting EKG suggesting infarction or other acute cardiac events. 
− Current symptoms of coronary insufficiency (i.e. - angina pectoris and/or ST segment 
depression on EKG). 
− Evidence of uncontrolled atrial or frequent or complex ventricular ectopy, or 
myocardial conduction defect which would increase the risk of syncope (for example, 
second degree or higher A-V block). 
7. Subject (or legally authorized representative) provides written informed consent prior to 
initiation of any study procedures. 
8. Men and women of childbearing potential and their partner must agree to use two medically 
accepted methods of contraception (e.g., barrier contraceptives [male condom, female 
condom, or diaphragm with a spermicidal gel], hormonal contraceptives [implants, 
injectables, combination oral contraceptives, transdermal patches, or contraceptive rings], 
or one of the following methods of birth control (intrauterine devices, bilateral tubal 
occlusion, or vasectomy) or must practice complete sexual abstinence for the duration of 
the study (excluding women who are not of childbearing potential and men who have been 
sterilized). 
9. Females of child-bearing potential must have a negative urine pregnancy test at Screening 
Visit and prior to receiving the first dose of study drug; and Male participants must agree 
to use contraception and refrain from donating sperm for at least 90 days after the last dose 
of study intervention. 
10. Subject is willing and able to comply with scheduled visits, drug administration plan, 
laboratory tests, other study procedures and study restrictions. 
3.3.2. Exclusion Criteria 
Potential subjects meeting any of the following criteria will be excluded from enrollment: 
1. Inability to provide informed consent or to return to the Investigator’s site for scheduled 
infusions and evaluations.  
2. Exhibiting signs of moderate or severe pulmonary disease (such as COPD, asthma, or 
pulmonary fibrosis). 
3. Ongoing requirement of oxygen therapy. 


 
 
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4. Pulse oxygen saturation (SpO2) of <94% on room air at the time of screening. 
5. Thrombocytopenia (platelets <100×109/L), anemia (hemoglobin <9.0 g/dL), or leukopenia 
(WBC <3×109/L) on screening labs 
6. History of splenectomy. 
7. Known hypercoagulable state or at increased risk of thrombosis (e.g., due to immobility) 
8. Liver cirrhosis or patient showing signs of clinical jaundice at the time of screening. 
9. Transaminase (ALT or AST) >3X ULN or total bilirubin >2X ULN at screening 
10. Chronic kidney disease stage 4 or requiring dialysis at the time of screening. 
11. Estimated GFR <60 mL/min/1.73 m2 at the time of screening  
12. NYHA Class III or IV congestive heart failure (CHF). 
13. Exhibiting signs of uncontrolled hypo-or hyper-thyroidism at the time of Screening. 
14. Diagnosis of autoimmune disease (e.g., SLE, rheumatoid arthritis, psoriasis) at the time of 
screening  
15. Uncontrolled rheumatologic disorders at the time of screening. 
16. Diagnosis of sleep apnea (central or obstructive) at the time of screening. 
17. History of organ transplantation or are candidates for organ transplantation at the time of 
screening. 
18. History of Chronic Fatigue Syndrome prior to COVID-19 infection. 
19. History of fibromyalgia prior to COVID-19 infection. 
20. History of major psychiatric disorder including psychotic or melancholic features, bipolar 
disorders, schizophrenia of any subtype, schizoaffective disorder, major depression 
delusional disorders of any subtype, dementias of any subtype, anorexia nervosa or bulimia 
nervosa.    
21. Any malignancy within the past 5 years, excluding successfully treated basal cell 
carcinoma or squamous cell carcinoma without evidence of metastases. 
22. Any other clinically significant serious systemic diseases, chronic or intercurrent active 
medical disorder and other reasons which would interfere with study conduct or study 
results interpretation per the Investigator. 
23. Chronic or intercurrent acute medical disorder or disease making implementation or 
interpretation of the protocol or results difficult or unsafe per the investigator. 
24. Therapy with interferons interleukins, or other cytokines or investigational drugs within 6 
weeks of beginning study medication.  Subjects must give written informed consent prior 
to discontinuation of investigational drugs. 


 
 
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25. Treatment with any of the following therapies within the eight (8) weeks immediately 
preceding the start of study baseline or during baseline: systemic glucocorticoids (i.e., 
hydrocortisone, prednisone, etc.) or mineralocorticoids (i.e., fludrocortisone (Florinef), 
etc.), interferons, interleukin-2, systemic antivirals, gamma globulin or investigational 
drugs or experimental agents not yet approved for use in the United States. 
26. Prior participation in an Ampligen® study. 
27. Medical necessity, as determined by the patient’s primary doctor or the principal 
investigator, to continue aspirin (ASA) or non-steroidal anti-inflammatory (NSAID) drugs 
for 20 consecutive days or for more than 10% of the study duration. 
28. History of congestive heart failure, suspected or known dissecting aneurysm, recent 
systemic or pulmonary embolus or myocardial infarction (≤ 6 months), severe valvular heart 
disease, ventricular aneurysm, active or suspected myocarditis or pericarditis, 
thrombophlebitis or intracardiac thrombi, or acute infection. 
29. Evidence of moderate or severe obstructive pulmonary disease. 
30. Resting diastolic blood pressure > 115 mm Hg or resting systolic blood pressure > 200 mm 
Hg. 
31. Uncontrolled metabolic disease (e.g., diabetes, thyrotoxicosis, or myxedema). 
32. Concurrent use of any beta blockers and/or bronchodilators which cannot remain at a stable 
dosage level during baseline and the study. 
33. History of alcohol or other substance abuse within two (2) years before the onset of acute 
COVID-19 or at any time afterward. 
34. History of suicidal ideation, suicide attempt, or suicidal behavior within two (2) years of 
baseline. A score of 10 or greater on the PHQ-9 at Baseline indicates symptoms of 
depression and will exclude subject. A score of greater than zero on question nine (9) of 
the PHQ-9 at Baseline indicates suicidal ideation and will exclude subject. 
35. Pregnant or breast feeding. 
36. Participation in another study for an investigational treatment. 


 
 
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4. 
STUDY SCHEDULE 
The study Schedule of Assessments is presented in Table 4-1 and Table 4-2. 
The study will have three phases: Screening Phase, Treatment Phase, and Follow-Up Phase. 
Note: During visits conducted at the study clinic, subjects and site personnel will use appropriate 
protective gear (e.g., masks, gloves) to prevent the spread of the infection. 
Screening Phase (up to 1 week):  
All subjects will provide written informed consent and have a Screening visit (V1) within 7 days 
prior to first treatment visit (V2) to determine eligibility for subject participation. 
All subjects who fail to meet eligibility criteria are considered screen failures and are exited from 
the study without further evaluation. 
Treatment Phase (12 weeks):  
Ampligen® and placebo will be administered via twice weekly infusions (Example: 
Monday/Thursday or Tuesday/Friday schedule) for 12 weeks. 
 
 
 
  
 
 
Follow-Up Phase (2 weeks): 
Two safety follow-up visits will be performed 3 to 4 days and 2 weeks after the End of Treatment 
(EOT) visit (V25).  












 
 
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SCREENING PHASE 
Screening phase is designed to determine whether subjects are eligible to proceed to the treatment 
phase of the study.  
4.1.1.  Screening Visit (V1) 
Screening assessments will commence at Visit 1 (V1) after obtaining signed informed consent, 
and will include:  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
All subjects who fail to meet eligibility criteria are considered screen failures and are exited from 
the study without further evaluation. 
 
 


 
 
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TREATMENT PHASE 
4.2.1. Randomization (V2) 
Visit 2 (Day 0) defined as day of first Ampligen® or placebo administration. 
Subjects who meet the eligibility criteria will have completed the following evaluations and 
assessments at V2: 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
  
 
 
  
 
 




 
 
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FOLLOW-UP PHASE 
4.3.1. Follow-Up visit 1 (V26) 


 
 
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Follow-Up visit (V26) will be performed 3 or 4 days after the End of Treatment (EOT) visit (visit 
25). The following assessments will be performed at V26: 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
4.3.2. Follow-Up visit 2 (V27) 
Follow-Up visit 2 will be performed at 2 weeks after the End of Treatment (EOT) visit (visit 25). 
The following assessments will be performed at V27: 
 
  
 
  
 
  
 
  
 
 
 
 
 
 
 
  


 
 
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UNSCHEDULED VISITS 
In the event that the subject will return to clinic at a time other than a regularly scheduled study 
visit, the visit will be regarded as an unscheduled visit. Assessments at unscheduled visits are at 
the discretion of the Investigator. All pertinent findings, including adverse events or changes in 
medications, will be noted in the eCRF. 


 
 
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5. 
SUBJECT COMPLETION, WITHDRAWAL AND CRITERIA FOR 
STOPPING THE STUDY 
 
SUBJECT COMPLETION 
A subject who completes the Treatment Phase will be considered as having completed the study. 
Note: Subjects who discontinue treatment (voluntarily or involuntarily) or withdrawn from study 
participation prior to completing visit 25 are considered as having not completed the study. 
 
SUBJECT TREATMENT DISCONTINUATION 
Patients who fail to comply with the requirements of the study will be discontinued from the study 
treatment.  Reasons for treatment discontinuation may include but are not limited to the following: 
• Lost to Follow-up 
• Voluntary patient or guardian withdrawal. 
• Protocol violation, such as failure to comply with the requirements of the study or use of 
prohibited concomitant medications. 
• Physician decision, such as significant intercurrent illness or surgery, as determined by the 
Investigator which prevents the patient from taking the study medication, or which requires 
administration of drugs disallowed in this study. 
• Adverse event, such as toxicity grading of 3 or 4 or serious adverse event (SAE) felt by the 
investigator to be related to the study medication. 
 
SUBJECT WITHDRAWAL FROM STUDY 
Subjects should only be considered withdrawn from the study if they withdraw consent. 
 
DATA COLLECTED FROM TREATMENT DISCONTINUED/WITHDRAWN STUDY SUBJECTS 
Every attempt should be made to collect follow-up information for the subjects who discontinued 
the treatment or were withdrawn from the study. 
 
 
 
 
 
 
 
 
  












 
 
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7. 
DESCRIPTION 
OF 
PROTOCOL 
ASSESSMENTS 
AND 
PROCEDURES 
 
INFORMED CONSENT 
A written informed consent will be obtained for this study by the Investigator or designee from all 
subjects prior to performance of any protocol-specific procedure. This study will be conducted in 
accordance with the provisions of the Declaration of Helsinki.  
The Investigator must comply with applicable regulatory requirements and must adhere to the 
Good Clinical Practice (GCP) in the process of obtaining and documenting the informed consent. 
The Investigator, or designee, must also inform subjects of all pertinent aspects of the study. Before 
written informed consent is obtained from the subject, the Investigator or a person designated by 
the Investigator, must provide the subject enough time and opportunity to inquire about the details 
of the study and to decide whether or not to participate in the trial. All questions addressed by the 
subject about the study must be answered to the satisfaction of the subject. Prior to the subject’s 
participation in the trial, the written informed consent must be signed and personally dated by the 
subject and by the person who conducted the informed consent discussion. Authorization for 
release of protected health information must also be obtained, as per local policies.  
 
ASSESSMENT OF ELIGIBILITY 
The Investigator must assess subject continued eligibility for the study as per the Inclusion and 
Exclusion criteria, during the Screening Phase. The eligibility criteria are described in Section 
3.3.1 (Inclusion Criteria) and Section 3.3.2 (Exclusion Criteria). In the event that the subject is not 
suitable or eligible for the study, the subject will be considered “screen failure”.  
7.2.1. Re-screening 
A subject who signed a consent form but did not meet the inclusion/exclusion criteria is classified 
as a screen failure.  
 
 
 
 
 
 
 
 
 
 


 
 
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DEMOGRAPHIC INFORMATION 
In this study the demographic information will include: 
• Dates of ICF signature  
• Date of birth 
• Gender 
• Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Not Reported, or Unknown) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, or Unknown) 
• Use of tobacco products 
 
MEDICAL HISTORY 
A medical history will be recorded during the Screening Phase and will include: 
• All ongoing medical conditions 
• All previously resolved medical conditions that are relevant in the judgment of the 
Investigator  
• Any prior medical conditions that have resolved within the last year  
Events that emerge prior to first dose of study medication on Day 1 will be recorded in the medical 
history and not as AEs. Aside from being used to determine subject eligibility, this information 
will permit the Investigator to record the nature, duration, and severity of any ongoing baseline 
medical conditions prior to the subject’s receiving investigational product treatment.  
For each relevant history, the following will be documented:  
• Disease/disorder/condition 
• Date of diagnosis 
• History status (resolved or ongoing). 
 
PHYSICAL EXAMINATION 
The physical examination will include routine examinations for the following: 
• Constitutional/General Appearance 
• Head, Ears, Eyes, Nose, Throat (HEENT) 
• Neurologic  
• Cardiovascular 


 
 
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• Musculoskeletal and Extremities 
• Dermatologic 
• Respiratory  
• Gastrointestinal 
• Genitourinary  
• Lymphatic 
• Psychiatric  
Each abnormality will be recorded, and the Investigator will record an assessment of its clinical 
significance. 
 
VITAL SIGNS, HEIGHT AND WEIGHT 
The following will be collected:  
• Systolic Blood Pressure  
• Diastolic Blood Pressure 
• Heart Rate (Pulse) 
• Temperature 
• Respiratory Rate  
• Height (Screening only) 
• Weight 
• Body Mass Index  
Note: During days of Ampligen® or Placebo administration, pre-infusion vitals (before the 
start of infusion) and post-infusion vitals (after the end of infusion) will be measured. Post-
infusion vitals will be limited to blood pressure and pulse only. 
Note:  During study visits when the 6MWT is performed, vitals should be collected before and 
after 6MWT (i.e., pre 6MWT, and post 6MWT), as clinically indicated per the discretion of 
the Investigator or designee. These should be documented in the source records as standard of 
care assessments; however, they will not be captured as a protocol assessment. 
Note: During study visits when the 6MWT and study drug administration is performed (i.e., 
Visit 6, 12, and 18), vitals should be collected as follows: pre 6MWT and post 6MWT, if  
clinically indicated per the discretion of the Investigator or designee. Subjects should be rested 


 
 
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for at least 10 minutes after completing the 6MWT before pre-infusion vitals are taken. Post-
infusion vitals should be taken after the completion of the study administration. 
 
30 MINUTE SITE CHECK 
Subjects will be monitored for 30 minutes after every infusion for evaluation of any unexpected 
adverse events.  
 
CONCOMITANT MEDICATION 
The subject may take any medications judged necessary by the Investigator, provided such 
medications are not listed in Section 6.4.1.  
All medications and therapies administered or taken by the subject beginning 30 days prior to 
Screening Visit and throughout the study will be recorded in the source documents and on the 
appropriate page of the case report form (CRF). Subjects must be questioned at each study visit 
concerning any new medications or changes in current medications including over-the-counter 
medication and topical medication. 
For each medication and non-study treatment, the following will be documented: 
• Medication/treatment name (generic name may be used if trade name is unknown) 
• Dose, unit, and frequency of dosing (individual dosages, not total daily dose).  
o Note: Each new dose of medication should be recorded as a separate entry, with 
the exception of medications that are given on a sliding scale. For these, it is 
acceptable to enter the range of the dosage, including the start and stop dates for 
which the specified dosage range was used. 
• Route of dosing  
• Indication for use 
• The start date  
• The stop date (if medication/therapy is not ongoing).  
 
CLINICAL LABORATORY ASSESSMENTS 
Blood samples will be collected for analysis of the following parameters described in Table 
7-1 (local lab) and Table 7-2 (central lab).  
 
 
  








 
 
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8. 
STATISTICAL ANALYSIS  
This Section presents general information about statistical considerations and concepts and a brief 
discussion on analysis methodology, as well as some data conventions. Detailed descriptions of 
the statistical analysis methods and data conventions that will be used in this study will be in a 
separate document, i.e., the Statistical Analysis Plan (SAP). 
 
TREATMENT GROUPS 
The following treatment groups will be assessed in the study:  
• Ampligen®  
• Placebo (normal saline) 
 
DESCRIPTION OF STUDY OUTCOMES AND ESTIMAND  
Refer to Section 2.2 for description of study outcome measures.  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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SAMPLE SIZE DETERMINATION AND RATIONALE 
The sample size of 80 subjects will be used in this study. The sample size is based on clinical 
judgment. No statistical power calculation is used to establish the sample size for this proof-of-
concept study. 
 
RANDOMIZATION AND STRATIFICATION 
A total of 80 subjects (40 per group) will be randomized in a 1:1 ratio (Ampligen®: placebo). 
 
 
 
 
 
 
 
 
 
 
 
BLINDING 
This is a double-blind study. The investigator and staff, subjects and Sponsor/CRO staff directly 
related to study conduct will be blinded to the treatment assignment.  
 
 
 
 
 
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TIME TO UNBLINDING 
8.6.1. Emergency Unblinding   
Breaking the blind prematurely will be allowed only if the subject’s well-being requires knowledge 
of the subject’s treatment allocation. Every attempt will be made to maintain the blind throughout 
the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INTERIM ANALYSIS 
There is no planned interim analysis for this early phase study. 
 
GENERAL STATISTICAL CONSIDERATIONS 
All collected study data will be presented in subject data listings. 
 
 
 
 
 
8.8.1. Analysis Populations 
 
 


 
 
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8.8.2. Covariates 
For efficacy analyses important prognostic factors that need adjustment will be specified in the 
Statistical Analysis Plan (SAP) for the study. 
8.8.3. Missing Data 
All efforts will be made to avoid missing data; however, there will be no imputation of missing 
data for this early phase study and primary analysis of efficacy data will be based on observed data 
only. 
 
 
 
 
 
 
 
 
  
8.8.4. Multiplicity 
No adjustment of multiplicity will be done for the efficacy analysis of the data for this early phase 
study. 
 
ANALYSIS METHODS 


 
 
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A Statistical Analysis Plan (SAP) will be developed and approved before the database is locked. 
The SAP will present the detailed statistical methodology to be used in analyzing the data from 
this trial. 
8.9.1. Subject Disposition 
The disposition of all subjects who signed an ICF will be provided. 
 
 
 
 
 
8.9.2. Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized by treatment group using 
appropriate descriptive statistics. 
Medical history will be presented as by-subject listing. 
8.9.3. Concomitant Medications/Therapies 
Concomitant medications/therapies will be summarized separately for the Safety population. All 
prior and concomitant medications recorded in the case report form will be coded to matching 
Anatomic Therapeutic Classification codes using the most recent version of the WHO Drug 
Dictionary. Descriptive summaries by treatment group will be prepared using the coded term. All 
concomitant medications/therapies recorded in the case report form will be listed. 
8.9.4. Efficacy Analyses 
8.9.4.1. 
Primary Analysis   
 
  
 
 
 
 
 
 
  


 
 
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• 
  
 
 
   
 
 
  
 
 
  
 
 
 
  
 
 
 
  
 
 
  
8.9.5. Safety Analyses  
8.9.5.1. 
Adverse Events  
Adverse events will be classified by system organ class (SOC) and preferred term (PT) according 
to the most recent version of MedDRA dictionary.     
 
 
 
 
 
 
 
 
 
 
 
 
 
8.9.5.2. 
Clinical Laboratory Data 
 
 
 
 


 
 
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8.9.5.3. 
Vital signs  
 
 
 
8.9.5.4. 
Physical Examination  
  
8.9.5.5. 
ECG  
 
 
 


 
 
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9. 
SAFETY REPORTING  
The Investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE, as provided in this protocol. During the study when there is a 
safety evaluation, the Investigator or site staff will be responsible for detecting, documenting, and 
reporting AEs and SAEs as detailed in this Section of the protocol.  
 
ADVERSE EVENT (AE) DEFINITION  
An adverse event (AE) is defined as any unfavorable or unintended sign, symptom, or disease that 
occurs or is reported by the patient to have occurred, or a worsening of a pre-existing condition. 
An adverse event may or may not be related to the study treatment.  
AEs will be elicited through direct questioning and subject reports. Any abnormality in physical 
examination findings or laboratory results that the investigator believes is clinically significant 
(CS) to the research subject and that occurred after initiation of the first study treatment will be 
reported as AEs. Abnormal findings that are NOT clinically significant should not be recorded as 
an AE. 
 
REPORTING OF ADVERSE EVENTS 
Report initiation for all AEs and SAEs will begin at the time of the first treatment visit and continue 
until the end of final study visit. All events will be followed to resolution or until the subject 
completes the study. A final assessment of outcome will be made at that time.  
All AEs must be recorded in the subject’s medical records and on the CRF. AEs will be reported 
using customary medical terminology along with the following information: the onset and end 
dates,  whether the event is considered to be an SAE (see Section 9.3), the impact the event had on 
study treatment (see Section 9.2.1), the Common Terminology Criteria for Adverse Events 
(CTCAE) grade (intensity) of the event (see Section 9.2.2), the causality of the event (see Section 
9.2.3), whether treatment was given as a result of the event (see Section 9.2.4), and the outcome 
of the event (see Section 9.2.5) 
9.2.1. Impact on Study Treatment 
The impact the event had on the study treatment will be assessed as either: dose increased, dose 
not changed, dose rate reduced, dose reduced, drug interrupted, drug withdrawn, not applicable, 
or unknown. The “not applicable” assessment will be used only when the subject is no longer in 
the Treatment Phase of the protocol. 
9.2.2. CTCAE Grade (Intensity) Assessment 
The guidelines outlined in CTCAE v5.0 will be used for assessing the intensity of the event. The 
general guidelines for assessing the AE grade appear below. Full guidelines may be obtained at 
http://evs.nci.nih.gov/ftp1/CTCAE. 




 
 
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readily have been produced by subject’s clinical state, environmental or toxic factors, or other 
therapies administered to the subject. (3) Disappears or is decreased upon discontinuation of 
the study treatment. (4) It follows a known response pattern to treatment with the study 
treatment.  
4. Unlikely related: In general, this category can be considered applicable to those AEs which, 
after careful medical consideration at the time they are evaluated, are judged likely to be 
unrelated to the study treatment. An AE may be considered unlikely if or when (must have 
two): (1) it does not follow a reasonable temporal sequence from administration of the study 
treatment. (2) It could not readily have been produced by subject’s clinical state, environmental 
or toxic factors, or other therapies administered to the subject. (3) Disappears or is decreased 
upon discontinuation of the study treatment. (4) It does not follow a known response pattern 
to treatment with the study treatment.  
5. Unrelated: This category applies to those AEs which, after careful consideration at the time 
they are evaluated, are clearly and incontrovertibly due to extraneous causes (disease, 
environment, etc.) and determined with certainty to have no relationship to the study treatment.  
9.2.4. Treatment Given as a Result of the Event 
The event impact in terms of treatment provided will be as either: none, medication administered, 
non-drug therapy administered, surgery performed, hospitalization, or other (with a specification). 
9.2.5. Outcome Assessment 
The outcome of the event will be assessed as either: fatal, not recovered/not resolved, 
recovered/resolved, recovered/resolved with sequelae, recovering/resolving, or unknown. Only 
one AE per subject is allowed to have an outcome assessment as “death.” If there are multiple 
causes of death for a given subject, only the primary cause of death will have an outcome of death.  
 
SERIOUS ADVERSE EVENT (SAE) DEFINITION 
An SAE is defined as any AE that: 
• Results in death 
• Is life threatening (the subject is at immediate risk of dying from the adverse experience) 
• Requires subject hospitalization or prolongs existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse effect when, based upon appropriate 
medical judgment, they may jeopardize the subject or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 


 
 
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REPORTING OF SERIOUS ADVERSE EVENTS   
The Investigator is required to report all SAEs that occur during the time period specified in 
Section 9.2. Once the Investigator becomes aware of an SAE, he/she must report the SAE to 
Medical Monitor within 24 hours. 
Medical Monitor 
 
 
 
 
 
 
 
 
 
 
The Medical Monitor may request additional supporting documentation as it becomes available, 
such as lab reports, electrocardiogram [ECG] reports, discharge summary, hospital notes, etc., if 
applicable. Additional follow-up information as it becomes available must be reported to the 
Medical Monitor. 
The Investigator is also responsible for reporting all SAEs to the appropriate Institutional Review 
Board (IRB) in accordance with local laws and regulations. The Investigator is responsible for 
maintaining documentation in the study file that indicates the IRB has been properly notified.  
9.4.1. SAE Follow-Up 
All subjects experiencing an SAE, including the discontinued subjects, must be closely followed 
until sufficient information is obtained to indicate a return to normal status or until the event 
stabilizes at a level acceptable to the investigator (i.e., recovery, return to baseline status, no further 
improvement expected, or death). 
For each SAE indicated as an unresolved event on the initial report, regardless of whether the 
subject completed the study or withdrew, the site should submit a follow-up report with updated 
information. 
 
EXPECTED/ANTICIPATED EVENTS 
Refer to Investigator Brochure for the expected/anticipated events. 
 
PREGNANCY REPORTING 
To ensure patient safety, any pregnancy that occurs  after the first treatment visit until the end of 
final study visit should be recorded using a Pregnancy Notification Form and reported immediately 
to Sponsor within 24 hours of learning of the pregnancy. 


 
 
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If a subject becomes pregnant during the study before the end of treatment phase, they will be a 
discontinued subject. If a subject becomes pregnant during the study after the end of treatment 
during the follow up portion, they can complete the remaining scheduled follow up unless there is 
a medical contraindication. 
9.6.1. AE and SAE Reporting  
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP may have interfered 
with the effectiveness of a contraceptive medication. Congenital abnormalities/birth defects and 
spontaneous miscarriages should be reported and handled as SAEs. 
9.6.1.1. 
Abortions 
An induced elective abortion to terminate a pregnancy without medical reason is not regarded as 
an AE. However, an induced therapeutic abortion to terminate a pregnancy because of 
complications or medical reasons must be reported as an SAE. The underlying medical diagnosis 
for this procedure should be reported as the SAE term. A spontaneous abortion in a study subject 
is always considered an SAE.  
9.6.2. Informed Consent  
The ICF will include information regarding reporting of pregnancy to the Sponsor and collection 
of information through the end of pregnancy that occurs in either a female subject or in a female 
partner of a male subject. If a female partner becomes pregnant, the Investigator will request 
consent from the partner to collect this information. 
9.6.3. Pregnancy Follow-Up 
The pregnancy will be followed-up to determine the outcome (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth, or congenital abnormality) and should include an 
assessment of the possible relationship to the study treatment of any pregnancy outcome. This 
information should also be documented on the Pregnancy Outcome Form and reported to the 
Sponsor. 
 


 
 
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10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION 
Subjects will be identified on eCRFs by a unique subject identification number and on source 
documents by name and date of birth. No personal identifier will be used in any publication or 
communication used to support this research study. The subject identification number will be used 
if it becomes necessary to identify data specific to a single subject.  
The local IRB, FDA, the monitors, auditors, and personnel authorized by the Sponsor are eligible 
to review the medical and research records related to this study as part of their responsibility to 
protect human subjects in clinical research. They will be given direct access to source data and 
documentation (e.g., medical charts/records, printouts etc.) for source data verification, provided 
that subject confidentiality is maintained in accordance with local requirements. Access to 
electronic medical records may be governed by institution policy. The study site will be required 
to ensure access while remaining compliant with institutional requirements. 
 
 
 


 
 
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11. 
QUALITY CONTROL AND QUALITY ASSURANCE 
 MONITORING REQUIREMENTS 
The specific obligations outlined in 21 Code of Federal Regulations (CFR) and ICH guidelines 
require the Sponsor to maintain current personal knowledge of the progress of a study. Therefore, 
the Sponsor's designated monitor will visit the site during the study as well as maintain frequent 
telephone and written communication. The Investigator will permit the Sponsor to monitor the 
study as frequently as is deemed necessary and provide access to medical records to ensure that 
data are being recorded adequately, that data are verifiable, and that protocol adherence is 
satisfactory.  
As delineated above, the Investigator will permit representatives of the Sponsor and/or designated 
CRO to inspect all CRFs and corresponding study subject original medical records (source 
documents) at regular intervals throughout the study. Subject original medical records and other 
relevant data must be available to support all data recorded in the eCRF. In addition to the original 
medical records, these data may include but are not limited to study, laboratory reports, etc.  
In accordance with federal regulations, site inspections will serve to verify strict adherence to the 
protocol and the accuracy of the data that is being entered on the case report forms. A Monitoring 
Log will be maintained at each study site. The Monitoring Log will be signed by the monitor, 
dated, and stated the type of visit. The Investigator should be aware that the study site and subject 
records may be inspected by the Sponsor and or representatives of the designated CRO, FDA or 
other regional regulatory authority. 
 ACCEPTABILITY OF CASE REPORT FORMS (CRFS) 
For each subject who has signed an informed consent form, a CRF must be completed. For subjects 
who are screen failures, this would be limited to the screen failure CRF page. All source documents 
and CRFs will be completed as soon as possible after the subject's visit and corrections to data on 
the CRFs will be documented, if applicable. The Investigator will review the CRFs to indicate that, 
to his/her knowledge, they are complete and accurate. CRFs will be reviewed by the Sponsor’s or 
designated CRO’s monitor, who will make a decision as to their acceptability.  
 MODIFICATION OF PROTOCOL 
The Investigator will not modify or alter this protocol without first obtaining the concurrence of 
the Sponsor. Approval by the Investigator’s IRB must also be obtained prior to implementation of 
the change, with two exceptions: 
1. When necessary to eliminate apparent immediate hazard to the subject; or 
2. When the modification does not involve the subject’s participation in the trial. 


 
 
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An amendment may also require modification of the informed consent form. The Investigator will 
provide an approval letter for the amendment and revised informed consent form, if applicable, to 
the Sponsor. An amendment must be provided in writing, and it must be dated by both the Sponsor 
and the Investigator. If necessary, the Sponsor will submit protocol amendments to FDA and other 
appropriate regulatory authorities and notify other Investigators using this protocol. 
 REPORTING PROTOCOL DEVIATIONS 
The Investigator is obligated to follow the protocol without departure from the requirements 
written in the protocol. If the Investigator deviates from the protocol requirements, the Sponsor 
will make the determination as to whether the subject will continue in the study. The Sponsor also 
has the right to discontinue the subject for protocol violations. The IRB may also have to be 
contacted if safety to the subject or if the scientific soundness of the study is involved. All protocol 
deviations must be documented in the CRFs. 
11.4.1. Major Protocol Deviation or Violation 
A major protocol deviation or violation is a deviation from the IRB approved protocol that may 
affect the subject's rights, safety, or well-being and/or the completeness, accuracy, and reliability 
of the study data. Examples of this include: 
• Failure to obtain informed consent prior to initiation of study-related procedures  
• A research subject does not meet the protocol's eligibility criteria but was enrolled without 
prior approval from the sponsor. 
• A research subject received the wrong treatment or incorrect dose. 
• A research subject met withdrawal criteria during the study but was not withdrawn. 
• A research subject received a prohibited concomitant medication. 
• Failure to treat research subjects per protocol procedures that specifically relate to primary 
efficacy outcomes. 
• Changing the protocol without prior sponsor and IRB approval. 
• Multiple minor violations of the same nature after multiple warnings. 
11.4.2.  Minor Protocol Deviation or Violation 
A minor protocol deviation is any change, divergence, or departure from the study design or 
procedures of a research protocol that has not been approved by the IRB and which DOES NOT 
have a major impact on the subject's rights, safety or well-being, or the completeness, accuracy, 
and reliability of the study data.  Examples of this include: 
• Follow-up visits that occurred outside the protocol required time frame because of the 
participant’s schedule. 


 
 
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• Blood samples obtained at times close to but not precisely at the time points specified in the 
protocol. 
 
 
 


 
 
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12. 
ETHICS AND REGULATORY REQUIREMENTS 
This study is to be conducted in accordance with the specifications of this protocol and in 
accordance with principles consistent with Declaration of Helsinki, GCP, 21 CFR, ICH E6, 
HIPAA regulations in 45 CFR Part 164 (US only), and the Belmont Principles of respect for 
persons, beneficence, and justice. No protocol changes will be implemented without the prior 
review and approval of the IRB, except when the modification does not involve the subject’s 
participation in the trial or where it may be necessary to eliminate an immediate hazard to a 
research subject. In the latter case, the change will be reported to the IRB as soon as possible, 
according to IRB regulations.  
Additionally, the study product used in this study is manufactured, handled, and stored in 
accordance with applicable GMP. The study product provided for this study will be used only in 
accordance with this protocol. 
 INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) 
The Principal Investigator (PI) at each site will provide the Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) with all appropriate materials as required by their 
IRB/IEC, including but not limited to the clinical study protocol, informed consent form, and any 
advertising materials. The study will not be initiated until the IRB/IEC provides written approval 
of the aforementioned documents and until approval documents have been obtained by the 
Principal Investigator and Sponsor or Sponsor designee. The Investigator will not participate in 
the decision. If the Investigator is an IRB or IEC member, documentation must be provided 
indicating recusal from the approval process. Appropriate reports on the progress of this study by 
the Principal Investigator will be made to the IRB/IEC as required by local and applicable 
government regulations and in agreement with policy established by the Sponsor. The Investigator 
is required to maintain an accurate and complete record of all written correspondence to and 
received from the IRB/IEC and must agree to share all such documents and reports with the 
Sponsor. 
No changes from the final approved protocol will be initiated without the IRB/IEC’s prior written 
approval or favorable opinion of a written amendment, except when necessary to eliminate 
immediate hazards to the subjects or when the modification does not involve the subject’s 
participation in the trial.  
 INVESTIGATOR’S RESPONSIBILITIES 
The Investigators are responsible for performing the study in full accordance with the protocol and 
the current revision of the Declaration of Helsinki, the Good Clinical Practice: Consolidated 
Guideline, approved by the ICH, and any applicable national and local laws and regulations. 


 
 
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Information regarding to the study center participating in this study that cannot comply with these 
standards will be documented. 
 SUBJECT INFORMED CONSENT REQUIREMENTS 
All subjects participating in this study will be given to by the Investigator and/or designee, written 
and oral information about the study in a language understandable by the subject. Written informed 
consent will be obtained from each subject prior to any procedures or assessments that would not 
otherwise be required for the care of the subject are done and after the aims, methods, anticipated 
benefits, potential hazards, and insurance arrangements in force are explained and the subject has 
been given sufficient time to ask questions and consider participation in the study. It will also be 
explained to the subjects that they are free to refuse entry into the study and free to withdraw from 
the study at any time without prejudice to future treatment. It is permissible for a third person (e.g., 
a family member) to be present during the explanation of the study. 
The written Informed Consent Form (ICF) will be in compliance with CFR 21 Part 50.27 and GCP 
guidelines. The Sponsor and/or designated CRO will approve the ICF and all amendments to the 
ICF prior to submission to the IRB/IEC. A copy of the ICF to be used will be submitted by the 
Investigator to the IRB/IEC for review and approval prior to the start of the study. The study site 
must provide the Sponsor with an unsigned copy of IRB/IEC-approved ICF along with applicable 
documentation to support this approval. The original signed ICF is retained in the subject's study 
records, and a copy is provided to the subject. A second copy may be filed in the subject’s medical 
record, if allowed by institutional policy.  
 


 
 
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13. 
DATA HANDLING AND RECORD KEEPING 
 RECORDING AND COLLECTION OF DATA 
The primary source document for this study will be the subject's medical record. If separate 
research records are maintained by the Investigator(s), the medical record and the research records 
will be considered the source documents for the purposes of auditing the study.  
Applicable source data will be manually transcribed to approve case report forms (CRF). The 
Investigator is ultimately responsible for the accuracy of the data transcribed on the forms. All 
source documents and CRFs will be completed as soon as possible after the subject's visit. 
The Investigator will review the CRFs to indicate that, to his/her knowledge, they are complete 
and accurate. Designated source documents will be signed and dated by the appropriate study 
personnel. The Investigator must agree to complete and maintain source documents and CRFs for 
each subject participating in the study. 
All research data will be entered, either electronically or manually, into a computerized database. 
The clinical database will be designed by the clinical data manager in accordance with 21 CFR 
Part 11 and based on protocol requirements defined by the Sponsor.  
The Investigator will maintain a confidential list of study subjects that will include each subject’s 
study number, name, date of birth, and unique hospital identification number if applicable. This 
list will be kept by the Investigator and will not be collected by the Sponsor. A notation will be 
made in the subject’s case history/medical chart that he/she is participating in a clinical study and 
has provided a signed and dated ICF as well as a release for protected health information as 
required by local policies. The Investigator must also maintain a separate screening log of all the 
subjects screened for participation in the study; it should include gender, age, eligibility status, 
reason for ineligibility, if applicable; and study allocated subject number, if applicable.  
 CLINICAL DATA MANAGEMENT 
The Sponsor and/or designated CRO will be responsible for the processing and quality control of 
the data. Data management will be carried out as described in the Sponsor’s or CRO’s standard 
operating procedures (SOPs) for clinical studies. 
The handling of data, including data quality control, will comply with regulatory guidelines 
(e.g., ICH E6 GCP, and local regulations where applicable) and the Sponsor’s or the CRO’s SOPs 
as well as provisions of the study-specific Data Management Plan. 
 
 


 
 
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 ARCHIVING 
All study documentation at the Investigator site and Sponsor site will be archived in accordance 
with ICH GCP E6 and the Sponsor’s quality standards and SOPs. 
The Investigator will maintain all research records, reports, and case history reports for a period 
of two (2) years after regulatory approval of the investigational product. If no application is filed 
or if the application is not approved, records must be maintained for two (2) years after all 
investigations have been completed, terminated or discontinued and the FDA has been notified.  
These documents should be retained for a longer period however, if required by the applicable 
regulatory requirements or if needed by Sponsor or its authorized representative (as per 
GCP 5.5.11). 
At the completion of the study, details of the archival process must be provided to the Sponsor. 
Study records are subject to inspection by applicable health and regulatory agencies at any time.  
Records to be retained by the Investigator include, but are not restricted to: 
• Source data and the primary records upon which they are based (e.g., subject’s progress 
notes, adverse event data, test results, and any other diagnostic procedures required to 
evaluate the progress of the study) 
• Completed CRFs 
• Signed protocols and protocol amendments 
• Laboratory results, ranges, and certifications 
• IP and accountability records 
• Study personnel signature log 
• Monitoring logs 
• Correspondence to and from the Sponsor, designee, and IRB 
• Investigator and sub-investigator CVs 
• Signed informed consent and protected health information consent forms 
• Subject screening  
• SAE reports 
• IRB approval and re-approval letters 
• Completed quality of life questionnaire 
• Other documents pertaining to the conduct of the study 
These documents must be maintained and kept on file by the Investigator so that the conduct of 
the study can be fully documented and monitored. 
Study records should not be transferred from site or destroyed without prior written agreement 
between the Sponsor and the study Investigator. Study records are subject to inspection by 
applicable health and regulatory agencies at any time.  


 
 
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14. 
PUBLICATION PLAN 
All information supplied by AIM ImmunoTech Inc. in connection with this study and not 
previously published, is considered confidential information. This information includes, but is 
not limited to, the Investigator’s Brochure, clinical protocol, case report forms and other 
scientific data. Any data collected during the study are also considered confidential. This 
confidential information shall remain the sole property of AIM ImmunoTech Inc., shall not be 
disclosed to others without the written consent of AIM ImmunoTech Inc., and shall not be used 
except in the performance of this study. 
It is understood by the Investigator that the Sponsor will use the information collected in this 
clinical trial in connection with the development of AIM ImmunoTech Inc. Therefore, this 
information may be disclosed as required to other Investigators or appropriate regulatory 
authorities. By agreeing to participate in this clinical trial, the Investigator understands that he/she 
has an obligation to provide the Sponsor with complete test results and all data developed during 
this trial. 
Publication and Disclosure: The site and Investigator agree to submit any proposed manuscript, 
presentation, or other public disclosure regarding the study to Sponsor for review at least thirty 
(30) days prior to submitting such proposed manuscript to a publisher or delivering or making such 
presentation or other public disclosure to any third party. Within thirty (30) days of its receipt, 
Sponsor shall advise the site and/or Investigator, as the case may be, in writing of any information 
contained therein that is confidential information (other than research results included in a 
proposed manuscript) or that may impair Sponsor’s ability to obtain patent protection. Sponsor 
shall have the right to require the site and/or Investigator, as applicable, to remove specifically 
identified confidential information (but may not require removal of research results from a 
proposed manuscript) and/or to delay the proposed submission or delivery of the proposed 
manuscript or presentation, or other public disclosure, for an additional sixty (60) days to enable 
Sponsor to seek patent protection. The site and Investigator shall not publish, publicly disclose, 
present or discuss any results of or information pertaining to the site’s and Investigator’s activities 
prior to completion of the trial, even if the study is terminated before its completion and the final 
clinical study report is signed off, or with respect to any endpoints or analyses other than those 
specified in this protocol. 


 
 
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15. 
REFERENCES 
Aldinucci, D. and Colombatti, A., 2014. The inflammatory chemokine CCL5 and cancer 
progression. Mediators of inflammation, 2014.Alexander SV, Philipp G, Marion S, Joachim SH, 
Anton SH, Max S, Matthias K, Boris B. von Bergwelt-Baildon Michael S. Cytokine release 
syndrome. J. Immunotherapy Cancer. 2018;6(1). 
Ampligen® in HIV Disease:  Monotherapy and Cohort Analysis, July 27, 1990.  HEM Research 
Report. 
Barnard, D.L., et al. Proceedings of the 16th International Conference on Antiviral Research, 
2003 
Barnard, D.L.; Day, C.W.; Bailey, K.; Heiner, M.; Montgomery, R.; Lauridsen, L.; Chan, P.K.; 
Sidwell, RW.  Evaluation of immunomodulators, interferons and known in vitro SARS-CoV 
inhibitors for inhibition of SARS-CoV replication in BALB/c mice. Antivir Chem Chemother, 
2006, 17(5), 275-84. 
Data on file, AIM ImmunoTech Inc. 
Day, C.W.; Baric, R.; Cai, S.X.; Frieman, M.; Kumaki, Y.; Morrey, J.D.; Smee, D.F.; Barnard, 
D.L. A new mouse-adapted strain of SARS-CoV as a lethal model for evaluating antiviral 
agents in vitro and in vivo. Virology, 2009, 395(2), 210-222. 
de Vega WC, Herrera S, Vernon SD, McGowan PO. Epigenetic modifications and glucocorticoid 
sensitivity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). BMC Medical 
Genomics. 2017 Dec 1;10(1):11. 
Fundenberg HH.  The Florence Nightingale Disease (FND):  A Multisystem Experiment of 
Nature:  A 50 Patient Five Year Analysis.  In:  Hyde B, ed.  The Clinical and Scientific Basis of 
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 641-653.  The Nightingale Research 
Foundation, Ottawa, Ontario, 1992. 
Greenstone, H, Experiment No NIAS 178, 24Aug2007. 
Hives L., Bradley A., Richards J. Can physical assessment techniques aid diagnosis in people 
with chronic fatigue syndrome/myalgic encephalomyelitis? A diagnostic accuracy study. BMJ 
Open. 2017;7 
Kida S., Pantazis A., Weller R.O. CSF drains directly from the subarachnoid space into nasal 
lymphatics in the rat. Anatomy, histology and immunological significance. Neuropathol Appl 
Neurobiol. 1993;19:480–488. Montoya JG. 
Law HKW, Cheung CY, Ng HY, et al. Chemokine up-regulation in SARS-coronavirus-infected, 
monocyte-derived human dendritic cells. Blood 2005;106:2366-2374. 


 
 
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Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, Grupp SA, Mackall CL. Current 
concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014 Jul 
10;124(2):188-95. 
Marra, MA, Jones, SJM, Astell, CR, et al., The Genome Sequence of the SARS-Associated 
Coronavirus, Science, 2003, 300(5624) 1399-1404, DOI: 10.1126/science.1085953 
Mogensen TH, Paludan SR. Molecular pathways in virus-induced cytokine production. 
Microbiology and Molecular Biology Reviews. 2001 Mar 1;65(1):131-50. 
Moldofsky H., Patcai J. Chronic widespread musculoskeletal pain, fatigue, depression and 
disordered sleep in chronic post-SARS syndrome; a case-controlled study. BMC Neurol. 
2011;11:1–7. 
Montoya JG, Holmes TH, Anderson JN, Maecker HT, Rosenberg-Hasson Y, Valencia IJ, Chu L, 
Younger JW, Tato CM, Davis MM. Cytokine signature associated with disease severity in chronic 
fatigue syndrome patients. Proceedings of the National Academy of Sciences. 2017 Aug 
22;114(34):E7150-8. 
Morris G, Maes M, Berk M, Puri BK. Myalgic encephalomyelitis or chronic fatigue syndrome: 
how could the illness develop?. Metabolic Brain Disease. 2019 Apr;34(2):385-415. 
Palaiodimos L, Kokkinidis DG, Karamanis LW et al. Severe obesity, increasing age and male sex 
are independently associated with worse in-hospital outcomes, and higher mortality, in a cohort 
of patients with COVID-19 in the Bronx, New York. Metabolism 2020;108:154262. 
Doi:10.1016/j.metab.2020.154262. 
Perrin R, Riste L, Hann M, et al. Into the looking glass: Post-viral syndrome post COVID-19. 
Med Hypotheses 2020;144:110055. doi.org/10.1016/j.mehy.2020.110055. 
Quin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y. Dysregulation of immune response in patients 
with COVID-19 in Wuhan, China. Clin infect dis. 2020;248:1-7. 
Rasa S, Nora-Krukle Z, Henning N, Eliassen E, Shikova E, Harrer T, Scheibenbogen C, 
Murovska M, Prusty BK. Chronic viral infections in myalgic encephalomyelitis/chronic fatigue 
syndrome (ME/CFS). Journal of Translational Medicine. 2018 Dec 1;16(1):268. 
Sotzny F, Blanco J, Capelli E, Castro-Marrero J, Steiner S, Murovska M, Scheibenbogen C. 
Myalgic encephalomyelitis/chronic fatigue syndrome–evidence for an autoimmune disease. 
Autoimmunity Reviews. 2018 Jun 1;17(6):601-9. 
Steiner S, Becker SC, Hartwig J, Sotzny F, Lorenz S, Bauer S, Löbel M, Stittrich AB, Grabowski 
P, Scheibenbogen C. Autoimmunity-related risk variants in PTPN22 and CTLA4 are associated 
with ME/CFS with infectious onset. Frontiers in Immunology. 2020;11. 
Strayer DR, Carter WA, Brodsky I, Cheney P, Peterson D, Salvato P, Thompson C, Loveless M, 
Shapiro DE, Elsasser W and Gillespie DH.  A controlled clinical trial with specifically configured 


 
 
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RNA drug, poly(I)poly(C12U), in chronic fatigue syndrome.  Clinical Infectious Diseases 
18(suppl 1):S88-S95, 1994. 
Strayer DR, Carter W, Strauss KI, Brodsky I, Suhadolnik RJ, Ablashi D, Henry B, Mitchell WM, 
Bastien S and Peterson D.  Long term improvement in patients with chronic fatigue syndrome 
treated with Ampligen®.  J Chronic Fatigue Syndrome, 1:35-53, 1995. 
Strayer DR, Carter WA, Stouch BC, Stevens SR, Bateman L, Cimoch PJ, et al. A double-blind, 
placebo-controlled, randomized, clinical trial of the TLR-3agonist rintatolimod in severe cases 
of chronic fatigue syndrome. PLoS ONE 2012;7(3):e31334. 
Strayer, DR, Dickey, R, Carter, WA, Sensitivity of SARS/MERS CoV to Interferons and Other 
Drugs Based on Achievable Serum Concentrations in Humans, Infectious Disorders – Drug 
Targets, 2014, Vol. 14, No.1 
Strayer DR, Stouch BC, Stevens SR, Bateman L, Lapp CW, Peterson DL. Chronic fatigue 
syndrome/myalgic encephalomyelitis (CFS/ME): characteristics of responders to rintatolimod. J 
Drug Res Dev. 2015;1(1):2470-1009. 
Strayer, DR, Young D, and Mitchell WM. "Effect of disease duration in a randomized Phase III 
trial of rintatolimod, an immune modulator for Myalgic Encephalomyelitis/Chronic Fatigue 
Syndrome." PloS one 15.10 (2020): e0240403. 
Yen, Yu-Ting, et al. "Modeling the early events of severe acute respiratory syndrome coronavirus 
infection in vitro." Journal of virology 80.6 (2006): 2684-2693. 
 


 
 
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16. 
APPENDIX 
 APPENDIX 1: COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS V5.03 
For complete detailed information please refer to the link below: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_5x7.pdf 
 APPENDIX 2: PROMIS® SLEEP DISTURBANCE – SHORT FORM 4A 
Appendix 2 found here.  
 APPENDIX 3: PROMIS® COGNITIVE FUNCTION- ABILITIES SHORT FORM 8A 
Appendix 3 found here.  
 APPENDIX 4: PROMIS® FATIGUE SCALE 
Appendix 4 found here.  
 APPENDIX 5: SYMPTOM BURDEN QUESTIONNAIRE FOR LONG COVID (SBQ-LC) 
Appendix 5 found here.  
 APPENDIX 6: PHQ-9 PATIENT DEPRESSION QUESTIONNAIRE 
Appendix 6 found here.  
 APPENDIX 7: 6-MINUTE WALK TEST 
For complete detailed information please refer to the link below: 
https://neuropt.org/docs/default-source/cpgs/core-outcome-measures/core-outcome-measures-
drafts--march-2018/6mwt_protocol_final.pdf?sfvrsn=36cd5443_4 
 APPENDIX 8: MONTREAL COGNITIVE ASSESSMENT (MOCA) 
 
 
 
  
 
 


 
 
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 APPENDIX 9: HOLIDAY/VACATION WEEK VISIT SCHEDULING GUIDANCE DOCUMENT 
Appendix 9 found here.  
 
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
FOR PROTOCOL AMP-518  
Sponsor: 
AIM ImmunoTech Inc. 
2117 SW Highway 484 
Ocala, FL 34473, USA 
Phone: 
Fax:  
Protocol Number: 
AMP-518 
Protocol Title: 
A Randomized, Double Blind, Placebo Controlled Study to 
Evaluate the Efficacy and Safety of Ampligen® in Patients 
with Post-COVID Conditions 
Protocol Version / Date: 
Version 4.0/ Aug-23-2023 
SAP Author: 
Amarex Clinical Research, 
LLC 
20201 Century Boulevard 
Germantown, MD   20874 
USA 
Telephone:  
Facsimile: 
Plan Version: 
SAP – Final Version 1.1 
Plan Date: 
6-Dec-2023
--- confidential--- 
Clinical Trials.gov Identifier: NCT05592418


Protocol: AMP-518 
Statistical Analysis Plan 
AIM ImmunoTech Inc. 
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Protocol Number:  
AMP-518  
Protocol Version / Date: 
Version 4.0/ Aug-23-2023 
Protocol Name: 
A Randomized, Double Blind, Placebo Controlled Study 
to Evaluate the Efficacy and Safety of Ampligen® in 
Patients with Post-COVID Conditions 
 
Sponsor: 
AIM ImmunoTech Inc.  
2117 SW Highway 484 
Ocala, FL 34473, USA 
Prepared by: 
Amarex Clinical Research 
20201 Century Boulevard 
Germantown, Maryland  20874 
SAP Version: 
SAP – Final Version 1.1 
SAP Date: 
6-Dec-2023 
 
 
 
 
 
I have read and approve the Statistical Analysis Plan specified above and agree on its 
content: 
 
 
 
 
Statistician, Amarex Clinical Research 
 
Date 
 
 
 
AIM ImmunoTech Inc.  
 
Date 


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Statistical Analysis Plan 
AIM ImmunoTech Inc. 
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TABLE OF CONTENTS 
 
Section   
Page 
ABBREVIATIONS, ACRONYMS, AND DEFINITIONS ................................................................. 5 
1. 
INTRODUCTION ............................................................................................................... 6 
2. 
PROTOCOL DESIGN ......................................................................................................... 6 
2.1 
Design Overview ...................................................................................................... 6 
2.1.1 
Study Design ............................................................................................... 6 
2.1.2 
Study Visits ................................................................................................ 9 
2.2 
Treatment Groups ................................................................................................... 10 
2.3 
Randomization and Stratification ............................................................................. 10 
2.4 
Blinding ................................................................................................................. 10 
2.4.1 
Emergency Un-Blinding............................................................................. 11 
2.4.2 
Final Analysis ........................................................................................... 11 
2.5 
Protocol Objective(s) .............................................................................................. 11 
2.6 
Efficacy Assessments/ Outcome Measures ................................................................ 12 
2.6.1 
Primary Efficacy Outcome Measure ............................................................ 12 
2.6.2 
Secondary Efficacy Outcome Measures ....................................................... 12 
2.6.3 
Exploratory Efficacy Outcome Measures ..................................................... 12 
2.6.4 
Safety Outcome Measures .......................................................................... 13 
3. 
SAMPLE SIZE DETERMINATION, STATISTICAL POWER, AND SIGNIFICANCE 
LEVEL .............................................................................................................................. 13 
4. 
INTERIM ANALYSIS ....................................................................................................... 13 
5. 
PRIMARY HYPOTHESIS TO BE TESTED ..................................................................... 13 
6. 
ANALYSIS POPULATIONS ............................................................................................. 13 
 
 
 
 
 
 
7. 
DATA CONVENTION AND RELATED DEFINITIONS .................................................. 14 
7.1 
Baseline Definition ................................................................................................. 14 
7.2 
Duplicate Data ....................................................................................................... 14 
7.3 
Handling of Missing Data ........................................................................................ 14 
7.3.1 
Handling of Missing Data for Efficacy Evaluations  ......................................... 14 
7.3.2 
Handling of Missing Data for Safety Evaluations  ............................................ 14 
7.4 
Multicenter Clinical Trials ....................................................................................... 15 
7.5 
Multiple Comparisons and Multiplicity .................................................................... 15 
7.6 
Covariates and Prognostic Factors ............................................................................ 15 
7.7 
Subgroups .............................................................................................................. 16 
7.8 
Standard Calculations ............................................................................................. 16 
7.8.1 
Body Mass Index (BMI)............................................................................. 16 
7.8.2 
Change from baseline ................................................................................ 16 
7.8.3 
Duration (days) of hospitalization during the treatment phase  ....................... 16 
8. 
STATISTICAL METHODS ............................................................................................... 17 
8.1 
Summarizing Disposition and Baseline Data ............................................................. 17 
8.1.1 
Subject Disposition and Withdrawals .......................................................... 17 
8.1.2 
Protocol Deviations ................................................................................... 17 


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8.1.3 
Demographics and Baseline Characteristics ................................................. 18 
8.1.4 
Medical History ......................................................................................... 18 
8.1.5 
Prior and Concomitant Medications ............................................................ 18 
8.1.6 
Extent of Exposure and Treatment Compliance ............................................ 19 
8.2 
Analysis of Efficacy Data ........................................................................................ 19 
8.2.1 
Primary Outcome Measure and Estimand .................................................... 19 
8.2.2 
Secondary Outcome Measures .................................................................... 21 
8.2.3 
Exploratory Outcome Measures .................................................................. 23 
8.3 
Analysis of Safety Data ........................................................................................... 24 
8.3.1 
Adverse Events ......................................................................................... 25 
8.3.2 
Clinical Laboratory Evaluations .................................................................. 25 
8.3.3 
Vital Signs ................................................................................................ 26 
8.3.4 
Electrocardiogram (ECGs) ......................................................................... 27 
8.3.5 
Pulse Oxygen Saturation (SpO2) ................................................................. 28 
8.3.6 
Physical Examination ................................................................................. 28 
8.3.7 
Urine Pregnancy Test ................................................................................. 28 
 
 
8.3.9 
SARS-CoV-2 (COVID-19) Qualitative Test ................................................ 28 
8.3.10 
COVID-19 History .................................................................................... 29 
9. 
APPENDIX 1 ..................................................................................................................... 30 
10. 
APPENDIX 2 ..................................................................................................................... 36 
10.1 
Planned by-subject listings ...................................................................................... 36 
10.2 
Planned Summary Tables ........................................................................................ 37 
11. 
APPENDIX 3 ..................................................................................................................... 38 
11.1 
PROMIS FATIGUE SCORING TABLE .................................................................. 38 
11.2 
PROMIS COGNITIVE FUNCTION SCORING TABLE ........................................... 39 
11.3 
PROMIS SLEEP DISTURBANCE SCORING TABLE ............................................. 40 
12. 
REFERENCES .................................................................................................................. 41 
13. 
VERSION HISTORY ........................................................................................................ 42 


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ABBREVIATIONS, ACRONYMS, AND DEFINITIONS 
Abbreviation/Acronym 
Definition 
ADSL 
Subject-Level Analysis Dataset 
ALT 
Amarex 
Alanine Transaminase 
Amarex Clinical Research, LLC. 
ANC 
ASA 
Absolute Neutrophil Count 
American Statistical Association 
AST 
Aspartate Aminotransferase 
BMI 
Body Mass Index 
COVID 
Coronavirus Disease 2019 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CTMS 
Clinical Trial Management System 
ECG 
Electrocardiogram 
EOT 
End of Treatment 
FDA 
U.S. Food and Drug Administration 
HCT 
Hematocrit 
ICH 
International Conference on Harmonization 
ITT 
Intention to Treat 
IWRS 
Interactive Web Based Response System 
IV 
Intravenous 
LDH 
MoCA  
Lactate dehydrogenase 
Montreal Cognitive Assessment 
MCID 
Minimal Clinically Important Difference 
PHQ 
Patient Health Questionnaire 
RBC 
Red Blood Cells 
SAE 
Serious Adverse Event 
SARS 
SAS 
SBQ-LC 
Severe Acute Respiratory Syndrome 
Statistical Analysis System 
Symptom Burden Questionnaire for Long COVID 
SLE 
SOC 
Systemic Lupus Erythematosus 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
WBC 
White Blood Cells 
 


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1. 
INTRODUCTION 
This Statistical Analysis Plan describes the planned analyses and reporting for the clinical 
trial protocol AMP-518, conducted by AIM ImmunoTech Inc.. The reader of this Statistical 
Analysis Plan (SAP) is encouraged to review the complete protocol and amendments as 
this plan contains only a limited overview of protocol information.  The main objectives of 
this plan are to provide details pertaining to statistical methodology, data conventions, and 
processes used for the analysis of data from this trial.  
The format and content of this SAP are structured to provide sufficient detail to meet the 
requirements specified by the International Council on Harmonization (ICH) E9: Guidance 
on Statistical Principles in Clinical Trials.  All work planned and presented in this Statistical 
Analysis Plan will follow the ethical guidelines published by the American Statistical 
Association (ASA). 
The following documents were reviewed in preparation of this Statistical Analysis Plan: 
• Protocol Version 4.0/ Aug-23-2023 
• ASA Ethical Guidelines for Statistical Practice (2016) 
• The Royal Statistical Society: Code of Conduct (2014) 
• ICH Guidance on the Structure and Content of Clinical Study Reports (ICH E3, 1996) 
• ICH Guidance on the Structure and Content of Clinical Study Reports (ICH E3(R1), 
2013) 
• ICH Guidance on the Statistical Principles for Clinical Trials (ICH E9, 1998) 
• ICH Guidance on the Statistical Principles for Clinical Trials (ICH E9(R1), 2017) 
2. 
PROTOCOL DESIGN 
2.1 
Design Overview 
2.1.1 Study Design 
This is a Phase 2, two-arm, randomized, double blind, placebo controlled multicenter study 
to evaluate the efficacy and safety of Ampligen® in patients experiencing the Post-COVID 
Condition of fatigue. Patients will be randomized 1:1 to receive twice weekly IV infusions 
of Ampligen® or placebo. 
Ampligen® and placebo will be administered via twice weekly infusions (Example: 






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2.1.2 Study Visits 
2.1.2.1 Study Schedule 
The study will have three phases: Screening Phase, Treatment Phase, and Follow-Up 
Phase. 
Screening Phase (up to 1 week):  
All subjects will provide written informed consent and have a Screening visit (V1) within 
7 days prior to first treatment visit (V2) to determine eligibility for subject participation. 
All subjects who fail to meet eligibility criteria are considered screen failures and are exited 
from the study without further evaluation. 
Treatment Phase (12 weeks):  
Ampligen® and placebo will be administered via twice weekly infusions (Example: 
Monday/Thursday or Tuesday/Friday schedule) for 12 weeks. 
 
 
 
 
Follow-Up Phase (2 weeks): 
Two safety follow-up visits will be performed 3 to 4 days and 2 weeks after the End of 
Treatment (EOT) visit (V25). 
2.1.2.2 Unscheduled Visits 
In the event that the subject will return to clinic at a time other than a regularly scheduled 
study visit, the visit will be regarded as an unscheduled visit. Assessments at unscheduled 
visits are at the discretion of the Investigator. All pertinent findings, including adverse 
events or changes in medications, will be noted in the eCRF. 


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2.2 
Treatment Groups 
The following treatment groups will be assessed in the study:  
• Ampligen®  
• Placebo (normal saline) 
 
2.3 
Randomization and Stratification 
A total of 80 subjects (40 per group) will be randomized in a 1:1 ratio (Ampligen®: 
placebo). 
 
 
 
 
 
 
 
 
 
 
2.4 
Blinding 
This is a double-blind study. The investigator and staff, subjects and Sponsor/CRO staff 
directly related to study conduct will be blinded to the treatment assignment.  
 
 
 
 
 
 
 
  
  
 
 


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2.4.1 Emergency Un-Blinding 
Breaking the blind prematurely will be allowed only if the subject’s well-being requires 
knowledge of the subject’s treatment allocation. Every attempt will be made to maintain 
the blind throughout the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.4.2 Final Analysis 
 
 
 
 
 
 
2.5 
Protocol Objective(s) 
The purpose of this study is to assess the efficacy and safety of Ampligen® administered 
twice weekly by IV infusions in subjects experiencing the Post-COVID Condition of 
fatigue. 


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2.6 
Efficacy Outcome Measures 
2.6.1 Primary Efficacy Outcome Measure 
• Change from baseline to week 13 in PROMIS® Fatigue Score (T-Score). 
2.6.2 Secondary Efficacy Outcome Measures 
• Change from baseline to week 6 in PROMIS® Fatigue Score (T-Score). 
Note: Additional PROMIS® Fatigue Score analysis (change from baseline) at week 6 
and 13 will be performed excluding response to item, “How often did you have enough 
energy to exercise strenuously?” 
• Change from baseline to week 6 and 13 in distance traveled during a 6-minute walk 
test. 
• Proportion of subjects with minimal clinically important difference (MCID), defined 
as at least 54 m, in the Six-Minute Walk Test (6MWT) at the end of 12-week treatment 
phase. 
• Change from baseline to week 6 and 13 in PROMIS® Cognitive Function Score (T-
Score).  
• Change from baseline to week 6 and 13 in PROMIS® Sleep Disturbance Score (T-
Score). 
2.6.3 Exploratory Outcome Measures 
• Changes from baseline in COVID-19-related symptoms using Symptom Burden 
Questionnaire for Long COVID (SBQ-LC) during the course of the treatment phase. 
Note: A set of common COVID-19-related symptoms (see Symptom Burden 
Questionnaire for Long COVID (SBQ-LC)) will be evaluated at each scheduled study 
visit by the patient regardless of which symptoms a subject had at baseline, as new 
symptoms may appear following the baseline assessment. 
• Change from baseline in cognitive function as measured by Montreal Cognitive 
Assessment (MoCA) at week 4, 8, and 13 during the treatment phase. 
• Incidence of hospitalization during the treatment phase. 
• Duration (days) of hospitalization during the treatment phase. 
• Evaluation of lymphocyte profile by flow cytometry in patients with post-COVID-19 
conditions. 


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• Identification and evaluation of plasma protein biomarkers in patients with post-
COVID-19 conditions.  
2.6.4 Safety Outcome Measures 
• Incidence of treatment-related adverse events. 
• Incidence and severity of treatment-emergent adverse events (TEAEs). 
• Incidence of serious adverse events (SAEs). 
• Incidence of TEAEs and SAEs leading to discontinuation of study medication. 
• Changes in blood chemistry, hematology, and coagulation results. 
• Changes in vital signs including temperature, pulse, respiratory rate, systolic and 
diastolic blood pressure. 
• Changes in physical examination results. 
• Change in electrocardiogram (ECG) results. 
3.       SAMPLE SIZE DETERMINATION, STATISTICAL POWER, AND   
SIGNIFICANCE LEVEL 
The sample size of 80 subjects will be used in this study. The sample size is based on 
clinical judgment. No statistical power calculation is used to establish the sample size for 
this proof-of-concept study. 
4. 
INTERIM ANALYSIS 
There is no planned interim analysis for this early phase study. 
5. 
PRIMARY HYPOTHESIS TO BE TESTED 
There is no formal hypothesis testing for this study as the study is a Phase II evaluation and 
is not intended to be hypothesis generating. The study is not powered to reliably yield 
statistically significant conclusions. 
6. 
ANALYSIS POPULATIONS 
 
 
 
 
 
 


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7. 
DATA CONVENTION AND RELATED DEFINITIONS   
7.1 
Baseline Definition 
For all parameters, baseline will be defined as the last available value before the first 
randomized treatment.  
7.2 
Duplicate Data  
 
 
  
7.3 
Handling of Missing Data 
7.3.1 Handling of Missing Data for Efficacy Evaluations  
Every effort will be made to obtain required data at each scheduled evaluation from all 
subjects who have been randomized to minimize missing data. 
 
 
7.3.2 Handling of Missing Data for Safety Evaluations  
The below imputation rules will be followed for imputation of missing dates: 
 
 
 
 
 


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7.4 
Multicenter Clinical Trials  
This is a multi-center clinical trial.  
7.5      Multiple Comparisons and Multiplicity 
There will be no adjustment for multiple testing or multiplicity for this phase II trial. For 
all effectiveness endpoints, inference will be based on type I error rate of 0.05. 
7.6 
Covariates and Prognostic Factors 
In the efficacy analysis, the stratification factors and baseline values will be used as 


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covariates in the analysis of all the primary, secondary, and additional efficacy endpoints.  
7.7 
Subgroups  
 
 
 
 
 
   
7.8 
Standard Calculations  
7.8.1 Body Mass Index (BMI) 
BMI will be calculated using height (in cm) and weight (in kg) according to the formula 
noted below. 
BMI (kg/m2) = Weight (kg)/[Height (cm)/100]2  
7.8.2 Change from baseline 
Change from baseline will be calculated for each post baseline visit as follows:  
Change From Baseline = Post baseline result at time - Baseline result 
 
7.8.3 Duration (days) of hospitalization during the treatment phase  
The duration (days) of hospitalization during the treatment phase will be calculated using 
the formula noted below. 
Duration (days) = (Date of discharge – Date of hospitalization) + 1 
Duration (days) of hospitalization during the treatment phase will only be calculated 
for hospitalization(s) occurring after the date of first study treatment administration 
and prior to the date of last study treatment administration. For subject who remain 
hospitalized at the time of last treatment administration, the date of last treatment will 
be used for the calculation. 
All deaths within 91 days will be considered censored on Day 91. Conceptually, a 
death corresponds to an infinite length of hospitalization but censoring at any time 
greater than or equal to Day 91 gives the same answer as censoring at Day 91; both 
correspond to giving deaths the worst rank. 
In the incidence where there are multiple hospitalizations for a subject, the durations 
from the multiple hospitalizations will be summed to provide total duration of 
hospitalization for the subject. 


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8. 
STATISTICAL METHODS 
All statistical analyses will be performed using SAS® for Windows, version 9.4 or later. 
All data collected during this study will be presented in subject data listings.  
All the efficacy analyses presented here will be conducted using mITT and PP populations. 
All safety analyses will be conducted using the Safety population.  
 
 
 
8.1    Summarizing Disposition and Baseline Data  
8.1.1 Subject Disposition and Withdrawals 
There will be a detailed accounting of all subjects who sign an informed consent to 
participate in this trial. 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
   
 
 
 
 
 
   
8.1.2 Protocol Deviations 
Protocol deviations will be identified and classified as minor or major before un-blinding 
according to the following categories:  


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8.1.3 Demographics and Baseline Characteristics 
 
 
 
  
8.1.4 Medical History 
Medical history will be coded using the most current available version of Medical 
Dictionary for Regulatory Activities (MedDRA) and will be summarized by system organ 
class (SOC) and preferred term (PT). 
 
 
8.1.5 Prior and Concomitant Medications 
Prior medication is defined as any medication with an end date prior to the first treatment 
date. 
 
 
 
  


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8.1.6 Extent of Exposure and Treatment Compliance 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2 
Analysis of Efficacy Data 
The primary analysis will be conducted on the mITT population. 
 
 
 
 
The statistical tests for the primary efficacy endpoint and secondary endpoints will be 
two-sided with α=0.05.   
8.2.1 Primary Outcome Measure and Estimand 
8.2.1.1 Primary Outcome Measure 
The primary efficacy outcome measure for this study is the change from baseline to week 
13 in PROMIS® Fatigue Score (T-Score). 
 
  
The Fatigue - Short Form 7a includes 7 questions and each question has a 5-point severity 
scale (Never, Rarely, Sometimes, Often, Always). The total score (range from 7-35) will 
be calculated and converted to the PROMIS® Fatigue Score (T-Score) per PROMIS 


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Fatigue Scoring Manual as which is included here as APPENDIX 3, Section 11.1. The 
higher in PROMIS® Fatigue Score (T-Score) represents the worsening of fatigue.  
 
 
 
 
 
8.2.1.2 Estimand 
The estimand for the primary outcome measure is described by the following attributes: 
Treatment: Ampligen® vs. Placebo  
Study Population: Adult patients with the Post-COVID Condition of fatigue. 
Primary Efficacy Variable: Change from baseline to week 13 in PROMIS® Fatigue 
Score (T-Score) 
Primary Efficacy Analysis Population: The Modified Intent-to-Treat (mITT) population 
is defined as the set of subjects who have received at least one dose of study treatment 
(Ampligen® or placebo). 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8.2.2 Secondary Outcome Measures  
8.2.2.1 Change from baseline to week 6 in PROMIS® Fatigue Score (T-Score) 
Note: Additional PROMIS® Fatigue Score analysis (change from baseline) at week 6 and 
13 will be performed excluding response to item, “How often did you have enough energy 
to exercise strenuously?” 
 
 Similar analysis methods used 
for the primary endpoint will be applied to analyze the data from this outcome measure. 
8.2.2.2 Change from baseline to week 6 and 13 in distance traveled during a 6-minute 
walk test 
The 6-minute walk test (6MWT) will be assessed throughout the study. The 6MWT is a 
sub-maximal exercise test used to assess aerobic capacity and endurance. The distance 
covered over a time of 6 minutes is used as the outcome by which to compare changes in 
performance capacity.  
 
 Similar analysis methods used for the 
primary endpoint will be applied to analyze the data from this outcome measure. 


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8.2.2.3 Proportion of subjects with minimal clinically important difference (MCID), 
defined as at least 54 m, in the Six-Minute Walk Test (6MWT) at the end of 12-week 
treatment phase 
 
 
 
 
  
8.2.2.4 Change from baseline to week 6 and 13 in PROMIS® Cognitive Function Score 
(T-Score) 
The Cognitive Function - Abilities - Short Form 8a includes 8 questions and each question 
has a 5-point severity scale from not at all to very much (1=Not at all, 2=A little bit, 
3=Somewhat, 4=Quite a bit, and 5=Very much) ranged from 8-40. PROMIS® Cognitive 
Function Score (T-Score) will be converted from the total Short Form 8a score per 
PROMIS Fatigue Scoring Manual which is included here as APPENDIX 3, Section 11.2. 
The higher in PROMIS® Cognitive Function Score (T-Score) represents the better 
cognitive function. 
 Similar 
analysis methods used for the primary endpoint will be applied to analyze the data from 
this outcome measure. 
8.2.2.5 Change from baseline to week 6 and 13 in PROMIS® Sleep Disturbance Score 
(T-Score) 
The Sleep Disturbance - Short Form 4a includes 4 questions with three 5-point severity 
scales from not at all to very much (1 or 5=Not at all, 2 or 4=A little bit, 3=Somewhat, 4 
or 2=Quite a bit, and 5 or 1=Very much) and very poor to very good (5=Very poor, 4=Poor, 
3=Fair, 2=Good, and 1=Very good) ranged from 4-20. PROMIS® Sleep Disturbance Score 
(T-Score) will be converted from the total Short Form 4a score per PROMIS Fatigue 
Scoring Manual which is included here as APPENDIX 3, Section 11.3. The higher in 


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PROMIS® Sleep Disturbance Score (T-Score) represents the worsening of sleep 
disturbance. 
 Similar 
analysis methods used for the primary endpoint will be applied to analyze the data from 
this outcome measure. 
8.2.3 Exploratory Outcome Measures  
8.2.3.1 Change from baseline in COVID-19-related symptoms using Symptom Burden 
Questionnaire for Long COVID (SBQ-LC) during the course of the treatment phase 
 
 
 
 
 
 
Similar analysis methods used for the primary endpoint will be applied to analyze the data 
from this outcome measure. 
8.2.3.2 Change from baseline in cognitive function as measured by Montreal Cognitive 
Assessment (MoCA) at week 4, 8, and 13 during the treatment phase 
 
 Similar analysis 
methods used for the primary endpoint will be applied to analyze the data from this 
outcome measure. 
8.2.3.3 Incidence of hospitalization during the treatment phase 
The proportion of subjects with at least one hospitalization during the treatment phase will 
be presented for the two treatment groups. 
 
 


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8.2.3.4 Duration (days) of hospitalization during the treatment phase 
The duration (days) of hospitalization during the treatment phase will be calculated using 
the formula stated in Section 7.8.4. 
  
 
 
 
 
 
8.2.3.5 Evaluation of lymphocyte profile by flow cytometry in patients with post-COVID-
19 conditions 
 
 
 
 
 
 Similar 
analysis methods used for the primary endpoint will be applied to analyze the data from 
this outcome measure. 
8.2.3.6 Identification and evaluation of plasma protein biomarkers in patients with post-
COVID-19 conditions 
 
 
 
8.3 
Analysis of Safety Data 
All safety analyses will be conducted using the Safety population. All data collected will 
be summarized according to the variable type. No inferential statistics are planned.  


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8.3.1 Adverse Events 
Adverse events will be classified by system organ class (SOC) and preferred term (PT) 
according to the most recent version of MedDRA dictionary.     
TEAE are defined as adverse events with onset date on or after the first treatment. TEAEs 
will be summarized by treatment group, System Organ Class, and preferred term. The 
following TEAE summaries will be provided: 
a) Overall (i.e., regardless of severity or relationship to treatment) 
b) Adverse events by severity 
c) Related adverse events by severity 
d) Adverse events leading to treatment discontinuation by severity 
e) Adverse events leading to death by severity 
 
 
 
 
   
 
8.3.2 Clinical Laboratory Evaluations  
 
8.3.2.1 Laboratory Values over Time  
 
 Data will be summarized 
as appropriate for the variable type. 
8.3.2.2 Individual Patient Changes  
 
 
 


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8.3.2.3 Individual Abnormalities 
 
8.3.3 Vital Signs 
Vital sign assessments are performed in order to characterize basic body function. The 
parameters collected in this study are: systolic BP (mmHg), diastolic BP (mmHg), 
temperature (0C), heart rate (bpm), respiratory rate (bpm). 
 
 
8.3.3.1 Vital Signs Values over Time  
 
 
 
 
 
8.3.3.2 Individual Patient Changes on Notable Vital Sign Values 
Clinically notable elevated values 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinically notable below normal values 
 
 
 
 
 
 
 
 
 
 
 


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8.3.4 Electrocardiogram (ECGs) 
The ECG parameters include ventricular rate (beats per minute), PR interval (msec), QRS 
interval (msec), QT interval (msec), and QTc interval (msec). 
 
 
8.3.4.1 ECG Values over Time  
 
 
 
 
 
8.3.4.2 Individual Patient Changes on Notable ECG Values 
 
 
 
   
 
 
  
 
 
 
 
  
 
 


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8.3.4.3 Individual Patient Changes on Interpretation 
 
 
 
 
  
8.3.5 Pulse Oxygen Saturation (SpO2) 
 
8.3.6 Physical Examination 
 
8.3.7 Urine Pregnancy Test 
  
 
 
  
8.3.9 SARS-CoV-2 (COVID-19) Qualitative Test 
 
  


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8.3.10 COVID-19 History 
 
 
 
 
 
 
 
 
 
 






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10. APPENDIX 2 
10.1 Planned by-subject listings  
 
 
 
 
 
 
 
 
 
 
 
 


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10.2 Planned Summary Tables 
 
 
 
 
  
  
  
 
  
 
 
 
 
 
 








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12. 
REFERENCES 
1. ASA Ethical Guidelines for Statistical Practice (2016) 
2. The Royal Statistical Society: Code of Conduct (2014) 
3. ICH Guidance on the Structure and Content of Clinical Study Reports (ICH E3, 1996) 
4. ICH Guidance on the Structure and Content of Clinical Study Reports (ICH E3(R1), 
2013) 
5. ICH Guidance on the Statistical Principles for Clinical Trials (ICH E9, 1998) 
6. ICH Guidance on the Statistical Principles for Clinical Trials (ICH E9(R1), 2017) 
 
 
 


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13. 
VERSION HISTORY  
Version 1.0 
This is the first final version of this document.