A Randomized, Double-Blind Placebo-Controlled Study to Evaluate the Safety and Efficacy of Rayaldee (Calcifediol) Extended-release Capsules to Treat Symptomatic Patients Infected With SARS-CoV-2 (REsCue)
Phase: PHASE2
Conditions: COVID-19, Coronavirus, SARS-CoV2 Infection
Sponsor: OPKO Health, Inc.

 
PROTOCOL CTAP101-CL-2014 
Study Title: 
A Randomized, Double-Blind Placebo-Controlled Study to Evaluate the 
Safety and  Efficacy of Rayaldee (calcifediol) Extended-release Capsules 
to Treat Symptomatic Patients Infected with SARS-CoV-2 (REsCue) 
Study Number: 
CTAP101-CL-2014 (Ver. 8.0, 12 November 2021) 
Short Title: 
Safety and Efficacy of Rayaldee for Treating Mild to Moderate COVID-
19  
Study Phase: 
2 
Product Name: 
Rayaldee® (calcifediol) Extended-release Capsules (30 mcg) 
Investigator: 
 
Sponsor: 
OPKO Pharmaceuticals, LLC 
4400 Biscayne Boulevard 
Miami, FL 33137 
Study Contact: 
Joel Melnick, MD 
 
  
 
4400 Biscayne Boulevard 
Miami, FL 33137 
 
 
 
   
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This study will be conducted in compliance with the protocol, US Code of Federal 
Regulations (CFR) applicable to clinical studies, principles of International Council on 
Harmonization (ICH) Good Clinical Practice (GCP), the Declaration of Helsinki, and all 
applicable regulatory requirements. 
Confidentiality Statement 
This protocol is the confidential information of  OPKO Pharmaceuticals, LLC and is intended solely for the guidance of 
the clinical investigation.  This protocol may not be disclosed to parties not associated with the clinical investigation or 
used for any purpose without the prior written consent of OPKO Pharmaceuticals, LLC 
 
 
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TABLE OF CONTENTS 
LIST OF IN-TEXT TABLES .................................................................................................5 
SYNOPSIS ................................................................................................................................6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................15 
1 
INTRODUCTION ..........................................................................................................17 
1.1 
Vitamin D Insufficiency .............................................................................................17 
1.2 
Vitamin D and Viral Infections ................................................................................17 
1.3 
Vitamin D and Cathelicidin Gene ............................................................................18 
1.4 
Preclinical Experience ...............................................................................................19 
1.5 
Previous Clinical Experience ....................................................................................19 
2 
STUDY OBJECTIVES ..................................................................................................21 
2.1 
Study Objectives.........................................................................................................21 
2.1.1 
Primary Objectives ..............................................................................................21 
2.1.2 
Estimand ...............................................................................................................21 
2.1.3 
Secondary Objectives: .........................................................................................21 
 
 
3 
INVESTIGATIONAL PLAN ........................................................................................23 
3.1 
Overall Study Design .................................................................................................23 
3.2 
Rationale for Study Design and Control Group .....................................................23 
3.3 
Evaluations .................................................................................................................24 
3.4 
Study Endpoints .........................................................................................................24 
3.4.1 
Primary Efficacy Endpoints................................................................................24 
3.4.2 
Secondary Efficacy Endpoints ............................................................................25 
 
 
3.4.4 
Primary Safety Endpoints ...................................................................................26 
3.5 
Study Duration ...........................................................................................................26 
4 
STUDY POPULATION SELECTION .........................................................................27 
4.1 
Study Population ........................................................................................................27 
4.2 
Inclusion Criteria .......................................................................................................27 
4.3 
Exclusion Criteria ......................................................................................................27 
5 
STUDY TREATMENTS ................................................................................................29 
5.1 
Description of Rayaldee (CTAP101 Capsules) ........................................................29 
5.2 
Description of Placebo Capsules ...............................................................................29 
5.3 
Treatments Administered .........................................................................................29 
5.3.1 
Dosing Instructions ..............................................................................................29 
5.3.2 
Dose Reduction and Stopping Rules ..................................................................30 
5.3.3 
Overdose and Toxicity .........................................................................................30 
5.3.4 
Method of Assigning Subjects to Treatment Groups .......................................31 
5.4 
Prior and Concomitant Therapy ..............................................................................31 
5.5 
Diet Restrictions .........................................................................................................31 
5.6 
Subject Activity Restrictions .....................................................................................31 
5.7 
Pregnancy and Contraception ..................................................................................31 
5.8 
Treatment Compliance ..............................................................................................32 
5.9 
Packaging and Labeling ............................................................................................32 
5.10 
Storage and Accountability .......................................................................................32 
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5.11 
Investigational Product Retention at Study Sites ...................................................32 
5.12 
Blinding .......................................................................................................................33 
6 
STUDY PROCEDURES ................................................................................................34 
6.1 
Informed Consent ......................................................................................................34 
6.2 
Medical History and Concomitant Medications .....................................................34 
6.3 
Brief Physical Examinations and Vital Signs ..........................................................34 
6.4 
Clinical Laboratory Tests..........................................................................................35 
6.4.1 
Laboratory Parameters .......................................................................................35 
6.4.2 
Sample Collection, Storage, and Shipping .........................................................36 
6.4.3 
Clinical Supplies ...................................................................................................37 
6.5 
Dispensing Study Drug ..............................................................................................37 
6.6 
Data Safety Monitoring Board (DSMB) ..................................................................37 
6.7 
Adverse Events Assessments .....................................................................................38 
6.7.1 
Definition ..............................................................................................................38 
6.7.2 
Performing Adverse Events Assessments ..........................................................38 
6.7.3 
AE Collection Period ...........................................................................................38 
6.7.4 
Severity..................................................................................................................39 
6.7.5 
Relationship ..........................................................................................................39 
6.7.6 
Clinical Significance.............................................................................................40 
6.7.7 
Serious Adverse Events .......................................................................................40 
6.7.7.1 
Definition ........................................................................................................40 
6.7.7.2 
Expectedness ...................................................................................................41 
6.7.7.3 
Reporting Serious Adverse Events ...............................................................41 
6.7.8 
Treatment-Emergent Adverse Events................................................................42 
6.8 
Concomitant Medication Assessments .....................................................................42 
6.9 
Removal of Subjects from the Study or Study Drug / Stopping Criteria .............42 
6.10 
Appropriateness of Measurements ...........................................................................42 
7 
STUDY ACTIVITIES ....................................................................................................43 
7.1 
Screening and Randomization (Visit 1/Day -3 to 1) ................................................43 
7.1.1 
Screening (Day -3 to 0) ........................................................................................43 
7.1.2 
Randomization and Initial Treatment (Day 1) ..................................................43 
7.2 
Days 2-6 .......................................................................................................................44 
7.3 
Visit 2 (Day 7 ± 2) .......................................................................................................44 
7.4 
Days 8-13 .....................................................................................................................44 
7.5 
Visit 3 (Day 14 ± 2) .....................................................................................................45 
7.6 
Days 15-20 ...................................................................................................................45 
7.7 
Visit 4 (Day 21 ± 2) .....................................................................................................45 
7.8 
Days 22-27 ...................................................................................................................46 
7.9 
Visit 5 (Day 28 + 2) (End of Treatment/Early Termination) .................................46 
7.10 
Days 29-41 ...................................................................................................................47 
7.11 
Visit 6 (Day 42 ± 4 (Follow-up – Telephone Visit)) .................................................47 
8 
QUALITY CONTROL AND ASSURANCE ...............................................................48 
9 
PLANNED STATISTICAL METHODS ......................................................................49 
9.1 
General Considerations .............................................................................................49 
9.2 
Missing Data ...............................................................................................................49 
9.3 
Planned Data Safety Monitoring: .............................................................................51 
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LIST OF IN-TEXT TABLES 
Table 1 
Evaluations .....................................................................................................35 
Table 2 
List of Laboratory Tests ................................................................................36 
Table 3  
Adverse Event Relationship Criteria ...........................................................40 
 
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SYNOPSIS 
Sponsor:  
OPKO Pharmaceuticals, LLC 
Name of Finished Product: 
Rayaldee® (calcifediol) Extended-release Capsules  
[Extended-release calcifediol, coded as CTAP101 Capsules] 
Name of Active Ingredient:  
Calcifediol, calcidiol, 25-hydroxyvitamin D3 
Test Products, Dose, and Mode of Administration:  
Rayaldee (900 mcg) or matching placebo in a 900 mcg loading dose split into three equal doses 
of 300 mcg each administered over three days (on Days 1, 2 and 3) followed by a maintenance 
dose of 60 mcg/day or matching placebo for 24 days by the oral route (Days 4-27). 
Study Title: 
A Randomized, Double-Blind Placebo-Controlled Study to Evaluate the Safety and  Efficacy of 
Rayaldee (calcifediol) Extended-release Capsules to Treat Symptomatic Patients Infected with 
SARS-CoV-2 (REsCue) 
Study Phase: 2 
Rationale:  
Insufficient vitamin D (vitD) has been linked to a large number of pathologies including 
immune disorders and infectious diseases. VitD functions as a key host defense regulator 
against viral pathogens. High levels of vitD in the blood have been associated with resistance to 
human immunodeficiency virus type 1 (HIV1) infection.  Moreover, low levels of vitD have 
been associated with higher levels of immune activation and inflammation in HIV and other 
diseases. While the results of clinical trials studying vitD supplementation have differed, there 
are several well-designed, large meta-analyses that have supported vitD supplementation as 
safe and protective against acute respiratory tract infections, with those that were severely vitD 
deficient receiving the most benefit. 
The innate immune response in antigen-presenting cells (monocyte/macrophages and dendritic 
cells) is initiated and perpetuated by pathogen-associated molecular patterns (PAMPs) of the 
infecting virus interacting with pattern recognition receptors (eg, Toll-like receptors [TLR]). 
TLR activation leads to up-regulation of expression of the intracellular vitD receptor (VDR) 
and CYP27B1 (25-hydroxyvitamin D [25D]-1α-hydroxylase); the latter event up-regulates 
local generation of the active vitD metabolite, 1,25-dihydroxyvitamin D (1,25D). 1,25D can 
then engage the VDR in an intracrine mode, which, in turn, controls cathelicidin antimicrobial 
peptide (CAMP) and interleukin 1ß (IL-1ß) gene expression, IL-1ß being a central initiator of 
the adaptive immune response. 
LL37 is a potent, central, endogenously synthesized antimicrobial protein in humans, the 
product of the CAMP gene. Early in infection, LL37 is made principally by innate immune 
cells, monocyte/macrophages and dendritic cells, initiators of the immune response to both 
bacterial and viral infections. Owing to serendipity, a retrotransposon bearing a perfect vitD 
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response element (VDRE: AGGTCAXXXAGGTCA) was inserted into the promoter of the 
cathelicidin gene in great apes and humans. This ancient event made LL37 production 
dependent on transactivation of CAMP by the 1,25D-activated VDR. 
Extensive recent work shows that an insufficient supply of 25D to activated VDR- and 
CYP27B1-expressing human monocytes/macrophages is associated with a decrease in CAMP 
expression. An insufficient level of 25D in human serum causes inadequate i) intracellular 
generation of 1,25D, ii) activation of the VDR, iii) transactivation of the CAMP gene and iv) 
production and release of LL37 to combat microbial invasion of the host. The end result is 
innate and subsequent adaptive immune deficiency.  
Raising serum total 25D to sufficiently high levels can resolve the immune-compromised state 
in the human host. Accomplishing this with vitD supplements is unreliable and is difficult in 
obesity owing to the increased volume of distribution of the non-polar vitamin. In contrast, 
treatment with the more polar and extended-release calcifediol (Rayaldee or CTAP101 
Capsules) is reliable and, depending on the administered dose, can take as little as 9-12 hours.  
Treatment with CTAP101 Capsules has been shown to be safe for administration to patients 
with stage 3 or 4 chronic kidney disease (CKD), as evidenced by United States (US) Food and 
Drug Administration (FDA) approval of the product in 2016 as Rayaldee® (calcifediol) 
Extended-release Capsules.   
Accumulating data suggest that hyperactive immune response to COVID-19 poses unique risks 
to the cardiovascular system and plays a role in disease severity. As the disease progresses, a 
concomitant rise in inflammatory cytokine levels may drive the depletion and exhaustion of T 
cell populations. On the other hand, vitD is an immune-modulating agent and has been 
implicated in the pathophysiology of autoimmune diseases, including systemic lupus 
erythematosus and multiple sclerosis. Vitamin D insufficiency (VDI) is a risk factor for 
multiple sclerosis and correlates with the disease severity. Thus, 
 
 appropriate treatment with 
Rayaldee may help to mitigate an overactive, adaptive T- and B-lymphocyte immune system 
and ameliorate immune cell exhaustion. 
We propose a double-blind randomized, placebo-controlled trial of extended-release calcifediol 
(commercially available as Rayaldee and coded herein as CTAP101 Capsules) in 160 patients 
presenting with unresolved symptoms of mild to moderate COVID-19 who test positive for 
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via nasopharynx swab reverse 
transcription polymerase chain reaction (RT-PCR) or any substitutable FDA-authorized 
diagnostic test.  The hypothesis is that the severity and duration of the disease will be attenuated 
with increase of serum 25D to levels of ≥50 ng/mL. 
Primary Objectives:  
The primary objectives of this study are to compare the effects of Rayaldee (CTAP101 
Capsules) vs. placebo treatment in patients with mild to moderate COVID-19 on the:  
1) Attainment of serum total 25D levels at or above 50 ng/mL by Day 14; and, 
2) Severity and duration of disease as evidenced by five COVID-19 symptoms (trouble 
breathing, chest congestion, dry or hacking cough, body aches and pains, and chills and 
shivering) using the FLU-PRO Plus© questionnaire as the data collection tool. 
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Estimand: 
The study treatment estimand is the difference between 28 days of Rayaldee and placebo 
treatment in adult patients with confirmed SARS-CoV-2 infection who have unresolved 
symptoms of mild to moderate COVID-19 in (a) the attainment of serum total 25D levels ≥50 
ng/mL as assessed at Day 14, and (b) the number of days to resolution of five symptoms 
(trouble breathing, chest congestion, dry or hacking cough, body aches and pains, and chills and 
shivering), as measured by the FLU-PRO Plus© questionnaire with resolution defined as the 
first aggregate FLU-PRO Plus© symptom score of ≤5 which is maintained for a minimum of 
three consecutive days. 
Secondary Objectives:  
The secondary objectives are to compare the effects of Rayaldee (CTAP101 Capsules) vs. 
placebo treatment on:  
1) The number of days to resolution of five symptoms (trouble breathing, chest congestion, 
dry or hacking cough, body aches and pains, and chills and shivering), as measured by 
the FLU-PRO Plus© questionnaire, with resolution defined as the first aggregate 
symptom score of ≤5 which is maintained for a minimum of three consecutive days, 
with no individual symptom score >1;  
2) Resolution, defined as the first score of ≤5 which is maintained for a minimum of three 
consecutive days (without subsequent relapse), for the aggregate five COVID-19 
symptoms (trouble breathing, chest congestion, dry or hacking cough, body aches and 
pains, and chills and shivering) and for each individual symptom, defined as a score of 0 
or 1, as measured by the FLU-PRO Plus© questionnaire as of Day 10; 
3) Incidence of emergency room/urgent care visits; 
4) Incidence of oxygen saturation below 94% (without supplemental oxygen); 
5) Incidence and duration of hospitalizations; 
6) Incidence of requirement for mechanical ventilation; 
7) Mortality rate (as incidence); 
8) Severity and duration of COVID-19 illness as evidenced by quality-of-life measures 
using the FLU-PRO Plus© questionnaire; and, 
9) Clinical course of COVID-19 as a function of serum 25D concentrations of <50 ng/mL, 
50 to 100 ng/mL and >100 ng/mL at Days 7, 14, 21 and 28, defined as the proportion of 
subjects in each treatment group with a total score of ≤5 for selected five COVID-19 
symptoms (trouble breathing, chest congestion, dry or hacking cough, body aches and 
pains, and chills and shivering) using the FLU-PRO Plus© questionnaire.  
 
 
 
 
 
 
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Number of Subjects: 
Approximately 80 subjects will be randomized to each of the Rayaldee (CTAP101 Capsules) 
and placebo treatment groups, for a total of 160 subjects.  
Safety Evaluations:   
The safety and tolerability of Rayaldee (CTAP101 Capsules) will be evaluated by adverse 
events (AEs), physical examinations (PE), vital signs (VS), electrocardiograms (ECGs), 
hematology and clinical chemistries. Special attention will be given to changes in the following 
parameters: 
1) Serum total calcium (corrected for serum albumin); 
2) Serum phosphorus; and, 
3) Estimated glomerular filtration rate (eGFR). 
Dose Reduction and Stopping Rules: 
Although hypercalcemia is unlikely given the extensive prior experience with Rayaldee 
(CTAP101 Capsules), any subject who exhibits a confirmed serum total calcium >10.5 and 
≤11.0 mg/dL (corrected for serum albumin) based on blood samples obtained on Days 7 and 14 
will reduce the daily maintenance dose by one capsule (from 60 mcg to 30 mcg) starting at Day 
21.  The dose will similarly be reduced based on blood samples obtained on Days 7 and 14 if 
serum total 25D is confirmed to exceed 100 ng/mL, the maximum targeted level in the FDA-
approved Package Insert for Rayaldee (see APPENDIX 2.), starting at Day 21.  
Subjects who exhibit confirmed serum total calcium >11.0 mg/dL (corrected for serum 
albumin) based on blood samples obtained on Days 7, 14 and 21 will suspend dosing until 
normalization of serum calcium at which time (if applicable) dosing will be resumed at one 
capsule per day (30 mcg per day).  Subjects will be requested to return to the clinic on the 
earliest possible day of their next scheduled visit (eg, Day 12 for the Day 14 visit) for the 
confirmatory blood draw. 
Subjects who develop severe (CTCAE ≥ 3) abnormalities (low or high) of serum phosphorus, 
uric acid or plasma iPTH will be withdrawn from study drug treatment. 
Enrollment of subjects into the study will be paused if mortality in the treatment arm is ≥ 7% 
higher compared to the placebo arm until the Data Safety Monitoring Board (DSMB) makes an 
assessment about causality, and may resume once the DSMB deems it acceptable to continue (if 
applicable).  
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symptoms at study drug initiation (Day 1) to or below 5 for a minimum of three consecutive 
days. The time to resolution is defined as the number of days from Day 1 to the first day of 
achieving the aggregate ≤5 score for a minimum of three consecutive days, provided that no 
score greater than 5 is recorded between the two qualifying scores. Resolution will be 
determined by the first two successive qualifying scores which span a minimum of three 
consecutive days. For clarity, resolution will be considered as having been achieved if two 
successive aggregate scores of ≤5 are recorded on the first day of this occurrence and on a 
subsequent day that is at least two days (but not more than 5 days) later even if no score has 
been recorded between the two days.  Missing symptom score values will be handled as 
described in Section 9.2. The number of days to resolution will be analyzed with a Cox 
proportional hazards model with covariates (baseline aggregate FLU-PRO Plus© score for the 
five COVID-19 symptoms, baseline serum 25D, and body weight).  
As a sensitivity analysis of the resolution of symptoms, a tipping point approach will be used 
starting with the analysis in which scores are available for three consecutive days, with no missing 
interval, followed by increasing numbers of missing days in the up to five-day interval, that is, 1, 
2 and 3 missing days between the two consecutive qualifying scores. 
Subgroup analyses for the primary efficacy endpoints will be based on age (≤40 or >40 years), 
severity of the selected five COVID-19 symptoms at baseline (aggregate FLU-PRO Plus© score 
of ≤ or > the median score), attained serum 25D at Day 14 (below, within or above the targeted 
range of 50 to 100 ng/mL), body weight (≤100 or >100 kg), body mass index (BMI; ≤30 or >30), 
dosing compliance (<80% or ≥80%), gender, race, ethnicity, comorbidities (<1 or ≥1), duration 
of treatment (≤10 or >10 days) and prior or intercurrent COVID-19 vaccination and/or 
monoclonal antibody therapy for COVID-19.   
In addition, the number of days to resolution of the five aggregated symptoms will be compared 
based on the serum 25D level at Day 14 (<50 ng/mL vs 50 to 100 ng/mL and 50 to 100 ng/mL 
vs >100 ng/mL), regardless of the assigned treatment group.  The comparison will be done 
using a Chi-square test.  Frequency of relapses will be calculated, if possible, to account for 
potential worsening of symptoms after resolution (defined immediately above), with relapse 
being defined as achieving an aggregate FLU-PRO Plus© score >5 for a minimum of three 
consecutive days.   
The following secondary endpoints will be tested statistically with methods described below, 
and the nominal p-value will be reported for evaluation:   
1. The number of days to resolution of five symptoms (trouble breathing, chest congestion, dry 
or hacking cough, body aches and pains, and chills and shivering), as measured by the FLU-
PRO Plus© questionnaire, with resolution defined as the first aggregate symptom score of 
≤5 which is maintained for a minimum of three consecutive days (see Section 5.2), with no 
individual symptom score >1;  
2. Resolution, defined as the first score of ≤5 which is maintained for a minimum of three 
consecutive days (without subsequent relapse), for the aggregate five COVID-19 symptoms 
(trouble breathing, chest congestion, dry or hacking cough, body aches and pains, and chills 
and shivering) and for each individual symptom, defined as a score of 0 or 1, as measured 
by the FLU-PRO Plus© questionnaire as of Day 10; 
3. Incidence of emergency room/urgent care visits;  
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4. Incidence of oxygen saturation below 94% (without supplemental oxygen); 
5. Incidence of hospitalizations (mean duration of hospitalization will also be presented); 
6. Incidence of requirement for mechanical ventilation; and, 
7. Mortality rate (as incidence). 
 
Endpoints listed will be summarized. For the analysis of individual symptoms in endpoint #2 
above, the threshold of ≤1 is appropriate because it describes minor symptom severity (at worst 
"a little bit") which seems unlikely to presage a poor outcome. Analysis of the resolution of 
individual symptoms will be performed using a logistic regression, with baseline symptom 
score, baseline 25D level, and body weight as covariates. Analysis of the secondary endpoints 
based on incidence will be performed with a Chi-square test. Mean duration will be analyzed 
with analysis of covariance (ANCOVA). Mortality will be analyzed as incidence, with logistic 
regression with baseline symptom score, baseline 25D level and body weight as covariates. 
Rates only will be reported if there are too few deaths to be formally analyzed. 
The severity, duration and clinical course of COVID-19 illness will be compared between 
treatment groups by analyzing changes in quality-of-life assessments recorded on the FLU-PRO 
Plus© questionnaire. Five of the six items from the questionnaire to be analyzed are: “Overall, 
how severe were your infection symptoms today?”, “Overall, how were your infection 
symptoms today compared to yesterday?”, “How much did your infection symptoms interfere 
with your usual activities today?”, “Have you returned to your usual activities today?”, “In 
general, how would you rate your physical health today?”, and “Have you returned to your 
usual health today?” The scores for: symptom severity range from 0 (no infection symptoms 
today) to 4 (very severe); symptoms today range from 1 (much better) to 7 (much worse); 
symptom interference range from 1 (not at all) to 5 (very much). The first of two consecutive 
scores of ≤1 spanning at least three days and no more than five days will be considered the day 
of resolution, provided that no intervening scores of >1 are recorded. The scores for return to 
usual activities or health are either “yes” or “no”, and the first occurrence of “yes” will be 
deemed to be day of resolution provided that a second “yes” is recorded no more than 5 days 
later without an intervening “no”. The remaining sixth item to be analyzed is: “physical health 
range from 1 (poor) to 5 (excellent). The first of two consecutive scores of >4 spanning at least 
three days and no more than five days will be considered the day of resolution, provided that no 
intervening scores of <4 are recorded. Each item will be compared between treatment groups 
using a Cox proportional hazards model with covariates (aggregate FLU-PRO Plus© score for 
the selected five COVID-19 symptoms at baseline, serum total 25D at baseline, and body 
weight). 
The clinical course of COVID-19 will be examined by subgroups defined by serum total 25D 
levels <50 ng/mL, 50 to 100 ng/mL and >100 ng/mL at Days 7, 14, 21 and 28. 
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled and randomized into one of the two 
treatment groups of this study: 
1) 
Male or female ≥18 years of age; 
 
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2) 
Confirmed within the past 3 days to have SARS-CoV-2 infection as evidenced by a 
positive nasopharyngeal swab test using RT-PCR or any substitutable FDA-authorized 
diagnostic test; 
3) 
Confirmed to have only mild or moderate COVID-19 based on the first of the patient 
reported scores obtained during screening which meets the criterion of a FLU-PRO Plus© 
score of ≥ 1.5 for each of the chest/respiratory and body/systemic domains, and the 
absence of clinical signs indicative of more severe disease (eg, oxygen saturation < 94% 
on room air or respiration rate > 30 bpm); 
4) 
Represents on self-assessment that the current COVID-19 symptoms are not consistent 
with usual health and that they are the same or worse than on the previous day; 
5) 
Willing to limit the use of vitD therapies or supplements except for normally fortified 
food products (eg, milk) during the course of the 6-week study; 
6) 
Must demonstrate the ability to comply with all study requirements; and, 
7) 
Must be without any disease state or physical condition that might impair evaluation of 
safety or which, in the investigator’s opinion, would interfere with study participation.   
Exclusion Criteria: 
Subjects who meet any of the following criteria will be excluded from the study: 
1) 
Clinical signs indicative of severe or critical COVID-19 disease (eg, oxygen saturation < 
94% on room air or respiration rate > 30 bpm); 
2) 
Pregnant or lactating women who are breastfeeding; 
3) 
Use of systemic glucocorticoid medications in the last six months; 
4) 
Recent history (previous 12 months) of primary hyperparathyroidism, kidney stones, 
hypercalciuria and/or hypercalcemia; 
5) 
History of a chronic granuloma-forming disease (eg, sarcoidosis); 
6) 
History of tuberculosis or histoplasmosis; 
7) 
History of chronic liver disease;  
8) 
History (previous 12 months) of cardiac event indicative of chronic cardiovascular 
diseases including congestive heart failure, poorly controlled hypertension and 
arrhythmias;  
9) 
History in the past five years of multiple myeloma or carcinoma of the breast, lung or 
prostate; 
10) Any surgical or medical condition which might significantly alter the absorption, 
distribution, metabolism, or excretion of vitD or 25D (eg, small bowel resection, history 
of Crohn’s disease or ulcerative colitis); 
11) Ongoing treatment with thiazide diuretics; 
12) History of hyperphosphatemia, hyperuricemia and gout; 
13) Renal impairment measured as eGFR< 15 mL/min/1.73m² on serum creatinine in the last 
three months; 
14) Serum calcium ≥9.8 mg/dL in the last three months; 
15) Evidence of existing or impending dehydration; 
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16) Known or suspected to have hypersensitivity to any of the constituents of the study drug; 
and/or, 
17) Currently participating in, or have participated in, an interventional/investigational study 
within 30 days prior to study screening. 
TEST PRODUCT, DOSE, AND ROUTE OF ADMINISTRATION 
Rayaldee (CTAP101 Capsules) in a 900 mcg loading dose split into three equal doses of 300 
mcg each administered over three days (on Days 1, 2 and 3) followed by a maintenance dose of 
60 mcg per day for the subsequent 24 days (Days 4-27). Doses will be administered orally at 
bedtime after fasting for at least 3 hours following dinner. Patients should remain fasted for at 
least 3 hours after administration of study drug. 
CONTROL PRODUCT, DOSE AND ROUTE OF ADMINISTRATION  
Placebo in a look-alike 900 mcg loading dose split into three equal doses of 300 mcg each 
administered over three days (on Days 1, 2, and 3) followed by a look-alike maintenance dose 
of 60 mcg per day for the subsequent 24 days (Days 4-27).  Doses will be administered orally at 
bedtime after fasting for at least 3 hours following dinner. Patients should remain fasted for at 
least 3 hours after administration of study drug. 
Duration of study 
Forty-five days 
Concomitant Medications 
Allowed, with the exception of:  
1) Calcitriol, paricalcitol and doxercalciferol; 
2) Thiazide diuretics;  
3) Medications that could impair the absorption of fat-soluble nutrients; and,  
4) Dietary supplements providing in excess of 0.55 g of elemental calcium per day. 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
1,25D 
1,25-dihydroxyvitamin D 
1,25D3 
1,25-dihydroxyvitamin D3, calcitriol 
25D 
25-hydroxyvitamin D 
25D3 
25-hydroxyvitamin D3, calcifediol, calcidiol 
24,25D3 
24,25-dihydroxyvitamin D3 
AE 
adverse event 
ALT 
alanine transferase 
ANCOVA 
analysis of covariance  
AST 
aspartate aminotransferase 
AUC 
area under the (concentration) curve 
BA 
bioavailability 
b-hCG 
beta-human chorionic gonadotropin  
BMI 
body mass index 
bpm 
breaths per minute 
CAMP 
cathelicidin antimicrobial peptide 
CFR 
Code of Federal Regulations 
CKD 
chronic kidney disease 
Cmax 
maximum concentration 
COVID-19 
coronavirus disease 2019 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture  
eGFR 
estimated glomerular filtration rate 
ER 
ET 
extended-release 
early termination 
FAS 
full analysis set (or population) 
FDA 
Food and Drug Administration 
FU 
follow-up 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
HDPE 
high-density polyethylene 
HIV(1) 
human immunodeficiency virus (type 1) 
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IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation  
iCLIP 
individual-nucleotide resolution cross-linking and immunoprecipitation 
IL-1β 
interleukin 1β 
IL-6 
interleukin 6 
iPTH 
intact parathyroid hormone 
IRB/EC 
Institutional Review Board/Ethics Committee 
IRT 
interactive response technology 
ISF 
investigator site file 
ITT 
Intent-to-Treat 
LAR 
legally authorized representative 
MedDRA 
Medical Dictionary for Regulatory Activities 
PAMPs 
pathogen-associated molecular patterns 
PBMCs 
peripheral blood mononuclear cells 
PE 
physical examinations 
PK 
pharmacokinetic(s) 
PP 
per-protocol 
PTH 
parathyroid hormone 
RT-PCR 
reverse transcription polymerase chain reaction 
SAE 
serious adverse event 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SD 
standard deviation 
SHPT 
secondary hyperparathyroidism 
SOC 
system organ class 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse events 
TLR 
Toll-like receptors 
tmax 
time to maximum concentration 
US 
United States 
VDI 
vitamin D insufficiency 
VDR 
vitamin D receptor 
VDRE 
vitamin D response element 
VitD 
vitamin D 
VS 
vital signs 
 
 
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1 INTRODUCTION 
1.1 
Vitamin D Insufficiency 
Calcifediol is 25-hydroxyvitamin D3 (25D3), the physiological precursor to the active vitamin D 
(vitD) hormone, 1,25-dihydroxyvitamin D3 (calcitriol or 1,25D3). This prohormone is 
synthesized by the liver from vitamin D3 (cholecalciferol) generated endogenously in skin 
following exposure to sunlight or obtained from the diet or supplements. Another prohormone, 
25-hydroxyvitamin D2, is synthesized hepatically from vitamin D2 (ergocalciferol), which cannot 
be produced endogenously but is obtained only from the diet or supplements. These two 
prohormones are collectively referred to as “25-hydroxyvitamin D (25D)”. Unless an individual 
is receiving significant ergocalciferol supplementation, essentially all of the 25D in blood 
consists of calcifediol.  
It is widely accepted that serum total 25D is the best indicator of a patient’s vitD status. Serum 
total 25D levels of ≥30 ng/mL are currently considered adequate while levels of <30 ng/mL are 
considered “insufficient” [Holick et al 2011]. The commonly used reference range for serum 
total 25D is 30 to 100 ng/mL [Souberbielle et al 2010]. Levels of serum total 25D in the general 
population vary according to many factors, including intensity of sunlight (varying with 
geographic location and season), exposure to sunlight (affected by skin pigmentation, use of 
sunscreen and other cultural factors), age and dietary intake [Holick 1995]. Levels tend to be 
lower during the winter and at higher latitudes. VitD deficiency (<20 ng/mL) in the US is most 
common in pigmented (decreased vitD production in skin) and obese (increased volume of 
distribution of vitD due to adiposity) subjects, the same population that appears to be most 
susceptible to infection with SARS-CoV-2. 
Serum 25D levels above of 40-60 ng/mL have recently been recommended to reduce the risk of 
infection with severe acute respiratory syndrome 2 (SARS-CoV-2) and higher levels are thought 
to be useful for patients who become infected [Grant et al, 2020]. Serum levels of  ≥50 ng/mL 
have recently been shown to be required for 25D to modulate vitD-responsive endpoints in 
patients with chronic kidney disease (CKD), probably via activation by innate immune cells,  
extra-renal CYP27B1 [Strugnell et al, 2019]. It appears likely that similar high levels are 
required for 25D to be activated in vivo by CYP27B1 expressed in virus-stimulated 
macrophages. 
1.2 
Vitamin D and Viral Infections 
Insufficient vitD has been linked to a large number of pathologies including immune disorders 
and infectious diseases. VitD functions as a key host defense regulator against viral pathogens. 
High levels of vitD has been associated with resistance to human immunodeficiency virus type 1 
(HIV1) infection [Jimenez-Souza et al 2018]. Moreover, low levels of vitD have been associated 
with higher levels of immune activation and inflammation in HIV and other diseases [Jimenez-
Souza et al 2018]. While the results of clinical trials studying vitD supplementation to reduce 
acute respiratory tract infections have differed, there are several well designed large meta-
analyses that have supported vitD supplementation as being safe and protective against acute 
respiratory tract infections with individuals that were severely vitD deficient receiving the most 
benefit [Martineau et al 2017; Bergman et al 2013]. 
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1.3 
Vitamin D and Cathelicidin Gene 
Despite extensive efforts to identify novel antimicrobials to address the treatment of patients 
with SARS-CoV-2 infection, little attention has been paid to endogenous human antimicrobial 
peptides, such as LL37, that can boost the host’s immune response to the virus. Arguably the 
most effective, endogenous antimicrobial agent known to man, LL37 is the product of the 
endogenous human cathelicidin antimicrobial peptide (CAMP) gene and is secreted from 
monocyte/macrophages, dendritic cells and neutrophils in response to viral or bacterial infection 
[Nizet et al 2001].  Expression and secretion of LL37, along with numerous other endogenous 
antimicrobial activities, requires induction and priming. A key regulatory signal that can prime 
human macrophages for rapid and robust antimicrobial responses, including deployment of LL37 
at the site of infection, is vitD, specifically calcifediol or 25D [Gombart et al 2009]. Like a 
loaded weapon with the safety left on, macrophages without sufficient serum total 25D as 
substrate are rendered unable to release LL37, and thus protect the host.  
The innate immune response in antigen-presenting cells (monocyte/macrophages and dendritic 
cells) is initiated and perpetuated by pathogen-associated molecular patterns (PAMPs) derived 
from the cell wall and other unique signatures of the infecting virus interacting with pattern 
recognition receptors (eg, Toll-like receptors [TLR]). TLR activation eventually leads to up-
regulation of expression of the intracellular vitD receptor (VDR) and CYP27B1 (25D-1α-
hydroxylase); the latter event up-regulates generation the active vitD metabolite, 1,25-
dihydroxyvitamin D (1,25D). That 1,25D can then engage the VDR in an intracrine mode and 
controls CAMP and interleukin 1ß (IL-1ß) gene expression; IL-1ß is a central initiator of the 
adaptive immune response. 
Using upregulated expression of the potent endogenous antimicrobial CAMP mRNA by primary 
cultures of human monocyte/macrophages as an ex vivo read-out, extensive recent work [Rosen 
et al 2012; Liu et al 2006; Adams et al 2007; Krutzik et al 2008; Liu et al 2009; Edfeldt et al 
2010; Fabri et al 2011; Montoya et al 2014; Chun et al 2014; Srikanth et al 2016] shows that 
insufficient serum levels of 25D (VDI) in the host induces an immune-compromised state. An 
insufficient level of 25D in human serum causes inadequate i) intracellular generation of 1,25D, 
ii) activation of the VDR, iii) transactivation of the CAMP gene and iv) production and release of 
LL37 to combat microbial invasion of the host. The end result is innate and subsequent adaptive 
immune deficiency.  
Raising serum total 25D to sufficiently high levels can resolve the immune-compromised state in 
the human host. Accomplishing this with vitD supplements is unreliable and is difficult in 
obesity owing to the increased volume of distribution of the non-polar vitamin. In contrast, 
treatment with the more polar and extended-release calcifediol (Rayaldee or CTAP101 Capsules) 
is reliable and, depending on the administered dose, can take as little as 9-12 hours. Treatment 
with CTAP101 Capsules has been shown to be safe for administration to patients with stage 3 or 
4 CKD, as evidenced by United States (US) Food and Drug Administration (FDA) approval of 
the product in 2016 as Rayaldee® (calcifediol) Extended-release Capsules.   
Accumulating data suggest that hyperactive immune response to COVID-19 poses unique risks 
to the cardiovascular system and plays a role in disease severity. As the disease progresses, a 
concomitant rise in inflammatory cytokine levels may drive the depletion and exhaustion of T 
cell populations [Diao et al 2020]. On the other hand, vitD is an immune-modulating agent and 
has been implicated in the pathophysiology of autoimmune diseases, including systemic lupus 
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erythematosus and multiple sclerosis. VDI is a risk factor for multiple sclerosis and correlates 
with the disease severity. Thus, 
 
 appropriate treatment with Rayaldee may help to mitigate 
an overactive, adaptive T- and B-lymphocyte immune system response to the virus and 
ameliorate immune cell exhaustion [Adams et al 2007; Rosen et al 2012]. 
1.4 
Preclinical Experience 
Toxicity associated with calcifediol is consistent with that observed due to vitD overdose and is 
similar to that seen with 1,25D or calcitriol. Generally, such toxicity is subsequent to 
hypercalcemia. To study the toxicity of CTAP101 Capsules, an earlier formulation of CTAP101 
Capsules was administered to dogs for 3 months and resulted in typical vitD-induced 
hypercalcemia, hypercalciuria, soft tissue mineralization (eg, kidney, stomach, aorta and heart) 
and death. Severe adverse reactions to CTAP101 Capsules were observed in dogs treated with 
500 or 1,000 mcg per day and were associated with serum 25D or calcifediol levels >450 ng/mL 
following 1 month of treatment. 
Using the current formulation of CTAP101 Capsules, dogs were treated daily for three months 
with doses up to 45 mcg (~4.5 mcg/kg/day). No signs of toxicity were observed at the highest 
dose tested which was associated with serum calcifediol levels >150 ng/mL.   
Calcifediol administration (orally through addition to the diet) to rats for 6 months has been 
reported to produce signs of toxicity at daily doses >40 mcg/kg. Toxicities included an increased 
incidence of nephrocalcinosis and uroliths.   
Results from in vitro drug release and nonclinical pharmacokinetic (PK) studies in male Yucatan 
swine (CTAP101-PK-0012) demonstrate that CTAP101 Capsules have an extended-release (ER) 
profile. In swine, the bioavailability (BA) of calcifediol following the administration of 
CTAP101 Capsules was approximately 30% lower than that from an immediate-release capsule 
preparation. Further, a delay in the release of the active ingredient (time of maximum 
concentration or tmax >7 hours) was observed as compared to the immediate-release formulation 
(tmax ~4 hours). 
1.5 
Previous Clinical Experience 
Rayaldee (CTAP101 Capsules) (30 mcg/capsule) have been approved by the US FDA for the 
treatment of secondary hyperparathyroidism (SHPT) in adults with stage 3 or 4 CKD and VDI, 
defined as serum total 25D levels less than 30 ng/mL. The clinical studies which supported FDA 
approval are described below. 
There have been three previous single-dose phase 1 studies with CTP101 Capsules (CTAP101-
CL-1005, CTAP101-CL-1011 and CTAP101-CL-1016), two phase 2 studies, of which one was a 
single-dose study (CTAP101-CL-2004) and one was a repeat-dose study (CTAP101-CL-2008), 
and three phase 3 studies (CTAP101-CL-3001, CTAP101-CL-3002 and CTAP101-CL-3003).  
Studies CTAP101-CL-1011, CTAP101-CL-1016 and CTAP101-CL-2008 were conducted with 
the current formulation of CTAP101 Capsules (30, 60 or 90 mcg per capsule). Two of the phase 
3 studies (CTAP101-CL-3001 and CTAP101-CL-3002) were identical double-blind, placebo-
controlled pivotal trials and the third (CTAP101-CL-3003) was a follow-on open-label extension 
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trial.  All phase 3 trials were conducted with the current formulation of CTAP101 Capsules (30 
mcg per capsule). 
The single-dose studies confirmed the ER characteristics of the investigational drug product and 
that the current formulation has a BA of approximately 25% when administered in the fasting 
state. Administration of a single supraphysiologic dose of CTAP101 Capsules following a high-
fat, high calorie meal resulted in a significantly higher exposure of calcifediol compared to when 
administered in a fasted state. An approximate 5-fold increase in the maximum concentration 
(Cmax) in the blood and a 3.5-fold increase in area under the concentration curve (AUC) was 
observed in the fed group compared to the fasted group (CTAP101-CL-1016). 
In CTAP101-CL-2008, a double-blind, placebo-controlled, randomized repeat-dose phase 2 
study, daily administration of CTAP101 Capsules increased serum total 25D levels to ≥30 ng/mL 
in nearly all subjects and decreased mean plasma intact parathyroid hormone (iPTH) from 
baseline and compared to placebo during 6 weeks of treatment [Sprague et al, 2014]. The mean 
% decrease in plasma iPTH from baseline in the per-protocol (PP) population was related to the 
administered dose: -20.9, -32.8, and -39.3 for the 30, 60 and 90 mcg groups, respectively.   
The efficacy was confirmed in a larger phase 3 program with nearly all subjects (97%) treated 
with CTAP101 Capsules who completed the program without a major protocol deviation 
achieving a normal serum total 25D level and with 50% of such subjects achieving a mean 
reduction in plasma iPTH from baseline of at least 30%.  Fewer than 9% of placebo subjects 
achieved a 30% reduction in plasma iPTH or achieved a normal 25D level. 
CTAP101 Capsules did not cause significant adverse effects on serum calcium or phosphorus.  
Treatment-emergent adverse events (TEAEs), including those related to the investigational study 
drug, were comparable across treatment groups, except for hyperphosphatemia which was 
observed in four subjects, none of which was considered by the investigator to be related to the 
investigational study drug.  Subjects in phase 3 trials who were treated with CTAP101 Capsules 
experience a mean increase in serum calcium of 0.2 mg/dL during a 26-week treatment period 
compared with a mean increase of 0.1 mg/dL in subjects treated with placebo.  Most (74%) of 
the subjects treated with CTAP101 Capsules received a dose of 60 mcg/day. A total of 4.2% of 
the active-treated subjects and 2.1% of placebo-treated subjects experienced at least 1 elevation 
in serum calcium above the upper limit of normal (10.5 mg/dL), none of which were clinically 
significant.  
For all clinical studies, the adverse event (AE) profiles did not identify any events specific to 
CTAP101 Capsules. After both single and repeat-dose administration, CTAP101 Capsules were 
generally well-tolerated. The overall treatment-emergent AE profile in the phase 3 program was 
comparable between CTAP101 Capsules and placebo groups.  Subjects receiving CTAP101 
Capsules had a greater increase in mean serum corrected calcium (P<0.001) than placebo 
patients (0.2 versus 0.1 mg/dL); for serum phosphorus, subjects receiving CTAP101 Capsules 
had a greater mean increase 
 than placebo patients (0.2 versus 0.1 mg/dL). 
 
 
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2 STUDY OBJECTIVES 
2.1 
Study Objectives 
2.1.1 
Primary Objectives  
The primary objectives of this study are to compare the effects of Rayaldee (CTAP101 Capsules) 
vs. placebo treatment in patients with mild to moderate COVID-19 on the:  
1) Attainment of serum total 25D levels at or above 50 ng/mL by Day 14; and,    
2) Severity and duration of disease as evidenced by five COVID-19 symptoms (trouble 
breathing, chest congestion, dry or hacking cough, body aches and pains, and chills and 
shivering) using the FLU-PRO Plus© questionnaire as the data collection tool.  
2.1.2 
Estimand 
The study treatment estimand is the difference between 28 days of Rayaldee and placebo 
treatment in adult patients with confirmed SARS-CoV-2 infection who have unresolved 
symptoms of mild to moderate COVID-19 in (a) the attainment of serum total 25D levels ≥50 
ng/mL as assessed at Day 14, and (b) the number of days to resolution of five symptoms (trouble 
breathing, chest congestion, dry or hacking cough, body aches and pains, and chills and 
shivering), as measured by the FLU-PRO Plus© questionnaire with resolution defined as the first 
aggregate FLU-PRO Plus© symptom score of ≤5 which is maintained for a minimum of three 
consecutive days. 
2.1.3 
Secondary Objectives:  
The secondary objectives are to compare the effects of Rayaldee (CTAP101 Capsules) vs. 
placebo treatment on: 
1) The number of days to resolution of five symptoms (trouble breathing, chest congestion, dry 
or hacking cough, body aches and pains, and chills and shivering), as measured by the FLU-
PRO Plus© questionnaire, with resolution defined as the first aggregate symptom score of ≤5 
which is maintained for a minimum of three consecutive days, with no individual symptom 
score >1;  
2) Resolution, defined as the first score of ≤5 which is maintained for a minimum of three 
consecutive days (without subsequent relapse), for the aggregate five COVID-19 symptoms 
(trouble breathing, chest congestion, dry or hacking cough, body aches and pains, and chills 
and shivering) and for each individual symptom, defined as a score of 0 or 1, as measured by 
the FLU-PRO Plus© questionnaire as of Day 10; 
3) Incidence of emergency room/urgent care visits; 
4) Incidence of oxygen saturation below 94% (without oxygen supplementation); 
5) Incidence and duration of hospitalizations; 
6) Incidence of requirement for mechanical ventilation; 
7) Mortality rate (as incidence); 
8) Severity and duration of COVID-19 illness as evidenced by quality-of-life measures using 
the FLU-PRO Plus© questionnaire; and,  
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9) Clinical course of COVID-19 as a function of serum 25D concentrations of <50 ng/mL, 50 
to 100 ng/mL and >100 ng/mL at Days 7, 14, 21 and 28, defined as the proportion of 
subjects in each treatment group with a total score of ≤5 for five symptoms (trouble 
breathing, chest congestion, dry or hacking cough, body aches and pains, and chills and 
shivering) using the FLU-PRO Plus© questionnaire.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
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3 INVESTIGATIONAL PLAN 
3.1 
Overall Study Design  
This is a phase 2, single or multi-center, randomized, double-blind placebo-controlled study to 
evaluate the safety and efficacy of Rayaldee (CTAP101 Capsules) to treat adult subjects with 
unresolved symptoms of mild to moderate COVID-19 who test positive for SARS-CoV-2 via 
nasopharynx swab and subsequent reverse transcription polymerase chain reaction (RT-PCR) or 
any substitutable FDA-authorized diagnostic test. Subjects will be randomized to receive either 
oral Rayaldee (CTAP101 Capsules) or matching placebo administered according to the 
following regimen: a loading dose (900 mcg split into three equal doses of 300 mcg each 
administered on Days 1, 2 and 3) followed by 24 daily maintenance doses (60 mcg on Days 4 to 
27) administered at bedtime after fasting for at least 3 hours following dinner.  
3.2 
Rationale for Study Design and Control Group 
The proposed study design is based on the hypothesis that the severity and duration of COVID-
19 symptoms will be attenuated with an increase of serum 25D to levels of  ≥50 ng/mL.  A 
placebo-controlled trial is appropriate because there is currently no therapy that has been 
demonstrated to be effective in treating COVID-19 symptoms. 
The FLU-PRO Plus© questionnaire [Powers et al, 2016 and 2018] will be used by the enrolled 
subjects to self-assess their COVID-19 symptoms on a daily basis at bedtime.  This questionnaire 
was specifically designed and validated to evaluate in clinical trials the presence, severity and 
duration of symptoms associated with viral infections.  It contains 32 items, grouped into 6 
domains, that provide a comprehensive evaluation of such symptoms. It supports the primary 
efficacy endpoint of the time to resolution of five COVID-19 symptoms (trouble breathing, chest 
congestion, dry or hacking cough, body aches and pains, and chills and shivering), defined as a 
reduction in the aggregate FLU-PRO Plus© symptom score for these five symptoms recorded at 
study drug initiation (Day 1) to or below 5 for a minimum of three consecutive days. These five 
symptoms are part of the chest/respiratory and body/systemic domains of the FLU-PRO Plus© 
questionnaire for which average scores of ≥1.5 were required for inclusion in the study.  Trouble 
breathing, chest congestion and dry or hacking cough are symptoms indicative of potentially 
inadequate oxygenation and an impending requirement for supplemental oxygen and 
hospitalization. Body aches and pains and chills and shivering are symptoms indicative of 
systemic inflammatory responses associated with active viral infection.  Resolution of each of 
these five symptoms will be analyzed separately, as well, as secondary efficacy endpoints. 
COVID-19 patients are expected to (but may not) present with serum total 25D levels averaging 
approximately 20-25 ng/mL, unless vitD becomes acknowledged as a possible prophylaxis 
against SARS-CoV-2 infection, based on information gathered from OPKO’s prior PK studies 
conducted in healthy US volunteers and based on information from many US studies published 
in the medical literature. CKD is known risk factor for COVID-19 and patients with CKD will 
present with even lower 25D levels as advancing kidney disease is known to be associated with 
declining 25D levels [Levin et al 2007]. Phase 3 studies conducted by OPKO in large numbers of 
patients with stage 3-4 CKD have shown that baseline serum total 25D levels average below 20 
ng/mL [Sprague et al 2016]. Further, these studies have shown that Rayaldee is safe in the CKD 
population at the proposed doses. 
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Few studies, to date, focused on treating COVID-19 have included CKD patients and many 
ongoing studies with anti-viral therapies have specifically excluded such patients.  COVID-19 
disproportionately affects patients with underlying disorders, and a significant percentage of 
COVID-19 patients have underlying CKD. Therefore, CKD patients with COVID-19 are 
available for recruitment and will be allowed to participate in the present study. Many subjects in 
each arm of this study may, therefore, have stage 3 or 4 CKD, defined as an estimated 
glomerular filtration rate (eGFR) of 15 to <60 mL/min/1.73m2. 
Data from Studies CTAP101-CL-1011, CTAP101-CL-1020 and 170074 show that an oral 
loading dose of 900 mcg of Rayaldee (CTAP101 Capsules) in the fasting state (approximately 
25% BA) will raise serum 25D levels within ~9-12 hours by about 20-35 ng/mL, depending on 
the subject’s body weight (the higher the body weight, the lower the expected increase in 25D). 
Many COVID-19 subjects are expected to have higher than normal body mass index (BMI) 
values in view of the latest reported US data. Each maintenance dose of Rayaldee (CTAP101 
Capsules) (60 mcg/day) will increase serum 25D by another 0.6 ng/mL, as shown in Studies 
CTAP101-CL-3001, CTAP101-CL-3002 and CTAP101-CL-3003 [Sprague et al, 2016]. It 
follows that subjects having a baseline 25D level of ~25 ng/mL will reach ~45-60 ng/mL after 
the loading dose and ~59-74 ng/mL after 24 days of maintenance dosing. Subjects with slightly 
lower baseline levels of 25D will reach proportionately lower levels on treatment. There will be 
some subjects who have a higher baseline 25D level. For this reason, 25D levels will be checked 
at Days 7, 14 and 21and dosing will be adjusted if levels exceed 100 ng/mL. FDA has approved 
Rayaldee (CTAP101 Capsules) to raise levels up to a target of 100 ng/mL in kidney patients (see 
APPENDIX 2.: Package Insert).  
3.3 
Evaluations  
Blood samples will be acquired periodically during the study (see APPENDIX 1: Schedule of 
Events). Blood samples will be assayed for: i) serum total 25D (primary efficacy measure), 
 
iv) plasma iPTH, v) clinical chemistries 
and hematology, and 
markers of the 
adaptive immune response to SARS-CoV-2 infection. 
 
 
 
  Daily assessments of disease severity and 
quality-of-life measures will be recorded by each subject using the FLU-PRO Plus© 
questionnaire.  
3.4 
Study Endpoints  
3.4.1 
Primary Efficacy Endpoints 
The primary efficacy endpoints are:  
1) Attainment of serum total 25D levels at or above 50 ng/mL, as assessed at Day 14; and, 
2) The number of days to resolution of the selected five COVID-19 symptoms (trouble 
breathing, chest congestion, dry or hacking cough, body aches and pains, and chills and 
shivering), defined as a reduction in the aggregate symptom score recorded on Day 0 (prior 
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to study drug initiation) by the FLU-PRO Plus© questionnaire to or below 5 for a minimum 
of three consecutive days. A statistically significant difference (P<0.025 one sided) between 
the treatment groups in the time to resolution of symptoms in favor of treatment with 
CTAP101 Capsules will be deemed a successful outcome.     
On each day during the study, subjects will record once daily (during a 24-hour period starting in 
the evening before the subject goes to sleep) the severity of COVID-19 symptoms using the 
FLU-PRO Plus© questionnaire.   
3.4.2 
Secondary Efficacy Endpoints 
The secondary endpoints are : 
1. The number of days to resolution of five symptoms (trouble breathing, chest congestion, dry 
or hacking cough, body aches and pains, and chills and shivering), as measured by the FLU-
PRO Plus© questionnaire, with resolution defined as the first aggregate symptom score of ≤5 
which is maintained for a minimum of three consecutive days, with no individual symptom 
score >1;  
2. Resolution, defined as the first score of ≤5 which is maintained for a minimum of three 
consecutive days (without subsequent relapse), for the aggregate five COVID-19 symptoms 
(trouble breathing, chest congestion, dry or hacking cough, body aches and pains, and chills 
and shivering) and for each individual symptom, defined as a score of 0 or 1, as measured by 
the FLU-PRO Plus© questionnaire as of Day 10; 
3. Incidence of emergency room/urgent care visits; 
4. Incidence of oxygen saturation below 94% (without supplemental oxygen); 
5. Incidence and duration of hospitalizations; 
6. Incidence of the requirement for mechanical ventilation; 
7. Mortality rate (as incidence);  
8. Severity and duration of COVID-19 illness as evidenced by quality-of-life measures 
including ability to perform usual activities and opinion of overall health status, using the 
FLU-PRO Plus© questionnaire; and, 
9. Clinical course of COVID-19 as a function of serum 25D concentrations of <50 ng/mL, 50 to 
100 ng/mL and >100 ng/mL at Days 7, 14, 21 and 28, defined as the proportion of subjects in 
each treatment group with a total score of ≤5 for the selected five COVID-19 symptoms 
(trouble breathing, chest congestion, dry or hacking cough, body aches and pains, and chills 
and shivering) using the FLU-PRO Plus© questionnaire.   
Endpoint items 3-7 are all based on incidence over the entire 42 day study period. 
Once daily (during a 24 hour period starting in the evening before bedtime), subjects will record 
their ability to perform usual activities and their opinion of overall health status in a diary using 
FLU-PRO© Plus questionnaire. 
3.4.3 
Exploratory Endpoints 
The exploratory endpoints include:  
 
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  Baseline is defined as values obtained 
at Visit 1. 
3.4.4 
Primary Safety Endpoints 
The safety and tolerability of Rayaldee (CTAP101 Capsules) will be evaluated by AEs, physical 
examinations (PE), vital signs (VS), electrocardiograms (ECGs), hematology and clinical 
chemistries. Special attention will be given to changes in the following parameters: 
1) Serum total calcium (corrected for serum albumin); 
2) Serum phosphorus; and, 
3) eGFR. 
3.5 
Study Duration 
The study is expected to be completed within approximately 8-12 weeks from the time of initial 
subject enrollment (first subject consented) to study completion for the last subject (last subject 
out/last visit complete). Each enrolled subject will participate in the study after randomization for 
up to 42 days (Day 1 through Day 42). 
 
 
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4 STUDY POPULATION SELECTION 
4.1 
Study Population 
The targeted population for this study is symptomatic male or nonpregnant female subjects 18 
years of age or older who have been recently diagnosed with unresolved symptoms of mild to 
moderate COVID-19. All prospective and enrolled subjects will be encouraged to make 
arrangements for transportation to the study site that are safe and do not adversely expose other 
people to infection. 
4.2 
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled and randomized into one of the two 
treatment groups of this study:  
1) Male or female ≥ 18 years of age;  
2) Confirmed within the past 3 days to have SARS-CoV-2 infection as evidenced by a positive 
nasopharyngeal swab test using RT-PCR or any substitutable FDA-authorized diagnostic 
test; 
3) Confirmed to have only mild or moderate COVID-19 based on the first of the patient 
reported scores obtained during screening which meets the criterion of a FLU-PRO Plus© 
score ≥ 1.5 for each of the chest/respiratory and body/systemic domains, and the absence of 
clinical signs indicative of more severe disease (eg, oxygen saturation < 94% on room air or 
respiration rate >30 bpm); 
4) Represents on self-assessment that the current COVID-19 symptoms are not consistent with 
usual health and that they are the same or worse than on the previous day; 
5) Willing to limit the use of vitD therapies or supplements except for normally fortified food 
products (eg, milk) during the course of the 6-week study; 
6) Must demonstrate the ability to comply with all study requirements; and, 
7) Must be without any disease state or physical condition that might impair evaluation of 
safety or which, in the investigator’s opinion, would interfere with study participation.   
4.3 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
1) Clinical signs indicative of severe or critical COVID-19 severity (eg, oxygen saturation < 
94% on room air or respiration rate > 30 bpm); 
2) Pregnant or lactating women who are breastfeeding; 
3) Use of systemic glucocorticoid medications in the last six months; 
4) Recent history (previous 12 months) of primary hyperparathyroidism, kidney stones, 
hypercalciuria and/or hypercalcemia; 
5) History of a chronic granuloma-forming disease (eg, sarcoidosis); 
6) History of tuberculosis or histoplasmosis; 
7) History of chronic liver disease;  
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8) History of (previous 12 months) of cardiac event indicative of chronic cardiovascular 
diseases including congestive heart failure, poorly controlled hypertension and arrhythmias;  
9) History in the past five years of multiple myeloma or carcinoma of the breast, lung or 
prostate; 
10) Any surgical or medical condition which might significantly alter the absorption, 
distribution, metabolism, or excretion of vitD or 25D (eg, small bowel resection, history of 
Crohn’s disease or ulcerative colitis); 
11) Ongoing treatment with thiazide diuretics; 
12) History of hyperphosphatemia, hyperuricemia and gout; 
13) Renal impairment measured as eGFR< 15 mL/min/1.73m² on serum creatinine in the last 
three months; 
14) Serum calcium ≥9.8 mg/dL in the last three months; 
15) Evidence of existing or impending dehydration; 
16) Known or suspected to have hypersensitivity to any of the constituents of the study drug; 
and/or, 
17) Currently participating in, or have participated in, an interventional/investigational study 
within 30 days prior to study screening. 
 
 
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5 STUDY TREATMENTS 
5.1 
Description of Rayaldee (CTAP101 Capsules) 
Dosage form: 
Soft gel capsule  
Dose strength: 
30 mcg calcifediol ER capsule  
Product description: 
Blue oval capsules printed single-sided, centered with the logo O 
in white.  Each bottle contains 30 capsules. 
Active component: 
Calcifediol 
Non-active components: 
Paraffin wax, mineral oil, mono- and diglycerides, dehydrated 
alcohol, lauroyl polyoxylglycerides, butylated hydroxytoluene, 
hypromellose, modified starch, carageenan, sodium phosphate 
dibasic, sorbitol and sorbitan solution, FD&C Blue #1, titanium 
dioxide, medium chain triglycerides (coconut oil) and ink (white, 
which may contain titanium dioxide, isopropyl alcohol, propylene 
glycol, hydroxypropylmethyl cellulose 2910)  
Storage conditions: 
20-25°C (68-77°F); excursions allowed to 15°C to 30°C (59°F to 
86°F); protect from light and heat. 
5.2 
Description of Placebo Capsules 
Dosage form: 
Soft gel capsule  
Dose strength: 
0 mcg calcifediol ER capsule  
Product description: 
Blue oval capsules printed single-sided, centered with the logo O 
in white.  Each bottle contains 30 capsules. 
Active component: 
None 
Non-active components: 
Paraffin wax, mineral oil, mono- and diglycerides, dehydrated 
alcohol, lauroyl polyoxylglycerides, butylated hydroxytoluene, 
hypromellose, modified starch, carageenan, sodium phosphate 
dibasic, sorbitol and sorbitan solution, FD&C Blue #1, titanium 
dioxide, medium chain triglycerides (coconut oil) and ink (white, 
which may contain titanium dioxide, isopropyl alcohol, propylene 
glycol, hydroxypropylmethyl cellulose 2910)  
Storage conditions: 
20-25°C (68-77°F); excursions allowed to 15°C to 30°C (59°F to 
86°F); protect from light and heat 
5.3 
Treatments Administered 
5.3.1 
Dosing Instructions 
Study drug should NOT be administered to individuals known to be allergic to any component 
of the drug.   
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Subjects will be instructed to take a loading dose of 10 capsules (300 mcg) of study drug per day 
on Days 1, 2 and 3 at bedtime after fasting for at least 3 hours following dinner, with any non-
alcoholic liquid, by the oral route. On Days 4-27, subjects will take a maintenance dose of 2 
capsules per day at bedtime unless otherwise directed. Patients should remain fasted for at least 3 
hours after administration of study drug.  
Study drug will be provided in containers labeled as investigational study drug as per the 
Packaging and Labeling below in Section 5.9. The interactive response technology (IRT) will 
dispense an appropriate bottle configuration to each patient per the dosing requirements. Each 
bottle will contain either active drug or a matching placebo. 
Drug accountability will be performed at each visit until the end of the 28-day treatment period.  
All procedures being performed during the course of this clinical study are listed sequentially by 
visit in Section 7: Study Activities, and may be found as a table in APPENDIX 1: Schedule of 
Events. 
5.3.2 
Dose Reduction and Stopping Rules 
Although hypercalcemia is unlikely given the extensive prior experience with Rayaldee 
(CTAP101 Capsules), any subject who exhibits a confirmed serum total calcium >10.5 and ≤11.0 
mg/dL (corrected for serum albumin) based on blood samples obtained on Days 7 and 14 will 
reduce the daily maintenance dose by one capsule (from 60 mcg to 30 mcg) starting at Day 21.  
The dose will similarly be reduced based on blood samples obtained on Days 7 and 14 if serum 
total 25D is confirmed to exceed 100 ng/mL, the maximum targeted level in the FDA-approved 
Package Insert for Rayaldee (see APPENDIX 2.), starting at Day 21.  
Subjects who exhibit confirmed serum total calcium >11.0 mg/dL (corrected for serum albumin) 
based on blood samples obtained on Days 7, 14 and 21 will suspend dosing until normalization 
of serum calcium at which time (if applicable) dosing will be resumed at one capsule per day (30 
mcg per day).  Subjects will be requested to return to the clinic on the earliest possible day of 
their next scheduled visit (eg, Day 12 for the Day 14 visit) for the confirmatory blood draw. 
Subjects who develop severe (CTCAE ≥ 3) abnormalities (low or high) of serum phosphorus, 
uric acid or plasma iPTH will be withdrawn from study drug treatment but will continue in the 
study. 
Enrollment of subjects into the study will be paused if mortality in the treatment arm is ≥ 7% 
higher compared to the placebo arm until the Data Safety Monitoring Board (DSMB) makes an 
assessment about causality, and may resume once the DSMB deems it acceptable to continue (if 
applicable).  
5.3.3 
Overdose and Toxicity 
Excessive administration of calcifediol can cause hypercalcemia, hyperphosphatemia, 
hypercalciuria, hypervitaminosis or over-suppression of iPTH. Common symptoms of vitD 
overdosage may include constipation, decreased appetite, dehydration, fatigue, irritability, 
muscle weakness, or vomiting. Treatment of acute accidental overdosage with calcifediol should 
consist of general supportive measures (eg, phosphate binders for hyperphosphatemia).  If the 
overdosage is discovered within a short time, emesis can be induced or gastric lavage performed 
to prevent further absorption. Serial serum calcium measurements should be obtained and any 
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electrocardiographic abnormalities due to hypercalcemia assessed. All supplemental calcium 
must be discontinued. Treatment with standard medical care is required if persistent and 
markedly elevated serum calcium levels occur. Any occurrence of accidental overdose or 
toxicity that requires medical intervention should be reported as an adverse event. 
5.3.4 
Method of Assigning Subjects to Treatment Groups  
After signing the informed consent form (ICF), prior to any study-related activities, each subject 
will be assigned a 5 digit identification number and will retain this number throughout the study.  
The 5 digit identification number (SS-EEE) will consist of a 2-digit study site number (SS) and a 
3-digit consecutive enrollment number (EEE). Should a subject be withdrawn from the study, 
that subject’s 5 digit identification number will not be reassigned.   
Approximately 250 subjects will be screened to enroll approximately 160 subjects who meet 
screening criteria. The IRT will provide study treatment group assignments for these subjects 
using a computer-generated randomization code. Subjects will be randomized in a blinded 
manner into 1 of 2 treatment groups (approximately 80 subjects per group) in a 1:1 ratio of 
Rayaldee (CTAP101 Capsules) or placebo, respectively.  
5.4 
Prior and Concomitant Therapy 
Subjects should be willing to limit the use of vitD therapy and vitD supplements except for 
normally fortified food products (eg, milk) during the course of the 6-week study other than the 
study drug. Standard of care medications for CKD (VitD, calcitriol, paricalcitol and 
doxercalciferol) should be suspended during the treatment period. Excluded therapies at 
enrollment include thiazide diuretics, 1α-hydroxylated vitD analogs (calcitriol, paricalcitol and 
doxercalciferol) and vitD supplements (cholecalciferol and ergocalciferol). Current treatment 
with cytochrome P450 inhibitors, such as ketoconazole, atazanavir, clarithromycin, indinavir, 
itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole, which 
may inhibit enzymes involved in vitD metabolism and may alter serum levels of calcifediol, 
must be evaluated by the investigator and may be a reason for exclusion from the study. 
Medications that could impair the absorption of fat-soluble nutrients and dietary calcium 
supplements providing more than 0.5 g of elemental calcium are not allowed. 
5.5 
Diet Restrictions 
Subjects should follow their dietary plan if one has been prescribed.   
5.6 
Subject Activity Restrictions 
Subjects should maintain their usual pattern of sun exposures and activities as allowed under any 
health, government or local isolation/quarantine or personal-protection requirements for infection 
containment. 
5.7 
Pregnancy and Contraception 
All female subjects who have the possibility to become pregnant (not surgically sterile or 
postmenopausal) and male subjects with female partners who have the possibility to become 
pregnant must agree to use effective contraception (such as implants, injectables, combined oral 
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contraceptives, intrauterine device, sexual abstinence, vasectomy or vasectomized partner) for 
the duration of the study. 
5.8 
Treatment Compliance 
Study treatment compliance during the treatment period will be assessed via a patient diary and 
at all specified visits in person. The Investigator, or assigned designee, will perform drug 
accountability and dosing compliance calculations for all study drugs (number of capsules that 
should have been taken versus actual number taken as evidenced by dosing records and the 
number of capsules remaining in bottles of study drug assigned to each subject) at Days 7, 14, 21 
and 28 (end of treatment). Overall dosing compliance is defined as taking between 80% and 
120% of the scheduled doses for the period of time that the subject participates in the study.   
5.9 
Packaging and Labeling 
Rayaldee (CTAP101 Capsules) and matching placebo capsules will be provided in white, round, 
wide-mouth, high-density polyethylene (HDPE) bottles with aluminum heat-induction safety 
seals with white, polypropylene, child-resistant (push down and turn) caps, 30 capsules per 
bottle.   
All study drug labels will include the protocol number, sponsor identification and address, bottle 
contents, route of administration, bottle number, area for subject identification, investigational 
use caution statements, storage conditions and instructions for use.   
5.10 
Storage and Accountability 
Rayaldee (CTAP101 Capsules) and matching placebo capsules will be shipped to each site using 
standardized shipment and temperature monitoring procedures. While at the study site, study 
drug will be stored at controlled room temperature (20-25°C or 68-77°F) with excursions 
allowed to 15°C to 30°C (59°F to 86°F), and protected from light and heat per label instructions 
in the supplied packaging, with access granted to authorized personnel only. A temperature log 
recording the daily storage temperatures will be maintained at the sites. Accountability for all 
study drugs, from receipt until final reconciliation and return of drug by the monitor or designee, 
will be the responsibility of the investigator or the assigned designee(s). In the case of 
temperature excursions, products should not be dispensed and the investigator or the assigned 
designee(s) should contact the clinical monitor or the sponsor representative as soon as possible 
to receive further instructions. 
The investigator or assigned designee(s) will maintain study drug accountability records 
throughout the course of the study. A study drug accountability and dispensing log will record 
the study drug disposition. Each site's overall inventory of study drug supplies will be verified 
periodically throughout the course of the study. All opened and unopened bottles of study drug 
capsules including subject returns are to be retained at each site until the sponsor or designee has 
performed a complete accountability, following which study drug will be returned to the sponsor 
or designee. 
5.11 
Investigational Product Retention at Study Sites 
At the conclusion of the study, a final accountability will be performed by the investigator (or 
designee) and verified by the study monitor. Any discrepancies identified will be indicated, with 
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a specific explanation of each discrepancy. The investigator (or designee) must return all unused 
medication in accordance with the sponsor’s instructions, and a copy of the clinical supplies 
return documentation will be returned to the sponsor or designee. Drug accountability records, 
clinical drug supply receipts, and return records must be maintained by the investigator. 
5.12 
Blinding 
All subjects, study personnel and the sponsor (and its designees, with the exception of unblinded 
member(s) of the DSMB and/or data management team) will be blinded as to whether a given 
subject is in the Rayaldee (CTAP101 Capsules) or placebo treatment group until after database 
lock or until the decision to break the blind is determined (eg, as a result of an emergent event).   
When the investigator determines that knowledge of treatment group assignment is required for 
medical management of an individual subject, the blind for the subject will be broken using the 
IRT system in accordance with sponsor instructions.      
Further, all subjects, study personnel and the sponsor (and its designees, with the exception of 
unblinded member(s) of the DSMB and/or data management team) will be blinded to serum total 
25D and 
 laboratory data obtained during treatment until 
after database lock.   
Final unblinded site-specific data will be provided to the study sites  within 3 months of 
finalizing the clinical study report. 
 
 
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6 STUDY PROCEDURES 
6.1 
Informed Consent 
A signed ICF will be obtained prior to any study related procedures. The subject or their legally 
authorized representative (LAR) will be permitted time and opportunity to inquire about details 
of the study and to decide whether or not to participate. The subject or their LAR will receive a 
copy of the signed and dated consent form and any written information provided to the study 
subjects in a format (digital or hardcopy) that is safe and prevents infection. If any material 
change occurs that affects the conduct of the study or the subject’s willingness to participate in 
the study, the subject or LAR will be required to sign an updated consent form. 
The investigator or his/her designee will explain the nature of all aspects of the study to the 
subject and/or their LAR, and answer all questions regarding this study, prior to obtaining 
informed consent. 
The process for obtaining consent will be in accordance with all applicable regulatory 
requirements. The subject or his/her LAR and the investigator or his/her designee must both sign 
and date the ICF before the subject can participate in the study. The original ICF (digital or 
hardcopy) will be retained in the site study records. The investigator or his/her designee will 
ensure documentation of the consent discussion is in the subject’s medical record/source 
document. The decision by the subject to participate in the study is entirely voluntary. The 
investigator or designee must emphasize to the subject that consent regarding study participation 
may be withdrawn at any time without penalty or loss of benefits to which the subject is 
otherwise entitled. 
If the ICF or patient information is amended during the study, the investigator must follow all 
applicable regulatory requirements pertaining to approval of the amended ICF by the 
Institutional Review Board/Ethics Committee (IRB/EC) and use of the amended form (including 
ongoing subjects). 
6.2 
Medical History and Concomitant Medications 
A medical history, including demographics and concomitant medications, will be recorded at the 
screening visit (Visit 1). Any symptom related to COVID-19 that started prior to initial dose, 
does not need to be reported as medical history. Concomitant medications will be recorded at 
each additional study visit. 
6.3 
Brief Physical Examinations and Vital Signs  
Brief PE and assessments of VS (to include height, weight and BMI) and COVID-19 disease 
severity will be performed at screening scheduled as soon as possible after a subject is verified to 
be infected with SARS-CoV-2.  Evaluations are presented in Table 1.  Routine monitoring of VS 
and ongoing assessments of COVID-19 disease severity will be performed at subsequent visits.  
 
 
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Table 1 
Evaluations 
Physical Examinations: 
Brief PE.  
Vital Sign Measurements: 
 
 
 
 
Height, weight and BMI determination at screening visit (Day -3 to 0) 
and weight and BMI determination using screening height at the end of 
the treatment period (Visit 5/Day 28+2). Blood pressure, heart and 
respiratory rate, temperature and oxygen saturation (pulse oximetry) will 
be measured and recorded after the subject has been sitting for at least 2 
minutes prior to any scheduled blood draws at every visit.  
Electrocardiogram (ECG) 
 
ECG will be performed at screening visit (Day -3 to 0), Visit 3 (Day 
14±2) and Visit 5 (Day 28+2), 
COVID-19 Severity and Quality-
of-life Assessments: 
On each day during the study, subjects will record once daily at bedtime 
the severity of COVID-19 symptoms and quality-of-life using the FLU-
PRO Plus© questionnaire. 
6.4 
Clinical Laboratory Tests 
6.4.1 
Laboratory Parameters 
Blood will be drawn at Screening and on Days 7, 14, 21 and 28 and analyzed as specified in 
Table 2. Samples also will be collected for analyses of biomarkers associated with SARS-CoV-2 
infection, host immune status and vitD metabolism.  
All serum calcium values will be adjusted for serum albumin level of <4.0 g/dL.  
All clinically significant abnormal laboratory values should be recorded as AEs and the 
investigator will follow-up (FU) according to Section 6.7.6 Clinical Significance. 
Subjects will be in a seated or supine position during blood collection.   
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Table 2 
List of Laboratory Tests 
Hematology: 
Hematocrit 
Hemoglobin 
Platelet count 
Red blood cell count  
White blood cell count  
Peripheral blood neutrophils 
Peripheral mononuclear monocytes 
 
Serum b-hCG Pregnancy Test (only for females of 
childbearing potential, defined as either not surgically sterile 
or not diagnosed as postmenopausal)1 
 
Biomarkers, PD and PK parameters: 
 
Plasma iPTH  
Serum total 25-hydroxyvitamin D (25D) (blinded)* 
 
 
 
 
 
  
 
*Data will not be available until after database lock. 
 
  
Serum Chemistry: 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Blood urea nitrogen 
Total calcium (corrected) 
Carbon dioxide  
Chloride 
Creatinine 
Estimated glomerular filtration rate (eGFR)2 
Glucose 
Lactate dehydrogenase 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
Total protein 
Triglycerides 
   Uric acid 
 
Urine Pregnancy Test (only for females of 
childbearing potential, defined as either not 
surgically sterile or not diagnosed as 
postmenopausal) 
 
6.4.2 
Sample Collection, Storage, and Shipping 
Missed blood samples should not be drawn or collected (unless the investigator considers the 
sample necessary for subject safety) and should be noted as “not done” in source documentation 
along with a reason.   
A central laboratory experienced in clinical research trials will be utilized. Collection, 
processing, storage and shipping procedures will be performed in accordance with the 
instructions provided by the central laboratory. Any detailed instructions will be provided 
                                                 
1 Performed at screening, and again at subsequent visits only after a positive urine pregnancy test.  
2 Calculated value. 
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separately from this protocol to the laboratory. Blood samples will be collected and analyzed for 
clinical laboratory and 
 biomarker tests.   
The laboratory may ship specimens to other designated outside specialty facilities as appropriate.  
Approximately 385 mL of blood will be drawn from each subject during the course of the study. 
This volume will include overage/backup volume as described in the study laboratory manual. 
Additional blood draws may be needed for unscheduled or repeat visits. Every effort has been 
made to minimize the total amount of blood to be drawn. Samples are to be shipped to the central 
laboratory for each subject as visits are completed.  
6.4.3 
Clinical Supplies 
All supply vacutainers, blood collection tubes, needles, pipettes, labels, boxes with labels for 
storage of serum and plasma samples and all necessary shipping supplies/containers will be 
supplied by the site. The site will supply all phlebotomy and centrifugation equipment including 
biohazard and/or safety supplies. The investigator will ensure that all biohazard wastes are 
disposed of in accordance with investigator site standard operating procedures (SOPs) and local 
regulations. 
6.5 
Dispensing Study Drug 
The IRT will provide study drug assignments. The study coordinator or pharmacist (or 
designated site personnel) will obtain the study drug assignments for each subject and dispense 
the appropriate number of containers/capsules, which will be recorded in the drug accountability 
records. Study drug will be shipped to the subject’s home after confirmation of randomization, or 
if appropriate and feasible under current site access procedures, study drug can be dispensed 
directly to subjects or hand-delivered by qualified site personnel for same day dispensing, as 
needed. 
All subjects, study personnel and the sponsor (and its designees, with the exception of unblinded 
member(s) of the DSMB and/or data management team) will be blinded to treatment and serum 
total 25D and 
data until the last subject completes the study 
and the data have been locked. 
6.6 
Data Safety Monitoring Board (DSMB) 
A five-member DSMB will be established which will be comprised of an expert in viral disease 
pathogenesis, a nephrologist who routinely treats patients with vitD repletion therapies, a 
statistician and a pulmonary medicine expert.  The DSMB will also include an unblinded safety 
monitor to identify potential safety hazards (eg, hypercalcemia) in order to maintain blinding of 
treatment assignment and ensure study integrity. The DSMB will meet by teleconference every 
3-4 weeks or at the Committee’s discretion. Meetings may occur more often should serious 
adverse events (SAEs) or other safety issues arise.Specific responsibilities and activities of the 
DSMB will be defined in the DSMB charter.   
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6.7 
Adverse Events Assessments 
6.7.1 
Definition 
An AE is defined as any untoward medical occurrence in a subject regardless of its causal 
relationship to study treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding or symptom deemed clinically significant) or disease 
temporally associated with the use of a medicinal product whether or not considered related to 
the medicinal product. 
6.7.2 
Performing Adverse Events Assessments 
The investigator or designee will monitor each subject for clinical and laboratory evidence of 
AEs on a routine basis throughout the study. The investigator or designee will assess and record 
any AE in detail in the source document and on the appropriate electronic case report form 
(eCRF) including the date of onset, description, severity, duration, relationship of the AE to the 
investigational study drug, action(s) taken and outcome. AEs, whether in response to a query, 
observed by site personnel, or reported spontaneously by the subject will be reported on the 
appropriate eCRF.   
6.7.3 
AE Collection Period 
Adverse events which are determined as non-serious events that occur after the ICF has been 
signed and after the initiation of study drug will be documented in the source document and 
followed to a satisfactory resolution, until the investigator deems the event to be chronic or the 
subject to be stable, or until the subject’s participation in the study ends. Adverse events that 
occur after the ICF has been signed but prior to the initiation of study drug will be captured as 
medical history. Serious adverse events that occur after the ICF has been signed must be reported 
to the sponsor (as per protocol Section 6.7.7.3) and will be documented in the source document 
and followed to a satisfactory resolution, until the investigator deems the event to be chronic or 
the subject to be stable, or until the subject’s participation in the study ends. 
New or changes in COVID-19 symptoms are expected over the course of the COVID-19 
infection and should not be reported as AEs unless intervention was required or in the opinion of 
the investigator they are considered clinically significant.  All COVID-19 SAEs should be 
reported regardless. 
Information to be collected includes description of the event (event term), date of onset, date of 
resolution, investigator-specified assessment of severity and relationship to the investigational 
study drug, seriousness, action taken with study drug (if applicable), as well as any required 
treatment or evaluations and outcome. 
AEs resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to concurrent 
medications, or progression of disease states must be documented as AEs. Pre-existing 
conditions (present before the start of the AE collection period) are considered concurrent 
medical conditions and should NOT be recorded as AEs, but must be documented in the medical 
history section of the eCRF and in the source document. However, if the subject experiences a 
clinically significant worsening or complication of such a concurrent condition (eg, pneumonia), 
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the worsening or complication should be recorded as an AE. Investigators should ensure that the 
AE term recorded captures the change in the condition. 
Each AE should be recorded to represent a single diagnosis. Accompanying signs or symptoms 
should NOT be recorded as additional AEs. If a diagnosis is unknown, then sign(s) or 
symptom(s) should be recorded as an AE(s). Changes in laboratory values are judged to be 
clinically significant if some action or intervention is required or if the investigator judges the 
change to be beyond the range of normal physiological fluctuation. If abnormal laboratory values 
are the result of pathology for which there is an overall diagnosis, the diagnosis only should be 
reported as an AE. 
Pre-planned procedures (surgeries or therapies) that were scheduled prior to the start of AE 
collection are not considered AEs. However, if a pre-planned procedure is performed early (eg, 
as an emergency) due to a worsening of the pre-existing condition, the worsening of the 
condition should be captured as an AE. Elective procedures performed where there is no change 
in the subject’s medical condition (including thought processes around the reason for the elective 
procedure) should not be recorded as AEs, but should be documented in the subject’s source 
document and captured in the eCRF as procedures. 
Any report of pregnancy identified for any female subject or for a female partner of a male 
subject should be reported immediately (within 24 hours of being informed) by submitting the 
Pregnancy Reporting Form to OPKO safety within 24 hours of awareness to 
safetyreporting@opko.com. 
Pregnancies will be considered ‘events of special interest’ and will not be captured as serious 
adverse events (SAEs). Investigators should follow specific procedures for reporting them to 
OPKO Pharmacovigilance. Pregnancies will be followed to termination or six weeks post-
delivery for determination of resolution to the event. Subjects who become pregnant during 
treatment must immediately be withdrawn from study drug treatment. 
The Medical Dictionary for Regulatory Activities (MedDRA), Version 23.0 or later, will be used 
to code all AEs. 
6.7.4 
Severity 
The intensity of the AE will be rated by the investigator per Common Terminology Criteria for 
Adverse Events (CTCAE), Version 5.0. 
It should be noted that the clinical severity and seriousness of an AE are not synonymous, eg, a 
severe headache is not classified as serious until it meets the required elements as an SAE. 
The maximum severity attained for each AE reported will be recorded in the eCRFs.   
6.7.5 
Relationship 
The investigator’s assessment of an AE's relationship to the investigational study drug is not a 
factor in determining whether the AE is reported in the AE section of the eCRF. If there is any 
doubt as to whether a clinical observation is an AE, the event should be reported.  
The relationship or association of the study drugs in causing or contributing to the AE will be 
characterized by the investigator using the classifications and criteria outlined in Table 3. 
 
 
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Table 3  Adverse Event Relationship Criteria 
Relationship 
Criteria 
Not related 
• 
The temporal sequence of the AE onset relative to administration of the investigational 
product is not reasonable. 
• 
Disease or other drugs provide plausible explanations. 
• 
Dechallenge (if performed) is negative or ambiguous. 
Unlikely related 
• 
The temporal sequence of the AE onset relative to the administration of the investigational 
product is reasonable. 
• 
Could also be explained by disease or other drugs. 
• 
Dechallenge (if performed) is positive or uncertain. 
• 
Rechallenge is negative. 
Possibly related 
• 
The temporal sequence of the AE onset relative to administration of the investigational is 
reasonable. 
• 
Unlikely to be attributed to disease or other drugs. 
• 
Dechallenge (if performed) is positive. 
Related 
• 
The temporal sequence of the AE onset relative to administration of the investigational 
product is reasonable. 
• 
Cannot be explained by disease or other drugs. 
• 
Dechallenge (if performed) is positive and pharmacologically/ pathologically plausible. 
• 
Rechallenge (if feasible) is positive. 
• 
The AE shows a pattern consistent with previous knowledge of the investigational product 
or product class, i.e., pharmacologically or phenomenologically recognized/plausible or an 
objective and specific medical disorder. 
6.7.6 
Clinical Significance 
Changes in unblinded laboratory values, vital signs or other diagnostic procedure 
outcomes/results are only considered to be AEs if they are judged to be clinically significant (ie, 
if some intervention or therapy is required or if the investigator judges the change to be beyond 
the expected variation).  Any abnormalities will automatically be considered clinically 
significant unless the investigator indicates not clinically significant directly on the laboratory 
paperwork or source documentation. 
6.7.7 
Serious Adverse Events 
6.7.7.1 
Definition 
An SAE is defined by the investigator or sponsor as any AE occurring during an investigational 
study that result in any of the following outcomes: 
• Death 
• Life-threatening AE 
• Hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability (substantial disruption of the ability to conduct normal 
life functions)/incapacity 
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• A congenital anomaly/birth defect 
• Important medical events that may not result in death, may be life threatening, or may require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in subject hospitalization, or the development of 
drug dependency or drug abuse.   
Research subjects will be instructed to notify the research center for any emergent condition and 
will be given the emergency contact number for the study during the consenting process. 
6.7.7.2 
Expectedness 
SAEs must be assessed as to whether they were expected to occur or unexpected, meaning not 
anticipated based on current knowledge about the investigational compound found in the 
protocol or Investigator Brochure (IB) for Rayaldee (CTAP101 Capsules).  Categories are: 
• Unexpected - nature or severity of the event is not consistent with the product information; 
• Expected - event is known based on the product information. 
6.7.7.3 
Reporting Serious Adverse Events 
Any AE considered serious by the investigator that meets the previously mentioned criteria must 
be reported to OPKO Pharmacovigilance at the following number within 24 hours from the time 
when site personnel first learn about the event. 
SAFETY REPORTING Contact: OPKO Pharmacovigilance 
Fax: 
 
E-mail: 
  
The IRB/IEC should be made aware according to currently prescribed institutional guidelines.  A 
written report should be provided consisting of the SAE Form and other necessary source 
documents. If the subject is hospitalized because of or during the course of an SAE, then the 
investigator should attempt to obtain a copy of the hospital discharge summary and any pertinent 
laboratory or diagnostic reports, and provide them to the sponsor or designee as soon as possible. 
For any information not available at the time of the first report that becomes available later, the 
investigator should update the SAE Form and eCRFs and provide any additional documentation 
to OPKO Pharmacovigilance and IRB/IEC within 1 working day of receipt. 
The sponsor or designee will notify the appropriate regulatory agencies of any serious and 
unexpected SAEs associated with the use of the investigational study drug according to 
regulations. Copies of any reports to regulatory agencies regarding serious and unexpected SAEs 
will be provided to the investigators by the sponsor or designee for review and submission to the 
DSMB and IRB/EC. 
If using a local IRB/EC, the investigator is responsible for informing his or her IRB/EC per its 
requirements of any SAEs at that site. Copies of SAE correspondence with the IRB/EC, 
regulatory authorities, and other physicians must be provided to the Study Contact.  
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A subject experiencing one or more SAEs will receive treatment and FU evaluations by the 
investigator, or they will be referred to another appropriate physician for treatment and FU.  
All SAEs will be followed to at least Day 42 or until resolution.  Should the event become 
indistinguishable from the chronic disease condition, the subject will be followed for 14 days 
after the last investigational study drug administration and subsequently all events will be closed.   
6.7.8 
Treatment-Emergent Adverse Events 
A TEAE is defined as any AE with onset or worsening reported by a subject from the time that 
the first dose of study drug is taken in this study until 14 days following discontinuation of study 
drug administration. 
6.8 
Concomitant Medication Assessments 
The study coordinator or designee will record concomitant medication history (previous three 
months) in the source document and eCRF.   
6.9 
Removal of Subjects from the Study or Study Drug / Stopping Criteria 
The investigator may discontinue a subject from study drug treatment for any of the following 
reasons: 
• A major protocol deviation occurs;  
• A serious or intolerable AE occurs; 
• The subject has a confirmed pregnancy; 
• A clinically significant change in a laboratory parameter occurs (eg, increase in serum 
calcium above upper limit allowed); and, 
• A clinically significant change in ECG at Visit 3 occurs as compared to baseline (eg, 
prolongation of QT interval). 
The investigator may withdraw a subject from the study for any of the following reasons: 
• The subject requests to be discontinued from the study (withdraws consent); or, 
• The subject is lost to follow-up. 
Subjects who develop severe (CTCAE ≥ 3) abnormalities (low or high) of serum phosphorus, 
uric acid or plasma iPTH will be withdrawn from study drug treatment. 
Enrollment of subjects into the study will be paused if mortality in the treatment arm is ≥ 7% 
higher compared to the placebo arm until the DSMB makes an assessment about causality, and 
may resume once the DSMB deems it acceptable to continue (if applicable).  
No subject replacement is planned. All subjects withdrawn from treatment will continue in the 
study until study completion and perform all assessments unless consent is withdrawn. The 
investigator will be requested to make all reasonable efforts to obtain clinical status at FU.   
6.10 
Appropriateness of Measurements 
The safety and tolerability of Rayaldee (CTAP101 Capsules) will be determined by analyzing 
AEs, serum 25D, calcium (corrected for serum albumin) and phosphorus, and eGFR.   
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7 STUDY ACTIVITIES 
7.1 
Screening and Randomization (Visit 1/Day -3 to 1) 
7.1.1 
Screening (Day -3 to 0) 
Visit to occur within 3 days after positive RT-PCR test or any substitutable FDA-authorized 
diagnostic test for SARS-CoV-2 infection.  
• Review study ICF (A signed ICF will be obtained from each subject prior to any study-related 
procedures). 
• Review of inclusion/exclusion criteria. 
• Medical history and demographics. 
• Review of prior medications (previous three months). 
• Brief PE. 
• VS assessment (weight, height and BMI). 
• ECG. 
• Blood samples will be obtained for the following: 
o Hematology, serum chemistry (full panel and eGFR determination) (see Table 2);  
o Serum b-hCG pregnancy test (for females of childbearing potential); 
o 
 
o Plasma iPTH and serum 25D; and, 
o 
 
• Training provided on study drug dosing, storage and use. 
• Diary instructions provided for assessment activities. Subject will be trained to assess and 
record in the diary AT VISIT the severity of COVID-19 symptoms and quality-of-life using 
the FLU-PRO Plus© questionnaire. 
• Subject will assess and record in the diary at bedtime the severity of COVID-19 symptoms 
and quality-of-life using the FLU-PRO Plus© questionnaire. 
7.1.2 
Randomization and Initial Treatment (Day 1) 
• Day 1 is considered to be the day on which the first loading dose is administered.  Initial 
dosing may not necessarily coincide with the day on which randomization occurs if study 
drug is not received by the subject on the day of randomization. 
• If qualified, subjects will be randomized to treatment with active or placebo study drug 
following receipt and review of laboratory test results. Study drug will be shipped to 
subject’s home or if appropriate and feasible under current site access procedures, study drug 
can be dispensed directly to subjects or hand-delivered by qualified site personnel for same 
day dispensing, as needed.  
• Subject will self-administer 10 study drug capsules at bedtime after fasting for at least 3 
hours following dinner and record the dose in the diary. Subject should remain fasted for at 
least 3 hours after administration of study drug.  
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7.2 
Days 2-6 
• No study site visits. 
• On each of Days 2 and 3, subject will self-administer 10 study drug capsules at bedtime after 
fasting for at least 3 hours following dinner and record the doses in the diary. Subject should 
remain fasted for at least 3 hours after administration of study drug. 
• From Day 4 onwards, subject will self-administer 2 study drug capsules each day, unless 
otherwise directed,  at bedtime after fasting for at least 3 hours following dinner and record 
the doses in the diary. Subject should remain fasted for at least 3 hours after administration of 
study drug. 
• Subjects will assess and record in the diary each day at bedtime the severity of COVID-19 
symptoms and quality-of-life using the FLU-PRO Plus© questionnaire. 
7.3 
Visit 2 (Day 7 ± 2) 
Activities to be performed during site visit: 
• Review of concomitant medications. 
• AE assessment. 
• VS assessment. 
• Blood samples will be obtained for the following: 
o Hematology, serum chemistry (full panel and eGFR Determination) (see Table 2); 
o 
 
o Plasma iPTH and serum 25D; and, 
o 
 
• Urine pregnancy test for females of childbearing potential (a positive test result will be 
confirmed with a serum b-hCG test). 
• Study drug reconciliation/compliance review with subject (study drug returned to subject 
after visit review). 
• Diary review with subject. 
• Subject will self-administer 2 study drug capsules, unless otherwise directed,  at bedtime and 
record the dose in the diary. Subject should remain fasted for at least 3 hours after 
administration of study drug. 
• Subject will assess and record in the diary at bedtime the severity of COVID-19 symptoms 
and quality-of-life using the FLU-PRO Plus© questionnaire. 
7.4 
Days 8-13 
• No study site visits. 
• Subject will self-administer 2 study drug capsules each day, unless otherwise directed, at 
bedtime after fasting for at least 3 hours following dinner and record the doses in the diary. 
Subject should remain fasted for at least 3 hours after administration of study drug. 
• Subject will assess and record in the diary each day at bedtime the severity of COVID-19 
symptoms using the FLU-PRO Plus© questionnaire. 
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7.5 
Visit 3 (Day 14 ± 2) 
Activities to be performed during site visit: 
• Review of concomitant medications. 
• AE assessment. 
• VS assessment. 
• ECG (prolonged QT-interval will be referred to a Cardiologist for review). 
• Blood samples will be obtained for the following analyses: 
o Hematology, serum chemistry (full panel and eGFR determination) (see Table 2);  
o 
 
o Plasma iPTH and serum 25D; and, 
 
 
• Urine pregnancy test for females of childbearing potential (a positive test result will be 
confirmed with a serum b-hCG test). 
• Study drug reconciliation/compliance review with subject (study drug returned to subject 
after visit review). 
• Diary review with subject. 
• Subject will self-administer 2 study drug capsules at bedtime, unless otherwise directed,  
after fasting for at least 3 hours following dinner and record the dose in the diary. Subject 
should remain fasted for at least 3 hours after administration of study drug. 
• Subject will assess and record in the diary at bedtime the severity of COVID-19 symptoms 
and quality-of-life using the FLU-PRO Plus© questionnaire. 
7.6 
Days 15-20 
• No study site visits. 
• Subject will self-administer 2 study drug capsules, unless otherwise directed, each day at 
bedtime after fasting for at least 3 hours following dinner and record the doses in the diary. 
Subject should remain fasted for at least 3 hours after administration of study drug. 
• Subject will assess and record in the diary each day at bedtime the severity of COVID-19 
symptoms and quality-of-life using the FLU-PRO Plus© questionnaire. 
7.7 
Visit 4 (Day 21 ± 2) 
Activities to be performed during site visit: 
• Review of concomitant medications. 
• AE assessment. 
• VS assessment. 
• Blood samples will be obtained for the following analyses: 
o Hematology, serum chemistry (full panel and eGFR determination) (see Table 2);  
o 
 
o Plasma iPTH and serum 25D; and, 
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o 
 
• Urine pregnancy test for females of childbearing potential (a positive test result will be 
confirmed with a serum b-hCG test). 
• Study drug reconciliation/compliance review with subject (study drug returned to subject 
after visit review). 
• Diary review with subject. 
• Subject will self-administer 2 study drug capsules, unless otherwise directed, at bedtime after 
fasting for at least 3 hours following dinner and record the dose in the diary. Subject should 
remain fasted for at least 3 hours after administration of study drug. 
• Subject will self-assess and record in the diary at bedtime the severity of COVID-19 
symptoms and quality-of-life using the FLU-PRO Plus© questionnaire. 
7.8 
Days 22-27 
• No study site visits. 
• Subject will self-administer 2 study drug capsules each day, unless otherwise directed, at 
bedtime after fasting for at least 3 hours following dinner and record the doses in the diary. 
Subject should remain fasted for at least 3 hours after administration of study drug. 
• Subject will assess and record in the diary each day at bedtime the severity of COVID-19 
symptoms and quality-of-life using the FLU-PRO Plus© questionnaire. 
7.9 
Visit 5 (Day 28 + 2) (End of Treatment/Early Termination) 
Activities to be performed during site visit: 
• Review of concomitant medications. 
• AE assessment. 
• VS assessment (weight and BMI). 
• Brief PE. 
• ECG (prolonged QT-interval will be referred to a Cardiologist for review). 
• Blood samples will be obtained for the following analyses: 
o Hematology, serum chemistry (full panel and eGFR determination) (see Table 2);  
 
 
o Plasma iPTH and serum 25D; and, 
o 
 
• Urine pregnancy test for females of childbearing potential (a positive test result will be 
confirmed with a serum b-hCG test). 
• Study drug reconciliation/compliance review with subject (treatment complete – no further 
study drug dispensed). 
• Diary review with subject. 
Subject will assess and record in the diary at bedtime the severity of COVID-19 symptoms using 
the FLU-PRO Plus© questionnaire. 
 
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7.10 
Days 29-41 
• No study site visits. 
• Subject will assess and record in the diary each day at bedtime the severity of COVID-19 
symptoms and quality-of-life using the FLU-PRO Plus© questionnaire. 
7.11 
Visit 6 (Day 42 ± 4 (Follow-up – Telephone Visit)) 
• Upon awakening in the morning, subject will assess and record in the diary the severity of 
COVID-19 and quality-of-life using the FLU-PRO Plus© questionnaire. 
Subject will self-report via telephone to site staff: 
• Review of concomitant medications. 
• AE assessment. 
• Diary review with subject. 
 
 
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8 QUALITY CONTROL AND ASSURANCE 
The study will be conducted in accordance with the protocol, ICH/GCP (International Council 
for Harmonisation [ICH] and Good Clinical Practice [GCP]), and applicable SOPs and 
regulations, to ensure that the safety and welfare of subjects are addressed, and to confirm that 
problems reported by study monitors are resolved. Verification of study documents and activities 
(if applicable) will be conducted to confirm accuracy of recorded data and its analysis.  Audit 
observations and findings will be documented and communicated to appropriate study personnel 
and management. An inspection may be conducted by regulatory authorities. The investigator 
must allow direct access to study documents during these inspections and audits.  
Monitoring visits (on site and/or remote) will evaluate study conduct, data integrity, protocol, 
and GCP compliance. The investigator is responsible for the accuracy, completeness, legibility, 
and timeliness of the data reported. All source documents are to be completed in a neat, legible 
manner to ensure accurate interpretation of data. Source documents and laboratory reports will 
be reviewed to ensure that they are accurate and complete. Any issues arising from these reviews 
will be communicated directly to the investigator in the monitoring report with recommendations 
for any Corrective and Preventive Action plans. The DSMB will be apprised of any serious 
continuing non-compliance.  
To ensure the quality of the clinical data across all subjects, a Clinical Data Management review 
will be performed by the Data Manager or designee on subject data entered or integrated into the 
electronic data capture (EDC) system.  During the review, subject data will be checked for 
consistency, omissions, and any apparent discrepancies. In addition, the data will be reviewed for 
adherence to the protocol, and ICH/GCP. To resolve any questions arising from the Data 
Management review process, data queries and/or data clarification notifications will be generated 
via the EDC system for completion and resolution. 
 
 
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9 PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
All analyses will be performed using SAS® or other appropriate statistical software. All data 
collected on eCRFs, diary (from ePRO) and from clinical laboratory evaluations will be grouped 
and listed by population sub-group, subject, visit, date and time as feasible. Summary tables will 
be presented by population as appropriate. Descriptive summaries of categorical outcomes will 
include the proportion of subjects. Descriptive summaries of quantitative measures will include 
the number of subjects, mean, standard deviation (SD), median, minimum, and maximum or as 
appropriate. In descriptive summary tables, if needed, the geometric mean will be calculated as 
the nth root of the resulting product of the values, and the coefficient of variation (in percent, 
%CV) will be calculated as 100* (SD/[arithmetic mean]). 
Arithmetic means, SDs, medians, and geometric means will be reported with two significant 
figures more than the reported values. Minimum and maximum values will be reported with the 
same accuracy as the reported source data. The %CV will be rounded to 1 decimal place. 
Denominators of percentage of subject calculations will be based on the number of subjects in 
the sub-group and selected population unless otherwise specified.   
In the event there are multiple results at a given visit and/or time point, the following logic will 
be applied for purposes of summarization by visit or time point: for pre-dose measurements and 
selection of a baseline value, the more recent non-missing result will be used, preferably the 
result recorded on Day 0 (the day prior to first administration of study drug), if available; for 
post-dose measurements, the earliest of the results will be selected. If multiple laboratory results 
are available for the same date and time and the discrepancy could not be resolved, then the 
arithmetic mean of the results could be used unless specified in the data management plan or data 
handling conventions finalized before breaking the study randomization blind. All subjects 
entered into the clinical database will be included in subject data listings. 
Specific analysis details will be provided in the Statistical Analysis Plan.   
9.2 
Missing Data 
For the primary endpoint based on achievement of serum 25D level ≥50 ng/mL at Day 14, 
missing results due to intercurrent illness, hospitalization or death will be imputed as lack of 
achieving serum 25D levels. For the time-to-event primary efficacy endpoint based on 
aggregated symptom scores, the analysis is based on the proportion of subjects resolved over the 
total population.  Missing scores occurring prior to resolution are considered as lack of resolution 
and kept in the denominator.  This should provide a conservative estimate of the proportion 
resolved.  Missing results after the first day of achieving a score of ≤5 and followed by up to 5 
days with score ≤5, as defined in Section 9.10.1 for determining resolution, will not be imputed 
as lack of resolution.  
For the time-to-event secondary efficacy endpoint based on aggregated symptom scores, the 
analysis is based on the proportion of subjects resolved over the total population.  Missing scores 
occurring prior to resolution are considered as lack of resolution, and kept in the denominator, 
but missing results after the first day of achieving a score of ≤5, and followed by up to 5 days 
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with score ≤5, provided that no individual score is ≥1, as defined in Section 5.2 for determining 
resolution, will not be imputed as lack of resolution. 
Similarly, for symptom scores, missing results prior to resolution of symptoms due to 
intercurrent illness, hospitalization, or death will be imputed as lack of resolution, and missing 
results after the first day of achieving a score of ≤1 and followed by up to 5 days with score ≤1, 
as defined in Section 9.10.1 for determining resolution, will not be imputed as lack of resolution. 
This strategy is appropriate given the consistent trend in symptoms toward improvement over 
time, as observed in blinded data from this ongoing study.   
For subjects who have achieved resolution of symptoms, missing daily symptom scores beyond 
the time of resolution will not be imputed.  Subjects will be instructed to report any symptoms 
that recur after resolution. 
If responder status is not determinable for a subject with missing serum 25D results used in the 
efficacy analyses, responder status will be imputed using multiple imputation.  The missing 
serum 25D results will be imputed 50 times to generate 50 complete data sets by using the SAS 
procedure MI using the logistic regression method with adjustment for covariates including 
treatment group, gender, age, race, dosing compliance and baseline and other serum 25D 
concentration determinations.  The seed used will be 201901.  Each of the 50 complete datasets 
will be analyzed using a Chi-square test and the SAS MIANALYZE procedure will be used to 
generate valid statistical inferences by combining results from the 50 analyses using Rubin’s 
formula. No other efficacy data will be imputed. 
The secondary endpoints based on incidence will not be imputed.  These endpoints, for example 
hospitalization or mechanical ventilation, will either occur, or will be assumed not to have 
occurred.  Since these items require clinical care, the occurrence will unlikely go unreported.  If 
there are more than 10% of subjects who are truly missing and lost to follow up, a tipping point 
approach will be used, first assuming that none of the events occurred in the missing subjects, 
and then if all missing subjects had the event.  If there is a difference based on these extremes, 
the number of missing subjects assumed to have the event will be increased by 2 in the treated 
group, while holding the incidence in the placebo group as observed, until the tipping point is 
found.  Missing values from the quality of life components of FLU-PRO Plus© questionnaire will 
not be imputed.  The analysis of these items will be based on observed cases only with resolution 
requiring at least a three-day duration.   
AEs with missing onset date will be treated as TEAEs and missing onset date will be imputed as 
Day 1, unless the event end date indicates that the event resolved prior to the administration of 
the investigational study drug.  In this case, it will be documented in medical history. AEs with 
partial onset date will similarly be treated as TEAEs unless the partial onset date or end date of 
the event is complete enough to indicate that the event started or resolved prior to the 
administration of the investigational study drug, in which case it will be documented in medical 
history. 
If an AE has missing severity or relationship to study drug, the missing severity will be set to 
severe and the missing relationship will be set to Related in all summary tables. 
For the purpose of inclusion in prior or concomitant medication tables, incomplete medication 
start and stop dates will be imputed and then categorized into prior or concomitant medication 
categories. 
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9.3 
Planned Data Safety Monitoring:  
A five-member DSMB will be established which will be comprised of an expert in viral disease 
pathogenesis, a nephrologist who routinely treats patients with vitD repletion therapies, a 
statistician and a pulmonary medicine expert. The DSMB will also include an unblinded safety 
monitor to identify potential safety hazards (eg, hypercalcemia) in order to maintain blinding of 
treatment assignment and ensure study integrity. The DSMB will meet by teleconference every 
3-4 weeks or at the Committee’s discretion. Meetings may occur more often should serious 
adverse events (SAEs) or other safety issues arise.issues. Specific responsibilities and activities 
of the DSMB will be defined in the DSMB charter.  
9.4 
Determination of Sample Size 
Primary outcome #1 (attainment of serum 25D levels at ≥50 ng/mL):  Assuming that no more 
than 25% of the control group will achieve an increase in serum 25D to ≥50 ng/mL by Day 28 
versus greater than 75% in the CTAP101 Capsules group, a sample size of 19 per group will 
provide 90% power at alpha 0.025 one sided for a Chi-square test of the two groups.    
Primary outcome #2 (severity of illness by five symptoms): A sample size of 80 per group (total 
of 160) is planned.  This will provide greater than 80% power at one sided alpha of 0.025 based 
on a log rank test assuming 50% of subjects in the control group and 70% of the CTAP101 
Capsules group will have achieved resolution of symptoms by Day 28.  This is based on an 
expected hazard ratio (of achieving resolution) of 1.74.   
9.5 
Analysis Populations 
The intent-to-treat (ITT) population will include all randomized subjects.   
The full analysis set (FAS) or population is a subset of the ITT set from which subjects are 
excluded who did not receive any study drug or have a baseline aggregate five symptom score of 
≤5.  For the secondary analyses of individual symptom scores and quality-of-life responses, 
further subjects who do not have a baseline score of >1 for that symptom or response will be 
excluded. 
A PP population, defined as subjects who do not have a major protocol deviation prior to resolution 
of the aggregated five symptoms, will also be used as supportive evidence of efficacy.  Subjects 
who are non-compliant with the requirements of the protocol after achieving resolution of the five 
COVID-19 symptoms will be included in the PP set due to the expectation that such subjects will 
likely discontinue prematurely from the study. 
The safety population includes all subjects who received any amount of study treatment and will 
be the population for safety evaluations.   
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For each analysis population, baseline subject characteristics, including age, sex, race, ethnicity, 
height, weight, BMI and eGFR will be summarized by study arm (CTAP101 Capsules and 
placebo). Primary, secondary 
 outcomes will be summarized by study arm and 
FU time points, using CONSORT guidelines to present descriptive statistics, including mean, 
median, standard deviation, quartiles, interquartile range, minimum, and maximum values for 
subjects within the site, overall and by treatment group. Continuous variables will be 
summarized using means, standard deviations, and quartiles, while categorical variables will be 
summarized using frequencies and percentages.  
9.6 
Demographics and Baseline Characteristics 
Baseline subject characteristics, including age, sex, race, ethnicity, height, weight, BMI and 
eGFR, will be tabulated for the both the treatment and placebo control population. Age (years) 
will be calculated as (date of ICF - date of birth + 1)/365, or as reported age (to the nearest 
month) at study entry if date of birth is not collected. 
9.7 
Subject Disposition and Withdrawal 
Subject disposition will be tabulated and descriptively summarized for all randomized subjects 
by population sub-groups separately and combined. The primary reason for premature study 
termination will be detailed together with the proportion of subjects discontinuing for each 
reason. The primary reason for premature study termination will be recorded.  
9.8 
Prior and Concomitant Medications 
Prior medications are defined as any continuing or new medication used within 12 weeks and 
discontinued before Visit 1. Concomitant medications are defined as any continuing or new 
medication taken from Visit 1 or anytime thereafter until the end of the study. World Health 
Organization Drug Dictionary Enhanced version September 2017, Format C, or later will be used 
to code concomitant and prior medications. Prior and concomitant medications will be tabulated 
by population sub-group. All medications recorded on the eCRF, including start and stop (or 
ongoing as of) dates, AE number (if applicable), indication, dose, unit, route, and frequency will 
be listed. For the purpose of inclusion in prior or concomitant medication tables, incomplete 
medication start and stop dates will be imputed and then categorized into prior or concomitant 
medication categories.  
9.9 
Safety Analyses 
All subjects in safety population will be included in the safety analysis. Statistical summary 
analysis of safety data will be descriptive and performed by study arms. No inferential 
hypothesis testing will be performed on the safety variables with the exception of comparisons of 
serum calcium and serum phosphorus between treatment groups.  
9.9.1 
Adverse Events 
All AEs will be collected on the eCRF and coded via SOC and preferred term using MedDRA 
version 23.0 or higher. Additionally, the intensity of all AEs will be coded using CTCAE v. 5.0.  
AEs with missing onset date will be treated as TEAEs and missing onset date will be imputed as 
the date of Visit 1, unless the event end date indicates that the event resolved prior to Visit 1, in 
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which case it will be documented in medical history. AEs with partial onset date will be treated 
as TEAEs unless the partial onset date or end date of the event is complete enough to indicate 
that the event started or resolved prior to the administration of the investigational study drug, in 
which case it will be documented in medical history. Detailed information collected for each 
TEAE will include: AE number, a description of the event, start date, end date or ongoing as of 
date, outcome, therapy for event, whether the AE is serious, seriousness criteria (life-threatening, 
death, hospitalization/prolongation of hospitalization, congenital anomaly, persistent or 
significant disability/incapacity, required intervention to prevent permanent impairment/ 
damage), severity, and relationship to the study drug. The incidence of the AEs will be 
summarized by population sub-group for all TEAEs, potentially drug-related TEAEs, serious 
TEAEs, discontinuation due to TEAEs, TEAEs by relationship to study drug (definite, probable, 
possible, unrelated) and TEAEs by severity (mild, moderate, severe). The number and 
percentages of subjects with a TEAE will be summarized by SOC and preferred term and 
presented overall and by population sub-group. TEAEs will be sorted in descending order of 
total incidence of SOC and preferred term within each SOC. The percentages will be based on 
the number of Safety subjects in a particular population sub-group. If a subject has more than 
one TEAE that code to the same preferred term, the subject will be counted only once for that 
preferred term. Similarly, if a subject has more than one TEAE within a SOC category, the 
subject will be counted only once in that SOC category. All AEs collected on the eCRF will be 
included in the listings. An additional listing of all subject deaths will also be provided.  
Diagnostic procedures will be collected separately in the eCRF and coded via SOC and preferred 
term using MedDRA version 23.0 or higher in a manner similar to AEs. 
9.9.2 
Vital Signs  
Observed VS values will be summarized descriptively at Visit 1 and changes from baseline will 
be descriptively summarized by treatment and control group. Summaries will include n (%), 
mean, SD, median, minimum, and maximum. Vital sign values will be listed.  
9.9.3 
Secondary Safety Analyses 
Secondary safety endpoints for will include incidence of hypercalcemia and drug-related 
hyperphosphatemia. The number (n, %) of subjects with hypercalcemia (serum calcium >10.5 
mg/dL) or hyperphosphatemia (> 4.5 mg/dL) will be compared between study arms using a Chi-
square test statistic (alpha=0.05).  
9.10 
 Efficacy Analyses 
9.10.1 
Primary Endpoints 
The two primary efficacy endpoints will be tested hierarchically to maintain an overall one-sided 
alpha level of 0.025.  Therefore, the test of resolution of symptoms based on the aggregate FLU-
PRO Plus© symptom score will be performed only if the attainment of serum 25D levels ≥50 
ng/mL at Day 14 is significant at <0.025.   
The first primary efficacy endpoint, attainment of serum 25D levels at ≥50 ng/mL, will be 
assessed with a Chi-square statistic at Day 14. The serum 25D levels will also be compared 
between treatment groups at Days 7, 21 and 28 with a Chi-square statistic.   
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The second primary efficacy endpoint is the time to resolution of symptoms, defined as a 
reduction in the aggregate FLU-PRO Plus© scores recorded on Day 0 (prior to study drug 
initiation) for the selected five COVID-19 symptoms to or below 5 for a minimum of three 
consecutive days. The time to resolution is defined as the number of days from Day 1 to the first 
day of achieving the aggregate ≤5 score for a minimum of three consecutive days, provided that 
no score greater than 5 is recorded between the two qualifying scores.  The number of days to 
resolution will be determined by the first two successive qualifying scores which span a 
minimum of three consecutive days, provided that no score greater than 5 is recorded between 
the two qualifying scores. For clarity, resolution will be considered as having been achieved if 
two successive aggregate scores of ≤5 are recorded on the first day of this period and on a 
subsequent day that is at least two days (but not more than 5 days) later even if no score has been 
recorded between the two days.  Missing symptom score values will be handled as described in 
Section 9.2. The number of days to resolution will be analyzed with a Cox proportional hazards 
model with covariates (baseline aggregate FLU-PRO Plus© score for the selected five symptoms, 
baseline serum 25D, and body weight).  
As a sensitivity analysis of the resolution of symptoms, a tipping point approach will be used 
starting with the analysis in which scores are available for three consecutive days, with no 
missing interval, followed by increasing numbers of missing days in the up to five-day interval, 
that is, 1, 2, and 3 missing days between the two consecutive qualifying scores.  The duration of 
resolved days, assessed as achieving resolution for four, five, six or seven consecutive days 
without evidence of relapse, will be summarized by treatment group. 
Subgroup analyses for the primary efficacy endpoints will be based on age (≤40 or >40 years), 
severity of the selected five COVID-19 symptoms at baseline (aggregate FLU-PRO Plus© score 
of ≤  or > the median score), attained serum 25D at Day 14 (below, within or above the targeted 
range of 50 to 100 ng/mL), body weight (≤100 or >100 kg), BMI (≤30 or >30), dosing compliance 
(<80% or ≥80%), gender, race, ethnicity, number of comorbidities (<1 or ≥1), duration of treatment 
(≤10 or >10 days) and prior or intercurrent COVID-19 vaccination and/or monoclonal antibody 
therapy for COVID-19.   
In addition, the number of days to resolution of the five aggregated symptoms will be compared 
based on the serum 25D level at Day 14 (<50 ng/mL vs 50 to 100 ng/mL and 50 to 100 ng/mL vs 
>100 ng/mL), regardless of the assigned treatment group.  The comparisons will be done using a 
Chi-square test.  Frequency of relapses will be calculated, if possible, to account for potential 
worsening of symptoms after resolution (defined above), with relapse being defined as achieving 
an aggregate score >5 for a minimum of three consecutive days.  
9.10.2 
Secondary Endpoints 
The following secondary endpoints will also be tested statistically with methods described 
below, and the resulting nominal p-value will be reported for evaluation:   
1) The number of days to resolution of five symptoms (trouble breathing, chest congestion, 
dry or hacking cough, body aches and pains, and chills and shivering), as measured by 
the FLU-PRO Plus© questionnaire, with resolution defined as the first aggregate symptom 
score of ≤5 which is maintained for a minimum of three consecutive days, with no 
individual symptom score >1;  
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2) Resolution, defined as the first score of ≤5 which is maintained for a minimum of three 
consecutive days (without subsequent relapse), for the aggregate five COVID-19 
symptoms (trouble breathing, chest congestion, dry or hacking cough, body aches and 
pains, and chills and shivering) and for each individual symptom, defined as a score of 0 
or 1, as measured by the FLU-PRO Plus© questionnaire as of Day 10; 
3) Incidence of emergency room/urgent care visits; 
4) Incidence of oxygen saturation below 94% (or requirement for supplemental oxygen); 
5) Incidence of hospitalizations (mean duration of hospitalization will also be presented); 
6) Incidence of requirement for mechanical ventilation; and, 
7) Mortality rate (as incidence). 
Endpoints listed will be summarized. For the analysis of individual symptoms in endpoint #2 
above, the threshold of ≤1 is appropriate because it describes minor symptom severity (at worst 
“a little bit”) which seems unlikely to presage a poor outcome. Analysis of the resolution of 
individual symptoms will be performed using a logistic regression, with baseline symptom score, 
baseline 25D level, and body weight as covariates. Analysis of the secondary endpoints based 
on incidence will be performed with a Chi-square test. Mean duration will be analyzed with 
analysis of covariance (ANCOVA). Mortality will be analyzed as incidence, with logistic 
regression with baseline symptom score, baseline 25D level and body weight as covariates. 
Rates only will be reported if there are too few deaths to be formally analyzed. 
The severity, duration and clinical course of COVID-19 illness will be compared between 
treatment groups by analyzing changes in quality-of-life assessments recorded on the FLU-PRO 
Plus© questionnaire. Five of the six items from the questionnaire to be analyzed are: : “Overall, 
how severe were your infection symptoms today?”, “Overall, how were your infection 
symptoms today compared to yesterday?”, “How much did your infection symptoms interfere 
with your usual activities today?”, “Have you returned to your usual activities today?”, “In 
general, how would you rate your physical health today?”, and “Have you returned to your usual 
health today?”  The scores for: symptom severity range from 0 (no infection symptoms today) to 
4 (very severe); symptoms today range from 1 (much better) to 7 (much worse); symptom 
interference range from 1 (not at all) to 5 (very much). The first of two consecutive scores of ≤1 
spanning at least three days and no more than five days will be considered the day of resolution, 
provided that no intervening scores of >1 are recorded.  The scores for return to usual activities 
or health are either “yes” or “no”, and the first occurrence of “yes” will be deemed to be day of 
resolution provided that a second “yes” is recorded no more than 5 days later without an 
intervening “no”.  The remaining sixth item to be analyzed is: “physical health range from 1 
(poor) to 5 (excellent). The first of two consecutive scores of >4 spanning at least three days and 
no more than five days will be considered the day of resolution, provided that no intervening 
scores of <4 are recorded. Each item will be compared between treatment groups using a Cox 
proportional hazards model with covariates (aggregate FLU-PRO Plus© score for the selected 
five COVID-19 symptoms at baseline, serum total 25D at baseline, and body weight). 
The clinical course of COVID-19 will be examined by subgroups defined by serum total 25D 
levels <50 ng/mL, 50 to 100 ng/mL and >100 ng/mL at Days 7, 14, 21 and 28. 
 
 
 
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10 ADMINISTRATIVE CONSIDERATIONS 
10.1 
Study Administrative Structure 
The sponsor and principal investigator will provide oversight and responsibility of all designated 
personnel, laboratories, and other participating organizations. 
10.2 
Institutional Review Board/Ethics Committee Approval 
GCP requires that the clinical protocol, any protocol amendments, the IB, the ICF, and all other 
forms of subject information related to the study and any other necessary documents be reviewed 
by an Independent Review Committee (eg, an IRB). 
10.3 
Ethical Conduct of the Study 
In accordance with applicable country-specific regulations, the sponsor will obtain approval from 
the appropriate regulatory authority(ies) prior to initiating the study in that country. This study 
will be conducted in accordance with the protocol, all ICH and GCP regulations governing 
clinical study conduct, ethical principles that have their origin in the Declaration of Helsinki, and 
all applicable local laws and regulations. The investigator must assure that the study is conducted 
in accordance with prevailing local laws and customs. 
It is the investigator’s responsibility to ensure that this protocol is reviewed and approved by the 
appropriate IRB/EC. The IB must be provided to the IRB/EC. 
The IRB/EC must also review and approve the site’s ICF and any other written information 
provided to the subject and any advertisement that will be used for subject recruitment prior to its 
use. 
10.4 
Subject Information and Consent 
Prior to screening for the study each patient and parent(s)/legal guardian /or LAR will be 
informed in detail about the study drugs to be administered and the nature of the clinical 
investigation with its risks and discomforts to be expected. The basic elements of informed 
consent as specified by the FDA (21 CFR 50.25) and ICH-GCP will be followed.  
The investigator or his/her designee will explain the nature of all aspects of the study to the 
subject and/or their LAR, and answer all questions regarding this study, prior to obtaining 
informed consent. 
The investigator or his/her qualified designee will obtain informed consent from each subject 
enrolled in the study, in accordance with the Declaration of Helsinki, the current version of the 
ICH guidelines and the local laws and applicable regulatory requirements. 
It is the responsibility of the investigator to assure that the subject or LAR has consented and has 
signed the ICF before any activity or treatment is undertaken which is not part of routine care.  
The subject and/or LAR will receive a signed copy of the ICF and the original (digital or 
hardcopy) will be retained in the site study records. The investigator or his/her designee will 
ensure documentation of the consent discussion in the subject’s medical record/source 
documents. The decision by the subject and/or LAR to participate in the study is entirely 
voluntary. The investigator or designate must emphasize to the subject and/or LAR that consent 
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regarding study participation may be withdrawn at any time without penalty or loss of benefits to 
which the subject is otherwise entitled. 
If the ICF or patient information is amended during the study, the investigator must follow all 
applicable regulatory requirements pertaining to approval of the amended ICF by the 
Institutional Review Board/Ethics Committee (IRB/EC) and use of the amended form (including 
ongoing subjects). 
10.5 
Subject Confidentiality 
Subject confidentiality will be strictly held in trust by the participating investigators, their staff, 
the sponsor and their authorized representatives. This confidentiality is extended to cover testing 
of biological samples in addition to the clinical information relating to participating subjects. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party, without prior written approval of the sponsor. 
Authorized representatives of the sponsor, the designated contract research organization (if 
applicable), the study monitor, employees of government authorities such as the US FDA or 
other government authorities, and members of the IRB may inspect all documents and records 
required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the subjects in this study. Each clinical 
study site will permit access to such records. 
No information that would permit the identification of a specific individual will be provided for 
entry into the study database or study report. Study documentation submitted to the sponsor will 
identify study participants by study code.  
10.6 
Study Monitoring 
The sponsor and/or its designee are responsible for monitoring the study in accordance with the 
requirements of the ICH/GCP, and in accordance with written SOPs and the Clinical Monitoring 
Plan. 
The investigator will allocate adequate time for such monitoring activities. This monitoring will 
be in the form of on-site and/or remote visits and other communication and will include review 
of original source documents, eCRFs, facilities and equipment, recruiting, record-keeping, 
protocol adherence, data collection, AE reporting, and other factors. The frequency of these 
visits will be reflected in the Clinical Monitoring Plan.  
The investigator will ensure that the monitor or other compliance or quality assurance reviewers 
are given access to all the above noted study-related documents and study related facilities (eg, 
pharmacy, diagnostic laboratory), and has adequate space to conduct the monitoring visit. If the 
monitoring visit is being conducted remotely, adequate precautions are to be taken to ensure the 
confidentiality of all study related documents.  
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10.7 
Essential Documents Required Prior to Study Initiation 
Prior to the start of the study, Investigator's and study site compliance with all pre-investigational 
requirements will be evaluated and confirmed based on the site essential documents. The list 
may include: 
• Appropriate local health authority documentation properly signed and dated by the required 
Investigators (i.e., the submission package); 
• Signed copy (original) of the approved protocol and Investigator’s Brochure; 
• Completed and signed statement of Investigator; 
• Signed Clinical Trial Agreement; 
• Curriculum vitae for the Investigator and sub-Investigators; 
• IRB/IEC name and address; and membership list; 
• Letter of approval from the IRB/IEC for both protocol (identified by protocol title and 
number), informed consent form (identified by protocol title and number) and other study 
related patient materials; 
• Provisions for direct access to source/data documents if necessary for study-related 
monitoring, audits, IRB/IEC review and regulatory inspection. 
Upon satisfactory receipt of all required regulatory documents, Sponsor will arrange that IP be 
delivered to each study site. Supply of all other study materials will be the responsibility of 
OPKO Pharmaceuticals, LLC and/or designee. Subject entry should not begin until after the 
required regulatory documents are confirmed as received and the Initiation Meeting has 
occurred. All personnel expected to be involved in the conduct of the study will undergo 
orientation to include review of study protocol, instructions for eCRF completion, AE reporting 
and overall responsibilities including those for drug accountability and study file maintenance. 
The investigator and/or designee or study monitor will prepare an investigator site file (ISF). 
This file should be used for all study related documents. The investigator will be responsible for 
keeping the ISF updated and ensuring that all required documents are filed. The file will be 
inspected during monitoring visits. 
10.8 
Investigator Site File (ISF) 
All documents required for the conduct of the study as specified in the ICH-GCP guidelines will 
be maintained by the Investigator in an orderly manner in the ISF and made available for 
monitoring and/or auditing by the Sponsor or designee, strategic partners and/or Regulatory 
Authorities. 
10.9 
Case Report Forms and Study Records 
Data capture and management will be consistent with applicable ICH/GCP guidelines. 
All data collected during the study for subjects who are enrolled will be recorded in an 
individual, subject-specific eCRF as part of an EDC system. The sponsor or designee will 
provide training to each investigative site on the EDC system and eCRFs. All eCRFs will be 
completed in a timely manner as data are available in the source for each subject. As EDC will 
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be utilized, instructions, training records, and a log will be maintained to identify the designated 
site personnel who can enter data and/or sign off on an eCRF. 
A subject eCRF must be completed for each subject who signs a consent form and undergoes any 
procedure related to the study. All data generated from external sources, (eg, central laboratory 
results), will be integrated with the subject eCRF data through programming or other data 
integration techniques. 
All eCRFs should be completed within 2 business days of the visit to enable the study monitor to 
review the subject’s status throughout the course of the study in real time. Queries also should be 
resolved in a timely manner. 
The investigator will sign and date the indicated places on the eCRF via the EDC system’s 
electronic signature. These signatures will indicate that the investigator reviewed the data on the 
eCRF, the data queries, and the data clarifications and agrees with the content. 
10.10 Protocol Deviations 
Protocol deviations are any intentional or unintentional changes from an IRB approved protocol 
that are not approved by the IRB prior to initiation of the change and are collected in EDC. 
Major protocol deviations are deviations that result in increased risk to subjects, affect the rights, 
safety, or welfare of the subjects or affect the integrity of the study. 
Major protocol deviations may include but are not limited to deviations from the 
inclusion/exclusion criteria, informed consent deviations, concomitant medication restrictions, 
and any other protocol requirement that results in a significant added risk to the subject or has an 
impact on the quality of the data collected or the outcome of the study. 
Protocol deviations and associated handling of these will be described in a separate study plan.  
Protocol deviations will be reported to the IRB as per IRB post-approval reporting requirements.   
10.11 Data Generation and Analysis 
The investigators are responsible for the accuracy, completeness, and timeliness of the data 
reported on the eCRF. Study data management, monitoring, statistical analysis, and reporting 
will be performed by the Data Manager using the sponsor’s SOPs. 
Completed eCRFs are required for each subject enrolled and signed an ICF.  Electronic data 
entry is accomplished through the 21CFR Part 11 compliant remote data capture application, 
which allows for on-site data entry and data management. Furthermore, the investigators retain 
full responsibility for the accuracy and authenticity of all data entered into the EDC system. The 
completed dataset and their associated files are the sole property of the sponsor and should not be 
made available in any form to third parties, except for authorized business representatives or 
appropriate governmental health or regulatory authorities, without written permission of the 
sponsor.  
Data management, data analysis and programming the submission-ready tables, listings and 
figures will be responsibility of the sponsor and will be performed and managed per the 
sponsor’s SOPs. 
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10.12 Retention of Data 
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRFs 
and all source documents that support the data collected from each subject, and all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial and as specified by the applicable regulatory requirement.  The 
investigator/institution will take measures to prevent accidental or premature destruction of these 
documents. 
Essential documents must be retained until at least two years after the last approval of a 
marketing application in an ICH region or at least two years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the study, 
the responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor or designee must be notified in writing of the name and 
address of the new custodian. Under no circumstances shall the investigator relocate or dispose 
of any study documents before having obtained written approval from the sponsor. 
10.13 Financial Disclosure 
The principal investigator and all sub-investigators are required to provide certification 
(Financial Disclosure Form) that no financial arrangements with the sponsor have been made 
where study outcome could affect compensation; that the investigator has no proprietary interest 
in the tested product; that the investigator does not have a significant equity interest in the 
sponsor; and that the investigator has not received significant payments of other sorts. The 
investigator/sub-investigator is responsible for informing the sponsor if these circumstances 
change during the course of the study or within one year of the end of his/her participation in the 
study. 
10.14 Publication and Disclosure Policy 
Data derived from the study are the exclusive property of OPKO Pharmaceuticals LLC.  Any 
publication or presentation related to the study must be approved by OPKO Pharmaceuticals 
LLC in writing before submission of the manuscript.   
The sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this study at least 60 days prior to submission for publication or 
presentation. Any information identified by the sponsor as confidential must be deleted prior to 
submission. 
10.15 Final Report 
A final study report will be developed at study closure. This report will comprise clinical and 
statistical integrated reports, according to the ICH E3 guidelines. 
 
 
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11 REFERENCE LIST 
Adams JS, Liu PT, Chun R et al. Vitamin D in defense of the human immune response. Ann 
N.Y. Acad Sci. 2007;1117:94-105.  
Bergman P, Lindh AU, Björkhem-Bergman L et al. Vitamin D and respiratory tract infections: A 
systematic review and meta-analysis of randomized controlled Trials. PLoS One. 
2013;8(6):e65835.  
Chun RF, Liu PT, Modlin RL et al. Impact of vitamin D on immune function: Lessons learned 
from genome-wide analysis. Front Physiol. 2014;5:151.  
Diao B, Wang C, Tan Y et al. Reduction and Functional Exhaustion of T Cells in Patients With 
Coronavirus Disease 2019 (COVID-19). Front Immunol. 2020;11:827 
Edfeldt K, Liu PT, Chun R et al. T-cell cytokines differentially control human monocyte 
antimicrobial responses by regulating vitamin D metabolism. Proc Natl Acad Sci USA. 
2010;107:22593-8.  
Fabri M, Stenger S, Shin DM et al. Vitamin D is required for IFN-gamma-mediated 
antimicrobial activity of human macrophages. Sci Transl Med. 2011;3:104ral102. 
Gombart AF, Saito T, Koeffler HP. Exaptation of an ancient Alu short interspersed element 
provides a highly conserved vitamin D-mediated innate immune response in humans and 
primates. BMC Genomics. 2009;10:321.  
Grant WB, Lahore H, McDonnell SL et al. Evidence that vitamin D supplementation could 
reduce risk of influenza and COVID-19 infections and deaths.  Nutrients 2020;12, 988; 
doi:10.3390/nu12040988. 
Holick MF, Binkley NC, Bischoff-Ferrari HA et al. Evaluation, treatment, and prevention of 
vitamin D deficiency: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 
2011;96:1911–1930. 
Holick MF. Environmental factors that influence the cutaneous production of vitamin D. Am J 
Clin Nutr.1995;61: 638S-645S. 
Jiménez-Sousa MÁ, Martínez I, Medrano LM et al. Vitamin D in human immunodeficiency 
virus infection: Influence on immunity and disease. Front Immunol. 2018;9:458.  
Krutzik SR, Hewison M, Liu PT et al. IL-15 links TLR2/1- induced macrophage differentiation 
to the vitamin D-dependent antimicrobial pathway. J Immunol. 2008;181:7115-20.  
Levin A, Bakris GL, Molitch M et al. Prevalence of abnormal serum vitamin D, PTH, calcium, 
and phosphorus in patients with chronic kidney disease:  results of the study to evealutate early 
kidney disease.  Kidney Int. 2007;71:31-8. 
Liu PT, Schenk M, Walker VP et al. Convergence of IL-1beta and VDR activation pathways in 
human TLR2/1-induced antimicrobial responses. PloS one. 2009;4:e5810.  
Liu PT, Stenger S, Li H et al. Toll-like receptor triggering of a vitamin D-mediated human 
antimicrobial response. Science. 2006;311:1770-3.  
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Martineau AR, Jolliffe DA, Hooper RL et al. Vitamin D supplementation to prevent acute 
respiratory tract infections: Systematic review and meta-analysis of individual participant 
data. BMJ. 2017;356:i6583.  
Montoya D, Inkeles MS, Liu PT et al. IL-32 is a molecular marker of a host defense network in 
human tuberculosis. Sci Transl Med. 2014;6:250ra114.  
Nizet V, Ohtake T, Lauth X et al. Innate antimicrobial peptide protects the skin from invasive 
bacterial infection. Nature. 2001;414:454-7.  
Powers JH, Guerrero ML, Leidy NK et al.  Development of the Flu-PRO: a patient-reported 
outcome (PRO) instrument to evaluate symptoms of influenza.  BMC Infectious Diseases 
2016;16-1-11. 
Powers JH, Bacci ED, Guerrero ML et al. Reliability, validity, and responsiveness of influenza 
patient-reported outcome (FLU-PRO©) scores in influenza-positive patients.  Value in Health 
2018;21:210-218. 
Rosen CJ, Adams JS, Bikle DD et al. The nonskeletal effects of vitamin D: An Endocrine 
Society scientific statement. Endocr Rev. 2012;33:456- 92. 
Souberbielle J, Body J, Lappe JM et al. Vitamin D and musculoskeletal health, cardiovascular 
disease, autoimmunity and cancer: Recommendations for clinical practice. Autoimmun Rev. 
2010;9:709-715. 
Sprague, SM, Silva, AL, Al-Saghir, F, et al.  Modified-Release Calcifediol Effectively Contarols 
Secondary Hyperparathyroidism Associated with Vitamin D Insufficiency in Chronic Kidney 
Disease.  Amer J of Nephrology 2014: 40:435-545; DOI: 10.1159/000369939 
Sprague, SM, Crawford, PW, Melnick, JZ, et al.  Use of Extended-Release Calcifediol to Treat 
Secondary Hyperparathyroidism in Stages 3 and 4 Chronic Kidney Disease.  Amer J of 
Nephrology 2016: 44:316-325; DOI: 10.1159/000450766 
Srikanth P, Chun RF, Hewison M et al. Osteoporotic Fractures in Men Study Research G. 
Associations of total and free 25OHD and 1,25(OH)2D with serum markers of inflammation in 
older men. Osteoporos Int. 2016;27:2291-300.  
Strugnell SA, Sprague SM, Ashfaq A et al. Rationale for raising current clinical practice 
guideline target for serum 25-hydroxyvitamin D in chronic kidney disease.  Am J Nephrol. 
2019;49:284-293. 
 
 
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APPENDIX 2. 
PACKAGE INSERT FOR RAYALDEE® (REV. APRIL 2021) 
 
 
  
   
    
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APPENDIX 4. 
INVESTIGATOR SIGNATURE 
Study Title: 
A Randomized, Double-Blind Placebo-Controlled Study to Evaluate 
the Safety and  Efficacy of Rayaldee (calcifediol) Extended-release 
Capsules to Treat Symptomatic Patients Infected with SARS-CoV-2 
(REsCue) 
Study Number: 
CTAP101-CL-2014 
Final Date: 
12 November 2021 
I agree: 
To assume responsibility for the proper conduct of the study at this site. 
To conduct the study in compliance with this protocol, with any future amendments, and with any other 
written study conduct procedures provided and reviewed and approved by OPKO Pharmaceuticals, LLC 
or its designee(s). 
Not to implement any deviations from or changes to the protocol without agreement from the sponsor and 
prior review and the written approval from IRB/EC, except where necessary to eliminate an immediate 
hazard to the subjects, or for administrative aspects of the study (where permitted by all applicable 
regulatory requirements). 
That I am thoroughly familiar with the appropriate use of the investigational drugs, as described in this 
protocol, and any other information provided by the sponsor including, but not limited to, the following: 
the current Investigator’s Brochure (IB) or equivalent document provided by OPKO Pharmaceuticals, 
LLC or its designee(s). 
To ensure that all persons assisting me with the study are adequately informed about the investigational 
drugs and of their study-related duties and functions as described in the protocol. 
That I have been informed that certain regulatory authorities require the sponsor to obtain and supply 
details about the investigator's ownership interest in the sponsor or the study drug, and more generally 
about his/her financial ties with the sponsor. OPKO Pharmaceuticals, LLC will use and disclose the 
information solely for the purpose of complying with regulatory requirements. 
Hence, I: 
• 
Agree to supply OPKO Pharmaceuticals, LLC with any information regarding ownership interest and 
financial ties (including those of my spouse and dependent children). 
• 
Agree to update this information if any relevant changes occur during the course of the study and for 
one year following completion of the study. 
• 
Agree that OPKO Pharmaceuticals, LLC may disclose this information about such ownership 
interests and financial ties to regulatory authorities. 
Signed: 
 
 
Date: 
 
 
 
Printed Name:_______________________________________ 
 
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