Clinical trial NCT05543928
Conditions: Chronic Kidney Disease stage3 Chronic Kidney Disease stage4 Vitamin d Deficiency Secondary Hyperparathyroidism
Sponsor: OPKO Health, Inc.
Start date: 2023-01-31; Completion date: 2024-06-19
Enrollment: 2 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a phase 3, multi-center, randomized, double-blind, placebo-controlled study in children with stage 3-4 chronic kidney disease (CKD), secondary hyperparathyroidism (SHPT) and vitamin D insufficiency.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: CTAP101 intervention 2: Placebo
Intervention descriptions: intervention 1: CTAP101 Capsules is an extended-release (ER) oral formulation of calcifediol which was approved as Rayaldee® ER Capsules in June 2016 by the United States (US) Food and Drug Administration (FDA) for the treatment of secondary hyperparathyroidism (SHPT) in adult patients with stage 3 or 4 chronic kidney disease (CKD) and vitamin D insufficiency (VDI), defined as serum total 25-hydroxyvitamin D levels less than 30 ng/mL. intervention 2: Placebo

Protocol documents:
Prot_SAP_000.pdf: 
 
PROTOCOL: CTAP101-CL-3007 
Study Title: 
A Multi-Center Study to Evaluate the Efficacy, Safety and 
Pharmacokinetics of CTAP101 Extended-release Capsules to Treat 
Secondary Hyperparathyroidism in Pediatric Subjects of Ages 8 to <18 
Years with Stage 3 or 4 Chronic Kidney Disease and Vitamin D 
Insufficiency 
Study Number: 
CTAP101-CL-3007 
Study Phase: 
3 
Product Name: 
CTAP101 Extended-release Capsules  
Investigators: 
Multi-Center 
Sponsor: 
EirGen Pharma Ltd. (EirGen) 
c/o OPKO Pharmaceuticals, LLC 
4400 Biscayne Boulevard 
Miami, FL 33137 
Sponsor Contact: 
 
 
Renal Division, OPKO Health  
4400 Biscayne Boulevard 
Miami, FL 33137  
 
 
 
 Monitor: 
 
 
4400 Biscayne Boulevard 
Miami, FL 33137 
 
 
 
 Contact: 
 
 
Renal Division, OPKO Health  
4400 Biscayne Boulevard 
Miami, FL 33137 
 
 
 
This study will be conducted in compliance with the protocol, United States (US) Code of Federal Regulations 
applicable to clinical studies, principles of International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP), the Declaration of Helsinki, and all applicable regulatory requirements. 
 
 
Date 
Version 3.0 
January 11, 2022 
 
Confidentiality Statement 
This protocol is the confidential information of EirGen Pharma Ltd. 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 EirGen Pharma, Ltd., or OPKO 
Pharmaceuticals, LLC on its behalf. 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 2 of 75 
Confidential 
 
SYNOPSIS 
Sponsor:  
EirGen Pharma Ltd. (EirGen) 
OPKO Pharmaceuticals, LLC, is an affiliate of the IND sponsor (EirGen) and performs 
clinical trial services on its behalf with respect to this study. 
Name of Finished Product: 
CTAP101 Extended-release Capsules (30 mcg) 
Name of Active Ingredient:  
Calcifediol, calcidiol, 25-hydroxyvitamin D3 
Test Products, Dose, and Mode of Administration: 
CTAP101 Extended-release (ER) Capsules (30 or 60 mcg/day) or matching placebo by the 
oral route, referred to as “CTAP101 Capsules” in this document. 
Study Title: 
A Multi-Center Study to Evaluate the Efficacy, Safety and Pharmacokinetics of CTAP101 
Extended-release Capsules to Treat Secondary Hyperparathyroidism in Pediatric Subjects of 
Ages 8 to <18 Years with Stage 3 or 4 Chronic Kidney Disease and Vitamin D Insufficiency 
Study Number: 
CTAP101-CL-3007 
Study Phase: 3   
Primary Objectives: 
The primary objectives of this study are: 
1. To evaluate the efficacy of repeated dosing with CTAP101 ER Capsules versus placebo in 
reducing plasma intact parathyroid hormone (iPTH) by ≥30% from pre-treatment 
baseline;  
2. To investigate the safety and tolerability of repeated dosing with CTAP101 Capsules; and, 
3. To assess the pharmacokinetic (PK) profile of 25-hydroxyvitamin D3 after repeated doses 
of CTAP101 Capsules in pediatric subjects of ages 8 to <18 years with secondary 
hyperparathyroidism (SHPT), stage 3 or 4 chronic kidney disease (CKD) and vitamin D 
insufficiency (VDI). 
Secondary Objectives:  
The secondary objectives of this study are: 
1. To evaluate the efficacy of repeated dosing with CTAP101 Capsules versus placebo in 
raising serum total 25-hydroxyvitamin D to ≥30 ng/mL;   
2. To determine the time courses of mean absolute changes from pre-treatment baseline in 
serum total 25-hydroxyvitamin D and plasma iPTH during administration of repeated 
doses of CTAP101 Capsules; 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 3 of 75 
Confidential 
 
3. To assess the pharmacodynamic (PD) effects of repeated doses of CTAP101 Capsules 
versus placebo on mean serum calcium (corrected for albumin), serum phosphorus and 
serum calcium-times-phosphorus (CaxP) product, and the change in mean urine 
calcium:creatinine ratio; and,  
4. To evaluate the safety of CTAP101 Capsules versus placebo with regard to the incidence 
of hypercalcemia and hyperphosphatemia. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Design:  
This is a phase 3, multi-center, randomized, double-blind, placebo-controlled study which will 
be conducted primarily or entirely within the United States (US).  The study will involve 
approximately 108 eligible subjects, balanced for gender and CKD stage, having ages of 8 to 
<18 years, SHPT, stage 3 or 4 CKD and VDI.   Approximately 72 subjects having ages of 12 
to <18 years will be enrolled initially (Cohort 1) and, after prior approval from the US Food 
and Drug Administration (FDA), another approximately 36 subjects having ages of 8 to <12 
years will be enrolled (Cohort 2). Subjects in both cohorts will be randomized in a 2:1 ratio 
into two treatment groups to receive a daily bedtime dosage of (a) CTAP101 Capsules, or (b) 
matching placebo for 26-weeks.  Subjects in Cohort 1 who are assigned to treatment with 
CTAP101 Capsules will start dosing at 30 mcg/day (1 CTAP101 Capsule) and, at the end of 
12-weeks of treatment, will undergo upward dose titration to 60 mcg per day (two CTAP101 
Capsules) provided that (a) plasma iPTH has not decreased by at least 30% from pretreatment 
baseline, (b) serum calcium (corrected for albumin) is <9.8 mg/dL, (c) serum phosphorus is 
≤5.5  mg/dL and (d) serum total 25-hydroxyvitamin D is ≤65 ng/mL.  The initial dosage in 
Cohort 2 will be determined based on an interim analysis of data obtained from Cohort 1, as 
described below.  The efficacy of CTAP101 Capsules (compared to placebo) in treating SHPT 
will be assessed from multiple plasma iPTH and serum 25-hydroxyvitamin D levels obtained 
in the efficacy assessment period (EAP), defined as the last 6 weeks of the 26-week treatment 
period.   
An Interactive Response System (IRS) will provide study treatment group assignments (using 
a computer-generated randomization code provided by the IRS vendor) and dosing 
adjustments.  An independent, unblinded Data Safety Monitoring Board (DSMB) will be 
established to oversee the IRS and verify the appropriateness of all dosing adjustments, and to 
monitor subject safety and the effectiveness of CTAP101 Capsules at regular intervals.  
Members of the DSMB will also conduct periodic reviews of study conduct to verify that all 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 4 of 75 
Confidential 
 
required data are captured to a sufficiently high degree (>95%) and within specified time 
frames (usually within 5 days), and to promptly recommend appropriate corrective actions to 
address any noted deficiencies, in an effort to minimize missing data.   Specific responsibilities 
and activities of the DSMB will be defined in the charter ratified at the pre-study 
organizational meeting.  These responsibilities will include the completion of an interim 
analysis of the data obtained from Cohort 1 to justify a starting dose for Cohort 2, and an 
interim analysis of the data obtained from Cohort 2 to justify a starting dose for a separate 
phase 2 study in subjects having ages of 1 month to <8 years. 
Subjects receiving treatment prior to study enrollment with calcitriol or another 1α-
hydroxylated vitamin D analog, or calcimimetics prior to study enrollment will forgo further 
dosing with these agents for the duration of the study and complete an 8-week washout period 
prior to baseline assessments.   
Subjects receiving vitamin D supplementation at a rate above 1,700 IU/day or 50,000 IU 
(1,250 mcg) per month prior to study enrollment must reduce the dose to ≤1,700 IU/day for the 
duration of the study and undergo an 8-week washout period prior to baseline assessments if 
serum total 25-hydroxyvitamin D is ≥30 ng/mL.  The washout period is unnecessary if serum 
total 25-hydroxyvitamin D is <30 ng/mL.  Subjects will complete a 6-week follow-up (FU) 
period after completing the 26-week treatment period or after early termination (ET).   
Blood samples will be collected at weekly, biweekly or monthly intervals during the 10-week 
pre-treatment screening/baseline period, the 26-week treatment period and the 6-week post-
treatment FU period.  Sparse PK samples will be collected from all subjects on Day 83 at 0 
(pre-dose), 6, 12, 24 hours (Day 84 pre-dose) and 48 hours (Day 85 pre-dose).   Additional PK 
blood samples will be collected in both Cohort 1 and Cohort 2 in subsets of 10 subjects treated 
with CTAP101 Capsules and 5 subjects treated with placebo during the last 3 days of the 12th 
week of treatment (prior to dose titration).  The additional PK samples will be collected as 
follows:  Day 83:  -2, 2, 4 and 8 hours.  End of study PK blood samples will be collected in 
other subsets of approximately 20 subjects (20 subjects from each cohort) during the post-
treatment FU period. In each cohort, an attempt will be made to collect PK samples from 10 
subjects on each ending daily dose level (30 or 60 mcg) of CTAP101 Capsules, in order to 
establish the terminal elimination half-lives (t1/2) of 25-hydroxyvitamin D3 at each of these 
dose levels. 
All subjects, study personnel and the sponsor will be blinded to the administered treatments 
and to plasma iPTH, serum total 25-hydroxyvitamin D and serum 25-hydroxyvitamin D3 data 
until the last subject completes 26 weeks of treatment.  Unblinded data will be provided to all 
study sites when the final clinical study report becomes available. 
An interim analysis of data obtained from the 15 subjects in Cohort 1 who provide intensive 
PK samples during the last three days of treatment week 12 will be undertaken by the DSMB 
to determine the appropriate starting dose for Cohort 2.  A second interim analysis of data 
obtained from 15 subjects in Cohort 2 who provide intensive PK samples during the last three 
days of treatment week 12 will be undertaken by the DSMB to determine the appropriate 
starting dose for a separate phase 2 study in subjects of ages 1 month to <8 years.   


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 5 of 75 
Confidential 
 
A diagram of the study design for Cohort 1 (n=~72) is shown below:  
 
A diagram of the study design for Cohort 2 (n=~36) is shown below:  
 
 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 6 of 75 
Confidential 
 
Duration of Study:  
Each subject will participate in the study for up to approximately 42 weeks (2-weeks 
screening/baseline, 8-weeks washout, if required, 26-weeks of treatment with CTAP101 
Capsules or matching placebo, and 6-weeks of FU evaluation). 
Study Parameters: 
Key parameters to be monitored at regular intervals during the study include: plasma iPTH, 
serum calcium (corrected for serum albumin), serum phosphorus, serum CaxP product, serum 
total 25-hydroxyvitamin D, serum 25-hydroxyvitamin D3, and urine calcium:creatinine ratio.  
Vital signs (VS) and adverse events (AEs) will be monitored at each study visit.  Other 
parameters to be monitored less frequently include brief physical examinations (PEs), clinical 
laboratory tests (hematology and clinical and urine chemistries) and patient-reported 
palatability and acceptability.  Twelve-lead electrocardiograms (ECGs) will be obtained at 
baseline and at the end of treatment or ET.  
 
 
   
Dosing Plan:  
Subjects in Cohort 1 will receive two capsules (CTAP101 Capsules and/or matching placebo 
capsules) every day at bedtime to achieve the targeted initial daily dose of 30 mcg of 
calcifediol (one CTAP101 capsule plus one placebo capsule) or 0 mcg of calcifediol (two 
placebo capsules).  Any food intake within 60 minutes of medication administration will also 
be recorded. At the end of 12 weeks of treatment, subjects assigned to active treatment will 
undergo upward dose titration to 60 mcg per day (two CTAP101 Capsules) provided that (a) 
plasma iPTH has not decreased by at least 30% from pretreatment baseline, (b) corrected 
serum calcium is <9.8 mg/dL, (c) serum phosphorus is ≤5.5 mg/dL and (d) serum total 25-
hydroxyvitamin D is ≤65 ng/mL.  Subjects in Cohort 2 will receive a starting daily bedtime 
dose which will be determined on the basis of the interim analysis of data obtained in Cohort 1 
(see above), and will undergo upward dose titration to a new daily dose that is two times 
higher than the starting dose at the end of 12 weeks of treatment, provided that (a) plasma 
iPTH has not decreased by at least 30% from pretreatment baseline, (b) corrected serum 
calcium is <9.8 mg/dL, (c) serum phosphorus is >6.0 mg/dL and (d) serum total 25-
hydroxyvitamin D is ≤65 ng/mL.   
Subjects in both cohorts will reduce the dose by one capsule per week, as necessary, and no 
more frequently than at biweekly intervals, in the event that any one of the following four 
criteria are met:  plasma iPTH is confirmed to be <35 pg/mL (for subjects with stage 3 CKD) 
or <70 pg/mL (for subjects with stage 4 CKD), serum calcium (corrected) is confirmed to be 
>10.3 mg/dL, serum total 25-hydroxyvitamin D is confirmed to be >100 ng/mL, or serum 
phosphorus is confirmed to be >5.5 mg/dL (ages 12 to <18 years) or >6.0 mg/dL  (ages 8 to 
<12 years), provided that the investigator has deemed the elevated serum phosphorus to be 
related to study drug administration and has taken appropriate and persistent actions to control 
serum phosphorus by initiating or adjusting any phosphate binder therapy.   
Dose reductions will be accomplished by consistently omitting doses on a specific day of the 
week, as follows:   




Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 8 of 75 
Confidential 
 
 
The following PK parameters will be calculated using observed and baseline-adjusted 25-
hydroxyvitamin D3 concentrations: (a) area under the concentration curve (AUC), maximum 
concentration, (Cmax), time to maximum concentration (tmax), and steady-state concentration 
(Css); and (b) t½, clearance (CL/F) and volume of distribution (Vd/F), as feasible.  Relative 
exposure and dose proportionality will be examined, if possible.   
Secondary Endpoints:  
Secondary efficacy endpoints include the proportion of subjects in the per-protocol (PP) 
population attaining a mean decrease in plasma iPTH of at least 30% from pre-treatment 
baseline during the EAP and the proportions of subjects in the ITT and PP populations 
attaining a mean serum total 25-hydroxyvitamin D of at least 30 ng/mL, in aggregate and by 
mean weekly study dose in the EAP.  Additional secondary endpoints include the time courses 
of mean absolute changes from pre-treatment baseline in serum total 25-hydroxyvitamin D and 
plasma iPTH;  PD effects on mean serum calcium (corrected), serum phosphorus, serum CaxP 
product, and the urine calcium:creatinine ratio; the proportion of subjects in each treatment 
group with hypercalciuria (>200 mg calcium/g creatinine), hypercalcemia (2 consecutive visits 
with serum calcium >10.3 mg/dL) or hyperphosphatemia (2 consecutive visits with serum 
phosphorus >5.5 mg/dL (ages 12 to <18 years) or >6.0 mg/dL (ages 8 to <12 years),  deemed 
to be study drug related); and the proportion of subjects who attain 2 consecutive plasma iPTH 
values ≤70 pg/mL.  
  
 
 
 
Additional Assessments: 
Patient reported outcomes on palatability and acceptability. 
Sample Size Estimation: 
Sample size has been calculated (using Fisher’s exact test statistics) to provide power of 80% 
for a two-sided, alpha 0.05 level test of equal proportions comparing the percentages of 
subjects attaining mean decreases of at least 30% in plasma iPTH (averaged over the last 6 
weeks of treatment) compared to baseline on daily dosages of CTAP101 Capsules versus 
placebo.  Assuming response rates of at least 0.4 (CTAP101 Capsules) versus 0.1 (placebo), 
and using a 2:1 ratio of CTAP101 Capsules:placebo subjects with an estimated 20% dropout 
rate over the course of the study, a sample size of approximately 108 subjects is required in the 
study with two-thirds apportioned to the 12 to <18 year age group (Cohort 1) and one-third 
apportioned to the 8 to <12 year age group (Cohort 2), allocated as 72 subjects to CTAP101 
Capsules and 36 subjects to placebo. 
Statistical Analyses: 
Efficacy analyses will be performed for the ITT and PP populations, as indicated.  The ITT 
population will be defined as all subjects who have been randomized to receive study 
medication.  The PP population will be defined as all subjects for whom at least two plasma 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 9 of 75 
Confidential 
 
iPTH determinations are included in the calculated baseline value, defined as weeks -2 through 
-1, and in the EAP, and who do not have a major protocol deviation.   
Primary efficacy will be assessed in the ITT population by comparing the proportions of 
subjects in each treatment group (CTAP101 Capsules versus placebo) attaining a mean 
decrease from baseline in plasma iPTH of ≥30% in the EAP using the Cochran-Mantel-
Haenszel test statistic (alpha=0.05) for overall efficacy of the multicenter results.  Subjects 
who do not have at least two plasma iPTH determinations in the EAP will be deemed non-
responders.   
Secondary efficacy will be assessed in the PP population by comparing the proportions of 
subjects in each active treatment group attaining mean decreases in plasma iPTH of ≥30% 
(from baseline) in the EAP to the corresponding proportion of subjects in the placebo group, 
and in the ITT and PP populations by comparing the proportions of subjects in each active 
treatment group attaining mean serum total 25-hydroxyvitamin D of ≥30 ng/mL in the EAP to 
the corresponding proportions of subjects in the placebo group, in aggregate and by mean 
weekly study dose in the EAP.  Mean weekly dose in the EAP will be calculated for three 
groups of subjects:  those receiving 0 mcg per day; those receiving >0 and ≤30 mcg per day; 
and, those receiving >30 mcg/day of calcifediol. 
Primary safety analyses will be conducted in the ITT population, and the statistical summary 
will be descriptive and performed by treatment group. No inferential hypothesis testing will be 
performed on the safety parameters with the exception of serum calcium, serum phosphorus, 
serum CaxP product, and urine calcium:creatinine ratio. 
Secondary safety analyses will compare the proportions of subjects with confirmed corrected 
serum calcium >10.3 mg/dL or confirmed serum phosphorus >5.5 mg/dL (ages 12 to <18 
years) or >6.0 mg/dL (ages 8 to <12 years)  (deemed to be study drug related) or serum 
confirmed CaxP product >55 (for Cohort 1) or >60 (for Cohort 2) between the CTAP101 
Capsules and placebo treatment groups using the Cochran-Mantel-Haenszel test statistic 
(alpha=0.05) for overall safety in the multicenter results.  
Descriptive statistics will be applied to evaluate patient reported palatability and acceptability. 
 
Inclusion Criteria: 
Each subject must meet the following criteria to be enrolled in this study: 
1. Cohort 1: Be 12 to <18 years of age and have a body weight of ≥40 kg; Cohort 2: be 8 to 
<12 years of age and have a body weight of ≥20 kg.  
2. Be diagnosed with stage 3 or 4 CKD at least six months prior to the screening visit, and 
have an estimated glomerular filtration rate (eGFR) of ≥15 to <60 mL/min/1.73m2 at 
screening. 
3. 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, including: 
a. Serum albumin ≤ 3.0 g/dL; 
b. Serum transaminase (alanine transaminase [ALT], glutamic pyruvic transaminase 
[SGPT], aspartate aminotransferase [AST] or glutamic oxaloacetic transaminase 
[SGOT]) > 2.5 times the upper limit of normal at screening, and, 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 10 of 75 
Confidential 
 
c. Urinary albumin excretion of >3000 mcg/mg creatinine. 
4. Exhibit during the initial or, if necessary, a screening visit after washout: 
a. Plasma iPTH >100 pg/mL (stage 3 CKD) or >160 pg/mL (stage 4 CKD) 
b. Serum calcium <9.8 mg/dL (corrected for albumin);  
c. Serum total 25-hydroxyvitamin D <30 ng/mL; and, 
d. Serum phosphorus >2.5 to ≤5.5 mg/dL (12 to <18 years) or ≤6.0 mg/dL (ages 8 to <12 
years). 
5. If taking calcitriol or other 1α-hydroxylated vitamin D analogs, or cinacalcet, be willing to 
forgo treatment with these agents for the duration of the study and complete an 8-week 
washout period prior to commencing treatment in the study. 
6. If taking more than 1,000 mg/day of elemental calcium, discontinue or reduce calcium use 
and/or use non-calcium based therapies for the duration of the study. 
7. If receiving ≤1,700 IU/day nutritional vitamin D (ergocalciferol or cholecalciferol) therapy, 
must agree to remain on a stable dose during the study. 
8. If taking more than 1,700 IU/day of nutritional vitamin D, must discontinue or decrease the 
dose to ≤1,700 IU/day, maintain that dose for the duration of the study, and complete an 8-
week washout period prior to commencing treatment in the study provided that serum total 
25-hydroxyvitamin D is ≥30 ng/mL. The washout period is not necessary if serum total 25-
hydroxyvitamin D is <30 ng/mL. 
9. If taking any bone metabolism therapy that could interfere with study endpoints, must 
discontinue use of such agent(s) for the duration of the study. 
10. Willing and able to comply with study instructions and commit to all clinic visits for the 
duration of the study. 
11. Female subjects of childbearing potential must be neither pregnant nor lactating and must 
have a negative urine pregnancy test at the first screening visit. 
12. All female subjects of childbearing potential and male subjects with female partners of 
childbearing potential must agree to use effective contraception (eg, implants, injectables, 
combined oral contraceptives, intrauterine device, sexual abstinence, vasectomy or 
vasectomized partner) for the duration of the study. 
13. Each subject or their legal representative must be able to read, understand and sign the 
Informed Consent Form (ICF). 
 
Exclusion Criteria: 
Subjects who meet any of the following criteria will be excluded from the study: 
1. History of or planned kidney transplant or parathyroidectomy. 
2. History (prior three months) of serum calcium ≥9.8 mg/dL  
3. Use of bisphosphonate therapy or other bone modifying treatment (eg, denosumab) within 
six months prior to enrollment. 
4. Known previous or concomitant serious illness or medical condition, such as malignancy, 
human immunodeficiency virus, significant gastrointestinal or hepatic disease or 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 11 of 75 
Confidential 
 
cardiovascular event or hepatitis, or physical condition that in the opinion of the 
investigator may worsen and/or interfere with participation in the study. 
5. History of neurological/psychiatric disorder, including psychotic disorder, or any reason 
which, in the opinion of the investigator makes adherence to a treatment or FU schedule 
unlikely. 
6. Known or suspected hypersensitivity to any of the constituents of either investigational 
product. 
7. Currently participating in, or has participated in, an interventional/investigational study 
within 30 days prior to study screening. 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 12 of 75 
Confidential 
 
TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................2 
TABLE OF CONTENTS ............................................................................................................12 
LIST OF IN-TEXT TABLES .....................................................................................................15 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................16 
1 
INTRODUCTION ................................................................................................................19 
1.1 
CTAP101 Capsules ..........................................................................................................19 
1.2 
Chronic Kidney Disease ..................................................................................................19 
1.3 
Secondary Hyperparathyroidism ...................................................................................19 
1.4 
Pathogenesis of Secondary Hyperparathyroidism ........................................................19 
1.5 
Treatment of Vitamin D Insufficiency ...........................................................................20 
1.6 
Vitamin D Insufficiency ...................................................................................................20 
1.7 
Treatment of Secondary Hyperparathyroidism ...........................................................20 
1.8 
The Unmet Medical Need ................................................................................................21 
1.9 
Nonclinical Experience with Calcifediol ........................................................................21 
1.10 
Metabolism of Calcifediol................................................................................................22 
1.11 
Pharmacodynamics of CTAP101 Capsules ...................................................................22 
1.12 
Pharmacokinetics of CTAP101 Capsules ......................................................................23 
1.13 
Clinical Efficacy and Safety ............................................................................................24 
2 
STUDY OBJECTIVES AND ENDPOINTS ......................................................................25 
2.1 
Study Objectives...............................................................................................................25 
2.1.1 
Primary Objectives ....................................................................................................25 
2.1.2 
Secondary Objectives.................................................................................................25 
2.1.3 
25 
3 
INVESTIGATIONAL PLAN ..............................................................................................26 
3.1 
Overall Study Design and Plan .......................................................................................26 
3.2 
Rationale for Study Design and Control Group ...........................................................29 
3.3 
Study Duration .................................................................................................................29 
4 
STUDY POPULATION SELECTION ...............................................................................30 
4.1 
Study Population ..............................................................................................................30 
4.2 
Inclusion Criteria .............................................................................................................30 
4.3 
Exclusion Criteria ............................................................................................................31 
5 
STUDY TREATMENTS ......................................................................................................32 
5.1 
Description of Treatments ...............................................................................................32 
5.1.1 
CTAP101 Capsules Description................................................................................32 
5.1.2 
Placebo Capsules Description ...................................................................................32 
5.2 
Treatments Administered ...............................................................................................32 
5.3 
Selection and Timing of Dose for Each Subject ............................................................33 
5.4 
Dose Reduction Criteria ..................................................................................................33 
5.5 
Overdose and Toxicity .....................................................................................................34 
5.6 
Method of Assigning Subjects to Treatment Groups ...................................................34 
5.7 
Blinding .............................................................................................................................35 
5.8 
Prior and Concomitant Therapy ....................................................................................36 
5.8.1 
Phosphate Binder and Elemental Calcium Therapy ..............................................36 
5.9 
Restrictions .......................................................................................................................36 
5.9.1 
Dietary Restrictions ...................................................................................................36 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 13 of 75 
Confidential 
 
5.9.2 
Subject Activity Restrictions .....................................................................................36 
5.10 
Treatment Compliance ....................................................................................................36 
5.11 
Packaging and Labeling ..................................................................................................37 
5.12 
Storage and Accountability .............................................................................................37 
5.13 
Investigational Product Retention at Study Site ...........................................................38 
6 
STUDY PROCEDURES ......................................................................................................39 
6.1 
Informed Consent ............................................................................................................39 
6.2 
Medical History ................................................................................................................39 
6.3 
Physical Examination, Vital Signs, Body Mass Index, Body Weight and Height, 12-
Lead Electrocardiogram, and Patient-Reported Palatability and Acceptability 
Assessments ......................................................................................................................40 
6.4 
Clinical Laboratory Tests................................................................................................41 
6.4.1 
Laboratory Parameters .............................................................................................41 
6.4.2 
Sample Collection, Storage, and Shipping ...............................................................43 
6.4.3 
Clinical Supplies .........................................................................................................43 
6.5 
Dispensing Study Drug ....................................................................................................43 
6.6 
Adverse Events Assessments ...........................................................................................44 
6.6.1 
Definition ....................................................................................................................44 
6.6.2 
Performing Adverse Events Assessments ................................................................44 
6.6.3 
AE Collection Period .................................................................................................44 
6.6.4 
Severity........................................................................................................................45 
6.6.5 
Relationship ................................................................................................................45 
6.6.6 
Expectedness ...............................................................................................................46 
6.6.7 
Clinical Significance...................................................................................................46 
6.6.8 
Serious Adverse Events .............................................................................................46 
6.6.8.1 
Definition ..............................................................................................................46 
6.6.8.2 
Reporting Serious Adverse Events .....................................................................47 
6.6.9 
Treatment-Emergent Adverse Events......................................................................48 
6.7 
Concomitant Medication Assessments ...........................................................................48 
6.8 
Removal of Subjects from the Study or Study Drug ....................................................48 
6.9 
Appropriateness of Measurements .................................................................................48 
7 
STUDY ACTIVITIES ..........................................................................................................50 
7.1 
Screening Period ..............................................................................................................50 
7.1.1 
Visit 1 (Day -70 to -63) ...............................................................................................50 
7.1.2 
Visit 2 (Day -7 to -1) ...................................................................................................50 
7.1.3 
Visit 3 (Day 1) .............................................................................................................51 
7.2 
Treatment Period (Weeks 1-26) ......................................................................................51 
7.2.1 
Visits 4-10 (Days 8-71) ...............................................................................................51 
7.2.2 
Visits 11-12 (Days 83-84) ...........................................................................................52 
7.2.3 
Visit 13 (Day 85): ........................................................................................................52 
7.2.4 
Visits 14-21 (Days 92-169) .........................................................................................53 
7.2.5 
Visit 22 (Day 183): ......................................................................................................53 
7.3 
Follow-up Period or Second PK Assessment .................................................................53 
7.3.1 
Visit 23 (Day 190) .......................................................................................................53 
7.3.2 
Visit 24 (Day 197) .......................................................................................................54 
7.3.3 
Visits 25-27 (Days 204-218) .......................................................................................54 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 14 of 75 
Confidential 
 
7.3.4 
Visit 28/ET (Day 225).................................................................................................54 
8 
QUALITY CONTROL AND ASSURANCE .....................................................................56 
9 
PLANNED STATISTICAL METHODS ............................................................................57 
9.1 
General Considerations ...................................................................................................57 
9.2 
Determination of Sample Size .........................................................................................57 
9.3 
Analysis Populations ........................................................................................................58 
9.3.1 
Analysis Populations ..................................................................................................58 
9.4 
Definition of Baseline .......................................................................................................58 
9.5 
Demographics Characteristics ........................................................................................58 
9.6 
Subject Disposition and Withdrawal .............................................................................58 
9.7 
Prior and Concomitant Medications ..............................................................................59 
9.8 
Analysis Endpoints...........................................................................................................59 
9.8.1 
Primary Efficacy Endpoint .......................................................................................59 
9.8.2 
Primary Safety Endpoints .........................................................................................59 
9.8.3 
Pharmacokinetic Endpoints ......................................................................................60 
9.8.4 
Secondary Endpoints .................................................................................................60 
9.8.5 
 
9.9 
Additional Assessments ...................................................................................................61 
9.10 
Efficacy Analysis ..............................................................................................................61 
9.10.1 
Primary Endpoint Analysis .......................................................................................61 
9.10.2 
Secondary Endpoint Analyses ..................................................................................61 
9.10.3 
 
9.11 
Safety Analyses .................................................................................................................62 
9.11.1 
Primary Endpoints Analyses ....................................................................................62 
9.11.1.1 
Adverse Events .....................................................................................................62 
9.11.1.2 
Laboratory Evaluations.......................................................................................62 
9.11.1.3 
Vital Signs .............................................................................................................63 
9.11.1.4 
Physical Examinations .........................................................................................63 
9.11.1.5 
ECG .......................................................................................................................63 
9.11.2 
Secondary Endpoint Analyses ..................................................................................63 
9.12 
Other Analysis ..................................................................................................................64 
10 ADMINISTRATIVE CONSIDERATIONS ....... ERROR! BOOKMARK NOT DEFINED. 
10.1 
Investigators and Study Administrative Structure .......................................................65 
10.2 
Institutional Review Board Approval ............................................................................65 
10.3 
Ethical Conduct of the Study ..........................................................................................65 
10.4 
Subject Information and Consent ..................................................................................65 
10.5 
Subject Confidentiality ....................................................................................................66 
10.6 
Study Monitoring .............................................................................................................66 
10.7 
Case Report Forms and Study Records .........................................................................66 
10.8 
Data Safety Monitoring Board .......................................................................................67 
10.9 
Protocol Deviations ..........................................................................................................67 
10.10 Source Documentation.....................................................................................................68 
10.11 Data Generation and Analysis ........................................................................................68 
10.12 Retention of Data .............................................................................................................69 
10.13 Financial Disclosure .........................................................................................................69 
10.14 Publication and Disclosure Policy ..................................................................................69 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 15 of 75 
Confidential 
 
11 REFERENCE LIST..............................................................................................................70 
APPENDIX 1 
SCHEDULE OF EVENTS ............................................................................72 
APPENDIX 2 
INVESTIGATOR’S SIGNATURE ..............................................................75 
 
 
LIST OF IN-TEXT TABLES 
 
Table 1. 
Evaluations ...........................................................................................................40 
Table 2. 
List of Laboratory Tests ......................................................................................42 
 
 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 16 of 75 
Confidential 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
 
 
 
25D3 
25-hydroxyvitamin D3, calcifediol, calcidiol 
25D 
25-hydroxyvitamin D 
AE 
adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase  
AUC 
area under the curve 
BA 
bioavailability 
 
 
BMI 
body mass index 
CaxP 
calcium-times-phosphorus product 
CFR 
Code of Federal Regulations 
CKD 
chronic kidney disease 
CL/F 
clearance 
Cmax 
maximum concentration 
CRF 
case report form 
Css 
steady-state concentration 
 
 
CV 
coefficient of variation 
DSMB 
Data Safety Monitoring Board 
EAP 
efficacy assessment period 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture  
eGFR 
estimated glomerular filtration rate 
ER 
extended-release 
ET 
early termination 
EU 
European Union 
FDA 
Food and Drug Administration 
 
 
FU 
follow-up 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
HDPE 
high-density polyethylene 
IB 
Investigator Brochure 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 17 of 75 
Confidential 
 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation  
iPTH 
intact parathyroid hormone 
IR 
immediate-release 
IRB 
Institutional Review Board/Ethics Committee 
IRS 
interactive response system 
ITT 
intent-to-treat 
IU 
International Units 
KDIGO 
Kidney Disease Improving Global Outcomes 
K/DOQI 
Kidney/Disease Outcomes Quality Initiative 
MedDRA 
Medical Dictionary for Regulatory Activities 
MBD 
metabolic bone disease 
 
 
PD 
pharmacodynamic 
PE 
physical examinations 
PK 
pharmacokinetic 
PP 
per-protocol 
PT 
Preferred Terms 
PTH 
parathyroid hormone 
RCT 
randomized clinical trial 
SAE 
serious adverse event 
SAS® 
Statistical Analysis Software 
SD 
standard deviation 
SE 
standard error 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamic-pyruvic transaminase 
SHPT 
secondary hyperparathyroidism 
SOC 
system organ class 
SOP 
standard operating procedure 
SUSAR 
serious unexpected suspected adverse event 
t1/2 
terminal elimination half-life 
 
 
TEAE 
treatment-emergent adverse events 
tmax 
time to maximum concentration 
Tss 
time to steady-state concentration 
US 
United States 
Vd/F 
volume of distribution 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 18 of 75 
Confidential 
 
VDI 
vitamin D insufficiency 
VDRA 
vitamin D receptor agonist 
VS 
vital signs 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 19 of 75 
Confidential 
 
1 INTRODUCTION 
1.1 
CTAP101 Capsules 
CTAP101 Capsules is an extended-release (ER) oral formulation of calcifediol which was 
approved as Rayaldee® ER Capsules in June 2016 by the United States (US) Food and Drug 
Administration (FDA) for the treatment of secondary hyperparathyroidism (SHPT) in adult 
patients with stage 3 or 4 chronic kidney disease (CKD) and vitamin D insufficiency (VDI), 
defined as serum total 25-hydroxyvitamin D levels less than 30 ng/mL.  EirGen is further 
developing CTAP101 Capsules for this same indication in pediatric patients. 
Calcifediol is 25-hydroxyvitamin D3, the physiological precursor to the vitamin D hormone, 
calcitriol (1,25-dihydroxyvitamin D3).  This prohormone is synthesized by the liver from 
cholecalciferol (vitamin D3) generated endogenously in skin following exposure to sunlight or 
obtained from the diet or supplements.  Another prohormone, 25-hydroxyvitamin D2, is 
synthesized hepatically from ergocalciferol (vitamin D2), which cannot be produced 
endogenously, but is obtained from diet or supplements.  These two prohormones are 
collectively referred to as “25-hydroxyvitamin D”.  Unless an individual is receiving significant 
ergocalciferol supplementation, essentially all of the 25-hydroxyvitamin D in blood consists of 
calcifediol.  
1.2 
Chronic Kidney Disease 
CKD is a worldwide public health problem with steadily increasing incidence, prevalence, and 
cost [Coresh 2007].  Key factors driving growth of CKD in developed countries include aging 
populations, the increasing incidence of obesity and its associated complications of hypertension 
and adult-onset diabetes. CKD is categorized into five successive stages on the basis of estimated 
glomerular filtration rate (eGFR), with each successive stage representing more advanced 
disease.  Stage 3 CKD is defined by an eGFR in the range of 30 to <60 mL/min/1.73m2, and 
stage 4 CKD is defined by an eGFR in the range of 15 to <30 mL/min/1.73m2.  CKD afflicts 
approximately 6-13% of the global population.  Despite treatment, CKD continues to be 
associated with poor outcomes, reflecting the inadequacies of the current standard of care 
[Nicola 2016, Levey 2005].  
1.3 
Secondary Hyperparathyroidism 
SHPT is a common condition that occurs with advancing CKD and is characterized by excessive 
production of parathyroid hormone (PTH), hypocalcemia and hypertrophy of the parathyroid 
glands.  SHPT affects 40% to 82% of patients with stage 3 or 4 CKD [Levin 2007].  SHPT 
requires prompt and effective treatment, as prolonged elevation of PTH causes calcium and 
phosphorus release from bone, leading to metabolic bone disease and extra-skeletal calcification.  
In the absence of effective treatment, SHPT becomes progressively more severe and 
unresponsive to medical treatment as the parathyroid gland becomes hyperplastic and less 
sensitive to calcium and vitamin D hormone signaling [Nigwekar 2014]. 
1.4 
Pathogenesis of Secondary Hyperparathyroidism 
CKD-associated SHPT develops as the result of phosphorus retention, mild hypocalcemia and 
VDI [Levin 2007]. VDI plays a central role in the pathogenesis of SHPT in CKD [Cunningham 
2011].  It limits the normal activation of 25-hydroxyvitamin D to vitamin D hormone (1,25-


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 20 of 75 
Confidential 
 
dihydroxyvitamin D) in the kidney and in other tissues which contain cytochrome P450 25-
hydroxyvitamin D-1α-hydroxylase (CYP27B1) by reducing the amount of available substrate for 
conversion.  Declining hormone concentrations increase PTH secretion by the parathyroid glands 
and decrease calcium absorption in the small intestine, leading to hypocalcemia. 
1.5 
Treatment of Vitamin D Insufficiency 
Vitamin D supplementation is recommended by both the K/DOQI and KDIGO Clinical Practice 
Guidelines, although there is no consensus in regarding how vitamin D supplements should best 
be administered.  Published studies have reported the use of daily doses of vitamin D (either 
cholecalciferol or ergocalciferol) of 700 to 4,000 International Units (IU), weekly doses of 5,000 
to 50,000 IU, and monthly doses of 50,000 to 300,000 IU.  Irrespective of the treatment regimen 
used, no or inadequate reductions in PTH levels have been observed in randomized clinical trials 
(RCTs) and nutritional vitamin D remains unproven as an effective treatment for SHPT in 
patients with stage 3-4 CKD [Agarwal 2016, Kalantar-Zadeh 2009].  Immediate-release (IR) 
formulations of calcifediol, used occasionally in the European Union (EU), have also shown no 
or inadequate reductions in PTH in clinical trials focused on stage 3-4 CKD. 
1.6 
Vitamin D Insufficiency 
VDI affects an estimated 71% to 83% of patients with stage 3 or 4 CKD [La Clair 2005, Wolf 
2007].  It is defined by the National Kidney Foundation as serum total 25-hydroxyvitamin D of 
≥15 to <30 ng/mL, and vitamin D deficiency as <15 ng/mL in its Kidney Disease Outcomes 
Quality Initiative (K/DOQI) Clinical Practice Guidelines for Bone Metabolism and Disease in 
Chronic Kidney Disease, [K/DOQI 2003].  The more recent Kidney Disease: Improving Global 
Outcomes (KDIGO) Guideline for Chronic Kidney Disease-Mineral and Bone Disorder (CKD-
MBD) [KDIGO 2009] points out that most published studies define VDI as serum 25-
hydroxyvitamin D levels down to 10 ng/mL and vitamin D deficiency as levels below 10 ng/mL.  
The Endocrine Society’s Guideline for the Treatment and Prevention of Vitamin D Deficiency 
[Holick 2011] defines vitamin D sufficiency as serum 25-hydroxyvitamin D concentrations 
between 30 and 100 ng/mL (inclusive).  The US Institute of Medicine expert committee noted in 
their 2011 report [Ross 2011] that the general population is at risk of vitamin D deficiency at 
serum 25-hydroxyvitamin D concentrations <12 ng/mL and some individuals are potentially at 
risk for inadequacy at levels ranging from 12 to 20 ng/mL.  Multiple factors contribute to VDI in 
CKD including nutritional inadequacy, decreased sunlight exposure, proteinuric loss and 
decreased hepatic synthesis of 25-hydroxyvitamin D, and increased expression of fibroblast 
growth factor (FGF23) and CYP24A1, the cytochrome P450 enzyme that specifically catabolizes 
vitamin D and its metabolites [Helvig 2010, Sprague 2014].  VDI is associated with increased 
morbidity and mortality [Fernandez-Juarez 2013, Ravani 2009]. 
1.7 
Treatment of Secondary Hyperparathyroidism 
In current clinical practice, therapy with a vitamin D receptor activator (VDRA) is typically 
initiated when vitamin D supplementation is found ineffective in controlling PTH in patients 
with stage 3 or 4 CKD. Three VDRAs are available in the US for oral administration: calcitriol, 
paricalcitol and doxercalciferol.  Another oral VDRA, alfacalcidol, is widely available outside of 
the US.  Although VDRAs can control elevated PTH, they leave serum total 25-hydroxyvitamin 
D uncorrected (and potentially lower), depriving tissues of adequate substrate for local hormone 
production [de Boer 2013]. Bolus oral administration of VDRAs produce supraphysiological 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 21 of 75 
Confidential 
 
surges in blood vitamin D hormone levels, causing unwanted elevation of FGF23 and CYP24A1-
mediated vitamin D catabolism, both of which are implicated in the observed development of 
resistance to vitamin D therapy [de Boer 2013].  VDRAs also stimulate intestinal absorption of 
calcium and phosphorus, leading to elevation of serum calcium and phosphorus which increase 
the risk of vascular calcification, the primary cause of morbidity and mortality in CKD [Paloian 
2014].  Both the original K/DOQI and KDIGO Clinical Practice Guidelines (Guideline 8A and 
Chapter 4.2, respectively) recommend the use of VDRAs in CKD, but the recently updated 
KDIGO Clinical Practice Guideline for CKD-MBD [KDIGO 2017] recommends against the 
routine use of VDRAs in patients with stage 3 or 4 CKD due to the increased risk of 
hypercalcemia and hyperphosphatemia (Chapter 4.2) 
1.8 
The Unmet Medical Need 
Prior to FDA approval of CTAP101 Capsules, healthcare professionals were limited to two 
therapeutic options for SHPT in patients with stage 3-4 CKD:  vitamin D supplements and 
VDRAs (calcitriol and its 1α-hydroxylated analogs).  Nutritional vitamin D supplements are safe 
and inexpensive, but published RCTs have shown that they are ineffective for reducing elevated 
PTH and often delay the initiation of effective therapy [Agarwal 2016].  In contrast, VDRA’s are 
effective for controlling PTH, but increase the risk of hypercalcemia, hyperphosphatemia and 
adynamic bone disease, and associated vascular calcification [KDIGO 2017].  Calcimimetic 
therapies (cinacalcet and etalcalcetide) are approved only for use in dialysis-dependent stage 5 
CKD and cause hypocalcemia and hyperphosphatemia in patients with stage 3-4 CKD [Chonchol 
2009].  CTAP101 Capsules address a pressing need for a new, improved treatment for SHPT in 
patients with stage 3-4 CKD.  This product needs to be developed for pediatric patients. 
1.9 
Nonclinical Experience with Calcifediol 
Toxicity associated with calcifediol is consistent with that observed due to vitamin D overdose 
and is similar to that seen with calcitriol.  Generally, such toxicity is subsequent to 
hypercalcemia.  Hypercalcemia and increased calcium loading can cause calcium deposits in 
kidneys and vasculature, and can cause parathyroid atrophy and generalized tissue deposition of 
calcium.  Vitamin D-related toxicity is generally characterized by increases in both urine and 
serum calcium levels, mineralization of soft tissues (believed to develop subsequent to 
hypercalcemia) and increases in bone formation with a resulting reduction in bone marrow space. 
An early (pre-commercial) formulation of CTAP101 Capsules was administered to dogs for  
three months (CTAP101-TX-0100) and resulted in typical vitamin D-induced toxicities including 
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 1000 µg/day and were associated with 25-hydroxyvitamin D3 levels >450 ng/mL 
following one month of treatment. 
The current (commercially available) formulation of CTAP101 Capsules was administered daily 
to dogs for three months (CTAP101-TX-0102) at doses of up to 45 µg (~4.5 µg/kg/day).  No 
signs of toxicity were observed at the highest dose tested which was associated with 25-
hydroxyvitamin D3 levels >150 ng/mL.   
Calcifediol administration (orally through addition to the diet) to rats for six months (Calderol 
NDA 018312) has been reported to produce signs of toxicity at daily doses >40 µg/kg.  


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 22 of 75 
Confidential 
 
Toxicities included an increased incidence of nephrocalcinosis and uroliths.  Oral administration 
of calcifediol to dogs at ≤2 µg/kg/day resulted in no compound-related findings. 
Results from in vitro drug release and nonclinical PK studies in male Yucatan swine (CTAP101-
PK-0012) demonstrated that CTAP101 Capsules have an ER profile.  In swine, the 
bioavailability (BA) of calcifediol following the administration of CTAP101 Capsules was 
approximately 30% lower than that from an IR capsule preparation.  Further, a delay in the 
release of the active ingredient (time to maximum concentration or tmax >7 hours) was observed 
as compared to the IR formulation (tmax ~4 hours). 
1.10 
Metabolism of Calcifediol 
The metabolism of calcifediol has been extensively reviewed in the literature [Bikle 2014, 
DeLuca 2004]. Calcifediol is metabolized by the following three routes: conversion to calcitriol 
by 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1), located in the kidney, parathyroid gland, 
and other tissues; hepatic catabolism to water-soluble forms excreted in bile, a significant 
fraction of which have been identified as glucuronide conjugates; and, conversion to 24,25-
dihydroxyvitamin D3, which is biologically inactive,  and subsequently calcitroic acid by 
CYP24A1.  Excretion of calcifediol occurs primarily through the biliary fecal route [Ledger 
1986] which can be inhibited by uremic toxins, causing the terminal elimination half-life (t1/2) to 
increase as CKD progresses [Dreisbach 2008]. 
1.11 
Pharmacodynamics of CTAP101 Capsules 
CTAP101 Capsules gradually release calcifediol and thereby prevent the abrupt increases in 
serum 25-hydroxyvitamin D3 and calcitriol seen with IR formulations. The gradual rise in 
systemic calcifediol is characterized by a lower maximum concentration (Cmax) and a longer tmax 
compared to IR formulations.  
The single-dose pharmacodynamic (PD) profile of CTAP101 Capsules was compared in a 
randomized, open-label study to IR calcifediol in adult patients with SHPT, stage 3 or 4 CKD 
and VDI [Petkovich 2015]. Patients were randomly assigned to receive a single oral dose of 
450 mcg or 900 mcg of CTAP101 (5 or 10 capsules each containing 90 µg) or a single IR 
(intravenous) dose of 448 mcg calcifediol.  All patients were followed for six weeks postdose.  
Blood samples were collected predose and postdose for the analysis of serum 25-hydroxyvitamin 
D3, 1,25-dihydroxyvitamin D and 24,25-dihydroxyvitamin D3. Serum levels of 24,25-
dihydroxyvitamin D3 were used to monitor the degree of CYP24A1 upregulation, since human 
tissue biopsy analysis was impractical. A total of 28 subjects were enrolled in this study; nine 
received 450 mcg oral CTAP101, nine received 900 mcg oral CTAP101, and 10 received 448 
g intravenous calcifediol.  Administration of 900 µg of CTAP101 resulted in gradual increases 
in serum 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D without significantly elevating 
serum 24,25-dihydroxyvitamin D3, and produced meaningful, sustained PTH suppression.  
Conversely, administration of IR calcifediol produced rapidly rising and higher drug exposures 
due to a substantially faster delivery and higher bioavailability.  IR dosing also caused abrupt, 
large increases in serum 25-hydroxyvitamin D3, 1,25-dihydroxyvitamin D and 24,25-
dihydroxyvitamin D3, consistent with greater CYP24A1 activity, and negligible PTH 
suppression.   
A parallel nonclinical study [Petkovich 2015] showed that renal production of calcitriol is driven 
by the supply of calcifediol until CYP27B1 is suppressed.  The faster calcifediol is supplied, the 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 23 of 75 
Confidential 
 
more calcitriol is produced.  However, the abrupt increase in serum 25-hydroxyvitamin D after 
bolus IR (intravenous) dosing produced a corresponding surge in serum 1,25-dihydroxyvitamin 
D, which in turn triggered massive upregulation of CYP24A1 in both kidney and parathyroid 
gland.  Increased expression of CYP24A1 in CKD patients attenuated the further rise of serum 
1,25-dihydroxyvitamin D, boosted serum levels of 24,25-dihydroxyvitamin D3, and blocked 
clinically meaningful reductions in plasma PTH.  In contrast, CTAP101 Capsules gradually 
increased both serum 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D, avoided excessive 
increases in 24,25-dihydroxyvitamin D3 and yielded serum 1,25-dihydroxyvitamin D 
concentrations that were similar despite much lower calcifediol exposures.  CTAP101 produced 
much greater and more prolonged suppression of plasma PTH in CKD patients.  These data 
showed that the rate at which exogenous calcifediol is supplied to a patient with SHPT, stage 3 
or 4 CKD and VDI has a significant effect on treatment outcome, with CTAP101 being more 
effective in reducing elevated plasma PTH than IR calcifediol. 
1.12 
Pharmacokinetics of CTAP101 Capsules 
Bioequivalence between CTAP101 Capsules and any IR preparation of calcifediol was not 
expected since the rate of absorption of calcifediol from CTAP101 Capsules is more gradual.  
The BA of calcifediol from an IR preparation was reported in the literature to be between 
approximately 62 to 77% of the administered dose [Haddad 1976]. The BA of CTAP101 
Capsules is lower (approximately 25%), consistent with a lower Cmax.  
Healthy adult volunteers treated in the fasted state (CTAP101-CL-1011) with a single oral dose 
of 900 µg of CTAP101 exhibited serum 25-hydroxyvitamin D3 concentrations that rose 
gradually to a mean baseline-corrected Cmax of 35.9 ng/mL at a median tmax of 21.0 hours. Serum 
25-hydroxyvitamin D3 concentrations in similar subjects given a single dose of 448 µg of 
intravenous calcifediol increased to a mean baseline-corrected Cmax of 133.7 ng/mL at a median 
tmax of 0.17 hours. The post-dose PK profiles for these two treatment groups demonstrated 
single-order characteristics with a mean t1/2 of approximately 11 days and a mean clearance 
(CL/F) of 0.027 to 0.028 L/h. The mean apparent volume of distribution (Vd/F) was 8.8 L after 
CTAP101 and 9.7 L after intravenous calcifediol. 
In a food effect study (CTAP101-CL-1016), a single oral dose of 450 µg of CTAP101 was given 
to healthy adult volunteers in the fed and fasting states. The median tmax was 11 hours in the fed 
group compared to 32 hours in the fasted group. Mean Cmax and area under the curve (AUC) 
were 5- and 3.5-fold higher, respectively, in fed versus fasted subjects.  
Another study conducted in adults with SHPT, stage 3 or stage 4 CKD and VDI provided 
multiple-dose data on serum 25-hydroxyvitamin D3, total 25-hydroxyvitamin D and total 1,25-
dihydroxyvitamin D for population PK analysis [Sprague 2014]. In this study, subjects received 
daily bedtime doses of 30, 60 or 90 µg of CTAP101 or placebo for six weeks and were 
monitored for six weeks after the last dose. Mean serum 25-hydroxyvitamin D3 increased 
gradually in a dose-proportional manner. The tmax after the last dose was 38–43 hours with a 
tendency toward higher values with increasing dose. Mean Cmax, after adjustment for baseline 
values, was 28, 60 and 86 ng/mL for the 30, 60 and 90 µg groups, respectively.  Calcifediol 
exposures, calculated as mean background-adjusted AUC, were dose proportional and the mean 
t1/2 was between 25 and 50 days. Steady-state serum 25-hydroxyvitamin D3 levels were not 
reached after six weeks of dosing.  


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 24 of 75 
Confidential 
 
The effect of alcohol on the release of calcifediol from CTAP101 Capsules was evaluated in an 
in vitro dissolution study. Concentrations of ethanol up to 40% by volume had no effect on the 
release of calcifediol.  
1.13 
Clinical Efficacy and Safety 
In CTAP101-CL-2008, a double-blind, placebo-controlled, randomized repeat-dose study, daily 
administration of CTAP101 Capsules increased serum total 25-hydroxyvitamin D levels to ≥30 
ng/mL in nearly all subjects and decreased mean plasma intact PTH  (iPTH) from baseline and 
compared to placebo during six weeks of treatment.  The mean % decrease in iPTH from 
baseline was related to the administered dose: 20.2±20.8 (standard deviation [SD]), 32.0±22.3, 
37.9±15.9 for the 30, 60 and 90 µg groups, respectively. 
The efficacy was confirmed in the phase 3 program with nearly all CTAP101 Capsules subjects 
(97%), who completed the study without a deviation, achieving a normal serum total 25-
hydroxyvitamin D level and with 60% of subjects achieving a mean reduction in iPTH from 
baseline of at least 30%.  Fewer than 9% of placebo subjects achieved a 30% reduction in iPTH 
or achieved a normal 25-hydroxyvitamin D 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 
study drug. 
For all clinical studies, the AE profiles did not identify any events specific to CTAP101 
Capsules.  After both single and repeat-dose administration, CTAP101 Capsules was generally 
well-tolerated.  The overall TEAE profile in the phase 3 program was comparable between 
CTAP101 Capsules and placebo groups.  Subjects receiving CTAP101 Capsules had a greater 
mean (standard error [SE]) increase in serum calcium (P<0.001) than placebo patients (ie, 0.2 
[0.02] versus 0.1 [0.03] mg/dL); for serum phosphorus, subjects receiving CTAP101 Capsules 
had a greater mean (SE) increase (P<0.05) than placebo patients ([ie, 0.2 [(0.03]) versus 0.1 
[(0.04]) mg/dL)]. 
CTAP101 Capsules have not been previously studied in pediatric patients. 
This protocol may be amended in due course to include subjects having ages less than 8 years.  
 
 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 25 of 75 
Confidential 
 
2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
2.1.1 
Primary Objectives  
The primary objectives of this study are: 
1. To evaluate the efficacy of repeated dosing with CTAP101 ER Capsules versus placebo in 
reducing plasma iPTH by ≥30% from pre-treatment baseline;  
2. To investigate the safety and tolerability of repeated dosing with CTAP101 Capsules; and, 
3. To assess the pharmacokinetic (PK) profile of serum 25-hydroxyvitamin D3 after repeated 
doses of CTAP101 Capsules in pediatric subjects of ages 8 to <18 years with SHPT, stage 3 
or 4 CKD and VDI. 
2.1.2 
Secondary Objectives 
The secondary objectives of this study are: 
1. To evaluate the efficacy of repeated dosing with CTAP101 Capsules versus placebo in 
raising serum total 25-hydroxyvitamin D to ≥30 ng/mL;   
2. To determine the time courses of mean absolute changes from pre-treatment baseline in 
serum total 25-hydroxyvitamin D and plasma iPTH during administration of repeated doses 
of CTAP101 Capsules; 
3. To assess the PD effects of repeated doses of CTAP101 Capsules versus placebo on mean 
serum calcium (corrected for albumin), serum phosphorus and serum calcium-times-
phosphorus (CaxP) product, and the change in mean urine calcium:creatinine ratio; and, 
4. To evaluate the safety of CTAP101 Capsules versus placebo with regard to the incidence of 
hypercalcemia and hyperphosphatemia. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 26 of 75 
Confidential 
 
3 INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a phase 3, multi-center, randomized, double-blind, placebo-controlled study which will be 
conducted primarily or entirely within the US.  The study will involve approximately 108 
eligible subjects, balanced for gender and CKD stage, having ages of 8 to <18 years, SHPT, 
stage 3 or 4 CKD and VDI.   Approximately 72 subjects having ages of 12 to <18 years will be 
enrolled initially (Cohort 1) and, after prior approval from the US FDA, another 36 subjects 
having ages of 8 to <12 years will be enrolled (Cohort 2).  Subjects in both cohorts will be 
randomized in a 2:1 ratio into two treatment groups to receive a daily bedtime dosage of (a) 
CTAP101 Capsules, or (b) matching placebo for 26-weeks.  Subjects in Cohort 1 who are 
assigned to treatment with CTAP101 Capsules will start dosing at 30 mcg/day (1 CTAP101 
Capsule) and, at the end of 12-weeks of treatment, will undergo upward dose titration to 60 mcg 
per day (two CTAP101 Capsules) provided that (a) plasma iPTH has not decreased by at least 
30% from pretreatment baseline, (b) serum calcium (corrected for albumin) is <9.8 mg/dL, (c) 
serum phosphorus is ≤5.5 mg/dL, and (d) serum total 25-hydroxyvitamin D is ≤65 ng/mL.  The 
initial dosage in Cohort 2 will be determined based on an interim analysis of data obtained from 
Cohort 1, as described below.  The efficacy of CTAP101 Capsules (compared to placebo) in 
treating SHPT will be assessed from multiple plasma iPTH and serum 25-hydroxyvitamin D 
levels obtained in the efficacy assessment period (EAP), defined as the last 6 weeks of the 26-
week treatment period.   
An Interactive Response System (IRS) will provide study treatment group assignments (using a 
computer-generated randomization code provided by the IRS vendor) and dosing adjustments.  
An independent, unblinded Data Safety Monitoring Board (DSMB) will oversee the IRS and 
verify the appropriateness of all dosing adjustments, and monitor subject safety and the 
effectiveness of CTAP101 Capsules at regular intervals.  Members of the DSMB will also 
conduct periodic reviews of study conduct to verify that all required data are captured to a 
sufficiently high degree (>95%) and within specified time frames (usually within 5 days), and to 
promptly recommend appropriate corrective actions to address any noted deficiencies, in an 
effort to minimize missing data.   Specific responsibilities and activities of the DSMB will be 
defined in the charter ratified at the pre-study organizational meeting.  These responsibilities will 
include the completion of an interim analysis of the data obtained in Cohort 1 to justify a starting 
dose for Cohort 2, and an interim analysis of the data obtained from Cohort 2 to justify a starting 
dose for a separate phase 2 study in subjects having ages of 1 month to <8 years. 
Subjects receiving treatment prior to study enrollment with calcitriol or another 1α-hydroxylated 
vitamin D analog, or calcimimetics prior to study enrollment will forgo further dosing with these 
agents for the duration of the study and complete an 8-week washout period prior to baseline 
assessments.  Subjects receiving vitamin D supplementation at a rate above 1,700 IU/day or 
50,000 IU (1,250 mcg) per month prior to study enrollment must reduce the dose to ≤1,700 
IU/day for the duration of the study and undergo an 8-week washout period prior to baseline 
assessments if serum total 25-hydroxyvitamin D is ≥30 ng/mL.  The washout period is 
unnecessary if serum total 25-hydroxyvitamin D is <30 ng/mL.  Subjects will complete a 6-week 
follow-up (FU) period after completing the 26-week treatment period or after early termination 
(ET). 
 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 27 of 75 
Confidential 
 
Key parameters to be monitored at regular intervals during the study include: plasma iPTH, 
serum calcium (corrected for serum albumin), serum phosphorus, serum CaxP product, serum 
total 25-hydroxyvitamin D, serum 25-hydroxyvitamin D3, and urine calcium:creatinine ratio.  
Vital signs (VS) and adverse events (AEs) will be monitored at each study visit.  Other 
parameters to be monitored less frequently include brief physical examinations (PEs), clinical 
laboratory tests (hematology and clinical and urine chemistries) and patient-reported palatability 
and acceptability.  Twelve-lead electrocardiograms (ECGs) will be obtained at baseline and at 
the end of treatment or ET.  
 
  All subjects, study personnel and the sponsor 
will be blinded to the administered treatments and to plasma iPTH, serum total 25-
hydroxyvitamin D and serum 25-hydroxyvitamin D3 data until the last subject completes 26 
weeks of treatment.  Unblinded data will be provided to all study sites when the final clinical 
study report becomes available. 
Blood samples will be collected at weekly, biweekly or monthly intervals during the 10-week 
pre-treatment screening/baseline period, the 26-week treatment period and the 6-week post-
treatment FU period.  Sparse PK samples will be collected from all subjects on Day 83 at 0 (pre-
dose), 6, 12, 24 hours (Day 84 pre-dose) and 48 hours (Day 85 pre-dose).  Additional PK blood 
samples will be collected in both Cohort 1 and Cohort 2 in subsets of 10 subjects treated with 
CTAP101 Capsules and 5 subjects treated with placebo during the last 3 days of the 12th week of 
treatment (prior to dose titration).  The additional PK samples will be collected as follows:  Day 
83: -2, 2, 4 and 8 hours.  End of study PK blood samples will be collected in other subsets of 20 
subjects (20 subjects from each cohort) during the post-treatment FU period, 10 subjects on each 
ending daily dose level (30 or 60 mcg) of CTAP101 Capsules, in order to establish the t1/2 of 
serum 25-hydroxyvitamin D3 at each of these dose levels. 
All subjects, study personnel and the sponsor will be blinded to the administered treatments and 
to plasma iPTH, serum total 25-hydroxyvitamin D and serum 25-hydroxyvitamin D3 data until 
the last subject completes 26 weeks of treatment.  
An interim analysis of data obtained from the 15 subjects in Cohort 1 who provide intensive PK 
samples during the last three days of treatment week 12 will be undertaken by the DSMB to 
determine the appropriate starting dose for Cohort 2.  A second interim analysis of data obtained 
from 15 subjects in Cohort 2 who provide intensive PK samples during the last three days of 
treatment week 12 will be undertaken by the DSMB to determine the appropriate starting dose 
for a separate phase 2 study in subjects of ages 1 month to <8 years.   
 
 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 28 of 75 
Confidential 
 
A diagram of the study design for Cohort 1 (n=~72) is shown below: 
 
 
 
A diagram of the study design for Cohort 2 (n=~36) is shown below:  
 
  


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 29 of 75 
Confidential 
 
3.2 
Rationale for Study Design and Control Group 
EirGen is developing CTAP101 Capsules for the treatment of SHPT in pediatric patients with 
stages 3 or 4 CKD and VDI.  The active ingredient in CTAP101 Capsules is calcifediol, which is 
formulated as ER capsules for oral administration.    
The present study is designed to compare the efficacy of CTAP101 Capsules to matching 
placebo with regard to reducing mean plasma iPTH levels by at least 30% from pre-treatment 
baseline in pediatric patients with stage 3 or 4 CKD and VDI.  The study will also examine the 
safety and tolerability of CTAP101 Capsules compared to placebo.  This adequate and well-
controlled, randomized and double-blind study provides the best means to evaluate efficacy, 
safety and tolerability of CTAP101 Capsules because no therapy has yet been approved by the 
FDA to treat elevated iPTH levels associated with low serum total 25-hydroxyvitamin D levels 
in pediatric CKD patients.  In other studies conducted in adult subjects with stage 3 or 4 CKD 
and SHPT, administration of placebo therapy for 26-weeks has not been shown to result in 
untoward effects [Coyne 2006; Coburn 2004].  However, since iPTH values >900 pg/mL have 
been associated with increased risk of fracture in hemodialysis patients [Jadoul 2006], subjects 
will be terminated from this study for confirmed iPTH levels >900 pg/mL. 
The starting dose of 30 mcg per day is based on the results from two phase 3 studies (CTAP101-
CL-3001 and CTAP101-CL-3002) conducted in adults with SHPT, stage 3 or 4 CKD and VDI.  
Data from these studies demonstrated that steady-state serum 25-hydroxyvitamin D3 levels were 
reached after 12 weeks of treatment at daily doses of 30 or 60 mcg of CTAP101 Capsules.  
Accordingly, upward dose titration is not allowed in the present study until after 12 weeks, when 
subjects receiving the initial dose of CTAP101 Capsules have attained steady-state blood levels 
of serum total 25-hydroxyvitamin D.  A 26-week treatment period was selected for this study to 
ensure that steady-state will be attained in subjects who undergo upward dose titration at the 
beginning of treatment week 13. 
Previous PK analyses in adult CKD patients have determined that the t1/2 of serum 25-
hydroxyvitamin D3 is approximately 30 days (CTAP101-CL-2008).  Consequently, the post-
dosing FU period of 6-weeks should be sufficient for determining the t1/2 in pediatric patients.  
Study drug will be reduced or suspended for confirmed excessive elevations in serum calcium, 
phosphorus or serum total 25-hydroxyvitamin D or for confirmed over suppression of plasma 
iPTH. 
 
 
 
 
   
3.3 
Study Duration 
Each subject will participate in the study for up to approximately 42-weeks (2-weeks 
screening/baseline, 8-weeks washout, if required, 26-weeks of treatment with CTAP101 
Capsules, and 6-weeks of FU evaluation). 
Subjects who participate in Cohort 1 will not be eligible for participation in Cohort 2.  


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 30 of 75 
Confidential 
 
4 STUDY POPULATION SELECTION 
4.1 
Study Population 
The target population for this study is subjects having ages of 8 to <18 years who have been 
diagnosed with stage 3 or 4 CKD (as demonstrated by medical history and by an eGFR of ≥15 
and <60 mL/min/1.73m2 at screening) who do not require regular hemodialysis, and present with 
both VDI (serum total 25-hydroxyvitamin D <30 ng/mL) and SHPT (plasma iPTH >100 pg/mL 
for stage 3 CKD and >160 pg/mL for stage 4 CKD). 
4.2 
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled in this study: 
1. Cohort 1:  Be 12 to <18 years of age and have a body weight of ≥40 kg; Cohort 2: be 8 to 
<12 years of age and have a body weight of ≥20 kg. 
2. Be diagnosed with stage 3 to 4 CKD at least six months prior to the screening visit, and have 
an eGFR of ≥15 to <60 mL/min/1.73m2 at screening. 
3. 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, including: 
a. Serum albumin ≤ 3.0 g/dL; 
b. Serum transaminase (ALT or SGPT, AST or SGOT) > 2.5 times the upper limit of 
normal at screening; and, 
c. Urinary albumin excretion of >3000 mcg/mg creatinine. 
4. Exhibit during the initial or, if necessary, a screening visit after washout: 
a. Plasma iPTH >100 pg/mL (stage 3 CKD) or >160 pg/mL (stage 4 CKD) 
b. Serum calcium <9.8 mg/dL (corrected for albumin); 
c. Serum total 25-hydroxyvitamin D <30 ng/mL; and, 
d. Serum phosphorus >2.5 to ≤5.5 mg/dL (12 to <18 years)  or ≤6.0 mg/dL (ages 8 to <12 
years); 
5. If taking calcitriol or other 1α-hydroxylated vitamin D analogs, or cinacalcet, be willing to 
forgo treatment with these agents for the duration of the study and complete an 8-week 
washout period prior to commencing treatment in the study. 
6. If taking >1,000 mg/day of elemental calcium, discontinue or reduce calcium use and/or use 
non-calcium based therapies for the duration of the study. 
7. If receiving ≤1,700 IU/day nutritional vitamin D (ergocalciferol or cholecalciferol) therapy, 
must agree to remain on a stable dose during the study. 
8. If taking >1,700 IU/day of nutritional vitamin D, must discontinue or decrease the dose to 
≤1,700 IU/day, maintain that dose for the duration of the study, and complete an 8-week 
washout period prior to commencing treatment in the study provided that serum total 25-
hydroxyvitamin D is ≥30 ng/mL.  The washout period is not necessary if serum total 25-
hydroxyvitami D is <30 ng/mL. 
9. If taking any bone modifying treatment that could interfere with study endpoints, must 
discontinue use of such agent(s) for the duration of the study. 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 31 of 75 
Confidential 
 
10. Willing and able to comply with study instructions and commit to all clinic visits for the 
duration of the study. 
11. Female subjects of childbearing potential must be neither pregnant nor lactating and must 
have a negative urine pregnancy test at the first screening visit. 
12. All female subjects of childbearing potential and male subjects with female partners of 
childbearing potential must agree to use effective contraception (eg, implants, injectables, 
combined oral contraceptives, intrauterine device, sexual abstinence, vasectomy or 
vasectomized partner) for the duration of the study. 
13. Each subject or their legal representative must be able to read, understand and sign the 
informed consent form (ICF). 
4.3 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
1. History of or planned kidney transplant or parathyroidectomy. 
2. History (prior three months) of serum calcium ≥9.8 mg/dL   
3. Use of bisphosphonate therapy or other bone modifying treatment (eg, denosumab) within 
six months prior to enrollment. 
4. Known previous or concomitant serious illness or medical condition, such as malignancy, 
human immunodeficiency virus, significant gastrointestinal or hepatic disease or 
cardiovascular event or hepatitis, or physical condition that in the opinion of the investigator 
may worsen and/or interfere with participation in the study. 
5. History of neurological/psychiatric disorder, including psychotic disorder, or any reason 
which, in the opinion of the investigator makes adherence to a treatment or FU schedule 
unlikely. 
6. Known or suspected hypersensitivity to any of the constituents of either investigational 
product. 
7. Currently participating in, or has participated in, an interventional/investigational study 
within 30 days prior to study screening. 
 
 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 32 of 75 
Confidential 
 
5 STUDY TREATMENTS 
5.1 
Description of Treatments 
5.1.1 
CTAP101 Capsules Description 
Dosage form:  
 
 
Soft capsule  
Dose strength: 
30 mcg capsule  
Product description: 
Blue oval soft capsules containing white to off-white to slightly blue 
waxy material; 30 capsules per bottle 
Active component: 
Calcifediol, calcidiol, 25-hydroxyvitamin D3 
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) 
Storage conditions: 
15°C to 30°C (59°F to 86°F); protect from light and heat 
5.1.2 
Placebo Capsules Description 
Dosage form:  
 
 
Soft capsule  
Dose strength: 
0 mcg capsule  
Product description: 
Blue oval soft capsules containing white to off-white to slightly blue 
waxy material; 30 capsules per bottle 
Active component: 
None 
Non-active components: Paraffin wax, mineral oil, mono- and diglycerides, dehydrated alcohol, 
lauroyl polyoxylglycerides, butylated hydroxytoluene, hypromellose, 
modified starch, carrageenan, sodium phosphate dibasic, sorbitol and 
sorbitan solution, FD&C Blue #1, titanium dioxide, medium chain 
triglycerides (coconut oil) 
Storage conditions: 
15°C to 30°C (59°F to 86°F); protect from light and heat 
5.2 
Treatments Administered 
Study drug should NOT be administered to individuals known to be allergic to any component 
of the drug.  All subjects should be observed for allergic reaction following study drug 
administration.  All allergic reactions will be documented as AEs in the source documents and 
the electronic case report forms (eCRF). 
Study drug will be provided in white, round, wide-mouth, high-density polyethylene (HDPE) 
bottles with 28-mm white, polypropylene, child-resistant (push down and turn) caps with 
aluminum heat induction seal liners and contain 30 capsules per bottle.  Each bottle will contain 
either active drug or a matching placebo. 
Drug accountability will be performed throughout the treatment period (Section 5.12 Storage and 
Accountability).  All procedures being performed during the course of this clinical study are 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 33 of 75 
Confidential 
 
listed sequentially by visit in Section 7  Study Activities and may be found as a table in 
Appendix 1 Schedule of Events. 
5.3 
Selection and Timing of Dose for Each Subject 
Subjects in Cohort 1 will receive two capsules (CTAP101 Capsules and/or matching placebo 
capsules) every day at bedtime to achieve the targeted initial daily dose of 30 mcg of calcifediol 
(one CTAP101 Capsule plus one placebo capsule) or 0 mcg of calcifediol (two placebo 
capsules).  Any food intake within 60 minutes of medication administration will also be 
recorded.  At the end of 12 weeks of treatment, subjects assigned to active treatment will 
undergo upward dose titration to 60 mcg per day (two CTAP101 Capsules) provided that (a) 
plasma iPTH has not decreased by at least 30% from pretreatment baseline, (b) corrected serum 
calcium is <9.8 mg/dL, (c) serum phosphorus is ≤5.5 mg/dL, and (d) serum total 25-
hydroxyvitamin D is ≤65 ng/mL.  Subjects in Cohort 2 will receive a starting daily bedtime dose 
which will be determined on the basis of the interim analysis of data obtained in Cohort 1, and 
will undergo upward dose titration at the end of 12 weeks of treatment to a new daily dose that is 
two times higher than the starting dose, provided that (a) plasma iPTH has not decreased by at 
least 30% from pretreatment baseline, (b) corrected serum calcium is <9.8 mg/dL, (c) serum 
phosphorus is ≤6.0 mg/dL and (d) serum total 25-hydroxyvitamin D is ≤65 ng/mL.   
In order to maintain blinding, subjects will receive periodic supplies of study drug in bottles of 
identical appearance, some labeled “Bottle 1” and some labeled “Bottle 2,” along with the same 
dosing instructions regardless of randomization group directing the subject to take one capsule 
from one bottle labeled “Bottle 1” and one bottle labeled “Bottle 2” every day at bedtime.  
An unblinded medical monitor who will be part of the independent, unblinded DSMB will 
oversee study drug assignments and dose adjustments (see below) by IRS. 
5.4 
Dose Reduction Criteria 
Subjects will reduce the dose through the IRS by one capsule per week, as necessary, and no 
more frequently than at biweekly intervals, in the event that any one of the following four criteria 
are met:  : 
1. 
Two consecutive visits with plasma iPTH <35 pg/mL (for subjects with stage 3 CKD) or 
<70 pg/mL (for subjects with stage 4 CKD),  
2. 
Two consecutive visits with serum calcium (corrected) >10.3 mg/dL,  
3. 
Two consecutive visits with serum total 25-hydroxyvitamin D >100 ng/mL, or  
4. 
Two consecutive visits with serum phosphorus >5.5 mg/dL (ages 12 to <18 years), or >6.0 
mg/dL (ages 8 to <12 years)  provided that the investigator has deemed the elevated serum 
phosphorus to be related to study drug administration and has taken appropriate and 
persistent actions to control serum phosphorus by initiating or adjusting any phosphate 
binder therapy. 
Dose reductions will be accomplished by consistently omitting doses on a specific day of the 
week, as follows:   
• 
First dose reduction:  Dosing will be omitted on all M.  
• 
Second dose reduction: Dosing will be omitted on all M and W 
• 
Third dose reduction:  Dosing will be omitted on all M, W and F 




Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 35 of 75 
Confidential 
 
In Cohort 1 (ages 12 to <18 years), approximately 72 subjects, balanced for gender and CKD 
stage, will be randomized in a 2:1 ratio to active or placebo treatment, respectively.  Ten (10) 
subjects will be randomly selected from the active group and five (5) subjects will be randomly 
selected from the placebo group for intensive PK evaluation during the last 3 days of the 12th 
week of treatment (prior to dose escalation).  Twenty other subjects will be randomly selected for 
end of study PK evaluations from the active group, ten of which will be receiving an end of 
study dose of 30 mcg/day and the other ten will receiving an end of study dose of 60 mcg/day. 
In Cohort 2 (ages 8 to <12 years), approximately 36 subjects, balanced for gender and CKD 
stage, will be randomized in a 2:1 ratio to active or placebo treatment, respectively.  Ten (10) 
subjects will be randomly selected from the active group and five (5) subjects will be randomly 
selected from the placebo group for intensive PK evaluation during the last 3 days of the 12th 
week of treatment (prior to dose escalation).  End of study PK evaluations will be made after 26 
weeks of treatment.  Twenty other subjects will be randomly selected for end of study PK 
evaluations from the active group, ten of which will be receiving an end of study dose of 30 
mcg/day and the other ten will receiving an end of study dose of 60 mcg/day. 
For both cohorts, an IRS will provide study treatment group assignments using the computer-
generated randomization code.   
5.7 
Blinding 
An IRS will provide study treatment group assignments (using a computer-generated 
randomization code provided by the IRS vendor) and dosing adjustments.  An independent, 
unblinded DSMB will oversee the IRS and verify the appropriateness of all dosing adjustments, 
and monitor subject safety and the effectiveness of CTAP101 Capsules at regular intervals.  
Members of the DSMB will also conduct periodic reviews of study conduct to verify that all 
required data are captured to a sufficiently high degree (>95%) and within specified time frames 
(usually within 5 days), and to promptly recommend appropriate corrective actions to address 
any noted deficiencies, in an effort to minimize missing data.   Specific responsibilities and 
activities of the DSMB will be defined in the charter ratified at the pre-study organizational 
meeting.  These responsibilities will include the completion of an interim analysis of the 
repeated-dose PK data obtained during treatment week 12 in Cohort 1 to justify a starting dose 
for Cohort 2. 
All subjects, site research staff and sponsor will be blinded as to whether a given subject is in the 
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, SUSAR).  When the primary 
investigator determines that knowledge of treatment group assignment is required for medical 
management of an individual subject, the sponsor will be contacted immediately.  The blind for 
the subject will be broken using the IRS system. 
Further, all subjects, site research staff and sponsor will be blinded to the administered 
treatments and plasma iPTH, serum total 25-hydroxyvitamin D, and serum 25-hydroxyvitamin 
D3  laboratory data until the last subject completes 26 weeks of treatment.  Unblinded data will 
be provided to all study sites when the final clinical study report becomes available.   


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 36 of 75 
Confidential 
 
5.8 
Prior and Concomitant Therapy 
Subjects receiving ergocalciferol or cholecalciferol must be taking ≤1,700 IU/day and must 
remain on that same dose during the study.   
Subjects receiving prior therapy with pharmacological doses (>1,700 IU/day) of ergocalciferol or 
cholecalciferol must be willing to discontinue or reduce the dose to ≤1,700 IU/day and agree to 
remain on a stable dose during the study.  
Subjects receiving other vitamin D analogs and/or bone metabolism therapy that could interfere 
with study endpoints must be willing and able to discontinue such therapy for the duration of the 
study.  This includes doses of vitamin D analogs (eg, Rocaltrol®, Zemplar®, Hectorol®, 
calcitriol), calcimimetics (Sensipar®, Pasabiv®), teriparatide (Forteo®), calcitonin, 
bisphosphonates, denosumab (Prolia®, Xgeva®) and other drugs that may affect calcium 
metabolism.   
All concomitant medication usage from the 28 days prior to visit 1 until completion of the study 
will be recorded. 
5.8.1 
Phosphate Binder and Elemental Calcium Therapy 
Use of calcium-based phosphate binder or antacid therapy such as calcium carbonate or calcium 
acetate (PhosLo®), are allowed up to 1000 mg/day of elemental calcium.  Calcium-based 
phosphate binder or antacid therapy in excess of 1000 mg/day of elemental calcium should be 
discontinued or reduced for the duration of the study.  Non-calcium based phosphate binder 
therapy such as sevelamer HCL (Renagel®) or lanthanum carbonate (Fosrenol®), and non-
calcium based antacids can be used at the discretion of the investigator during the treatment and 
FU periods.  Phosphate binder and calcium therapy should remain constant throughout the study.  
Any changes should be captured in the eCRF on the Phosphate Binder/Calcium Therapy page. 
5.9 
Restrictions 
5.9.1 
Dietary Restrictions  
There are no study specific dietary restrictions.  Subjects should follow their dietary plan if one 
has been prescribed.  Any changes in prescribed dietary phosphorus or calcium therapy during 
the study should be captured in the eCRF. 
5.9.2 
Subject Activity Restrictions 
Subjects should maintain their usual pattern of sun exposures (including use of tanning beds) and 
activities. 
5.10 
Treatment Compliance 
During certain study visits, the study coordinator or designee will perform drug accountability 
and dosing compliance calculations (number of capsules that should have been taken versus 
actual number taken as evidenced by number of returned capsules).  Dosing compliance at less 
than 80% should be reported as a protocol deviation. 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 37 of 75 
Confidential 
 
5.11 
Packaging and Labeling 
Study drug will be provided in white, round, wide-mouth, HDPE bottles with 28-mm white, 
polypropylene, child-resistant (push down and turn) caps with aluminum heat induction seal 
liners and contain 30 capsules per bottle.  Each bottle will contain either active drug or a 
matching placebo. 
Study drug labels will include protocol number, name and address of the sponsor, investigational 
statement, storage conditions and instructions for use.  Bottles will be assigned numbers that are 
linked to the randomization schedule through IRS to provide each subject with the appropriate 
dose per the schedule and the instructions of the IRS.  
Do NOT dispense the bottle of capsules if the seal of the primary package appears compromised. 
The subject will be instructed as follows: 
NOT to take the drug if the product appears discolored or damaged upon visual inspection and to 
NOTIFY the site immediately of the condition of the study drug and the need to obtain 
replacement. 
5.12 
Storage and Accountability 
CTAP101 Capsules will be shipped to sites following standardized shipment and temperature 
monitoring procedures. 
While at the study site, CTAP101 Capsules will be stored at room temperature, 15-30°C (59-
86°F) in the supplied packaging, with access granted to authorized personnel only. 
All sites must ensure that study drug has been kept under required conditions prior to dispensing.  
A temperature log recording the daily storage temperatures will be maintained at each site for 
study drug.  Accountability for study drug, 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 for 
study drug throughout the course of the study.  Specifically, the investigator or assigned designee 
will confirm that all study drug supplies are received intact and in the correct amounts per the 
shipping forms.  This will be documented by signing and dating the shipping forms and 
providing a copy to the sponsor or designee.  A study drug accountability and dispensing log will 
record the study drug disposition, including dates, quantity of drug received, to whom dispensed 
(participant-by-participant accounting), and accounts of any drug accidentally destroyed.  The 
site's running inventory of study drug supplies will be verified routinely throughout the course of 
the study.  All opened and unopened containers of CTAP101 Capsules bottles are to be retained 
at the site until the sponsor or designee has performed a complete verification of the 
dispensation, following which study drug will be returned to the sponsor or designee. 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 38 of 75 
Confidential 
 
5.13 
Investigational Product Retention at Study Site 
At the conclusion of the study, a final inventory will be performed by the investigator (or 
designee) and verified by the study monitor.  Any discrepancies identified will be indicated, with 
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 returns must be maintained by the investigator. 
 
 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 39 of 75 
Confidential 
 
6 STUDY PROCEDURES 
6.1 
Informed Consent 
A signed informed consent will be obtained from the subject’s parent or legally appointed 
guardian prior to any study related procedures.  The subject or their legally acceptable 
representative 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 legally acceptable representative will 
receive a copy of the signed and dated consent form and any written information provided to the 
study subjects.  If any material change occurs that affects the conduct of the study, the subject 
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, answer all questions regarding this study, and emphasize that missing data and 
premature termination of study participation will diminish the scientific value of the data 
obtained, prior to obtaining informed consent. 
The process for obtaining subject informed consent will be in accordance with all applicable 
regulatory requirements.  The subject or legally acceptable representative 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 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 
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 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 (IRB) 
and use of the amended form (including for ongoing subjects). 
6.2 
Medical History 
A detailed medical history will be recorded at visit 1. The PE which is outlined in the following 
Table 1 Evaluations will be performed by a licensed physician or by another suitably-qualified 
person where permitted by local regulations.  
 
 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 40 of 75 
Confidential 
 
6.3 
Physical Examination, Vital Signs, Body Mass Index, Body Weight and Height, 12-
Lead Electrocardiogram, and Patient-Reported Palatability and Acceptability 
Assessments 
Table 1. Evaluations 
Physical Examination (PE): 
• Organized by body system (excluding a urogenital examination) at 
visits 1, 3 and 28/ET 
Vital Signs (VS) Measurements: 
• Scheduled pulse, respirations and blood pressure will be measured 
prior to any scheduled blood draws and after the subject has been 
sitting for at least two minutes 
• Body temperature (oral) in degrees Celsius 
• VS are measured at all visits 
Body Weight and Height: 
• Height will be recorded to the nearest 1 cm at visits 1, 3 and 28/ET. 
• Body weight will be recorded to the nearest 0.1 kg at  visits 1, 3 and 
28/ET 
Body Mass Index (BMI): 
• Defined as the subject’s weight in kilograms divided by the square 
of the subject’s height in meters (kg/m2). This is a derived variable 
and recorded at PE visits 1, 3 and 28/ET. 
eGFR 
• This is a derived variable based in the Modification of Diet in Renal 
Disease equation. Visit 1 creatinine value to be used for eGFR 
calculation. 
12-Lead Electrocardiogram 
(ECG):   
• Each 12-lead ECG will be started after the subject has been in the 
supine position for at least five minutes 
• The original ECG tracings, with global interpretation and signature 
of qualified medical personnel will be retained in the subject’s 
records at the study site. Global interpretation categories are: 
Normal ECG, Abnormal ECG – not clinically significant, 
Abnormal ECG – clinically significant 
• 12-lead ECG will be performed once during visits 3 and 28/ET 
• For consistency of ECG data, every effort will be made to utilize 
the same facility and reader for all ECGs at each site 
Patient-Reported Palatability and 
Acceptability Assessments 
• 
Patient-reported palatability and acceptability assessments will be 
performed at Visits 13 and 22 in accordance with the Schedule of 
Events (see APPENDIX 1).  Age-appropriate assessments will be 
used based on already-established and standardized versions of the 
combined hedonic facial and 10 cm visual analog scale. Site staff 
will be trained to give standardized, age-appropriate, brief and 
clear instructions to the subjects or, where appropriate, to the 
parents/guardians. 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 41 of 75 
Confidential 
 
6.4 
Clinical Laboratory Tests 
6.4.1 
Laboratory Parameters 
Blood will be drawn and analyzed as specified in Table 2 List of Laboratory Tests.  
 
 
.  All serum calcium values will be adjusted based on serum albumin level 
of <4.0 g/dL.  Urine samples will be collected and analyzed as specified in Table 2 List of 
Laboratory Tests. 
Please refer to Appendix 1 Schedule of Events for specific visits when each laboratory parameter 
will be determined. 
All clinically significant laboratory values will be recorded as AEs and the investigator will FU 
according to Section 6.6.7 Clinical Significance. 
Subjects will be in a seated position during blood collection.   
 
 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 42 of 75 
Confidential 
 
Table 2. List of Laboratory Tests 
 
Hematology: 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin concentration 
Mean corpuscular volume 
Platelet count 
Red blood cell count  
White blood cell count  
Urine Chemistry and Urinalysis:  
Albumin 
Albumin/Creatinine ratio 
Appearance 
Bilirubin 
Calcium 
Calcium/Creatinine ratio 
Color 
Creatinine 
Glucose 
Ketones 
Nitrite  
Occult blood 
pH 
Phosphorus 
Protein 
Specific gravity 
Urobilinogen 
Urine pregnancy test (only for females of childbearing 
potential) 
 
 
 
 
 
 
 
 
Serum Full Chemistry: 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase (ALT) / Serum glutamic-
pyruvic transaminase  (SGPT) 
Aspartate aminotransferase (AST) / Serum glutamic-
oxaloacetic transaminase  (SGOT) 
Blood urea nitrogen 
Calcium (corrected for serum albumin) 
Carbon dioxide  
Chloride 
Creatinine*  
Gamma-glutamyl transferase  
Globulin 
Glucose 
Lactate dehydrogenase 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
Total protein 
Triglycerides 
Uric acid 
 
Serum Partial Chemistry:  
Calcium (corrected for serum albumin) 
Phosphorus 
Albumin 
 
 
Plasma iPTH (blinded) 
Serum total 25-hydroxyvitamin D (blinded) 
Serum 25-hydroxyvitamin D3 (blinded) 
*Note: Visit 1 creatinine value to be used for eGFR calculation. 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 43 of 75 
Confidential 
 
6.4.2 
Sample Collection, Storage, and Shipping 
Redraws for missing samples or samples resulting in values outside entrance criteria ranges 
should be performed during screening only.  Any other missed samples at any other visits should 
not be redrawn and noted as not done in source documentation along with a reason.  Laboratory 
samples not done should be noted as a protocol deviation. 
A central laboratory experienced in clinical research studies will be utilized.  Collection, 
processing, storage and shipping procedures will be performed in accordance with the 
instructions provided by the central laboratory.  Detailed instructions will be provided separately 
from this protocol in the laboratory manual.  Blood samples will be collected and analyzed for 
clinical laboratory 
 tests.  Approximately 357 mL of blood will be 
collected over the entire duration of the study from each of the 15 subjects who provide intensive 
PK samples during the last three days of treatment week 12.  Approximately 373 mL of blood 
will be collected over the entire duration of the study from each of the 20 subjects who provide 
PK samples during the post-treatment FU period.  Approximately 323 mL of blood will be 
collected over the entire duration of the study from all other subjects. 
Additional blood draws may be needed for unscheduled or repeat visits.  Given the nature of this 
pediatric patient population, care should be taken with the amount of blood drawn at any one 
study visit or cumulative over a four week period.  
 
 
 
Samples are to be shipped to the central laboratory for each subject as visits are completed. The 
investigator will provide a limited access, and a -20°C or lower freezer space for respective 
serum and plasma aliquots. 
6.4.3 
Clinical Supplies 
The sponsor or assigned designee will supply vacutainers, blood collection tubes, labels, boxes 
with labels for storage of serum and plasma samples and all necessary shipping 
supplies/containers.  The investigator 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 
As described in Section 5.6 Method of Assigning Subjects to Treatment Groups, the IRS will 
assign the study drug bottle(s) to the subject at the time of randomization (Visit 3) and at Visit 
13.  The study coordinator (or designated site personnel) will obtain the study drug assignment 
from the IRS for each subject and dispense the appropriate drug.  
Subjects and their appointed guardians are to be instructed NOT to take study drug if it appears 
discolored or damaged. Subjects are to be advised that the study drug is to be stored at room 
temperature, 15-30°C (59-86°F).  Protect from light and heat. 
Subjects will receive a sufficient number of bottles of study drug at visits 3 and 13.  Some bottles 
will contain CTAP101 Capsules and others may contain a matching placebo, dependent on 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 44 of 75 
Confidential 
 
individual subject dose assignment.  Throughout the treatment period the number of capsules 
remaining in the bottle will be counted by the investigator or designee and recorded on the drug 
accountability log at Visits 13 and 22.  The bottles will then be returned to the subject.  Prior to 
dispensing new bottle(s) of study drug, the coordinator will collect the previous bottle(s) of study 
drug.  See Section 5.3 Selection and Timing of Dose for Each Subject for further details of drug 
dispensation. 
6.6 
Adverse Events Assessments 
6.6.1 
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) or disease temporally associated with the 
use of a medicinal product whether or not considered related to the medicinal product. 
6.6.2 
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 eCRF including the date of onset, 
description, severity, duration, relationship of the AE to study drug(s), 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. 
6.6.3 
AE Collection Period 
All AEs that occur after the ICF has been signed must be reported in detail in the AE section of 
the eCRFs, 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.  
Information to be collected includes type of event, date of onset, date of resolution, investigator-
specified assessment of severity and relationship to study drugs, seriousness, 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, 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 (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs.  If a diagnosis is unknown, sign(s) or symptom(s) should be recorded as an 
AE(s).  Changes in laboratory values or ECG parameters are only considered to be AEs if they 
are judged to be clinically significant (ie, if some action or intervention is required or if the 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 45 of 75 
Confidential 
 
investigator judges the change to be beyond the range of normal physiological fluctuation).  If 
abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased liver enzymes in hepatitis), 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 preexisting 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 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) to the medical 
monitor.  Pregnancies will be considered ‘events of special interest’ and will not be captured as 
serious adverse events (SAEs).  The Pregnancy Reporting form will be utilized to obtain baseline 
and FU information.  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 the study. 
The Medical Dictionary for Regulatory Activities (MedDRA), Version 20.0 or later, will be used 
to code all AEs. 
6.6.4 
Severity 
The intensity of the AE will be rated by the investigator as mild, moderate or severe using the 
following criteria: 
• Mild: Symptoms causing no or minimal interference with usual social and functional 
activities 
• Moderate: Symptoms causing greater than minimal interference with usual social and 
functional activities 
• Severe: Symptoms causing inability to perform usual social and functional activities 
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.   
6.6.5 
Relationship 
The investigator’s assessment of an AE's relationship to 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 following classifications and criteria: 
Definite – The AE: 
• Follows a reasonable temporal sequence from drug administration; 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 46 of 75 
Confidential 
 
• Abates upon discontinuation of the drug (dechallenge); and/or 
• Is confirmed by reappearance of the reaction on repeat exposure (rechallenge). 
Probable – The AE: 
• Follows a reasonable temporal sequence from drug administration; 
• Abates upon discontinuation of the drug; and/or 
• Cannot be reasonably explained by the known characteristics of the subject’s clinical state. 
Possible – The AE: 
• Follows a reasonable temporal sequence from drug administration; 
• Could have been produced by the subject’s clinical state or by other modes of therapy 
administered to the subject. 
Unrelated – The AE: 
• Is definitely produced by the subject’s clinical state or by other modes of therapy administered 
to the subject. 
6.6.6 
Expectedness 
AEs 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, Investigator Brochure (IB), product insert, or label.  Categories are: 
• Unexpected - nature or severity of the event is not consistent with information about the 
condition under study or intervention in the protocol, consent form, product brochure, or IB. 
• Expected - event is known to be associated with the intervention or condition under study. 
6.6.7 
Clinical Significance 
Changes in laboratory values, ECG parameters or other diagnostic procedures 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 changes or abnormalities will be assessed by the investigator, indicating whether the value 
is clinically significant or not clinically significant directly on the laboratory report or ECG 
tracing. 
6.6.8 
Serious Adverse Events 
6.6.8.1 
Definition 
An SAE is defined by the investigator or sponsor as any AE occurring during an investigational 
study that results in any of the following outcomes: 
• Death 
• Life-threatening AE 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 47 of 75 
Confidential 
 
• Hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability (substantial disruption of the ability to conduct normal 
life functions)/incapacity 
• A congenital anomaly/birth defect 
• Important medical event requiring medical or surgical intervention 
The report of an SAE may require information about the study procedures or about the study 
drug that will result in the need to unblind the treatment.  Codes linking randomization number 
for each subject to actual treatment will be secured in a sealed, opaque envelope and maintained 
in a locked drawer in the research center and/or the research pharmacy. 
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. 
Important medical events that may not be life threatening, result in death, or 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.  Hospitalizations to conduct diagnostic procedures will be captured in 
the eCRF on the PROCEDURES AND DIAGNOSTICS page. 
6.6.8.2 
Reporting Serious Adverse Events 
Any AE considered serious (see Section 6.6.8 Serious Adverse Events) by the investigator that 
meets the previously mentioned criteria must be reported to the following numbers within 24 
hours from the time when site personnel first learn about the event.  
SAE Fax line: 
 
SAE email:
  
A written report will follow as soon as possible and should consist of the SAE report and other 
documents, including the following pages from the eCRF: the demographics page(s), the medical 
history page(s), the AE page(s), and the concomitant medications page(s).  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 add this information to the initial SAE section of the eCRFs and provide any 
additional written documentation to the above number immediately or within 24 hours of receipt. 
The sponsor or designee will notify the appropriate regulatory agencies of any serious and 
unexpected SAEs associated with the use of the study drugs according to regulations.  Copies of 
any reports to regulatory agencies regarding serious and unexpected suspected adverse reactions 
(SUSAR) will be provided to the investigators by the sponsor or designee for review and 
submission to the IRB. A report received for a serious, unexpected, suspected adverse reactions 
(SUSAR) will be unblinded for regulatory reporting. 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 48 of 75 
Confidential 
 
The investigator is responsible for informing his or her IRB of any SAEs at that site.  Copies of 
SAE correspondence with the IRB, ethics committees, regulatory authorities, and other 
physicians must be submitted to the sponsor’s Clinical Services Department.  
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.  
Withdrawal from the study and all therapeutic measures will be at the discretion of the 
investigator at the site. 
All SAEs will be followed until resolution or should the event become indistinguishable from the 
chronic disease condition, the subject will be followed for a minimum of 30 days after study 
drug administration and subsequently all events will be closed.  Pregnancies will be followed 
until six weeks following delivery to determine the outcome. 
6.6.9 
Treatment-Emergent Adverse Events 
A TEAE is defined as any adverse event with onset or worsening reported by a subject from the 
time that the first dose of study drug is taken until 30 days following discontinuation of study 
drug administration. 
6.7 
Concomitant Medication Assessments 
The study coordinator or designee will record concomitant medication history in the source 
document and eCRF.  Changes in phosphate binder and calcium supplement therapy will be 
collected in the eCRFs. 
6.8 
Removal of Subjects from the Study or Study Drug 
The investigator may withdraw a subject from the study for any of the following reasons: 
• A major protocol deviation occurs; 
• A serious or intolerable AE occurs; 
• A clinically significant change in a laboratory parameter occurs; 
• The sponsor or investigator terminates the study; 
• The subject requires more than four dose reductions; 
• The subject requests to be discontinued from the study;  
• If the investigator believes it is no longer in the best interests of the subject to continue 
• A subject experiences more than a 100% increase in plasma iPTH after 26 weeks of 
treatment from pre-treatment baseline; or 
• A subject exhibits plasma iPTH above 600 pg/mL on consecutive visits (if at least 2 weeks 
apart) after 12-weeks of treatment. 
6.9 
Appropriateness of Measurements 
Reduction in plasma iPTH is an accepted marker for improvement of SHPT in the CKD 
population.  The efficacy of CTAP101 Capsules will be determined by comparing the effect of 
CTAP101 Capsules to that observed with placebo to lower elevated iPTH levels and to 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 49 of 75 
Confidential 
 
normalize vitamin D levels.  Pre- and postdose averages will be used to minimize the effect of 
any intrasubject and interassay variability.  The post-dose average will be obtained over the last 
six-weeks of treatment (visits 19-22) to allow subjects to achieve steady state serum 25-
hydroxyvitamin D levels. 
AEs, serum calcium and phosphorus have been used to assess safety of vitamin D compounds 
and will be monitored in this study.  The safety and tolerability of CTAP101 Capsules will be 
determined by comparing each active group to placebo. 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 50 of 75 
Confidential 
 
7 STUDY ACTIVITIES 
7.1 
Screening Period 
7.1.1 
Visit 1 (Day -70 to -63) 
• AE Assessment 
• A signed ICF will be obtained from the subject prior to any study related procedures 
• Review of inclusion/exclusion criteria, including eGFR measurement 
• Medical history and demographics:  date of birth, gender, race, ethnicity, cause and date of 
CKD.  A complete medical history, including alcohol, tobacco and nicotine-containing 
product use histories and method of contraception, as appropriate, will be recorded 
• Medication History: All prescription and over the counter medication usage for the 28 days 
prior to visit 1 will be recorded 
• General PE (including weight, height and BMI)  
• VS measurements  
• Urine chemistry 
• Blood samples to be drawn prior to dosing and washout (if required): 
◦ Chemistry (full panel) and hematology 
◦ Plasma iPTH 
◦ Serum total 25-hydroxyvitamin D 
• Urine pregnancy test (only for females of childbearing potential) 
• Washout assessment: Subjects who are taking any vitamin D and/or bone metabolism 
therapy, including vitamin D supplements (>1,700 IU/day of ergocalciferol or 
cholecalciferol), will discontinue or reduce therapy to ≤1700 IU/day for the duration of the 
study.  Subjects taking more than 1000 mg/day of elemental calcium will discontinue or 
reduce therapy for the duration of the study. 
- 
If washout is not required proceed to visit 3. 
- 
If washout is required, proceed to visit 2 after completion of at least 8 weeks of washout. 
If the screening values do not meet study entry criteria after visit 1, subject may receive 
supportive care per the investigator’s discretion and be retested once.  If values do not fall within 
study entry criteria on retest, the subject will be considered a screen failure and be withdrawn 
from the study.  Only the screening test(s) that did not meet entry criteria at visit 1 are required to 
be re-drawn and meet entry criteria at the time of the visit 1 retest. 
7.1.2 
Visit 2 (Day -7 to -1) 
This visit is only applicable for subjects requiring washout.  Subjects requiring washout will 
need to undergo visit 2 to confirm study entry laboratory values meet or continue to meet study 
entrance criteria.  
• Review of inclusion/exclusion criteria 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 51 of 75 
Confidential 
 
• Concomitant medications 
• AE assessment 
• VS measurements 
• Blood samples will be drawn for the following analyses: 
◦ Chemistry (full panel) and hematology 
◦ Plasma iPTH 
◦ Serum total 25-hydroxyvitamin D 
7.1.3 
Visit 3 (Day 1) 
Subjects will need to confirm study entry laboratory values continue to meet study entrance 
criteria for serum calcium, phosphorus, total 25-hydroxyvitamin D, and plasma iPTH.  This visit 
should occur after screening values from visit 1 (visit 2 for subjects requiring washout) meet 
study entry criteria. 
• Review of inclusion/exclusion criteria 
• Concomitant medications 
• AE assessment 
• General PE (including weight, height and BMI) 
• VS measurements  
• 12-lead ECG  
• Urine chemistry and urinalysis 
• Blood samples will be drawn for the following: 
◦ Chemistry (partial panel) 
◦ Plasma iPTH 
◦ Serum total 25-hydroxyvitamin D 
◦ Serum 25-hydroxyvitamin D3, 
 
◦
 
• Urine pregnancy (only for females of childbearing potential) 
• Randomization of subject 
• Dispense assigned bottles of study drug with dosing instructions 
7.2 
Treatment Period (Weeks 1-26) 
7.2.1 
Visits 4-10 (Days 8-71) 
• May occur ±3 days of scheduled day 
• AE assessment 
• Concomitant medications 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 52 of 75 
Confidential 
 
• VS measurements 
• Blood samples drawn for: 
◦ Chemistry (partial panel)  
◦ Plasma iPTH 
◦ Serum total 25-hydroxyvitamin D 
7.2.2 
Visits 11-12 (Days 83-84) 
• Must occur on the scheduled days 
• AE Assessment 
• Concomitant medications 
• VS measurements 
• Blood samples drawn for all subjects at 0 (pre-dose), 6 and 12 hours and additionally, only 
for subjects assigned to intensive PK evaluation, at -2, 2, 4 and 8 hours after dosing on Day 
83 for: 
◦ Chemistry (partial panel)  
◦ Serum 25-hydroxyvitamin D3, 
 
• Blood samples drawn at 24 hours ±4 hours  before dosing on Day 84 for: 
◦ Chemistry (partial panel)  
◦ Serum 25-hydroxyvitamin D3, 
 
7.2.3 
Visit 13 (Day 85): 
• Must occur on the scheduled day 
• Urine pregnancy (for females of childbearing potential) 
• AE assessment 
• Concomitant medications 
• Urine pregnancy (only for females of childbearing potential) 
• VS measurement 
• Urine chemistry and urinalysis 
• Blood samples drawn at 48 hours ±4 hours before dosing for: 
◦ Chemistry (full panel) and hematology 
◦ Plasma iPTH 
◦ Serum total 25-hydroxyvitamin D 
◦ Serum 25-hydroxyvitamin D3, 
 
◦ 
 
• Drug accountability 
• Patient reported palatability and acceptability 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 53 of 75 
Confidential 
 
• Dispense assigned bottles of study drug 
7.2.4 
Visits 14-21 (Days 92-169) 
• May occur ±3 days of scheduled day 
• Visits 14 and 16 are required only for subjects who underwent upward dose titration at visit 
13 
• AE assessment 
• Concomitant medications 
• VS measurements 
• Blood samples drawn for: 
◦ Chemistry (partial panel)  
◦ Plasma iPTH 
◦ Serum total 25-hydroxyvitamin D 
7.2.5 
Visit 22 (Day 183): 
• Must occur on the scheduled day 
• Urine pregnancy (only for females of childbearing potential) 
• AE assessment 
• Concomitant medications 
• VS measurements 
• Urine chemistry and urinalysis 
• Blood samples drawn for: 
◦ Chemistry (full panel) and hematology 
◦ Plasma iPTH 
◦ Serum total 25-hydroxyvitamin D 
◦ Serum 25-hydroxyvitamin D3, 
 
◦ 
 
• Patient reported palatability and acceptability 
• Drug accountability 
7.3 
Follow-up Period or Second PK Assessment 
7.3.1 
Visit 23 (Day 190) 
• Must occur on the scheduled day 
• Required only for subjects participating in the second PK assessment 
• AE Assessment 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 54 of 75 
Confidential 
 
• Concomitant medications 
• VS measurements 
• Blood samples drawn for: 
◦ Chemistry (partial panel)  
◦ Serum 25-hyroxyvitamin D3, 
 
7.3.2 
Visit 24 (Day 197) 
• May occur ±3 day of scheduled day 
• Required only for subjects participating in the second PK assessment 
• Concomitant medications 
• AE assessment 
• VS measurements 
• Blood samples drawn for: 
◦ Chemistry (full panel) and hematology 
◦ Plasma iPTH 
◦ Serum total 25-hydroxyvitamin D 
◦ Serum 25-hydroxyvitamin D3,  
   
7.3.3 
Visits 25-27 (Days 204-218) 
• Must occur on the scheduled days 
• Required only for subjects participating in the second PK assessment 
• AE Assessment 
• Concomitant medications 
• VS measurements 
• Blood samples drawn for: 
◦ Chemistry (partial panel)  
◦ Serum 25-hyroxyvitamin D3, 
 
7.3.4 
Visit 28/ET (Day 225) 
• May occur ±3 day of scheduled day 
• Concomitant medications 
• AE assessment 
• PE (including weight, height and BMI) 
• VS measurements 
• 12-lead ECG 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 55 of 75 
Confidential 
 
• Urine chemistry and urinalysis 
• Urine pregnancy (only for females of childbearing potential) 
• Blood samples drawn for: 
◦ 
Chemistry (full panel) and hematology 
◦ 
Plasma iPTH 
◦ 
Serum total 25-hydroxyvitamin D 
◦ 
Serum 25-hydroxyvitamin D3,  
   
◦ 
 
 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 56 of 75 
Confidential 
 
8 QUALITY CONTROL AND ASSURANCE 
A quality assurance audit may be performed by the sponsor and/or its designee at selected site(s) 
to verify that the study was conducted in accordance with the protocol, ICH/GCP, and applicable 
SOP and regulations, to ensure that the safety and welfare of subjects are addressed, and to 
confirm that problems reported by study monitors have been resolved.  Verification of study 
documents and study 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 will be performed to evaluate study conduct, data integrity, protocol, and GCP 
compliance and safety.   
Each 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. 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 57 of 75 
Confidential 
 
9 PLANNED STATISTICAL METHODS 
9.1 
General Considerations  
All analyses will be performed using Statistical Analysis Software (SAS®) version 9.3 or higher 
(SAS® Institute, Cary, NC). All data collected on eCRFs and from clinical laboratory evaluations 
will be grouped and listed by treatment, subject, visit, date and time as feasible.  Summary tables 
will be presented by treatment group where appropriate.  Descriptive summaries of categorical 
outcomes will include the number and percent of subjects.  Descriptive summaries of 
quantitative measures will include the number of subjects, mean, 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 the same number of 
significant figures as 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 one decimal place. 
Denominators of percentage of subject calculations will be based on the number of subjects in 
the treatment 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 (see Section 9.4 Definition of Baseline), the more recent non-
missing result will be selected; 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. 
For certain analyses, a one-sided familywise type 1 error rate of 2.5% may be appropriately 
applied.  More details will be captured in the Statistical Analysis Plan. 
9.2 
Determination of Sample Size 
Sample size has been calculated (using Fisher’s exact test statistics) to provide power of 80% for 
a two-sided, alpha 0.05 level test of equal proportions comparing the percentages of subjects 
attaining a mean decrease of at least 30% in plasma iPTH (averaged over the last 6 weeks of 
treatment) compared to baseline on daily dosages of CTAP101 Capsules (active) versus placebo.  
Assuming response rates of at least 0.4 (CTAP101 Capsules) versus 0.1 (placebo), and using a 
2:1 ratio of CTAP101 Capsules:placebo subjects with an estimated 20% dropout rate over the 
course of the study, a sample size of approximately 108 subjects is required in the study with 
two-thirds apportioned to the 12 to <18 year age group (Cohort 1) and one-third apportioned to 
the 8 to <12 year age group (Cohort 2), allocated as 72 subjects to CTAP101 Capsules and 36 
subjects to placebo. 
No subject replacement is planned. 




Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 59 of 75 
Confidential 
 
• Violation of the protocol and/or subject non-compliance 
• Lost to FU 
• Pregnancy 
• Withdrawal of consent at any time, for any reason, at the discretion of the enrolled subject 
• Requirement for a 5th reduction in dose 
• Other (specific reason) 
Screen failure information will be collected regularly by the sponsor. Medical history will be 
collected on the eCRF at visit 1 and displayed in a data listing as well as summarized by 
treatment group.  Date of diagnoses of CKD and SHPT, stage of CKD, underlying diagnosis of 
the CKD, and previous and concurrent diseases will be collected in the eCRF and documented on 
the history of CKD page or as medical history.  Medical history events will be sorted 
alphabetically by System Organ Class (SOC).  The coding of the data will be performed with 
MedDRA version 20.0 or higher, using Preferred Terms (PT). 
9.7 
Prior and Concomitant Medications 
Prior medications are defined as any continuing or new medication used within 28 days before 
visit 1 and discontinued prior to the day of study drug administration.  Concomitant medications 
are defined as any continuing or new medication taken from time of first dose of study drug 
(visit 3) or anytime thereafter until the end of the study.  Type and dose of concomitant 
medications used for phosphate binder therapy will be collected on a separate eCRF page at each 
visit. Medication information will be collected through to the visit 28/ET visit.  World Health 
Organization Drug Dictionary Enhanced version March 2018, Format C, or later will be used to 
code concomitant and prior medications.  Prior and concomitant medications will be tabulated by 
treatment group using frequency counts and percents for each anatomical/therapeutic/chemical 
Class Level 2 and 4 and generic drug name.  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.  
9.8 
Analysis Endpoints 
9.8.1 
Primary Efficacy Endpoint 
The primary estimand is the reduction of mean plasma iPTH by at least 30% from pre-treatment 
baseline.  The primary efficacy endpoint is the proportion of subjects in the ITT population (age 
8 to <18 years) attaining a mean decrease in plasma iPTH from pre-treatment baseline of ≥30% 
compared to placebo in the EAP.  
9.8.2 
Primary Safety Endpoints 
The primary safety endpoints are: 
• AEs  
• Laboratory parameters (clinical chemistry, hematology, urine chemistry and urinalysis) 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 60 of 75 
Confidential 
 
• PEs 
• VS 
• 12-lead ECGs 
9.8.3 
Pharmacokinetic Endpoints 
For the interim analysis, repeated-dose (steady-state) PK determinations will be performed in 
subsets of subjects in both Cohort 1 and Cohort 2 by analyzing intensive serum 25-
hydroxyvitamin D3 concentrations versus time recorded during dosing with CTAP101 Capsules 
(n=10) or placebo (n=5) in the last three days of the 12th week of treatment. 
For the final analysis, repeated-dose (steady-state) PK determinations will be performed in both 
Cohort 1 and Cohort 2 by analyzing serum 25-hydroxyvitamin D3 concentrations versus time 
recorded (a) during dosing with CTAP101 Capsules or placebo in the last three days of the 12th 
week of treatment and (b) after the last administered dose in each active treatment group.   
The following PK parameters will be calculated using observed and baseline-adjusted serum 25-
hydroxyvitamin D3 concentrations: (a) AUC, Cmax, tmax, and Css; time to steady-state 
concentration (tss), and (b) t½, CL/F, and Vd/F, as feasible.  Relative exposure and dose 
proportionality will be examined, if possible.   
9.8.4 
Secondary Endpoints 
The secondary endpoints of the study will be: 
• Proportion of subjects in the PP population with a mean decrease of at least 30% in plasma 
iPTH from pre-treatment baseline in the EAP, in aggregate and by mean weekly study dose 
in the EAP 
• Proportion of subjects in the ITT and PP populations attaining adequate serum total 25-
hydroxyvitamin D (≥ 30 ng/mL) in the EAP, in aggregate and by mean weekly study dose in 
the EAP 
• The time courses of mean absolute changes from pre-treatment baseline in serum total 25-
hydroxyvitamin D and plasma iPTH 
• Proportion of subjects who attain 2 consecutive plasma iPTH values ≤70 pg/mL 
• PD effects on mean serum calcium (corrected), serum phosphorus, serum CaxP product, 
serum calcitriol, serum 24,25-dihydroxyvitamin D3, and the urine calcium:creatinine ratio 
• Proportion of subjects with hypercalciuria (>200 mg calcium/g creatinine) 
• Proportion of subjects with hypercalcemia (2 consecutive visits with serum calcium >10.3 
mg/dL) 
• Proportion of subjects with hyperphosphatemia (2 consecutive visits with serum phosphorus 
>5.5 mg/dL deemed to be study drug related)  
 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 61 of 75 
Confidential 
 
9.8.5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.9 
Additional Assessments 
Patient reported outcomes on palatability and acceptability. 
9.10 
Efficacy Analysis 
9.10.1 
Primary Endpoint Analysis 
Primary efficacy will be assessed in the ITT population by comparing the proportions of subjects 
in each treatment group (CTAP101 Capsules versus placebo) attaining a mean decrease from 
baseline in plasma iPTH of ≥30% in the EAP using the Cochran-Mantel-Haenszel test statistic 
(alpha=0.05) for overall efficacy of the multicenter results.  Subjects who do not have at least 
two plasma iPTH determinations in the EAP will be deemed non-responders.  
9.10.2 
Secondary Endpoint Analyses 
Secondary efficacy will be assessed in the PP population by comparing the proportions of 
subjects in each active treatment group attaining mean decreases in plasma iPTH of ≥30% from 
baseline in the EAP to the corresponding proportion of subjects in the placebo group, and in the 
ITT and PP populations by comparing the proportions of subjects in each active treatment group 
attaining mean serum total 25-hydroxyvitamin D of ≥30 ng/mL in the EAP to the corresponding  
proportions of subjects in the placebo group, in aggregate and by mean weekly study dose in the 
EAP.  Mean weekly dose in the EAP will be calculated for two groups of subjects:  those 
receiving ≤30 mcg per day; and those receiving >30 mcg/day.  Secondary efficacy will also be 
assessed by the time courses of mean absolute changes from pre-treatment baseline in serum 
total 25-hydroxyvitamin D and plasma iPTH (i.e., continuous iPTH change); and 
pharmacodynamic (PD) effects on mean serum calcium (corrected), serum phosphorus, serum 
, and the urine calcium:creatinine ratio. 
 
 
 
 
 
 
   


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 62 of 75 
Confidential 
 
The number (n, %) of subjects attaining two consecutive reductions in plasma iPTH values 
≥30% from baseline, as well as, the number (n, %) subjects with two consecutive plasma iPTH 
values ≤70 pg/mL will be compared between treatment groups. 
9.11 
Safety Analyses 
All subjects who have received at least one dose of study drug (the “safety population”) will be 
included in the safety analyses.  Statistical summary analysis of safety data will be descriptive 
and performed by treatment group and by stratum (age and gender groups).  No inferential 
hypothesis testing will be performed on the safety variables with the exception of serum calcium, 
serum phosphorus, serum CaxP product and urine calcium to creatinine ratio.   
9.11.1 
Primary Endpoints Analyses 
9.11.1.1 
Adverse Events 
All AEs will be collected on the eCRF and coded via SOC and preferred term using MedDRA 
version 20.0 or higher.  After randomization, AEs with missing onset date will be treated as 
TEAEs and missing onset date will be imputed as the date of study drug administration, unless 
the event end date indicates that the event resolved prior to administration of study drug, in 
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 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 was 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 study drug.  The incidence of the AEs will be summarized by treatment 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 treatment 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 ITT subjects in a particular treatment 
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.  
9.11.1.2 
Laboratory Evaluations 
Clinical laboratory data will be listed and summarized using conventional units.  All laboratory 
parameters will be listed and sorted by subject, collection date and laboratory test.  Shift tables 
will capture change from baseline (see Section 9.4 Definition of Baseline) to visit 28/ET for each 
laboratory parameter, if feasible.  Separate summary tables will be provided for mean absolute 
and percent change in plasma iPTH and serum total 25-hydroxyvitamin D, serum calcium, serum 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 63 of 75 
Confidential 
 
CaxP product and phosphorus, and urine calcium:creatinine ratio.  Proportions will be compared 
using a z-test or t-test, as appropriate.   
9.11.1.3 
Vital Signs  
Observed VS values will be summarized descriptively at baseline and changes from baseline will 
be descriptively summarized by treatment group, CKD stage, age group and gender.  Summaries 
will include n (%), mean, SD, median, minimum, and maximum.  VS values will be listed.  
9.11.1.4 
Physical Examinations 
Physical examination dates, whether a PE (including weight and height) is performed or not, 
abnormalities, if any, will be added to the medical history or reported as AEs as appropriate, and 
summarized by SOC and preferred term using MedDRA version 24.0 or higher. 
9.11.1.5 
ECG  
12-lead ECG measurements will be assessed at the study sites at visit 3, 22 and visit 28/ET and 
results will be collected on the eCRF.  
Observed ECG values for heart rate and the corrected QT interval will be descriptively 
summarized at baseline and changes from baseline will be summarized descriptively by 
treatment group at visit 28/ET.  Summaries will include n, mean (%), SD, median, minimum, 
and maximum. 
Shift in ECG categories (normal ECG, abnormal ECG – not clinically significant, abnormal ECG 
– clinically significant, missing) from baseline to visit 28/ET will be summarized descriptively in 
the form of frequencies and percentages.  
The paired t-test will be used to perform within-subject comparisons between baseline and post-
baseline values for heart rate and the corrected QT interval, if feasible. 
Additionally, the two sample t-test will be used to perform pair-wise comparisons of change 
from baseline heart rate and corrected QT intervals between the treatment groups.  
In the event of gross violations from the normality assumptions, the signed rank test will be used 
to perform the within-subject comparisons and a Wilcoxon rank sum test will be used to perform 
the pair-wise comparisons. 
All ECG values will be listed. 
9.11.2 
Secondary Endpoint Analyses 
The number (n, %) of subjects with hypercalciuria (>200 mg Ca/g creatinine), hypercalcemia 
(two consecutive visits with serum calcium >10.3 mg/dL) or hyperphosphatemia (two 
consecutive visits with serum phosphorus >5.5 mg/dL deemed to be study drug related) or serum 
confirmed CaxP product >55 (for Cohort 1) or >60 (for Cohort 2) will be compared between the 
treatment groups (active versus placebo) using the Cochran-Mantel-Haenszel test statistic 
(alpha=0.05) for overall efficacy of the multicenter results; the Chi-square test or Fisher’s Exact 
test will be used for reporting the results in the separate strata. 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 64 of 75 
Confidential 
 
9.12 
Other Analysis 
Descriptive statistics will be applied to evaluate patient reported palatability and acceptability.  
In addition, the proportion of subjects attaining the mean decrease from baseline in plasma iPTH 
of ≥30% in the subgroup of subjects with and without nutritional intake within 60 minutes of 
medication administration will be evaluated using the analysis methods described above.  


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 65 of 75 
Confidential 
 
10 ADMINISTRATIVE CONSIDERATIONS 
10.1 
Investigators and Study Administrative Structure 
Investigators will be chosen based on their experience in treating SHPT in pediatric patients with 
stage 3 or 4 CKD with vitamin D therapies, their past successful and compliant conduct of 
clinical trials and their track records for subject recruitment, subject retention and high rates of 
data capture. 
At screening, investigators will offer subjects notification of their primary care physician or 
nephrologist that he/she is participating in a clinical study.  If the subject accepts, a brief letter 
outlining the study and identifying the study drug should be sent once the subject is enrolled. 
10.2 
Institutional Review Board Approval 
GCP requires that the clinical protocol, any protocol amendments, the IB, the informed consent, 
and all other forms of subject information related to the study and any other necessary 
documents be reviewed by 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. 
10.4 
Subject Information and Consent 
The investigator or his/her qualified designee will explain the nature of the study to the subject 
and legal guardian, answer all questions regarding this study, and emphasize that missing data 
and premature termination of study participation will diminish the scientific value of the data 
obtained, prior to obtaining informed consent. 
The investigator or his/her qualified designee will obtain informed consent from each subject or 
legal representative 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 and legal guardian has signed 
the informed consent before any activity or treatment is undertaken which is not part of routine 
care.  The subject will receive a signed copy of the ICF and the original 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 
legal guardian to participate in the study is entirely voluntary.  The investigator or designate must 
emphasize to the subject and legal guardian 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 is amended during the study, the investigator must follow all applicable regulatory 
requirements pertaining to approval of the amended ICF by the IRB and use of the amended 
form (including for ongoing subjects). 
 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 66 of 75 
Confidential 
 
10.5 
Subject Confidentiality 
Subject confidentiality will be strictly held in trust by the participating investigators, their staff, 
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.  The 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 and initials.  The investigator will keep a separate 
confidential enrollment log that matches identifying study codes with the subjects’ names and 
residencies. 
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 study will be monitored by the sponsor or designee at all stages of study conduct from 
inception to completion in accordance with current ICH/GCP protocol compliance.  The 
investigator will allocate adequate time for such monitoring activities.  This monitoring will be 
in the form of site visits and other communication and will include review of original source 
documents, CRFs, facilities and equipment, recruiting, record-keeping, protocol adherence, data 
collection, AE reporting, and other factors.  The frequency of these visits will depend upon the 
progress of the study. 
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, etc), and has adequate space to conduct the monitoring visit. 
10.7 
Case Report Forms and Study Records 
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from automated 
instruments, microfiches, photographic negatives, microfilm or magnetic media, and/or x-rays.  
Data collected during this study must be recorded on the appropriate source documents.  All 
source documents should be completed using blue or black ink, in a neat, legible manner to 
ensure accurate interpretation of data.  
Data capture and management will be consistent with applicable ICH/GCP guidelines. 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 67 of 75 
Confidential 
 
All data collected during the study for subjects who are randomized will be recorded in an 
individual, subject-specific eCRF as part of an electronic data capture (EDC) system.  The 
sponsor or designee will provide training to the investigative site on the EDC system and 
eCRFs.  All eCRFs will be completed as soon as data are available in the source for each 
subject.  As electronic data capture will 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.  Data for subjects who fail screening, including the reason for screen failure, will be 
recorded on a screening log which will be provided to the sponsor. 
A subject eCRF must be completed for each subject (or legal representative) who signs a consent 
form and undergoes randomization.  All data generated from external sources, (eg, central 
laboratory and PK/PD processing/analysis), will be integrated with the subject eCRF data 
through programming or other data integration techniques. 
All eCRFs should be completed within five 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.   
To ensure the quality of the clinical data across all subjects and sites, a Clinical Data 
Management review will be performed by the sponsor or designee on subject data entered or 
integrated into the 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.  Moreover, all data from external sources, eg, central laboratory 
and PD processing/analysis will be reconciled with subject eCRF data.  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. 
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. 
10.8 
Data Safety Monitoring Board 
An independent, external unblinded Member of the DSMB will be responsible and will oversee 
the IRS and verify the appropriateness of all dosing adjustments, and to monitor subject safety 
and the effectiveness of CTAP101 Capsules at regular intervals.  Members of the DSMB will 
also conduct periodic reviews of study conduct to verify that all required data are captured to a 
sufficiently high degree (>95%) and within specified time frames (usually within 5 days), and to 
promptly recommend appropriate corrective actions to address any noted deficiencies, in an 
effort to minimize missing data.  Specific responsibilities and activities of the DSMB will be 
defined in the charter ratified at the organizational meeting of the DSMB.  These responsibilities 
will include the completion of an interim analysis of the repeated-dose PK data obtained in 
Cohort 1 to justify a starting dose for Cohort 2. 
10.9 
Protocol Deviations 
Protocol deviations are any intentional or unintentional change from an IRB approved protocol 
that was not approved by the IRB prior to initiation of the change. 
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. 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 68 of 75 
Confidential 
 
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. 
The sponsor requires that all major protocol deviations be reported to the IRB.  
In addition, the investigator is responsible for adhering to his/her IRB’s protocol deviation 
reporting requirements. 
10.10 Source Documentation 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical study necessary for the reconstruction and evaluation of the study.  Source 
data are contained in source documents.  Examples of these original documents, and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical study. 
Data collected during this study must be recorded on the appropriate source documents.  
The investigator is responsible for the accuracy, completeness, legibility and timeliness of the 
data reported on the source documents.  All source documents should be completed using blue or 
black ink, in a neat, legible manner to ensure accurate interpretation of data. 
The subject screening log should list all consented subjects contacted by the investigator to 
participate in the study, regardless of the outcome. 
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 sponsor using the sponsor’s SOPs. 
Completed eCRFs are required for each subject randomly assigned to study medication.  
Electronic data entry is accomplished through the 21CFR Part 11 compliant OmniComm 
eClinical System Solution for Life (Ft. Lauderdale, FL) 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. 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 69 of 75 
Confidential 
 
10.12 Retention of Data 
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRFs 
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 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 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 the sponsor.  Any publication or 
presentation related to the study must be approved by the sponsor before submission of the 
manuscript.  After publication of the results of the study, any participating center may publish or 
otherwise use its own data provided that any publication of data from the study gives recognition 
to the study group.  In addition, the sponsor shall be associated with all such publications, it 
being understood that the sponsor is entitled to refuse the association. 
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, it being understood that the results of this study are not to be considered 
confidential. 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 70 of 75 
Confidential 
 
11 REFERENCE LIST 
1. Agarwal R, Georgianos PI. Con: Nutritional vitamin D replacement in chronic kidney disease 
and end-stage renal disease. Nephrol Dial Transplant 2016;31:706-713. 
2. Bikle DD. Vitamin D metabolism, mechanism of action, and clinical applications. Chem 
Biol. 2014;21:319-329. 
3. Coburn JW, Maung HM, Elangovan L, et al. Doxercalciferol safely suppresses PTH levels in 
patients with secondary hyperparathyroidism associated with chronic kidney disease stages 3 
and 4. Am J Kidney Dis. 2004;43:877-890. 
4. Chonchol M, Locatelli F, Abboud HE, et al. A randomized, double-blind, placebo-controlled 
study to assess the efficacy and safety of cinacalcet HCl in participants with CKD not 
receiving dialysis. Am J Kidney Dis. 2009;53:197-207. 
5. Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, et al. Prevalence of chronic 
kidney disease in the United States. JAMA 2007;298:2038-2047. 
6. Coyne D, Acharya M, Qiu P, et al. Paricalcitol capsule for the treatment of secondary 
hyperparathyroidism in stages 3 and 4 CKD. Am J Kidney Dis. 2006;47:263-76. 
7. Cunningham J, Locatelli F, Rodriguez M. Secondary hyperparathyroidism: pathogenesis, 
disease progression, and therapeutic options. Clin J Am Soc Nephrol 2011:913-921. 
8. de Boer IH, Thadhani R. Vitamin D deficiency: consequence or cause of CKD? Clin J Am 
Soc Nephrol 2013;8:1844-1846. 
9. DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin 
Nutr 2004;80:1689S-1696S. 
10. Dreisbach AW, Lertora JJ. The effect of chronic renal failure on drug metabolism and 
transport. Expert Opin Drug Metab Toxicol 2008;4:1065-1074. 
11. Fernandez-Juarez G, Luno J, Barrio V, de Vinuesa SG, Praga M, Goicoechea M, et al. 25 
(OH) vitamin D levels and renal disease progression in patients with type 2 diabetic 
nephropathy and blockade of the renin-angiotensin system. Clin J Am Soc Nephrol 
2013;8:1870-1876. 
12. Fleming TR.  Addressing missing data in clinical trials.  Ann Intern Med 2011;154:113-117. 
13. Haddad JG, Jr., Rojanasathit S. Acute administration of 25-hydroxycholecalciferol in man. J 
Clin Endocrinol Metab 1976;42:284-290. 
14. Helvig CF, Cuerrier D, Hosfield CM, et al. Dysregulation of renal vitamin D metabolism in 
the uremic rat. Kidney Int 2010;78: 463-72.  
15. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. 
Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical 
practice guideline. J Clin Endocrinol Metab 2011;96:1911-1930. 
16. Jadoul M, Albert JM, Akiba T, et al. Incidence and risk factors for hip or other bone fractures 
among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study. Kidney 
Int. 2006;70:1358-66. 
17. Kalantar-Zadeh K and Kovesdy CP. Clinical outcomes with active versus nutritional vitamin 
D compounds in chronic kidney disease. Clin J Amer Soc Nephrol. 2009;4:1529-39. 


Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 71 of 75 
Confidential 
 
18. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO 
clinical practice guideline for diagnosis, evaluation, prevention, and treatment of chronic 
kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int 2009 76: S1-S130. 
19. Kidney Disease Improving Global Outcomes (KDIGO) 2017 clinical practice guideline 
update for the diagnosis, evaluation, prevention and treatment of chronic kidney disease – 
mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2017;7:S1–S59. 
20. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney 
disease. Am J Kidney Dis 2003;42:S84-89. 
21. LaClair RE, Hellman RN, Karp SL, Kraus M, Ofner S, Li Q, et al. Prevalence of calcidiol 
deficiency in CKD: a cross-sectional study across latitudes in the United States. Am J Kidney 
Dis. 2005;45:1026-1033. 
22. Ledger JE, Watson GJ, Compston JE. Biliary excretion of radioactivity after intravenous 
administration of [3H]25-hydroxyvitamin D3 in man. Dig Dis Sci 1986;31:361-368. 
23. Levey AS, Eckardt KU, Tsukamoto Y, Levin A, Coresh J, Rossert J, et al. Definition and 
classification of chronic kidney disease: a position statement from Kidney Disease: 
Improving Global Outcomes (KDIGO). Kidney Int 2005;67:2089-2100. 
24. 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 
evaluate early kidney disease. Kidney Int 2007;71: 31-8.  
25. Nicola LD, Zoccali C.  Chronic kidney disease prevalence in the general population:  
heterogeneity and concerns.  Nephrol Dial Transplant 2016;31:331-335. 
26. Nigwekar SU, Tamez H, Thadhani RI. Vitamin D and chronic kidney disease-mineral bone 
disease (CKD-MBD). Bonekey Rep 2014;3:498. 
27. Paloian NJ and Giachelli CM. A current understanding of vascular calcification in CKD. Am 
J Physiol Renal Physiol 2014;307:F891-F900. 
28. Petkovich M, Melnick J, White J, Tabash S, Strugnell S, Bishop CW. Modified-release oral 
calcifediol corrects vitamin D insufficiency with minimal CYP24A1 upregulation. J Steroid 
Biochem Mol Biol 2015;148:283-289. 
29. Ravani P, Malberti F, Tripepi G, Pecchini P, Cutrupi S, Pizzini P, et al. Vitamin D levels and 
patient outcome in chronic kidney disease. Kidney Int 2009;75:88-95. 
30. Ross A, Manson J, Abrams S, Aloia J, Brannon P, Clinton S, et al. The 2011 report on 
dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what 
clinicians need to know. J Clin Endocrinol Metab 2011;96:53-8. 
31. Sprague SM, Silva AL, Al-Saghir F, Damle R, Tabash SP, Petkovich M, et al. Modified-
release calcifediol effectively controls secondary hyperparathyroidism associated with 
vitamin D insufficiency in chronic kidney disease. Am J Nephrol 2014;40:535-545.   
32. Wolf M, Shah A, Gutierrez O, Ankers E, Monroy M, Tamez H, et al. Vitamin D levels and 
early mortality among incident hemodialysis patients. Kidney Int 2007;72:1004-1013. 
 








Protocol CTAP101-CL-3007 V3.0 11 January 2022 
EirGen Pharma Ltd. 
CTAP101 Extended-release Capsules 
Page 75 of 75 
 
Confidential 
 
 APPENDIX 2 INVESTIGATOR’S SIGNATURE 
Study Title: 
A Multi-Center Study to Evaluate the Efficacy, Safety and 
Pharmacokinetics of CTAP101 Extended-release Capsules to Treat 
Secondary Hyperparathyroidism in Pediatric Subjects of Ages 8 to 
<18 Years with Stage 3 or 4 Chronic Kidney Disease and Vitamin D 
Insufficiency 
Study Number: 
CTAP101-CL-3007 
Final Date: 
11 January 2022 
I agree: 
 
1. To assume responsibility for the proper conduct of the study at this site. 
2. 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 EirGen Pharma Ltd 
or its designee(s). 
3. 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/IEC, 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). 
4. That I am thoroughly familiar with the appropriate use of the investigational drug, 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 EirGen 
Pharma Ltd or its designee(s). 
5. To ensure that all persons assisting me with the study are adequately informed about the 
investigational drug and of their study-related duties and functions as described in the protocol. 
6. 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. EirGen Pharma Ltd will use and disclose the 
information solely for the purpose of complying with regulatory requirements. 
Hence, I: 
• 
Agree to supply EirGen Pharma Ltd., 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 EirGen Pharma Ltd. may disclose this information about such ownership interests and 
financial ties to regulatory authorities. 
 
 
Signed: 
 
 
Date:  
 
 
Printed Name: