Clinical trial NCT03602261
Conditions: Secondary Hyperparathyroidism Due to Renal Causes Chronic Kidney Diseases Vitamin D Deficiency Stage 5 Chronic Kidney Disease
Sponsor: OPKO Health, Inc.
Start date: 2018-07-09; Completion date: 2021-02-24
Enrollment: 44 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Safety, Efficacy, PK and PD of CTAP101 (calcifediol) ER Capsules for SHPT in HD Patients VDI

Detailed description:
A Multi-Center, Randomized, Two-Cohort Phase 2 Study to Evaluate the Safety, Efficacy, Pharmacokinetics (PK) and Pharmacodynamics (PD) of CTAP101 (calcifediol) Extended-Release Capsules to Treat Secondary Hyperparathyroidism (SHPT) in Subjects with Vitamin D Insufficiency (VDI) and Chronic Kidney Disease Requiring Regular Hemodialysis.

Arms: arm 1: CTAP101 Oral Capsules/Calcifediol, calcidiol, 25-hydroxyvitamin D3, 900mcg/weekly for 26 weeks arm 2: Placebo Oral Capsules/weekly for 26 weeks
Interventions: intervention 1: Calcifediol Oral Capsule intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: Capsule, weekly intervention 2: Capsule, weekly

Protocol documents:
Prot_000.pdf: 
 
PROTOCOL CTAP101-CL-2010 
Study Title: 
A Multi-Center, Randomized, Two-Cohort Phase 2 Study to Evaluate the 
Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of CTAP101 
(calcifediol) Extended-Release Capsules to Treat Secondary 
Hyperparathyroidism in Subjects with Vitamin D Insufficiency and 
Chronic Kidney Disease Requiring Regular Hemodialysis.   
Study Number: 
CTAP101-CL-2010 
Short Title: 
Safety, Efficacy, PK and PD of CTAP101 (calcifediol) ER Capsules for 
SHPT in HD Patients VDI 
Study Phase: 
2 
Product Name: 
CTAP101 Capsules  
Investigators: 
Multi-center 
Sponsor: 
OPKO Ireland Global Holdings Ltd. 
4400 Biscayne Boulevard 
Miami, FL 33137 
Sponsor Contact: 
 
Clinical R&D, and Medical Affairs   
OPKO Pharmaceuticals, Renal Division 
4400 Biscayne Boulevard 
Miami, FL 33137 
 
  
   
Study Medical Monitor: 
 
 
 
  
 
  
  
  
 
Study Contact: 
 
 
 
 
 
  
This study will be conducted in compliance with the protocol, US Code of Federal Regulations (CFR) applicable 
to clinical studies, principles of ICH Good Clinical Practice (GCP), the Declaration of Helsinki, and all applicable 
regulatory requirements. 
 
 
Date 
Version 11.0 
05 May 2020 


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Confidentiality Statement 
This protocol is the confidential information of OPKO Ireland Global Holdings 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 OPKO Ireland Global 
Holdings Ltd. 
 
 


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TABLE OF CONTENTS 
PROTOCOL CTAP101-CL-2010 ..........................................................................................1 
TABLE OF CONTENTS ........................................................................................................3 
LIST OF IN-TEXT TABLES .................................................................................................6 
SYNOPSIS ................................................................................................................................7 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................20 
1 
INTRODUCTION ..........................................................................................................23 
1.1 
Chronic Kidney Disease and Vitamin D Insufficiency ...........................................23 
1.2 
Chronic Kidney Disease, SHPT and Vitamin D Insufficiency ...............................23 
1.3 
Nonclinical Experience ..............................................................................................24 
1.4 
Previous Clinical Experience ....................................................................................25 
2 
STUDY OBJECTIVES AND ENDPOINTS ................................................................27 
2.1 
Study Objectives.........................................................................................................27 
2.1.1 
Primary Objectives ..............................................................................................27 
2.1.2 
Secondary Objectives...........................................................................................27 
 
 
3 
INVESTIGATIONAL PLAN ........................................................................................29 
3.1 
Overall Study Design and Plan .................................................................................29 
3.2 
Rationale for Study Design and Control Group .....................................................33 
3.3 
Study Duration ...........................................................................................................34 
3.4 
Study Endpoints .........................................................................................................35 
3.4.1 
Pharmacokinetic Endpoints ................................................................................35 
3.4.2 
Pharmacodynamic Endpoints .............................................................................35 
3.4.3 
Primary Safety Endpoints ...................................................................................35 
3.4.4 
Efficacy Endpoints ...............................................................................................35 
 
 
4 
STUDY POPULATION SELECTION .........................................................................37 
4.1 
Study Population ........................................................................................................37 
4.2 
Inclusion Criteria .......................................................................................................37 
4.3 
Exclusion Criteria ......................................................................................................39 
5 
STUDY TREATMENTS ................................................................................................40 
5.1 
Description of CTAP101 Capsules ...........................................................................40 
5.2 
Description of Placebo Capsules ...............................................................................40 
5.3 
Description of Cinacalcet ..........................................................................................40 
5.4 
Treatments Administered .........................................................................................41 
5.5 
Dose Reduction Criteria ............................................................................................42 
5.5.1 
Overdose and Toxicity .........................................................................................43 
5.6 
Method of Assigning Subjects to Treatment Groups .............................................43 
5.7 
Prior and Concomitant Therapy ..............................................................................44 
5.7.1 
Phosphate Binder and Elemental Calcium Therapy ........................................44 
5.7.2 
Dialysate Calcium Concentration .......................................................................44 
5.7.3 
Diet Restrictions ...................................................................................................44 
5.7.4 
Subject Activity Restrictions ...............................................................................44 
5.8 
Treatment Compliance ..............................................................................................45 
5.9 
Packaging and Labeling ............................................................................................45 
5.10 
Storage and Accountability .......................................................................................45 


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5.11 
Investigational Product Retention at Study Site .....................................................46 
6 
STUDY PROCEDURES ................................................................................................47 
6.1 
Informed Consent ......................................................................................................47 
6.2 
Medical History and Concomitant Medications .....................................................47 
6.3 
Physical Examination, Vital Signs and Electrocardiogram ...................................47 
6.4 
Clinical Laboratory Tests..........................................................................................48 
6.4.1 
Laboratory Parameters .......................................................................................48 
6.4.2 
Sample Collection, Storage, and Shipping .........................................................50 
6.4.3 
Clinical Supplies ...................................................................................................50 
6.5 
Dispensing Study Drug ..............................................................................................50 
6.6 
Adverse Events Assessments .....................................................................................51 
6.6.1 
Definition ..............................................................................................................51 
6.6.2 
Performing Adverse Events Assessments ..........................................................51 
6.6.3 
AE Collection Period ...........................................................................................51 
6.6.4 
Severity..................................................................................................................52 
6.6.5 
Relationship ..........................................................................................................52 
6.6.6 
Clinical Significance.............................................................................................53 
6.6.7 
Serious Adverse Events .......................................................................................53 
6.6.7.1 
Definition ........................................................................................................53 
6.6.7.2 
Expectedness ...................................................................................................54 
6.6.7.3 
Reporting Serious Adverse Events ...............................................................54 
6.6.8 
Treatment-Emergent Adverse Events................................................................55 
6.7 
Concomitant Medication Assessments .....................................................................55 
6.8 
Removal of Subjects from the Study or Study Drug ..............................................55 
6.9 
Appropriateness of Measurements ...........................................................................56 
7 
STUDY ACTIVITIES ....................................................................................................57 
7.1 
Cohort 1 ......................................................................................................................57 
7.1.1 
Non-PK Sites.........................................................................................................57 
7.1.1.1 
Screening and Baseline Periods ....................................................................57 
7.1.1.2 
Treatment Period (26 weeks) ........................................................................58 
7.1.1.3 
Follow-up Period ............................................................................................60 
7.1.2 
PK Sites .................................................................................................................61 
7.1.2.1 
Screening and Baseline Periods ....................................................................61 
7.1.2.2 
Treatment Period (26 weeks) ........................................................................62 
7.1.2.3 
Follow-up Period ............................................................................................66 
7.2 
Cohort 2 ......................................................................................................................69 
7.2.1 
Screening and Baseline Periods ..........................................................................69 
7.2.1.1 
Visit 1 (Days -83 to -69) .................................................................................69 
7.2.1.2 
Visit 2 (Days -13 to -7) ...................................................................................69 
7.2.2 
Treatment Period (26 weeks) ..............................................................................70 
7.2.2.1 
Visit 3 (Day 1) .................................................................................................70 
7.2.2.2 
Single-dose PK Assessment (PK Sub-Groups Only) ..................................71 
7.2.2.3 
Visits 10-16 (Days 22-85) ...............................................................................72 
7.2.2.4 
Visit 17 (Day 99) .............................................................................................72 
7.2.2.5 
Visits 18-25 (Days 106-183) ...........................................................................73 
7.2.2.6 
Visit 26 (Day 197) or Early Termination (ET) ............................................73 


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7.2.2.7 
Repeated-dose PK Assessment (Active PK Sub-Groups Only) .................74 
7.2.3 
Extension Treatment Period (26 weeks) ............................................................76 
7.2.3.1 
Visits 36-42 (Days 267-407) ...........................................................................76 
7.2.3.2 
Visit 43 (Day 421) ...........................................................................................76 
7.2.4 
Follow-up Period ..................................................................................................77 
7.2.4.1 
Visit 44 (Day 449) ...........................................................................................77 
7.2.4.2 
Visit 45 (Day 463) ...........................................................................................77 
8 
QUALITY CONTROL AND ASSURANCE ...............................................................78 
9 
PLANNED STATISTICAL METHODS ......................................................................79 
9.1 
General Considerations .............................................................................................79 
9.2 
Determination of Sample Size ...................................................................................79 
9.3 
Analysis Populations ..................................................................................................79 
9.4 
Demographics and Baseline Characteristics ...........................................................80 
9.5 
Subject Disposition and Withdrawal .......................................................................80 
9.6 
Prior and Concomitant Medications ........................................................................80 
9.7 
Pharmacokinetic Analysis .........................................................................................80 
9.8 
Pharmacodynamic Analysis ......................................................................................81 
9.9 
Safety Analysis ...........................................................................................................82 
9.9.1 
Primary Endpoints Analyses ..............................................................................82 
9.9.1.1 
Adverse Events ...............................................................................................82 
9.9.1.2 
Vital Signs .......................................................................................................82 
9.9.1.3 
Physical Examination ....................................................................................83 
9.9.2 
Secondary Endpoint Analyses ............................................................................83 
9.10 
Efficacy Analyses .......................................................................................................83 
9.10.1 
Primary Endpoint Analyses ................................................................................83 
9.10.2 
Secondary Endpoint Analyses ............................................................................83 
 
 
9.11 
Statistical Analyses.....................................................................................................84 
10 ADMINISTRATIVE CONSIDERATIONS .................................................................86 
10.1 
Study Administrative Structure ...............................................................................86 
10.2 
Notification of Primary Care Physician ...................................................................86 
10.3 
Institutional Review Board/Ethics Committee Approval ......................................86 
10.4 
Ethical Conduct of the Study ....................................................................................86 
10.5 
Subject Information and Consent ............................................................................86 
10.6 
Subject Confidentiality ..............................................................................................87 
10.7 
Study Monitoring .......................................................................................................87 
10.8 
Case Report Forms and Study Records ...................................................................88 
10.9 
Protocol Deviations ....................................................................................................88 
10.10 Data Generation and Analysis ..................................................................................89 
10.11 Retention of Data .......................................................................................................89 
10.12 Financial Disclosure ...................................................................................................89 
10.13 Publication and Disclosure Policy ............................................................................90 
11 REFERENCE LIST........................................................................................................91 
APPENDIX 1. 
SCHEDULE OF EVENTS ......................................................................93 
APPENDIX 2. 
CINACALCET (CIPLA) APRIL 2019 LABEL .................................100 
APPENDIX 3. 
INVESTIGATOR’S SIGNATURE ......................................................119 


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LIST OF IN-TEXT TABLES 
Table 1 
Initial Weekly Dosing Schedule for Study Drugs .......................................42 
Table 2 
Evaluations .....................................................................................................48 
Table 3 
List of Laboratory Tests ................................................................................49 
Table 4  
Adverse Event Relationship Criteria ...........................................................53 
Table 5  
Pharmacokinetic Parameters ........................................................................81 
 


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SYNOPSIS 
Sponsor:  
OPKO Ireland Global Holdings Ltd. 
Name of Finished Products: 
CTAP101 Capsules (150 mcg strength) 
Cinacalcet Tablets (30 mg strength) 
Name of Active Ingredients:  
Calcifediol, calcidiol, 25-hydroxyvitamin D3 
Hydrochloride salt of cinacalcet 
Test Products, Dose, and Mode of Administration:  
CTAP101 Capsules (300, 600 and 900 mcg/week) or matching placebo by the oral route.  
Cinacalcet (30 mg tiw) by the oral route.  
Study Title: 
A Multi-Center, Randomized, Two-Cohort Phase 2 Study to Evaluate the Safety, Efficacy,  
Pharmacokinetics and Pharmacodynamics of CTAP101 (calcifediol) Extended-Release 
Capsules to Treat Secondary Hyperparathyroidism in Subjects with Vitamin D Insufficiency 
and Chronic Kidney Disease Requiring Regular Hemodialysis.   
Study Number: 
CTAP101-CL-2010 
Study Phase: 2 
Primary Objectives:  
The primary objectives of this study are: 
1. To evaluate the efficacy of repeated dosing with three dose levels of CTAP101 extended-
release (ER) Capsules versus placebo in raising mean serum total 25-hydroxyvitamin D to 
≥50 ng/mL and in reducing mean plasma intact parathyroid hormone (iPTH) by at least 
30% from pre-treatment baseline;   
2. To investigate the safety and tolerability of repeated dosing with three dose levels of 
CTAP101 Capsules; and, 
3. To assess the pharmacokinetic (PK) profiles and PK linearity of serum calcifediol after 
single and repeated doses of CTAP101 Capsules at three dose levels in subjects with 
secondary hyperparathyroidism (SHPT), vitamin D insufficiency (VDI) and chronic 
kidney disease (CKD) who are undergoing hemodialysis (HD) three times per week (tiw).  
Secondary Objectives:  
The secondary objectives of this study are: 
1. To evaluate the efficacy of repeated dosing with three dose levels of CTAP101 ER 
Capsules versus placebo in raising mean serum total 25-hydroxyvitamin D to ≥50 ng/mL 
and in reducing mean plasma iPTH by at least 10 or 20% from pre-treatment baseline;   


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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 at three dose levels; 
3. To assess the effects of body weight, age, gender, race, dose, severity of SHPT and VDI, 
dialysis vintage, etiology of CKD and prior treatment with 1α-hydroxylated  D analogs 
and/or calcimimetics on the efficacy and safety of repeated doses of CTAP101 Capsules at 
three dose levels versus placebo in raising serum total 25-hydroxyvitamin D to ≥50 ng/mL 
and in reducing plasma iPTH by at least 10, 20 and 30% from pre-treatment baseline; 
4. To assess the pharmacodynamic (PD) effects of repeated doses of CTAP101 Capsules at 
three dose levels versus placebo on mean serum calcium (corrected for albumin), 
phosphorus, vitamin D binding protein (DBP), total free 25-hydroxyvitamin D, total 1,25-
dihydroxyvitamin D, 1,25-dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3;  
5. To characterize the population PK of serum calcifediol relative to body weight, age, 
gender, race, dose, severity of SHPT and VDI, dialysis vintage, etiology of CKD and prior 
treatment with 1α-hydroxylated vitamin D analogs and/or calcimimetics; and, 
6. To evaluate the safety of CTAP101 Capsules versus placebo with regard to the incidence 
of hypercalcemia and hyperphosphatemia. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Design:  
This is a phase 2, multi-center, randomized, two-cohort study to evaluate the safety, efficacy, 
PK and PD of CTAP101 Capsules to treat SHPT in male and female subjects aged at least 18 
years with VDI and CKD requiring thrice weekly in-center HD.  The study will be conducted 
in two successive cohorts at multiple sites within the United States (US).  Subjects in Cohort 1 
will participate in a randomized, single-blinded (subjects only), placebo-controlled repeated 
dose 
safety and efficacy study of CTAP101 Capsules administered at one, high 
dose level (900 mcg per week). Subjects in Cohort 2 will not be enrolled until sufficient data 
have been obtained from Cohort 1 and reviewed with the US Food and Drug Administration 
(FDA) to make a reasonable decision to proceed with the second cohort, potentially under a 
further amendment to this protocol. Subjects in Cohort 2 will participate in a randomized, 
double-blinded, placebo-controlled repeated-dose, dose-ranging safety and efficacy study of 
CTAP101 Capsules administered at three different dose levels (300, 600 or 900 mcg per 
week). 
In Cohort 1, approximately 100 subjects will be screened to randomize approximately 44 
eligible subjects in a 3:1 ratio into two groups receiving the following treatments in a single-
blinded fashion (subjects only) for 26 weeks: (a) CTAP101 Capsules at 900 mcg per week or 
(b) matching placebo. Randomization will be accomplished in blocks of four subjects using 
two computer-generated codes, one for the PK sub-group (n=28) and one for the non-PK sub-
group (n=16).  
In Cohort 1, subjects who have been consented and did not meet eligibility criteria at the 
conclusion of the Screening Visit (Visit 1) are considered a Screen Failure.  Subjects who are 
eligible after Visit 1, but do not meet eligibility criteria at either Visit 2 or Visit 3 are 
considered a Pre-Treatment Failure.  Only subjects who are randomized to a treatment at Visit 
3 who are then withdrawn during the study will complete early termination (ET) study 
procedures. 
In Cohort 2, approximately 480 subjects will be screened to randomize approximately 212 
eligible subjects, stratified for severity of SHPT, in a 1:1:1:1 ratio into four groups receiving 
the following treatments in a double-blinded fashion for 26 weeks: (aa) CTAP101 Capsules at 
300 mcg per week, (bb) CTAP101 Capsules at 600 mcg per week, (cc) CTAP101 Capsules at 
900 mcg per week or (dd) matching placebo.  Randomization will be accomplished in blocks 
of four subjects using two computer-generated codes, one for the PK sub-group (n=72) and 
one for the non-PK sub-group (n=140).  A subset of subjects will undergo a subsequent 26 
weeks of open-label treatment (for a total of 52 weeks) depending on their prior participation 
in the PK assessments described below.   


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An Interactive Response Technology system (IRT) will provide study treatment group 
assignments for both cohorts (using computer-generated randomization codes provided by the 
IRT vendor) and dosing adjustments.  For Cohort 2 only, an independent, unblinded Data 
Safety Monitoring Board (DSMB) will be established to oversee the IRT and verify the 
appropriateness of all dosing adjustments, to monitor subject safety and the effectiveness of 
CTAP101 Capsules at regular intervals.  Specific responsibilities and activities of the DSMB 
will be defined in the charter ratified at a pre-Cohort 2 organizational meeting.  Also, for 
Cohort 2 only, subjects, dialysis facilities, study personnel and the sponsor will be blinded to 
the administered treatments and to plasma iPTH, serum total 25-hydroxyvitamin D and serum 
calcifediol data until the last subject completes the first 26 weeks of treatment. 
All subjects will undergo regular HD during the study.  Subjects receiving treatment with 
calcitriol or other 1α-hydroxylated vitamin D analog, vitamin D supplements or calcimimetics 
prior to study enrollment will forgo further dosing with these agents after confirmed eligible at 
Visit 1 and for the duration of the study and complete an 8-week washout period prior to 
baseline assessments.  Subjects will undergo a 6-week FU period after completing treatment 
with CTAP101 Capsules or corresponding placebo.  
On two occasions, a subset of subjects (n=~21) from Cohort 1 who are assigned to treatment 
with CTAP101 Capsules and, on one or two occasions, a subset of subjects (n=~18) from each 
of the four treatment groups in Cohort 2 will be housed after the end-of-week HD (on Friday 
or Saturday) in a nearby phase 1 unit for 3 days in order to provide blood samples for 
determination of single-dose (all groups) and repeated-dose (active groups only) PK profiles of 
serum calcifediol and associated PD profiles for serum calcium (corrected), phosphorus, DBP, 
total free 25-hydroxyvitamin D, total 1,25-dihydroxyvitamin D, 1,25-dihydroxyvitamin D3 and 
24,25-dihydroxyvitamin D3.  Subjects receiving CTAP101 Capsules will complete a 26-week 
treatment period between the two PK profile assessments.  Subjects in Cohort 2 receiving 
treatment with placebo will complete a 26-week treatment period after the single-dose PK 
assessment, and then receive CTAP101 Capsules at a dose of 300, 600 or 900 mcg per week, 
assigned randomly with stratification by severity of SHPT, during a second 26-week treatment 
period, after which they will complete a 6-week follow-up period.  Blood samples for the first 
PK profile assessment will be collected at -12, -3, 0, 4, 8, 12, 16, 20, 24, 30, 36 and 42 hours, 
and on Days 4, 6, 8, 11 and 15 following a single dose (0, 300, 600 or 900 mcg) administered 
as 6 capsules (CTAP101 and/or placebo) 2 weeks prior to the start of the first 26-week 
treatment period. Blood samples for the second PK profile assessment will be collected at -12, 
-3, 0, 4, 8, 12, 16, 20, 24, 30, 36 and 42 hours, and on Days 4, 6, 8, 11 and 15 following the 
last administered dose in treatment week 26 for subjects receiving dosages of 300 or 600 mcg 
per week of CTAP101 Capsules, and at -12, -3, 0, 4, 8, 12, 16, 20, 24, 30, 36 and 42 hours, and 
on Days 4, 6, 8, 11, 15, 22, 29 and 43 following the last administered dose in treatment week 
26 for subjects receiving 900 mcg per week of CTAP101 Capsules.  On specified and 
subsequent HD days, blood samples will be collected just before dialysis. Subjects who 
received treatment with CTAP101Capsules at 900 mcg per week will terminate further 
participation in the study after the second PK profile assessment.  Subjects who received 
treatment with CTAP101 Capsules at 300 or 600 mcg per week will resume dosing, as before, 
and complete a second 26-week treatment period and a subsequent 6-week follow-up period.   


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The remaining subjects from each treatment group will forgo all PK assessments and complete 
26 or 52 weeks of treatment.  Subjects assigned to CTAP101 Capsules will remain on this 
study drug for the entire period.  Subjects assigned to placebo will be treated with placebo for 
the 26 weeks of treatment and, subsequently, if in Cohort 2, with CTAP101 Capsules at a dose 
of 300, 600 or 900 mcg per week, assigned randomly with stratification for severity of SHPT, 
during another 26 weeks of treatment.  All of these subjects will complete a 6-week follow-up 
period at the end of treatment with CTAP101 Capsules or placebo.   
Subjects in Cohort 1 only, who have completed 6 months of treatment with either CTAP101 
Capsules or placebo will receive, at their election, sub-therapeutic doses of cinacalcet (30 mg 
tiw at the end of HD) during 3 weeks of the 6-week FU observation period in order to observe 
its effects on plasma iPTH when serum total 25-hydroxyvitamin D is still elevated relative to 
pre-treatment baseline values.  Subjects who will begin treatment with cinacalcet must have a 
serum calcium of ≥8.6 mg/dL and a plasma iPTH ≥300 pg/mL. Dosing with cinacalcet will be 
suspended if plasma iPTH is <150 pg/mL or serum calcium is <7.5 mg/dL. 
For all subjects, pre-dialysis blood samples will be collected at weekly, biweekly or monthly 
intervals (see Section 7 Study Activities) during the pre-treatment washout period, the 26- and 
52-week treatment periods and the 6-week post-treatment follow-up period.  These samples 
will be collected at the start of either the 2nd or 3rd HD session of the week  
(Wednesday/Thursday or Friday/Saturday).  Key parameters to be analyzed in the collected 
samples include: plasma iPTH, serum calcium (corrected for serum albumin), serum 
phosphorus, serum total 25-hydroxyvitamin D, serum total 1,25-dihydroxyvitamin D, serum 
calcifediol, serum 1,25-dihydroxyvitamin D3, and serum 24,25-dihydroxyvitamin D3.  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) and clinical 
laboratory tests (hematology and clinical chemistries).  ECGs (12-lead) will be obtained at 
baseline and the end of treatment (EOT) only, or at early termination (ET).  
 
 
  
 
 
 
  
 
 
 
   
A diagram of the study design is shown below: 
 
 
 
 


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Cohort 1 (randomized, single-blinded design):  
 
Cohort 2 (randomized, double-blinded placebo-controlled design for the first 6 months of the 
treatment period followed by open-label, non-placebo-controlled design for the second 6 
months of the treatment period): 
 


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Dosing Plan: 
Subjects will receive two capsules (one or two CTAP101 Capsules, 150 mcg strength, and/or 
matching placebo) tiw in the dialysis center at approximately one hour (+/- 30 minutes) into 
the regularly scheduled HD session to achieve the total cumulative weekly dose.  The time 
between dosing and any food intake during or immediately after HD will be monitored and 
recorded for all subjects.  Subjects will be requested to abstain from eating within one hour of 
starting dialysis, and a small snack will be allowed (if requested) during dialysis.  After 12 
weeks of treatment, subjects in Cohort 2 who are receiving 300 or 600 mcg per week of 
CTAP101 Capsules and who are not participating in PK determinations will undergo upward 
dose titration provided that (a) the plasma iPTH has not decreased by at least 30% from 
pretreatment baseline and remains >300 pg/mL, (b) corrected serum calcium is <9.8 mg/dL, 
and (c) serum phosphorus is <6.0 mg/dL.  Subjects in Cohorts 1 or 2 who are receiving 900 
mcg per week of CTAP101 Capsules or placebo, or are participating in PK assessments, will 
not undergo upward dose titration at any time.  Upward dose titration will occur in a single 
increment of 300 mcg (two CTAP101 Capsules).  After 26 weeks of treatment, subjects who 
were assigned to placebo will commence treatment with 300, 600 or 900 mcg of CTAP101 
Capsules, assigned randomly with stratification for severity of SHPT. 
Subjects will reduce the dose at any time in increments of 300 mcg (two CTAP101 Capsules) 
per week in the event that plasma iPTH is confirmed to be <150 pg/mL, corrected serum 
calcium is confirmed to be >10.4 mg/dL, or serum phosphorus is confirmed to be >6.5 mg/dL, 
provided that that the investigator has deemed the elevated serum phosphorus to be related to 
study drug administration and has previously taken appropriate and persistent actions to 
control serum phosphorus by initiating or adjusting phosphate binder therapy.  In the event that 
a dose reduction is required for a subject receiving the minimum dosage of 300 mcg per week, 
the subject will suspend dosing and resume when plasma  iPTH is ≥150 pg/mL and corrected 
serum calcium is <9.8 mg/dL at the minimum dosage of 300 mcg per week.  Subjects assigned 
to treatment with CTAP101 Capsules will suspend dosing if plasma iPTH is confirmed to be 
<100 pg/mL or corrected serum calcium is confirmed to be >11.0 mg/dL, and will resume 
when plasma iPTH is ≥150 pg/mL and corrected serum calcium is <9.8 mg/dL at a dose that 
has been reduced by 300 mcg per week or at the minimum dosage of 300 mcg per week.   
After 12 weeks of treatment, subjects who have experienced more than a 100% increase in 
plasma iPTH from pre-treatment baseline or whose plasma iPTH has increased above 1,200 
pg/mL on two consecutive visits (if at least 2 weeks apart) will terminate dosing with study 
drugs and further participation in the treatment period and immediately enter the 6-week post-
treatment follow-up period.  Such subjects may be immediately removed from the study and 
placed on standard of care therapy, at the discretion of the Investigator. 
Subjects in Cohort 1 only, who have completed 6 months of treatment with either CTAP101 
Capsules or placebo will receive, at their election, sub-therapeutic doses of cinacalcet (30 mg 
tiw at the end of HD) during 3 weeks of the 6-week FU observation period in order to observe 
its effects on plasma iPTH when serum total 25-hydroxyvitamin D is still elevated relative to 
pre-treatment baseline values.  Subjects who will begin treatment with cinacalcet must have a 
serum calcium of ≥8.6 mg/dL and a plasma iPTH ≥300 pg/mL. Dosing with cinacalcet will be 
suspended if plasma iPTH is <150 pg/mL or serum calcium is <7.5 mg/dL. 


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Duration of Treatment: 
Subjects will participate in Cohort 1 of the study for up to the following number of weeks:  
• PK sub-group randomized to CTAP101 Capsules:  46 weeks (2 weeks screening, 8 
weeks washout, 2 weeks baseline, 2 weeks for single-dose PK determination, 26 weeks of 
treatment with CTAP101 Capsules, and 6 weeks for repeated-dose/steady-state PK 
determination and follow-up (FU) evaluation from CTAP101 treatment and inclusive of 3 
weeks of cinacalcet dosing). 
• PK sub-group randomized to placebo and Non-PK sub-group:  44 weeks (2 weeks 
screening, 8 weeks washout, 2 weeks baseline, 26 weeks of treatment with either 
CTAP101 Capsules or matching placebo, and 6 weeks of follow-up (FU) evaluation from 
CTAP101/placebo treatment and inclusive of 3 weeks of cinacalcet dosing). 
• Subjects who participate in Cohort 1 will not be eligible for participation in Cohort 2. 
Subjects will participate in Cohort 2 of the study for up to the following number of weeks: 
• PK sub-groups: 74 weeks (2 weeks screening, 8 weeks washout, if required, 2 weeks 
baseline, 2 weeks for single-dose PK determination, 26 weeks of treatment with either 
CTAP101 Capsules or matching placebo, 0-6 weeks for repeated-dose (steady-state) PK 
determination, 26 weeks of further treatment with CTAP101 Capsules, and 6 weeks of 
follow-up evaluation). 
• Non-PK sub-groups:  70 weeks (2 weeks screening, 8 weeks washout, if required, 2 
weeks baseline, 26 weeks of treatment with either CTAP101 Capsules or matching placebo 
followed by 26 weeks of treatment with CTAP101 Capsules only, and 6 weeks of follow-
up evaluation). 
Primary Efficacy Endpoint: 
There is no primary efficacy endpoint for Cohort 1, as efficacy in this part of the study is 
merely observational. The primary efficacy endpoint for Cohort 2 is the proportion of subjects 
in the intent-to-treat (ITT) population attaining both a mean serum total 25-hydroxyvitamin D 
of ≥50 ng/mL and a mean decrease in plasma iPTH of at least 30% from pre-treatment 
baseline, defined in Section 9.10.1, during the first efficacy assessment period (EAP), defined 
as the average of values obtained in the last 6 weeks of the first 26 weeks of treatment. 
Primary Safety Endpoints: 
The safety and tolerability will be evaluated for both cohorts in the Safety population (defined 
as all subjects who have received at least one dose of study drug) by AEs, PEs, VS, 
hematology and clinical chemistries, and ECGs. 
Pharmacokinetic and Pharmacodynamic Endpoints: 
Single-dose and repeated-dose (steady-state) PK determinations will be performed by 
analyzing serum calcifediol concentrations versus time recorded in both cohorts after (a) a 
single, initial dose of 0 mcg (placebo) or 300, 600 or 900 mcg (CTAP101 Capsules) and (b) 
after the last administered dose in the first 26 weeks of treatment in a subset of approximately 
21 (Cohort 1) or 18 (Cohort 2) subjects in each active treatment group.  The following PK 
parameters will be calculated using observed and baseline-adjusted serum calcifediol 


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concentrations: area under the concentration curve (AUC), maximum concentration, (Cmax), 
time to maximum concentration (tmax), steady-state concentration (Css), time to steady-state 
concentration (tss), terminal elimination half-life (t½) in subjects treated with CTAP101 
Capsules at a dose of 900 mcg per week, clearance (CL/F), and volume of distribution (Vd/F), 
as feasible.  Relative exposure and dose proportionality will be examined, if possible.   
In an effort to characterize the dose-exposure-response relationships and to determine the 
impact of intrinsic and extrinsic factors on these relationships, population PK and PD models 
will be developed from pooled serum calcifediol data collected from subjects in both cohorts.  
PD markers to be considered in the population PD analysis include: plasma iPTH, and serum 
calcium (corrected), phosphorus and 1,25-dihydroxyvitamin D3.  The effect of the following 
covariates will be examined: body weight, age, gender, race, SHPT severity, dialysis vintage, 
etiology of CKD and prior treatment with 1α-hydroxylated vitamin D analogs and/or 
calcimimetics. 
Secondary Endpoints: 
The key secondary efficacy endpoint for Cohort 1 is the proportion of subjects in the intent-to-
treat (ITT) population attaining both a mean serum total 25-hydroxyvitamin D of ≥50 ng/mL 
and a mean decrease in plasma iPTH of at least 30% from pre-treatment baseline, defined in  
Section 9.10.1, during the EAP, defined as the average of values obtained in the last 6 weeks 
of the 26 weeks of treatment, calculated for each treatment group and for each final dose 
group, defined in Section 9.11. 
Secondary efficacy endpoints for Cohorts 1 and 2 include the proportion of subjects in the per-
protocol (PP) population attaining both a mean serum total 25-hydroxyvitamin D of ≥50 
ng/mL and a mean decrease in plasma iPTH of at least 30% from pre-treatment baseline 
during the first EAP.  Additional secondary endpoints include the proportion of subjects in the 
PP population attaining both a mean serum total 25-hydroxyvitamin D of ≥50 ng/mL and a 
mean decrease in plasma iPTH of at least 10, 20 or 30% from pre-treatment baseline during 
the first and/or second EAP, as applicable, the latter being defined as the average of values 
obtained in the last 6 weeks of the second 26 weeks of treatment; the time courses of mean 
absolute changes from pre-treatment baseline in serum total 25-hydroxyvitamin D and plasma 
iPTH; categorical comparisons of safety and efficacy based on body weight, age, gender, race, 
dose, severity of SHPT and VDI, dialysis vintage, etiology of CKD and prior treatment with 
1α-hydroxylated vitamin D analogs and/or calcimimetics; PD effects on mean serum calcium 
(corrected), phosphorus, DBP, total free 25-hydroxyvitamin D, total 1,25-dihydroxyvitamin D, 
1,25-dihydroxyvitamin D3, and 24,25-dihydroxyvitamin D3; and, population PK of serum 
calcifediol relative to body weight, age, gender, race, dose, severity of SHPT and VDI, dialysis 
vintage, etiology of CKD and prior treatment with 1α-hydroxylated vitamin D analogs and/or 
calcimimetics. 
  
 
 
 
 
   


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Sample Size Estimation: 
Formal power calculations have not been undertaken for Cohort 1.  For Cohort 2, sample size 
has been calculated to provide power of 80% for a two-sided, alpha 0.05 level test of equal 
proportions comparing the numbers of subjects attaining both a mean serum total 25-
hydroxyvitamin D level of ≥50 ng/mL and a mean decrease from pre-treatment baseline of at 
least 30% in plasma iPTH (averaged over the last 6 weeks of the first 26-week treatment 
period) on each of the three different weekly dosages of CTAP101 Capsules (active) versus 
placebo.  Assuming response rates of at least 0.4 (CTAP101 Capsules) versus 0.1 (placebo), 
and using a 1:1 ratio of each dose of CTAP101 Capsules:placebo subjects with an estimated 
30% dropout rate over the course of the study, a sample size of 53 subjects is required in each 
treatment arm of the study, allocated as 53 to CTAP101 Capsules at 300 mcg per week, 53 to 
CTAP101 Capsules at 600 mcg per week, 53 to CTAP101 Capsules at 900 mcg per week, and 
53 to placebo. 
Statistical Analyses: 
Efficacy analyses will be performed for the ITT and PP populations in both cohorts, as 
indicated.  The ITT population will be defined as all subjects (up to approximately 212) who 
have been randomized to receive study medication.  Subjects who do not have at least one 
recorded value at baseline, defined in Section 9.10.1, for serum total 25-hydroxyvitamin D and 
for plasma iPTH will be excluded from all efficacy analyses. The PP population will be 
defined as all subjects for whom at least two serum total 25-hydroxyvitamin D and two plasma 
iPTH determinations are included in the calculated baseline value, and in the respective EAP, 
and who do not have a major protocol deviation.   
Primary efficacy will be assessed in the ITT population of Cohort 2 by comparing the 
proportions of subjects in all three active groups versus those in the placebo group and, 
subsequently, each active dose group versus placebo (in the order of dose group bb, then cc, 
then aa versus dose group dd) attaining both a mean serum total 25-hydroxyvitamin D level of 
≥50 ng/mL and a mean decrease from baseline in plasma iPTH of ≥30% in the first EAP using 
the Cochran-Mantel-Haenszel test statistic (alpha=0.05).  Subjects who do not have at least 
two serum total 25-hydroxyvitamin D and plasma iPTH determinations in the EAP will be 
deemed non-responders.  Dose groups will be defined for analysis of the first 26 weeks of 
treatment by the average weekly dose administered in the first EAP, as follows: dose group dd 
 = 0 mcg; dose group aa = 1-300 mcg, dose group bb = 301-600 mcg and dose group cc = 601-
900 mcg.  Statistical comparisons will not be made between the active treatment groups 
receiving different average weekly dosages of CTAP101 Capsules. 
Key secondary efficacy for Cohort 1 will be assessed in the ITT population by comparing the 
proportions of subjects in the active group versus those in the placebo group attaining both a 
mean serum total 25-hydroxyvitamin D level of ≥50 ng/mL and a mean decrease from baseline 
in plasma iPTH of at least 30% in the EAP using the Cochran-Mantel-Haenszel test statistic 
(alpha=0.05).  Subjects who do not have at least two serum total 25-hydroxyvitamin D and 
plasma iPTH determinations in the EAP will be deemed non-responders.   


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Secondary efficacy will be assessed in the PP population of Cohort 2 by comparing the 
proportions of subjects in each active dose group versus those in the placebo group attaining a 
mean serum total 25-hydroxyvitamin D of ≥50 ng/mL and a mean decrease from baseline in 
plasma iPTH of at least 10, 20 or 30% in the first and/or second EAP, as applicable, using the 
Cochran-Mantel-Haenszel test statistic (alpha=0.05).  Dose groups will be defined as described 
above.  Statistical comparisons will not be made between the active treatment groups receiving 
different average weekly dosages of CTAP101 Capsules.   
Primary safety analyses will be conducted in the Safety populations of both cohorts, and the 
statistical summary will be descriptive and performed by dose group (defined above).  No 
inferential hypothesis testing between each active group and the placebo group will be 
performed on the safety parameters with the exception of mean serum calcium and phosphorus. 
Secondary safety analyses in both cohorts will compare the proportions of subjects with 
confirmed corrected serum calcium >10.4 mg/dL or confirmed serum phosphorus >6.5 mg/dL 
(deemed to be study drug related) between the CTAP101 Capsules and placebo dose groups 
using the Cochran-Mantel-Haenszel test statistic (alpha=0.05).  
In addition to assessing the safety and efficacy evaluations for the full study population in 
Cohort 2, categorical comparisons (by dose group) will be conducted for sub-groups based on 
body weight, age, gender, race, dose and severity of SHPT and VDI, dialysis vintage, etiology 
of CKD and prior treatment with 1α-hydroxylated vitamin D analogs and/or calcimimetics. 
Also, mean plasma iPTH in the EAP of Cohort 1 and in the first EAP of Cohort 2 will be 
compared, by treatment group, to the mean pre-washout screening value for subjects who were 
previously treated with 1α-hydroxylated vitamin D analogs and/or calcimimetics.  An interim 
analysis of safety and efficacy will be completed for Cohort 2 after the last subject has 
completed the first 26 weeks of treatment.   
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled into the two cohorts of this study: 
1. Be at least 18 years of age. 
2. Be diagnosed with CKD requiring in-center HD tiw for the preceding 6 months, as 
confirmed by medical history. 
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; and, 
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. 
4 Be receiving calcimimetic therapy (either etelcalcetide or cinacalcet) and/or calcitriol or 
other 1α-hydroxylated vitamin D analog (paricalcitol or doxercalciferol) for at least 1 
month at the time of screening for enrollment in Cohort 1.  Approximately 50% of enrolled 
subjects will have been receiving calcimimetic therapy. 
5. Exhibit during the initial screening visit: 


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a. Plasma iPTH ≥150 pg/mL and <600 pg/mL if receiving etelcalcetide, cinacalcet, 
calcitriol or other 1α-hydroxylated vitamin D analog (paricalcitol or doxercalciferol); 
or  
b. Plasma iPTH ≥300 pg/mL and <900 pg/mL if not receiving etelcalcetide, cinacalcet, 
calcitriol or other 1α-hydroxylated vitamin D analog; and,  
c. Serum total 25-hydroxyvitamin D <50 ng/mL if not receiving vitamin D 
supplementation. 
6. When otherwise confirmed eligible at Visit 1, must forgo any further treatment with 
etelcalcetide and cinacalcet for the duration of the study and undergo an 8-week washout 
period. 
7. When otherwise confirmed eligible at Visit 1, must forgo any further treatment with 
calcitriol or other 1α-hydroxylated vitamin D analogs or vitamin D supplements for the 
duration of the study and undergo an 8-week washout period.  
8. Exhibit after the 8-week washout period (if required due to prior use of etelcaclcetide, 
cinacalcet, calcitriol or other 1α-hydroxylated vitamin D analogs, or vitamin D 
supplementation): 
Cohort 1: 
a. Plasma iPTH increased by at least 50%; and, 
b. Plasma iPTH ≥300 pg/mL and <1,200 pg/mL; or, 
Cohort 2:  
f. Plasma iPTH ≥300 pg/mL and <1,200 pg/mL (approximately half of the subjects will 
be enrolled in each of these two plasma  iPTH strata: ≥300 to <600 and ≥600 to <1,200 
pg/mL); and 
Cohorts 1 and 2: 
c. Corrected serum calcium <9.8 mg/dL; 
d. Serum total 25-hydroxyvitamin D <50 ng/mL; and, 
e. Serum phosphorus <6.5 mg/dL. 
9. When otherwise confirmed eligible at Visit 1, if taking more than 1,000 mg per day of 
elemental calcium, reduce calcium use (to ≤1,000 mg per day) and/or use non-calcium 
based phosphate binder therapies (as needed) for the duration of the study. 
10. When otherwise confirmed eligible at Visit 1, if taking bone metabolism therapies that 
may interfere with study endpoints, must discontinue use of these agents for the duration of 
the study. 
11. Willing and able to comply with study instructions and commit to all clinic visits for the 
duration of the study. 
12. Female subjects of childbearing potential must be neither pregnant nor lactating and must 
have a negative serum beta-human chorionic gonadotropin (b-hCG) pregnancy test at the 
first screening visit and at other scheduled times. 
13. All female subjects of childbearing potential and male subjects with female partners of 
childbearing potential must agree to use effective contraception (eg, implants, injectables, 


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combined oral contraceptives, intrauterine device, sexual abstinence, vasectomy or 
vasectomized partner) for the duration of the study. 
14. Be able to read, understand and sign the subject Informed Consent Form (ICF) or have a 
legal representative sign the ICF. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
1. Scheduled kidney transplant or parathyroidectomy. 
2. History (prior 2 months) of corrected serum calcium ≥9.8 mg/dL or serum phosphorus 
≥6.5 mg/dL if not receiving calcitriol or other 1α-hydroxylated vitamin D analog. 
3. Receipt of bisphosphonate therapy or other bone modifying treatment (eg, denosumab) 
within 6 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, intestinal 
malabsorption disorder, hepatitis or cardiovascular event that in the opinion of the 
investigator may worsen or reduce life expectancy, and/or interfere with participation in 
the study. 
5. History of neurological/psychiatric disorder, including psychotic disorder or dementia, or 
any reason which, in the opinion of the investigator makes adherence to a treatment or 
follow-up schedule unlikely. 
6. Known or suspected hypersensitivity to any of the constituents of the study drugs. 
7. Currently participating in, or has participated in, an interventional/investigational study 
within 30 days prior to study screening. 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
1,25D3 
1,25-dihydroxyvitamin D3, calcitriol 
24,25D3 
24,25-dihydroxyvitamin D3 
25D3 
25-hydroxyvitamin D3, calcifediol, calcidiol 
 
 
AE 
adverse event 
ALT 
alanine transferase 
AST 
aspartate aminotransferase 
AUC 
area under the (concentration) curve 
BA 
Bioavailability 
 
 
b-hCG 
beta-human chorionic gonadotropin  
BMI 
body mass index 
CFR 
Code of Federal Regulations 
 
 
CKD 
chronic kidney disease 
CL/F 
Clearance 
Cmax 
maximum concentration 
 
 
Css 
steady-state concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
 
 
CV 
coefficient of variation 
 
 
DBP 
vitamin D binding protein 
DSMB 
data safety monitoring board 
EAP 
efficacy assessment period 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture  
EOT 
end of treatment 
ER 
extended-release 


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ET 
early termination 
FDA 
Food and Drug Administration 
 
 
FU 
GCP 
follow-up 
Good Clinical Practice 
GFR 
glomerular filtration rate 
HD 
Hemodialysis 
HDPE 
high-density polyethylene 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation  
 
 
IP 
iPTH 
investigational product 
intact parathyroid hormone 
IRB/EC 
Institutional Review Board/Ethics Committee 
IRT 
interactive response technology 
ITT 
intent-to-treat 
K/DOQI 
Kidney Disease Outcomes Quality Initiative 
KDIGO 
Kidney Disease Improving Global Outcomes 
LAR 
legally authorized representative 
MBD 
mineral and bone disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
 
 
PD 
pharmacodynamic(s) 
PE 
physical examinations 
PK 
pharmacokinetic(s) 
PP 
per-protocol 
PTH 
parathyroid hormone 
SAE 
serious adverse event 
SD 
standard deviation 
SGOT 
serum glutamic oxaloacetic transaminase 


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SGPT 
serum glutamic pyruvic transaminase 
SHPT 
secondary hyperparathyroidism 
SOC 
system organ class 
SOP 
standard operating procedure 
 
 
t1/2 
terminal elimination half-life 
TEAE 
treatment-emergent adverse events 
tiw 
three times per week 
tmax 
time to maximum concentration 
 
  
tss 
time to steady-state concentration 
US 
United States 
Vd/F 
volume of distribution 
VDI 
vitamin D insufficiency 
VS 
vital signs 
WO 
wash-out 


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1 INTRODUCTION 
1.1 
Chronic Kidney Disease and Vitamin D Insufficiency 
CTAP101 is an extended-release (ER) oral formulation of calcifediol which OPKO Ireland 
Global Holdings Ltd. (OPKO) is developing as a treatment for secondary hyperparathyroidism 
(SHPT) in patients with vitamin D insufficiency (VDI) and stage 5 chronic kidney disease 
(CKD) requiring regular hemodialysis (HD). 
Calcifediol is 25-hydroxyvitamin D3, the physiological precursor to the vitamin D hormone, 
1,25-dihydroxyvitamin D3 (calcitriol).  This prohormone is synthesized by the liver from vitamin 
D3 (cholecalciferol) generated endogenously in skin following exposure to sunlight or obtained 
from the diet or supplements.  Another prohormone, 25-hydroxyvitamin D2, is synthesized 
hepatically from vitamin D2 (ergocalciferol), which cannot be produced endogenously but is 
obtained only from the diet or supplements.  These two prohormones are collectively referred to 
as “25-hydroxyvitamin D.”  Unless an individual is receiving significant ergocalciferol 
supplementation, essentially all of the 25-hydroxyvitamin D in blood consists of calcifediol.  
It is widely accepted that serum total 25-hydroxyvitamin D is the best indicator of a patient’s 
vitamin D status.  Serum total 25-hydroxyvitamin D levels of ≥30 ng/mL are currently 
considered adequate in CKD patients while levels of <30 ng/mL are considered “insufficient” 
[Holick et al 2011].  The commonly used reference range for serum total 25-hydroxyvitamin D is 
30 to 100 ng/mL [Souberbielle et al 2010].  Observational studies suggest that in CKD patients, 
as glomerular filtration rate (GFR) declines, higher 25-hydroxyvitamin D levels may be required 
to achieve plasma intact parathyroid hormone (iPTH) targets [Ennis et al 2016].  A secondary 
analysis of two prospective randomized clinical trials conducted in patients with stage 3 or 4 
CKD concluded that 25-hydroxyvitamin D levels above 50 ng/mL were required for significant 
plasma iPTH reduction [Strugnell et al 2019]. Levels of serum total 25-hydroxyvitamin D in the 
general population vary according to many factors, including intensity of sunlight (varying with 
geographic location and season), exposure to sunlight (affected by skin pigmentation, use of 
sunscreen and other cultural factors), age and dietary intake [Holick 1995].  Levels tend to be 
lower during the winter and at higher latitudes.  In patients with CKD, low serum total 25-
hydroxyvitamin D levels (VDI) are unrelated to season or latitude and become more prevalent as 
kidney disease advances. 
1.2 
Chronic Kidney Disease, SHPT and Vitamin D Insufficiency 
CKD is a steadily-increasing health problem in the United States (US) driven by an aging 
population and an increasing prevalence of obesity with associated complications of 
hypertension and diabetes mellitus.  CKD is categorized into five stages, each defined by a GFR 
range that progressively decreases from stage 1 to 5.  Aberrations in mineral metabolism and 
bone histology begin early in the course of CKD, worsening as GFR declines [Levin et al 2007].  
Even minimal reductions in GFR have been linked to increased risk of bone loss (osteoporosis), 
and the incidence of hip fracture increases as CKD progresses.  Co-morbidities associated with 
CKD include SHPT, VDI, pervasive soft tissue calcification, cardiovascular disease, infections 
and reduced quality of life [Souberbielle et al 2010].   
VDI in patients with CKD is driven by nutritional inadequacy, decreased exposure to sunlight, 
proteinuria, decreased hepatic synthesis of calcifediol and excessive expression of the vitamin D 


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catabolic enzyme, CYP24 [Helvig et al 2010].  Because renal and extra-renal production of 1,25-
dihydroxyvitamin D3 is dependent on an adequate supply of calcifediol, VDI causes inadequate 
1,25-dihydroxyvitamin D3 production.  Declining renal function further impairs the conversion 
of calcifediol to 1,25-dihydroxyvitamin D3 by the renal 1α-hydroxylase (CYP27B1).  
Chronically low circulating 1,25-dihydroxyvitamin D3 results in decreased intestinal absorption 
of dietary calcium, increased secretion of parathyroid hormone (PTH) by the parathyroid glands 
and, ultimately, SHPT. 
Clinical practice guidelines for the treatment of metabolic bone disease in CKD recommend 
regular screening for elevated PTH beginning in patients with stage 3 CKD.  The guidelines, 
issued by the National Kidney Foundation from the Kidney Disease Outcomes Quality Initiative 
(K/DOQI) [National Kidney Foundation. KDOQI Clinical Practice Guidelines for Bone 
Metabolism and Disease in Chronic Kidney Disease 2003, Guideline 8A], the more recent 
Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the 
Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone 
Disorder (CKD-MBD) [Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD 
Work Group 2009] and the recent update to the KDIGO guideline [KDIGO 2017 Clinical 
Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of CKD-
MBD], also recommend testing for VDI when elevated PTH is encountered, and correcting with 
aggressive vitamin D supplementation.  However, the medical literature documents that low 
serum total 25-hydroxyvitamin D is inconsistently or inadequately treated in patients with stage 
3 or 4 CKD by vitamin D (ergocalciferol or cholecalciferol) supplementation, and that elevated 
PTH remains uncorrected.  More than 30 studies have been published since 1973 in which 
ergocalciferol or cholecalciferol was administered to patients with stage 3 to 5 CKD.  The overall 
conclusion from this body of work is summarized by Kalantar-Zadeh and Kovesdy: “Most of 
these studies have shown either no or minimal to inadequate changes in PTH levels, usually only 
in some stages of CKD, or changes that still would not satisfy the K/DOQI recommended target 
ranges for PTH” [Kalantar-Zadeh  and Kovesdy 2009].  A more recent review of the published 
randomized clinical trials concluded that vitamin D had no efficacy in lowering plasma iPTH 
levels in patients with stage 3 to 5 CKD [Agarwal and Georgianos 2016]. Hence, there is a need 
for effective treatment to increase serum total 25-hydroxyvitamin D and control elevated plasma 
iPTH in this patient population. 
1.3 
Nonclinical Experience 
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 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. 


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To study the toxicity of CTAP101 Capsules, an earlier formulation of CTAP101 Capsules was 
administered to dogs for 3 months 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 per day and were associated with serum calcifediol levels >450 ng/mL following 
1 month of treatment. 
Using the current formulation of CTAP101 Capsules, dogs were treated daily for three months 
with doses up to 45 µg (~4.5 µg/kg/day).  No signs of toxicity were observed at the highest dose 
tested which was associated with serum calcifediol levels >150 ng/mL.   
Calcifediol administration (orally through addition to the diet) to rats for 6 months has been 
reported to produce signs of toxicity at daily doses >40 µg/kg.  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) demonstrate 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 immediate-release capsule preparation.  Further, a delay in the release of 
the active ingredient (time of maximum concentration or tmax >7 hours) was observed as 
compared to the immediate-release formulation (tmax ~4 hours). 
1.4 
Previous Clinical Experience 
CTAP101 Capsules (30 mcg/capsule) have been approved by  the US Food and Drug 
Administration (FDA) for the treatment of SHPT in adults with stage 3 or 4 CKD and VDI, 
defined as serum total 25-hydroxyvitamin D levels less than 30 ng/mL.  The clinical studies 
which supported FDA approval are described below. 
There have been three previous single-dose phase 1 studies with CTAP101 Capsules (CTAP101-
CL-1005, CTAP101-CL-1011 and CTAP101-CL-1016), two phase 2 studies, of which one was a 
single-dose study (CTAP101-CL-2004) and one was a repeat-dose study (CTAP101-CL-2008), 
and three phase 3 studies (CTAP101-CL-3001, CTAP101-CL-3002 and CTAP101-CL-3003).  
Studies CTAP101-CL-1011, CTAP101-CL-1016 and CTAP101-CL-2008 were conducted with 
the current formulation of CTAP101 Capsules (30 mcg per capsule).  Two of the phase 3 studies 
(CTAP101-CL-3001 and CTAP101-CL-3002) were identical double-blind, placebo-controlled 
pivotal trials and the third (CTAP101-CL-3003) was a follow-on open-label extension trial.   
The single-dose studies confirmed the ER characteristics of the investigational drug product and 
that the current formulation has a BA of approximately 25% when administered in the fasting 
state.  Administration of a single pharmacologic dose of CTAP101 Capsules following a high-
fat, high calorie meal resulted in a significantly higher exposure of calcifediol compared to when 
administered in a fasted state.  An approximate 5-fold increase in Cmax and a 3.5-fold increase in 
area under the concentration curve (AUC) was observed in the fed group compared to the fasted 
group (CTAP101-CL-1016). 
In CTAP101-CL-2008, a double-blind, placebo-controlled, randomized repeat-dose 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 iPTH from baseline and compared to 


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placebo during 6 weeks of treatment.  The mean % decrease in plasma iPTH from baseline in the 
per-protocol (PP) population was related to the administered dose: -20.9, -32.8, and -39.3 for the 
30, 60 and 90 mcg groups, respectively.   
The efficacy was confirmed in the phase 3 program with nearly all subjects (97%) treated with 
CTAP101Capsules who completed the program without a major protocol deviation, achieving a 
normal serum total 25-hydroxyvitamin D level and with 50% of such subjects achieving a mean 
reduction in plasma iPTH from baseline of at least 30%.  Fewer than 9% of placebo subjects 
achieved a 30% reduction in plasma iPTH or achieved a normal 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 
investigational study drug. 
For all clinical studies, the adverse event (AE) profiles did not identify any events specific to 
CTAP101 Capsules.  After both single and repeat-dose administration, CTAP101 Capsules were 
generally well-tolerated.  The overall treatment emergent AE profile in the phase 3 program was 
comparable between CTAP101 Capsules and placebo groups.  Subjects receiving CTAP101 
Capsules had a greater increase in mean serum calcium (P<0.001) than placebo patients (0.2 
versus 0.1 mg/dL); for serum phosphorus, subjects receiving CTAP101 Capsules had a greater 
mean increase (P<0.05) than placebo patients (0.2 versus 0.1 mg/dL). 
 
 


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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 three dose levels of CTAP101 ER Capsules 
versus placebo in raising mean serum total 25-hydroxyvitamin D to ≥50 ng/mL and in 
reducing mean plasma iPTH by at least 30% from pre-treatment baseline;  
2. To investigate the safety and tolerability of repeated dosing with three dose levels of 
CTAP101 Capsules;  
3. To assess the pharmacokinetic (PK) profiles and PK linearity of serum calcifediol after single 
and repeated doses of CTAP101 Capsules at three dose levels in subjects with SHPT, VDI 
and CKD who are undergoing HD three times per week (tiw).  
2.1.2 
Secondary Objectives  
The secondary objectives of this study are: 
1. To evaluate the efficacy of repeated dosing with three dose levels of CTAP101 ER Capsules 
versus placebo in raising mean serum total 25-hydroxyvitamin D to ≥50 ng/mL and in 
reducing mean plasma iPTH by at least 10 and 20% from pre-treatment baseline;   
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 at three dose levels; 
3. To assess the effects of body weight, age, gender, race, dose, severity of SHPT and VDI, 
dialysis vintage, etiology of CKD and prior treatment with 1α-hydroxylated vitamin D 
analogs and/or calcimimetics on the safety and efficacy of repeated doses of CTAP101 
Capsules at three dose levels versus placebo in raising serum total 25-hydroxyvitamin D to 
≥50 ng/mL and in reducing plasma iPTH by at least 10, 20 and 30% from pre-treatment 
baseline; 
4. To assess the pharmacodynamic (PD) effects of repeated doses of CTAP101Capsules at three 
dose levels versus placebo on mean serum calcium (corrected for albumin), phosphorus, 
vitamin D binding protein (DBP), total free 25-hydroxyvitamin D, total 1,25-
dihydroxyvitamin D, 1,25-dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3;  
5. To characterize the population PK of serum calcifediol relative to body weight, age, gender 
race, dose, severity of SHPT and VDI, dialysis vintage, etiology of CKD and prior treatment 
with 1α-hydroxylated vitamin D analogs and/or calcimimetics; and, 
6. To evaluate the safety of CTAP101 Capsules versus placebo with regard to the incidence of 
hypercalcemia and hyperphosphatemia. 
 
 


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3 INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a phase 2, multi-center, randomized, two-cohort study to evaluate the safety, efficacy, PK 
and PD of CTAP101 Capsules to treat SHPT in male and female subjects aged at least 18 years 
with VDI and CKD requiring thrice weekly in-center HD.  The study will be conducted in two 
successive cohorts at multiple sites within the US.  Subjects in Cohort 1 will participate in a 
randomized, single-blinded (subjects only), placebo-controlled repeated-dose exploratory safety 
and efficacy study of CTAP101 Capsules administered at one, high dose level (900 mcg per 
week).  Subjects in Cohort 2 will not be enrolled until sufficient data have been obtained from 
Cohort 1 and reviewed with the US Food and Drug Administration (FDA) to make a reasonable 
decision to proceed with the second cohort, potentially under a further amendment to this 
protocol.  Subjects in Cohort 2 will participate in a randomized, double-blinded, placebo-
controlled repeated-dose, dose-ranging safety and efficacy study of CTAP101 Capsules 
administered at three different dose levels (300, 600 or 900 mcg per week). 
In Cohort 1, approximately 100 subjects will be screened to randomize approximately 44 eligible 
subjects in a 3:1 ratio into two groups receiving the following treatments in a single-blinded 
(subjects only) fashion for 26 weeks: (a) CTAP101 Capsules at 900 mcg per week or (b) 
matching placebo.  Randomization will be accomplished in blocks of four subjects using two 
computer-generated codes, one for the PK sub-group (n=28) and one for the non-PK sub-group 
(n=16). 
In Cohort 1, subjects who have been consented and did not meet eligibility criteria at the 
conclusion of the Screening Visit (Visit 1) are considered a Screen Failure.  Subjects who are 
eligible after Visit 1, but do not meet eligibility criteria at either Visit 2 or Visit 3 are considered 
a Pre-Treatment Failure.  Only subjects who are randomized to a treatment at Visit 3 who are 
then withdrawn during the study will complete ET study procedures. 
In Cohort 2, approximately 480 subjects will be screened to randomize approximately 212 
eligible subjects, stratified for severity of SHPT, in a 1:1:1:1 ratio into four groups receiving the 
following treatments in a double-blinded fashion for 26 weeks: (aa) CTAP101 Capsules at 300 
mcg per week, (bb) CTAP101 Capsules at 600 mcg per week, (cc) CTAP101 Capsules at 900 
mcg per week or (dd) matching placebo.  Randomization will be accomplished in blocks of four 
subjects using two computer-generated codes, one for the PK sub-group (n=72) and one for the 
non-PK sub-group (n=140).  A subset of subjects will undergo a subsequent 26 weeks of 
treatment (for a total of 52 weeks) depending on their participation in the PK determinations 
described below.   
An Interactive Response Technology system (IRT) will provide study treatment group 
assessments for both cohorts (using computer-generated randomization codes provided by the 
IRT vendor) and dosing adjustments.  For Cohort 2 only, an independent, unblinded Data Safety 
Monitoring Board (DSMB) will be established to oversee the IRT and verify the appropriateness 
of all dosing adjustments, to monitor subject safety and the effectiveness of CTAP101 Capsules 
at regular intervals.  Specific responsibilities and activities of the DSMB will be defined in the 
charter ratified at the pre-Cohort 2 organizational meeting.  Also, for Cohort 2 only, subjects, 
dialysis facilities, study personnel and the sponsor will be blinded to the administered treatments 


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and to plasma iPTH, serum total 25-hydroxyvitamin D and serum calcifediol 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. 
All subjects will undergo regular HD during the study.  Subjects receiving treatment with 
calcitriol or other 1α-hydroxylated vitamin D analog, vitamin D supplements, or calcimimetic 
prior to study enrollment will forgo further dosing with these agents after confirmed eligible at 
Visit 1 and for the duration of the study and complete an 8-week washout period prior to baseline 
assessments.  Subjects will undergo a 6-week FU observation period after completing treatment.   
On two occasions, a subset of subjects (n=~21) from Cohort 1 who are assigned to treatment 
with CTAP101 Capsules and, on one or two occasions, a subset of subjects (n=~18) from each of 
the four treatment groups in Cohort 2 will be housed after the end-of-week HD (on Friday or 
Saturday) in a nearby phase 1 unit for 3 days in order to provide blood samples for determination 
of single-dose (all groups) and repeated dose (active groups) PK profiles of serum calcifediol and 
associated PD profiles for serum calcium (corrected), phosphorus, DBP, total free 25-
hydroxyvitamin D, total 1,25-dihydroxyvitamin D, 1,25-dihydroxyvitamin D3 and 24,25-
dihydroxyvitamin D3.  Subjects receiving CTAP101 Capsules will complete a 26-week treatment 
period between the two PK profile assessments.  Subjects in Cohort 2 receiving treatment with 
placebo will complete a 26-week treatment period after the single-dose PK assessment, and then 
receive CTAP101 Capsules at a dose of 300, 600 or 900 mcg per week, assigned randomly with 
stratification by severity of SHPT, during a second 26-week treatment period, after which they 
will complete a 6-week follow-up period.  Blood samples for the first PK profile assessments 
will be collected at -12, -3, 0, 4, 8, 12, 16, 20, 24, 30, 36 and 42 hours, and on Days 4, 6, 8, 11 
and 15 following a single dose (0, 300, 600 or 900 mcg) administered as 6 capsules (CTAP101 
and/or placebo) 2 weeks prior to the start of the first 26-week treatment period and, again, after 
the last administered dose in treatment week 26.  Blood samples for the second PK profile 
assessment will be collected at -12, -3, 0, 4, 8, 12, 16, 20, 24, 30, 36 and 42 hours, and on Days 
4, 6, 8, 11 and 15 following the last administered dose in treatment week 26 for subjects 
receiving dosages of 300 or 600 mcg per week of CTAP101 Capsules, and at -12, -3, 0, 4, 8, 12, 
16, 20, 24, 30, 36 and 42 hours, and on Days 4, 6, 8, 11, 15, 22, 29 and 43 following the last 
administered dose in treatment week 26 for subjects receiving 900 mcg per week of CTAP101 
Capsules. On specified and subsequent HD days, blood samples will be collected just before 
dialysis.  Subjects who received treatment with CTAP101 Capsules at 900 mcg per week will 
terminate further participation in the study after the second PK profile assessment.  Subjects who 
received treatment with CTAP101 at 300 or 600 mcg per week will resume dosing, as before, 
and complete a second 26-week treatment period and a subsequent 6-week follow-up period.   
The remaining subjects from each treatment group will forgo all PK assessments and complete 
26 or 52 weeks of treatment.  Subjects assigned to CTAP101 Capsules will remain on this study 
drug for the entire period.  Subjects assigned to placebo will be treated with placebo for the 26 
weeks of treatment and, subsequently, if in Cohort 2, with CTAP101 Capsules at a dose of 300, 
600 or 900 mcg per week, assigned randomly with stratification by severity of SHPT, during 
another 26 weeks of the treatment.  All of these subjects will complete a 6-week follow-up 
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Subjects in Cohort 1 only, who have completed 6 months of treatment with either CTAP101 
Capsules or placebo will receive, at their election, sub-therapeutic doses of cinacalcet (30 mg tiw 
at the end of HD) during 3 weeks of the 6-week FU observation period in order to observe its 
effects on plasma iPTH when serum total 25-hydroxyvitamin D is still elevated relative to pre-
treatment baseline values.   
For all subjects, pre-dialysis blood samples will be collected at weekly, biweekly or monthly 
intervals (see Section 7 Study Activities) during the pre-treatment washout period, the 26- and 
52-week treatment periods and the 6-week post-treatment follow-up period.  These samples will 
be collected at the start of either the 2nd or 3rd HD session of the week (Wednesday/Thursday or 
Friday/Saturday).  Key parameters to be analyzed in the collected samples include: 
 
corrected serum calcium (adjusted for serum albumin), serum phosphorus, serum total 25-
hydroxyvitamin D, serum total 1,25-dihydroxyvitamin D, 
 serum 1,25-
dihydroxyvitamin D3, and serum 24,25-dihydroxyvitamin D3.  VS and AEs will be monitored at 
each study visit.  Other parameters to be monitored less frequently include brief PEs and clinical 
laboratory tests (hematology and clinical chemistries).  12-lead ECGs will be obtained at 
baseline and end of treatment (EOT) only, or at early termination (ET).  
 
 
  
 
 
  
 
 
 
   
A diagram of the study design is shown below: 
 
 


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Cohort 1 (randomized, single-blinded design):  
 
 
Cohort 2 (randomized, double-blinded placebo-controlled design for the first 6 months of the 
treatment period followed by open-label, non-placebo-controlled design for the second 6 months 
of the treatment period): 
 


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3.2 
Rationale for Study Design and Control Group 
OPKO is developing CTAP101 Capsules for the treatment of SHPT in patients with VDI and 
stage 5 CKD requiring regular HD.  The active ingredient in CTAP101 Capsules is calcifediol, 
which is formulated as ER capsules for oral administration.  The formulation is designed to raise 
serum total 25-hydroxyvitamin D in a gradual (physiological) manner.  Raising blood levels of 
25-hydroxyvitamin D too rapidly produces a surge in 1,25-dihydroxyvitamin D production 
which increases the expression of CYP24 in both the kidney and in peripheral target tissues and 
has significant adverse effects on the expression of other key factors associated with bone and 
mineral metabolism, including FGF23, CYP27B1, calcium and phosphorus [Petkovich et al 
2015]. 
The principal aim of the present study is to:  
1) Explore, in Cohort 1, the safety, efficacy, PK and PD of CTAP101 Capsules administered for 
26 weeks at a weekly dose of 900 mcg to treat SHPT in subjects aged 18 years or older with 
VDI and stage 5 CKD receiving regular HD; and, if appropriate (based on a review of the 
data obtained by the Sponsor and the FDA),  
2) Further evaluate, in Cohort 2, the safety, efficacy, PK and PD of CTAP101 Capsules 
administered for up to 52 weeks.   
Cohort 2 of the present study is designed to evaluate the efficacy of CTAP101 Capsules with 
regard to raising mean serum total 25-hydroxyvitamin D to ≥50 ng/mL and reducing mean 
plasma iPTH levels by at least 30% from pre-treatment baseline.  The study also will examine 
the safety and tolerability of CTAP101 Capsules.  This placebo-controlled study provides the 
best means to evaluate safety, efficacy and tolerability of CTAP101 Capsules because no therapy 
has yet been approved to treat elevated plasma iPTH levels associated with low serum total 25-
hydroxyvitamin D levels in patients with stage 5 CKD. Single-dose and repeated-dose PK 
profiles of serum calcifediol and associated PD profiles for serum DBP, total free 25-
hydroxyvitamin D, total 1,25-dihydroxyvitamin D, 1,25-dihydroxyvitamin D3 and 24,25-
dihydroxyvitamin D3 will be determined in a subset of subjects in Cohort 2. 
The starting dose and dose titration criteria are based on the results from prior repeat-dose, 
placebo-controlled, double-blind studies with CTAP101 Capsules (30 mcg) in patients with VDI 
and stage 3-4 CKD. These studies demonstrated that CTAP101 Capsules increased mean serum 
total 25-hydroxyvitamin D and decreased mean plasma iPTH in a dose-proportional manner.  
CTAP101 Capsules administered at daily doses of 30, 60 and 90 mcg (or 210, 420 and 630 
µg/week) for six weeks produced mean plasma iPTH changes from baseline of -20.9, -32.8 and -
39.3%, respectively, and elevated serum total 25-hydroxyvitamin D levels ≥30 ng/mL in almost 
all subjects (CTAP101-CL-2008).  AE rates were comparable across the treatment groups, 
indicating that therapy with CTAP101 Capsules had no adverse effect on mean serum calcium or 
phosphorus or on any other monitored parameters during the 6-week treatment period.  PK 
analyses determined that the terminal elimination half-life t1/2 after repeat dosing was 
approximately 30 days but that steady state was not yet achieved after 6 weeks of treatment.  
Steady state in phase 3 studies was attained after 12 weeks of treatment (CTAP101-CL-3001 and 
CTAP101-CL-3002).  Thus, in the present study (CTAP101-CL-2010), subjects will complete up 
to 52 weeks of therapy with a tiw dose of CTAP101 Capsules of 300, 600 and 900 mcg/week.  
Study drug will be reduced or discontinued for confirmed excessive elevations in serum calcium 
or phosphorus or for confirmed over suppression of plasma iPTH.   


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The pivotal phase 3 studies (CTAP101-CL-3001 and CTAP101-CL-3002) showed that 
CTAP101 Capsules suppressed plasma iPTH to the same degree in both stage 3 and stage 4 
CKD, a finding which is at odds with conventional wisdom that 25-hydroxyvitamin D is less 
likely to be converted to 1,25-dihydroxyvitamin D as CKD advances, due to declining 
expression of CYP27B1 in the failing kidneys. This finding indicates that (a) there is adequate 
renal CYP27B1 activity in predialysis patients to activate 25-hydroxyvitamin D and/or that (b) 
25-hydroxyvitamin D is activated by CYP27B1 expressed outside the kidneys.  It is well 
established that CYP27B1 is expressed and functional in the parathyroid glands and in many 
other extra-renal tissues [Adams et al 2014], presumably for local hormone production, and that 
extra-renal expression of CYP27B1 can be stimulated by further cinacalcet therapy [Ritter el al 
2012].  Further, it has been demonstrated that serum levels of 1,25-dihydroxyvitamin D rise in 
response to administered calcifediol in anephric patients [Dusso et al 1990].  It is plausible, 
therefore, that CTAP101 Capsules raise serum total 25-hydroxyvitamin D to high enough levels 
to enable sufficient extra-renal 1,25-dihydroxyvitamin D production for PTH control. 
3.3 
Study Duration 
Cohort 1 of the study is expected to be conducted in approximately 14 months from time of 
initial subject enrollment (first subject consented) to study completion for the last subject (last 
subject out/last visit complete).  Cohort 2 is expected to be conducted in approximately 27 
months.  Subjects will participate in the study for up to approximately: 
• PK sub-group randomized to CTAP101 Capsules:  46 weeks (2 weeks screening, 8 weeks 
washout, 2 weeks baseline, 2 weeks for single-dose PK determination, 26 weeks of treatment 
with CTAP101 Capsules, and 6 weeks for repeated-dose/steady-state PK determination and 
follow-up (FU) evaluation from CTAP101 treatment and inclusive of 3 weeks of cinacalcet 
dosing). 
• PK sub-group randomized to placebo and Non-PK sub-group: 44 weeks (2 weeks 
screening, 8 weeks washout, 2 weeks baseline, 26 weeks of treatment with either CTAP101 
Capsules or matching placebo, and 6 weeks of follow-up (FU) evaluation from 
CTAP101/placebo treatment and inclusive of 3 weeks of cinacalcet dosing).  
• Subjects who participate in Cohort 1 will not be eligible for participation in Cohort 2. 
Subjects will participate in Cohort 2 of the study for up to approximately: 
• PK sub-groups: 74 weeks (2 weeks screening, 8 weeks washout, if required, 2 weeks 
baseline, 2 weeks for single-dose PK determination, 26 weeks of treatment with either 
CTAP101 Capsules or matching placebo, 0-6 weeks for repeated-dose (steady-state) PK 
determination, 26 weeks of further treatment with CTAP101 Capsules, and 6 weeks of 
follow-up evaluation); or, 
• Non-PK sub-groups:  70 weeks (2 weeks screening, 8 weeks washout, if required, 2 weeks 
baseline, 26 weeks of treatment with either CTAP101 Capsules or matching placebo 
followed by 26 weeks of treatment with CTAP101 Capsules only, and 6 weeks of follow-up 
evaluation). 


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3.4 
Study Endpoints 
3.4.1 
Pharmacokinetic Endpoints 
Single-dose and repeated-dose (steady-state) PK determinations will be performed by analyzing 
serum calcifediol concentrations versus time recorded in both cohorts after (a) a single, initial 
dose of 0 mcg (placebo) or 300, 600 or 900 mcg (CTAP101 Capsules) and (b) after the last 
administered dose in the first 26 weeks of treatment in a subset of approximately 21 (Cohort 1) 
or 18 (Cohort 2) subjects in each active treatment group.  The following PK parameters will be 
calculated using observed and baseline-adjusted serum calcifediol concentrations: AUC, Cmax, 
time to maximum concentration (tmax), steady-state concentration (Css), time to steady-state 
concentration (tss), terminal elimination half-life (t½) in subjects treated with CTAP101 Capsules 
at a dose of 900 mcg per week), clearance (CL/F), and volume of distribution (Vd/F), as feasible.  
Relative exposure and dose proportionality will be examined, if possible.     
3.4.2 
Pharmacodynamic Endpoints  
In an effort to characterize the dose-concentration-response relationships and to determine the 
impact of intrinsic and extrinsic factors on these relationships, population PK and PD models 
will be developed from serum calcifediol data collected from subjects in Cohort 2.  PD markers 
to be considered in the population PD analysis include: plasma iPTH, and serum calcium 
(corrected), phosphorus, and 1,25-dihydroxyvitamin D3. The effect of the following covariates 
will be examined: body weight, age, gender, race, CKD stage, SHPT severity, dialysis vintage, 
etiology of CKD and prior treatment with 1α-hydroxylated vitamin D analogs and/or 
calcimimetics. 
3.4.3 
Primary Safety Endpoints 
The safety and tolerability of CTAP101 Capsules will be evaluated for both cohorts in the intent-
to-treat Safety population (defined as all subjects who received at least on dose of study drug) by 
AEs, physical examinations (PEs), vital signs (VS), hematology and clinical chemistries, and 12-
lead electrocardiograms (ECGs). 
3.4.4 
Efficacy Endpoints 
There is no primary efficacy endpoint for Cohort 1, as this part of the study is merely 
observational. The primary efficacy endpoint for Cohort 2 is the proportion of subjects in the ITT 
population attaining both a mean serum 25-hydroxyvitamin D of ≥50 ng/mL and a mean 
decrease in plasma iPTH of at least 30% from pre-treatment baseline during the first efficacy 
assessment period (EAP), defined as the average of values obtained in the last 6 weeks of the 
first 26-weeks of treatment.  
The key secondary efficacy endpoint for Cohort 1 is the proportion of subjects in the intent-to-
treat (ITT) population attaining both a mean serum total 25-hydroxyvitamin D of ≥50 ng/mL and 
a mean decrease in plasma iPTH of at least 30% from pre-treatment baseline, defined in Section 
9.10.1, during the EAP, defined as the average of values obtained in the last 6 weeks of the 26 
weeks of treatment, calculated for each treatment group and for each final dose group, defined in 
Section 9.11. 


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Secondary efficacy endpoints for Cohorts 1 and 2 include the proportion of subjects in the per-
protocol (PP) population attaining both a mean serum total 25-hydroxyvitamin D of ≥50 ng/mL 
and a mean decrease in plasma iPTH of at least 30% from pre-treatment baseline during the first 
EAP.  Additional secondary endpoints include the proportion of subjects in the PP population 
attaining both a mean serum total 25-hydroxyvitamin D of ≥50 ng/mL and a mean decrease in 
plasma iPTH of at least 10, 20 or 30% from pre-treatment baseline during the first and/or second 
EAP, as applicable, the latter being defined as the average of values obtained in the last 6 weeks 
of the second 26-weeks of treatment; the time courses of mean absolute changes from pre-
treatment baseline in serum total 25-hydroxyvitamin D and plasma iPTH; categorical 
comparisons of safety and efficacy based on body weight, age, gender, race, dose, severity of 
SHPT and VDI, dialysis vintage, etiology of CKD and prior treatment with 1α-hydroxylated 
vitamin D analogs and/or calcimimetics; PD effects on mean serum calcium (corrected), 
phosphorus, DBP, total free 25-hydroxyvitamin D, total 1,25-dihydroxyvitamin D, 1,25-
dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3; and, population PK of serum calcifediol 
relative to body weight, age, gender, race, dose, severity of SHPT and VDI, dialysis vintage, 
etiology of CKD and prior treatment with lα-hydroxylated vitamin D analogs and/or 
calcimimetics. 
 
 
 
 
 
 
  
 


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4 STUDY POPULATION SELECTION 
4.1 
Study Population 
The target population for this study is subjects at least 18 years old diagnosed with SHPT, VDI 
(serum total 25-hydroxyvitamin D <50 ng/mL) and stage 5 CKD requiring regular HD tiw for at 
least the prior six months.  All subjects will be U.S. residents. 
For Cohort 1, approximately 100 subjects will be screened to randomize in a 3:1 ratio 
approximately 44 eligible subjects into two groups receiving the following treatments in a single-
blinded (subjects only) fashion for 26 weeks: (a) CTAP101 Capsules at 900 mcg per week or (b) 
matching placebo.  An attempt will be made to enroll 4 Japanese subjects (first, second or third 
generation in the U.S.).  Randomization will be accomplished in blocks of four subjects using 
two computer-generated codes, one for the PK sub-group (n=28) and one for the non-PK sub-
group (n=16).  If four qualified Japanese subjects are successfully enrolled into Cohort 1, they 
will be randomized within in the same block to treatment arms in the PK sub-group. 
For Cohort 2, approximately 480 subjects will be screened to randomize in a 1:1:1:1 ratio 
approximately 212 eligible subjects, stratified for severity of SHPT, into four treatment groups 
receiving the following treatments in a double-blinded fashion for 26 weeks: (aa) CTAP101 
Capsules at 300 mcg per week, (bb) CTAP101 Capsules at 600 mcg per week, (cc) CTAP101 
Capsules at 900 mcg per week or (dd) matching placebo.  Randomization will be accomplished 
in blocks of four subjects using two computer-generated codes, one for the PK sub-group (n=72) 
and one for the non-PK sub-group (n=140).  In this cohort, approximately half of the subjects 
will have baseline plasma iPTH values in the range of ≥300 to <600 pg/mL, and approximately 
half will have values in the range of ≥600 to <900 pg/mL. 
4.2 
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled into the two cohorts of this study: 
1. Be at least 18 years of age. 
2. Be diagnosed with CKD requiring in-center HD tiw for the preceding 6 months, as confirmed 
by medical history. 
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; and, 
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. 
4. Be receiving calcimimetic therapy (either etelcalcetide or cinacalcet) and/or calcitriol or 
other 1α-hydroxylated vitamin D analog (paricalcitol or doxercalciferol) for at least 1 month 
at the time of screening for enrollment in Cohort 1.  Approximately 50% of enrolled subjects 
will have been receiving calcimimetic therapy. 
5. Exhibit during the initial screening visit: 
 


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a. Plasma iPTH ≥150 pg/mL and <600 pg/mL if receiving etelcalcetide, cinacalcet, 
calcitriol or other 1α-hydroxylated vitamin D analog (paricalcitol or doxercalciferol); or  
b. Plasma iPTH ≥300 pg/mL and <900 pg/mL if not receiving etelcalcetide, cinacalcet, 
calcitriol or other 1α-hydroxylated vitamin D analog; and,  
c. Serum total 25-hydroxyvitamin D <50 ng/mL if not receiving vitamin D 
supplementation. 
6. When otherwise confirmed eligible at Visit 1, must forgo any further treatment with 
etelcalcetide and cinacalcet for the duration of the study and undergo an 8-week washout 
period. 
7. When otherwise confirmed eligible at Visit 1, must forgo any further treatment with calcitriol 
or other 1α-hydroxylated vitamin D analogs or vitamin D supplements for the duration of the 
study and undergo an 8-week washout period.  
8. Exhibit after the 8-week washout period (if required due to prior use of etelcalcetide, 
cinacalcet, calcitriol or other 1α-hydroxylated vitamin D analogs, or vitamin D 
supplementation): 
Cohort 1: 
a. Plasma iPTH increased by at least 50%; and, 
b. Plasma iPTH ≥300 pg/mL and <1,200 pg/mL; or, 
Cohort 2: 
f. Plasma iPTH ≥300 pg/mL and <1,200 pg/mL (approximately half of the subjects will be 
enrolled in each of these two plasma iPTH strata: ≥300 to <600 and ≥600 to <1,200 
pg/mL); and 
Cohorts 1 and 2: 
c. Corrected serum calcium <9.8 mg/dL; 
d. Serum total 25-hydroxyvitamin D <50 ng/mL; and, 
e. Serum phosphorus <6.5 mg/dL. 
9. When otherwise confirmed eligible at Visit 1, if taking more than 1,000 mg per day of 
elemental calcium, reduce calcium use (to ≤1,000 mg per day) and/or use non-calcium based 
phosphate binder therapies (as needed) for the duration of the study. 
10. When otherwise confirmed eligible at Visit 1, if taking bone metabolism therapies that may 
interfere with study endpoints, must discontinue use of these agents for the duration of the 
study. 
11. Willing and able to comply with study instructions and commit to all clinic visits for the 
duration of the study. 
12. Female subjects of childbearing potential must be neither pregnant nor lactating and must 
have a negative serum beta-human chorionic gonadotropin (b-hCG) pregnancy test at the first 
screening visit and at other scheduled times. 
13. 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. 


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14. Be able to read, understand and sign the subject Informed Consent Form (ICF) or have a 
legal representative sign the ICF. 
4.3 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
1. Scheduled kidney transplant or parathyroidectomy. 
2. History (prior 2 months) of corrected serum calcium ≥9.8 mg/dL or serum phosphorus ≥6.5 
mg/dL if not receiving calcitriol or other 1α-hydroxylated vitamin D analog. 
3. Receipt of bisphosphonate therapy or other bone modifying treatment (eg, denosumab) 
within 6 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, intestinal 
malabsorption disorder, hepatitis or cardiovascular event that in the opinion of the 
investigator may worsen or reduce life expectancy, and/or interfere with participation in the 
study. 
5. History of neurological/psychiatric disorder, including psychotic disorder or dementia, or any 
reason which, in the opinion of the investigator makes adherence to a treatment or follow-up 
schedule unlikely. 
6. Known or suspected hypersensitivity to any of the constituents of the study drugs. 
7. Currently participating in, or has participated in, an interventional/investigational study 
within 30 days prior to study screening. 
 
 


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5 STUDY TREATMENTS 
5.1 
Description of CTAP101 Capsules 
Dosage form: 
Soft gel capsule  
Dose strength: 
150 mcg calcifediol ER capsule  
Product description: 
Blue oval capsules printed single-sided, centered with the logo O 
in white.  Each bottle contains 30 capsules. 
Active component: 
Calcifediol 
Non-active components: 
Paraffin wax, mineral oil, mono- and diglycerides, dehydrated 
alcohol, lauroyl polyoxylglycerides, butylated hydroxytoluene, 
hypromellose, modified starch, carageenan, sodium phosphate 
dibasic, sorbitol and sorbitan solution, FD&C Blue #1, titanium 
dioxide, medium chain triglycerides (coconut oil) and ink (white, 
which may contain titanium dioxide, isopropyl alcohol, propylene 
glycol, hydroxypropylmethyl cellulose 2910)  
Storage conditions: 
25°C (77°F); excursions allowed to 15°C to 30°C (59°F to  86°F); 
protect from light and heat. 
5.2 
Description of Placebo Capsules 
Dosage form: 
Soft gel capsule  
Dose strength: 
0 mcg calcifediol ER capsule  
Product description: 
Blue oval capsules printed single-sided, centered with the logo O 
in white.  Each bottle contains 30 capsules. 
Active component: 
None 
Non-active components: 
Paraffin wax, mineral oil, mono- and diglycerides, dehydrated 
alcohol, lauroyl polyoxylglycerides, butylated hydroxytoluene, 
hypromellose, modified starch, carageenan, sodium phosphate 
dibasic, sorbitol and sorbitan solution, FD&C Blue #1, titanium 
dioxide, medium chain triglycerides (coconut oil) and ink (white, 
which may contain titanium dioxide, isopropyl alcohol, propylene 
glycol, hydroxypropylmethyl cellulose 2910)  
Storage conditions: 
25°C (77°F); excursions allowed to 15°C to 30°C (59°F to  86°F); 
protect from light and heat 
5.3 
Description of Cinacalcet 
Dosage form:  
 
Film-coated tablet 
Dose strength: 
 
30 mg cinacalcet tablet 
Product description: 
Light-green, film-coated, oval-shaped biconvex tablets marked  
with “CL” on one side and “410” on the opposite side.  Each bottle 


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contains 30 tablets, or an equivalent, U.S approved generic 
alternate source. 
Active component:  
cinacalcet hydrochloride 
Non-active components: 
microcrystalline cellulose, corn starch, povidone K30, isopropyl 
alcohol, magnesium stearate, crospovidone, lactose monohydrate, 
titanium dioxide, triacetin, FD&C blue #2, ferric oxide yellow, and 
hypromellose 2910. 
Storage conditions: 
25°C (77°F);  excursions permitted from 15°C to 30°C (59°F to 
86°F). (See USP controlled room temperature) 
For product information, refer to Appendix 2. 
5.4 
Treatments Administered 
Subjects will receive two capsules (one or two CTAP101 Capsules, 150 mcg strength, and/or 
matching placebo) tiw in the dialysis center at approximately one hour (± 30 minutes) into the 
regularly scheduled HD session to achieve the total cumulative weekly dose (see Table 1 below).  
The time between dosing and any food intake during or immediately after HD will be monitored 
and recorded for all subjects.  Subjects will be requested to abstain from eating within one hour 
of starting dialysis, and a small snack will be allowed (if requested) during dialysis.  After 12 
weeks of treatment, subjects in Cohort 2 who are receiving 300 or 600 mcg per week of 
CTAP101 Capsules and who are not participating in PK determinations will undergo upward 
dose titration provided that (a) the plasma iPTH has not decreased by at least 30% from 
pretreatment baseline and remains >300 pg/mL, (b) corrected serum calcium is <9.8 mg/dL, and 
(c) serum phosphorus is <6.0 mg/dL.  Subjects in Cohorts 1 or 2 who are receiving 900 mcg per 
week of CTAP101 Capsules or placebo, or are participating in PK assessments, will not undergo 
upward dose titration at any time.  Upward dose titration will occur in a single increment of 300 
mcg (two CTAP101 Capsules).  After 26 weeks of treatment, subjects in Cohort 2 who were 
assigned to placebo will commence treatment with 300, 600 or 900 mcg of CTAP101 Capsules, 
assigned randomly with stratification by severity of SHPT. 
Subjects in Cohort 1 only, who have completed 6 months of treatment with either CTAP101 
Capsules or placebo will receive, at their election, sub-therapeutic doses of cinacalcet (30 mg tiw 
at the end of HD) during 3 weeks of the 6-week FU observation period in order to observe its 
effects on plasma iPTH when serum total 25-hydroxyvitamin D is still elevated relative to pre-
treatment baseline values.  Subjects who will begin treatment with cinacalcet must have a serum 
calcium of ≥8.6 mg/dL and a plasma iPTH ≥300 pg/mL. Dosing with cinacalcet will be 
suspended if plasma iPTH is <150 pg/mL or serum calcium is <7.5 mg/dL. 
 
 
 




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After 12 weeks of treatment, subjects who have experienced more than a 100% increase in 
plasma iPTH from pre-treatment baseline or whose plasma iPTH has increased above 1,200 
pg/mL on consecutive visits (if at least 2 weeks apart) will terminate dosing with study drugs and 
further participation in the treatment period and immediately enter the 6-week post-treatment 
follow-up period.  Such subjects may be immediately removed from the study and placed on 
standard of care therapy, at the discretion of the Investigator. 
Subjects who have received cinacalcet (30 mg tiw at the end of HD) during 3 weeks of the 6-
week FU observation period (Study Weeks 27-29 for non-PK active and placebo and PK placebo 
subjects and Study Weeks 29-31 for PK active subjects) who have a serum calcium <7.5 mg/dL 
or a plasma iPTH <150 pg/mL should discontinue cinacalcet immediately.  The investigator 
should continue to monitor and evaluate these laboratory values until values have stabilized and 
follow the standard of care.  
5.5.1 
Overdose and Toxicity 
Excessive administration of calcifediol can cause hypercalcemia, hyperphosphatemia, or over 
suppression of intact PTH. Common symptoms of vitamin D overdosage may include 
constipation, decreased appetite, dehydration, fatigue, irritability, muscle weakness, or vomiting.  
Treatment of acute accidental overdosage with calcifediol should consist of general supportive 
measures.  If the overdosage is discovered within a short time, induce emesis or perform gastric 
lavage to prevent further absorption. Obtain serial serum calcium measurements and assess any 
electrocardiographic abnormalities due to hypercalcemia.  Discontinue supplemental calcium. 
Treat with standard medical care if persistent and markedly elevated serum calcium levels occur. 
5.6 
Method of Assigning Subjects to Treatment Groups  
After signing the ICF, prior to any study-related activities, each subject will be assigned a 5 digit 
identification number and will retain that number throughout the study.  The 5 digit identification 
number (C-SS-EE) will consist of a 1-digit cohort number (C), a 2-digit site number (SS) and a 
2-digit consecutive enrollment number (EE) at the applicable clinical site.  Should a subject be 
withdrawn from the study, that subject’s 5 digit identification number will not be reassigned.   
Study treatment arm assignments will be made via the IRT system using two computer-generated 
randomization codes for each cohort (one for the PK sub-group and one for the non-PK sub-
groups) provided by the IRT vendor.  Randomization will be accomplished in blocks of 4 
subjects, with 3 subjects being assigned to treatment with CTAP101 Capsules and 1 subject 
being assigned to treatment with placebo.  If four qualified Japanese subjects are successfully 
enrolled into Cohort 1 (see Section 4.1 Study Population), they will be randomized within in the 
same block to treatment arms in the PK sub-group.  Randomization will occur during Visit 3 
provided that each subject is deemed eligible for enrollment based, in part, on laboratory 
assessments obtained at the preceding visit (Visit 2).  Laboratory assessments obtained at Visit 3 
will not be considered in the determination of enrollment eligibility.  
 


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5.7 
Prior and Concomitant Therapy 
Subjects should not take any vitamin D and/or bone metabolism therapy other than the study 
drug.  Excluded therapies include 1α-hydroxylated vitamin D analogs (calcitriol, paricalcitol and 
doxercalciferol), calcimimetics, bisphosphonates, denosumab, teriparatide, preotact, calcitonin 
and other drugs that may affect bone metabolism.  Glucocorticoids and hormone replacement 
therapy should remain at the same dose throughout the study.  
All medication usage from 12 weeks prior to Visit 1, during study and until completion of the 
study will be recorded.  
Cytochrome P450 inhibitors, such as ketoconazole, atazanavir, clarithromycin, indinavir, 
itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole, may 
inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1), and may alter 
serum levels of calcifediol. Dose adjustment of CTAP101 Capsules may be required if a patient 
initiates or discontinues therapy with a strong CYP3A4 inhibitor. 
Cholestyramine has been reported to reduce intestinal absorption of fat-soluble vitamins and may 
impair the absorption of calcifediol, the active ingredient in CTAP101 Capsules. Dose 
adjustment of CTAP101 Capsules may be required if a patient initiates or discontinues therapy 
with cholestyramine. 
Phenobarbital and other anticonvulsants or other compounds that stimulate microsomal 
hydroxylation reduce the half-life of calcifediol. Dose adjustment of CTAP101 Capsules if a 
patient initiates or discontinues therapy with phenobarbital or other anticonvulsants. 
5.7.1 
Phosphate Binder and Elemental Calcium Therapy  
Use of calcium-based phosphate binders or antacid therapies such as calcium carbonate or 
calcium acetate are allowed up to 1000 mg per day of elemental calcium.  Non calcium-based 
phosphate binder therapy such as sevelamer HCL or lanthanum carbonate and non-calcium-
based antacids can be used at the discretion of the investigator. Any changes in phosphate binder 
therapy should be captured in the electronic case report form (eCRF).  
5.7.2 
Dialysate Calcium Concentration 
The dialysate calcium concentration should remain unchanged throughout the study.  Any 
changes in dialysate calcium concentration will be captured in the eCRF. 
5.7.3 
Diet 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. 
Subjects who participate in PK determinations will receive standardized meals while housed in 
the phase 1 unit.  These meals will be administered at approximately 12 hours prior to dosing and 
5, 10, 23, 28 and 33 hours post-dose. 
5.7.4 
Subject Activity Restrictions 
Subjects should maintain their usual pattern of sun exposures and activities. 


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5.8 
Treatment Compliance 
Study treatment compliance will be assessed at all specified visits.  The Investigator, or assigned 
designee will perform drug accountability and dosing compliance calculations for all study drugs 
(number of capsules that should have been taken versus actual number taken as evidenced by 
written dosing records and the number of capsules remaining in bottles of study drug assigned to 
each subject).  Dosing compliance at <80% or >120% should be reported as a major protocol 
deviation. 
5.9 
Packaging and Labeling 
CTAP101 Capsules and matching placebo capsules will be provided in white, round, wide-
mouth, high-density polyethylene (HDPE) bottles with aluminum heat-induction safety seals 
with white, polypropylene, child-resistant (push down and turn) caps, 30 capsules per bottle.   
For Cohort 1 cinacalcet dosing in FU period of study, cinacalcet will be provided in bottles, 30 
tablets per bottle. 
All study drug labels will include the protocol number, sponsor identification and address, bottle 
contents, bottle number, area for subject and investigator identification as applicable, 
investigational use statements, storage conditions and instructions for use.   
5.10 
Storage and Accountability 
CTAP101 Capsules, matching placebo capsules and cinacalcet will be shipped to sites using 
standardized shipment and temperature monitoring procedures.  While at the study site, study 
drugs will be stored at controlled room temperature (25°C or 77°F) with excursions allowed to 
15°C to 30°C (59°F to 86°F), and protected from light and heat per label instructions in the 
supplied packaging, with access granted to authorized personnel only.  
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.  
Accountability for all study drugs, from receipt until final reconciliation and return of drug by 
the monitor or designee, will be the responsibility of the investigator or the assigned designee(s). 
In the case of temperature excursions, products should not be dispensed and the investigator or 
the assigned designee(s) should contact the clinical monitor or the sponsor representative as soon 
as possible to receive further instructions. 
The investigator or assigned designee(s) will maintain study drug accountability records 
throughout the course of the study.  Specifically, the investigator or assigned designee will 
confirm that 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 by site, to whom and amount 
dispensed\returned and accounts of any drug accidentally destroyed, or not returned, or lost.  The 
site's overall inventory of study drug supplies will be verified routinely throughout the course of 
the study.  All opened and unopened bottles of study drug capsules are to be retained at the site 
until the sponsor or designee has performed a complete accountability, following which study 
drug will be returned to the sponsor or designee. 


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5.11 
Investigational Product Retention at Study Site 
At the conclusion of the study, a final accountability of all study IP 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 return records must be maintained by 
the investigator. 


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6 STUDY PROCEDURES 
6.1 
Informed Consent 
A signed ICF will be obtained prior to any study related procedures.  The subject or their legally 
authorized representative (LAR) will be permitted time and opportunity to inquire about details 
of the study and to decide whether or not to participate.  The subject or their LAR will receive a 
copy of the signed and dated consent form and any written information provided to the study 
subjects.  If any material change occurs that affects the conduct of the study or the subject’s 
willingness to participate in the study, the subject or LAR will be required to sign an updated 
consent form. 
The investigator or his/her designee will explain the nature of all aspects of the study to the 
subject and/or their LAR, and answer all questions regarding this study, prior to obtaining 
informed consent. 
The process for obtaining consent will be in accordance with all applicable regulatory 
requirements.  The subject or his/her LAR and the investigator or his/her designee must both sign 
and date the ICF before the subject can participate in the study.  The original ICF will be retained 
in the site study records.  The investigator or his/her designee will ensure documentation of the 
consent discussion is in the subject’s medical record/source document.  The decision by the 
subject to participate in the study is entirely voluntary.  The investigator or designee must 
emphasize to the subject that consent regarding study participation may be withdrawn at any 
time without penalty or loss of benefits to which the subject is otherwise entitled. 
If the ICF or patient information is amended during the study, the investigator must follow all 
applicable regulatory requirements pertaining to approval of the amended ICF by the 
Institutional Review Board/Ethics Committee (IRB/EC) and use of the amended form (including 
ongoing subjects). 
6.2 
Medical History and Concomitant Medications 
A detailed medical history, including demographics and concomitant medications, will be 
recorded at Visit 1/Screening.  
6.3 
Physical Examination, Vital Signs and Electrocardiogram 
VS and PE will be performed by a licensed physician or by another suitably-qualified person 
where permitted by local regulations.  Evaluations are presented in Table 2.  
 
 


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Table 2 
Evaluations 
Physical Examination: 
PE including BMI determination and excluding a urogenital 
examination at the following visits: 
o 
Cohort 1: Visits 1, 24, 32 or ET; 
o 
Cohort 2: Visits 1, 26 and 35 or 43 or ET. 
Vital Sign measurements: 
Blood pressure and heart rate will be measured and recorded before 
dialysis after the subject has been sitting for at least 2 minutes prior to 
any scheduled blood draws at every study visit. 
As part of standard of care, blood pressure will also be monitored during 
dialysis. Symptomatic episodes of hypotension will be recorded. 
Subjects assigned to single dose or repeated dose PK assessments will 
have their vital signs assessed throughout their stay in the phase 1 unit.  
12-Lead Electrocardiogram 
(ECG) 
Each 12-lead ECG will be started after the subject has been in 
recumbent position for at least 5 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. Interval measures and rhythm will also be reported. 
12-lead ECG will be performed at the following visits: 
o 
Cohort 1:  Visits 3,  24 or  ET; 
o 
Cohort 2:  Visits 3, 26, and 35 or 43 or ET. 
For consistency of ECG data, every effort will be made to utilize the 
same facility and reader for all ECGs at each site. 
Body height 
Body height will be recorded in centimeters to the nearest 1.0 cm during 
every scheduled PE. 
Body weight: 
Body weight will be recorded in kilograms to the nearest 0.1 kg during 
every scheduled PE. 
Other Assessments: 
 
 
: 
o 
Cohort 1:  Visits 3,  24 or  ET; 
o 
Cohort 2:  Visits 3, 26 and 35 or 43 or ET. 
 
6.4 
Clinical Laboratory Tests 
6.4.1 
Laboratory Parameters 
Blood will be drawn before dialysis and analyzed as specified in Table 3.  
 
 
  
All serum calcium values will be adjusted based on serum albumin level of <4.0 g/dL.  
All clinically significant abnormal laboratory values should be recorded as AEs and the 
investigator will follow-up according to Section 6.6.6 Clinical Significance. 


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Please refer to Appendix 1 Schedule of Events for specific time points. 
Subjects will be in a seated or supine position during blood collection.  Clinical laboratory tests 
are listed in Table 3.  
Table 3 
List of Laboratory Tests 
Hematology: 
Hematocrit 
Hemoglobin 
Platelet count 
Red blood cell count  
White blood cell count  
 
Serum b-hCG Pregnancy Test (only for females of child 
bearing potential, defined as either not surgically sterile or 
not diagnosed as postmenopausal) 
 
 PD and PK parameters: 
Serum total 1,25-dihydroxyvitamin D 
Serum 1,25-dihydroxyvitamin D3 
Plasma iPTH (blinded*) 
Serum total 25-hydroxyvitamin D (blinded*) 
Serum calcifediol (blinded*) 
Serum 24,25-dihydroxyvitamin D3 
 
 
 
 
 
 
 
 
 
 
 
     Vitamin D binding protein (DBP) 
     
 
     
 
 
 
 
 
 
 
 
 
 
      
 
      
  
Serum Chemistry: 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Blood urea nitrogen 
Calcium (corrected) 
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) 
Phosphorus 
Albumin 
 


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6.4.2 
Sample Collection, Storage, and Shipping 
Missed blood samples should not be redrawn or recollected (unless the investigator considers the 
sample necessary for subject safety) and should be noted as “not done” in source documentation 
along with a reason.   
A central laboratory experienced in clinical research trials will be utilized.  Collection, 
processing, storage and shipping procedures will be performed in accordance with the 
instructions provided by the central laboratory.  Detailed instructions will be provided separately 
from this protocol in the laboratory manual.  Blood samples will be collected and analyzed for 
clinical laboratory 
 tests.   
 
 
  In Cohort 1, up to 
approximately 230 mL of blood will be drawn from each subject who is assigned to treatment 
with placebo or is assigned to treatment with CTAP101 Capsules in one of the non-PK sites, and 
up to approximately 691 mL will be drawn from each subject who is assigned to treatment with 
CTAP101 Capsules in one of the PK sites.  These amounts of blood will be drawn in increments 
over a period of approximately 44-46 weeks.  In Cohort 2, up to 382 mL of blood will be drawn 
from each subject who does not participate in the PK assessments, and up to 775 mL will be 
drawn from each subject who does participate in the PK assessments, over approximately 70-74 
weeks.  Additional blood draws may be needed for unscheduled or repeat visits.  Every effort has 
been made to minimize the total amount of blood to be drawn. 
Samples are to be shipped to the central laboratory for each subject as visits are completed.  
6.4.3 
Clinical Supplies 
The sponsor or their assigned designee will supply vacutainers, blood collection tubes, needles, 
pipettes, 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 
The IRT will provide study drug assignments and dosing adjustments.  The study coordinator (or 
designated site personnel) at each site will obtain the study drug assignments from the IRT for 
each subject and administer the appropriate number of capsules at each HD, which will be 
recorded in the eCRF. 
All subjects in Cohorts 1 and 2 will be blinded to CTAP101 Capsule and placebo treatment 
group assignments and to plasma iPTH, serum total 25-hydroxyvitamin D, and serum calcifediol 
data until the last subject completes 26 weeks of treatment and the data have been locked.  For 
Cohort 1 cinacalcet dosing in the FU period of study only, subjects, dialysis study personnel and 
sponsor (and its’ designee) will be unblinded to this treatment. 


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For Cohort 2 only, dialysis staff, study personnel and the sponsor (and its’ designees) will be 
blinded to treatment group assignments and to plasma iPTH, serum total 25-hydroxyvitamin D, 
and serum calcifediol data until after the last subject has completed 26 weeks of treatment and 
the data have been locked, or until a decision has been made to break the blind (eg, as a result of 
an emergent event).   
For Cohort 2 only, an independent, unblinded DSMB will be established to oversee the IRT and 
verify the appropriateness of all dosing adjustments, to monitor subject safety and the 
effectiveness of CTAP101 Capsules at regular intervals.  Specific responsibilities and activities 
of the DSMB will be defined in the charter ratified at the pre-Cohort 2 organizational meeting.   
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 the investigational study drug, action(s) 
taken and outcome.  AEs, whether in response to a query, observed by site personnel, or reported 
spontaneously by the subject will be reported on the appropriate eCRF.   
6.6.3 
AE Collection Period 
All AEs that occur after the ICF has been signed will be documented in the source document and 
followed to a satisfactory resolution, until the investigator deems the event to be chronic or the 
subject to be stable, or until the subject’s participation in the study ends. 
Information to be collected includes description of the event (event term), date of onset, date of 
resolution, investigator-specified assessment of severity and relationship to the investigational 
study drug, seriousness, 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, x-ray or ECG findings) or symptoms should NOT be recorded as 


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additional AEs.  If a diagnosis is unknown, then sign(s) or symptom(s) should be recorded as an 
AE(s).  Changes in laboratory values, 
 assessments or ECGs 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 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 pre-existing condition, the worsening of the 
condition should be captured as an AE.  Elective procedures performed where there is no change 
in the subject’s medical condition (including thought processes around the reason for the elective 
procedure) should not be recorded as AEs, but should be documented in the subject’s source 
document and captured in the eCRF as procedures. 
Any report of pregnancy identified for any female subject or for a female partner of a male 
subject should be reported immediately (within 24 hours of being informed) by submitting the 
Pregnancy Reporting Form to 
Pharmacovigilance: 
Fax:  
 
E-mail:  s
 
Pregnancies will be considered ‘events of special interest’ and will not be captured as serious 
adverse events (SAEs).  Investigators should follow specific procedures for reporting them to 
Pharmacovigilance.  Pregnancies will be followed to termination or six weeks post-
delivery for determination of resolution to the event.  Subjects who become pregnant during 
treatment must immediately be withdrawn from 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 per Common Terminology Criteria for 
Adverse Events (CTCAE), Version 5.0. 
It should be noted that the clinical severity and seriousness of an AE are not synonymous, eg, a 
severe headache is not classified as serious until it meets the required elements as an SAE. 
The maximum severity attained for each AE reported will be recorded in the eCRFs.   
6.6.5 
Relationship 
The investigator’s assessment of an AE's relationship to the investigational study drug is not a 
factor in determining whether the AE is reported in the AE section of the eCRF.  If there is any 
doubt as to whether a clinical observation is an AE, the event should be reported.  
The relationship or association of the study drugs in causing or contributing to the AE will be 
characterized by the investigator using the classifications and criteria outlined in Table 4. 
 


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Table 4  Adverse Event Relationship Criteria 
Relationship 
Criteria 
Not related 
• 
The temporal sequence of the AE onset relative to administration of the 
investigational product is not reasonable. 
• 
Disease or other drugs provide plausible explanations. 
• 
Dechallenge (if performed) is negative or ambiguous. 
Unlikely related 
• 
The temporal sequence of the AE onset relative to the administration of the 
investigational product is reasonable. 
• 
Could also be explained by disease or other drugs. 
• 
Dechallenge (if performed) is positive or uncertain. 
• 
Rechallenge is negative. 
Possibly related 
• 
The temporal sequence of the AE onset relative to administration of the 
investigational product is reasonable. 
• 
Unlikely to be attributed to disease or other drugs. 
• 
Dechallenge (if performed) is positive. 
Related 
• 
The temporal sequence of the AE onset relative to administration of the 
investigational product is reasonable. 
• 
Cannot be explained by disease or other drugs. 
• 
Dechallenge (if performed) is positive and pharmacologically/ 
pathologically plausible. 
• 
Rechallenge (if feasible) is positive. 
• 
The AE shows a pattern consistent with previous knowledge of the 
investigational product or product class, i.e., pharmacologically or 
phenomenologically recognized/plausible or an objective and specific 
medical disorder. 
 
 
6.6.6 
Clinical Significance 
Changes in laboratory values, 
, vital signs, ECG findings 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 considered clinically significant 
unless the investigator indicates not clinically significant directly on the laboratory paperwork or 
source documentation. 
6.6.7 
Serious Adverse Events 
6.6.7.1 
Definition 
An SAE is defined by the investigator or sponsor as any AE occurring during an investigational 
study that result in any of the following outcomes: 
• Death 
• Life-threatening AE 


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• 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 events that may not result in death, may be life threatening, or may require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in subject hospitalization, or the development of 
drug dependency or drug abuse.   
Hospitalizations to conduct diagnostic procedures will be captured separately from AEs in the 
eCRF.   
Research subjects will be instructed to notify the research center for any emergent condition and 
will be given the emergency contact number for the study during the consenting process. 
6.6.7.2 
Expectedness 
SAEs must be assessed as to whether they were expected to occur or unexpected, meaning not 
anticipated based on current knowledge about the investigational compound found in the 
protocol or Investigator Brochure (IB) for CTAP101 Capsules.  Categories are: 
• Unexpected - nature or severity of the event is not consistent with the product information; 
• Expected - event is known based on the product information. 
6.6.7.3 
Reporting Serious Adverse Events 
Any AE considered serious (see Section 6.6.7 Serious Adverse Events) by the investigator that 
meets the previously mentioned criteria must be reported to 
Pharmacovigilance at 
the following number within 24 hours from the time when site personnel first learn about the 
event.  
SAFETY REPORTING Contact:  
 Pharmacovigilance 
Fax:  
 
E-mail:  
  
A written report should be provided consisting of the SAE Form and other necessary source 
documents.  If the subject is hospitalized because of or during the course of an SAE, then the 
investigator should attempt to obtain a copy of the hospital discharge summary and any pertinent 
laboratory or diagnostic reports, and provide them to the sponsor or designee as soon as possible. 
For any information not available at the time of the first report that becomes available later, the 
investigator should update the SAE Form and eCRFs and provide any additional documentation 
to 
Pharmacovigilance immediately or within 1 working day of receipt. 
The sponsor or designee will notify the appropriate regulatory agencies of any serious and 
unexpected SAEs associated with the use of the investigational study drug according to 


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regulations.  Copies of any reports to regulatory agencies regarding serious and unexpected 
SAEs will be provided to the investigators by the sponsor or designee for review and submission 
to the IRB/EC. 
If using a local IRB/EC, the investigator is responsible for informing his or her IRB/EC per its 
requirements of any SAEs at that site.  Copies of SAE correspondence with the IRB/EC, 
regulatory authorities, and other physicians must be provided to the Study Contact.  
A subject experiencing one or more SAEs will receive treatment and follow-up evaluations by 
the investigator, or they will be referred to another appropriate physician for treatment and 
follow-up.  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 
investigational study drug administration and subsequently all events will be closed.   
6.6.8 
Treatment-Emergent Adverse Events 
A TEAE is defined as any AE with onset or worsening reported by a subject from the time that 
the first dose of study drug is taken in this study until 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 on a separate page 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 (e.g., failure to record at least one baseline value for serum 
total 25-hydroxyvitamin D and for plasma iPTH); 
• A serious or intolerable AE occurs; 
• A clinically significant change in a laboratory parameter occurs; 
• The sponsor or investigator terminates the study; 
• 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 becomes pregnant; 
• A subject experiences more than a 100% increase in plasma iPTH after 12 weeks of 
treatment from pre-treatment baseline; or 
• A subject exhibits plasma iPTH above 1,200 pg/mL on consecutive visits (if at least 2 weeks 
apart) after 12 weeks of treatment. 
• Dosing with cinacalcet will be discontinued if a subject has a serum calcium of <7.5 mg/dL 
or a plasma iPTH <150 pg/mL.. 


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Subjects who are withdrawn from the study prematurely for any reason, should have the noted 
assessments completed for the Early Termination Visit.  No subject replacement is planned. 
6.9 
Appropriateness of Measurements 
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 analyzing AEs, serum calcium and phosphorus.   
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 summarizing the effect of 
CTAP101 Capsules to lower elevated iPTH levels and to normalize vitamin D levels.  Pre and 
post-dose averages will be used to minimize the effect of any intrasubject and interassay 
variability. 
 
 


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7 STUDY ACTIVITIES 
7.1 
Cohort 1  
7.1.1 
Non-PK Sites 
Note: Any subject who terminates participation in the study prematurely will complete the 
procedures listed under Visit 24 (Day 183) at the ET Visit. 
7.1.1.1 
Screening and Baseline Periods 
Subjects will not discontinue any medications or adjust any medications as noted in the inclusion 
criteria until they are confirmed as eligible (including confirmation of clinical laboratory 
parameters) to begin the washout period.  If subject is found to be a screen failure after Visit 1, 
the subject may be rescreened one additional time. 
7.1.1.1.1 
Visit 1 (Days -83 to -69) 
• A signed ICF will be obtained from the subjects prior to any study-related procedures 
• Review of inclusion/exclusion criteria 
• Medical history and demographics 
• Review of prior medications 
• AE assessment 
• PE (including weight, height and BMI) 
• VS assessment 
• Serum b-hCG pregnancy test (for females of child bearing potential) 
• Blood samples will be drawn for the following: 
o Clinical chemistry (full panel) and hematology 
o Plasma iPTH and serum total 25-hydroxyvitamin D 
7.1.1.1.2 
Washout Period (Days -68 to -14)  
7.1.1.1.3 
Visit 2 (Days -13 to -7) 
• Must be within ±3 days of scheduled visit 
• Review of inclusion/exclusion criteria 
• Review of concomitant medications 
• AE assessment 
• VS Assessment 
• Blood samples will be drawn for the following: 
o Clinical chemistry (full panel) 
o Plasma iPTH and serum total 25-hydroxyvitamin D 
o 
, 1,25-dihydroxyvitamin D3 and 24,25-
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7.1.1.2 
Treatment Period (26 weeks) 
• Study drug (CTAP101 Capsules or placebo) is administered tiw at each HD session 
throughout the Treatment Period beginning with Visit 3 (Day 1) and continuing through Day 
181.  No study drug will be administered at Visit 24 (Day 183) or on later study Visits/Days. 
7.1.1.2.1 
Visit 3 (Day 1) 
• Must be within ±3 days of scheduled visit 
• Review of inclusion/exclusion criteria 
• Subjects randomized to treatment with active or placebo drug product 
• Review of concomitant medications 
• AE assessment 
• VS assessment 
• Serum b-hCG pregnancy test (for females of child bearing potential) 
• 12-Lead ECG  
• Blood samples will be drawn for the following analyses: 
o Chemistry (full panel) and hematology 
o Plasma iPTH and serum total 25-hydroxyvitamin D 
o 
, 1,25-dihydroxyvitamin D3 and 24,25-
dihydroxyvitamin D3  
• 
 
 
• Subjects will receive initial dose of study drug during HD and will continue thrice weekly 
dosing during each successive HD session through Day 181. 
7.1.1.2.2 
Visit 4 
• All subjects skip Visit 4. 
7.1.1.2.3 
Visits 5 and 6 (Days 4 and 6) 
• No study procedures are scheduled on Visits 5 and 6. 
7.1.1.2.4 
Visits 7-9 
• All subjects skip Visits 7-9. 
7.1.1.2.5 
Visits 10-16 (Days 8-71) 
• Must be within ±3 days of scheduled visit 
• Review of concomitant medications 
• AE assessment 
• VS assessment 
• Blood samples will be drawn for the following analyses: 
o Clinical chemistry (partial panel) 


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o Plasma iPTH and serum total 25-hydroxyvitamin D  
7.1.1.2.6 
Visit 17 (Day 85) 
• Must be within ±3 days of scheduled visit 
• Review of concomitant medications 
• AE assessment 
• VS assessment 
• Serum b-hCG pregnancy test (for females of child bearing potential) 
• Blood samples will be drawn for the following analyses: 
o Chemistry (full panel) and hematology 
o Plasma iPTH and serum total 25-hydroxyvitamin D 
o 
, 1,25-dihydroxyvitamin D3 and 24,25-
dihydroxyvitamin D3  
7.1.1.2.7 
Visits 18-23 (Days 99-169)  
• Must be within ±3 days of scheduled visit 
• Review of concomitant medications 
• AE assessment 
• VS assessment 
• Blood samples will be drawn for the following analyses: 
o Clinical chemistry (partial panel) 
o Plasma iPTH and serum total 25-hydroxyvitamin D  
• Note:  The last dose of study drug will be administered on Day 181. 
7.1.1.2.8 
Visit 24 (Day 183) or Early Termination (ET) 
• Must be within ±3 days of scheduled visit 
• Review of concomitant medications 
• AE assessment 
• PE (including height, weight and BMI) 
• VS assessment 
• 12-Lead ECG  
• Serum b-hCG pregnancy test (for females of child bearing potential) 
• Blood samples will be drawn for the following analyses: 
o Chemistry (full panel) and hematology 
o Plasma iPTH and serum total 25-hydroxyvitamin D 
o 
 1,25-dihydroxyvitamin D3 and 24,25-
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• 
 
 
• Subjects will not receive study drug (CTAP101 Capsules or placebo) during this visit or any 
later visits. 
7.1.1.3 
Follow-up Period 
Study drug (cinacalcet) is administered at a sub-therapeutic dose of 30 mg tiw at the end each 
HD session to all subjects, previously treated with CTAP101 Capsules/placebo study drug, 
during 3 weeks of the 6-week FU observation period (Weeks 27-29), specifically beginning with 
Week 27 (Day 190) and continuing through Week (Day 209) for non-PK active and placebo 
subjects. Subjects must have a serum calcium of  ≥8.6 mg/dL and a plasma iPTH of  ≥300 pg/mL 
prior to beginning cinacalcet dosing. No cinacalcet will be administered at Visit 31 (Day 211) or 
any subsequent days for non-PK active and and PK placebo subjects.  Subjects will proceed with 
FU period schedule and activities listed below. 
7.1.1.3.1 
Visit 25 
• All subjects skip Visit 25.   
7.1.1.3.2 
Visits 26-29 (Days 186-193) 
• No study procedures are scheduled for Visits 26-29. 
7.1.1.3.3 
Visits 30-31 (Days 197-211) 
• Must be within ±3 days of scheduled visit 
• Review of concomitant medications 
• AE assessment 
• VS assessment 
• Blood samples will be drawn for the following analyses: 
o Clinical chemistry (partial panel) 
o Plasma iPTH and serum total 25-hydroxyvitamin D  
Placebo and active subjects will receive cinacalcet on Day 209, but will not receive 
cinacalcet during Visit 31 (Day 211). 
7.1.1.3.4 
Visit 32 (Day 225) 
• Must be within ±3 days of scheduled visit 
• Review of concomitant medications 
• AE assessment 
• PE (including height, weight and BMI) 
• VS assessment 
• Serum b-hCG pregnancy test (for females of child bearing potential) 


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• Blood samples drawn for: 
o Chemistry (full panel) and hematology 
o Plasma iPTH and serum total 25-hydroxyvitamin D 
• No active or placebo subject will receive cinacalcet during this visit. 
• Subjects terminate further participation in the study. 
7.1.2 
PK Sites 
7.1.2.1 
Screening and Baseline Periods 
Subjects will not discontinue any medications or adjust any medications as noted in the inclusion 
criteria until they are confirmed as eligible (including confirmation of clinical laboratory 
parameters) to begin the washout period. If subject is found to be a screen failure after Visit 1, 
the subject may be rescreened one additional time. 
Note: Any subject who terminates participation in the study prematurely will complete the 
procedures listed under Visit 24 (Day 183 for subjects randomized to placebo; Day 197 for 
subjects randomized to active) at the ET Visit. 
7.1.2.1.1 
Visit 1 (Days -83 to -69) 
• A signed ICF will be obtained from the subjects prior to any study-related procedures 
• Review of inclusion/exclusion criteria 
• Medical history and demographics 
• Review of prior medications 
• AE assessment 
• PE (including weight, height and BMI) 
• VS assessment 
• Serum b-hCG pregnancy test (for females of child bearing potential) 
• Blood samples will be drawn for the following: 
o Clinical chemistry (full panel) and hematology 
o Plasma iPTH and serum total 25-hydroxyvitamin D 
7.1.2.1.2 
Washout Period (Days -68 to -14) 
7.1.2.1.3 
Visit 2 (Days -13 to -7) 
• Must be within ±3 days of scheduled visit 
• Review of inclusion/exclusion criteria 
• Review of concomitant medications 
• AE assessment 
• VS Assessment 
• Blood samples will be drawn for the following: 


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o Clinical chemistry (full panel) 
o Plasma iPTH and serum total 25-hydroxyvitamin D 
7.1.2.2 
Treatment Period (26 weeks) 
Placebo study drug is administered tiw at each HD session throughout the Treatment Period 
beginning with Visit 3 (Day 1) and continuing through Day 181.  No study drug will be 
administered at Visit 24 (Day 183) or on later study Visits/Days. 
Active study drug is administered for single-dose PK assessments at t=0 on Visit 4 (Day 2), tiw 
at each HD session throughout the Treatment Period beginning with Visit 9 (Day 15) and 
continuing through Day 195, and for repeat-dose PK assessments at t=0 on Visit 25 (Day 198).  
No study drug will be administered at Visit 26 (Day 200) or on later study Visits/Days.   
7.1.2.2.1 
Visit 3 (Day 1) 
• Review of inclusion/exclusion criteria 
• Subjects randomized to treatment with active or placebo drug product 
• Review of concomitant medications 
• AE assessment 
• VS assessment 
• Serum b-hCG pregnancy test (for females of child bearing potential) 
• 12-Lead ECG  
• Blood samples will be drawn for the following analyses: 
o Chemistry (full panel) and hematology 
o Plasma iPTH and serum total 25-hydroxyvitamin D 
o 
, total free 25-hydroxyvitamin D, 
and 24,25-
dihydroxyvitamin D3 
o Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3 
• 
 
 
• Subjects randomized to placebo will: 
o Receive initial dose of study drug during HD. 
o Receive additional doses of study drug at every subsequent HD until Visit 24. 
o Will skip Visits 4-9 and complete Visit 10 one week later. 
• Subjects randomized to active study drug will: 
o Receive no study drug or food in the hemodialysis clinic. 
• Be transported to/admitted into a nearby phase 1 unit (for 3 successive nights).  
o Receive a standardized dinner.  
o Review of concomitant medications 
o AE assessment 
o VS assessment 


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o Provide blood samples at t=~-12 hours for the following analyses: 
▪ Chemistry (partial panel) 
▪ 
, total free 25-hydroxyvitamin D,
 and 24,25-
dihydroxyvitamin D3 
▪ Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3 
o Receive no further food after dinner and remain in the phase 1 unit overnight. 
7.1.2.2.2 
Single-dose PK Assessment (Only Subjects Randomized to Active Drug) 
7.1.2.2.2.1 
Visit 4 (Days 2-3) 
• Subjects assigned to placebo treatment will skip this visit. 
• AE assessment (once per day) 
• VS assessment (3 times per day) 
• Fasting blood samples will be drawn from subjects housed in the phase 1 unit at t=~-3 hours, 
and t=0 hours and precisely (plus or minus 5 minutes, with exact time noted) at t=4, 8, 12, 
16, 20, 24, 30, 36 and 42 hours post-dose for the following analyses: 
o Chemistry (partial panel) 
o 
, total free 25-hydroxyvitamin D, 
 and 24,25-
dihydroxyvitamin D3 
o Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3 
• Subjects take first dose of study drug (900 mcg given as 6 CTAP101 Capsules of 150 mcg 
strength) with a sufficient quantity of a non-alcoholic beverage to enable swallowing of the 
capsules immediately after the t=0 blood draw, with the exact time of dosing noted. 
• Standardized meals will be administered at approximately t=5 hours (lunch), 10 hours 
(dinner), 23 hours (breakfast), 28 hours (lunch) and 33 hours (dinner) post-dose. 
• Subjects will remain in the phase 1 unit for a second and third night. 
7.1.2.2.2.2 
Visit 5 (Day 4) 
• No study procedures are scheduled at this visit for subjects assigned to placebo treatment. 
• Subjects will receive a standardized meal (breakfast) in the phase 1 unit at approximately 
t=47 hours post-dose. 
• AE assessment 
• VS assessment 
• Blood samples will be drawn precisely at t=48 hours for the following analyses: 
o Chemistry (partial panel) 
o 
, total free 25-hydroxyvitamin D, 
and 24,25-
dihydroxyvitamin D3 
o Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3 
• Subjects will be discharged from the phase 1 unit and transported to the clinic for the 
regularly scheduled HD session. 


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• Once at the dialysis clinic and prior to HD session: 
o Review of concomitant medications 
o AE assessment 
o VS assessment  
7.1.2.2.2.3 
Visits 6-8 (Days 6-11) 
• No study procedures are scheduled at Visit 6 for subjects assigned to placebo treatment. 
• Subjects assigned to placebo treatment will skip Visits 7-8. 
• Review of concomitant medications 
• AE assessment 
• VS assessment 
• Blood samples will be drawn (with exact time noted) for the following analyses: 
o Chemistry (partial panel) 
o 
, total free 25-hydroxyvitamin D, 
, and 24,25-
dihydroxyvitamin D3 
o Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3 
7.1.2.2.2.4 
Visit 9 (Day 15) 
• Subjects assigned to placebo treatment will skip this visit. 
• Review of concomitant medications 
• AE assessment 
• VS assessment 
• Blood samples will be drawn (with the time noted) for the following analyses: 
o Chemistry (partial panel) 
o Plasma iPTH and serum total 25-hydroxyvitamin D 
o 
, total free 25-hydroxyvitamin D, 
 and 24,25-
dihydroxyvitamin D3 
o Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3 
• Subjects receive initial thrice weekly dose of study drug during HD 
• Subjects will receive additional doses of study drug at every subsequent HD until Visit 24. 
7.1.2.2.3 
Visits 10-16 (Days 8-71 for subjects randomized to placebo; Days 22-85 for 
subjects randomized to active) 
• Must be within ±3 days of scheduled visit 
• Review of concomitant medications 
• AE assessment 
• VS assessment 
• Blood samples will be drawn for the following analyses: 
o Clinical chemistry (partial panel) 


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o Plasma iPTH and serum total 25-hydroxyvitamin D  
7.1.2.2.4 
Visit 17 (Day 85 for subjects randomized to placebo; Day 99 for subjects 
randomized to active) 
• Must be within ±3 days of scheduled visit 
• Review of concomitant medications 
• AE assessment 
• VS assessment 
• Serum b-hCG pregnancy test (for females of child bearing potential) 
• Blood samples will be drawn for the following analyses: 
o Chemistry (full panel) and hematology 
o Plasma iPTH and serum total 25-hydroxyvitamin D 
o 
, total free 25-hydroxyvitamin D, 
, and 24,25-
dihydroxyvitamin D3 
o Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3 
7.1.2.2.5 
Visits 18-23 (Days 99-169 for subjects randomized to placebo; Days 113-183 
for subjects randomized to active)  
• Must be within ±3 days of scheduled visit 
• Review of concomitant medications 
• AE assessment 
• VS assessment 
• Blood samples will be drawn for the following analyses: 
o Clinical chemistry (partial panel) 
o Plasma iPTH and serum total 25-hydroxyvitamin D  
7.1.2.2.6 
Visit 24 (Day 183 for subjects randomized to placebo; Day 197 for subjects 
randomized to active) or Early Termination (ET) 
• Must be within ±3 days of scheduled visit 
• Review of concomitant medications 
• AE assessment 
• PE (including height, weight and BMI)  
• VS assessment 
• 12-Lead ECG  
• Serum b-hCG pregnancy test (for females of child bearing potential) 
• Blood samples will be drawn for the following analyses: 
o Chemistry (full panel) and hematology 
o Plasma iPTH and serum total 25-hydroxyvitamin D 


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o 
, total free 25-hydroxyvitamin D, 
 and 24,25-
dihydroxyvitamin D3 
o Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3 
• 
 
 
[Note:  the remaining instructions for this Visit do not apply to an Early Termination Visit.] 
• Subjects randomized to placebo will: 
o Not receive a dose of study drug (CTAP101 placebo) during this HD session and will 
stop all further dosing with study drug. 
o Skip Visits 25-29 and complete Visit 30 two weeks later. 
• Subjects randomized to active study drug will: 
o Receive no study drug (CTAP101 Capsules) or food in the HD clinic 
o Be transported to/admitted into a nearby phase 1 unit (for 3 successive nights) 
o Review of concomitant medication 
o AE assessment 
o VS assessment 
o Receive a standardized dinner.  
o Provide blood samples at t=~-12 hours for the following analyses: 
▪ Chemistry (partial panel) 
▪ 
, total free 25-hydroxyvitamin D,
 and 24,25-
dihydroxyvitamin D3 
▪ Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3 
o Receive no further food after dinner and remain in the phase 1 unit overnight. 
7.1.2.3 
Follow-up Period 
Note:  No study procedures are scheduled on Visits 25-29 (Days 184-193) for subjects assigned 
to placebo treatment. 
Study drug (cinacalcet) is administered at a sub-therapeutic dose of 30 mg tiw at the end each 
HD session to all subjects, previously treated with CTAP101 Capsules/placebo study drug, 
during 3 weeks of their respective 6-week FU observation periods, specifically beginning with 
Week 27 (Day 190) and continuing through Week 29 (Day 209) for PK placebo subjects or 
beginning with Week 29 (Day 204) and continuing through Week 31 (Day 223) for PK active 
subjects. Subjects must have a serum calcium of  ≥8.6 mg/dL and a plasma iPTH of  ≥300 pg/mL 
prior to beginning cinacalcet dosing. No cinacalcet will be administered at Visit 31 (Day 211) or 
any subsequent days for PK placebo subjects or Visit 32 (Day 225) for PK active subjects.  
Subjects will proceed with FU period schedule and activities listed below. 
 


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7.1.2.3.1 
Repeated-dose PK Assessment (Only Subjects Randomized to Active) 
7.1.2.3.1.1 
Visit 25 (Days 198-199) 
• AE assessment (once per day) 
• VS assessment (3 times per day) 
• Fasting blood samples will be drawn from subjects housed in the phase 1 unit at t=~-3 hours, 
and t=0 hours and precisely (plus or minus 5 minutes, with exact time noted) at t=4, 8, 12, 
16, 20, 24, 30, 36 and 42 hours post-dose for the following analyses: 
o Chemistry (partial panel) 
o 
, free 25-hydroxyvitamin D, 
, and 24,25-dihydroxyvitamin D3 
o Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3 
• Subjects take last dose of study drug (current dose given as 2 capsules) with a sufficient 
quantity of a non-alcoholic beverage to enable swallowing of the capsules immediately after 
the t=0 blood draw, with the exact time of dosing noted. 
• Standardized meals will be administered at approximately t=5 hours (lunch), 10 hours 
(dinner), 23 hours (breakfast), 28 hours (lunch) and 33 hours (dinner) post-dose. 
• Subjects will remain in the phase 1 unit for a second and third night. 
7.1.2.3.1.2 
Visit 26 (Day 200) 
• Subjects will receive a standardized meal (breakfast) in the phase 1 unit at approximately 
t=47 hours post-dose. 
• AE assessment 
• VS assessment 
• Blood samples will be drawn precisely at t=48 hours for the following analyses: 
o Chemistry (partial panel) 
o 
, free 25-hydroxyvitamin D, 
and 24,25-
dihydroxyvitamin D3 
o Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3 
• Subjects will be discharged from the phase 1 unit and transported to the clinic for the 
regularly scheduled HD session  
• Once at the dialysis clinic and prior to HD session: 
o Review of concomitant medications 
o AE assessment 
o VS assessment  
• No study drug (CTAP101 Capsules) will be administered during this HD session or at any 
subsequent visit. 
7.1.2.3.1.3 
Visits 27-29 (Days 202-207) 
• Review of concomitant medication 
• AE assessment 


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• VS assessment 
• Blood samples will be drawn (with the time noted) for the following analyses: 
o Chemistry (partial panel) 
o 
 total free 25-hydroxyvitamin D, 
and 24,25-
dihydroxyvitamin D3 
o Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3 
7.1.2.3.2 
Visits 30-31 (Days 197-211 for subjects randomized to placebo; Days 211-
225 for subjects randomized to active) 
• Must be within ±3 days of scheduled visit 
• Review of concomitant medication 
• AE assessment 
• VS assessment 
• Blood samples will be drawn (with the time noted) for the following analyses: 
o Chemistry (partial panel) 
o Plasma iPTH and serum total 25-hydroxyvitamin D 
• Additional blood samples will be drawn from subjects randomized to active for: 
o 
, total free 25-hydroxyvitamin D, 
and 24,25-
dihydroxyvitamin D3 
o Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3  
• Placebo subjects will receive cinacalcet on Day 209, but will not receive cinacalcet during 
Visit 31 (Day 211). 
• Active subjects will receive cinacalcet on Day 223, but will not receive cinacalcet during 
Visit 32 (Day 225). 
7.1.2.3.3 
Visit 32 (Day 225 for subjects randomized to placebo; Day 239 for subjects 
randomized to active) 
• Must be within ±3 days of scheduled visit 
• Review of concomitant medication 
• AE assessment 
• PE (including height, weight and BMI)  
• VS assessment 
• Blood samples will be drawn for the following analyses: 
o Serum b-hCG pregnancy test (for females of child bearing potential) 
o Chemistry (full panel) and hematology 
o Plasma iPTH and serum total 25-hydroxyvitamin D  
• Additional blood samples will be drawn (with the time noted) from subjects randomized to 
active for: 


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o 
, total free 25-hydroxyvitamin D, 
and 24,25-
dihydroxyvitamin D3 
o Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3 
• No placebo or active subjects will receive cinacalcet during this visit. 
• Subjects terminate further participation in the study. 
7.2 
Cohort 2  
Note: Any subject who terminates participation in the study prematurely will complete the 
procedures listed under Visit 26 (Day 197) at the ET Visit. 
7.2.1 
Screening and Baseline Periods 
Subjects will not discontinue any medications or adjust any medications as noted in the inclusion 
criteria until they are confirmed as eligible (including confirmation of clinical laboratory 
parameters) to begin the washout period. 
7.2.1.1 
Visit 1 (Days -83 to -69) 
• A signed ICF will be obtained from the subjects prior to any study-related procedures 
• Review of inclusion/exclusion criteria 
• Medical history and demographics 
• Review of prior medications 
• AE assessment 
• PE (including weight, height and BMI) 
• VS assessment 
• Serum b-hCG pregnancy test (for females of child bearing potential) 
• Blood samples will be drawn for the following: 
o Clinical chemistry (full panel) and hematology 
o Plasma iPTH and serum total 25-hydroxyvitamin D 
7.2.1.2 
Visit 2 (Days -13 to -7) 
• Must be within ±3 days of scheduled visit 
• Review of inclusion/exclusion criteria 
• Review of concomitant medications 
• AE assessment 
• VS assessment 
• Blood samples will be drawn for the following: 
o Clinical chemistry (partial panel) 
o Plasma iPTH and serum total 25-hydroxyvitamin D 
o 
   
• Blood samples will be drawn for non-PK subjects for: 


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o 
, total free 25-hydroxyvitamin D, 
; and 24,25-
dihydroxyvitamin D3 
o Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3 
7.2.2 
Treatment Period (26 weeks) 
7.2.2.1 
Visit 3 (Day 1) 
• Review of inclusion/exclusion criteria 
• Subjects randomized to treatment with active or placebo drug product 
• Review of concomitant medications  
• AE assessment 
• VS assessment 
• Serum b-hCG pregnancy test (for females of child bearing potential) 
• 12-Lead ECG  
• Blood samples will be drawn for the following analyses: 
o Chemistry (full panel) and hematology 
o Plasma iPTH and serum total 25-hydroxyvitamin D 
o 
, total free 25-hydroxyvitamin D, 
; and 24,25-
dihydroxyvitamin D3 
o Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3 
o 
 
• 
 
 
 
 
• Non-PK subjects will:  
o Skip Visits 4 through 9 and complete Visit 10 one week later 
o Receive initial dose of study drug during HD 
o Receive additional doses of study drug at every subsequent HD until Visit 43 
• Subjects in the PK sub-groups will: 
o Receive no study drug or food prior to departure from the clinic, and will be transported 
to/admitted into a nearby phase 1 unit (for 3 successive nights) 
o Review of concomitant medications 
o AE assessment 
o VS assessment 
o Receive a standardized dinner  
o Provide blood samples at t=~-12 hours for the following analyses: 
▪ Chemistry (partial panel) 
▪ 
, total free 25-hydroxyvitamin D, 
 and 24,25-
dihydroxyvitamin D3 


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▪ Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3 
o Receive no further food after dinner and remain in the phase 1 unit overnight. 
7.2.2.2 
Single-dose PK Assessment (PK Sub-Groups Only) 
7.2.2.2.1 
Visit 4 (Days 2-3, Saturday-Sunday or Sunday-Monday) 
• AE assessment (once daily) 
• VS assessment (3 times per day) 
• Fasting blood samples will be drawn from subjects housed in the phase 1 unit at t=~-3 hours, 
and t=0 hours and precisely (plus or minus 5 minutes, with exact time noted) at t=4, 8, 12, 
16, 20, 24, 30, 36 and 42 hours post-dose for the following analyses: 
o Chemistry (partial panel) 
o 
 total free 25-hydroxyvitamin D, 
 and 24,25-
dihydroxyvitamin D3 
o Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3 
• Subjects take assigned dose of study drug with up to 250 mL of water immediately after the 
t=0 blood draw, with the exact time of dosing noted. 
• Standardized meals will be administered at approximately t=5 hours (lunch), 10 hours 
(dinner), 23 hours (breakfast), 28 hours (lunch) and 33 hours (dinner) post-dose. 
• Subjects will remain in the phase 1 unit for a second and third night. 
7.2.2.2.2 
Visit 5 (Day 4, Monday or Tuesday) 
• Subjects will receive a standardized meal (breakfast) in the phase 1 unit at approximately 
t=47 hours post-dose. 
• AE assessment 
• VS assessment 
• Blood samples will be drawn precisely at t=48 hours for the following analyses: 
o Chemistry (partial panel) 
o 
, total free 25-hydroxyvitamin D, 
and 24,25-
dihydroxyvitamin D3 
o Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3 
• Subjects will be discharged from the phase 1 unit and transported to the clinic for the 
regularly scheduled HD session. 
• Once at the dialysis clinic and prior to HD session: 
o Review of concomitant medications 
o AE assessment 
o VS assessment  
7.2.2.2.3 
Visits 6-8 (Days 6-11) 
• Review of concomitant medications 




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o 
 total free 25-hydroxyvitamin D, 
and 24,25-
dihydroxyvitamin D3 
o Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3 
o 
 
• Qualified subjects will titrate dose upwards, starting with this visit. 
7.2.2.5 
Visits 18-25 (Days 106-183) 
• Visits 18 and 20 are not required for subjects who do not undergo upward dose titration at 
Visit 17. 
• Must be within ±3 days of scheduled visit 
• Review of concomitant medications 
• AE assessment 
• VS assessment 
• Blood samples will be drawn for the following analyses: 
o Clinical chemistry (partial panel) 
o Plasma iPTH and serum total 25-hydroxyvitamin D  
7.2.2.6 
Visit 26 (Day 197) or Early Termination (ET) 
• Must be within ±3 days of scheduled visit 
• Review of concomitant medication 
• AE assessment 
• VS assessment 
• Physical exam (height, weight and BMI)  
• 12-Lead ECG (only for subjects in the PK sub-group receiving 900 mcg per week or ET) 
• Serum b-hCG pregnancy test (for females of child bearing potential) 
• Blood samples will be drawn for the following analyses: 
o Chemistry (full panel) and hematology 
o Plasma iPTH and serum total 25-hydroxyvitamin D 
o 
, total free 25-hydroxyvitamin D, 
 and 24,25-
dihydroxyvitamin D3 
o Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3 
o 
  
• 
  
 
 
 
[Note:  the remaining instructions for this Visit do not apply to an Early Termination Visit.] 
• Non-PK subjects will:  
o Continue dosing with study drugs 


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o Skip Visits 27 through 35  
o Complete Visit 36 after 4 weeks 
• Subjects who have been treated with placebo will: 
o Skip Visits 27 through 35 
o Complete Visit 36 after 4 weeks 
o Commence dosing with CTAP101 Capsules at a dosage of 300, 600 or 900 mcg per 
week, assigned randomly with stratification by severity of SHPT, and continue dosing 
through Day 419. 
• Subjects in the active PK sub-groups will: 
• Receive no study drug or food prior to departure from the clinic, and will be transported 
to/admitted into a nearby phase 1 unit (for 3 successive nights) 
• Once at the dialysis clinic and prior to HD session: 
o Review of concomitant medications 
o AE assessment 
o VS assessment  
o Receive a standardized dinner 
o Provide blood samples at t=~-12 hours for the following analyses: 
▪ 
, free 25-hydroxyvitamin D, 
 and 24,25-
dihydroxyvitamin D3 
▪ Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3 
o Receive no further food after dinner and remain in the phase 1 unit overnight. 
7.2.2.7 
Repeated-dose PK Assessment (Active PK Sub-Groups Only) 
7.2.2.7.1 
Visit 27 (Days 198-199, Saturday-Sunday or Sunday-Monday) 
• AE assessment (once daily) 
• VS assessment (3 times per day) 
• Fasting blood samples will be drawn from subjects housed in the phase 1 unit at t=~-3 hours, 
and t=0 hours and precisely (plus or minus 5 minutes, with exact time noted) at t=4, 8, 12, 
16, 20, 24, 30, 36 and 42 hours post-dose for the following analyses: 
o Chemistry (partial panel) 
o 
, total 25-hydroxyvitamin D, free 25-hydroxyvitamin D, 
, and 24,25-dihydroxyvitamin D3 
o Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3 
• Subjects take assigned dose of study drug with up to 250 mL of water immediately after the 
t=0 blood draw, with the exact time of dosing noted. 
• Standardized meals will be administered at approximately t=5 hours (lunch), 10 hours 
(dinner), 23 hours (breakfast), 28 hours (lunch) and 33 hours (dinner) post-dose. 
• Subjects will remain in the phase 1 unit for a second and third night. 


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7.2.2.7.2 
Visit 28 (Day 200, Monday or Tuesday) 
• Subjects will receive a standardized meal (breakfast) in the phase 1 unit at approximately 
t=47 hours post-dose. 
• AE assessment 
• VS assessment 
• Blood samples will be drawn precisely at t=48 hours for the following analyses: 
o Chemistry (partial panel) 
o 
, total 25-hydroxyvitamin D, free 25-hydroxyvitamin D, 
 and 24,25-dihydroxyvitamin D3 
o Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3 
• Subjects will be discharged from the phase 1 unit and transported to the clinic for the 
regularly scheduled HD session. 
• Once at the dialysis clinic and prior to HD session: 
o Review of concomitant medications 
o AE assessment 
o VS assessment  
7.2.2.7.3 
Visits 29-34 (Days 202-225) 
• Review of concomitant medications   
• AE assessment   
• VS assessment   
• Blood samples will be drawn for the following analyses: 
o Chemistry (partial panel) 
o 
, total free 25-hydroxyvitamin D, 
, and 24,25-
dihydroxyvitamin D3 
o Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3 
• Subjects who had been receiving CTAP101 Capsules at weekly doses of 300 or 600 mcg 
during the first 26 weeks of treatment will: 
o Skip Visits 32-35 
o Complete Visit 36 4 days after Visit 31 
7.2.2.7.4 
Visit 35 (Day 239) 
• Review of concomitant medications 
• AE assessment 
• PE (including height, weight and BMI)  
• VS assessment 
• Blood samples will be drawn for the following analyses: 
o Serum b-hCG pregnancy test (for females of child bearing potential; only for subjects in 
the PK sub-group receiving 900 mcg per week) 


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o Chemistry (full panel) and hematology 
o Plasma iPTH and serum total 25-hydroxyvitamin D  
o 
, total free 25-hydroxyvitamin D,
 and 24,25-
dihydroxyvitamin D3 
o Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3  
• Subjects in the 900 mcg group will undergo the following tests: 
o 
 
 
• Subjects in the PK sub-group receiving 900 mcg per week of CTAP101 Capsules will 
terminate any further participation in the study. 
7.2.3 
Extension Treatment Period (26 weeks) 
• Subjects who had been receiving CTAP101 Capsules at weekly doses of 300 or 600 mcg 
during the first 26 weeks of treatment will resume dosing with CTAP101 Capsules, as before, 
at a dose of 300 or 600 mcg per week starting at Visit 36. 
7.2.3.1 
Visits 36-42 (Days 267-407) 
• Must be within ±3 days of scheduled visit 
• Review of concomitant medications 
• AE assessment 
• VS assessment 
• Blood samples will be drawn for the following analyses: 
o Clinical chemistry (partial panel) 
o Plasma iPTH and serum total 25-hydroxyvitamin D  
7.2.3.2 
Visit 43 (Day 421) 
• Must be within ±3 days of scheduled visit 
• Review of concomitant medications 
• AE assessment 
• PE (including height, weight and BMI) 
• VS assessment 
• 12-Lead ECG 
• Serum b-hCG pregnancy test (for females of child bearing potential) 
• Blood samples will be drawn for the following analyses: 
o Chemistry (full panel) and hematology 
o Plasma iPTH and serum total 25-hydroxyvitamin D 
o 
, total free 25-hydroxyvitamin D, 
 and 24,25-
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o Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3 


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o 
 
• 
 
• 
 
 
• Subjects will not be dosed with study drug during hemodialysis and will discontinue further 
dosing with study drug. 
7.2.4 
Follow-up Period 
7.2.4.1 
Visit 44 (Day 449) 
• Must be within ±3 days of scheduled visit 
• Review of concomitant medications 
• AE assessment 
• VS assessment 
• Blood samples will be drawn for the following analyses: 
o Clinical chemistry (partial panel) 
o Plasma iPTH and serum total 25-hydroxyvitamin D  
7.2.4.2 
Visit 45 (Day 463) 
• Must be within ±3 days of scheduled visit 
• Review of concomitant medications 
• AE assessment 
• VS assessment 
• Blood samples drawn for: 
o Chemistry (full panel) and hematology 
o Plasma iPTH and serum total 25-hydroxyvitamin D 
o 
, total 25-hydroxyvitamin D, free 25-hydroxyvitamin D, 
 and 24,25-dihydroxyvitamin D3  
o Serum total 1,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D3 
• Subjects terminate further participation in the study 
 
 


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8 QUALITY CONTROL AND ASSURANCE 
A quality assurance audit may be performed by the sponsor and/or its designee at selected sites 
to verify that the study is conducted in accordance with the protocol, ICH/GCP (International 
Conference on Harmonisation [ICH] and Good Clinical Practice [GCP]), and applicable SOPs 
and regulations, to ensure that the safety and welfare of subjects are addressed, and to confirm 
that problems reported by study monitors are resolved.  Verification of study documents and 
activities (if applicable) will be conducted to confirm accuracy of recorded data and its analysis.  
Audit observations and findings will be documented and communicated to appropriate study 
personnel and management.  An inspection may be conducted by regulatory authorities.  The 
investigator must allow direct access to study documents during these inspections and audits.  
Monitoring visits will be performed to evaluate study conduct, data integrity, protocol, and GCP 
compliance.  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. 
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 electronic data capture (EDC) system.  During the review, subject data will be 
checked for consistency, omissions, and any apparent discrepancies.  In addition, the data will be 
reviewed for adherence to the protocol, and ICH/GCP.  Moreover, all data from external sources, 
(eg., central laboratory and PK 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. 
 
 


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9 PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
A detailed description of the planned statistical methods can be found in the associated Statistical 
Analysis Plan.  All analyses will be performed using appropriate statistical software.  All data 
collected on eCRFs and from clinical laboratory evaluations will be grouped and listed by 
population sub-group, subject, visit, date and time as feasible.  Summary tables will be presented 
by population sub-group as appropriate.  Descriptive summaries of categorical outcomes will 
include the proportion of subjects.  Descriptive summaries of quantitative measures will include 
the number of subjects, mean, standard deviation (SD), median, minimum, and maximum or as 
appropriate.  In descriptive summary tables, if needed, the geometric mean will be calculated as 
the nth root of the resulting product of the values, and the coefficient of variation (in percent, 
%CV) will be calculated as 100* (SD/[arithmetic mean]). 
Arithmetic means, SDs, medians, and geometric means will be reported with 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 1 decimal place. 
Denominators of percentage of subject calculations will be based on the number of subjects in 
the sub-group and selected population unless otherwise specified.   
In the event there are multiple results at a given visit and/or time point, the following logic will 
be applied for purposes of summarization by visit or time point: for pre-dose measurements and 
selection of a baseline value, the more recent non-missing result will be 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. 
9.2 
Determination of Sample Size 
Formal power calculations have not been undertaken for Cohort 1.  For Cohort 2, sample size has 
been calculated to provide power of 80% for a two-sided, alpha 0.05 level test of equal 
proportions comparing the numbers of subjects attaining both a mean serum total 25-
hydroxyvitamin D level of ≥50 ng/mL and a mean decrease from pre-treatment baseline of at 
least 30% in plasma iPTH (averaged over the last 6 weeks of the 26-week treatment periods) on 
each of the three different weekly dosages of CTAP101 Capsules (active) versus placebo.  
Assuming response rates of at least 0.4 (CTAP101 Capsules) versus 0.1 (placebo), and using a 
1:1 ratio of each dose of CTAP101 Capsules:placebo subjects with an estimated 30% dropout 
rate over the course of the study, a sample size of 53 subjects is required in each treatment arm of 
the study, allocated as 53 to CTAP101 Capsules at 300 mcg per week, 53 to CTAP101 Capsules 
at 600 mcg per week, 53 to CTAP101 Capsules at 900 mcg per week, and 53 to placebo. 
9.3 
Analysis Populations 
Efficacy analyses will be conducted for the ITT and PP populations in Cohort 2, as indicated.  
The ITT populations will include all subjects who have been randomized to receive study drug.  


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The Safety population will include all subjects who have received at least one dose of study drug 
and will be used for assessing safety.  Subjects who do not have at least one recorded value at 
baseline, defined in Section 9.10.1, for serum total 25-hydroxyvitamin D and for plasma iPTH 
will be excluded from all efficacy analyses.  The PP population will be defined as all subjects for 
whom at least two serum total 25-hydroxyvitamin D and two plasma iPTH determinations are 
included in the calculated baseline value and in the EAP(s), and who do not have a major 
protocol deviation.  
9.4 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized for the ITT and PP populations by 
sub-groups separately and combined.  Baseline height, weight, body mass index (BMI), age, sex, 
race, ethnicity, tobacco and nicotine history, and alcohol history will be tabulated for the safety 
population.  Age (years) will be calculated as (date of ICF - date of birth + 1)/365. 
9.5 
Subject Disposition and Withdrawal 
Subject disposition will be tabulated and descriptively summarized for all randomized subjects 
by population sub-groups separately and combined.  The primary reason for premature study 
termination will be detailed together with the proportion of subjects discontinuing for each 
reason.  The primary reason for premature study termination will be collected from the ET eCRF 
page.  
Medical history will be displayed in a data listing.  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. 
9.6 
Prior and Concomitant Medications 
Prior medications are defined as any continuing or new medication used within 12 weeks and 
discontinued before Visit 1.  Concomitant medications are defined as any continuing or new 
medication taken from Visit 1 or anytime thereafter until the end of the study.  Type and dose of 
concomitant medications used for phosphate binder therapy will be collected on a separate eCRF 
page at each visit.  World Health Organization Drug Dictionary Enhanced version September 
2017, Format C, or later will be used to code concomitant and prior medications.  Prior and 
concomitant medications will be tabulated by population sub-group using frequency counts and 
percentages for each anatomical/therapeutic/chemical Class Level 4 and drug trade 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.  
9.7 
Pharmacokinetic Analysis 
Parameters to be calculated from observed and baseline-adjusted serum calcifediol (if data are 
sufficient for estimation) include, but may not be limited to the parameters listed in Table 5. 




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9.9 
Safety Analysis 
All subjects in Safety population will be included in the safety analysis.  Statistical summary 
analysis of safety data will be descriptive and performed by study arms.  No inferential 
hypothesis testing will be performed on the safety variables with the exception of comparisons of 
serum calcium and serum phosphorus between treatment groups with different CTAP101 
Capsules dosing regimens and the placebo group.  
9.9.1 
Primary Endpoints Analyses 
9.9.1.1 
Adverse Events 
All AEs will be collected on the eCRF and coded via SOC and preferred term using MedDRA 
version 20.0 or higher.  Additionally, the intensity of all AEs will be coded using CTCAE v. 5.0.  
AEs with missing onset date will be treated as TEAEs and missing onset date will be imputed as 
the date of Visit 1, unless the event end date indicates that the event resolved prior to Visit 1, in 
which case it will be documented in medical history.  AEs with partial onset date will be treated 
as TEAEs unless the partial onset date or end date of the event is complete enough to indicate 
that the event started or resolved prior to the administration of the investigational study drug, in 
which case it will be documented in medical history.  Detailed information collected for each 
TEAE will include: AE number, a description of the event, start date, end date or ongoing as of 
date, outcome, therapy for event, whether the AE is serious, seriousness criteria (life-threatening, 
death, hospitalization/prolongation of hospitalization, congenital anomaly, persistent or 
significant disability/incapacity, required intervention to prevent permanent 
impairment/damage), severity, and relationship to the study drug.  The incidence of the AEs will 
be summarized by population sub-group for all TEAEs, potentially drug-related TEAEs, serious 
TEAEs, discontinuation due to TEAEs, TEAEs by relationship to study drug (definite, probable, 
possible, unrelated) and TEAEs by severity (mild, moderate, severe).  The number and 
percentages of subjects with a TEAE will be summarized by SOC and preferred term and 
presented overall and by population sub-group.  TEAEs will be sorted in descending order of 
total incidence of SOC and preferred term within each SOC.  The percentages will be based on 
the number of Safety subjects in a particular population sub-group.  If a subject has more than 
one TEAE that code to the same preferred term, the subject will be counted only once for that 
preferred term.  Similarly, if a subject has more than one TEAE within a SOC category, the 
subject will be counted only once in that SOC category.  All AEs collected on the eCRF will be 
included in the listings.  An additional listing of all subject deaths will also be provided.  
Diagnostic procedures will be collected separately in the eCRF and coded via SOC and preferred 
term using MedDRA version 20.0 or higher in a manner similar to AEs. 
9.9.1.2 
Vital Signs  
Observed VS values will be summarized descriptively at baseline and changes from baseline will 
be descriptively summarized by study arms.  Summaries will include n (%), mean, SD, median, 
minimum, and maximum.  Vital sign values will be listed.  


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9.9.1.3 
Physical Examination 
Physical examination dates, whether a PE 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 20.0 or higher. 
9.9.2 
Secondary Endpoint Analyses 
Secondary safety endpoints for Cohort 2 will include incidence of hypercalcemia and drug-
related hyperphosphatemia.  The number (n, %) of subjects with hypercalcemia (two consecutive 
visits with serum calcium >10.4 mg/dL) or hyperphosphatemia (two consecutive visits with 
serum phosphorus >6.5 mg/dL deemed to be related to the investigational study drug) will be 
compared between study arms using a Chi-square test statistic (alpha=0.05).  
9.10 
Efficacy Analyses 
9.10.1 
Primary Endpoint Analyses 
There is no primary efficacy endpoint for Cohort 1, as efficacy in this part of the study is merely 
observational.  Primary efficacy will be assessed in the ITT population for Cohort 2 by 
comparing each active treatment group to the placebo group with regard to the proportion of 
subjects achieving a mean serum total 25-hydroxyvitamin D ≥50 ng/mL and a mean ≥30% 
decrease in plasma iPTH from pre-treatment baseline in the first EAP, defined as the average of 
values obtained in the last 6 weeks of the first 26 weeks of treatment (Visits 24, 25 and 26).  
Baseline will be defined as the average of values obtained before receiving the first dose of study 
drug at screening Visit 1 (if an 8-week washout period is not required), pre-dose Visit 2, and 
Visit 3 (pre-dose).  Visits are defined in Appendix 1 Schedule of Events.  
9.10.2 
Secondary Endpoint Analyses 
The key secondary efficacy endpoint for Cohort 1 is the proportion of subjects in the intent-to-
treat (ITT) population attaining both a mean serum total 25-hydroxyvitamin D of ≥50 ng/mL and 
a mean decrease in plasma iPTH of at least 30% from pre-treatment baseline during the EAP, 
calculated for each treatment group.  
Secondary efficacy endpoints for Cohorts 1 and 2 include the proportion of subjects in the per-
protocol (PP) population attaining both a mean serum total 25-hydroxyvitamin D of ≥50 ng/mL 
and a mean decrease in plasma iPTH of at least 30% from pre-treatment baseline during the first 
EAP.  Additional secondary endpoints include the proportion of subjects in the PP population 
attaining both a mean serum total 25-hydroxyvitamin D of ≥50 ng/mL and a mean decrease in 
plasma iPTH of at least 10, 20 or 30% from pre-treatment baseline during the first and/or second 
EAP, as applicable, defined as the average of values obtained in the last 6 weeks of the second 
26 weeks of treatment; the time courses of mean absolute changes from pre-treatment baseline in 
serum total 25-hydroxyvitamin D and plasma iPTH; categorical comparisons of safety and 
efficacy based on body weight, age, gender, race, dose, severity of SHPT and VDI, dialysis 
vintage, etiology of CKD and prior treatment with 1α-hydroxylated vitamin D analogs and/or 
calcimimetics; PD effects on mean serum calcium (corrected), phosphorus, DBP, 
 total 
free 25-hydroxyvitamin D, total 1,25-dihydroxyvitamin D, 1,25-dihydroxyvitamin D3, and 
24,25-dihydroxyvitamin D3; and, population PK of serum calcifediol relative to body weight, 


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age, gender, race, dose, severity of SHPT and VDI, dialysis vintage, etiology of CKD and prior 
treatment with 1α-hydroxylated vitamin D analogs and/or calcimimetics. 
 
  
 
 
 
 
 
 
   
9.11 
Statistical Analyses 
Primary efficacy will be assessed in the ITT population of Cohort 2 by comparing the 
proportions of subjects in all three active groups versus those in the placebo group and, 
subsequently, each active dose group versus placebo (in the order of dose group bb, then cc, then 
aa versus dose group dd) attaining both a mean serum total 25-hydroxyvitamin D level of ≥50 
ng/mL and a mean decrease from baseline in plasma iPTH of ≥30% in the first EAP using the 
Cochran-Mantel-Haenszel test statistic (alpha=0.05).  Subjects who do not have at least two 
serum total 25-hydroxyvitamin D and plasma iPTH determinations in the EAP will be deemed 
non-responders.  Dose groups will be defined for analysis of the first 26 weeks of treatment by 
the average weekly dose administered in the first EAP, as follows: dose group dd = 0 mcg; dose 
group aa = 1-300 mcg, dose group bb = 301-600 mcg and dose group cc = 601-900 mcg.  
Statistical comparisons will not be made between the active treatment groups receiving different 
average weekly dosages of CTAP101 Capsules. 
Key secondary efficacy for Cohort 1 will be assessed in the ITT population by comparing the 
proportions of subjects in the active group versus those in the placebo group attaining both a 
mean serum total 25-hydroxyvitamin D level of ≥50 ng/mL and a mean decrease from baseline 
in plasma iPTH of ≥30% in the EAP using the Cochran-Mantel-Haenszel test statistic 
(alpha=0.05).  Subjects who do not have at least two serum total 25-hydroxyvitamin D and 
plasma iPTH determinations in the EAP will be deemed non-responders.  Dose groups will be 
defined for analysis of the 26 weeks of treatment by the average weekly dose administered in the 
EAP, as follows: dose group b = 0 mcg; dose group d = 1-300 mcg, dose group c = 301-600 mcg 
and dose group b = 601-900 mcg.  Statistical comparisons will not be made between the active 
treatment groups receiving different average weekly dosages of CTAP101 Capsules. 
Secondary efficacy will be assessed in the PP population of both cohorts by comparing the 
proportions of subjects in each active dose group versus those in the placebo group attaining a 
mean serum total 25-hydroxyvitamin D of ≥50 ng/mL and a mean decrease from baseline in 
plasma iPTH of ≥10, 20 and 30% in the first and/or second EAP, as applicable, using the 
Cochran-Mantel-Haenszel test statistic (alpha=0.05).  Dose groups will be defined as described 
above.  Statistical comparisons will not be made between the active treatment groups receiving 
different average weekly dosages of CTAP101 Capsules.   
Primary safety analyses will be conducted in the Safety populations of both cohorts, and the 
statistical summary will be descriptive and performed by dose group (defined above).  No 


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inferential hypothesis testing between each active group and the placebo group will be performed 
on the safety parameters with the exception of mean serum calcium and phosphorus. 
Secondary safety analyses in both cohorts will compare the proportions of subjects with 
confirmed corrected serum calcium >10.4 mg/dL or confirmed serum phosphorus >6.5 mg/dL 
(deemed to be study drug related) between the CTAP101 Capsules and placebo dose groups 
using the Cochran-Mantel-Haenszel test statistic (alpha=0.05).  
In addition to assessing the safety and efficacy evaluations for the full study population in Cohort 
2, categorical comparisons (by dose group) will be conducted for sub-groups based on body 
weight, age, gender, race, dose and severity of SHPT and VDI, dialysis vintage, etiology of CKD 
and prior treatment with 1α-hydroxylated vitamin D analogs and/or calcimimetics.  Also, mean 
plasma iPTH in the EAP of Cohort 1 and in the first EAP of Cohort 2 will be compared, by 
treatment group, to the mean pre-washout screening value for subjects who were previously 
treated with 1α-hydroxylated vitamin D analogs and/or calcimimetics.   
An interim analysis of safety and efficacy will be completed for Cohort 2 after the last subject 
has completed the first 26 weeks of treatment.   
 
 


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10 ADMINISTRATIVE CONSIDERATIONS 
10.1 
Study Administrative Structure 
Details of contract research organizations, central laboratories and other participating 
organizations will be provided in the laboratory manual supplied to each site. 
10.2 
Notification of Primary Care Physician 
At Visit 1, the subject will be provided with a notification for his/her primary care physician and 
nephrologist that he/she is participating in this clinical study and that no further measurements of 
plasma iPTH, serum total 25-hydroxyvitamin D or serum calcifediol should be ordered.   
10.3 
Institutional Review Board/Ethics Committee Approval 
Good Clinical Practice requires that the clinical protocol, any protocol amendments, the IB, the 
ICF, and all other forms of subject information related to the study and any other necessary 
documents be reviewed by an Independent Review Committee (eg, an IRB). 
10.4 
Ethical Conduct of the Study 
In accordance with applicable country-specific regulations, the sponsor will obtain approval from 
the appropriate regulatory authority(ies) prior to initiating the study in that country.  This study 
will be conducted in accordance with the protocol, all ICH and GCP regulations governing 
clinical study conduct, ethical principles that have their origin in the Declaration of Helsinki, and 
all applicable local laws and regulations. The investigator must assure that the study is conducted 
in accordance with prevailing local laws and customs. 
It is the investigator’s responsibility to ensure that this protocol is reviewed and approved by the 
appropriate IRB/EC.  The IB must be provided to the IRB/EC. 
The IRB/EC must also review and approve the site’s ICF and any other written information 
provided to the subject and any advertisement that will be used for subject recruitment prior to its 
use. 
10.5 
Subject Information and Consent 
The investigator or his/her qualified designee will explain the nature of the study to the subject, 
and answer all questions regarding this study, prior to obtaining informed consent. 
The investigator or his/her qualified designee will obtain informed consent from each subject 
enrolled in the study, in accordance with the Declaration of Helsinki, the current version of the 
ICH guidelines and the local laws and applicable regulatory requirements. 
It is the responsibility of the investigator to assure that the subject or LAR has consented and has 
signed the ICF before any activity or treatment is undertaken which is not part of routine care.  
The subject and/or LAR will receive a signed copy of the ICF and the original will be retained in 
the site study records.  The investigator or his/her designee will ensure documentation of the 
consent discussion in the subject’s medical record/source documents. The decision by the subject 
and/or LAR to participate in the study is entirely voluntary.  The investigator or designate must 
emphasize to the subject and/or LAR that consent regarding study participation may be 


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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). 
10.6 
Subject Confidentiality 
Subject confidentiality will be strictly held in trust by the participating investigators, their staff, 
the sponsor and their authorized representatives.  This confidentiality is extended to cover testing 
of biological samples in addition to the clinical information relating to participating subjects. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence.  No information concerning the study or the data will be released to any 
unauthorized third party, without prior written approval of the sponsor. 
Authorized representatives of the sponsor, the designated contract research organization (if 
applicable), the study monitor, employees of government authorities such as the US FDA or 
other government authorities, and members of the IRB may inspect all documents and records 
required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the subjects in this study.  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. 
10.7 
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.  The investigator will allocate 
adequate time for such monitoring activities.  This monitoring will be in the form of site or 
remote visits and/or other monitoring surveillance approaches and communication and will 
include review of original source documents, eCRFs, facilities and equipment, recruiting, record-
keeping, protocol adherence, data collection, AE reporting, and other factors.  The frequency of 
these visits will depend upon the progress of the study and managed under the Clinical 
Monitoring Plan. 
The investigator will ensure that the monitor or other compliance or quality assurance reviewers 
are given access to all the above noted study-related documents and study related facilities (eg, 
pharmacy, diagnostic laboratory), and has adequate space to conduct the monitoring visit. 


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10.8 
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 in a neat, legible manner to ensure accurate interpretation 
of data.  
Data capture and management will be consistent with applicable ICH/GCP guidelines. 
All data collected during the study for subjects who are enrolled will be recorded in an 
individual, subject-specific eCRF as part of an EDC system.  The sponsor or designee will 
provide training to the investigative site on the EDC system and eCRFs.  All eCRFs will be 
completed in a timely manner as data are available in the source for each subject.  As EDC will 
be utilized, instructions, training records, and a log will be maintained to identify the designated 
site personnel who can enter data and/or sign off on an eCRF. 
A subject eCRF must be completed for each subject who signs a consent form and undergoes any 
procedure related to the study.  All data generated from external sources, (eg, central laboratory 
results), will be integrated with the subject eCRF data through programming or other data 
integration techniques. 
All eCRFs should be completed within 5 business days of the visit to enable the study monitor to 
review the subject’s status throughout the course of the study in real time.  Queries also should 
be resolved in a timely manner. 
The investigator will sign and date the indicated places on the eCRF via the EDC system’s 
electronic signature.  These signatures will indicate that the investigator reviewed the data on the 
eCRF, the data queries, and the data clarifications and agrees with the content. 
10.9 
Protocol Deviations 
Protocol deviations are any intentional or unintentional change from an IRB approved protocol 
that are not approved by the IRB prior to initiation of the change and are collected in EDC. 
Major protocol deviations are deviations that result in increased risk to subjects, affect the rights, 
safety, or welfare of the subjects or affect the integrity of the study. 
Major protocol deviations may include but are not limited to deviations from the 
inclusion/exclusion criteria), informed consent deviations, concomitant medication restrictions, 
and any other protocol requirement that results in a significant added risk to the subject or has an 
impact on the quality of the data collected or the outcome of the study. 
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. 


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10.10 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 enrolled and signed an ICF.  Electronic data 
entry is accomplished through the 21CFR Part 11 compliant remote data capture application, 
which allows for on-site data entry and data management.  Furthermore, the investigators retain 
full responsibility for the accuracy and authenticity of all data entered into the EDC system.  The 
completed dataset and their associated files are the sole property of the sponsor and should not be 
made available in any form to third parties, except for authorized business representatives or 
appropriate governmental health or regulatory authorities, without written permission of the 
sponsor.  
Data management, data analysis and programming the submission-ready tables, listings and 
figures will be responsibility of the sponsor and will be performed and managed per the 
sponsor’s SOPs. 
10.11 Retention of Data 
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRFs 
and all source documents that support the data collected from each subject, and all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial and as specified by the applicable regulatory requirement.  The 
investigator/institution will take measures to prevent accidental or premature destruction of these 
documents. 
Essential documents must be retained until at least two years after the last approval of a 
marketing application in an ICH region or at least two years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor.  It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the study, 
the responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility.  The sponsor or designee must be notified in writing of the name and 
address of the new custodian.  Under no circumstances shall the investigator relocate or dispose 
of any study documents before having obtained written approval from the sponsor. 
10.12 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 


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change during the course of the study or within one year of the end of his/her participation in the 
study. 
10.13 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 trial 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. 
 
 


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11 REFERENCE LIST 
Adams JS, Rafison B, Witzel S, et al. Regulation of the extrarenal CYP27B1-hydroxylase.  J 
Steroid Biochem Mol Biol. 2014;144:22–27. 
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. 
Dusso A, Finch J, Delmez J, et al. Extrarenal production of calcitriol.  Kidney Int. 
1990;38(29):S36–S40. 
Ennis JL, Worcester EM, Coe FL et al. Current recommended 25-hydroxyvitamin D targets for 
chronic kidney disease management may be too low. J Nephrol. 2016 29: 63-70. 
Helvig CF, Cuerrier D, Hosfield CM et al. Dysregulation of renal vitamin D metabolism in the 
uremic rat. Kidney Int. 2010 78: 463-472  
Holick MF. Environmental factors that influence the cutaneous production of vitamin D. Am J 
Clin Nutr. 1995 61: 638S-645S 
Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of 
vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 
2011;96:1911–1930. 
Kalantar-Zadeh K, Kovesdy CP. Clinical outcomes with active versus nutritional vitamin D 
compounds in chronic kidney disease. Clin J Am Soc Nephrol. 2009 4: 1529-1539 
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 
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. 
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: 31-38  
National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Bone Metabolism and 
Disease in Chronic Kidney Disease. Am J Kidney Dis. 2003 42: S1-S202 
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. 
Ritter CS, Haughey BH, Armbrecht HJ, Brown AJ. Distribution and regulation of the 25-
hydroxyvitamin D 1a-hydroxylase in human parathyroid glands, J Steroid Biochem Mol Biol 
2012 130:73-80. 
Souberbielle J, Body J, Lappe JM et al. Vitamin D and musculoskeletal health, cardiovascular 
disease, autoimmunity and cancer: Recommendations for clinical practice. Autoimmun Rev. 
2010 9: 709-715. 


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Strugnell SA, Sprague SM, Ashfaq A et al.  Rationale for raising current clinical practice 
guideline target for serum 25-hydroxyvitamin D in chronic kidney disease.  Am J Nephrol 
2019;49:284-293. 
















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Appendix 2. Cinacalcet (Cipla) April 2019 Label 
 
 


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Appendix 3. Investigator’s Signature 
Study Title: 
A Multi-Center, Randomized, Two-Cohort Phase 2 Study to Evaluate 
the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of 
CTAP101 (calcifediol) Extended-Release Capsules  to Treat 
Secondary Hyperparathyroidism in Subjects with Vitamin D 
Insufficiency and Chronic Kidney Disease Requiring Regular 
Hemodialysis.   
Study Number: 
CTAP101-CL-2010 
Final Date: 
05 May 2020 
I agree: 
To assume responsibility for the proper conduct of the study at this site. 
To conduct the study in compliance with this protocol, with any future amendments, and with any other 
written study conduct procedures provided and reviewed and approved by OPKO Ireland Global 
Holdings Ltd. or its designee(s). 
Not to implement any deviations from or changes to the protocol without agreement from the sponsor and 
prior review and the written approval from IRB/EC, except where necessary to eliminate an immediate 
hazard to the subjects, or for administrative aspects of the study (where permitted by all applicable 
regulatory requirements). 
That I am thoroughly familiar with the appropriate use of the investigational drugs, as described in this 
protocol, and any other information provided by the sponsor including, but not limited to, the following: 
the current Investigator’s Brochure (IB) or equivalent document provided by OPKO Ireland Global 
Holdings Ltd. or its designee(s). 
To ensure that all persons assisting me with the study are adequately informed about the investigational 
drugs and of their study-related duties and functions as described in the protocol. 
That I have been informed that certain regulatory authorities require the sponsor to obtain and supply 
details about the investigator's ownership interest in the sponsor or the study drug, and more generally 
about his/her financial ties with the sponsor. OPKO Ireland Global Holdings Ltd. will use and disclose 
the information solely for the purpose of complying with regulatory requirements. 
Hence, I: 
• 
Agree to supply OPKO Ireland Global Holdings 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 OPKO Ireland Global Holdings Ltd. may disclose this information about such ownership 
interests and financial ties to regulatory authorities. 
Signed: 
 
 
Date: 
 
 
 
Printed Name:_______________________________________ 
 


Signature Page for CTAP101-CL-2010 Protocol v14.0
Signature Page for RIM-CLIN-000472 v14.0
Approval
06-May-2020 15:19:16 GMT+0000
Approval
ger
06-May-2020 15:50:25 GMT+0000
Approval
06-May-2020 15:55:54 GMT+0000

SAP_001.pdf: 
 
  
STATISTICAL ANALYSIS PLAN 
 
A Multi-Center, Randomized, Two-Cohort Phase 2 Study to Evaluate 
the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of 
CTAP101 (calcifediol) Extended-Release Capsules to Treat Secondary 
Hyperparathyroidism in Subjects with Vitamin D Insufficiency and 
Chronic Kidney Disease Requiring Regular Hemodialysis. 
 
 
Sponsor:   
 
EirGen Pharma Ltd. 
 
 
 
c/o OPKO Pharmaceuticals, Inc. 
4400 Biscayne Boulevard 
Miami, FL 33137 
 
 
 
Protocol Number: 
CTAP101-CL-2010, Cohort 1 
 
 
Author:   
 
 
 
 
 
Principal Biostatistician 
 
 
Date:    
 
12SEP2022 
Version:  
 
1.0 
 
















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λz 
Terminal Rate Constant 
LSMeans 
Least Squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
MMRM 
Mixed Model Repeated Measures 
NCS 
Not Clinically Significant 
PD 
Pharmacodynamic(s) 
PDF 
Portable Document Format 
PE 
Physical Examinations 
PK 
Pharmacokinetic(s) 
PP 
Per Protocol 
PT 
Preferred Term 
RTF 
Rich Text Format 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
Scr 
Screening 
SD 
Standard Deviation 
 
 
SDTM 
Study Data Tabulation Model 
SHPT 
Secondary Hyperparathyroidism 
SOC 
System Organ Class 
 
 
t1/2 
Terminal Elimination Half-life 
TEAE 
Treatment-Emergent Adverse Event 
tiw 
Three Times per Week 
tmax 
Time to Maximum Concentration 
tss 
Time to Steady-State Concentration 
US 
United States of America 
VZ/F 
Volume of Distribution based on the terminal phase divided by the 
bioavailable fraction 
VDI 
Vitamin D Insufficiency 
WHO 
World Health Organization 
WO 
Washout 










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2.9 Subgroup Analyses 
The safety and efficacy of CTAP101 will be compared based on categories of body weight, age, gender, 
race, dose, severity of SHPT and VDI, dialysis vintage, etiology of CKD, and prior treatment with 1α-
hydroxylated vitamin D analogs and/or calcimimetics. 
2.10 
Statistical Hypotheses 
No formal hypothesis testing will be concluded; all inferential testing will be considered exploratory and 
hypothesis-generating. 
3. Study Design and Procedures 
3.1 General Study Design  
This is a phase 2, multi-center, randomized, two-cohort study to evaluate the safety, efficacy, PK, and PD 
of CTAP101 Capsules to treat SHPT in male and female subjects aged at least 18 years with VDI and CKD 
requiring thrice weekly in-center HD. The study will be conducted in two successive cohorts at multiple sites 
within the United States (US). Subjects in Cohort 1 will participate in a randomized, single-blinded (subjects 
only), placebo-controlled, repeated-dose exploratory safety and efficacy study of CTAP101 Capsules 
administered at one, high dose level (900 mcg per week). Subjects in Cohort 2 will not be enrolled until 
sufficient data have been obtained from Cohort 1 and reviewed with the US Food and Drug Administration 
(FDA) to make a reasonable decision to proceed with the second cohort, potentially under a further 
amendment to the study protocol. This SAP only focuses on analysis of data from Cohort 1 of the study. 
In Cohort 1, approximately 100 subjects will be screened to randomize approximately 44 eligible subjects 
in a 3:1 ratio into two groups receiving the following treatments in a single-blinded fashion (subjects only) 
for 26 weeks: (a) CTAP101 Capsules at 900 mcg per week or (b) matching placebo. Cohort 1 consists of 
two subgroups (PK subgroup and non-PK subgroup). The schedule of events differs between the 
subgroups of Cohort 1. Randomization will be accomplished in blocks of four subjects using two computer-
generated codes, one for the PK subgroup (n=~28) and one for the non-PK subgroup (n=~16). Cohort 1 
consists of a single 26-week treatment period followed by a 6-week FU period in which cinacalcet dosing 
occurred for some subjects. 
In Cohort 1, subjects who have been consented and did not meet eligibility criteria at the conclusion of the 
Screening Visit (Visit 1, Days -83 to -69) are considered a Screen Failure. Subjects who are eligible after 
Visit 1 but do not meet eligibility criteria at either Visit 2 (Days -13 to -7) or Visit 3 (Day 1; pre-randomized) 
are considered a Pre-Treatment Failure. Only subjects who are randomized to a treatment at Visit 3 (Day 
1) who are then withdrawn during the study will complete early termination (ET) study procedures. 
An Interactive Response Technology (IRT) system will provide study treatment group assignments using 
computer-generated randomization codes and dispense study drug according to randomized, dosing 
assignments and dosing adjustments as required.  


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All subjects will undergo regular HD during the study. Subjects receiving treatment with calcitriol or other 
1α-hydroxylated vitamin D analog, vitamin D supplements, or calcimimetic prior to study enrollment will 
forgo further dosing with these agents after confirmed eligible at Visit 1 and for the duration of the study 
and complete an 8-week washout (WO) period prior to baseline assessments. Subjects will undergo a 6-
week FU observation period after completing treatment.  
On two occasions which bracket the 26-week treatment period, a subset of subjects (n=~21) from Cohort 
1 who are assigned to treatment with CTAP101 Capsules will be housed after the end-of-week HD (on 
Friday or Saturday) in a nearby phase 1 unit for 3 days in order to provide blood samples for determination 
of single-dose and repeated-dose PK profiles of serum calcifediol and associated PD profiles for serum 
calcium (corrected), phosphorus, 
 DBP, total free 25D, total 1,25D, 1,25D3, and 24,25D3. The 
remaining subjects from each treatment group will forgo all PK assessments and complete 26 weeks of 
treatment and undergo a 6-week FU observation period after completing treatment.  Subjects who have 
completed 6 months of treatment with either CTAP101 Capsules or placebo will receive, at their election, 
sub-therapeutic doses of cinacalcet (30 mg tiw at the end of HD) during 3 weeks of the 6-week FU 
observation period in order to observe its effects on plasma iPTH when serum total 25-hydroxyvitamin D is 
still elevated relative to pre-treatment baseline values.  
Subjects who participate in Cohort 1 will not be eligible for participation in Cohort 2. 
A diagram of the study design is shown in Figure 1. 


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Figure 1. Cohort 1 (randomized, single-blinded design) 
 








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identification number (C-SS-EE) will consist of a 1-digit cohort number (C), a 2-digit site number (SS), 
and a 2-digit consecutive enrollment number (EE) at the applicable clinical site. Should a subject be 
withdrawn from the study, that subject’s 5-digit identification number will not be reassigned.  
Study treatment arm assignments will be made via the IRT system using two computer-generated 
randomization codes for each subgroup in Cohort 1 (one for the PK subgroup and one for the non-PK 
subgroup). Randomization will be accomplished in blocks of 4 subjects, with 3 subjects being assigned 
to treatment with CTAP101 Capsules and 1 subject being assigned to treatment with placebo. If four 
qualified Japanese subjects are successfully enrolled into Cohort 1 they will be randomized within in the 
same block to treatment arms in the PK subgroup. Randomization will occur during Visit 3 provided that 
each subject is deemed eligible for enrollment based, in part, on laboratory assessments obtained at 
the preceding visit (Visit 2). Laboratory assessments obtained at Visit 3 will not be considered in the 
determination of enrollment eligibility.  
4.3 Blinding and Unblinding 
The IRT will provide study drug assignments and dosing adjustments. The study coordinator (or 
designated site personnel) at each site will obtain the study drug assignments from the IRT for each 
subject and administer the appropriate number of capsules at each HD, which will be recorded in the 
electronic case report form (eCRF). 
All subjects in Cohort 1 will be blinded to CTAP101 Capsule and placebo treatment group assignments 
and to plasma iPTH, serum total 25D, and serum calcifediol data until the last subject completes 26 
weeks of treatment, 6 weeks of FU and the data have been locked. However, subjects at PK sites will 
undergo differential assessments depending on treatment and may become unblinded. Site personnel 
and clinical study team members will not be blinded. 
5. Sample Size and Power Considerations 
Formal power calculations have not been undertaken for Cohort 1.  
6. Data Preparation 
6.1 Input Data 
All reported study data will be recorded on the eCRFs supplied by Statistics & Data Corporation (SDC) 
using iMedNet™. Only the Principal Investigator and authorized study staff according to the Delegation 
of Responsibilities log are entitled to make entries in the eCRF.  


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After data are entered into the clinical study database, electronic edit checks and data review will be 
performed. All data validation specifications and procedures are detailed in the Data Validation Manual 
as a separate document. When the database has been declared to be complete and accurate, the 
database will be locked. Any changes to the database after data have been locked can only be made 
with the approval of the Sponsor in consultation with SDC. 
External data (i.e., data not entered on the eCRF by the clinical sites but sent separately to SDC) will 
be reconciled with the clinical database by the Data Management team. External data will then be 
transferred to Biostatistics and incorporated into the Study Data Tabulation Model (SDTM) datasets. 
Refer to the study’s Data Management Plan for information on external data sources and reconciliation 
and other data management considerations. 
All analyses outlined in this document will be carried out after the following have occurred: 
 
All data management requirements are met according to SDC standard operating procedures, 
including data entry; edit and validation checks performance;, documentation and resolution of 
data queries, and database lock with written authorization provided by appropriate SDC and 
Sponsor personnel. 
 
Protocol deviations have been identified, categorized and classified for severity 
(i.e.,major/minor deviations, COVID-19 related). 
 
Analysis populations have been determined. 
6.2 Output Data  
Data from iMedNet™ and external data will be transferred to Biostatistics and incorporated into standard 
formats following the SDTM. Data will then be mapped to analysis datasets using the Analysis Data 
Model (ADaM).  Both SDTM- and ADaM-formatted data will be used to create the subject listings, while 
all tables and figures will be based on the ADaM-formatted data.  
Output data will implement the latest applicable SDTM and ADaM models and guidelines, and will be 
validated with the latest Pinnacle 21 version which will be identified within the output data. Any 
discrepancies in the validation will be noted in reviewer’s guides accompanying the final data transfers.  
Define.xml will be created for SDTM and ADaM using the Define-XML version 2.0 model. 




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8. General Statistical Considerations 
8.1 Missing or Inconclusive Data Handling 
In general, there will be no imputation of missing data except for partial or missing dates. For AE and 
medication missing or partial dates, dates will be imputed for the purpose of determining whether the 
AE is treatment-emergent and whether a medication was concomitant with study treatment. If the event 
or medication could have been concurrent with study treatment based on the available information, then 
it will be considered either treatment-emergent or concomitant. 
Partial/missing start and end dates for AEs and concomitant medications will be imputed as follows: 
Partial/missing start date:  
 
Dates with missing day only will be imputed as the 1st of the month unless month and year are 
same as month and year of first dose of study medication in which case missing day will be 
imputed as the first dose day.  
 
Dates with both day and month missing will be imputed as 1 Jan unless year is same as year 
of first dose of study medication in which case missing day and month will be imputed as the 
first dose day and month. 
 
Completely missing dates will be imputed as first dose date unless end date indicates it could 
have started prior to this in which case missing date will be impute as 1 Jan of the same year 
as the end date. 
Partial/missing end date:  
 
Dates with missing day only will be imputed as the last day of the month unless month and year 
are same as month and year of the last dose in which case missing day will be imputed as the 
last dose date.  
 
Dates with both day and month missing will be imputed as 31 Dec unless year is same as year 
of the last dose in which case missing day and month will be imputed as the last dose day and 
month.  
 
If the ongoing flag is missing or “Yes” then date will not be imputed. If ongoing is “No” then it will 
be imputed as the last dose date. 
The original dates will be displayed in data listings and the imputed dates will be used in derivations only 
(study day, treatment-emergent status, etc.). 
AEs with missing onset date will be treated as TEAEs and missing onset date will be imputed as the 
date of Visit 3, unless the event end date indicates that the event resolved prior to Visit 3, in which case 




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In the event there are multiple results at a given visit and/or time point, the following logic will be applied 
for purposes of summarization by visit or time point: for pre-dose measurements and selection of a 
baseline value, the more recent non-missing result will be 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 will be used unless otherwise specified. 
 
8.3 Data Analysis Conventions 
All data analysis will be performed by SDC after the study is completed and the database has been 
locked and released for unblinding. Statistical programming and analyses will be performed using SAS® 
Version 9.4 or higher. Output will be provided in rich text format (RTF) for tables and portable document 
format (PDF) for tables, listings, and figures using landscape orientation. All study data will be listed by 
subject, treatment, treatment subgroup, and visit (as applicable) based on all randomized subjects 
unless otherwise specified. 
All data collected on eCRFs and from clinical laboratory evaluations will be grouped and listed by 
population subgroup (PK subgroup, non-PK subgroup), subject, visit, and date and time as feasible. 
Summary tables will be presented by subgroup (PK subgroup, non-PK subgroup) as appropriate. 
Descriptive summaries of categorical outcomes will include the proportion of subjects. Denominators for 
percentage of subject calculations will be based on the number of subjects with nonmissing data in the 
subgroup and selected population unless otherwise specified. All percentages will be rounded to one 
decimal place (i.e., XX.X%).  
Descriptive summaries of quantitative measures will include the number of subjects, mean, standard 
deviation (SD), median, minimum, and maximum or as appropriate. In PK and PD summaries, 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 x (SD/[Arithmetic Mean]). Arithmetic means, 
SDs, medians, and geometric means will be reported with the same number of significant figures as the 
reported values.. The %CV will be rounded to 1 decimal place.  
Differences between active treatment groups and placebo will be calculated as Active minus Placebo 
and change from baseline will be calculated as post-baseline minus baseline. Continuous descriptive 
statistics (n, mean [SD], median, minimum, maximum)  of measurements at each visit will be presented 
and t-test will be performed to compare active group from placebo. The mean difference between the 
CTAP101 group and placebo, the corresponding 95% CIs, and the p-values will be presented for each 






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 
Using continuous descriptive statistics (n, mean [SD], median, minimum, maximum) for height, 
weight, body mass index (BMI), plasma iPTH, and serum 25(OH)D, 1,25D, calcium and 
phosphorus 
 
Tobacco history (never, former, current) including time (months) since last use for former users. 
Time will be calculated relative to first dose date.  
 
Alcohol history (never, former, current)  
 
Time (months) since diagnosis of CKD and time (months) since diagnosis of SHPT will be 
calculated from the medical history case report form. Time will be calculated relative to first dose 
date. 
 
Prior use of calcitriol, 1α-hydroxyvitamin D analogs, calcimimetics, and prior use of 1α-
hydroxyvitamin D analogs and/or calcimimetics will be summarized from concomitant 
medication data. 
All pretreatment variables will be listed with their respective FU data, and subject listings of disease 
history will also be provided. 
11. Medical History and Concomitant Medications 
11.1 
Medical History 
Medical history will be summarized for the Safety population by subgroup (PK subgroup, non-PK 
subgroup) separately and combined. Medical history will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) version 21.0 or higher and will be summarized using discrete summary 
statistics and presented by treatment group at the subject and event level by System Organ Class (SOC) 
and Preferred Term (PT). Subjects who have more than one medical history within a given SOC or PT 
are only counted once within that SOC or PT. All SOCs are listed in alphabetical order; PTs within a 
SOC are listed in order of descending frequency across all subjects. Percentages are based on the total 
number of subjects in each respective treatment group. 
Medical history will be displayed in a data listing.  
11.2 
Prior and Concomitant Medications 
Prior medications are defined as any continuing or new medication used within 12 weeks and 
discontinued before study treatment. Concomitant medications are defined as any continuing or new 
medication taken from study treatment or anytime thereafter until the end of the study. Medications that 
start before study treatment and continue anytime during study treatment will be defined as both prior 
and concomitant medications. Type and dose of concomitant medications used for phosphate binder 




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separately and combined by the four treatment groups in EAP: 0 mcg (placebo), 1-300 mcg, 301-600 
mcg and 601-900 mcg. 
Dosing compliance (% compliance) will be assessed by calculating the number of actual doses received 
and comparing that to the number of expected doses (number of capsules that should have been taken 
versus actual number taken as evidenced by the number of capsules remaining in bottles of study drug 
assigned to each subject). The following formula is for dosing compliance (%) calculation: 
Compliance (%) = 
Number of Actual Doses Received 
x 100% 
Number of Expected Doses 
Dosing compliance at <80% or >120% should be reported as a major protocol deviation. Compliance 
will be summarized as <80%, 80-120%, and >120% compliant categories. A subject listing of overall 
dosing compliance will also be produced. 
Dosing compliance for cinacalcet will be calculated and summarized as above but cinacalcet compliance 
will not be included as a protocol deviation.  Unlike CTAP101 dosing, not all subjects were able to 
participate in voluntary cinacalcet dosing due to late addition to protocol at which time subjects had 
already completed study, subject not eligible or subject did not consent to participate in this aspect of 
the study.   
12.2 
Treatment Exposure 
Extent of treatment exposure (days) will be summarized with continuous descriptive statistics for the 
Safety population by subgroups (PK subgroup, non-PK subgroup) separately and combined for each 
treatment group. The table will be summarized by the initial treatment groups: 0 mcg (placebo) and 
900 mcg per week. 
Extent of treatment exposure for completed or discontinued subjects will be calculated in days using 
the following: 
Extent of Treatment Exposure (days) = (Date of Last Dose – Date of Visit 3 [Day 1]) + 1 
Extent of treatment exposure for subjects who were lost to FU will be calculated in days using the 
following: 
Extent of Treatment Exposure (days) = (Date of Last Recorded Dose – Date of Visit 3 [Day 1]) + 1 
A subject listing of treatment exposure will be produced. 












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Non-PK and PK Placebo 
 
PK Active 
Visit# 
Day# 
 
Visit# 
Day# 
 
 
 
9 
15 
10 
8 
 
10 
22 
11 
15 
 
11 
29 
12 
22 
 
12 
36 
13 
29 
 
13 
43 
14 
43 
 
14 
57 
15 
57 
 
15 
71 
16 
71 
 
16 
85 
17 
85 
 
17 
99 
18 
99 
 
18 
113 
19 
113 
 
19 
127 
20 
127 
 
20 
141 
21 
141 
 
21 
155 
22 
155 
 
22 
169 
23 
169 
 
23 
183 
24 
183 
 
24 
197 
 
 
 
24 PM 
NA 
 
 
 
 
 
30 
197 
 
30 
211 
31 
211 
 
31 
225 
32 
225 
 
32 
239 
ET 
 
 
ET 
 
The analysis will be performed in non-PK and PK subgroups separately and combined, including only 
those visits where all subjects in the summary were planned to have the visit. At visits where both non-
PK and PK subgroups collected plasma iPTH and for summaries of all subjects, p-values will be 
generated. Otherwise, due to small numbers of subjects in each subgroup, the model may be 
underpowered and p-values will not be calculated. An analysis of plasma iPTH which utilizes fewer visits 
will also be performed as part of the PD analysis (Section 16). 


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13.2.4 Subgroup Analyses of Key Secondary Outcomes 
The following key secondary efficacy outcomes will also be compared on below subgroups within the 
mITT population, using all subjects in both the non-PK and PK subgroups:  
 
BMI and body weight (<median, ≥median) 
 
Age (<median, ≥median) 
 
Gender 
 
Race (white, non-white) 
 
Time since initiation of dialysis (<median, ≥median) 
 
Baseline serum phosphorus (<median, ≥median) 
 
Baseline corrected serum calcium (<median, ≥median) 
 
Baseline plasma iPTH (<median, ≥median) 
 
Etiology of CKD 
 
Prior Calcimimetics (Yes, No) 
 
Prior treatment with 1α-hydroxyvitamin D analogs and cinacalcet. 
Within each level of the subgroup, the sample size, number of responders, and percent responders for 
each treatment group will be displayed as well as differences in response rates between active group 
and placebo with corresponding 95% CIs. CMH tests will be performed for each subgroup category to 
assess a relationship between treatment (placebo vs. all CTAP101 subjects) and each category with 
respect to responders.  In addition, a logistic regression analysis will be performed with the explanatory 
variables of treatment and the subgroup category. 
Similar subgroup analyses will be performed for the response criteria using alternative responder criteria 
based on modifying the efficacy endpoint by changing the mean percent decrease in plasma iPTH 
criteria (mean decrease of 20% and 10% thresholds). 
 
 
 
 
 
 
  








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14. Safety Analyses 
All subjects in Safety population will be included in the safety summaries. Statistical summaries of safety 
data will be descriptive and performed by study arm. No inferential hypothesis testing will be performed 
on the safety variables.  












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Non-PK and PK Placebo 
 
PK Active 
Visit# 
Day# 
 
Visit# 
Day# 
32 
225 
 
32 
239 
ET 
 
 
ET 
 
 
14.1.5.2 The Partial Blood Chemistry Panel, (consisting of calcium corrected for albumin, phosphorus 
and albumin) will be performed at the following visits: 
Non-PK and PK Placebo 
 
PK Active 
Visit# 
Day# 
 
Visit# 
Day# 
 
 
 
4 
2-3 
 
 
 
5 
5 
 
 
 
6 
6 
 
 
 
7 
8 
 
 
 
8 
11 
 
 
 
9 
15 
10 
8 
 
10 
22 
11 
15 
 
11 
29 
12 
22 
 
12 
36 
13 
29 
 
13 
43 
14 
43 
 
14 
57 
15 
57 
 
15 
71 
16 
71 
 
16 
85 
 
 
 
 
 
18 
99 
 
18 
113 
19 
113 
 
19 
127 
20 
127 
 
20 
141 
21 
141 
 
21 
155 
22 
155 
 
22 
169 
23 
169 
 
23 
183 
 
 
 
 
 
 
 
 
25 
198-199 








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AUCinf 
Area under the serum concentration time curve from time zero 
extrapolated to time infinity, estimated as AUC0-t + Cpred/z, where Cpred 
is the predicted concentration at Tlast 
λz  
Terminal rate constant, determined by linear regression of the terminal 
points of the log-linear serum concentration-time curve. 
t1/2  
Terminal half-life, estimated as ln (2)/ λz. 
CL/F 
Clearance divided by the bioavailable fraction, estimated as 
dose/AUCinf. 
Vz/F 
Volume of distribution based on the terminal phase divided by the 
bioavailable fraction, estimated as dose/(AUCinf x λz).  
AUC parameters will not be generated unless there are at least three measurable calcifediol 
concentrations in the PK profile.  Parameters based on sufficient characterization of the terminal phase 
of the concentration versus time profile (λz, t1/2, CL/F, and Vz/F) will only be reported if the goodness-of-
fit parameter R2 is greater than 0.8 and the percent of AUC extrapolated to time infinity (AUC%extrap) is 
less than 25%.  Additional PK parameters, such as partial AUCs or accumulation ratios, may be 
generated to aid with interpretation of the data if needed. 
PK parameters will also be summarized relative to  BMI, body weight,  age, gender, race, severity of 
SHPT and dialysis vintage, etiology of CKD and prior treatment with calcimimetics. For each of these 
factors when appropriate, the PK parameters will be summarized by PK period for subgroups, where 
the median values are based on the PK population only.  
All parameters will be reported to three significant figures. The following descriptive statistics will be 
calculated for the PK parameters: number of subjects (n), arithmetic mean, SD, minimum, median, 
maximum, geometric mean, %CV and the 25th and 75th percentiles. Listings and summary tables of 
the concentration versus time data and PK parameters will be generated using SAS 9.4 or higher.  
 
16. Pharmacodynamic Analyses 
PD profiles for serum DBP, 
total free 25D, 1,25D, 1,25D3, and 24,25D3 will be collected at 
the following visits:  
Non-PK and PK Placebo 
 
PK Active 
Visit# 
Day# 
 
Visit# 
Day# 
2 
-13 to -7 
 
2 
-13 to -7 


















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24. Appendix 
1.Cohort 1 - Non-PK Sites 
 
a Last dose of CTAP101/Placebo treatment administered on Day 181; ᵇLast dose of cinacalcet administered on Day 209. 




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a Last dose of CTAP101/Placebo treatment administered on Day 181; ᵇLast dose of cinacalcet administered on Day 209. 








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aLast dose of CTAP101/Placebo Treatment administered on Day 181; bLast dose administered on Day 195; cFirst PK dose (900 mcg) administered at 
t=0 on Day 2; dSecond PK dose administered at t=0 on Day 198; eVital Signs taken three times per day on Days 2 and 3; fAdverse Events assessed 
daily at Days 2 and 3; gActivity performed at Phase 1 unit or equivalent; hLast dose administered on Day 209 for Placebo; iLast dose administered on 
Day 223 for Active