Clinical trial NCT03588884
Conditions: Secondary Hyperparathyroidism Due to Renal Causes Vitamin D Insufficiency CKD Stage 3 CKD Stage 4
Sponsor: OPKO Health, Inc.
Start date: 2018-06-08; Completion date: 2020-04-24
Enrollment: 69 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
An Open-Label, Repeated-Dose Safety, Efficacy, Pharmacokinetic and Pharmacodynamic Study of Oral CTAP101 Capsules, Immediate- Release (IR) Calcifediol, High-Dose Cholecalciferol, and Paricalcitol Plus Low-Dose Cholecalciferol in Patients with Secondary Hyperparathyroidism, Stage 3 or 4 Chronic Kidney Disease and Vitamin D Insufficiency

Detailed description:

Arms: arm 1: CTAP101/Calcifediol Capsules 60 micrograms (mcg) once daily at bedtime, except on Days 1 and 29 when dosing will occur in the morning before breakfast arm 2: Immediate-release (IR) calcifediol/266 micrograms (mcg) capsule before breakfast on the mornings of Day 1 and Day 29 arm 3: Cholecalciferol/Capsules 300,000 International Units (IU) (high-dose) before breakfast on the mornings of Day 1 and Day 29 arm 4: Paricalcitol/Capsules 1 mcg plus cholecalciferol capsules 800 IU (low-dose) once daily in the morning before breakfast, except on Days 1 and29 when dosing will occur before breakfast
Interventions: intervention 1: Calcifediol Oral Capsule intervention 2: Calcifediol Oral Product intervention 3: Cholecalciferol intervention 4: Paricalcitol Oral Capsule
Intervention descriptions: intervention 1: Capsule, daily intervention 2: Capsule, once a month intervention 3: Capsule, once a month intervention 4: Capsule, daily

Protocol documents:
Prot_000.pdf: 
 
Protocol:  CTAP101-CL-4001 
Study Title: 
An Open-Label, Repeated-Dose Safety, Efficacy, Pharmacokinetic and 
Pharmacodynamic Study of Oral CTAP101 Capsules, Immediate-Release 
(IR) Calcifediol, High-Dose Cholecalciferol, and Paricalcitol Plus Low-
Dose Cholecalciferol in Patients with Secondary Hyperparathyroidism, 
Stage 3 or 4 Chronic Kidney Disease and Vitamin D Insufficiency 
Study Number: 
CTAP101-CL-4001 
Short Title: 
Repeated-dose safety, efficacy, PK and PD of CTAP101, IR Calcifediol, 
high-dose cholecalciferol, and paricalcitol plus low-dose cholecalciferol 
in patients with SHPT, CKD 3-4 and VDI 
Study Phase: 
4 
Product Names: 
CTAP101 Capsules, IR calcifediol, cholecalciferol, paricalcitol 
Investigator(s): 
Multi-Center 
Sponsor: 
OPKO Ireland Global Holdings Ltd. 
4400 Biscayne Boulevard 
Miami, FL 33137 
Sponsor Contact: 
 MD, FACP, FASN 
 
Clinical R & D, and Medical Affairs   
 
OPKO Pharmaceuticals 
4400 Biscayne Boulevard 
Miami, FL 33137 
 
 – Office  
 – Cell   
Study Medical Monitor: 
 MD 
Safe Harbor Pharmacovigilance 
5205 Indigo Moon Way 
Raleigh, NC  27613 
 - Cell 
 – Fax 
 
 
Study Contact: 
 MD 
Spaulding Clinical Research, LLC 
525 S. Silverbrook Drive 
West Bend, WI  53095 
 - Office 
 – Fax 
 
 
This study will be conducted in compliance with the protocol, US Code of Federal Regulations applicable to 
clinical studies, principles of ICH Good Clinical Practice (GCP), the Declaration of Helsinki, and all applicable 
regulatory requirements. 
 
Version 7.0 
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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-4001 ..............................................................................................1 
TABLE OF CONTENTS ..............................................................................................................3 
LIST OF TABLES .........................................................................................................................7 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................8 
SYNOPSIS ....................................................................................................................................11 
1 
INTRODUCTION ................................................................................................................17 
1.1 
Medications .......................................................................................................................17 
1.1.1 
CTAP101 Capsules ....................................................................................................17 
1.1.2 
Calcifediol Capsules ...................................................................................................17 
1.1.3 
Cholecalciferol Capsules ...........................................................................................17 
1.1.4 
Paricalcitol Capsules ..................................................................................................17 
1.2 
Metabolism of Calcifediol and Related Metabolites .....................................................17 
1.3 
Vitamin D Insufficiency ...................................................................................................18 
1.4 
Chronic Kidney Disease ..................................................................................................18 
1.5 
Secondary Hyperparathyroidism ...................................................................................19 
1.6 
Clinical Practice Guidelines ............................................................................................19 
1.7 
The Current Unmet Medical Need .................................................................................19 
1.8 
Nonclinical Experience with Study Medications ...........................................................20 
1.8.1 
CTAP101 Capsules ....................................................................................................20 
1.8.2 
Cholecalciferol, Calcifediol and Paricalcitol ...........................................................20 
1.9 
Previous Clinical Experience with CTAP101 ................................................................20 
1.10 
Previous Clinical Experience with IR Calcifediol Capsules ........................................22 
1.11 
Previous Clinical Experience with Cholecalciferol Capsules.......................................22 
1.12 
Previous Clinical Experience with Paricalcitol Capsules .............................................22 
2 
STUDY OBJECTIVES AND ENDPOINTS ......................................................................24 
2.1 
Study Objectives...............................................................................................................24 
2.2 
Study Endpoints ...............................................................................................................24 
2.2.1 
Pharmacokinetic Endpoints ......................................................................................24 
 
 
2.2.3 
Primary Safety Endpoints .........................................................................................24 
2.2.4 
Secondary Safety Endpoints .....................................................................................24 
2.2.5 
Efficacy Endpoints .....................................................................................................24 
3 
INVESTIGATIONAL PLAN ..............................................................................................25 
3.1 
Overall Study Design and Plan .......................................................................................25 
3.2 
Rationale for Study Design .............................................................................................26 
3.3 
Study Duration .................................................................................................................27 
4 
STUDY POPULATION SELECTION ...............................................................................28 
4.1 
Study Population ..............................................................................................................28 
4.2 
Inclusion Criteria .............................................................................................................28 
4.3 
Exclusion Criteria ............................................................................................................29 
5 
STUDY TREATMENTS ......................................................................................................30 
5.1 
Description of Study Medications...................................................................................30 
5.1.1 
Description of CTAP101 Capsules ...........................................................................30 
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5.1.2 
Description of Calcifediol IR Capsules ....................................................................30 
5.1.3 
Description of High-Dose Cholecalciferol Capsules ...............................................30 
5.1.4 
Description of Low-Dose Cholecalciferol Capsules ................................................31 
5.1.5 
Description of Paricalcitol Capsules.........................................................................31 
5.2 
Dosing Plan .......................................................................................................................31 
5.3 
Dose Reduction Criteria ..................................................................................................32 
5.3.1 
Overdose and Toxicity ...............................................................................................32 
5.4 
Method of Assigning Subjects to Treatment Groups ...................................................33 
5.5 
Prior and Concomitant Therapy ....................................................................................33 
5.5.1 
Phosphate Binder and Elemental Calcium Therapy ..............................................34 
5.5.2 
Diet Restrictions .........................................................................................................34 
5.5.3 
Subject Activity Restrictions .....................................................................................34 
5.6 
Treatment Compliance ....................................................................................................34 
5.7 
Labeling ............................................................................................................................35 
5.8 
Storage and Accountability .............................................................................................35 
5.9 
Investigational Product Retention at Study Site ...........................................................35 
6 
STUDY PROCEDURES ......................................................................................................36 
6.1 
Informed Consent ............................................................................................................36 
6.2 
Medical History and Concomitant Medications ...........................................................36 
6.3 
Physical Examination and Vital Signs ...........................................................................36 
6.4 
Clinical Laboratory Tests................................................................................................37 
6.4.1 
Laboratory Parameters .............................................................................................37 
6.4.2 
Sample Collection, Storage, and Shipping ...............................................................39 
6.4.3 
Clinical Supplies .........................................................................................................39 
6.5 
Dispensing Study Drug ....................................................................................................39 
6.6 
Adverse Events Assessments ...........................................................................................39 
6.6.1 
Definition ....................................................................................................................39 
6.6.2 
Performing Adverse Events Assessments ................................................................39 
6.6.3 
AE Collection Period .................................................................................................40 
6.6.4 
Severity........................................................................................................................41 
6.6.5 
Relationship ................................................................................................................41 
6.6.6 
Clinical Significance...................................................................................................42 
6.6.7 
Serious Adverse Events .............................................................................................42 
6.6.7.1 
Definition ..............................................................................................................42 
6.6.7.2 
Expectedness .........................................................................................................43 
6.6.7.3 
Reporting Serious Adverse Events .....................................................................43 
6.6.8 
Treatment-Emergent Adverse Events......................................................................44 
6.7 
Concomitant Medication Assessments ...........................................................................44 
6.8 
Removal of Subjects from the Study or Study Drug (Early Termination) ................44 
6.9 
Appropriateness of Measurements .................................................................................44 
7 
STUDY ACTIVITIES ..........................................................................................................46 
7.1 
Screening Period ..............................................................................................................46 
7.1.1 
Visit 1 (Days -70 or -42 to -36) ..................................................................................46 
7.1.2 
Visits 2 and 3 (Within Days -7 to -1) ........................................................................46 
7.2 
Treatment Period .............................................................................................................47 


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7.2.1 
Visit 4 (Day 1) .............................................................................................................47 
7.2.2 
Visits 5 & 6 (Day 2 & 3) .............................................................................................48 
7.2.3 
Visits 7, 8, 9 (Day 8, 15, 22) .......................................................................................48 
7.2.4 
Visit 10 (Day 29) .........................................................................................................48 
7.2.5 
Visits 11 & 12 (Days 30 & 31) ...................................................................................50 
7.2.6 
Visits 13, 14, 15 (Day 36, 43, 50) ...............................................................................50 
7.3 
End of Study (EOS) .........................................................................................................50 
7.3.1 
Visit 16 (Day 57) Last study visit (or Early Termination) .....................................50 
8 
QUALITY CONTROL AND ASSURANCE .....................................................................52 
9 
PLANNED STATISTICAL METHODS ............................................................................53 
9.1 
General Considerations ...................................................................................................53 
9.2 
Determination of Sample Size .........................................................................................53 
9.3 
Randomization .................................................................................................................53 
9.4 
Analysis Populations ........................................................................................................54 
9.5 
Demographics and Baseline Characteristics .................................................................54 
9.6 
Subject Disposition and Withdrawal .............................................................................54 
9.7 
Prior and Concomitant Medications ..............................................................................55 
9.8 
Pharmacokinetic Analysis ...............................................................................................55 
9.10 
Safety Analysis .................................................................................................................56 
9.10.1 
Primary Endpoints Analyses ....................................................................................56 
9.10.1.1 
Adverse Events .....................................................................................................56 
9.10.1.2 
Vital Signs .............................................................................................................57 
9.10.1.3 
Physical Examination ..........................................................................................57 
9.10.2 
Secondary Endpoint Analyses ..................................................................................57 
9.11 
Efficacy Analyses .............................................................................................................57 
9.11.1 
Primary Endpoint Analyses ......................................................................................57 
10 ADMINISTRATIVE CONSIDERATIONS .......................................................................58 
10.1 
Study Administrative Structure .....................................................................................58 
10.2 
Institutional Review Board/Ethics Committee Approval ............................................58 
10.3 
Ethical Conduct of the Study ..........................................................................................58 
10.4 
Subject Information and Consent ..................................................................................58 
10.5 
Subject Confidentiality ....................................................................................................59 
10.6 
Study Monitoring .............................................................................................................59 
10.7 
Case Report Forms and Study Records .........................................................................59 
10.8 
Protocol Deviations ..........................................................................................................60 
10.9 
Data Generation and Analysis ........................................................................................60 
10.10 Retention of Data .............................................................................................................61 
10.11 Financial Disclosure .........................................................................................................61 
10.12 Publication and Disclosure Policy ..................................................................................61 
11 REFERENCE LIST..............................................................................................................63 
APPENDIX 1  SCHEDULE OF EVENTS ................................................................................65 
APPENDIX 2  CALCIFEDIOL IR CAPSULES (HIDROFEROL) .......................................67 
APPENDIX 3  HIGH DOSE CHOLECALCIFEROL CAPSULES (INVITA D3 50,000 
IU) ...........................................................................................................................................75 
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APPENDIX 4  LOW DOSE CHOLECALCIFEROL CAPSULES (INVITA D3 800 IU) ....81 
APPENDIX 5  INVESTIGATOR’S SIGNATURE ..................................................................86 
 
 
 


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LIST OF TABLES 
Table 1 
Evaluations ...........................................................................................................37 
Table 2 
List of Laboratory Tests ......................................................................................38 
Table 3  
Adverse Event Relationship Criteria .................................................................42 
Table 4  
Pharmacokinetic Parameters ..............................................................................55 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
1,25D3 
1,25-dihydroxyvitamin D3, calcitriol 
25D3 
25-hydroxyvitamin D3, calcifediol, calcidiol 
AE 
adverse event 
AUC 
area under the (concentration) curve 
BA 
bioavailability 
BL 
baseline 
BMI 
body mass index 
Ca 
calcium 
CFR 
Code of Federal Regulations 
CKD 
chronic kidney disease 
CL/F 
clearance 
Cmax 
maximum concentration 
Cr 
creatinine 
CRF 
case report form 
Css 
steady-state concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DBP 
vitamin D binding protein 
eCRF 
electronic case report form 
EDC 
electronic data capture  
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
ER 
extended-release 
ET 
early termination 
EU 
European Union 
FDA 
Food and Drug Administration 
FGF23 
fibroblast growth factor 23 
GCP 
Good Clinical Practice 
GCRC 
General Clinical Research Center 
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GFR 
glomerular filtration rate 
HDPE 
high-density polyethylene 
HIV 
human immunodeficiency virus 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation  
iPTH 
intact parathyroid hormone 
IR 
immediate-release 
IRB/EC 
Institutional Review Board/Ethics Committee 
ITT 
intent-to-treat 
IU 
International Units 
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 
P 
phosphorus 
PD 
pharmacodynamic(s) 
PE 
physical examinations 
PK 
pharmacokinetic(s) 
PP 
per-protocol 
PTH 
parathyroid hormone 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SHPT 
secondary hyperparathyroidism 
SOC 
system organ class 
SOP 
standard operating procedure 
t1/2 
terminal elimination half-life 
TEAE 
treatment-emergent adverse events 
tmax 
time to maximum concentration 
tss 
time to steady-state concentration 
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US 
United States 
Vd/F 
volume of distribution 
VDI 
vitamin D insufficiency 
VDR 
vitamin D receptor 
VS 
vital signs 


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SYNOPSIS 
Sponsor:  
OPKO Ireland Global Holdings Ltd. 
Name of Finished Products: 
CTAP101 Capsules 
Immediate-release (IR) calcifediol capsules 
Cholecalciferol capsules 
Paricalcitol capsules 
Name of Active Ingredients:  
Calcifediol, calcidiol, 25-hydroxyvitamin D3 
Cholecalciferol, vitamin D3 
Paricalcitol, 19-nor-1-alpha,25-dihydroxyvitamin D2 
Test Products, Dose, and Mode of Administration:  
CTAP101 Capsules (30 mcg/capsule), 60 mcg, by the oral route 
Calcifediol immediate-release (IR) (266 mcg/capsule), 266 mcg, by the oral route 
Cholecalciferol (50,000 International Units (IU)/capsule), 300,000 IU, by the oral route 
Paricalcitol (1 mcg/capsule) plus cholecalciferol (800 IU/capsule), 1 or 2 mcg plus 800 IU, by 
the oral route 
Study Title:  
An Open-Label, Repeated-Dose Safety, Efficacy, Pharmacokinetic and Pharmacodynamic 
Study of Oral CTAP101 Capsules, IR Calcifediol, High-Dose Cholecalciferol, and Paricalcitol 
Plus Low-Dose Cholecalciferol in Patients with Secondary Hyperparathyroidism, Stage 3 or 4 
Chronic Kidney Disease and Vitamin D Insufficiency. 
Study Number: 
CTAP101-CL-4001 
Study Phase: 4 
Objectives:  
The objectives of this study are to assess the repeated-dose safety, efficacy, pharmacokinetic (PK) 
 profiles of CTAP101 Capsules, IR calcifediol, high-dose 
cholecalciferol, and paricalcitol plus low-dose cholecalciferol in patients with secondary 
hyperparathyroidism (SHPT), stage 3 or 4 chronic kidney disease (CKD) and vitamin D 
insufficiency (VDI). 
Study Design:  
This is a phase 4, multi-center, 4-arm, open-label study to gather comparative data evaluating 
the safety, efficacy and PK 
 profiles for CTAP101 Capsules, IR calcifediol, high-dose 
cholecalciferol, and paricalcitol plus low-dose cholecalciferol to treat SHPT in male and female 
subjects aged at least 18 years with stage 3 or 4 CKD and VDI.  The study will be conducted at 
multiple sites within the United States (US).  Approximately 160 subjects will be screened to  
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enroll approximately 80 eligible subjects who will be randomized 1:1:1:1 (approximately 20 per 
arm, balanced for body weight) to receive 8 weeks of treatment as follows: CTAP101 Capsules 
at a dose of 60 mcg per day; IR calcifediol at a dose of 266 mcg on Day 1 and Day 29; high-
dose cholecalciferol at a dose of 300,000 IU on Day 1 and Day 29; and paricalcitol at a dose of 
1 mcg per day (possibly increasing to 2 mcg per day at Day 29) plus low-dose cholecalciferol 
800 IU per day. If a significant difference in average weight among subjects by treatment group 
emerges during the course of the study, subjects may be placed into specific treatment groups 
rather than randomly assigned, in order to try and achieve more balance in the treatment groups 
by body weight. 
The subjects will be housed in a phase 1 unit for approximately 14 to 26 hours at the beginning 
of the study and on study Day 29 to provide the blood samples required for a detailed 
determination of the PK profiles for serum calcifediol (25D3) 
 
 
 
 
 
 
 
 
 
 
 
  Blood samples for some of the PK/
 assessments will be collected 
in the phase 1 unit at -2, 0, 2, 4, 6, and 12 hours; either in the phase 1 unit or  during outpatient 
visit, at 24 hours; during outpatient visit for 48 hours; and then weekly following the first dose 
and the Day 29 dose of each medication.  
 
  Urine collections (24-hour) will be obtained at pre-
treatment baseline (Visits 2 and 3), starting immediately after dosing on Day 1 (Visit 4) and 
Day 29 (Visit 10) and at the end of study (Visit 16) or early termination (ET).  The schedule for 
collection of blood and urine samples is delineated in Section 7 (Study Activities) and in 
APPENDIX 1.   
Subjects receiving treatment with calcitriol or another 1α-hydroxylated vitamin D analog, must 
forgo treatment with these non-study agents and complete a 4-week washout period prior to 
baseline (BL) assessments and will remain off these non-study medications for the duration of 
the study.  For subjects who are taking vitamin D supplementation (including multivitamins and 
fish oil), they must forgo treatment with these non-study agents for the duration of the study and 
undergo a 4 week washout.  If at the end of the 4-week washout the serum total 25-
hydroxyvitamin D level is still ≥30 ng/mL, washout may be extended by up to another four 
weeks for a maximum total of 8 weeks.  Subjects will be excluded from enrollment if they have 
received calcimimetic therapy within 12 weeks preceding screening.   
Blood samples will be collected from all subjects at weekly intervals during the screening and 
BL periods; during the 8-week treatment period; and at the specified times during the PK/
 
assessments.  Key parameters to be analyzed in the collected samples include some or all of the 
following: serum calcifediol, 
  
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. 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 routine clinical chemistries).  
Subjects will maintain a dietary intake during the study of approximately 1,000-1,500 mg of 
elemental calcium per day by dietary counseling and, if necessary, a prescribed daily calcium 
supplement. 
Dosing Plan:  
Approximately 80 subjects will be randomized 1:1:1:1 (approximately 20 per arm) to receive 
one of the listed study medications with a sufficient quantity of a non-alcoholic beverage to 
enable swallowing of the capsules: 
1) CTAP101 Capsules 60 mcg once daily outside of the phase 1 unit at bedtime, except on Days 
1 and 29 when dosing will occur in the phase 1 unit in the morning before breakfast. 
2) IR calcifediol 266 mcg in the phase 1 unit before breakfast on the mornings of Day 1 and 
Day 29. 
3) Cholecalciferol 300,000 IU (high-dose) in the phase 1 unit before breakfast on the mornings 
of Day 1 and Day 29. 
4) Paricalcitol 1 mcg plus cholecalciferol 800 IU (low-dose) once daily outside of the phase 1 
unit in the morning before breakfast, except on the mornings of Days 1 and 29 when dosing 
will occur in the phase 1 unit before breakfast. 
After 4 weeks of treatment, subjects who are receiving paricalcitol will double the dose to 2 
mcg plus cholecalciferol 800 IU once daily in the morning before breakfast provided that (a) the 
plasma iPTH has not decreased by at least 30% from pretreatment BL and remains above 70 
pg/mL, (b) corrected serum calcium is <9.8 mg/dL, and (c) serum phosphorus is <5.5 mg/dL.  
Subjects who are receiving CTAP101 Capsules, IR calcifediol or cholecalciferol (300,000 IU) 
will not undergo upward dose titration.  
Subjects will reduce the dose of study medication per the schedule below in the event that 
plasma iPTH is confirmed to be <30 pg/mL, corrected serum calcium is confirmed to be >10.3 
mg/dL, or serum phosphorus is confirmed to be >5.5 mg/dL. Subjects will suspend dosing if 
plasma iPTH is confirmed to be <15 pg/mL or corrected serum calcium is confirmed to be 
>11.0 mg/dL, and will resume dosing when plasma iPTH is ≥30 pg/mL and corrected serum 
calcium is <9.8 mg/dL per the dose schedule below.   
Dose reduction (if needed): 
CTAP101: decrease to 30 mcg per day (from 60 mcg per day) 
IR calcifediol: hold Day 29 dose 
Cholecalciferol 300,000 IU: hold Day 29 dose 
Paricalcitol: decrease dose to 1 mcg per day (from 2 mcg per day) 
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Cholecalciferol 800 IU will not be adjusted 
In the event that a dose reduction is required for a subject receiving the minimum dosage of 
CTAP101 Capsules (30 mcg per day) or paricalcitol (1 mcg per day), the subject will suspend 
dosing and resume when iPTH is ≥30 pg/mL and corrected serum calcium is <9.8 mg/dL at the 
same minimum dosage.   
Dose resumption (if needed): 
CTAP101: 30 mcg per day 
Paricalcitol 1 mcg per day 
Duration of Treatment: 
Subjects will participate in the study for up to approximately 14 weeks (1 week for screening, 4 
weeks for washout (if required), 1 week for BL, and 8 weeks for treatment). 
Primary Efficacy Endpoint: 
This study is descriptive and no primary or secondary efficacy endpoints are defined. 
Descriptive analysis and plots will be created of serum calcifediol, 
 
 
 
 
 
 
Primary Safety Endpoints: 
Safety and tolerability of each medication will be evaluated in the Safety population by AEs, 
PEs, VS, and hematology and clinical chemistries. 
Pharmacokinetic 
 Endpoints: 
The following PK parameters will be calculated using observed and BL-adjusted serum 
calcifediol 
 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), 
clearance (CL/F), and volume of distribution (Vd/F), as feasible.   
Secondary Safety Endpoints: 
The number (n, %) of subjects with hypercalcemia (two consecutive visits with serum calcium 
greater than 10.3 mg/dL) or hyperphosphatemia (two consecutive visits with serum phosphorus 
greater than 5.5 mg/dL) will be calculated. 
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Sample Size Estimation: 
No formal sample size estimation has been performed for the study. 
Statistical Analyses: 
Descriptive statistical plan will be specified in an accompanying SAP. 
Primary safety analyses will be conducted in the Safety population.   
Secondary safety analyses will calculate the number and percentage of subjects in each 
treatment group with confirmed corrected serum calcium or serum phosphorus values above 
10.3 mg/dL and 5.5 mg/dL, respectively.  
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled in this study: 
1. Be at least 18 years of age. 
2. Have stage 3 or 4 CKD (estimated glomerular filtration rate (eGFR) of ≥15 to <60 
mL/min/1.73m2 using the Modification of Diet in Renal Disease equation). 
3. Be without any disease state or physical condition that might impair evaluation or 
which, in the Investigator’s opinion, would interfere with study participation, including: 
a. Serum albumin ≤ 3.0 g/dL;  
b. Serum transaminase (alanine transaminase, glutamic pyruvic transaminase, aspartate 
aminotransferase or glutamic oxaloacetic transaminase) > 2.5 times the upper limit 
of normal at screening; and, 
c. Urinary albumin excretion >3000 µg/mg creatinine. 
4. Exhibit during the initial screening visit: 
a. Plasma iPTH ≥65 pg/mL and <400 pg/mL if receiving calcitriol or 1α-hydroxylated 
vitamin D analog (paricalcitol or doxercalciferol); or  
b. Plasma iPTH ≥85 pg/mL and <500 pg/mL if not receiving calcitriol or 1α-
hydroxylated vitamin D analog; and, 
c. Serum total 25-hydroxyvitamin D <30 ng/mL, unless taking vitamin D 
supplementation (including multivitamins and fish oil); and,   
d. If taking calcitriol, or another 1α-hydroxylated vitamin D analog, subjects must 
forgo treatment with these non-study agents for the duration of the study and 
undergo a 4-week washout period and meet inclusion criterion 5.   
e. For subjects who are taking vitamin D supplementation (including multivitamins or 
fish oil), they must forgo treatment with these non-study agents for the duration of 
the study.  If the serum 25-hydroxyvitamin D level is <30 ng/mL, there is no need 
for the subjects to complete a washout period as a result of vitamin D 
supplementation.  If, however, serum 25-hydroxyvitamin D level is ≥30 ng/mL, the 
subjects must undergo a 4-week washout period and meet inclusion criterion 5.  If at 
the end of 4 weeks of washout, the 25 hydroxyvitamin D level is still ≥30 ng/mL, the 
washout may be extended by up to another four weeks for a total of 8 weeks. 


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5. Exhibit after the washout period (if required): 
a. Plasma iPTH ≥85 pg/mL and <500 pg/mL; 
b. Corrected serum calcium <9.8 mg/dL; (corrected for serum albumin) 
c. Serum total 25-hydroxyvitamin D <30 ng/mL; and, 
d. Serum phosphorus <5.5 mg/dL. 
6. If taking more than 1,500 mg/day of elemental calcium, reduce calcium use (to 
approximately 1,000 to ≤1,500 mg/day) for the duration of the study. 
7. Willing and able to comply with study instructions and commit to all clinic visits for the 
duration of the study. 
8. Female subjects of childbearing potential must be neither pregnant nor lactating and 
must have a negative blood pregnancy test at the first screening visit. 
9. All female subjects of childbearing potential and male subjects with female partners of 
childbearing potential must agree to use effective contraception (implants, injectables, 
combined oral contraceptives, intrauterine device, sexual abstinence, vasectomy or 
vasectomized partner) for the duration of the study. 
10. Be able to read, understand and sign the subject Informed Consent Form (ICF) or have a 
legal authorized representative (LAR) sign the ICF. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
1. History of or planned kidney transplant or parathyroidectomy. 
2. History (prior 3 months) of corrected serum calcium ≥9.8 mg/dL or serum 
phosphorus ≥5.5 mg/dL if not receiving calcitriol or other 1α-hydroxylated vitamin D 
analog. 
3. Need for phosphate binders to maintain the serum phosphorus < 5.5 mg/dL or use of 
phosphate binders within 4 weeks prior to screening. 
4. Use of calcimimetic therapy (cinacalcet or etelcalcetide) within 12 weeks of 
screening.  
5. Receipt of bisphosphonate therapy or other bone modifying treatment within 1 year 
prior to enrollment. 
6. 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. 
7. 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. 
8. Known or suspected hypersensitivity to any of the constituents of the study drugs. 
9. Currently participating in, or has participated in, an interventional/investigational 
study within 30 days prior to study screening. 


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1 INTRODUCTION 
1.1 
Medications 
1.1.1 
CTAP101 Capsules  
CTAP101 Capsules 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 stage 3 or 4 chronic kidney disease (CKD) and 
vitamin D insufficiency (VDI).  Calcifediol is 25-hydroxyvitamin D3, the physiological precursor 
to the vitamin D3 hormone, 1,25-dihydroxyvitamin D3 (calcitriol). 
1.1.2 
Calcifediol Capsules  
Calcifediol capsules are available in the US and in certain countries of the European Union (EU) 
in immediate-release (IR) or ER formulations.  Hidroferol is an IR oral formulation of calcifediol 
which Faes Farma is developing for the same indication.  Hidroferol is on the market in Spain 
and will soon be marketed in certain other countries of the EU.  Calcifediol is not approved in 
Japan. 
1.1.3 
Cholecalciferol Capsules  
Cholecalciferol capsules are available in most countries of the world.  None are available in ER 
oral formulations. They are used to treat VDI and are frequently used as a treatment for SHPT in 
patients with stage 3 or 4 CKD and VDI, although not formally approved for this use.   
Published studies have reported the use of daily doses of vitamin D (either cholecalciferol or 
ergocalciferol) of 700 to 4,000 International Units (IU), weekly doses of 5,000 to 50,000 IU, and 
monthly doses of 50,000 to 300,000 IU.  Irrespective of the treatment regimen used, no or 
inadequate reductions in parathyroid hormone (PTH) levels have been observed in randomized 
clinical trials and nutritional vitamin D remains unproven as an effective treatment for SHPT in 
patients with stage 3-4 CKD. 
1.1.4 
Paricalcitol Capsules 
Paricalcitol capsules are available in the US and in the EU as a treatment for SHPT in patients 
with stage 3 or 4 CKD. Paricalcitol is a 1α-hydroxylated vitamin D analog which is active on 
administration and interacts with the vitamin D receptor (VDR) in the parathyroid gland to 
suppress the synthesis and secretion of PTH.  Paricalcitol is frequently combined with 
cholecalciferol in order to both correct VDI and suppress elevated PTH in pre-dialysis patients, 
but the safety and efficacy of this combination of therapies has never been demonstrated in 
randomized clinical trials. 
1.2 
Metabolism of Calcifediol and Related Metabolites 
Calcifediol 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.  


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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.  
The two vitamin D prohormones are activated by healthy kidneys into hormones by CYP27B1, 
located in the proximal kidney tubule [DeLuca 2004].  Activation occurs under tight regulation 
by PTH, which is secreted by the parathyroid glands.  The prohormones (25-hydroxyvitamin D2 
and 25-hydroxyvitamin D3) are metabolized directly to 1α,25-dihydroxyvitamin D2 (ercalcitriol) 
and 1α,25-dihydroxyvitamin D3 (calcitriol), respectively.  These two vitamin D hormones, 
collectively referred to as “1,25-dihydroxyvitamin D”, are secreted by the kidneys into the blood 
for systemic delivery.  
The two vitamin D prohormones are also activated extra-renally by CYP27B1 in parathyroid and 
many other cells [Adams et al 2014] to provide a local supply of hormones that may prove 
critical to cell growth regulation and the prevention of cancer, autoimmune disorders (such as 
psoriasis) and certain types of infection.  Adequate local hormone production depends entirely on 
sufficient levels of circulating 25-hydroxyvitamin D.   
1.3 
Vitamin D Insufficiency 
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 considered 
adequate in CKD patients while levels of <30 ng/mL are considered “insufficient” [Holick et al 
2011].  The normal 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 
intact parathyroid hormone (iPTH) targets [Ennis 2016].  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. 
1.4 
Chronic Kidney Disease  
CKD is a steadily-increasing health problem 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, including urinary loss of vitamin D binding protein (DBP), decreased hepatic 


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synthesis of calcifediol and excessive expression of the vitamin D catabolic enzyme, CYP24A1 
[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 PTH by the parathyroid glands and, ultimately, SHPT. 
1.5 
Secondary Hyperparathyroidism 
SHPT is a condition commonly associated with CKD in which the parathyroid glands secrete 
excessive amounts of PTH.  SHPT affects 40% to 82% of patients with stage 3 or 4 CKD [Levin 
et al 2007] and frequently arises as a result of either VDI or impaired kidney function, both of 
which can prevent sufficient production of vitamin D hormone to properly regulate calcium and 
phosphorus metabolism and PTH secretion.  Impaired kidney function can also cause elevated 
serum phosphorus and fibroblast growth factor 23 (FGF23) which exacerbate SHPT.  SHPT 
requires prompt and effective treatment, as prolonged elevation of PTH causes excessive calcium 
and phosphorus to be released from bone, leading to metabolic bone disease and calcification of 
cardiovascular and renal tissues.  In the absence of effective treatment, SHPT becomes 
progressively more severe and unresponsive to treatment [Nigwekar et al 2014].   
1.6 
Clinical Practice Guidelines 
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.  
1.7 
The Current Unmet Medical Need 
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 et al: “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 et al 
2009].  A more recent review of the published randomized clinical trials concluded that vitamin 


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D had no efficacy in lowering iPTH levels in patients with stage 3 to 5 CKD [Agarwal 2016]. 
Hence, there is a need for effective treatment to increase serum total 25-hydroxyvitamin D and 
control elevated iPTH in this patient population. 
1.8 
Nonclinical Experience with Study Medications 
1.8.1 
CTAP101 Capsules 
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 (e.g., kidney, stomach, aorta and heart) 
and death.  Severe adverse reactions to CTAP101 Capsules were observed in dogs treated with 
500 or 1,000 mcg/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 mcg/kg/day).  No signs of toxicity were observed at the highest 
dose tested which was associated with serum calcifediol levels >150 ng/mL.   
Calcifediol administration (orally through addition to the diet) to rats for 6 months has been 
reported to produce signs of toxicity at daily doses >40 mcg/kg.  Toxicities included an increased 
incidence of nephrocalcinosis and uroliths.  Oral administration of calcifediol to dogs at ≤2 
mcg/kg/day resulted in no compound-related findings. 
Results from in vitro drug release and nonclinical PK studies in male Yucatan swine 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 IR 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 IR formulation (tmax 
~4 hours). 
1.8.2 
Cholecalciferol, Calcifediol and Paricalcitol 
Toxicity associated with cholecalciferol, calcifediol and paricalcitol is well understood in the 
medical literature.  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 urine calcium levels; 
 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. 
1.9 
Previous Clinical Experience with CTAP101 
CTAP101 Capsules (30 mcg) have been approved as Rayaldee® by the US Food and Drug 
Administration (FDA) for the treatment of SHPT in adults with stage 3 or 4 CKD and VDI, 


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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, CTAP-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 maximum serum concentration 
(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 pre-treatment baseline (BL) 
and compared to placebo during 6 weeks of treatment.  The mean % decrease in iPTH from BL 
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.   
Efficacy was confirmed in the phase 3 program with nearly all subjects (97%) treated with 
CTAP101 Capsules who completed the program without a major protocol deviation, achieving a 
normal serum total 25-hydroxyvitamin D level and with 50% of such subjects achieving a mean 
reduction in plasma iPTH from BL of at least 30%.  Fewer than 9% of placebo subjects achieved 
a 30% reduction in iPTH or achieved a normal 25-hydroxyvitamin D level. 
CTAP101 Capsules did not cause significant adverse effects on serum calcium or phosphorus.  
Treatment-emergent adverse events (TEAEs), including those related to the investigational study 
drug, were comparable across treatment groups, except for hyperphosphatemia which was 
observed in four subjects, none of which was considered by the Investigator to be related to the 
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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1.10 
Previous Clinical Experience with IR Calcifediol Capsules 
IR formulations of calcifediol have been available for decades in the EU for indications such as 
rickets, prevention of calcium disorders secondary to corticosteroid or anticonvulsant therapy 
and treatment of osteomalacia, renal osteodystrophy, hypoparathyroidism, familial 
hypophosphatemia and vitamin D malabsorption. In the US, IR calcifediol was marketed from 
1980 to 2002 as Calderol® for the treatment of metabolic bone disease in dialysis patients and 
was withdrawn from the market in 2002 for commercial reasons not associated with safety or 
efficacy.  
Published clinical studies have clearly shown that IR calcifediol increased serum 25-
hydroxyvitamin D far more quickly and effectively than vitamin D supplements but failed to 
produce clinically meaningful reductions in PTH (≥30% from pre-treatment levels) in many 
patients with stage 3 or 4 CKD at doses considered to be safe [Bordier 1975; Letteri 1977; 
Fournier 1988]. 
1.11 
Previous Clinical Experience with Cholecalciferol Capsules 
Oral formulations of cholecalciferol have been available for decades in many countries of the 
world, frequently evaluated in clinical studies and used (frequently in the absence of regulatory 
approval) for indications such as rickets, prevention of calcium disorders secondary to 
corticosteroid or anticonvulsant therapy and treatment of osteomalacia, renal osteodystrophy, 
hypoparathyroidism, familial hypophosphatemia and vitamin D malabsorption.  
1.12 
Previous Clinical Experience with Paricalcitol Capsules 
Oral paricalcitol has been demonstrated in randomized clinical trials to be effective in controlling 
elevated PTH which characterizes SHPT but it frequently causes hypercalcemia in pre-dialysis 
patients.  In the PRIMO trial [Thadhani 2012], paricalcitol, administered orally at 2 mcg per day, 
lowered mean PTH from a BL level of approximately 130 pg/mL to the normal range within 8 
weeks, and maintained it normal for another 40 weeks of treatment.  No PTH reduction was 
observed in the parallel placebo group.  Mean serum calcium and phosphorus rose with 
paricalcitol treatment by 0.57 mg/dL (P<0.001) and 0.19 mg/dL (P=0.05), respectively, versus 
placebo.  Nearly 23% of subjects experienced hypercalcemia, defined as 2 consecutive 
measurements above 10.5 mg/dL, on paricalcitol versus 0.9% on placebo (P<0.001).  In the 
OPERA Trial [Wang 2014], paricalcitol, administered orally at 1 mcg per day, reduced median 
PTH by 86 pg/mL (55%) from a BL level of 156 pg/mL while placebo treatment increased PTH 
by 21 pg/mL (16%) from a BL level of 129 pg/mL.  Mean serum calcium rose with paricalcitol 
treatment but not with placebo, and 43% of subjects on paricalcitol experienced hypercalcemia, 
defined as serum calcium above 10.2 mg/dL, versus 3% on placebo (P<0.001).  In US phase 3 
trials, paricalcitol produced a mean decrease of 45% in PTH after 24 weeks compared with a 
mean increase of 14% with placebo, and raised serum calcium and phosphorus by 0.2 and 0.1 
mg/dL, respectively [Coyne 2006].  Hypercalcemia, defined as two consecutive serum calcium 
determinations above 10.5 mg/dL, was observed in 2% of subjects receiving paricalcitol versus 0 
% on placebo. 
As mentioned above, oral paricalcitol is often used in combination with oral cholecalciferol to 
control elevated PTH and correct VDI in patients with stage 3 or 4 CKD, although this 


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combination of therapies has not been shown in randomized clinical trials to be either safe or 
effective for this purpose. 
 
 


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2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
The objectives of this study are to assess the repeated-dose safety, efficacy, pharmacokinetic (PK) 
and 
 profiles of CTAP101 Capsules, IR calcifediol, high-dose 
cholecalciferol, and paricalcitol plus low-dose cholecalciferol in patients with SHPT, stage 3 or 4 
CKD and VDI. 
2.2 
Study Endpoints 
2.2.1 
Pharmacokinetic Endpoints 
The following PK parameters will be calculated using observed and BL-adjusted serum 
calcifediol 
 concentrations: AUC, Cmax, tmax, steady-state 
concentration (Css), time to steady-state concentration (tss), terminal elimination half-life (t½), 
clearance (CL/F), and volume of distribution (Vd/F), as feasible.   
2.2.3 
Primary Safety Endpoints 
Safety and tolerability of each medication will be evaluated in the Safety population by AEs, 
physical examinations (PEs), vital signs (VS), hematology and clinical chemistries. 
2.2.4 
Secondary Safety Endpoints 
Secondary safety endpoints will include incidence of hypercalcemia and drug-related 
hyperphosphatemia.  The number (n, %) of subjects with hypercalcemia (two consecutive visits 
with serum calcium greater than 10.3 mg/dL) or hyperphosphatemia (two consecutive visits with 
serum phosphorus greater than 5.5 mg/dL) will be calculated. 
2.2.5 
Efficacy Endpoints 
This study is descriptive and no primary or secondary efficacy endpoints are defined. Descriptive 
analysis and plots for the ITT and PP populations will be created of serum calcifediol, 
 
 
 
 
 
 
 which will be specified in an accompanying statistical analysis 
plan (SAP). 
 
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3 INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a phase 4, multi-center, open-label study to evaluate the comparative safety, efficacy, and 
PK and 
 profiles of CTAP101 Capsules, IR calcifediol, high-dose cholecalciferol, and 
paricalcitol plus low-dose cholecalciferol to treat SHPT in male and female subjects aged at least 
18 years with stage 3 or 4 CKD and VDI.  The study will be conducted at multiple sites within 
the US.  Approximately 160 subjects will be screened to enroll approximately 80 eligible 
subjects who will be randomized 1:1:1:1 (approximately 20 per arm, balanced for body weight) 
to receive the following medications: 
Test Products, Dose, and Mode of Administration:  
CTAP101 Capsules (30 mcg/capsule), 60 mcg, by the oral route 
Calcifediol immediate-release (IR) (266 mcg/capsule), 266 mcg, by the oral route 
Cholecalciferol (50,000 IU/capsule), 300,000 IU, by the oral route 
Paricalcitol (1 mcg/capsule) plus cholecalciferol (800 IU/capsule), 1 or 2 mcg plus 800 IU, 
by the oral route. 
If a significant difference in average weight among subjects by treatment group emerges during 
the course of the study, subjects may be placed into specific treatment groups rather than 
randomly assigned, in order to try and achieve more balance in the treatment groups by body 
weight.   
The subjects will be housed in a phase 1 unit for approximately 14 to 26 hours at the beginning 
of the study and on study Day 29 to provide the blood samples required for a detailed 
determination of the PK profiles for serum calcifediol and 
 
 
 
 
 
 
 
 
 
  Blood 
samples for some of the PK/
 assessments will be collected in the phase 1 unit at -2, 0, 2, 4, 6, 
and 12 hours either in the phase 1 unit or during outpatient visit, at 24 hours; during outpatient 
visit for 48 hours; and then weekly following the first dose and the Day 29 dose of each 
medication.  Blood samples for other 
 assessments will be collected at less frequent intervals.  
Urine collections (24-hour) will be obtained at pre-treatment baseline (Visits 2 and 3), starting 
immediately after dosing on Day 1 (Visit 4) and Day 29 (Visit 10) and at the end of study (Visit 
16) or early termination (ET).  The schedule for blood and urine sample collections is delineated 
in Section 7 (Study Activities) and in APPENDIX 1. 
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Subjects receiving treatment with calcitriol or another 1α-hydroxylated vitamin D analog, or if 
serum total 25-hydroxyvitamin D ≥30 ng/mL when taking vitamin D supplementation (including 
multivitamins and fish oil), will complete a 4-week washout period prior to BL assessments.  
Subjects will forgo further dosing with these none study medications for the duration of the 
study.  Subjects receiving calcimimetic therapy within 12 weeks preceding screening will be 
ineligible for enrollment.   
Blood samples will be collected from all subjects at weekly intervals during the screening and 
BL periods, during the 8-week treatment period, and at the specified times during the PK/
 
assessment.  Key parameters to be analyzed in the collected samples include some or all of the 
following: serum calcifediol, 
 
 
 
  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 routine clinical chemistries).  
Subjects will maintain a dietary intake during the study of approximately 1,000-1,500 mg of 
elemental calcium per day with dietary counseling and, as necessary, administration of a daily 
calcium supplement. 
3.2 
Rationale for Study Design 
OPKO is developing CTAP101 Capsules for the treatment of SHPT in patients with stage 3 or 4 
CKD and VDI.  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 CYP24A1 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, iPTH, calcium and phosphorus [Petkovich et 
al 2015]. 
The principal aims of the present study are to compare the safety and efficacy of CTAP101 
Capsules, IR calcifediol, high-dose cholecalciferol, and paricalcitol plus low-dose cholecalciferol 
for up to 8 weeks to treat SHPT in subjects aged 18 years or older with stage 3 or 4  CKD and 
VDI and to better characterize the repeated-dose PK profiles for serum calcifediol 
 
 
 
.   
The starting dose of CTAP101 Capsules of 30 mcg/day is the lowest dose approved for 
marketing in the US.  This dose is based on the results from prior repeat-dose, placebo-
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controlled, double-blind studies with CTAP101 Capsules in patients with VDI and stage 3-4 
CKD. These studies demonstrated that 30 mcg/day of CTAP101 Capsules safely and effectively 
decreased mean plasma iPTH by clinically meaningful amounts and increased mean serum total 
25-hydroxyvitamin D within the currently accepted target range of 30-100 ng/mL.   
A phase 2b dose ranging study in which CTAP101 Capsules were administered at daily doses of 
30, 60 and 90 mcg (or 210, 420 and 630 mcg/week) for six weeks showed that mean plasma 
iPTH decreased from pre-treatment BL in a dose-proportional manner by 20.9, 32.8 and 39.3%, 
respectively, and that serum total 25-hydroxyvitamin D rose to levels ≥30 ng/mL in almost all 
subjects (CTAP101-CL-2008).  The daily doses of 30 and 60 mcg increased serum 25-
hydroxyvitamin D to a mean levels of 37 and 67 ng/mL, respectively, well within the range of 30 
to 100 ng/mL.  The daily dose of 90 mcg raised mean serum 25-hydroxyvitamin D at EOT to 85 
ng/mL causing levels to exceed 100 ng/mL in a substantial proportion of subjects.  This dose was 
considered too high for further evaluation in the phase 3 studies. 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 was determined in phase 3 studies to be attained after 12 weeks of 
treatment (CTAP101-CL-3001 and CTAP101-CL-3002).   
3.3 
Study Duration 
This study is expected to be conducted in approximately 26 weeks from time of initial subject 
enrollment (first subject consented) to study completion for the last subject (last subject out/last 
visit complete).  Subjects will participate in the study for up to approximately 14 weeks (1 week 
for screening, 4 weeks for washout (if required), 1 week for BL, and 8 weeks for treatment). 
 
 


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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, stage 
3 or 4 CKD and VDI (serum total 25-hydroxyvitamin D <30 ng/mL). 
Approximately 160 patients will be screened to enroll approximately 80 eligible subjects, 
approximately 20 per treatment arm. 
4.2 
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled in this study: 
1. Be at least 18 years of age. 
2. Have stage 3 or 4 CKD (eGFR of ≥15 to <60 mL/min/1.73m2 using the Modification of 
Diet in Renal Disease equation). 
3. Be without any disease state or physical condition that might impair evaluation of safety 
and efficacy or which, in the Investigator’s opinion, would interfere with study 
participation, including: 
a. Serum albumin ≤ 3.0 g/dL;  
b. Serum transaminase (alanine transaminase, glutamic pyruvic transaminase, aspartate 
aminotransferase or glutamic oxaloacetic transaminase) > 2.5 times the upper limit of 
normal at screening; and, 
c. Urinary albumin excretion >3000 µg/mg creatinine. 
4. Exhibit during the initial Screening Visit: 
a. Plasma iPTH ≥65 pg/mL and <400 pg/mL if receiving calcitriol or other 1α-
hydroxylated vitamin D analog (paricalcitol or doxercalciferol); or  
b. Plasma iPTH ≥85 pg/mL and <500 pg/mL if not receiving calcitriol or other 1α-
hydroxylated vitamin D analog;  
c. Serum total 25-hydroxyvitamin D <30 ng/mL, unless taking vitamin D 
supplementation (including multivitamins and fish oil); and,  
d. If taking calcitriol or another 1α-hydroxylated vitamin D analog, subjects must forgo 
treatment with these non-study agents for the duration of the study and undergo a 4-
week washout period and meet inclusion criterion 5.   
e. For subjects who are taking vitamin D supplementation (including multivitamins or 
fish oil), they must forgo treatment with these non-study agents for the duration of the 
study.  If the serum 25-hydroxyvitamin D level is <30 ng/mL, there is no need for the 
subjects to complete a washout period as a result of vitamin D supplementation.  If, 
however, serum 25-hydroxyvitamin D level is ≥30 ng/mL, the subjects must undergo 
a 4-week washout period and meet inclusion criterion 5.  If at the end of 4 weeks of 
washout, the 25 hydroxyvitamin D level is still ≥30 ng/mL, the washout may be 
extended by up to another four weeks for a total of 8 weeks. 
5. Exhibit after the washout period (if required): 
a. Plasma iPTH ≥85 pg/mL and <500 pg/mL; 


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b. Corrected serum calcium <9.8 mg/dL; (corrected for serum albumin) 
c. Serum total 25-hydroxyvitamin D <30 ng/mL; and, 
d. Serum phosphorus <5.5 mg/dL. 
6. If taking more than 1,500 mg/day of elemental calcium, reduce calcium use (to 
approximately 1,000 to ≤1,500 mg/day) for the duration of the study. 
7. Willing and able to comply with study instructions and commit to all clinic visits for the 
duration of the study. 
8. Female subjects of childbearing potential must be neither pregnant nor lactating and must 
have negative blood pregnancy tests at the first screening visit. 
9. All female subjects of childbearing potential and male subjects with female partners of 
childbearing potential must agree to use effective contraception (implants, injectables, 
combined oral contraceptives, intrauterine device, sexual abstinence, vasectomy or 
vasectomized partner) for the duration of the study. 
10. Be able to read, understand and sign the subject Informed Consent Form (ICF) or have a 
legal authorized representative (LAR) sign the ICF. 
4.3 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
1. History of or planned kidney transplant or parathyroidectomy. 
2. History (prior 3 months) of corrected serum calcium ≥9.8 mg/dL or serum phosphorus 
≥5.5 mg/dL if not receiving calcitriol or other 1α-hydroxylated vitamin D analog. 
3. Need for phosphate binders to maintain the serum phosphate < 5.5 mg/dL or use of 
phosphate binders within 4 weeks prior to screening. 
4. Use of calcimimetic therapy (cinacalcet or etelcalcetide) within 12 weeks of screening.  
5. Receipt of bisphosphonate therapy or other bone modifying treatment within 6 months 
prior to enrollment. 
6. 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.  
7. 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. 
8. Known or suspected hypersensitivity to any of the constituents of the study drugs.  
9. 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 Study Medications 
Five study medications will be used in the execution of this protocol which are described in 
sections 5.1.1 through 5.1.5.  All study medications will be securely stored for light and heat 
protection and in accordance to USP Controlled Room Temperature, defined as 20°C to 25°C 
(68°F to 77°F) with excursions permitted between 15°C to 30°C (59°F to 86°F).   
5.1.1 
Description of CTAP101 Capsules 
Dosage form: 
Soft gel capsule  
Dose strength: 
30 mcg calcifediol ER capsule  
Product description: 
Blue oval capsules printed single-sided, centered with the logo O 
in white.  Each bottle contains 30 capsules. 
Active component: 
Calcifediol 
Non-active components: 
Paraffin wax, mineral oil, mono- and diglycerides, dehydrated 
alcohol, lauroyl polyoxylglycerides, butylated hydroxytoluene, 
hypromellose, modified starch, carageenan, sodium phosphate 
dibasic, sorbitol and sorbitan solution, FD&C Blue #1, titanium 
dioxide, medium chain triglycerides (coconut oil) and ink (white, 
which may contain titanium dioxide, isopropyl alcohol, propylene 
glycol, hydroxypropylmethyl cellulose 2910)  
5.1.2 
Description of Calcifediol IR Capsules 
Dosage form: 
Soft gel capsule  
Dose strength: 
266 mcg calcifediol IR capsule  
Product description: 
Orange capsule. Each Al-Al blister or PVC/PVDC-Al blister pack 
carton contains 10 capsules.  
Active component: 
Calcifediol 
Non-active components: 
Absolute anhydrous ethanol, medium chain triglycerides, gelatin, 
vegetable glycerin, sorbitol (70%) (E-420), titanium dioxide (E-
171), yellow-orange dye S (E-110) and purified water. 
For product information, refer to APPENDIX 2. 
5.1.3 
Description of High-Dose Cholecalciferol Capsules 
Dosage form: 
Soft gel capsule  
Dose strength: 
50,000 IU cholecalciferol capsule  
Product description: 
Red, oval-shaped capsule with “50” printed in white ink. Each 
PVDC/aluminum foil blister pack with cardboard carton contains 3 
capsules. 


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Active component: 
Cholecalciferol 
Non-active components: 
All-rac-α-tocopherol (E307), medium chain triglycerides, glycerol, 
gelatin, Allura Red AC (E129), Opacode® white imprinting ink, 
shellac (E904), titanium dioxide (E171) and simethicone.  
For product information, refer to APPENDIX 3. 
5.1.4 
Description of Low-Dose Cholecalciferol Capsules 
Dosage form: 
Soft gel capsule  
Dose strength: 
800 IU cholecalciferol capsule  
Product description: 
Pink, oval-shaped capsule with “0.8” printed in white ink.  Each 
PVDC/aluminum foil blister with cardboard carton contains 28 
capsules.  
Active component: 
Cholecalciferol 
Non-active components: 
All-rac-α-tocopherol (E307), medium chain triglycerides, glycerol, 
gelatin, Allura Red AC (E129), Opacode® white imprinting ink, 
shellac (E904), titanium dioxide (E171) and simethicone.   
For product information, refer to APPENDIX 4. 
5.1.5 
Description of Paricalcitol Capsules 
Dosage form: 
Soft gel capsule  
Dose strength: 
1 mcg paricalcitol capsule  
Product description: 
The 1 mcg capsule is an oval, gray, soft gelatin capsule imprinted 
with Abbott “a” logo and ZA, and is packaged in bottles of 30  
(NDC 0074-4317-30), or an equivalent, U.S. approved generic 
alternate source. 
Active component: 
Paricalcitol 
Non-active components: 
Medium chain triglycerides, alcohol and butylated hydroxytoluene, 
gelatin, glycerin, titanium dioxide, iron oxide black and water. 
5.2 
Dosing Plan 
Approximately 80 subjects will be randomized 1:1:1:1 (approximately 20 per arm) to receive one 
of the listed study medications with a sufficient quantity of a non-alcoholic beverage to enable 
swallowing of the capsules: 
1) CTAP101 Capsules 60 mcg once daily outside of the phase 1 unit at bedtime, except on Days 
1 and 29 when dosing will occur in the phase 1 unit in the morning before breakfast. 
2) IR calcifediol 266 mcg in the phase 1 unit before breakfast on the mornings of Day 1 and 
Day 29. 
3) Cholecalciferol 300,000 IU (high-dose) in the phase 1 unit before breakfast on the mornings 
of Day 1 and Day 29. 


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4) Paricalcitol 1 mcg plus cholecalciferol 800 IU (low-dose) once daily outside of the phase 1 
unit in the morning before breakfast, except on Days 1 and 29 when dosing will occur in the 
phase 1 unit before breakfast. 
After 4 weeks of treatment, subjects who are receiving paricalcitol will double the dose to 2 mcg 
plus cholecalciferol 800 IU once daily in the morning before breakfast provided that (a) the 
plasma iPTH has not decreased by at least 30% from pretreatment BL and remains above 70 
pg/mL, (b) corrected serum calcium is <9.8 mg/dL, and (c) serum phosphorus is <5.5 mg/dL.  
Subjects who are receiving CTAP101 Capsules, IR calcifediol or cholecalciferol (300,000 IU) 
will not undergo upward dose titration.  
5.3 
Dose Reduction Criteria 
Subjects will reduce the dose of medication at any time by the schedule below in the event that 
plasma iPTH is confirmed to be <30 pg/mL, corrected serum calcium is confirmed to be >10.3 
mg/dL, or serum phosphorus is confirmed to be >5.5 mg/dL.  Subjects will suspend dosing if 
plasma iPTH is confirmed to be <15 pg/mL or corrected serum calcium is confirmed to be >11.0 
mg/dL, and will resume when plasma iPTH is ≥30 pg/mL and corrected serum calcium is <9.8 
mg/dL per the dose schedule below. 
Dose reduction: 
CTAP101: decrease to 30 mcg per day (from 60 mcg per day) 
IR calcifediol: hold Day 29 dose 
Cholecalciferol 300,000 IU: hold Day 29 dose 
Paricalcitol: decrease dose to 1 mcg per day (from 2 mcg per day). 
Cholecalciferol 800 IU will not be adjusted during the study period 
In the event that a dose reduction is required for a subject receiving the minimum dosage of 
CTAP101 Capsules (30 mcg per day) or paricalcitol (1 mcg per day), the subject will suspend 
dosing and resume when iPTH is ≥30 pg/mL and corrected serum calcium is <9.8 mg/dL at the 
same minimum dosage.   
Dose resumption: 
CTAP101: 30 mcg per day 
Paricalcitol: 1 mcg per day 
5.3.1 
Overdose and Toxicity 
Excessive administration of calcifediol, cholecalciferol, or paricalcitol can cause hypercalciuria, 
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, cholecalciferol, or paricalcitol 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 and 


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urine 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. 
5.4 
Method of Assigning Subjects to Treatment Groups 
After signing the ICF, prior to any study-related activities, each subject will be assigned a unique 
7 digit subject identification number which will be retained throughout the study and that will be 
unique across all sites.  The 7 digit subject identification number (SSSNNNN) will consist of a 
3-digit site number (SSS) and a 4-digit subject number (NNNN) at the applicable clinical 
site.  Should a subject be withdrawn from the study, that subject’s 7 digit identification number 
will not be reassigned.   
Randomization will be accomplished in blocks of 4 subjects in a 1:1:1:1 ratio with subjects being 
assigned to treatment with CTAP101 Capsules, IR calcifediol, high-dose cholecalciferol or 
paricalcitol plus low-dose cholecalciferol.  Randomization will occur during Visit 4 provided 
that each subject is deemed eligible for enrollment based, in part, on laboratory assessments 
obtained at the preceding visit (Visit 1).  Laboratory assessments obtained at Visits 2-3 will not 
be considered in the determination of enrollment eligibility. 
In the event that a significant difference in mean baseline body weight among subjects by 
treatment group emerges as enrollment progresses, the randomization scheme (described 
immediately above) will be suspended and subjects will be assigned to a specific treatment group 
using the following alternative procedure: 
Step 1:  Calculate the mean body weight for subjects who have been previously entered into the 
treatment period, in aggregate and by treatment group. 
Step 2: Compare the subject’s body weight (measured at Visit 1) with the current mean body 
weight of all subjects who have previously been entered into the treatment period.  If the 
subject’s weight is equal to or higher than the current mean body weight of all previously treated 
subjects, then assign the subject to a treatment group (which still has less than 20 subjects) 
having the lowest mean body weight.  If the subject’s weight is lower than the current mean body 
weight of all previously treated subjects, then assign the subject to a treatment group (which still 
has less than 20 subjects) having the highest mean body weight. 
Step 3 (if needed):  If a subject cannot be assigned to a treatment group according to Step 2 
(above) and there are fewer than 80 subjects assigned to treatment, then assign the subject to a 
treatment group (which still has less than 20 subjects) with the most similar mean body weight. 
5.5 
Prior and Concomitant Therapy 
Subjects should not take any vitamin D and/or bone metabolism therapy other than the study 
drug.  Excluded therapies include any non-study prescribed dose of 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 concomitant medication usage from Visit 1 until completion of the study will be recorded.  


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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.  
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.  Phenobarbital 
or other anticonvulsants or other compounds that stimulate microsomal hydroxylation reduce the 
half-life of calcifediol.  
5.5.1 
Phosphate Binder and Elemental Calcium Therapy  
Use of phosphate binders is prohibited throughout the study. Elemental calcium may be 
prescribed during the screening visit to ensure the dietary intake is within the range of 1,000-
1,500 mg per day. The overall dose of elemental calcium intake should remain stable throughout 
the study. 
5.5.2 
Diet Restrictions 
There are no study specific dietary restrictions.  Subjects should follow their dietary plan if one 
has been prescribed.  Changes in prescribed dietary phosphorus or calcium therapy are 
discouraged and any changes during the study should be captured in the electronic case report 
form (eCRF). 
Subjects will maintain a dietary intake during the study of approximately 1,000-1,500 mg per 
day of elemental calcium per dietary counseling and, as necessary, administration of a daily 
calcium supplement.  Subjects will complete a dietary questionnaire on Visit 1 and receive 
counseling from a dietician on their dietary calcium intakes, if needed. 
Subjects will report to the phase 1 unit on the mornings of Day 1 and Day 29 after an overnight 
fast.  They will receive standardized meals while housed in the phase 1 unit. These meals will 
contain 400 mg of elemental calcium and will be administered at approximately 2, 6, and 10 
hours post-dose. 
5.5.3 
Subject Activity Restrictions 
Subjects should maintain their usual pattern of sun exposures and activities. 
5.6 
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, subject dosing diaries, 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 protocol deviation. 


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5.7 
Labeling 
All study drug labels will include the protocol number, sponsor identification and address, study 
drug container contents, unique container number, area for subject and Investigator identification 
as applicable, investigational use statements, storage conditions, expiry date and instructions for 
use.   
5.8 
Storage and Accountability 
All medications will be shipped to sites using standardized shipment and temperature monitoring 
procedures.  While at the study site, all study drug will be stored in an area with light and heat 
protection and in accordance to USP Controlled Room Temperature (20-25°C or 68-77°F) and 
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, and 
verify that the supplies were maintained within an appropriate temperature range during 
shipment.  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. 
5.9 
Investigational Product Retention at Study Site 
At the conclusion of the study, a final accountability will be performed by the Investigator (or 
designee) and verified by the study monitor.  Any discrepancies identified will be indicated, with 
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 
ICF. 
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 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 
for ongoing subjects). 
6.2 
Medical History and Concomitant Medications 
A detailed medical history, including demographics, will be recorded at Visit 1/screening. 
Concomitant medications will be reviewed with each subject and recorded at specified visit 
intervals throughout the study. 
6.3 
Physical Examination and Vital Signs 
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 1.  
 
 
 


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Table 1 
Evaluations 
Physical Examination: 
• A brief PE including weight and height and excluding a urogenital 
examination will be performed during Visit 1 and Visit 16 or ET. 
Vital Sign measurements: 
• Blood pressure, heart rate and respiratory rate, and body 
temperature in degrees Celsius will be measured prior to any 
scheduled blood draws or at ET after the subject has been sitting for 
at least 2 minutes.  
Body height 
• Body height will be recorded to the nearest 1.0 cm at Visit 1 and 
Visit 16 or ET. 
Body weight: 
• Body weight will be recorded to the nearest 0.1 kg at Visit 1 and 
Visit 16 or ET. 
 
BM1 
• BMI will be calculated using the body weight divided by the body 
height squared and recorded to the nearest   tenth of a decimal point 
at Visit 1 and Visit 16 or ET. 
6.4 
Clinical Laboratory Tests 
6.4.1 
Laboratory Parameters 
Blood will be drawn and analyzed as specified in Table 2.  Urine samples will be collected and 
analyzed as specified in Table 2. 
All serum calcium values will be adjusted based on serum albumin level of <4.0 g/dL.  
All clinically significant abnormal laboratory values will be recorded as AEs and the Investigator 
will follow-up according to Section 6.6.6 Clinical Significance.  
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 2.  
 
 


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Table 2 
List of Laboratory Tests 
Hematology: 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin concentration 
Mean corpuscular volume 
Platelet count 
Red blood cell count  
White blood cell count  
 
Drugs of Abuse Screen (Urine) 
 
Serum pregnancy test (only for females of child 
bearing potential) 
 
PK and 
 parameters: 
Serum calcifediol 
 
 
Serum Chemistry: 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Blood urea nitrogen 
Calcium (corrected) 
Carbon dioxide  
Chloride 
Creatinine 
Globulin 
Glucose 
Glutamic oxaloacetic transaminase  
Glutamic pyruvic transaminase  
Lactate dehydrogenase 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
Total protein 
Triglycerides 
   Uric acid 
 
Serum Partial Chemistry:  
Calcium (corrected) 
Phosphorus 
Albumin 
 
Serum hepatitis B & C screen 
 
Serum HIV screen 
 
eGFR 
 
Urinary albumin excretion 
 
 
CCI
CCI
CCI
CCI


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6.4.2 
Sample Collection, Storage, and Shipping 
Missed blood and urine 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 and urine samples will be collected and 
analyzed for clinical laboratory tests.  During the entire study, approximately 870 mL of blood 
will be drawn.  Additional blood draws may be needed for any additional, unscheduled visits 
which are medically necessary. 
Blood samples for measurement of certain clinical laboratory tests will be collected and shipped 
to the central laboratory.  The central laboratory will ship the frozen specimens to the designated 
analytical facilities as detailed in the laboratory manual. 
Samples are to be shipped to the central laboratory for each subject as visits are completed. The 
Investigator will provide a limited access, temperature monitored space for the study drug and a -
80°C freezer space for respective serum and plasma aliquots. 
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 study coordinator (or designated site personnel) at the site will dispense the appropriate 
quantity of study drug to each subject, which will be recorded in the source document and on the 
appropriate eCRF. 
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 


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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 recorded in the source document and on the appropriate 
eCRF.   
6.6.3 
AE Collection Period 
All AEs that occur after the ICF has been signed must be reported in detail in the source 
document and in the appropriate eCRFs 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) or symptoms should NOT be recorded as additional AEs.  If a 
diagnosis is unknown, sign(s) or symptom(s) should be recorded as an AE(s).  Changes in 
laboratory values 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 are the result of 
pathology for which there is an overall diagnosis (e.g., 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 (e.g., 
as an emergency) due to a worsening of the preexisting condition, the worsening of the condition 
should be captured as an AE.  Elective procedures performed where there is no change in the 
subject’s medical condition (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 source documentation and eCRF as procedures. 
Any report of pregnancy identified for any female subject or for a female partner of a male 
subject should be reported immediately (within 24 hours of being informed) to the medical 
monitor.  Pregnancies will be considered ‘events of special interest’ and will not be captured as 
serious adverse events (SAEs).  The Pregnancy Report Form will be utilized to obtain BL and 
follow-up information.  Pregnancies will be followed to termination or six weeks post-delivery 


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for determination of resolution to the event.  Subjects who become pregnant during treatment 
must immediately be withdrawn from the study (classified as ET). 
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, e.g., 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 source 
documentation and in the appropriate 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 source documentation and the appropriate 
section of the eCRF.  If there is any doubt as to whether a clinical observation is an AE, the event 
should be reported.  
The relationship or association of the study drugs in causing or contributing to the AE will be 
characterized by the Investigator using the classifications and criteria outlined in Table 3. 


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Table 3  
Adverse Event Relationship Criteria 
Relationship 
Criteria 
Not related 
 
The temporal sequence of the AE onset relative to administration of the 
investigational product is not reasonable. 
 
Disease or other drugs provide plausible explanations. 
 
Dechallenge (if performed) is negative or ambiguous. 
Unlikely related 
 
The temporal sequence of the AE onset relative to the administration of the 
investigational product is reasonable. 
 
Could also be explained by disease or other drugs. 
 
Dechallenge (if performed) is positive or uncertain. 
 
Rechallenge is negative. 
Possibly related 
 
The temporal sequence of the AE onset relative to administration of the 
investigational is reasonable. 
 
Unlikely to be attributed to disease or other drugs. 
 
Dechallenge (if performed) is positive. 
Related 
 
The temporal sequence of the AE onset relative to administration of the 
investigational product is reasonable. 
 
Cannot be explained by disease or other drugs. 
 
Dechallenge (if performed) is positive and pharmacologically/ 
pathologically plausible. 
 
Rechallenge (if feasible) is positive. 
 
The AE shows a pattern consistent with previous knowledge of the 
investigational product or product class, i.e., pharmacologically or 
phenomenologically recognized/plausible or an objective and specific 
medical disorder. 
 
 
6.6.6 
Clinical Significance 
Changes in laboratory values and vital signs 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, eCRF 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.   
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, IR calcifediol, Cholecalciferol, or 
Paricalcitol.  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 the following numbers within 24 
hours from the time when site personnel first learn about the event.  
SAE Fax line:  
 
SAE email:  safety@safeharborpv.com 
A written report will follow as soon as possible and should consist of the SAE report 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 add this information to both the source documentation and the initial SAE 
section of the eCRFs, and provide any additional written documentation to the above number 
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 
regulations.  Copies of any reports to regulatory agencies regarding serious and unexpected 
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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 sponsor’s Clinical Services 
Department.  
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.  
Pregnancies will be followed until six weeks following delivery to determine the outcome. 
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 (Early Termination) 
The Investigator may withdraw a subject from the study for any of the following reasons: 
 A major protocol deviation occurs; 
 A serious or intolerable AE occurs; 
 A clinically significant change in a laboratory parameter occurs; 
 The sponsor or Investigator terminates the study; 
 The subject 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; 
No subject replacement is planned. 
6.9 
Appropriateness of Measurements 
AEs, corrected serum calcium and serum phosphorus have been used to assess safety of vitamin 
D compounds and will be monitored in this study.  The safety and tolerability of each study 


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medication will be determined by analyzing AEs, corrected serum calcium and serum 
phosphorus.   
 
 
  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 
Screening Period 
7.1.1 
Visit 1 (Days -70 or -42 to -36) 
 A signed ICF will be obtained from the subject prior to any study-related procedures 
 Review of inclusion/exclusion criteria 
 Medical history and demographics 
 Review of prior and current medications 
 PE (including weight, height and BMI) 
 VS assessment 
 Serum pregnancy test (for females of child bearing potential) 
 Serum hepatitis B and C/HIV screen 
 Drugs of abuse screen 
 eGFR 
 Urinary albumin excretion 
 Blood samples will be drawn for the following: 
o Clinical chemistry (full panel) and hematology 
 Dietary questionnaire for calcium intake and counseling, if needed. 
If the screening values do not meet study entry criteria after visit 1, subject may receive 
supportive care per the investigator’s discretion and may be retested once. If values do not fall 
within study entry criteria on retest, the subject will be considered a screen failure and be 
withdrawn from the study. Only the screening values that did not meet entry criteria at visit 1 are 
required to be re-drawn and meet entry criteria at the time of the visit 1 retest. 
7.1.2 
Visits 2 and 3 (Within Days -7 to -1) 
 Review of inclusion/exclusion criteria 
 Review of concomitant medications 
 AE assessment 
 VS assessment 
 Serum pregnancy test (for females of child bearing potential) (Visit 2 only) 
 Blood samples will be drawn for the following: 
o Clinical chemistry (full panel) and hematology 
 Blood samples will be drawn for: 
o 
 calcifediol, and 
 
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 
 Subjects will be instructed to report to the phase 1 unit for Visit 4 after an overnight fast. 
7.2 
Treatment Period 
7.2.1 
Visit 4 (Day 1) 
Randomization will occur at the start of this visit. 
 Subjects admitted into the phase 1 unit (for approximately 14 to 26 hours) after an overnight 
fast. 
 Subjects will receive standardized meals while housed in the phase 1 unit. These meals will 
contain approximately 400 mg of elemental calcium and will be administered at 
approximately 2 (breakfast), 6 (lunch), and 10 (dinner) hours post-dose. 
 Review of concomitant medications 
 VS assessment 
 Blood samples will be drawn from subjects housed in the phase 1 unit at approximately 6:00 
a.m. (t=~-2 hours), and 8:00 a.m. (t=~0 hours) and precisely (plus or minus 5 minutes, with 
exact time noted) at t=2, 4, 6, 12 and 24 hours (for subjects opting overnight stays), post-dose 
for the following analyses: 
o Chemistry (partial panel) 
o Serum calcifediol, 
 
 Additional blood samples will be drawn from subjects housed in the phase 1 unit at 
approximately 8:00 a.m. (t=~0 hours) and precisely (plus or minus 5 minutes, with exact time 
noted) at t=12 and 24 hours (for subjects opting overnight stays) post-dose for the following 
analysis: 
 AE assessments will be completed at each timed blood draw (n=6) 
 Subjects take first dose of study drug 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. 
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 Subjects will be discharged from the phase 1 unit after the blood draw at 12 hours post-dose 
unless Subject chooses to stay overnight.  Subjects opting to remain in the phase 1 unit for 
overnight will have 24 hour read completed.  Those who do not opt to stay overnight, 
advance to Visit 5. 
 Balance of monthly study drug supply dispensed at discharge to subjects assigned to 
CTAP101 Capsules and paricalcitol capsules plus low-dose cholecalciferol. 
7.2.2 
Visits 5 & 6 (Day 2 & 3) 
 Visit 5 is only required for subjects not opting overnight stays for Visit 4.  Visit 6 is required 
for all subjects.  
Visits 5 and 6 must be completed at exactly 24 and 48 hours from dose received in Visit 4.   
 Review of concomitant medications 
 AE assessment 
 VS assessment 
 Blood samples will be drawn for the following analyses: 
o Chemistry (partial panel) 
o Serum calcifediol, 
 
7.2.3 
Visits 7, 8, 9 (Day 8, 15, 22) 
 Review of concomitant medications 
 Dosing compliance and dosing diary assessed for subjects assigned to CTAP101 Capsules 
and paricalcitol capsules plus low-dose cholecalciferol. 
 AE assessment 
 VS assessment 
 Blood samples for the following analyses: 
o Chemistry (partial panel)  
 Subjects instructed to report to the phase 1 unit for Visit 10 after an overnight fast, and to 
bring along the previously dispensed study drug containers along with any unused study 
drug. 
7.2.4 
Visit 10 (Day 29) 
 Subjects admitted into the phase 1 unit (for approximately 14 to 26 hours) after an overnight 
fast unless Subject chooses to stay overnight.  Subjects opting to remain in the phase 1 unit 
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for overnight will have 24 hour read completed.  Those who do not opt to stay overnight, 
advance to Visit 11. 
 Dosing compliance and dosing diary assessed for subjects assigned to CTAP101 Capsules 
and paricalcitol capsules plus low-dose cholecalciferol. 
 Subjects will receive standardized meals while housed in the phase 1 unit. These meals will 
contain 400 mg of elemental calcium and will be administered at approximately 2 
(breakfast), 6 (lunch), and 10 (dinner) hours post-dose. 
 Review of concomitant medications 
 VS assessment 
 Pre-dose blood samples will be drawn for the following: 
o Clinical chemistry (full panel) and hematology 
 Blood samples will be drawn from subjects housed in the phase 1 unit at approximately 6:00 
a.m. (t=~-2 hours), and 8:00 a.m. (t=~0 hours) and precisely (plus or minus 5 minutes, with 
exact time noted) at t=2, 4, 6, 12 and 24 hours (for subjects opting overnight stays) post-dose 
for the following analyses: 
o Clinical chemistry (partial panel)  
o Serum calcifediol, 
 
o Additional blood samples will be drawn from subjects housed in the phase 1 unit at 
approximately 8:00 a.m. (t=~0 hours) and precisely (plus or minus 5 minutes, with exact 
time noted) at t=12 and 24 hours (for subjects opting overnight stays), post-dose for the 
following analysis: 
 AE assessments will be completed at each timed blood draw (n=6) 
 Subjects take next dose of study drug 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. 
 Subjects will be discharged from the phase 1 unit after the blood draw at 12 hours post-dose. 
 Balance of monthly study drug supply dispensed at discharge to subjects assigned to 
CTAP101 Capsules and paricalcitol capsules plus low-dose cholecalciferol. 
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7.2.5 
Visits 11 & 12 (Days 30 & 31) 
 Visit 11 is only required for subjects not opting overnight stays for Visit 10.  Visit 12 is 
required for all subjects.  
Visits 11 and 12 must be completed at exactly 24 and 48 hours from dose received in Visit 
10. 
 Review of concomitant medications 
 AE assessment 
 VS assessment 
 Blood samples will be drawn for the following analyses: 
o Chemistry (partial panel) 
o Serum calcifediol, 
 
7.2.6 
Visits 13, 14, 15 (Day 36, 43, 50) 
 Review of concomitant medications 
 Dosing compliance and dosing diary assessed for subjects assigned to CTAP101 Capsules 
and paricalcitol capsules plus low-dose cholecalciferol. 
 AE assessment 
 VS assessment 
 Blood samples for the following analyses: 
o Chemistry (partial panel)  
 Subjects instructed to report to the phase 1 unit for Visit 16 with the previously dispensed 
study drug containers along with any unused study drug. 
7.3 
End of Study (EOS) 
7.3.1 
Visit 16 (Day 57) Last study visit (or Early Termination) 
 Dosing compliance and dosing diary assessed for subjects assigned to CTAP101 Capsules 
and paricalcitol capsules plus low-dose cholecalciferol. 
 Review of concomitant medications 
 AE assessment 
 PE (including weight, height and BMI) 
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 VS assessment 
 Serum pregnancy test (for females of child bearing potential) 
 Blood samples for the following analyses: 
o Chemistry (full panel) plus hematology 
o 
 calcifediol, 
 
 
 
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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 
Council 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, 
e.g., 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 PK and 
 for each medication will be described.  All data 
collected on eCRFs and from clinical laboratory evaluations will be grouped and listed by 
population subgroup, subject number, visit, date and time as feasible.  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 subgroup 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 BL 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 database lock.  All subjects entered into the clinical 
database will be included in subject data listings. 
9.2 
Determination of Sample Size 
No formal sample size estimation has been performed for the study. 
9.3 
Randomization 
Each subject will be assigned a unique 7 digit subject identification number which will be 
retained throughout the study and that will be unique across all sites.  The 7 digit subject 
identification number (SSSNNNN) will consist of a 3-digit site number (SSS) and a 4-digit 
subject number (NNNN) at the applicable clinical site.  Should a subject be withdrawn from the 
study, that subject’s 7 digit identification number will not be reassigned.   
Randomization will be accomplished in blocks of 4 subjects in a 1:1:1:1 ratio with subjects being 
assigned to treatment with CTAP101 Capsules, IR calcifediol, high-dose cholecalciferol or 
paricalcitol plus low-dose cholecalciferol.  Randomization will occur during Visit 4 provided 
that each subject is deemed eligible for enrollment based, in part, on laboratory assessments 
obtained at two preceding visits (Visits 1 and 2).  Laboratory assessments obtained at Visit 3 will 
not be considered in the determination of enrollment eligibility.  In the event that the treatment 
groups become unbalanced for mean baseline body weight as enrollment progresses, the 
randomization scheme (described immediately above) will be suspended and subjects will be 
assigned to treatment groups by the following alternative procedure: 
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Step 1:  Calculate the mean body weight for subjects who have been previously entered into the 
treatment period, in aggregate and by treatment group. 
Step 2: Compare the subject’s body weight (measured at Visit 1) with the current mean body 
weight of all subjects who have previously been entered into the treatment period.  If the 
subject’s weight is equal to or higher than the current mean body weight of all previously treated 
subjects, then assign the subject to a treatment group (which still has less than 20 subjects) 
having the lowest mean body weight.  If the subject’s weight is lower than the current mean body 
weight of all previously treated subjects, then assign the subject to a treatment group (which still 
has less than 20 subjects) having the highest mean body weight. 
Step 3 (if needed):  If a subject cannot be assigned to a treatment group according to Step 2 
(above) and there are fewer than 80 subjects assigned to treatment, then assign the subject to a 
treatment group (which still has less than 20 subjects) with the most similar mean body weight. 
9.4 
Analysis Populations 
   
The safety population will include all subjects who are randomly assigned to treatment and 
receive at least 1 dose of study drug. 
 
 
 
 The PK 
population will include all subjects who are randomly assigned to treatment, receive at least 1 
dose of study drug, have no major protocol deviations, have at least 1 PK data point at BL, and 
sufficient measureable serum calcifediol or paricalcitol concentrations to facilitate the calculation 
of at least 1 postdose PK parameter using validated methods.  
All planned analyses will be specified in an accompanying statistical analysis plan (SAP).   
9.5 
Demographics and Baseline Characteristics 
Demographic and BL characteristics will be summarized for the ITT, Safety, PP and PK 
populations.  BL 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. 
9.6 
Subject Disposition and Withdrawal 
Subject disposition will be tabulated and descriptively summarized for all randomized subjects 
by population subgroups separately and combined.  Subject disposition will be summarized by 
presenting the number and percent of subjects randomized, ITT, Safety, PP and PK subjects, 
subjects who completed investigational study drug administration, subjects who completed the 
study, and subjects who discontinued prematurely from the study.  The primary reason for 
premature study termination will be detailed together with the number and percent of subjects 
discontinuing for each reason.  The primary reason for premature study termination will be 
collected from the ET eCRF page.  
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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. 
9.7 
Prior and Concomitant Medications 
Prior medications are defined as any continuing or new medication used within 12 weeks and 
discontinued before Visit 1.  Concomitant medications are defined as any continuing or new 
medication taken from Visit 1 or anytime thereafter until the end of the study.  World Health 
Organization Drug Dictionary Enhanced version September 2017, Format C, or later will be used 
to code concomitant and prior medications.  Prior and concomitant medications will be tabulated 
by population subgroup using frequency counts and percentages for each 
anatomical/therapeutic/chemical Class Level 2 and 4 and generic drug name.  All medications 
recorded on the eCRF, including start and stop (or ongoing as of) dates, AE number (if 
applicable), indication, dose, unit, route, and frequency will be listed.  For the purpose of 
inclusion in prior or concomitant medication tables, incomplete medication start and stop dates 
will be imputed and then categorized into prior or concomitant medication categories.  
9.8 
Pharmacokinetic Analysis 
Parameters to be calculated in the PK population from observed and BL-adjusted serum 
calcifediol 
 include, but may not be 
limited to the parameters listed in Table 4. 
Table 4  
Pharmacokinetic Parameters 
Parameter 
Definition 
Cmax   
Maximum serum concentration.  
Css 
Steady state concentration 
tmax  
Time of maximum serum concentration.  
AUC0-t  
Area under the serum concentration time curve from time zero to the last measurable 
time point, calculated by linear-log trapezoidal summation.  
AUC0-t’  
Area under the serum concentration time curve from time zero to a fixed time point t, 
calculated by linear-log trapezoidal summation.  
λz  
Terminal rate constant (if estimable), determined by linear regression of the terminal 
points of the log-linear serum concentration-time curve.  
t1/2   
Terminal elimination half-life (if estimable), determined as ln (2) / λz.  
Non-compartmental method or PK modeling method will be used for the estimation. 
Graphical presentation of the concentrations will be provided as needed. 
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As an exploratory analysis, PK parameters for serum calcifediol will be compared between study 
arms.  These analyses could include simple statistical summaries or using an ANOVA model, if 
feasible.  
9.10 
Safety Analysis 
All Safety subjects will be included in the safety analysis.  Statistical summary analysis of safety 
data will be descriptive only.   
9.10.1 
Primary Endpoints Analyses 
9.10.1.1 
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 subgroup 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 subgroup.  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 subgroup.  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.  
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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. 
9.10.1.2 
Vital Signs  
Observed VS values will be summarized descriptively at BL and changes from BL will be 
descriptively summarized by study arms.  Summaries will include n (%), mean, SD, median, 
minimum, and maximum.  Vital sign values will be listed.  
9.10.1.3 
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. 
9.10.2 
Secondary Endpoint Analyses 
Secondary safety endpoints will include incidence of hypercalcemia and drug-related 
hyperphosphatemia.  The number (n, %) of subjects with hypercalcemia (two consecutive visits 
with serum calcium above 10.3 mg/dL) or hyperphosphatemia (two consecutive visits with 
serum phosphorus above 5.5 mg/dL) will be calculated. 
9.11 
Efficacy Analyses 
9.11.1 
Primary Endpoint Analyses 
As this study is descriptive in nature there is no planned primary endpoint analyses. Descriptive 
analysis and plots will be created for the ITT and PP populations of serum calcifediol, 
 
 
 
 
 
 
 
 
 
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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 
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 (e.g., an IRB). 
10.3 
Ethical Conduct of the Study 
In accordance with applicable country-specific regulations, the sponsor will obtain approval from 
the appropriate regulatory authority(ies) prior to initiating the study in that country.  This study 
will be conducted in accordance with the protocol, all ICH and GCP regulations governing 
clinical study conduct, ethical principles that have their origin in the Declaration of Helsinki, and 
all applicable local laws and regulations. The Investigator must assure that the study is conducted 
in accordance with prevailing local laws and customs. 
It is the Investigator’s responsibility to ensure that this protocol is reviewed and approved by the 
appropriate IRB/EC.  The IB must be provided to the IRB/EC. 
The IRB/EC must also review and approve the site’s ICF and any other written information 
provided to the subject and any advertisement that will be used for subject recruitment prior to its 
use. 
10.4 
Subject Information and Consent 
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 
withdrawn at any time without penalty or loss of benefits to which the subject is otherwise 
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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). 
10.5 
Subject Confidentiality 
Subject confidentiality will be strictly held in trust by the participating Investigators, their staff, 
the sponsor and their authorized representatives.  This confidentiality is extended to cover testing 
of biological samples in addition to the clinical information relating to participating subjects. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence.  No information concerning the study or the data will be released to any 
unauthorized third party, without prior written approval of the sponsor. 
Authorized representatives of the sponsor, the designated contract research organization (if 
applicable), the study monitor, employees of government authorities such as the US FDA or 
other government authorities, and members of the IRB may inspect all documents and records 
required to be maintained by the Investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the subjects in this study.  The clinical study 
site will permit access to such records. 
No information that would permit the identification of a specific individual will be provided for 
entry into the study database or study report.  Study documentation submitted to the sponsor will 
identify study participants by study code and initials.  The Investigator will keep a separate 
confidential enrollment log that matches identifying study codes with the subjects’ names and 
residencies. 
10.6 
Study Monitoring 
The sponsor and/or its designee are responsible for monitoring the study in accordance with the 
requirements of the ICH/GCP, and in accordance with written SOPs and the Clinical Monitoring 
Plan. 
The study will be monitored by the sponsor or designee at all stages of study conduct from 
inception to completion in accordance with current ICH/GCP.  The Investigator will allocate 
adequate time for such monitoring activities.  This monitoring will be in the form of site visits 
and other communication and will include review of original source documents, 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. 
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 (e.g., 
pharmacy, diagnostic laboratory), and has adequate space to conduct the monitoring visit. 
10.7 
Case Report Forms and Study Records 
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from automated 
instruments, microfiches, photographic negatives, microfilm or magnetic media, and/or x-rays.  


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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 is 
randomized.  All data generated from external sources, (e.g., 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. 
10.8 
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, 
dosing non-compliance, and any other protocol requirement that results in a significant added 
risk to the subject or has an impact on the quality of the data collected or the outcome of the 
study. 
The sponsor requires that all major protocol deviations be reported to the IRB.  In addition, the 
Investigator is responsible for adhering to his/her IRB’s protocol deviation reporting 
requirements. 
10.9 
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, 


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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. 
10.10 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. 
10.11 Financial Disclosure 
The principal Investigator and all sub-Investigators are required to provide certification 
(Financial Disclosure Form) that no financial arrangements with the sponsor have been made 
where study outcome could affect compensation; that the Investigator has no proprietary interest 
in the tested product; that the Investigator does not have a significant equity interest in the 
sponsor; and that the Investigator has not received significant payments of other sorts.  The 
Investigator/sub-Investigator is responsible for informing the sponsor if these circumstances 
change during the course of the study or within one year of the end of his/her participation in the 
study. 
10.12 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 


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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. 
Bordier PJ, Marie PJ, Arnaud CD. Evolution of renal osteodystrophy: correlation of bone 
histomorphometry and serum mineral and immunoreactive parathyroid hormone values before 
and after treatment with calcium carbonate or 25-hydroxycholecalciferol. Kidney Int Suppl. 1975 
Jan;(2):S102–112. 
Coyne D, Acharya M, Qiu P, et al. Paricalcitol capsule for the treatment of secondary 
hyperparathyroidism in stages 3 and 4 CKD. Am J Kidney Dis. 2006;47:263–276. 
DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin 
Nutr. 2004;80:1689S–1696S. 
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. 
Fournier A, Idrissi A, Sebert JL, et al. Preventing renal bone disease in moderate renal failure 
with CaCO3 and 25(OH) vitamin D3. Kidney Int Suppl. 1988;24:S178–179. 
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. 
Letteri JM, Kleinman LM, Ellis KN, et al. Effects of 25-hydroxycholecalciferol on calcium 
metabolism in chronic renal failure. Adv Exp Med Biol. 1977;81:591–601. 


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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 
Nigwekar SU, Tamez H, Thadhani RI. Vitamin D and chronic kidney disease-mineral bone 
disease (CKD-MBD). Bonekey Rep. 2014;3:498. 
Petkovich M, Melnick J, White J, et al. Modified-release oral calcifediol corrects vitamin D 
insufficiency with minimal CYP24A1 upregulation. J Steroid Biochem Mol Biol. 2015;148:283–
289. 
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 
Thadhani R, Appelbaum E, Pritchett Y, et al. Vitamin D therapy and cardiac structure and 
function in patients with chronic kidney disease: the PRIMO randomized controlled trial. J Am 
Med Assoc. 2012;307:674–684. 
Wang AY-M, Fang F, Chan J, et al. Effect of paricalcitol on left ventricular mass and function in 
CKD: the OPERA trial. J Am Soc Nephrol. 2014;25:175–186. 


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APPENDIX 1  SCHEDULE OF EVENTS 
 
Screen 
Wash
out 
Baseline 
Treatment  
EOS
/ET 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 
1 
 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Week 
-5 
 
-1 
-1 
1 
1 
1 
2 
3 
4 
5 
5 
5 
6 
7 
8 
9 
Day 
-70 or  
-42 to -
36 
-63 
or  
-35 
to -8 
-7 to 
-2 
-1 
1 
2 
3 
8 
15 
22 
29 
30 
31 
36 
43 
50 
57 
 
 
 
 
 
(GCRC) 
 
 
 
 
 
(GCRC) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hours 
 
 
 
 
-2, 0, 2, 
4, 6, 12  
24 
hrs 
48 
hrs 
 
 
 
-2, 0, 2, 
4, 6, 12 
24 
hrs 
48 
hrs 
 
 
 
 
Study drug dispensed 
 
 
 
 
1a,b 
 
 
 
 
 
1a,b 
 
 
 
 
 
 
Dosing compliance and dosing 
diary assessed 
 
 
 
 
 
 
 
1 
1 
1 
1 
 
 
1 
1 
1 
1 
Sign ICF 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review inclusion/exclusion 
criteria 
1 
 
1 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
demographics 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diet history and counseling for 
(as needed) calcium intake 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medications review 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications review 
1 
 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
Adverse events 
 
 
1 
1 
6 
1 
1 
1 
1 
1 
6 
1 
1 
1 
1 
1 
1 
Physical exam (including weight, 
height and BMI) 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
Vital Signs Assessment 
1 
 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
Blood pregnancy test (for females 
of child bearing potential) 
1 
 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
Serum Hepatitis B & C/HIV 
screen 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eGFR 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinary albumin excretion 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical chemistry (full panel) 
1 
 
1 
1 
 
 
 
 
 
 
1 
 
 
 
 
 
1 
Hematology 
1 
 
1 
1 
 
 
 
 
 
 
1 
 
 
 
 
 
1 
Clinical chemistry (partial panel) 
 
 
 
 
6 
1 
1 
1 
1 
1 
6 
1 
1 
1 
1 
1 
 
Washout 


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Screen 
Wash
out 
Baseline 
Treatment  
EOS
/ET 
(Continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 
1 
 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Week 
-5 
 
-1 
-1 
1 
1 
1 
2 
3 
4 
5 
5 
5 
6 
7 
8 
9 
Day 
-70 or  
-42 to -
36 
-63 
or  
-35 
to -8 
-7 to 
-2 
-1 
1 
2 
3 
8 
15 
22 
29 
30 
31 
36 
43 
50 
57 
 
 
 
 
 
(GCRC) 
 
 
 
 
 
(GCRC) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hours 
 
 
 
 
-2, 0, 2, 
4, 6, 12  
24 
hrs 
48 
hrs 
 
 
 
-2, 0, 2, 
4, 6, 12 
24 
hrs 
48 
hrs 
 
 
 
 
Urine drugs of abuse screen 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NOTE: The number listed under each respective event reflects the number of occurrences for that specific type of event on the specific visit designations; absence of number 
designation indicates that no occurrence of such event is required. 
a Study drug dispensing for subjects assigned to CTAP101 Capsules and paricalcitol capsules plus low-dose cholecalciferol 
b Study drug dispensed for t=0 dose on Day 1 and 29 from monthly study drug supply. 
  
 
 
 
 
C
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APPENDIX 2  CALCIFEDIOL IR CAPSULES (HIDROFEROL) 
SUMMARY OF PRODUCT CHARACTERISTICS 
(Translation) 
1.  
NAME OF THE MEDICINAL PRODUCT 
Hidroferol 0.266 mg soft capsules 
2.  
QUALITATIVE AND QUANTITATIVE COMPOSITION 
Each capsule contains 0.266 mg (266 micrograms) of calcifediol (15,960 IU of vitamin D). 
Excipients with known effect: 
Each capsule contains 4.98 mg of ethanol, 31.302 mg of sorbitol (70% v/v) (E-420), 0.958 mg of 
sunset yellow (E-110) and other excipients. 
For the full list of excipients, see section 6.1. 
3.  
PHARMACEUTICAL FORM 
Soft capsule 
Soft gelatine orange-coloured capsule. 
4.  
CLINICAL PARTICULARS 
4.1  
Therapeutic indications 
In adults: 
Treatment of vitamin D deficiency in cases in which the initial administration of high doses is 
required or where administration spaced out over time may be preferred, as in the following 
situations: 
 
As an adjuvant for treating osteoporosis; 
 
In patients with malabsorption syndrome 
 
Renal osteodystrophy 
 
Bone problems caused by treatment with corticosteroids. 
4.2  
Posology and method of administration 
Posology 
The dietary intake of vitamin D and exposure to sunlight varies between patients and must be 
taken into account when calculating the appropriate dose of vitamin D analogues, such as 
calcifediol. 
The dose, frequency and duration of treatment will be determined according to the plasma levels 
of 25-OH-cholecalciferol, the type and situation of the patient and other comorbidities such as 
obesity, malabsorption syndrome and corticosteroid treatment. The dose which generates serum 
calcium levels of between 9–10 mg/dL should be administered. 
The plasma determination of 25-OH-cholecalciferol is considered the most acceptable way of 
diagnosing vitamin D deficiency. It can be accepted that there is vitamin D deficiency with serum 
levels of 25-OH-cholecalciferol < 20 ng/mL and vitamin D insufficiency with serum levels of 
25-OH-cholecalciferol between 20 and 24 ng/mL. 
In normal subjects, the mean serum concentrations range between 25 and 40 ng/mL of 25-OH-
cholecalciferol. 
The recommended dose is one capsule (0.266 mg of calcifediol) once a month. 


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 
Vitamin D insufficiency: The administration of one capsule (0.266 mg of calcifediol) a month 
for 2 months is recommended. 
 
Vitamin D deficiency: The initial administration of one capsule (0.266 mg of calcifediol) a 
month for 4 months is recommended. 
 
As an adjuvant in the treatment of osteoporosis in patients with vitamin D deficiency, the 
administration of one capsule (0.266 mg of calcifediol) a month for 3–4 months is 
recommended. 
There are populations at high risk of vitamin D deficiency in whom it may be necessary to 
administer higher doses or more prolonged regimens, after analytically testing the extent of the 
deficiency and completing regular checks of serum levels of 25-OH-cholecalciferol. 
 
Renal osteodystrophy: Taking one capsule (0.266 mg of calcifediol) per week or every two 
weeks is recommended. 
 
Bone problems caused by corticosteroids: Taking one capsule (0.266 mg of calcifediol) a 
month is recommended. 
 
In patients with higher vitamin D deficiencies or malabsorption syndrome, repeating the 
initial dose weekly (0.266 mg of calcifediol) is recommended, followed by one capsule once 
a month for 4 months, checking the plasma concentration of 25-OH-cholecalciferol. 
Depending on these levels, an increase in the dose or frequency of administration may be 
required. Once the value within the interval has been established, the treatment will be 
suspended or the regimen will be more spaced out. 
In general, the doses must be reduced when symptoms improve because the requirements for 
vitamin D analogues normally decrease after recovery of the bone. 
It is useful to know the serum concentrations of 25-OH-cholecalciferol 3 months after starting the 
supplementation to confirm that they are within the desirable or preferred interval (30–60 ng/mL). 
Once the value within the interval has been established, the treatment will be suspended or the 
regimen will be more spaced out. 
Paediatric population 
The medicinal product Hidroferol 0.1 mg/mL oral drops in solution has been authorised for use in 
children, with lower dose concentration. 
Method of administration 
Oral route. 
The capsule may be taken with water, milk or juice. 
4.3  
Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients included in section 6.1. 
 
Hypercalcaemia (calcaemia > 10.5 mg/dL), hypercalciuria (abnormally high excretion of 
calcium in the urine). 
 
Calcium lithiasis. 
 
Hypervitaminosis D. 
4.4  
Special warnings and precautions for use 
 
The serum levels of 25-OH-cholecalciferol reflect the patient’s vitamin D status, but in order 
to obtain an adequate clinical response to the oral administration of calcifediol, there must 
also be adequate calcium intake in the diet. Therefore, to control the therapeutic effects, in 
addition to the 25-OH-cholecalciferol, the calcium, phosphorous, alkaline phosphatase, and 
urinary calcium and phosphorous in the serum must be monitored over 24 hours; a drop in the 


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serum levels of alkaline phosphatase normally precedes the appearance of hypercalcaemia. 
Once these parameters are normal in the patient and the patient is on a maintenance treatment 
regimen, the above-mentioned measurements must be taken, in particular the serum levels of 
25-OH-calciferol and calcium. 
 
Hepatic or gallbladder insufficiency: In the event of hepatic insufficiency, an inability to 
absorb calcifediol may occur through bile salts not being produced. 
 
Renal insufficiency: Administration with caution is advised. The use of this medicinal 
product in patients with chronic kidney disease must be accompanied by regular checks of 
plasma calcium and phosphorous, and to prevent hypercalcaemia. As the kidneys will give 
rise to calcitriol, in the event of severe renal insufficiency (renal creatinine clearance less than 
30 mL/minute) a very significant decrease in the pharmacological effects may occur. 
 
Cardiac insufficiency: Particular caution is required. The individual’s calcium level must be 
monitored at all times, particularly in patients undergoing treatment with digitalis medication, 
as it may cause hypercalcaemia and the appearance of arrhythmia; it is advised to perform 
these measurements twice a week at the start of treatment. 
 
Hypoparathyroidism: 1-alpha-hydroxylase shall be activated by the 
, 
therefore in the event of parathyroid insufficiency, the calcifediol activity may decrease. 
 
Renal calculi: The calcium level must be controlled as vitamin D, by increasing calcium 
absorption, may aggravate the symptoms. Vitamin D levels must only be administered in 
these patients if the benefits outweigh the risks. 
 
In patients with long-term immobilisation, dose reduction may be necessary on occasion to 
avoid hypercalcaemia. 
 
There are diseases that affect the intestine’s capacity to absorb vitamin D, as in the case of 
malabsorption syndrome or Crohn’s disease. 
 
Patients with sarcoidosis, tuberculosis or other granulomatous diseases: It must be used with 
caution, given that in these diseases there is greater sensitivity to the effect of vitamin D and 
increase the risk of suffering from adverse reactions at lower doses of the medicinal product 
than the recommended ones. The serum and urinary calcium concentrations should be 
checked in these patients. 
 
The patient and their family and/or carers must be informed of the importance of complying 
with the indicated posology and the recommendations regarding diet and taking calcium 
supplements concomitantly in order to prevent overdose. 
 
Interference with laboratory tests: Patients must be advised that this medicinal product 
contains a component that may cause changes in laboratory test results: 
Measurement of cholesterol: Calcifediol may interfere with the Zlatkis-Zak method, giving rise to 
false increases in serum cholesterol levels. 
Elderly patients: 
Elderly patients generally have a greater need for vitamin D due to a decrease in the capacity of 
the skin to produce cholecalciferol from its precursor 7-dehydrocholesterol, due to a reduction in 
exposure to sunlight, and due to changes in renal function or digestive dysfunctions that may 
reduce vitamin D absorption. 
Excipients warnings 
This medicinal product contains 1% of ethanol (alcohol), which corresponds to a quantity of 
4.98 mg/capsule. 
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This medicinal product contains sorbitol. Patients with hereditary intolerance to fructose must not 
take this medicinal product. 
This medicinal product may cause allergic reactions because it contains sunset yellow S (E-110). 
It may cause asthma, especially in patients who are allergic to acetylsalicylic acid. 
4.5  
Interaction with other medicinal products and other forms of interaction 
 
Phenytoin, phenobarbital, primidone and other enzyme inducers: Enzyme inducers can 
reduce the plasma concentrations of calcifediol and inhibit their effects through induction of 
their hepatic metabolism. 
 
Cardiac glycosides: Calcifediol may cause hypercalcaemia, which can in turn strengthen the 
inotropic effects of digoxin and its toxicity, causing cardiac arrhythmia. 
 
Medicinal products that reduce the absorption of calcifediol, such as cholestyramine, 
colestipol or orlistat, may cause a decrease of the effects. Spacing out the doses of these 
medicinal products and vitamin D supplements by at least 2 hours is recommended. 
 
Paraffin and mineral oil: Due to the liposolubility of calcifediol, it can be dissolved in 
paraffin and decrease its intestinal absorption. The use of another type of laxative or at least 
spacing out the doses is recommended. 
 
Thiazide diuretics: Concomitant administration of a thiazide diuretic (hydrochlorothiazide) 
with vitamin D supplements, in patients with hypoparathyroidism can give rise to 
hypercalcaemia, which can be temporary or require suspension of treatment with the 
vitamin D analogue. 
 
Some antibiotics, such as penicillin, neomycin and chloramphenicol, can increase calcium 
absorption. 
 
Phosphate binders such as magnesium salts: As vitamin D has an effect on the transport of 
phosphate in the intestine, kidneys and bones, it may cause hypermagnesaemia; the dose of 
phosphate binders must be adjusted in accordance with serum phosphate concentrations. 
 
Verapamil: There are studies in which possible inhibition of anti-angina action has been 
recorded, through antagonism of its actions. 
 
Vitamin D: The concomitant administration of any vitamin D analogue must be avoided as 
this may cause additive positive effects and hypercalcaemia. 
 
Calcium supplements: The uncontrolled intake of additional preparations containing 
calcium must be avoided. 
 
Corticosteroids: counteract the effects of vitamin D analogues, such as calcifediol. 
Interaction with food and drink 
Foods that can be supplemented with vitamin D must be taken into account as this may cause 
additive effects. 
4.6  
Fertility, pregnancy and lactation 
Pregnancy 
No controlled studies with calcifediol have been carried out in pregnant women. 
Animal studies have demonstrated toxicity for reproduction (see section 5.3). 
Hidroferol 0.266 mg soft capsules must not be used during pregnancy. 


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Breast-feeding 
Calcifediol is excreted in breast milk. 
The risk for newborn babies/children cannot be ruled out. Maternal intake of high doses of 
calcifediol may cause high levels of calcitriol in breast milk and cause hypercalcaemia in the 
breastfed baby. 
Hidroferol 0.266 mg soft capsules must not be used while breastfeeding. 
4.7  
Effects on ability to drive and use machines 
Hidroferol has no or negligible influence on the ability to drive and use machines. 
4.8  
Undesirable effects 
The undesirable effects of calcifediol are, generally, rare (≥1/1,000 to <1/100) although 
sometimes they are moderately significant. 
The most significant undesirable effects relate to the excessive intake of vitamin D, which means 
they are usually associated with overdose or prolonged treatments, in particular when it is 
combined with high doses of calcium. Doses of vitamin D analogues required to produce 
hypervitaminosis vary considerably between individuals. The most typical undesirable effects are 
due to possible hypercalcaemia, and they can appear at an early or a late stage. 
Endocrine disorders: 
Pancreatitis, among the delayed symptoms of hypercalcaemia. 
Metabolism and nutrition disorders: 
Increase in blood urea nitrogen (BUN), albuminuria, hypercholesterolaemia, hypercalcaemia 
Nervous system disorders: 
If moderate hypercalcaemia has occurred, the following may appear: weakness, fatigue, 
drowsiness, headache, irritability. 
Eye disorders: 
On rare occasions (≥1/10,000 to <1/1,000), photophobia and conjunctivitis with corneal 
calcifications may occur at very high doses. 
Cardiac disorders: 
In the event of hypercalcaemia, cardiac arrhythmia may occur. 
Gastrointestinal disorders: 
Nausea, vomiting, dryness of the mouth, constipation, taste disorders, with a metallic taste, 
abdominal cramps; in the event of progressive hypercalcaemia, anorexia may occur. 
Hepatobiliary disorders: 
With high levels of calcaemia, an increase in transaminase (ALT and AST) may occur. 
Musculoskeletal and connective tissue disorders: 
In the event of hypercalcaemia, initially bone and muscle pain, and calcifications in the  soft 
tissues may occur. 
Renal and urinary disorders: 
Manifestations of hypercalcaemia are: nephrocalcinosis and deterioration of renal function (with 
polyuria, polydipsia, nocturia and proteinuria) 
General disorders and administration site conditions: 
Delayed symptoms of hypercalcaemia are: rhinorrhea, pruritus, hyperthermia, and decrease in 
libido. 


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Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the Spanish System of 
Pharmacovigilance of Medicinal Products for Human Use: www.notificaRAM.es. 
4.9  
Overdose 
Symptoms: 
The administration of vitamin D at high doses or over long periods of time may cause 
hypercalcaemia, hypercalciuria, hyperphosphataemia and renal insufficiency. Initial symptoms of 
intoxication may include the following: weakness, fatigue, drowsiness, headache, anorexia, 
dryness of the mouth, metallic taste, nausea, vomiting, abdominal spasms, polyuria, polydipsia, 
nocturia, constipation or diarrhoea, dizziness, tinnitus, ataxia, exanthema, hypotony (in particular 
in babies), muscle or bone pain and irritability. 
Among the most delayed symptoms of hypercalcaemia are: rhinorrhea, pruritus, decrease in 
libido, nephrocalcinosis, renal insufficiency, osteoporosis in adults, arrested growth in children, 
weight loss, anaemia, conjunctivitis with calcification, photophobia, pancreatitis, increase in the 
blood urea nitrogen (BUN), albuminuria, hypercholesterolaemia, increase in transaminase (ALT 
and AST), hyperthermia, generalised vascular calcification, convulsions and calcification of the 
soft tissue. Rarely, patients may develop hypertension or psychotic symptoms; serum alkaline 
phosphatase can decrease; water-electrolyte imbalance together with moderate acidosis may give 
rise to cardiac arrhythmia. 
In more serious situations in which calcaemia exceeds 12 mg/dL, fainting, metabolic acidosis and 
coma may occur. Although the symptoms of overdose are usually reversible, renal or heart failure 
may occur. 
It is accepted that serum levels of 25-OH-cholecalciferol greater than 150 ng/mL may be 
associated with an increase in the incidence of undesirable effects. 
The increase in calcium, phosphate, albumin and blood urea nitrogen, and cholesterol and 
transaminase in the blood is typical of this overdose. 
Treatment: 
The treatment for intoxication by calcifediol consists of: 
1. Withdrawing treatment (with calcifediol) and any calcium supplement that is being 
administered. 
2. Following a low-calcium diet. To increase the excretion of calcium, administering large 
volumes of fluids, both orally and parenterally, is recommended, and if necessary, to 
administer glucocorticoids and forced loop diuretics such as furosemide. 
3. If the intake has occurred within the last 2 hours, gastric lavage and forced emesis can be 
performed. If the vitamin D has already passed through the stomach, a paraffin or mineral oil 
laxative can also be administered. If the vitamin D has already been absorbed, haemodialysis 
or peritoneal dialysis with a calcium-free dialysis solution can be used. 
As a consequence of long-term administration of calcifediol, Hypercalcaemia may persist for 
approximately 4 weeks after the suspension of treatment. The signs and symptoms of 
hypercalcaemia are normally reversible, but metastatic calcification may cause severe renal 
insufficiency, cardiac insufficiency or death. 
 
 


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5.  
PHARMACOLOGICAL PROPERTIES 
5.1  
 properties 
Pharmacological group: Vitamin D and analogues. Calcifediol. ATC code: A11CC06 
Mechanism of action 
Vitamin D has two main forms: D2 (ergocalciferol) and D3 (cholecalciferol). Vitamin D3 is 
synthesised in the skin through exposure to sunlight (ultraviolet radiation) and it is obtained in the 
diet. Vitamin D3 must undergo a two-step metabolic process to be active; the first step occurs in 
the microsomal fraction of the liver where it is hydroxylated in position 25 
(25-hydroxycholecalciferol or calcifediol); the second process takes place in the kidneys where 
1.25-dihydroxycholecalciferol or calcitriol is formed through intervention of the enzyme 
25-hydroxycholecalciferol 1-hydroxylase; the conversion to 1.25-hydroxycholecalciferol is 
regulated by its own concentration, by the 
 and by the calcium and 
phosphate serum concentration; there are other metabolites with unknown function. From the 
kidneys, 1.25-hydroxycholecalciferol is transported to the destination tissues (intestine, bone, 
possibly kidney and parathyroid glands) by binding to specific plasma proteins. 
 effects 
Vitamin D primarily increases the absorption of calcium and phosphorus in the intestine and 
promotes normal bone formation and mineralisation, and acts on three levels: 
Intestine: it stimulates the absorption of calcium and phosphorus in the small intestine. 
Bone: calcitriol stimulates bone formation by increasing calcium and phosphate levels and it 
stimulates the actions of the osteoblasts. 
Kidneys: calcitriol stimulates the tubular reabsorption of calcium. 
In the parathyroid glands: vitamin D inhibits the secretion of the 
. 
5.2  
Pharmacokinetic properties 
Absorption 
Calcifediol or 25-hydroxycholecalciferol, such as vitamin D analogues, is absorbed in the 
intestine if the absorption of fats is normal, through the chylomicrons, principally in the middle 
sections of the small intestine; approximately 75–80% is absorbed this way. 
Distribution 
Calcifediol is the main circulating form of vitamin D. The serum concentrations of 25(OH)-
cholecalciferol reflect the organism’s vitamin D reserves which are usually between 25 and 
40 ng/mL (62.5 to 100 nmol/L) in healthy individuals. Following the oral administration of 
calcifediol, the time in which the maximum serum concentration is reached is approximately 
4 hours. Its half-life is around 18 to 21 days and its storage in the adipose tissue is less significant 
than that of vitamin D, due to its lower liposolubility; calcifediol is stored in the adipose and 
muscle tissue for extended periods of time. The pharmaceutical form of soft capsules offers a 
22% higher bioavailability than the pharmaceutical form of an oral solution in vials. This 
difference is not considered clinically significant given that the dose must be determined on an 
individual basis depending on the serum levels of 25-OH-cholecalciferol and calcium, and these 
levels must be controlled during the treatment. 
Metabolism or Biotransformation 
Elimination 
Calcifediol is principally excreted in the bile. 
 
CCI
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5.3  
Preclinical safety data 
High doses of vitamin D (from 4 to 15 times the recommended doses in humans) have been 
shown to be teratogenic in animals, but there are only a few studies that have been carried out in 
humans. Vitamin D may cause hypercalcaemia in the mother which also gives rise to 
supravalvular aortic stenosis syndrome, retinopathy and mental delay in children or newborn 
infants. 
6.  
PHARMACEUTICAL PARTICULARS 
6.1  
List of excipients 
Absolute anhydrous ethanol 
Medium-chain triglycerides 
Gelatine 
Vegetable glycerine 
Sorbitol (70%) (E-420) 
Titanium dioxide (E-171) 
Sunset yellow (E-110) 
Purified water 
6.2  
Incompatibilities 
Not applicable 
6.3  
Shelf life 
30 months 
6.4  
Special precautions for storage 
No special precautions for storage are required. 
6.5  
Nature and contents of container 
Container containing 5 or 10 capsules in Al-Al blister or in PVC/PVDC-Al blister. 
6.6  
Special precautions for disposal and other handling 
No special requirements for disposal. 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
7.  
MARKETING AUTHORISATION HOLDER 
FAES FARMA S.A. 
Máximo Aguirre, 14 
ES-48940 Leioa (Bizkaia) 
8.  
MARKETING AUTHORISATION NUMBER(S) 
9. 
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
August 2015 
10.  
DATE OF REVISION OF THE TEXT 
August 2015 
 


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APPENDIX 3  HIGH DOSE CHOLECALCIFEROL CAPSULES (InVita D3 
50,000 IU)  
SUMMARY OF PRODUCT CHARACTERISTICS 
1  
NAME OF THE MEDICINAL PRODUCT 
InVita D3 50,000 IU soft capsules 
2  
QUALITATIVE AND QUANTITATIVE COMPOSITION 
Each capsule contains 50,000 IU colecalciferol (equivalent to 1.25 mg vitamin D3) 
Excipients with known effect: 
Each capsule contains 0.082 mg Allura Red AC (E129).  
For the full list of excipients, see section 6.1. 
3  
PHARMACEUTICAL FORM 
Soft capsule 
Red, oval-shaped, soft capsule. It contains a slightly yellow oily liquid. Each capsule has “50” 
printed in white ink. Capsule dimensions are 12.5mm x 8.5mm. 
4  
CLINICAL PARTICULARS 
4.1  
Therapeutic indications 
The treatment of vitamin D3 deficiency. 
4.2  
Posology and method of administration 
Posology 
1 capsule contains 50,000 IU vitamin D3. 
 
 
Paediatric posology 
- 
Due to lack of clinical data, InVita D3 is not recommended. 
 
 
Pregnancy and breastfeeding 
- 
Due to lack of clinical data, InVita D3 is not recommended. 
 
Adults 
- 
Higher doses may be required in certain situations, see below. 
- 
Treatment of vitamin D3 deficiency (<25 nmol/l) 50,000 IU/week (1 capsule) for 6-8 
weeks, followed by maintenance therapy (1400-2000 IU/day may be required, such 
as 1 capsule per month; follow up 25(OH)D measurements should be made 
approximately three to four months after initiating maintenance therapy to confirm 
that the target level has been achieved.) 
 
Certain populations are at high risk of Vitamin D3 deficiency, and may require higher 
doses and monitoring of serum 25(OH)D: 
- 
Institutionalised or hospitalised individuals 
- 
Dark skinned individuals 
- 
Individuals with limited effective sun exposure due to protective clothing or 
consistent use of sun screens 
- 
Obese individuals 
- 
Patients being evaluated for osteoporosis 


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- 
Use of certain concomitant medications (eg, anticonvulsant medications, 
glucocorticoids) 
- 
Patients with malabsorption, including inflammatory bowel disease and coeliac 
disease 
- 
Those recently treated for Vitamin D3 deficiency, and requiring maintenance 
therapy. 
Special populations 
Renal impairment 
InVita D3 should not be used in combination with calcium in patients with severe renal 
impairment. 
Hepatic impairment 
No posology adjustment is required in patients with hepatic impairment.  
Method of administration 
Oral – The capsules should be swallowed whole with water. 
Patients should be advised to take InVita D3 preferably with a meal (see section 5.2 
Pharmacokinetic properties - “Absorption”). 
 4.3 
Contraindications 
• 
Hypersensitivity to the active substance(s) or to any of the excipients. 
• 
Hypercalcaemia and/or hypercalciuria. 
• 
Nephrolithiasis and/or nephrocalcinosis 
• 
Serious renal impairment 
• 
Hypervitaminosis D 
• 
Pseudohypoparathyroidismas the vitamin D requirement may be reduced due to phases of 
normal vitamin D sensitivity, involving the risk of prolonged overdose. Better-regulatable 
vitamin D derivatives are available for this. 
• 
Pregnancy 
• 
Children and adolescents (under 18 years of age) 
4.4  
Special warnings and precautions for use 
Vitamin D3 should be used with caution in patients with impairment of renal function and the 
effect on calcium and phosphate levels should be monitored. The risk of soft tissue calcification 
should be taken into account. 
Caution is required in patients receiving treatment for cardiovascular disease (see section 4.5 
Interaction with other medicinal products and other forms of interaction - cardiac glycosides 
including digitalis). 
InVita D3 should be prescribed with caution in patients with sarcoidosis, due to a possible 
increase in the metabolism of Vitamin D3 in its active form. In these patients the serum and 
urinary calcium levels should be monitored. 
Allowances should be made for the total dose of Vitamin D3 in cases associated with treatments 
already containing Vitamin D3, foods enriched with Vitamin D3, cases using milk enriched with 
Vitamin D3, and the patient’s level of sun exposure. 
There is no clear evidence for causation between Vitamin D3 supplementation and renal stones, 
but the risk is plausible, especially in the context of concomitant calcium supplementation. The 


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need for additional calcium supplementation should be considered for individual patients. 
Calcium supplements should be given under close medical supervision. 
Oral administration of high-dose Vitamin D3 (500,000 IU by single annual bolus) was reported to 
result in an increased risk of fractures in elderly subjects, with the greatest increase occurring 
during the first 3 months after dosing. 
 4.5 
Interaction with other medicinal products and other forms of interaction 
Concomitant use of anticonvulsants (such as phenytoin) or barbiturates (and possibly other drugs 
that induce hepatic enzymes) may reduce the effect of Vitamin D3 by metabolic inactivation. 
In cases of treatment with thiazide diuretics, which decrease urinary elimination of calcium, 
monitoring of serum calcium concentration is recommended. 
Concomitant use of glucocorticoids can decrease the effect of Vitamin D3. 
In cases of treatment with drugs containing digitalis and other cardiac glycosides, the 
administration of Vitamin D3 may increase the risk of digitalis toxicity (arrhythmia). 
Strict medical supervision is needed, together with serum calcium concentration and 
electrocardiographic monitoring if necessary. 
Simultaneous treatment with ion exchange resin such as cholestyramine, colestipol hydrochloride, 
orlistat or laxative such as paraffin oil may reduce the gastrointestinal absorption of Vitamin D3. 
The cytotoxic agent actinomycin and imidazole antifungal agents interfere with Vitamin D3 
activity by inhibiting the conversion of 25-hydroxyVitamin D3 to 1,25- dihydroxyVitamin D3 by 
the kidney enzyme, 25-hydroxyVitamin D3-1-hydroxylase. 
4.6  
Fertility, pregnancy and lactation 
In pregnancy and lactation the high strength formulation is not recommended and a low strength 
formulation should be used. 
Pregnancy 
There are no or limited amount of data from the use of colecalciferol in pregnant women. Studies 
in animals have shown reproductive toxicity (see section 5.3 Preclinical safety data). The 
recommended daily intake for pregnant women is 400 IU, however, in women who are 
considered to be Vitamin D3 deficient a higher dose may be required (up to 2000 IU/day- 10 
drops with the oral drops presentation). 
During pregnancy women should follow the advice of their medical practitioner as their 
requirements may vary depending on the severity of their disease and their response to treatment 
Vitamin D3 and its metabolites are excreted in breast milk. 
Breast-feeding 
Vitamin D3 can be prescribed while the patient is breast-feeding if necessary. This 
supplementation does not replace the administration of Vitamin D3 in the neonate 
Fertility 
There is no data regarding treatment with vitaminD3 and its effects on fertility. 
4.7  
Effects on ability to drive and use machines 
There are no data on the effects of InVita D3 on the ability to drive. However, an effect on this 
ability is unlikely. 
4.8  
Undesirable effects 
Adverse reactions are listed below, by system organ class and frequency. Frequencies are defined 
as: uncommon (>1/1,000, <1/100) or rare (>1/10,000, <1/1,000). 


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Metabolism and nutrition disorders   
Uncommon: Hypercalcaemia and hypercalciuria  
Skin and subcutaneous disorders: 
Rare: pruritus, rash, and urticaria. 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorization of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme 
Website: www.mhra.gov.uk/yellowcard. 
4.9  
Overdose 
Symptoms of overdose 
Ergocalciferol (vitamin D2) and colecalciferol (vitamin D3) have a relatively low therapeutic 
index. The threshold for vitamin D intoxication is between 40,000 and 100,000 IU daily for 1 to 2 
months in adults with normal parathyroid function. Infants and small children may react 
sensitively to far lower concentrations. Therefore, it is warned against intake of vitamin D 
without medical supervision. 
Overdose leads to increased serum and urinary phosphorus levels, as well as hypercalcaemic 
syndrome and consequently calcium deposits in the tissues and above all in the kidneys 
(nephrolithiasis, nephrocalcinosis) and the vessels. 
Discontinue InVita D3 when calcaemia exceeds 10.6 mg/dl (2.65 mmol/l) or if the calciuria 
exceeds 300 mg/24 hours in adults or 4-6 mg/kg/day in children. 
Chronic overdosage may lead to vascular and organ calcification, as a result of hypercalcaemia. 
The symptoms of intoxication are little characteristic and manifest as nausea, vomiting, initially 
also diarrhoea, later constipation, loss of appetite, weariness, headache, muscle pain, joint pain, 
muscle weakness, persistent sleepiness, azotaemia, polydipsia and polyuria and, in the final stage, 
dehydration. Typical biochemical findings include hypercalcaemia, hypercalciuria, as well as 
increased serum 25 hydroxy colecalciferol concentrations. 
Treatment of overdose 
Symptoms of chronic vitamin D overdosage may require forced diuresis as well as administration 
of glucocorticoids or calcitonin. 
Overdosage requires measures for treating the - often persisting and under certain circumstances 
life- threatening - hypercalcaemia. 
The first measure is to discontinue the vitamin D preparation; it takes several weeks to normalise 
hypercalcaemia caused by vitamin D intoxication. 
Depending on the degree of hypercalcaemia, measures include a diet that is low in calcium or free 
of calcium, abundant liquid intake, increase of urinary excretion by means of the drug 
furosemide, as well as the administration of glucocorticoids and calcitonin. 
If kidney function is adequate, calcium levels can be reliably lowered by infusions of isotonic 
sodium chloride solution (3–6 liters in 24 hours) with addition of furosemide and, in some 
circumstances, also 15 mg/kg body weight/hour sodium edetate accompanied by continuous 
calcium and ECG monitoring. In oligoanuria, in contrast, haemodialysis (calcium-free dialysate) 
is necessary. 
No special antidote exists. 


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It is recommended to point out the symptoms of potential overdose to patients under chronic 
therapy with higher doses of vitamin D (nausea, vomiting, initially also diarrhoea, later 
constipation, anorexia, weariness, headache, muscle pain, joint pain, muscle weakness, persistent 
sleepiness, azotaemia, polydipsia and polyuria). 
5  
PHARMACOLOGICAL PROPERTIES 
5.1  
5.2  
Pharmacokinetic properties 
The pharmacokinetics of Vitamin D3 is well known.  
Absorption 
Vitamin D3 is well absorbed from the gastro-intestinal tract in the presence of bile, so the 
administration with the major meal of the day might therefore facilitate the absorption of Vitamin 
D3. 
Distribution and biotransformation 
It is hydroxylated in the liver to form 25-hydroxy-cholecalciferol and then undergoes further 
hydroxylation in the kidney to form the active metabolite 1, 25-dihydroxy- cholecalciferol 
(calcitriol). 
Elimination 
The metabolites circulate in the blood bound to a specific α – globin, Vitamin D3 and its 
metabolites are excreted mainly in the bile and faeces. 
Characteristics in Specific Groups of Subjects or Patients 
A 57% lower metabolic clearance rate is reported in subjects with renal impairment as compared 
with that of healthy volunteers. 
Decreased absorption and increased elimination of Vitamin D3 occurs in subjects with 
malabsorption. 
Obese subjects are less able to maintain Vitamin D3 levels with sun exposure, and are likely to 
require larger oral doses of Vitamin D3 to replace deficits. 
5.3  
Preclinical safety data 
Pre-clinical studies conducted in various animal species have demonstrated that toxic effects occur 
in animals at doses much higher than those required for therapeutic use in humans. 
In toxicity studies at repeated doses, the effects most commonly reported were increased calciuria 
and decreased phosphaturia and proteinuria. Hypercalcaemia has been reported in high doses. In a 
state of prolonged hypercalcaemia, histological alterations (calcification) were more frequently 
borne by the kidneys, heart, aorta, testes, thymus and intestinal mucosa. 
Colecalciferol has been shown to be teratogenic at high doses in animals. 
At doses equivalent to those used therapeutically, colecalciferol has no teratogenic activity. 
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Colecalciferol has no potential mutagenic or carcinogenic activity. 
6  
PHARMACEUTICAL PARTICULARS 
6.1  
List of excipients 
all-rac-α-tocopherol (E307) 
Medium Chain Triglycerides  
Glycerol 
Gelatine 
Allura Red AC (E129)  
Opacode® White imprinting ink 
Shellac (E904) 
Titanium dioxide (E171) 
Simethicone 
6.2  
Incompatibilities 
Not applicable 
6.3  
Shelf life 
24 months 
6.4  
Special precautions for storage 
Do not store above 30°C. 
Store in the original package in order to protect from light. 
6.5  
Nature and contents of container 
3 capsules packed in PVDC/Aluminium foil blisters, inserted into a cardboard carton. 
6.6  
Special precautions for disposal 
Any unused product should be disposed of in accordance with the local requirements. 
 7  
MARKETING AUTHORISATION HOLDER 
Consilient Health Limited,  
5th Floor, Beaux Lane House,  
Mercer Street Lower, 
Dublin 2,  
Ireland 
8  
MARKETING AUTHORISATION NUMBER(S) 
PL 24837/0074 
9 
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
21/07/2016 
10  
DATE OF REVISION OF THE TEXT 
21/07/2016 
 


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APPENDIX 4  LOW DOSE CHOLECALCIFEROL CAPSULES (InVita D3 
800 IU)  
SUMMARY OF PRODUCT CHARACTERISTICS 
1. 
Name of the medicinal product 
InVita D3 800 IU soft capsules 
2. 
Qualitative and quantitative composition 
Each capsule contains colecalciferol (vitamin D3) 800 IU (equivalent to 0.02 mg vitamin D3).  
Excipients with known effect: 
Each capsule contains 0.01 mg Allura Red AC (E129).  
For the full list of excipients, see section 6.1. 
3. 
Pharmaceutical form 
Soft capsule 
Pink, oval-shaped, soft capsule. It contains a slightly yellow oily liquid. Each capsule has “0.8” 
printed in white ink. Capsule dimensions are 10.5mm x 7mm. 
4. 
Clinical particulars 
4.1  
Therapeutic indications 
Prophylaxis and treatment of vitamin D deficiency in adults and adolescents with an identified 
risk. 
In addition to specific osteoporosis treatment of patients who are at risk of vitamin D deficiency, 
preferably in combination with calcium. 
4.2  
Posology and method of administration 
Posology  
Recommended dose: One capsule per day. 
Higher doses can be necessary in treatment of vitamin D deficiency, where the dose should be 
adjusted dependent upon desirable serum levels of 25-hydroxycolecalciferol (25(OH)D), the 
severity of the disease and the patient´s response to treatment.  
The daily dose should not exceed 4,000 IU (5 capsules per day). 
Dosage in hepatic impairment  
No dose adjustment is required. 
Dosage in renal impairment  
InVita D3 should not be used in patients with severe renal impairment (see section 4.3).  
Paediatric population  
InVita D3 is not recommended in children under 12 years of age 
Method of administration  
The capsules should be swallowed whole with water. 
4.3  
Contraindications 
• Diseases and/or conditions resulting in hypercalcaemia or hypercalciuria. 
• Nephrolithiasis. 
• Nephrocalcinosis 
• Hypervitaminosis D. 


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• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
4.4  
Special warnings and precautions for use 
InVita D3 should be prescribed with caution to patients suffering from sarcoidosis due to risk of 
increased metabolism of vitamin D into its active form. These patients should be monitored with 
regard to the calcium content in serum and urine. 
During long-term treatment, serum calcium levels should be followed and renal function should 
be monitored through measurements of serum creatinine. Monitoring is especially important in 
elderly patients on concomitant treatment with cardiac glycosides or diuretics (see section 4.5) 
and in patients with a high tendency to calculus formation. In case of hypercalciuria (exceeding 
300 mg (7.5 mmol)/24 hours) or signs of impaired renal function the dose should be reduced or 
the treatment discontinued. 
InVita D3 should be used with caution in patients with impairment of renal function and the 
effect on calcium and phosphate levels should be monitored. The risk of soft tissue calcification 
should be taken into account. In patients with severe renal insufficiency, vitamin D in the form of 
cholecalciferol is not metabolised normally and other forms of vitamin D should be used.  
The content of vitamin D (800 IU) in InVita D3 should be considered when prescribing other 
medicinal products containing vitamin D. Additional doses of vitamin D should be taken under 
close medical supervision. In such cases it is necessary to monitor serum calcium levels and 
urinary calcium excretion frequently. 
4.5  
Interaction with other medicinal products and other forms of interaction 
Thiazide diuretics reduce the urinary excretion of calcium. Due to the increased risk of 
hypercalcaemia, serum calcium should be regularly monitored during concomitant use of thiazide 
diuretics. 
Concomitant use of phenytoin or barbiturates may reduce the effect of vitamin D since the 
metabolism increases. 
Excessive dosing of vitamin D can induce hypercalcaemia, which may increase the risk of 
digitalis toxicity and serious arrhythimias due to the additive inotropic effects. The 
electrocardiogram (ECG) and serum calcium levels of patients should be closely monitored. 
Glucocorticoid steroids may increase vitamin D metabolism and elimination. During concomitant 
use, it may be necessary to increase the dose of InVita D3 tablets. 
Simultaneous treatment with ion exchange resins such as cholestyramine or laxatives such as 
paraffin oil may reduce the gastrointestinal absorption of vitamin D. Orlistat may potentially 
impair the absorption of colecalciferol as it is fat-soluble. 
The cytotoxic agent actinomycin and imidazole antifungal agents interfere with vitamin D 
activity by inhibiting the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by the 
kidney enzyme, 25-hydroxyvitamin D-1-hydroxylase. 
4.6  
Fertility, pregnancy and lactation 
Pregnancy  
Vitamin D deficiency is harmful for mother and child. There are no signals that recommended 
doses of vitamin D3 are harmful for the embryo/fetus. High doses of vitamin D have been shown 
to have teratogenic effects in animal experiments. Overdose of vitamin D must be avoided during 
pregnancy, as prolonged hypercalcaemia can lead to physical and mental retardation, 
supravalvular aortic stenosis and retinopathy of the child.  
InVita D3 can be used up to 2,000 IU/day only in case of a Vitamin D deficiency.  


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InVita D3 is not recommended during pregnancy in patients without a vitamin D deficiency as 
the daily intake should not exceed 600 IU vitamin D. 
Breast-feeding  
Vitamin D3 and metabolites pass into the breast-milk. No adverse events have been observed in 
infants. InVita D3 can be used at recommended doses during lactation in case of a vitamin D 
deficiency. 
Fertility  
Normal endogenous levels of vitamin D are not expected to have any adverse effects on fertility. 
4.7  
Effects on ability to drive and use machines 
There are no data about the effect of this product on driving capacity. An effect is, however, 
unlikely. 
4.8  
Undesirable effects 
Adverse reactions frequencies are defined as: uncommon ≥ 1/1,000, < 1/100), rare ≥1/10,000, 
<1/1,000) or not known (cannot be estimated from the available data 
Immune system disorders  
Not known (cannot be estimated from the available data): Hypersensitivity reactions such as 
angio-oedema or laryngeal oedema. 
Metabolism and nutrition disorders  
Uncommon: Hypercalcaemia and hypercalciuria. 
Skin and subcutaneous disorders  
Rare: Pruritus, rash and urticaria. 
Reporting of suspected adverse reactions  
Reporting suspected adverse reactions after authorization of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme 
Website: www.mhra.gov.uk/yellowcard 
4.9  
Overdose 
Overdose can lead to hyper-vitaminosis D. An excess of vitamin D causes abnormally high levels 
of calcium in the blood, which can eventually severely damage the soft tissues, and kidneys. 
Tolerable Upper Intake Level for vitamin D3 (colecalciferol) is set at 4000 IU (100 µg) per day. 
Vitamin D3 should not be confused with its active metabolites. colecalciferol 
Symptoms of hypercalcaemia may include anorexia, thirst, nausea, vomiting, constipation, 
abdominal pain, muscle weakness, fatigue, mental disturbances, polydipsia, polyuria, bone pain, 
nephrocalcinosis, renal calculi and in severe cases, cardiac arrhythmias. Extreme hypercalcaemia 
may result in coma and death. 
Persistently high calcium levels may lead to irreversible renal damage and soft tissue 
calcification. 
Treatment of hypercalcaemia: The treatment with vitamin D must be discontinued. Treatment 
with thiazide diuretics, lithium, vitamin A, and cardiac glycosides must also be discontinued. 
Rehydration, and, according to severity, isolated or combined treatment with loop diuretics, 
bisphosphonates, calcitonin and corticosteroids should be considered. Serum electrolytes, renal 
function and diuresis must be monitored. In severe cases, ECG and CVP should be followed. 
 


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5.  
Pharmacological properties 
5.1  
5.2  
Pharmacokinetic properties 
Vitamin D  
Sun exposure: UVB light converts 7-dehydrocholesterol, found in the skin, to colecalciferol. 
Absorption: Vitamin D is easily absorbed in the small intestine. Food intake potentially increases 
the absorption of vitamin D. 
Distribution and biotransformation: Colecalciferol and its metabolites circulate in the blood 
bound to a specific globulin. Colecalciferol is converted in the liver by hydroxylation to 25-
hydroxycholecalciferol. It is then further converted in the kidneys to 1,25- 
dihydroxycholecalciferol. 1,25-dihydroxycholecalciferol is the active metabolite responsible for 
increasing calcium absorption. Vitamin D, which is not metabolised, is stored in adipose and 
muscle tissues. 
After a single oral dose of colecalciferol, the maximum serum concentrations of the primary 
storage form are reached after approximately 7 days. 25(OH)D3 is then slowly eliminated with an 
apparent half-life in serum of about 50 days. Colecalciferol and its metabolites are excreted 
mainly in the bile and faeces. 
Elimination: Vitamin D is excreted mainly in bile and faeces with a small percentage found in 
urine. 
5.3  
Preclinical safety data 
At doses far higher than the human therapeutic range teratogenicity has been observed in animal 
studies. No other relevant data is available that has not been mentioned elsewhere in the SmPC 
(see section 4.6 and 4.9). 
6.   
Pharmaceutical particulars 
6.1  
List of excipients 
Capsule fill  
all-rac-α-tocopherol (E307) 
Medium Chain Triglycerides 
Capsule shell  
Glycerol 
Gelatine 
Medium Chain Triglycerides 
Allura Red AC (E129)  
Printing ink  
Shellac (E904)  
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Titanium dioxide (E171) 
Simethicone 
6.2  
Incompatibilities 
Not applicable. 
6.3  
Shelf life 
2 years 
6.4  
Special precautions for storage 
Do not store above 30°C. 
Keep the blister(s) in the outer carton to protect from light. 
6.5  
Nature and contents of container 
28 or 90 capsules packed in PVDC/Aluminium foil blisters, inserted into a cardboard carton. 
Not all pack sizes may be marketed. 
6.6  
Special precautions for disposal and other handling 
No special requirements. 
7.   
Marketing authorisation holder 
Consilient Health Limited, 
5th Floor, Beaux Lane House, 
Mercer Street Lower, 
Dublin 2, 
Ireland 
8.   
Marketing authorisation number(s) 
PL 24837/0070 
9.   
Date of first authorisation/renewal of the authorisation 
18/03/2016 
10.  
Date of revision of the text 
23rd December 2016 
 
 
 


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APPENDIX 5  INVESTIGATOR’S SIGNATURE 
Study Title: 
An Open-label, Repeated-Dose Safety, Efficacy, Pharmacokinetic 
and Pharmacodynamic Study of Oral CTAP101 Capsules, 
Immediate-release (IR) Calcifediol, High-Dose Cholecalciferol, and 
Paricalcitol Plus Low-Dose Cholecalciferol in Patients with 
Secondary Hyperparathyroidism, Stage 3 or 4 Chronic Kidney 
Disease and Vitamin D Insufficiency 
Study Number: 
CTAP101-CL-4001 
Final Date: 
16 August 2019 
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/IEC/REB, 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 drug, as described in this protocol, 
and any other information provided by the sponsor including, but not limited to, the following: the current 
Investigator’s Brochure (IB) or equivalent document provided by 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 drug 
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-4001 Protocol v11.0
Signature Page for RIM-CLIN-000570 v11.0
Approval
Medical
19-Aug-2019 16:50:36 GMT+0000
Approval
19-Aug-2019 17:45:42 GMT+0000
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SAP_001.pdf: 
 
 
 
 
 
CLINICAL STUDY PROTOCOL: CTAP101-CL-4001 
 
An Open-Label, Repeated-Dose Safety, Efficacy, Pharmacokinetic, 
and Pharmacodynamic Study of Oral CTAP101 Capsules, 
Immediate-Release (IR) Calcifediol, High-Dose Cholecalciferol, and 
Paricalcitol Plus Low-Dose Cholecalciferol in Patients with Secondary 
Hyperparathyroidism, Stage 3 or 4 Chronic Kidney Disease and 
Vitamin D Insufficiency 
 
 
Statistical Analysis Plan 
 
 
 
Version 1.0: 19 December 2018 
 
 
 
 
 
CONFIDENTIAL AND PROPRIETARY INFORMATION 
 
This statistical analysis plan is the confidential information of OPKO Ireland Global Holdings Ltd. and 
Spaulding Clinical Research, LLC and is intended solely for the guidance of the clinical investigation. This 
statistical analysis plan 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 
LIST OF ABBREVIATIONS ..............................................................................................4 
1 
Introduction ...................................................................................................................6 
2 
Objectives and Parameters ............................................................................................7 
2.1 Objectives ............................................................................................................7 
2.2 Endpoints .............................................................................................................7 
2.2.1 Efficacy Endpoints ..................................................................................7 
2.2.2 Pharmacokinetic Endpoints .....................................................................7 
2.2.4 Safety Endpoints......................................................................................9 
3 
Study Design ...............................................................................................................10 
3.1 Number of Subjects ...........................................................................................10 
3.2 Sample Size Considerations ..............................................................................10 
3.3 Study Design .....................................................................................................10 
4 
General Statistical Considerations ..............................................................................15 
5 
Analysis Populations ...................................................................................................16 
5.1 Intent-to-Treat Population .................................................................................16 
5.2 Per-Protocol Population ....................................................................................16 
5.3 Safety Population ..............................................................................................16 
5.4 Pharmacokinetic Population ..............................................................................16 
5.5 Handling of Missing Data .................................................................................16 
5.6 Key Definitions .................................................................................................17 
6 
Subject Disposition and Baseline Characteristics .......................................................18 
6.1 Subject Discontinuation ....................................................................................18 
6.2 Protocol Deviations ...........................................................................................18 
6.3 Demographics and Baseline Characteristics .....................................................18 
6.4 Medical History .................................................................................................18 
6.5 Inclusion and Exclusion Criteria .......................................................................18 
6.6 Substance Use....................................................................................................18 
7 
Pharmacokinetic Analyses ..........................................................................................19 
7.1 Serum and Plasma Concentrations ....................................................................19 
7.2 Serum and Plasma Pharmacokinetic Parameters ...............................................19 
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9 
Safety Analysis ............................................................................................................27 
9.1 Adverse Events ..................................................................................................27 
9.2 Clinical Laboratory Evaluations (Hematology and Serum Chemistry) ............28 
9.3 Hypercalcemia and Hyperphosphatemia ...........................................................28 
9.4 Vital Signs .........................................................................................................28 
9.5 Concomitant Medications..................................................................................28 
9.6 Extent of Exposure ............................................................................................29 
9.7 Dosing Compliance ...........................................................................................29 
9.8 Ancillary Data ...................................................................................................29 
9.9 Other Safety Assessments .................................................................................29 
10 References ...................................................................................................................30 
APPENDIX A: LIST OF TABLES, LISTINGS, AND FIGURES ...................................31 
 


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LIST OF ABBREVIATIONS 
λz 
terminal elimination rate constant 
1,25D3 
1,25-dihydroxyvitamin D3, calcitriol 
24,25D3 
24,25-dihydroxyvitamin D3 
25D 
25-hydroxyvitamin D 
25D3 
25-hydroxyvitamin D3, calcifediol, calcidiol 
AE 
adverse event 
Ae0-24h 
amount excreted in urine over 24 hours 
AUC 
area under the concentration curve 
AUC0-24h 
AUC from time 0 to 24 hours 
AUC0-28d 
AUC from time 0 to 28 days 
AUC0-56d 
AUC over the entire study period (56 days) 
AUC0-inf 
AUC from time 0 extrapolated to infinity 
AUC0-t 
AUC from time 0 to the last measurable time point 
AUC0-t’ 
AUC from time 0 to a fixed time point t 
AUCext 
percentage of AUC0-inf obtained by extrapolation 
AUCtau 
AUC during the dosing interval (tau) 
BL 
baseline 
BLQ 
below the limit of quantitation  
BMI 
body mass index 
Cavg 
average concentration over a dosing interval after multiple doses 
Cavg,24h 
Cavg over the 24-hour dosing interval 
Cavg,28d 
Cavg over the 28-day dosing interval 
Cavg,56d 
Cavg over the entire study period (56 days) 
CKD 
chronic kidney disease 
Clast 
last measurable concentration 
CL/F 
apparent clearance after extravascular administration 
CLss/F 
apparent clearance after multiple extravascular administrations 
Cmax 
maximum concentration 
Cmax,0-24h 
maximum concentration during a 24-hour interval 
CV% 
percent coefficient of variation 
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dL 
deciliter 
EAP 
efficacy assessment period 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
ET 
early termination 
iPTH 
intact parathyroid hormone 
IR 
immediate release 
ITT 
intent-to-treat 
IU 
international unit 
LF 
linearity factor 
ln 
natural log 
MedDRA 
Medical Dictionary for Regulatory Activities 
mcg 
microgram 
mg 
milligram 
mL 
milliliter 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PP 
per protocol 
PT 
preferred term 
R2-adj 
adjusted coefficient of determination 
RA,AUC 
accumulation ratio based on AUC 
RA,Cmax 
accumulation ratio based on Cmax 
SAP 
statistical analysis plan 
SD 
standard deviation 
SHPT 
secondary hyperparathyroidism 
SOC 
system organ class 
t1/2 
terminal elimination half-life 
TEAE 
treatment-emergent AE 
Tmax 
time of maximum concentration 
Tmax,0-24h 
time of maximum concentration during a 24-hour interval 
Tss 
predicted time to steady state 
Vd/F 
apparent volume of distribution after extravascular administration 
VDI 
vitamin D insufficiency 
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1 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentation to be used for the analysis and summarization of pharmacokinetic (PK), 
 and safety data from Protocol CTAP101-CL-4001.  
 
The SAP will be finalized before database lock. Any changes made after finalization of 
the SAP will be documented, by either an amendment or addendum if prior to database 
lock; otherwise, changes made to the planned analyses after database lock will be 
documented in the clinical study report as post hoc analyses and any updates to the shell 
document will be made with changes documented in the revision history of that 
document. Related documents are the study protocol, study drug dispensing, protocol 
deviations, informed consent form, and electronic case report forms.  
 
 
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2 
OBJECTIVES AND PARAMETERS 
2.1 
Objectives 
The objectives of this study are to assess the repeated-dose safety, efficacy, PK, 
 
profiles of CTAP101 Capsules, immediate-release (IR) calcifediol, high-dose 
cholecalciferol, and paricalcitol plus low-dose cholecalciferol in patients with secondary 
hyperparathyroidism (SHPT), stage 3 or 4 chronic kidney disease (CKD), and vitamin D 
insufficiency (VDI). 
2.2 
Endpoints 
2.2.1 
Efficacy Endpoints 
This study is descriptive and no primary or secondary efficacy endpoints are defined.  
2.2.2 
Pharmacokinetic Endpoints 
The following PK parameters will be calculated for observed and baseline (BL)-adjusted 
serum calcifediol (also known as 25-hydroxyvitamin D3 [25D3]) 
 
concentrations using noncompartmental methods (data permitting), where additional 
parameters may be evaluated based on the concentration-time data: 
1. Cmax – maximum concentration (including Cmax during a 24-hour interval 
[Cmax,0-24h]); 
2. Tmax – time of maximum concentration (including Tmax during a 24-hour interval 
[Tmax,0-24h]); 
3. AUC0-t – area under the concentration-time curve (AUC) from time 0 to the last 
measurable time point; 
4. AUC0-t’ – AUC from time 0 to a fixed time point t. This will include the AUC 
from time 0 to 24 hours (AUC0-24h) for all dosing regimens and AUC from time 0 
to 28 days (AUC0-28d) for the monthly dosing regimens only; 
5. AUC0-56d – AUC over the entire study period (56 days); 
6. AUCtau – AUC during the dosing interval (tau), where tau = 24 hours for the daily 
dosing regimens and tau = 28 days for the monthly dosing regimens. AUCtau will 
only be calculated for the monthly dosing regimens if deemed appropriate; 
7. AUC0-inf – AUC from time 0 extrapolated to infinity (paricalcitol only); 
8. AUCext – percentage of AUC0-inf obtained by extrapolation (a diagnostic 
parameter calculated and listed in the data listing, but not included in the 
descriptive statistics) (paricalcitol only); 
9. Cavg – average concentration over a dosing interval after multiple doses. For the 
monthly dosing regimens, average exposure may be calculated over a 24-hour 
interval (Cavg,24h = AUC0-24h/24 hours), the entire dosing interval 
(Cavg,28d = AUC0-28d/28 days), and/or over the entire study period 
Cavg,56d = AUC0-56d/56 days); 
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10. Tss – predicted time to steady state (paricalcitol only); 
11. λz – terminal elimination rate constant (paricalcitol only); 
12. t1/2 –terminal elimination half-life (paricalcitol only); 
13. CL/F – apparent clearance after extravascular administration (paricalcitol only); 
14. CLss/F – apparent clearance after multiple extravascular administrations; 
15. Vd/F – apparent volume of distribution after extravascular administration 
(paricalcitol only); 
16. RA,Cmax – accumulation ratio based on Cmax; 
17. RA,AUC – accumulation ratio based on AUC; 
18. LF – linearity factor (paricalcitol only). 
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2.2.4 
Safety Endpoints 
The safety and tolerability of each study drug will be evaluated using the following 
parameters: 
1. Adverse events (AEs); 
2. Physical examinations; 
3. Vital signs; 
4. Clinical laboratory test results (hematology and serum chemistry); 
5. Incidence of hypercalcemia and drug-related hyperphosphatemia. 
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3 
STUDY DESIGN 
3.1 
Number of Subjects 
Approximately 160 subjects will be screened to enroll approximately 80 eligible subjects 
with approximately 20 subjects per treatment arm. After signing the informed consent 
form, prior to any study-related activities, each subject will be assigned a unique 7-digit 
subject identification number (SSSNNNN) which will be retained throughout the study 
and that will be unique across all sites. The number will consist of a 3-digit site number 
(SSS), followed by a 4-digit subject number (NNNN) at the applicable clinical site. 
Should a subject be withdrawn from the study, that subject’s number will not be 
reassigned. 
Randomization will be accomplished in blocks of 4 subjects in a 1:1:1:1 ratio, with 
subjects assigned to treatment with either CTAP101 Capsules, IR calcifediol, high-dose 
cholecalciferol, or paricalcitol plus low-dose cholecalciferol. Randomization will occur 
on Day 1 (Visit 4) provided that each subject is deemed eligible for enrollment based, in 
part, on laboratory assessments obtained at screening (Days –42 to –36, Visit 1). 
Laboratory assessments obtained at Days –7 to –1 (Visits 2-3) will not be considered in 
the determination of enrollment eligibility. 
3.2 
Sample Size Considerations 
The total sample size of approximately 80 subjects was based on practical, clinical 
considerations and is typical for such studies. No formal sample size estimation was 
performed.   
3.3 
Study Design 
This is a phase 4, single- or multi-center, open-label study to evaluate the comparative 
safety, efficacy, and PK and 
 profiles of CTAP101 Capsules, IR calcifediol, high-dose 
cholecalciferol, and paricalcitol plus low-dose cholecalciferol 
 in male and 
female subjects at least 18 years of age with stage 3 or 4 CKD and VDI. The study will 
be conducted at up to 3 sites within the United States. Subjects (approximately 20 per 
arm) will receive the following treatments: 
1) CTAP101 Capsules (30 mcg/capsule), 60 mcg by the oral route, once daily for 
56 days; 
2) Calcifediol IR (266 mcg/capsule), 266 mcg by the oral route, on Days 1 and 29; 
3) Cholecalciferol (50,000 IU/capsule), 300,000 International Units (IU) by the oral 
route (6 capsules), on Days 1 and 29; and, 
4) Paricalcitol (1 mcg/capsule) plus cholecalciferol (800 IU/capsule), 1 or 2 mcg 
plus 800 IU by the oral route, once daily for 56 days. 
After 4 weeks of treatment, subjects who are receiving paricalcitol will double the dose to 
2 mcg plus cholecalciferol 800 IU once daily in the morning before breakfast if all of the 
following conditions are met: the plasma iPTH has not decreased by at least 30% from 
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pretreatment BL and remains above 70 pg/mL, corrected serum total calcium is 
<9.8 mg/dL, and serum phosphorus is <5.5 mg/dL. Subjects who are receiving CTAP101 
Capsules, IR calcifediol, or cholecalciferol (300,000 IU) will not undergo upward dose 
titration. 
Subjects will reduce the dose of study drug per the following schedule if any of the 
following conditions are met: plasma iPTH is confirmed to be <30 pg/mL, corrected 
serum total calcium is confirmed to be >10.3 mg/dL, or serum phosphorus is confirmed 
to be >5.5 mg/dL. 
Dose reduction (if needed): 
CTAP101: decrease to 30 mcg per day (from 60 mcg per day) 
IR calcifediol: hold Day 29 dose 
Cholecalciferol 300,000 IU: hold Day 29 dose 
Paricalcitol: decrease dose to 1 mcg per day (from 2 mcg per day) 
Cholecalciferol 800 IU will not be adjusted 
Subjects will suspend dosing if plasma iPTH is confirmed to be <15 pg/mL or corrected 
serum total calcium is confirmed to be >11.0 mg/dL, and will resume dosing when 
plasma iPTH is ≥30 pg/mL and corrected serum total calcium is <9.8 mg/dL per the 
following schedule. In the event that a dose reduction is required for a subject receiving 
the minimum dosage of CTAP101 Capsules (30 mcg per day) or paricalcitol (1 mcg per 
day), the subject will suspend dosing and resume when iPTH is ≥30 pg/mL and corrected 
serum total calcium is <9.8 mg/dL at the same minimum dosage.   
Dose resumption (if needed): 
CTAP101: 30 mcg per day 
Paricalcitol 1 mcg per day 
The subjects will be housed in a phase 1 unit for approximately 14 to 26 hours at the 
beginning of the study and on study Day 29 to provide the blood samples required for a 
detailed determination of the PK profiles for serum calcifediol 
 
 
 
 
 
 
 Blood samples for some of the PK and 
 assessments will be 
collected in the phase 1 unit at –2, 0, 2, 4, 6, and 12 hours, either in the phase 1 unit or 
during an outpatient visit at 24 hours, during the outpatient visit at 48 hours, and then 
weekly following the first dose and the Day 29 dose of study drug. Blood samples for 
other 
 assessments will be collected at less frequent intervals. Urine collections (over 
24 hours) will be obtained at pretreatment BL (Visits 2 and 3), starting immediately after 
dosing on Day 1 (Visit 4) and Day 29 (Visit 10), and at the end of study (EOS) visit 
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(Visit 16) or at early termination (ET). The full schedule of assessments is provided in 
Table 1. 
Subjects receiving treatment with calcitriol or another 1α-hydroxylated vitamin D analog, 
or if serum total 25D >30 ng/mL when taking vitamin D supplementation (including 
multivitamins and fish oil), will complete a 4-week washout period before BL 
assessments. Subjects will forgo further dosing with these nonstudy drugs for the 
duration of the study. Subjects receiving calcimimetic therapy within the 12 weeks 
preceding Screening will be ineligible for enrollment. 
Blood samples will be collected from all subjects at weekly intervals during the screening 
and BL periods, during the 8-week treatment period, and at the specified times during the 
PK/
 assessment. Key parameters to be analyzed in the collected samples include some 
or all of the following: serum calcifediol, 
 
 
 serum 24,25D3, 
 
 
 
Vitals signs and AEs will be monitored at each study visit. Other safety parameters to be 
monitored less frequently include 
 
 brief physical examinations, and clinical laboratory tests 
(hematology and serum chemistry). The number and percentage of subjects with 
hypercalcemia (defined as 2 consecutive visits with serum total calcium >10.3 mg/dL) or 
hyperphosphatemia (defined as 2 consecutive visits with serum phosphorus >5.5 mg/dL) 
will be calculated as a secondary safety endpoint. 
Subjects will maintain a dietary intake during the study of approximately 1,000 to 
1,500 mg of elemental calcium per day with dietary counseling and, as necessary, 
administration of a daily calcium supplement.
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Table 1. Schedule of Assessments 
 
Screening 
Washout 
Baseline 
Treatment 
EOS/
ET 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 
1 
 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 12 13 14 15 
16 
Week 
–5 
 
–1 
–1 
1 
1 
1 
2 
3 
4 
5 
5 
5 
6 
7 
8 
9 
Day(s) 
–42 to –36 –35 to –8 –7 to –2 –1 
1 
2 
3 
8 
15 22 
29 
30 31 36 43 50 
57 
 
 
 
 
 
(GCRC) 
 
 
 
 
 
(GCRC) 
 
 
 
 
 
 
Hour(s) 
 
 
 
 
–2, 0, 2, 
4, 6, 12  
24 
48 
 
 
 
–2, 0, 2, 
4, 6, 12 
24 48 
 
 
 
 
Study drug dispensed 
 
 
 
 
1a,b 
 
 
 
 
 
1a,b 
 
 
 
 
 
 
Dosing compliance and dosing diary 
assessed 
 
 
 
 
 
 
 
1 
1 
1 
1 
 
 
1 
1 
1 
1 
Sign informed consent form 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review inclusion/exclusion criteria 
1 
 
1 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and demographics 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diet history and counseling for (as needed) 
calcium intake 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medications review 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications review 
1 
 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
Adverse events 
 
 
1 
1 
6 
1 
1 
1 
1 
1 
6 
1 
1 
1 
1 
1 
1 
Physical exam (including weight, height, 
and BMI) 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
Vital signs assessment 
1 
 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
Blood pregnancy test (for females of 
childbearing potential) 
1 
 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
Serum hepatitis B, hepatitis C, and HIV 
screen 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eGFR 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinary albumin excretion 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical chemistry (full panel) 
1 
 
1 
1 
 
 
 
 
 
 
1 
 
 
 
 
 
1 
Hematology 
1 
 
1 
1 
 
 
 
 
 
 
1 
 
 
 
 
 
1 
Clinical chemistry (partial panel)d 
 
 
 
 
6 
1 
1 
1 
1 
1 
6 
1 
1 
1 
1 
1 
 
Urine drugs of abuse screen 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Washout 
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Screening 
Washout 
Baseline 
Treatment 
EOS/
ET 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 
1 
 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 12 13 14 15 
16 
Week 
–5 
 
–1 
–1 
1 
1 
1 
2 
3 
4 
5 
5 
5 
6 
7 
8 
9 
Day(s) 
–42 to –36 –35 to –8 –7 to –2 –1 
1 
2 
3 
8 
15 22 
29 
30 31 36 43 50 
57 
 
 
 
 
 
(GCRC) 
 
 
 
 
 
(GCRC) 
 
 
 
 
 
 
Hour(s) 
 
 
 
 
–2, 0, 2, 
4, 6, 12  
24 
48 
 
 
 
–2, 0, 2, 
4, 6, 12 
24 48 
 
 
 
 
Abbreviations: 1,25D3, 1,25-dihydroxyvitamin D3; 24,25D3, 24,25-dihydroxyvitamin D3; 
, 25-hydroxyvitamin D; 25D3, calcifediol; BMI, body mass index; 
 
 eGFR, estimated glomerular 
filtration rate; EOS, end of study; ET, early termination; 
 GCRC, general clinical research center; HIV, human immunodeficiency virus; 
 
ionized calcium; iPTH, intact parathyroid hormone; 
 
NOTE: The number listed under each respective event reflects the number of occurrences for that specific type of event on the specific visit designations; absence of number 
designation indicates that no occurrence of such event is required. 
a Study drug dispensing for subjects assigned to CTAP101 Capsules and paricalcitol capsules plus low-dose cholecalciferol. 
b Study drug dispensed for t = 0 dose on Days 1 and 29 from monthly study drug supply. 
d Partial chemistry panel includes serum calcium, calcium (corrected), phosphorus, and albumin. 
 
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4 
GENERAL STATISTICAL CONSIDERATIONS 
All analyses described in this plan are considered a priori analyses in that they have been 
defined before locking the database. All other analyses, if any, designed subsequent to 
locking the database will be considered post hoc analyses and will be applied as 
exploratory methodology. All post hoc analyses will be identified as such in the clinical 
study report. 
All statistical tests will be tested at α = 0.05, 2-sided significance level, unless otherwise 
stated. Descriptive statistics for continuous variables will include number of subjects, 
mean, standard deviation (SD), median, minimum, and maximum, unless otherwise 
noted. In descriptive summary tables of PK 
 data, if needed, the geometric mean, 
geometric percent coefficient of variation (CV%), and arithmetic CV% will be included, 
where the geometric mean will be calculated using the exponential function (exp) of the 
mean of the natural log (ln)-transformed data, the geometric CV% will be calculated as 
[exp(SD2)-1]1/2 × 100, where SD is the standard devation for ln-transformed data, and the 
CV% will be calculated as 100×(SD/[arithmetic mean]). Descriptive statistics for 
categorical variables will consist of counts and percentages. 
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% and geometric 
CV% will be rounded to 1 decimal place. 
Denominators for percentage of subject calculations will be based on the number of 
subjects in the subgroup and selected population unless otherwise specified. 
All analyses will be conducted with SAS version 9.4 or later using procedures 
appropriate for the particular analysis. 
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5 
ANALYSIS POPULATIONS 
5.1 
Intent-to-Treat Population 
The intent-to-treat (ITT) population will include all subjects who are randomly assigned 
to treatment. If actual treatment differs from the randomized treatment, the randomized 
treatment will be used. 
5.2 
Per-Protocol Population 
 
 
 
 
 
 If actual treatment differs from the randomized treatment, 
additional analyses using the actual treatment may be provided. 
5.3 
Safety Population 
The safety population will include all subjects who are randomly assigned to treatment 
and receive at least 1 dose of study drug. The safety population will be used for all safety 
assessments. 
5.4 
Pharmacokinetic Population 
The PK population will include all subjects who are randomly assigned to treatment, 
receive at least 1 dose of study drug, have no major protocol deviations, have at least 
1 PK data point at BL, and sufficient measureable serum calcifediol or paricalcitrol 
concentrations to facilitate the calculation of at least 1 postdose PK parameter using 
validated methods. Presentation of data will use the actual treatment. In cases where a 
subject’s dosing compliance is found to be an issue, PK parameters may not be calculated 
for that subject.  
5.5 
Handling of Missing Data 
Missing data will not be imputed with the exception of incomplete medication start and 
stop dates and missing onset dates for AEs. Data that are excluded from the descriptive or 
inferential analyses will be included in the data listings. This will include those 
measurements from excluded subjects or measurements from unscheduled 
visits/collections. In calculation of the concentration summaries and displays in graphs, if 
values are below the limit of quantitation (BLQ) predose they will be set to zero and 
postdose they will be set to ‘missing’; however, they will be presented as BLQ in data 
listings. If all concentrations at a given time point predose are BLQ, the mean will be 
presented as zero and the SD and CV% will be reported as not applicable.  
For the calculation of PK parameters, BLQ values will be treated as follows: 
• BLQ values in samples collected before administration or before the first 
measurable concentration will be set to zero. 
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• BLQ values that occur after the first measurable concentration will be set to 
‘missing.’ 
• BLQ values that occur at the end of the concentration-time profile will be set to 
‘missing.’ 
If both values of the predose average (–2 and 0 hour samples) on Day 29 are missing or 
BLQ, the minimum concentration for the dosing interval will be used for the calculation 
of AUC and associated PK parameters, as deemed appropriate. For BL-adjusted profiles, 
the negative values will be retained for calculation of PK parameters. 
5.6 
Key Definitions 
In the event that there are multiple results at a given visit or time point, the following 
logic will be applied for purposes of summarization by visit or time point: 
Baseline value for safety endpoints is defined as the most recent nonmissing result before 
the time of the first dose for all treatments. Baseline value for PK 
 endpoints is 
defined as the average of all predose Day 1 samples excluding data collected on  
Days –42 to –36 (Visit 1).  
Predose value for the PK 
 endpoints in calculation of the PK 
 parameters is 
defined as the average of the –2 and 0 hour samples predose on Day 1 for calculations 
following the first dose (Day 1) and the average of the –2 and 0 hour samples predose on 
Day 29 for the calculations following the last dose (Day 29). 
Relative study day is defined as the number of days from the first dose date (Day 1) and 
will be presented in all data listings where a complete date is presented. Dates before the 
first dose date are decreased by 2 so there is no study Day 0, where the day before dosing 
is considered study Day –1. 
 
 
 
 
 
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6 
SUBJECT DISPOSITION AND BASELINE 
CHARACTERISTICS 
6.1 
Subject Discontinuation 
The number of subjects who enroll in the study and the number and percentage of 
subjects who complete treatment and complete the study will be presented by treatment 
and overall for all enrolled subjects. A summary of the number of subjects within each 
population, along with the frequency and percentage of subjects who withdraw or 
discontinue from the study and the primary reason for withdrawal or discontinuation, will 
be summarized for each treatment and overall. 
A data listing of subject disposition, including treatment and study completion status and 
reason for study discontinuation, will be provided. In addition, subject populations and 
reasons for exclusion from the population will be provided in a data listing. 
6.2 
Protocol Deviations 
Major protocol deviations will be captured as a log by the clinical research coordinator, 
exported into a clinical dataset, and presented in a data listing. 
6.3 
Demographics and Baseline Characteristics 
Descriptive statistics (ie, number of subjects, mean, SD, median, minimum, and 
maximum) will be calculated for continuous demographic and BL characteristic variables 
(age at Screening, weight at BL, height at Screening, and body mass index [BMI] at BL) 
and counts and percentages will be tabulated for categorical demographic variables (sex, 
race, and ethnicity) for each analysis population by treatment and overall. 
A data listing will be provided for all demographic data. In addition, the BL 
characteristics of weight, height, and BMI will be included in the vital sign data listing. 
6.4 
Medical History 
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 documented. Medical history data will be mapped using the Medical Dictionary 
for Regulatory Activities (MedDRA) Version 21.0 or higher to system organ class (SOC) 
and preferred term (PT) and will be listed by subject identification, medical condition 
reported term, onset date, and ongoing status/resolution date for all enrolled subjects and 
summarized by SOC and PT by treatment and overall for the safety population. 
6.5 
Inclusion and Exclusion Criteria 
Inclusion and exclusion criteria not met by randomized subjects will be provided in a data 
listing. 
6.6 
Substance Use 
Substance use history, including historical use of tobacco, nicotine, and alcohol, will be 
provided in a data listing by subject. 
 


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7 
PHARMACOKINETIC ANALYSES 
7.1 
Serum and Plasma Concentrations 
Blood samples will be collected from all subjects to determine the observed serum 
calcifediol 
 concentrations. Baseline-adjusted serum calcifediol 
concentrations will be calculated by subtracting the average of the BL concentrations. 
Negative BL-adjusted values will be retained in the analysis. 
For each analyte, observed and BL-adjusted serum calcifediol 
 
 concentrations will be summarized 
using descriptive statistics (number of subjects, mean, SD, CV%, median, minimum, 
maximum, geometric mean, and geometric CV%) by visit, time point, and treatment for 
the PK population. Concentrations that are BLQ will be treated as outlined in Section 5.5. 
Mean serum and plasma concentration-time profiles will be plotted by treatment on linear 
(both calcifediol and paricalcitol) and semilogarithmic scales (only paricalcitol) using 
nominal times for the PK population. Individual concentration-time plots and spaghetti 
plots with subject concentration-time profiles overlaid by treatments will be included in 
the appendices using linear (both calcifediol and paricalcitol) and semilogarithmic scales 
(only paricalcitol).  
Subgroups will also be presented for subjects who received the full dose of study drug 
versus those who received dose adjustments (ie, summaries provided for paricalcitol 
1 mcg and 2 mcg on Day 29, where further categorization will be determined once the 
study is complete). 
7.2 
Serum and Plasma Pharmacokinetic Parameters 
All PK analyses will be performed, as feasible, according to applicable standard 
operating procedures and protocol specifications. Pharmacokinetic parameters will be 
calculated using Phoenix® WinNonlin® Version 8.0 or later (Certara, Princeton, NJ, 
USA) and actual sampling times. If actual times are missing, nominal times may be used 
and will be noted in the appropriate data listing. 
The PK parameters for observed and BL-adjusted serum calcifediol 
 
 will be calculated as follows (data permitting): 
Pharmacokinetic Parameters Following the First Dose (Day 1): 
Note: The following parameters will be calculated using the data through 24 hours 
(once daily dosing regimens) or 28 days (monthly dosing regimens) after the first dose 
on Day 1 for each of the analytes, as indicated. 
Cmax: 
Maximum concentration, observed by inspection of individual study 
participant concentration-time profiles. 
Cmax,0-24h: 
Maximum concentration over a 24-hour interval, observed by inspection 
of individual study participant concentration-time profiles. Presented for 
the monthly dosing regimens only. (For the daily dosing regimens, Cmax 
will be equivalent to Cmax,0-24h.) 
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Tmax: 
Time of maximum concentration, obtained directly from the observed 
concentration-time data. 
Tmax,0-24h: 
Time of maximum concentration over a 24-hour interval, obtained 
directly from the observed concentration-time data. Presented for the 
monthly dosing regimens only. (For the daily dosing regimens, Tmax will 
be equivalent to Tmax,0-24h.) 
AUC0-t: 
AUC from time 0 to the last measurable time point, calculated by 
linear-log trapezoidal summation. 
AUC0-t’: 
AUC from time 0 to a fixed time point t, calculated by linear-log 
trapezoidal summation. This will include the AUC from time 0 to 
24 hours (AUC0-24h) for all dosing regimens and AUC from time 0 to 28 
days (AUC0-28d) for the monthly dosing regimens only.  
AUC0-inf: 
AUC from time 0 extrapolated to infinity, calculated as AUC0-t + Clast/λz, 
where Clast is the last measurable concentration (paricalcitol only).  
The reliability of AUC0-inf values is contingent upon the percentage 
obtained by extrapolation (AUCext), where AUCext is >40%, AUC0-inf 
values are considered unreliable. 
AUCext: 
Percentage of AUC0-inf obtained by extrapolation, calculated as 
[(AUC0-inf – AUC0-t)/AUC0-inf] × 100; (a diagnostic parameter calculated 
and listed in the data listing, but not included in the descriptive statistics; 
paricalcitol only). 
λz: 
Terminal elimination rate constant (if estimable), determined by linear 
regression of the terminal points of the log-linear concentration-time 
profile (paricalcitol only). 
Calculation of λz requires a minimum of 3 data points after (and not 
including) Cmax. The adjusted coefficient of determination (R2-adj) for the 
linear regression must be at least 0.80. 
t1/2: 
Terminal elimination half-life (if estimable), determined as [ln(2)/λz] 
(paricalcitol only). 
CL/F: 
Apparent clearance after extravascular administration, calculated as 
Dose/AUC0-inf (paricalcitol only). 
Vd/F: 
Apparent volume of distribution after extravascular administration, 
calculated as Dose/(λz × AUC0-inf) (paricalcitol only). 
Tss: 
Predicted time to steady state, calculated as (t1/2 × 5) (paricalcitol only). 
 


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Pharmacokinetic Parameters Following the Last Dose (Day 29): 
Note: The following parameters will be calculated using the data through 24 hours for 
the once daily dosing regimens or through the EOS/ET sample on Day 57 (ie, 28 days 
post Day 29 dose) for the monthly dosing regimens, where possible. 
Cmax: 
Maximum concentration during the dosing interval (24 hours for once 
daily and 28 days for monthly), observed by inspection of individual 
study participant concentration-time profiles. 
Cmax,0-24h: 
Maximum concentration over a 24-hour interval, observed by inspection 
of individual study participant concentration-time profiles. Presented for 
the monthly dosing regimens only. (For the daily dosing regimens, Cmax 
will be equivalent to Cmax,0-24h.) 
Tmax: 
Time of maximum concentration during the dosing interval (24 hours for 
once daily and 28 days for monthly), obtained directly from the observed 
concentration-time data. 
Tmax,0-24h: 
Time of maximum concentration over a 24-hour interval, obtained 
directly from the observed concentration-time data. Presented for the 
monthly dosing regimens only. (For the daily dosing regimens, Tmax will 
be equivalent to Tmax,0-24h.) 
AUC0-t: 
AUC from time 0 to the last measurable time point, calculated by 
linear-log trapezoidal summation. 
AUCtau: 
AUC during the dosing interval (tau), where tau = 24 hours for the daily 
dosing regimens and tau = 28 days for the monthly dosing regimens. 
AUC0-t’: 
AUC from time 0 to a fixed time point t, calculated by linear-log 
trapezoidal summation. This will include the AUC0-24h for the monthly 
dosing regimens (equivalent to AUCtau for the daily dosing regimens).  
Cavg: 
Average concentration over a dosing interval after multiple doses, 
calculated as AUCtau/tau. For the monthly dosing regimens, average 
exposure over a 24-hour interval (Cavg,24h = AUC0-24h/24 hours) and/or 
over the entire dosing interval (Cavg,28d = AUC0-28d/28 days). 
RA,Cmax 
Accumulation ratio based on Cmax, calculated as (Cmax, Day 29)/(Cmax, 
Day 1). 
RA,AUC 
Accumulation ratio based on AUC. For once daily dosing regimens, 
calculated as (AUCtau, Day 29)/(AUC0-24h, Day 1). For monthly dosing 
regimens, AUCs from 0 to 24 hours or 28 days may be used, as deemed 
appropriate. 
LF 
Linearity factor, calculated as (AUCtau, Day 29)/(AUC0-inf, Day 1) 
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λz: 
Terminal elimination rate constant (if estimable), determined by linear 
regression of the terminal points of the log-linear concentration-time 
profile (paricalcitol only). 
Calculation of λz requires a minimum of 3 data points after (and not 
including) Cmax. The R2-adj for the linear regression must be at least 0.80. 
t1/2: 
Terminal elimination half-life (if estimable), determined as [ln(2)/λz] 
(paricalcitol only). 
CLss/F: 
Apparent clearance after multiple extravascular administrations, 
calculated as Dose/AUCtau (calculated for paricalcitol and for BL-adjusted 
calcifediol following the calcifediol treatments only, where possible). 
In addition to the above parameters, measures of exposure over the entire 56-day study 
period will be determined for calcifediol (for the monthly dosing regimens only), 
according to the following calculations:  
• AUC0-56d: AUC over the entire study period (56 days), calculated as 
(AUC0-28d, Day 1) + (AUCtau, Day 29); 
• Cavg,56d: Average concentration over the entire study period (56 days), calculated 
as AUC0-56d/56 days. 
All subjects in the PK population will be included in the descriptive statistics for the PK 
parameters. No value for λz, AUC0-inf, AUCext, CL/F, Vd/F, Tss, or t1/2 will be reported for 
cases that do not exhibit a terminal log-linear phase in the concentration-time profile. No 
PK parameters will be calculated for subjects with insufficient data following BLQ 
imputation, see Section 5.5 (eg, fewer than 3 quantifiable postdose concentrations for 
AUC, λz, and associated parameters; Cmax and Tmax parameters may be presented for 
subjects with fewer quantifiable concentrations, if deemed appropriate). 
Descriptive statistics of PK parameters for calcifediol and paracalcitol will be provided 
for the PK population by visit and treatment and will include number of subjects, mean, 
SD, CV%, median, minimum, maximum, geometric mean and geometric CV%. 
Subgroups will also be presented for subjects who received the full dose of study drug 
versus those who received dose adjustments (ie, summaries provided for paricalcitol 
1 mcg and 2 mcg on Day 29, where categories will be determined once the study is 
complete). 
All calculated PK parameters will be presented in a data listing. 
7.3 
Statistical Analysis of Pharmacokinetic Parameters 
As an exploratory analysis, PK parameters for observed and BL-adjusted serum 
calcifediol will be compared between treatments using a mixed-effects model for the PK 
population. The dependent variable will be the value of the PK parameter. The model will 
include a term for treatment and BL calcifediol as a covariate. The PK parameters 


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compared may include Cmax and AUC0-24h for Day 1 and Cmax, AUC0-24h (ie, AUCtau for 
daily dosing regimen), and Cavg for Day 29. Additional parameters (eg, alternative 
AUC0-t’ parameters) may be compared (and/or substituted) as deemed appropriate.  
Treatment least-squares means and least-squares differences and 95% confidence 
intervals for the difference will be constructed for the values of each parameter. In 
addition, the P values will be presented for treatment and BL in the analysis table. 
The SAS Proc Mixed code is as follows:  
PROC MIXED DATA = adpc;  
  BY paramn paramcd param;  
  CLASS trtp;  
  MODEL aval = trtp base_calcifediol;  
  ESTIMATE ‘CTAP101 Capsules vs. Calcifediol IR' trtp 1 –1 0 0 / cl; 
  ESTIMATE ‘CTAP101 Capsules vs. Cholecalciferol' trtp 1 0 –1 0 / cl; 
  ESTIMATE ‘CTAP101 Capsules vs. Paracalcitol plus cholecalciferol' trtp 1 0 0 –1 / cl;  
RUN; 
Alternative statistical analyses may be provided if insufficient data or issues with the 
model are found.  
 


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9 
SAFETY ANALYSIS 
9.1 
Adverse Events 
Adverse events will be coded using MedDRA (Version 21.0 or higher). Each verbatim 
term will be mapped to a SOC and PT. Severity grades for safety parameters will be 
assigned using the Common Terminology Criteria for Adverse Events (Version 5.0). 
When changes in the severity of an AE occur more frequently than once a day, the 
maximum severity for the experience that day will be noted. 
Treatment-emergent AEs (TEAE) are events with onset dates and times on or after the 
administration of the first dose of study drug and within 30 days after the last dose of 
study drug, or a continuing AE diagnosed before the date of the first dose of study drug, 
which increases in frequency, severity, or character during the course of the study. 
An overall summary of TEAEs will be provided for the safety population summarizing 
subjects with at least 1: TEAE, related TEAE, grade 3, 4, or 5 TEAE, serious TEAE, 
related serious TEAE, TEAE leading to study discontinuation, or related TEAE leading 
to study discontinuation as well as the number of events within each of the previously 
mentioned categories by treatment. 
In addition, summaries of unique TEAEs will be presented for the safety population by 
SOC, PT, and by treatment and overall, and will include the number and percentage of 
subjects who experience the unique event for:   
1. All TEAEs, 
2. All TEAEs by relationship, 
3. All TEAEs by severity grade, 
4. All TEAEs leading to study discontinuation, 
5. All serious TEAEs, if more than 1 serious TEAE is recorded. 
Related TEAEs include all those classified by the investigator as possibly related or 
related. Unrelated TEAEs are those events classified as not related or unlikely related.  
For summaries by relationship, the most related event will be selected. For summaries by 
severity, the most severe grade will be selected.  
Multiple events will be counted only once per subject and treatment in each of the 
previously mentioned summaries by treatment and overall. In the presentation, SOC and 
PT will be sorted in alphabetical order.  
All AEs captured in the database will be presented in by-subject data listings; however, 
only TEAEs will be summarized. 
MedDRA version will be provided in a footnote in both tables and data listings.  


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9.2 
Clinical Laboratory Evaluations (Hematology and Serum 
Chemistry)  
Clinical laboratory evaluations of hematology and serum chemistry will be performed. 
Results and change from BL will be summarized by treatment and scheduled visit and 
time point for the safety population, using descriptive statistics for numeric parameters 
and using counts and percentages for categorical parameters. Baseline is defined as stated 
in Section 5.6. Values reported with a ‘<’ or ‘>’ sign will be converted to numeric values 
and summarized. 
Shifts from BL to values outside of the normal range will be presented for the safety 
population by parameter and summarized using the number and percentage of subjects 
with clinical laboratory test results below, within, and above normal ranges for numeric 
parameters, and normal or abnormal for categorical parameters, and will be tabulated by 
treatment and scheduled visit/time point. The denominators for calculating the 
percentages will be based on the number of subjects with nonmissing assessments for 
each parameter. 
Clinically significant laboratory values (as determined by the investigator) will be 
provided in a data listing including all values for a given parameter for subjects who had 
at least 1 postbaseline clinically significant value. 
All clinical laboratory data will also be presented in data listings in chronological order 
by date if unscheduled or repeated values.  
9.3 
Hypercalcemia and Hyperphosphatemia 
A summary will be provided for the safety population indicating the number and 
percentage of subjects with hypercalcemia (1 and 2 consecutive visits with serum 
corrected total calcium >10.3 mg/dL) or drug-related hyperphosphatemia (1 and 2 
consecutive visits with serum phosphorus >5.5 mg/dL) by treatment. 
9.4 
Vital Signs 
Descriptive statistics for vital sign measurements, obtained at BL and each scheduled 
postbaseline visit, will be summarized for the safety population by treatment. In addition, 
change from BL will be calculated, where BL is defined as stated in Section 5.6. If a 
parameter is repeated for a visit, the first value reported will be used in the summary.  
Vital sign measurements will also be presented in a data listing.   
9.5 
Concomitant Medications 
Prior and concomitant medications will be classified according to the World Health 
Organization Drug dictionary (WHO-DDE March 2018 Version, format C or higher) and 
summarized by treatment using frequency counts and percentages for each Anatomical 
Therapeutic Chemical Class Level 2 and 4, and generic drug name for the safety 
population. Prior and concomitant medications, including start and stop (or ongoing as 
of) dates, AE number (if applicable), indication, dose, unit, route, and frequency will be 
presented in a data listing. 


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Prior medications are defined as any continuing or new medication used within 12 weeks 
and discontinued before Screening (Days –42 to –36; Visit 1). Concomitant medications 
are defined as any continuing or new medication taken from Screening (Days –42 to –36; 
Visit 1) or anytime thereafter until the end of the study.   
9.6 
Extent of Exposure 
The extent of exposure will be summarized in terms of the number of doses using counts 
and percentages. Study drug administration dates and times will be presented in a data 
listing. 
9.7 
Dosing Compliance 
Dosing compliance information for subjects assigned to CTAP101 Capsules and 
paricalcitol capsules plus low-dose cholecalciferol, including the number of capsules 
returned, the actual number of capsules taken, the number that should have been taken, 
and the calculated dosing compliance value will be provided for Visits 7 through 10 
(Days 8, 15, 22, and 29) and 13 through 16 (Days 36, 43, 50, and EOS/ET) and presented 
in a data listing. Dose dispensing information will be provided for these same treatments, 
along with dose diary (reduction, suspension, and resumption) and dosing plan (type of 
change to treatment, reason, and the actual dose change) information for all treatments, in 
the data listings. 
Summaries of the number of capsules returned, the actual number of capsules taken, the 
number that should have been taken, and the calculated dosing compliance will be 
provided by visit and overall for each treatment for the safety, ITT, and PP populations. 
9.8 
Ancillary Data 
Dietary counseling information, including whether or not a subject required calcium 
supplementation as a concomitant medication, will be presented in a data listing. 
9.9 
Other Safety Assessments 
The physical examination findings, unscheduled electrocardiogram safety assessments, 
and all other clincial laboratory parameters will be presented in data listings. 


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10 
REFERENCES 
Not applicable. 


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Shells of the PK, 
 and safety tables, listings, and figures will be provided as a separate 
document and titles may change slightly from what is presented here in this appendix, 
where this appendix is designed to give the reader an understanding of what is intended 
to be presented. In creating the shells, the tables may need to be presented differently to 
adhere to the actual data collected.   
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14 
TABLES, LISTINGS, AND FIGURES REFERRED TO BUT 
NOT PRESENTED IN THE TEXT 
14.1 
Disposition and Demographic Data Summary Tables 
Table 14.1.1 
Subject Disposition (Enrolled Subjects) 
Table 14.1.2 
Demographic and Baseline Characteristics (Safety Population) 
Table 14.1.3 
Demographic and Baseline Characteristics (ITT Population) 
Table 14.1.4 
Demographic and Baseline Characteristics (PP Population) 
Table 14.1.5 
Demographic and Baseline Characteristics (PK Population) 
Table 14.1.6 
Summary of Medical History (Safety Population) 
Table 14.1.7 
Summary of Prior Medications (Safety Population) 
Table 14.1.8 
Summary of Concomitant Medications (Safety Population) 
14.2 
Pharmacokinetic 
 Summary Tables, 
Figures, and Analyses 
14.2.1 
Serum and Plasma Concentration and Pharmacokinetic 
Summaries, Figures, and Analyses 
Table 14.2.1.1 
Summary of Concentrations (PK Population)  
Table 14.2.1.2 
Summary of Pharmacokinetic Parameters (PK Population) 
Table 14.2.1.3 
Summary of Statistical Analyses of the Pharmacokinetic Parameters 
(PK Population) 
Figure 14.2.1.1 
Mean ±SD Serum Calcifediol Concentration (ng/mL)-Time Profile, 
Linear Scale (PK Population) 
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14.2.3 
Urine Concentration and Pharmacodynamic Parameter 
Summaries 
Table 14.2.3.1 
Summary of Urinary Excretion (ITT Population) 
Table 14.2.3.2 
Summary of Urinary Excretion (PP Population) 
14.2.4 
Pharmacokinetic/
 Figures 
Figure 14.2.4.2 
Plot of Time-Matched Serum 1,25-dihydroxyvitamin D3 (1,25D3) 
Change From Baseline Concentration Versus Serum Calcifediol 
Concentrations (PK Population)  
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14.3 
Safety Data Summary Tables 
14.3.1 
Adverse Events 
Table 14.3.1.1 
Overall Summary of Treatment-Emergent Adverse Events (Safety 
Population) 
Table 14.3.1.2 
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term (Safety Population) 
Table 14.3.1.3 
Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term, and Relationship to Study Drug (Safety Population) 
Table 14.3.1.4 
Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term, and Maximum Severity (Safety Population) 
Table 14.3.1.5 
Treatment-Emergent Adverse Events Leading to Study 
Discontinuation by System Organ Class, Preferred Term, and 
Relationship to Study Drug (Safety Population) 
Add Table 14.3.1.6 Serious TEAEs by System Organ Class and Preferred Term (Safety 
Population) and Table 14.3.1.7 Serious Related TEAEs by System 
Organ Class and Preferred Term (Safety Population), if more than 
1 SAE is reported. Follow the same format as the 14.3.1.2 table. 
14.3.2 
Listing of Deaths, Other Serious and Significant Adverse Events 
Listing 14.3.2.1 
Serious Adverse Events and Deaths (Safety Population) 
14.3.3 
Narratives of Deaths, Other Serious and Certain Other 
 
Significant Adverse Events 
Provided by Clinical, if applicable. 
14.3.4 
Abnormal Laboratory Value Listings 
Listing 14.3.4.1 
Clinically Significant Laboratory Results (Safety Population) 
14.3.5 
Other Observations Related to Safety 
Table 14.3.5.1 
Extent of Exposure (Safety Population) 
Table 14.3.5.2 
Dosing Plan Summary (Safety Population) 
Table 14.3.5.3 
Dosing Compliance (Safety Population) 
Table 14.3.5.4 
Vital Sign Results and Change From Baseline (Safety Population) 
Table 14.3.5.5 
Hematology Parameter Results and Change From Baseline 
(Safety Population) 
Table 14.3.5.6 
Hematology Parameter Shifts From Baseline (Safety Population) 
Table 14.3.5.7 
Serum Chemistry Parameter Results and Change From Baseline 
(Safety Population) 
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Table 14.3.5.8 
Serum Chemistry Parameter Shifts From Baseline (Safety Population) 
Table 14.3.5.9 
Summary of Incidence of Hypercalcemia and Hyperphosphatemia 
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16.1      Study Information 
Appendix 16.1.7.1 Randomization Schedule 
Appendix 16.1.10.1 Clinical Laboratory Reference Ranges 
16.2 
Subject Data Listings 
16.2.1 
Subject Discontinuation 
Appendix 16.2.1.1  Subject Disposition  
16.2.2 
Protocol Deviations 
Appendix 16.2.2.1  Protocol Deviations  
16.2.3 
Subject Populations and Excluded Reasons 
Appendix 16.2.3.1  Subjects in the Safety, ITT, PP, and PK Populations and Excluded 
Reasons 
16.2.4 
Demographic Data 
Appendix 16.2.4.1  Demographics and Baseline Characteristics 
Appendix 16.2.4.2  Inclusion/Exclusion Criteria Not Met 
Appendix 16.2.4.3  Medical History 
Appendix 16.2.4.4  Substance Use 
16.2.5 
Compliance and Drug Concentration Data 
Appendix 16.2.5.1   Study Drug Administration at the Clinic 
Appendix 16.2.5.2  Dosing Compliance Information 
Appendix 16.2.5.3  Dose Dispensed Information 
Appendix 16.2.5.4  Dose Diary and Dosing Plan 
Appendix 16.2.5.5  Dietary Counseling Information 
Appendix 16.2.5.6 
Pharmacokinetic Concentrations and Sampling Times 
Appendix 16.2.5.8    Urine Concentrations, Amount Excreted, Volume, and Sampling 
Times 
16.2.6 
Pharmacokinetic 
 Data 
Appendix 16.2.6.1  Pharmacokinetic Parameters 
Appendix 16.2.6.3  Figures for Serum Calcifediol Individual Concentration (ng/mL)-
Time Profiles, Linear Scale 
Appendix 16.2.6.4  Spaghetti Plots for Serum Calcifediol Individual Concentration 
(ng/mL)-Time Profiles, Linear Scale 
Appendix 16.2.6.5  Figures for Baseline-Adjusted Serum Calcifediol Individual 
Concentration (ng/mL)-Time Profiles, Linear Scale 
Appendix 16.2.6.6  Spaghetti Plots for Baseline-Adjusted Serum Calcifediol Individual 
Concentration (ng/mL)-Time Profiles, Linear Scale 
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Appendix 16.2.6.31 Figures for Serum 1,25-dihydroxyvitamin D3 (1,25D3) Individual 
Concentration (ng/mL)-Time Profiles, Linear Scale 
Appendix 16.2.6.32 Spaghetti Plots for Serum 1,25-dihydroxyvitamin D3 (1,25D3) 
Individual Concentration (ng/mL)-Time Profiles, Linear Scale 
Appendix 16.2.6.33 Figures for Baseline-Adjusted Serum 1,25-dihydroxyvitamin D3 
(1,25D3) Individual Concentration (ng/mL)-Time Profiles, Linear 
Scale 
Appendix 16.2.6.34 Spaghetti Plots for Baseline-Adjusted Serum 1,25 dihydroxyvitamin 
D3 (1,25D3) Individual Concentration (ng/mL)-Time Profiles, 
Linear Scale 
16.2.7 
Adverse Events and Other Safety Data 
Appendix 16.2.7.1  Adverse Events  
Appendix 16.2.7.2  Adverse Events Leading to Study Discontinuation  
Appendix 16.2.7.3  Prior and Concomitant Medications 
Appendix 16.2.7.4  Vital Sign Measurements 
Appendix 16.2.7.5  Unscheduled Safety 12-Lead Electrocardiogram 
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Appendix 16.2.7.6  Physical Examination 
Appendix 16.2.7.7  Meal Information 
Appendix 16.2.7.8  Calcium Assessment 
16.2.8  Individual Laboratory Safety Response Data 
Appendix 16.2.8.1    Clinical Laboratory Results for Hematology 
Appendix 16.2.8.2    Clinical Laboratory Results for Serum Chemistry 
Appendix 16.2.8.3  Urine Drug and Alcohol Screen Results 
Appendix 16.2.8.4  HIV and Hepatitis Screen Results 
Appendix 16.2.8.5   Serum Pregnancy Test Results (Female Subjects Only)