Conditions: Hyperphosphatemia
Keywords: PA21 phosphate binder
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 85
Healthy volunteers: no

Brief summary:
This is a Phase 3, Open-label, Randomised, Active-controlled, Parallel Group, Multicentre Study to Investigate the Safety and Efficacy of PA21 (Velphoro®) and Calcium Acetate (Phoslyra®) in Paediatric and Adolescent CKD Patients with Hyperphosphataemia. The aim of this Phase 3 clinical study is to demonstrate similar efficacy of PA21 (Velphoro) in paediatric and adolescent patients with CKD, and to provide safety and dosing information for this patient population. The Phoslyra (comparator) group provides information for a descriptive comparison of PA21 against a commonly used calcium-based phosphate binder (calcium acetate).

Detailed description:

Arms:
arm 1: PA21 (Velphoro®), chewable tablets 500 mg iron

PA21 (Velphoro®), chewable tablets 250 mg iron

PA21 (Velphoro®), powder for oral suspension 500 mg iron

PA21 (Velphoro®), powder for oral suspension 250 mg iron

PA21 (Velphoro®), powder for oral suspension 125 mg iron arm 2: Calcium Acetate (Phoslyra®) - Oral Solution: 667 mg calcium acetate per 5 mL.

Interventions: intervention 1: PA21 (Velphoro®) intervention 2: Calcium Acetate (Phoslyra®)
Intervention descriptions: intervention 1: During Stage 1 (Open-Label Dose Titration; up to 10 weeks), PA21 subjects will receive PA21 at a starting dose based on their age. Dose of PA21 will be increased or decreased as required for efficacy (to achieve age specific target serum phosphorus level), provided a subject has been receiving that dose for a minimum of 2 weeks, and for safety or tolerability reasons at any time.

During Stage 2 (Open-Label Safety Extension, 24 week safety extension),subjects will continue on the dose received at the end of Stage 1, unless a dose change is required. Doses may be titrated for efficacy (to achieve age specific target Serum phosphorus levels), provided a subject has been receiving that dose for a minimum of 2 weeks, and for safety or tolerability reasons at any time during Stage 2. intervention 2: During Stage 1 (Open-Label Dose Titration; up to 10 weeks), Phoslyra subjects will receive Phoslyra either at a starting dose based on their weight or, if considered more appropriate by the Investigator, at an equivalent dose of their previous phosphate binder (PB), calcium-based or sevelamer. Dose of Phoslyra will be increased or decreased as required for efficacy (to achieve age specific target serum phosphorus level), provided a subject has been receiving that dose for a minimum of 2 weeks, and for safety or tolerability reasons at any time.

During Stage 2 (Open-Label Safety Extension, 24 week safety extension),subjects will continue on the dose received at the end of Stage 1, unless a dose change is required. Doses may be titrated for efficacy (to achieve age specific target Serum phosphorus levels), provided a subject has been receiving that dose for a minimum of 2 weeks, and for safety or tolerability reasons at any time during Stage 2.

Protocol document:
Prot_000.pdf: 
 
 
 
This trial will be conducted in compliance with this protocol, ICH GCP and applicable regulatory requirements. 
The information contained in this document is proprietary to Vifor Pharma and is not to be copied, disclosed or otherwise 
distributed by an outside authority to any person or persons without the prior written permission of Vifor Pharma. 
 
 
 
An Open-label, Randomised, Active-controlled, Parallel 
Group, Multicentre, Phase 3 Study to Investigate the Safety 
and Efficacy of PA21 (Velphoro®) and Calcium Acetate 
(Phoslyra®) in Paediatric and Adolescent CKD Patients with 
Hyperphosphataemia 
 
 
Clinical Protocol Number: 
PA-CL-PED-01 
 
 
Date: 
22 September 2015 
 
 
Version: 
2.0 
 
 
Prior Version/Amendments: 
Version 1.0, 29 October 2014 
Version 1.0, 6 June 2014 
Version 1.0, 26 March 2015 
 
 
IND Number: 
75610 
 
 
EudraCT Number: 
2015-004155-43 
 
 
Co-ordinating Investigator: 
To be confirmed 
 
 
Sponsor Contact: 
 
 
 
Sponsor Address:  
Vifor Fresenius Medical Care Renal Pharma 
France 
7-13, Boulevard Paul-Emile Victor 
92521 Neuilly-sur-Seine 
France 
 
PPD


 
 
Velphoro Protocol PA-CL-PED-01 Version 2.0 
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SIGNATURE PAGE 
Declaration of Sponsor 
Title: An Open-label, Randomised, Active-controlled, Parallel Group, Multicentre, 
Phase 3 Study to Investigate the Safety and Efficacy of PA21 and Calcium Acetate 
(Phoslyra®) in Paediatric and Adolescent CKD Patients with Hyperphosphataemia 
Version Number/Date: Version 2.0, 22 September 2015 
This study protocol was subjected to critical review. The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational product, 
as well as with the moral, ethical and scientific principles governing clinical research as 
set out in the Declaration of Helsinki, and the International Conference on Harmonisation 
Guidelines on Good Clinical Practice. 
 
 
 
Clinical Representative, Vifor Pharma 
 
Date (day month year) 
 
 
 
Trial Statistician, Vifor Pharma 
 
Date (day month year) 
 
 
 
Regulatory Representative, Vifor Pharma 
 
Date (day month year) 
 
 
Sponsor Medical Expert, Vifor Pharma 
 
Date (day month year) 
 
PPD
PPD
PPD
PPD
PPD
PPD


 
 
Velphoro Protocol PA-CL-PED-01 Version 2.0 
Confidential 
22 September 2015 
Page 2 of 114 
 
SIGNATURE PAGE 
Declaration of Sponsor 
Title: An Open-label, Randomised, Active-controlled, Parallel Group, Multicentre, 
Phase 3 Study to Investigate the Safety and Efficacy of PA21 and Calcium Acetate 
(Phoslyra®) in Paediatric and Adolescent CKD Patients with Hyperphosphataemia 
Version Number/Date: Version 2.0, 22 September 2015 
This study protocol was subjected to critical review. The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational product, 
as well as with the moral, ethical and scientific principles governing clinical research as 
set out in the Declaration of Helsinki, and the International Conference on Harmonisation 
Guidelines on Good Clinical Practice. 
 
 
 
Clinical Representative, Vifor Pharma 
 
Date (day month year) 
 
 
 
Trial Statistician, Vifor Pharma 
 
Date (day month year) 
 
 
 
Regulatory Representative, Vifor Pharma 
 
Date (day month year) 
 
 
 
Sponsor Medical Expert, Vifor Pharma 
 
Date (day month year) 
 
PPD
PPD
PPD
PPD
PPD


 
 
Velphoro Protocol PA-CL-PED-01 Version 2.0 
Confidential 
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Page 2 of 114 
 
SIGNATURE PAGE 
Declaration of Sponsor 
Title: An Open-label, Randomised, Active-controlled, Parallel Group, Multicentre, 
Phase 3 Study to Investigate the Safety and Efficacy of PA21 and Calcium Acetate 
(Phoslyra®) in Paediatric and Adolescent CKD Patients with Hyperphosphataemia 
Version Number/Date: Version 2.0, 22 September 2015 
This study protocol was subjected to critical review. The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational product, 
as well as with the moral, ethical and scientific principles governing clinical research as 
set out in the Declaration of Helsinki, and the International Conference on Harmonisation 
Guidelines on Good Clinical Practice. 
 
 
Clinical Representative, Vifor Pharma 
 
Date (day month year) 
 
 
 
Trial Statistician, Vifor Pharma 
 
Date (day month year) 
 
 
 
Regulatory Representative, Vifor Pharma 
 
Date (day month year) 
 
 
 
Sponsor Medical Expert, Vifor Pharma 
 
Date (day month year) 
 
PPD
PPD
PPD
PPD
PPD


 
 
Velphoro Protocol PA-CL-PED-01 Version 2.0 
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SYNOPSIS 
PA-CL-PED-01 
Title: 
An Open-label, Randomised, Active-controlled, Parallel Group, Multicentre, Phase 3 
Study to Investigate the Safety and Efficacy of PA21 and Calcium Acetate (Phoslyra®) 
in Paediatric and Adolescent CKD Patients with Hyperphosphataemia 
Short Title: 
PA21 safety and efficacy, paediatrics 
Study Product: 
PA21 
Indication: 
Control of serum phosphorus levels in paediatric and adolescent subjects with chronic 
kidney disease (CKD).  
Phase: 
3 
Sponsor: 
Vifor Fresenius Medical Care Renal Pharma, France 
Study Code: 
PA-CL-PED-01 
Co-ordinating 
Investigator:  
To be confirmed 
Objectives: 
Primary Objective 
• 
To evaluate the efficacy of PA21 in reducing serum phosphorus levels in paediatric 
and adolescent subjects with CKD at the end of Stage 1. 
Secondary Objectives 
• 
To evaluate the efficacy of PA21 in maintaining the serum phosphorus lowering 
effects in paediatric and adolescent subjects with CKD at the end of Stage 2. 
• 
To evaluate the safety of PA21 in paediatric and adolescent subjects with CKD.  
• 
To evaluate the efficacy of Phoslyra in reducing and maintaining serum phosphorus 
levels in paediatric and adolescent subjects with CKD at the end of Stages 1 and 2. 
• 
To evaluate the safety of Phoslyra in paediatric and adolescent subjects with CKD. 
Design: 
The study has a 2-stage design. 
In total, approximately 100 subjects will be randomised to PA21 treatment and 
approximately 30 subjects to Phoslyra treatment. 
In addition, the study will aim to randomise a minimum number of subjects from each 
age group as detailed in Table A. 
Table A Minimum Number of Randomised Subjects by Age Group 
Age 
PA21 
Phoslyra 
0 to <1 year 
4 
1 
≥1 year to <6 years 
10 
3 
≥6 years to <9 years 
10 
3 
≥9 years to <18 years 
10 
3 
 
• 
Screening period: up to 4 weeks. 
• 
Washout period: up to 3 weeks. 


 
 
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Design: 
(Cont’d) 
• 
Stage 1: Open-label, randomised, active-controlled, dose titration of PA21 and 
Phoslyra: up to 10 weeks. 
• 
Stage 2: Open-label long-term safety extension: 24 weeks. 
• 
Follow-up: 14 days. 
Treatment: 
The study formulations are detailed in Table B. 
Table B Summary of Formulations 
Age 
PA21 
Phoslyra Oral 
Solution 
(mL) 
Powder for Oral 
Suspension 
(mg Iron) 
Chewable 
Tablet 
(mg Iron) 
0 to <1 year 
125, 250, 500 
– 
Multiple-dose 
PET bottles 
473 mL with a 
child-resistant 
closure 
≥1 year to <6 years 
125, 250, 500 
– 
≥6 years to <9 years 
125, 250, 500 
250, 500 
≥9 years to <18 years 
250, 500 
250, 500 
Note: 
PET=Polyethylene terephthalate. 
 
PA21 contains approximately 20% m/m of elemental iron. PA21 (sucroferric 
oxyhydroxide) is a mixture of polynuclear iron (III)-oxyhydroxide (about 33% m/m), 
sucrose (about 30% m/m), and starches (about 28% m/m) and contains ≤10% m/m 
water.  
Hence, PA21 125 mg (iron) powder will contain approximately 625 mg PA21 drug 
substance, a PA21 250 mg (iron) tablet/powder will contain approximately 1.25 g PA21 
drug substance and a PA21 500 mg (iron) tablet/powder will contain approximately 
2.5 g PA21 drug substance  
Each 5 mL of Phoslyra contains 667 mg calcium acetate equal to 169 mg calcium 
i.e., each 1 mL contains 33.8 mg of elemental calcium.  
At any time during the study, subjects randomised to receive PA21 will be provided with 
the formulation considered to be the most appropriate for them i.e., either powder for 
oral suspension (for subjects <6 years) or chewable tablet (for subjects ≥6 years). Due to 
the increments for dose changes subjects in the 6 to 9 year age group will ideally receive 
powder for oral suspension throughout the study. If required, subjects in the older age 
groups may change to the alternative PA21 formulation, but should remain on the same 
dose. For example, a subject may begin treatment with the chewable tablet but at a 
subsequent study visit change to the powder for oral suspension. 
Stage 1: Open-Label Dose Titration 
Subjects will be randomised to receive either PA21 or Phoslyra. PA21 subjects will 
receive PA21 at a starting dose based on their age, as detailed in Table C. Phoslyra 
subjects will receive Phoslyra either at a starting dose, as detailed in Table F, or, if 
considered more appropriate by the Investigator, at an equivalent dose of their previous 
phosphate binder (PB), calcium-based or sevelamer. 


 
 
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Treatment: 
(Cont’d) 
Dose of PA21 (100 subjects) or Phoslyra (30 subjects) will be increased or decreased as 
required for efficacy (to achieve age specific target serum phosphorus level as indicated 
in Table D), provided a subject has been receiving that dose for a minimum of 2 weeks, 
and for safety or tolerability reasons at any time. Increases or decreases in dose and 
maximum doses are detailed in Table E, Table F and Table G. From Week 4, once a 
subject achieves the age specific target serum phosphorus level, as indicated in Table D, 
they can move to Stage 2. 
Table C Stage 1 Starting Dose of PA21 
Age 
PA21 
(mg Iron/Day) 
0 to <1 year 
125 
≥1 year to <6 years 
500 
≥6 years to <9 years 
750 
≥9 years to <18 years 
1,250 
 
Table D Age Related Serum Phosphorus Targets Post-Randomisation 
Age 
mmol/L 
mg/dL 
0 to <1 year 
1.62-2.52 
5.0-7.8 
≥1 year to <6 years 
1.45-2.10 
4.5-6.5 
≥6 years to <13 years 
1.16-1.87 
3.6-5.8 
≥13 years to <18 years 
0.74-1.45 
2.3-4.5 
Source: National Kidney Foundation Kidney Disease Outcomes Quality Initiative Nutrition Guidelines, 2008. 
 
Table E PA21 Dosing Regimens 
Age 
PA21 
(mg Iron/Day) 
Dose Increases 
or Decreases 
Maximum 
Dose 
0 to <1 year 
125 or 250 
1,000 
≥1 year to <6 years 
125 or 250 
1,250 
≥6 years to <9 years 
125, 250 or 375 
2,500 
≥9 years to <18 years 
250 or 500 
3,000 
 
 
Table F Stage 1 Starting Dose and Dosing Regimen of Phoslyra (All Age Group) 
Initial Dose 
Dose Increase 
or Decrease 
Maximum Dose 
(up to 35 kg) 
Maximum Dose 
(above 35 kg) 
0.45 mL/kg/day 
0.1 to 0.2 mL/kg/day 
1.25 mL/kg/day 
44 mL/day 
 


 
 
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Treatment: 
(Cont’d) 
Table G Maximum Daily Dose of Phoslyra 
Body Weight 
(kg)  
Phoslyra Maximum Dose 
mL/day 
5 
6.0 
10 
12.5 
15 
18.5 
20 
25 
25 
31.0 
30 
37.5 
35 
43.5 
40 
44 
45 
44 
50 
44 
60 
44 
70 
44 
 
Stage 2: Open-Label Safety Extension 
All subjects will enter this safety extension stage. Subjects will continue on the dose 
received at the end of Stage 1, unless a dose change is required.  
For all subjects, doses may be titrated for efficacy (to achieve age specific target serum 
phosphorus levels, see Table D), provided a subject has been receiving that dose for a 
minimum of 2 weeks, and for safety or tolerability reasons at any time during Stage 2. 
Increases or decreases in dose and maximum doses are detailed in Table E, Table F and 
Table G. 
Inclusion 
Criteria: 
1. Subjects 0 to <18 years at time of consent. 
2. Subjects with hyperphosphataemia i.e., with serum phosphorus levels indicated in 
Table H.  
3. Subjects who are PB naïve or have been receiving stable doses of a PB(s) for at least 
1 month prior to screening. Subjects may be on stable doses of a maximum of 
2 PBs. Subjects who have been receiving PBs will enter an obligatory washout 
period and may be randomised once their serum phosphorus levels are as indicated 
in Table H. Subjects already receiving a PB but with serum phosphorus levels 
indicated in Table H may be eligible for randomisation without a washout period.  
4. Subjects ≥1 year with CKD Stages 4-5 defined by a glomerular filtration rate 
<30 mL/min/1.73 m2 or with CKD Stage 5D receiving adequate maintenance 
haemodialysis (HD) or peritoneal dialysis (PD) for at least 2 months prior to 
screening. 
5. Subjects <1 year must have CKD. 
6. PD subjects must have had 1 month of unchanged PD prescription (volume and 
number of exchanges). Home HD subjects may be included (no nocturnal HD 
(overnight stay at site) will be allowed). 
7. Appropriate written informed consent and, where appropriate/required assent, have 
been provided. Written informed consent (and, where appropriate/required, assent) 
must be provided before any study-specific procedures are performed, including 
screening procedures. 


 
 
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Inclusion 
Criteria: 
(Cont’d) 
8. Parents/legal guardians and, where appropriate/required, subjects with the ability to 
provide written informed consent, and where appropriate/required, assent, to 
understand the requirements of the study and abide by the study restrictions, and 
who agree to return for the required assessments, in the Investigator’s opinion. 
Exclusion 
Criteria: 
1. Subjects with hypercalcaemia at screening as indicated in Table J. 
2. Subjects with intact parathyroid hormone (iPTH) levels >700 pg/mL at screening. 
3. Subjects who are PB naïve who weigh <5 kg at screening. Subjects receiving stable 
doses of PBs who weigh <6 kg at screening (in order to comply with maximum 
blood sample volumes in paediatric clinical trials). 
4. Subjects requiring feeding tube sizes ≤6 FR (French catheter scale). 
5. Subjects with planned or expected parathyroidectomy within the next 12 months, in 
the Investigator’s opinion. 
6. Subjects with history of: 
• 
Major gastrointestinal surgery which, in the Investigator’s opinion, is likely 
to influence the outcome of treatment with PBs. 
• 
Significant gastrointestinal disorders. 
7. Subjects with estimated life expectancy of less than 12 months. 
8. Subjects with known seropositivity to human immunodeficiency virus. 
9. Subjects with a history of haemochromatosis or other iron accumulation disorders.  
10. Subjects on PD with a history of peritonitis in the last 3 months or ≥3 episodes in 
the last 12 months. 
11. Subjects with hypocalcaemia (serum total corrected calcium <1.9 mmol/L; 
<7.6 mg/dL) at screening. 
12. Subjects 
with 
raised 
alanine 
aminotransferase 
or 
aspartate 
aminotransferase >3 times the upper limit of the normal range based on central 
laboratory results at screening. 
13. Subjects taking more than 2 PBs concomitantly prior to screening. 
14. Subjects taking any prohibited medication(s) (See Section 7.7). 
15. Subject has known hypersensitivity and/or intolerance to any of the active 
substances or to any of the excipients to be administered. 
16. Subject has previously been randomised into this study. 
17. Subject is currently enrolled in or has completed any other investigational device or 
drug study <30 days prior to screening, or is receiving other investigational agent(s). 
18. Subject is pregnant (e.g., positive human chorionic gonadotropin test) or breast 
feeding.  


 
 
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Exclusion 
Criteria: 
(Cont’d) 
19. If of child-bearing potential, subject is not using adequate contraceptive precautions. 
Subject must agree to use a highly effective method of birth control during the study 
and for 1 month after the last dose of study medication. Adequate methods of birth 
control are defined as those which result in a low failure rate (i.e., <1% per year) 
when used consistently and correctly such as implants, injectables, combined oral 
contraceptives, some intra-uterine devices, sexual abstinence or vasectomised 
partner. Non-child-bearing potential includes being surgically sterilised at least 
6 months prior to the study. 
20. Subject has a history of drug or alcohol abuse within 2 years prior to screening. 
21. Subject has a significant medical condition(s) e.g., uncontrolled diabetes, known 
hepatitis B surface antigen positivity and/or hepatitis C virus ribonucleic acid 
positivity or anticipated need for major surgery during the study, or any other kind 
of disorder that may be associated with increased risk to the subject, or may 
interfere with study assessments or outcomes. 
Primary and 
Secondary 
Endpoints: 
Primary Efficacy Endpoint 
• 
Change in serum phosphorus from baseline in the PA21 group at the end of Stage 1. 
Primary Safety Endpoint 
• 
Adverse events (AEs) profile. 
• 
Percentage of withdrawals due to AEs. 
Secondary Efficacy Endpoints 
• 
Change in serum phosphorus from baseline in the Phoslyra group at the end of 
Stage 1. 
• 
Change in serum phosphorus from baseline in the PA21 and Phoslyra groups at the 
end of Stage 2. 
• 
Percentage of subjects in each stage during which the subject has serum phosphorus 
levels in the age dependent target ranges. 
• 
Serum phosphorus levels at each time point and change from baseline. 
Secondary Safety Endpoints 
• 
Serum total corrected calcium levels at each time point and change from baseline. 
• 
Percentage of subjects that develop at least 1 episode of sustained hypercalcaemia 
(as indicated in Table J) during study participation (confirmed by repeat sample 
1 week later). 
• 
Serum total corrected calcium x phosphorus levels at each time point and change 
from baseline. 
• 
Serum iPTH levels at each time point and change from baseline. 
• 
Biochemical/haematological laboratory tests (including blood iron parameters, 
Vitamin D parameters and bone markers). 
Additional Assessments 
• 
Patient reported outcomes on palatability and acceptability. 


 
 
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Procedures: 
See Schedule of Events, Table 1 for full details of protocol required procedures, visits 
and timings. 
Table 2 (Summary of Blood Samples) details visits where blood samples must be 
analysed at a central laboratory and visits where there is the option of having blood 
samples analysed by a local laboratory  
Screening Period 
Subjects for whom signed and dated informed consent (and, where appropriate/required, 
assent) has been provided will be enrolled in the study and screened. 
Washout Period 
Subjects who are PB Naïve 
Subjects who are PB naïve and whose serum phosphorus levels values are as indicated in 
Table H will be eligible for randomisation when the results from the screening visit are 
available for assessment of study eligibility. In centre HD subjects must be randomised 
after a maximum interdialytic period of 48 hours, once qualifying screening results are 
received. Home HD, pre-dialysis and PD subjects should be randomised as soon as 
feasible after qualifying screening results are received, and preferably within 4 days. 
Subjects Taking PBs 
Subjects already receiving a PB but with serum phosphorus levels indicated in Table H 
may be randomised without a washout period when the results from the screening visit 
are available for assessment of study eligibility. For subjects taking PBs the washout 
period cannot begin until the results from the screening visit are available for assessment 
of study eligibility. Subjects who are eligible for inclusion (or their parent/legal 
guardian) will then be contacted by the site and asked to stop taking their current PBs. 
The dose of previous PB treatment should remain stable until the subject, or their 
parent/legal guardian, is contacted by the site. Subjects who are eligible for inclusion 
will then undergo a washout from their previous PBs for up to 3 weeks. Serum 
phosphorus levels will be monitored weekly for up to 3 weeks of washout. 
Table H Age Related Serum Phosphorus Targets for Washout Period 
Age 
mmol/L 
mg/dL 
0 to < 6 months 
>2.62 
>8.1 
≥6 months to <1 year 
>2.29 
>7.1 
≥1 year to <6 years 
>2.02 
>6.3 
≥6 years to <13 years 
>1.77 
>5.5 
≥13 years to <18 years 
>1.36 
>4.2 
Note: 
Adapted from National Kidney Foundation Kidney Disease Outcomes Quality Initiative Nutrition 
Guidelines, 2008 and personal communication. 
 
Subjects whose serum phosphorus levels have risen to the values indicated in Table H 
will be eligible for randomisation at any time during the washout period. Subjects who 
have serum phosphorus levels below the values indicated in Table H can continue in the 
washout period for up to 3 weeks. As soon as their serum phosphorus level has risen to 
the value indicated in Table H they can be randomised into the study. 


 
 
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Procedures: 
(Cont’d) 
In centre HD subjects must begin their washout after a maximum interdialytic period of 
48 hours, once qualifying screening results are received. Subsequent visits during the 
washout period should take place after a maximum interdialytic period of 48 hours. 
Home HD, pre-dialysis and PD subjects should begin their washout as soon as feasible 
after qualifying screening results are received, and preferably within 4 days. If, after 
3 weeks of washout, the serum phosphorus remains below the values indicated in 
Table H the subject is not eligible for randomisation and must be withdrawn from the 
study. 
Randomisation and Study Visits 
Subjects who are eligible will be randomised via an IRT to either PA21 (100 subjects) or 
Phoslyra (30 subjects), and will enter Stage 1, the open-label, dose titration period. 
For in centre HD subjects study visits must be planned after a maximum interdialytic 
period of 48 hours and on the same day and same session each week, as far as possible. 
Collection of laboratory samples and completion of all other procedures required by the 
protocol, except the physical examination and the patient reported palatability and 
acceptability will be completed before dialysis is initiated. Subjects that are on home 
HD, pre-dialysis or on PD will be free to select a weekday for the study visits that 
coincides best with their weekly routine, preferably in the first half of the week. All 
subsequent study visits will be scheduled on the same weekday, wherever possible. For 
these subjects all laboratory samples and other procedures required by the protocol will, 
where possible, be taken at a consistent time for each visit. 
Concomitant medications that have a direct influence on serum phosphorus levels 
(e.g., Vitamin D, Vitamin D analogues and calcimimetics), dietary restrictions 
(e.g., phosphate and calcium intake) and dialysis regimens (e.g., duration of dialysis, 
number of HD sessions per week, number of PD exchanges/day, modality of dialysis, 
calcium concentration) should remain unchanged as far as possible in both the PA21 and 
Phoslyra groups throughout the study in accordance with local clinical practice. This 
does not apply if changes are indicated for safety or tolerability reasons. 
AEs and concomitant medication will be recorded from screening (following informed 
consent, and where appropriate/required, assent signature) to the end of study 
participation. 
Stage 1: Open-Label Dose Titration Period 
Visits and assessments will be as detailed in the Schedule of Events, Table 1. During this 
period, dose titrations will be based on laboratory values taken at regular study intervals. 
If a dose adjustment is indicated, i.e., the serum phosphorus level is outside the target 
serum phosphorus levels indicated in Table D, the Investigator will inform the subject 
and, where appropriate, parent/legal guardian (either directly or by phone) whether a 
dose increase or a dose decrease is indicated. Subjects will thereafter follow the new 
dose regimen for a minimum of 2 weeks. 
Stage 2: Open-Label Safety Extension 
Visits and assessments will be as detailed in the Schedule of Events, Table 1. During this 
period, dose titrations will be based on laboratory values taken at regular study intervals. 
If a dose adjustment is indicated, i.e., if the serum phosphorus level is outside the target 
serum phosphorus levels indicated in Table D, the Investigator will inform the subject 
and, where appropriate, parent/legal guardian (either directly or by phone) whether a 
dose increase or a dose decrease is indicated. Subjects will thereafter follow the new 
dose regimen for a minimum of 2 weeks. 


 
 
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Procedures: 
(Cont’d) 
Early Discontinuation and Stopping Rules 
Phosphorus 
At any time during the study, if a subject’s phosphorus level exceeds or is below the 
safety limits indicated in Table I: 
Table I Age Related Safety Limits of Serum Phosphorus 
Age 
Upper Safety Limit 
Lower Safety Limit 
mmol/L 
mg/dL 
mmol/L 
mg/dL 
0 to <1 year 
2.91 
9.0 
1.62 
5.0 
≥1 year to <6 years 
2.42 
7.5 
1.45 
4.5 
≥6 years to <13 years 
2.26 
7.0 
1.13 
3.5 
>13 years to <18 years 
2.26 
7.0 
0.81 
2.5 
Note: 
Limits calculated as upper limit of normal ±20% based on National Kidney Foundation Kidney 
Disease Outcomes Quality Initiative Nutrition Guidelines, 2008. 
 
• 
The subject’s study medication must be adjusted and the subject must be asked to 
return for a visit 1 week after the value outside the safety limits indicated in Table I 
was first seen i.e., irrespective of whether this was during Stage 1 or 2.  
• 
At the next visit, 1 week after the value outside the safety limits indicated in Table I 
was first seen a blood sample for serum phosphorus will be taken. Once the site 
receives the blood sample result, if the serum phosphorus level is outside the target 
safety limits indicated in Table I, the Investigator will inform the subject and, where 
appropriate, parent/legal guardian, (either directly or by phone) whether a dose 
increase or a dose decrease of study medication is indicated. The subject must return 
for a visit 1 week after the change in study medication dose.  
• 
At the next visit, 1 week after the change in study medication dose, a blood sample 
for serum phosphorus will be taken. Once the site has the blood sample result, if the 
subject’s phosphorus level still exceeds or is below the safety limits indicated in 
Table I, then the subject must be withdrawn from the study. 
In addition, at each of the above visits, if the subject’s phosphorus level exceeds the 
upper safety limit indicated in Table I, the site must advise the subject and parent/carer 
regarding a low phosphorus diet. 
The subject does not need to be withdrawn if the 2 follow-up results are outside of the 
safety limit, but in the opposite direction (i.e., one too high and one too low). In this 
situation, the subject’s PB dose must be adjusted and the subject must return in 1 week 
to provide a blood sample for serum phosphorus. Once the site has the blood sample 
result, if the subject’s phosphorus level still exceeds or is below the safety limits 
indicated in Table I, then the subject must be withdrawn from the study. 
Calcium 
At any time during the study, subjects will be withdrawn immediately if their serum 
corrected total calcium level exceeds 3.0 mmol/L (12 mg/dL) or is below 1.63 mmol/L 
(6.5 mg/dL). 


 
 
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Procedures: 
(Cont’d) 
At any time during the study if a subject’s corrected total calcium level exceeds or is 
below the safety limits indicated in Table J: 
• 
The subject should receive appropriate rescue intervention and must be asked to 
return for a visit 1 week after the value outside the safety limits indicated in Table J 
was first seen.  
• 
At the next visit, 1 week after the value outside the safety limits indicated in Table J 
was first seen, a blood sample for serum corrected total calcium will be taken. Once 
the site has the blood sample result, if the level is outside the target safety limits 
indicated in Table J, the Investigator will inform the subject and, where appropriate, 
parent/legal guardian, (either directly or by phone) whether a dose increase or a dose 
decrease in rescue medication or an alternative rescue medication is indicated. The 
subject must return for a visit 1 week after the change in rescue medication. 
• 
At the next visit, 1 week after the change in rescue medication, a blood sample will 
be taken. Once the site has the blood sample result, if the subject’s corrected total 
calcium level still exceeds or is below the safety limits indicated in Table J, then the 
subject must be withdrawn from the study. 
The subject does not need to be withdrawn if the 2 follow-up results are outside of the 
safety limit, but in the opposite direction (i.e., one too high and one too low). In this 
situation, the subject’s rescue medication must be adjusted and the subject must return in 
1 week to provide a blood sample for serum total corrected calcium. Once the site has 
the blood sample result, if the subject’s serum corrected total calcium level still exceeds 
or is below the safety limits indicated in Table J, then the subject must be withdrawn 
from the study 
Appropriate rescue intervention for hypercalcaemia may include: 
• 
Reduce or stop dose of active Vitamin D metabolite 
• 
Increase dose of calcimimetic 
• 
Reduce calcium content in dialysate 
• 
Reduce the dose of Phoslyra 
Appropriate rescue intervention for hypocalcaemia may include: 
• 
Increase dose of active Vitamin D metabolite 
• 
Decrease dose of calcimimetic 
• 
Increase calcium content in dialysate 
Table J Age Related Safety Limits for Total Calcium 
Age 
Upper Safety Limit 
Lower Safety Limit 
mmol/L 
mg/dL 
mmol/L 
mg/dL 
0 to <1 year 
2.75 
11.0 
<1.9 
<7.6 
≥1 year to <6 years 
2.70 
10.8 
<1.9 
<7.6 
≥6 years to <13 years 
2.60 
10.3 
<1.9 
<7.6 
≥13 years to <18 years 
2.60 
10.2 
<1.9 
<7.6 
Note: 
Upper safety limits based on National Kidney Foundation Kidney Disease Outcomes Quality Initiative 
Nutrition Guidelines, 2008. Lower limit based on literature (Paediatric Nephrology, 2nd edition) and 
personal communication. 


 
 
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Procedures: 
(Cont’d) 
General 
Subjects will also be withdrawn if it is necessary to add an additional PB to the treatment 
regimen or if they receive a kidney transplant, or they initiate dialysis during the study. 
All withdrawn subjects will be asked to complete the end of study assessments. 
Follow-Up 
Any subject who has been treated with study medication, whether completing the study 
or withdrawn prematurely, will be followed up 14 days after their last scheduled study 
visit to collect any new AEs and concomitant medications. 
External Data and Safety Monitoring Board 
There will be an external Data and Safety Monitoring Board. 
Post Study Treatment 
The Investigator is responsible for ensuring that consideration is given to the appropriate 
post study care of the subject's medical condition. 
Sample Size: 
One hundred-thirty subjects will be randomised in the study (PA21: 100, Phoslyra: 30). 
The study will aim to randomise the number of subjects from each age group as detailed 
in Table A. 
Statistical 
Methods: 
The primary efficacy analysis will be conducted on the change from baseline in the 
PA21 group at the end of Stage 1. The change from baseline in the PA21 group will be 
analysed using a paired t-test, and also summarised descriptively.  
Additional descriptive analyses will be conducted on the serum phosphorus changes 
from baseline to the end of Stage 1(Phoslyra) and to the end of Stage 2 (both PA21 and 
Phoslyra treatment groups).  
Demographic and baseline disease characteristics will be summarised and compared 
between the PA21 and Phoslyra groups. 
Subject exposure and compliance will be calculated and summarised by treatment 
groups, and by stage. 
AE, laboratory values, vital signs and other safety parameters will be summarised.  
Patient palatability and acceptability assessments will be summarised and analysed by 
treatment groups. 
All analyses will be described in a statistical analysis plan that will be finalised before 
database lock. 
 


 
 
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Figure 1 
Study Design 
 
Stage 2
24 week safety extension 
End of 
Study
Stage 1
Up to 
4 
weeks
Screen
Up to
3 
weeks
Up to 10 weeks
Randomisation
PA21: 100 subjects:
≥ 0 to < 1 yr: minimum n=4
≥ 1 yr to < 6 yrs; minimum n=10
≥6 yrs to < 9 yrs; minimum n=10
≥9 yrs to < 18 yrs; minimum n=10
Phoslyra: 30 subjects
≥ 0 to < 1 yr: minimum n=1
≥1 yr to < 6 yrs; minimum n=3
≥6 yrs to < 9 yrs; minimum n=3
≥9 yrs to < 18 yrs; minimum n=3
All subjects enter Stage 2 on their end of Stage 1 dose
Titration Phase
Safety Extension (Maintenance Phase)
Wash 
Out


 
 
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Table 1 
Schedule of Events 
 
Screen(1,2,3) 
Washout(2) 
(Visits Only for 
Subjects on PBs) 
Treatment Period 
Follow-Up: 
2 Weeks After 
Last Visit(4) 
Stage 1(4,5) 
Titration Period 
Stage 2 
Safety Extension(4) 
Week (PB washout)(2) 
Up to -7 
-3 
-2 
-1 
BL 
1 
2 
4 
6 
8 
10 
14 
18 
22 
28 
34 
36 
Week (PB naïve)(3) 
Up to -4 
Not Required 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 16(6) 
17(7) 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Height and weight 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
X 
 
X 
 
Vital signs (blood pressure, heart rate, temperature) 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
X 
 
X 
 
Blood samples: details in Table 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Call to IRT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense subject identification card 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dialysis parameters 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dialysis parameters for Kt/V(8) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Randomization 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense study medication 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Returned study medication count 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient reported palatability and acceptability 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
AE/SAE monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


 
 
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Table 1 
Schedule of Events (Cont’d) 
 
Screen(1,2,3) 
Washout(2) 
(Visits Only for 
Subjects on PBs) 
Treatment Period 
Follow-Up: 
2 Weeks After 
Last visit(4) 
Stage 1(4,5) 
Titration Period 
Stage 2 
Safety Extension(4) 
Week (PB washout)(2) 
Up to -7 
-3 
-2 
-1 
BL 
1 
2 
4 
6 
8 
10 
14 
18 
22 
28 
34 
36 
Week (PB naïve)(3) 
Up to -4 
Not Required 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 16(6) 
17(7) 
Discuss and advise on subject’s diet 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
1 Laboratory data must be available prior to washout and randomization to check that all laboratory eligibility criteria have been met. Subjects may be rescreened once if, for example, they have a positive 
pregnancy test, have an active infection or if they are taking antibiotics. Subjects who need to be rescreened will be withdrawn from the study (as screen failures) and enrolled again. 
2 For subjects requiring a washout period, Visit 2 to be scheduled 5 to 28 days after the screening visit. Washout visits to be scheduled in relation to Visit 2: Visit 3 is 7 ±2 days, Visit 4 is 14 ±2 days, and 
baseline is 21 ±2 days. The washout period, if required, is up to 3 weeks ±2 days and cannot begin until the results from the screening visit are available for assessment of study eligibility.  
3 For subjects not requiring a washout period, the baseline visit to be scheduled 5 to 28 days after the screening visit. These subjects will not be required to attend Visits 2, 3 and 4.  
4 All other visits should be scheduled in relation to baseline Visit ±3 days. 
5 From Visit 8, subjects can move to Stage 2 if they have been on a stable dose for a minimum of 2 weeks. 
6 All subjects must complete the assessments for this visit on completion of the study or early discontinuation/withdrawal at any time (Stage 1 and Stage 2). 
7 Visit 17 can be conducted by a telephone call. 
8 Any visit where this value is available from routine clinical assessment. 
Notes: AE=Adverse event; BL=Baseline; PB=Phosphate binder; SAE=Serious adverse event. 
 


 
 
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Table 2 
Summary of Blood Samples 
 
Screen 
Washout 
(Visits Only for 
Subjects on PBs) 
Treatment Period 
Follow-Up: 
2 Weeks After 
Last Visit(1) 
Stage 1 
Titration Period 
Stage 2 
Safety Extension 
Week (PB washout) 
Up to -7 
-3 
-2 
-1 
BL 
1 
2 
4 
6 
8 
10 
14 
18 
22 
28 
34 
36 
Week (PB naïve) 
Up to -4 
Not Required 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 16(2) 
17 
Central laboratory blood sample required 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
Option to use local laboratory 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
Pregnancy test(3) 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Haematology 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Intact parathyroid hormone 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Clinical chemistry, iron status (excluding ferritin) 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Separate serum phosphorus, serum total corrected 
calcium and albumin(4,5) 
 
X 
X 
X 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
Bone markers and vitamins (excluding 
1,25(OH)2D)(6) 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
Ferritin(6) 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
Coagulation and Vitamin 1,25(OH)2D(7) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Visit 17 can be conducted by a telephone call. 
2 All subjects must complete the assessments for this visit on completion of the study or early discontinuation/withdrawal at any time (Stage 1 and Stage 2). 
3 In females of child-bearing potential, the serum pregnancy tests will be performed at site. Positive pregnancy tests will be repeated 2 weeks later, to check for false positive results. 
4 Where clinical chemistry test is conducted, serum phosphorus, serum total corrected calcium and albumin will be included therefore separate tests are not required at these visits.  
5 Wherever possible a sample for central laboratory analysis of these parameters should be obtained at the final visit of Stage 1. 
6 Exclude these blood tests in subjects <36 months but provide value if available from routine clinical assessment. Samples for bone marker assessment will be obtained and may be stored (frozen) for later 
analysis. 
7 Any visit where this value is available from routine clinical assessment. 
Notes: BL=Baseline; PB=Phosphate binder. 
 


 
 
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TABLE OF CONTENTS 
Page 
SIGNATURE PAGE ..........................................................................................................2 
SYNOPSIS ..........................................................................................................................3 
TABLE OF CONTENTS ................................................................................................18 
LIST OF TABLES ...........................................................................................................22 
LIST OF FIGURES .........................................................................................................24 
LIST OF APPENDICES .................................................................................................25 
LIST OF ABBREVIATIONS .........................................................................................26 
1. 
INTRODUCTION AND BACKGROUND ............................................................28 
1.1 
Background of the Disease and Treatment Options ..............................................28 
1.2 
Summary of Nonclinical and Clinical Data ...........................................................30 
2. 
RATIONALE ...........................................................................................................34 
3. 
STUDY OBJECTIVES ............................................................................................41 
3.1 
Primary Objective ..................................................................................................41 
3.2 
Secondary Objectives.............................................................................................41 
4. 
INVESTIGATIONAL PLAN .................................................................................42 
4.1 
Overall Study Design .............................................................................................42 
4.2 
Duration of Subject Participation and Study .........................................................43 
5. 
SELECTION AND WITHDRAWAL OF SUBJECTS ........................................45 
5.1 
Number of Subjects................................................................................................45 
5.2 
Inclusion Criteria ...................................................................................................45 
5.3 
Exclusion Criteria ..................................................................................................46 
5.4 
Withdrawal of Subjects ..........................................................................................47 
5.4.1 
Stopping Rules for Serum Phosphorus Levels ...................................................47 
5.4.2 
Stopping Rules for Serum Corrected Total Calcium Levels ..............................48 
5.4.3 
Other Reasons for Withdrawal ...........................................................................49 
6. 
RANDOMISATION PROCEDURES ....................................................................51 
6.1 
Randomisation .......................................................................................................51 
6.2 
Blinding..................................................................................................................51 
7. 
STUDY TREATMENTS .........................................................................................52 
7.1 
Dosage Forms/Formulation ...................................................................................52 
7.1.1 
PA21 Chewable Tablet .......................................................................................53 
7.1.2 
PA21 Powder for Oral Suspension .....................................................................53 
7.1.3 
Phoslyra Oral Solution (Comparator Group) ......................................................54 
7.1.3.1 
Primary Packaging ...........................................................................................54 
7.2 
Drug Dosage and Administration ..........................................................................54 


 
 
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7.2.1 
Treatment Arms ..................................................................................................54 
7.2.1.1 
Dosing of PA21 Powder for Oral Suspension .................................................56 
7.2.1.2 
Dosing of PA21 Tablet ....................................................................................57 
7.2.1.3 
Dosing of Phoslyra ...........................................................................................58 
7.2.2 
Dosing and Administration Guidelines...............................................................60 
7.2.2.1 
PA21 – Investigational Treatment ...................................................................60 
7.2.2.3 
Phoslyra Oral Solution - Active Control ..........................................................61 
7.3 
Package and Labelling ...........................................................................................61 
7.4 
Study Treatment Allocation ...................................................................................61 
7.5 
Site Supply, Storage, Accountability .....................................................................61 
7.5.1 
Site Supply ..........................................................................................................61 
7.5.2 
Storage ................................................................................................................61 
7.5.3 
Accountability .....................................................................................................62 
7.6 
Drug Dose Modification ........................................................................................62 
7.6.1 
Procedures for Overdose .....................................................................................62 
7.6.1.1 
PA21 ................................................................................................................62 
7.6.1.2 
Phoslyra............................................................................................................63 
7.7 
Prohibited Therapy and Concomitant Treatment ...................................................63 
7.7.1 
PA21 Interactions ...............................................................................................64 
7.7.2 
Phoslyra Interactions...........................................................................................64 
8. 
RISKS/PRECAUTIONS .........................................................................................65 
8.1 
PA21 – Investigational Treatment .........................................................................65 
8.2 
Phoslyra – Active Control ......................................................................................66 
9. 
STUDY PROCEDURES .........................................................................................68 
9.1 
Description of Study Assessments .........................................................................68 
9.1.1 
Laboratory Assessments .....................................................................................68 
9.1.2 
Physical Examinations ........................................................................................70 
9.1.3 
Vital Signs...........................................................................................................70 
9.1.4 
Patient Reported Palatability and Acceptability Assessments ............................70 
9.1.5 
Dialysis Parameters.............................................................................................71 
9.1.6 
Diet......................................................................................................................71 
9.2 
Schedule of Assessments .......................................................................................71 
9.2.1 
Screening Visit (Visit 1) Procedures ..................................................................71 
9.2.2 
Washout Visit (Visits 2 to 4) Procedures ...........................................................72 
9.2.3 
Baseline Visit (Visit 5) Procedures .....................................................................73 
9.2.4 
Treatment Visit (Visits 6 to 16) Procedures .......................................................74 
9.2.4.1 
Stage 1 Visit (Visits 6 to 11) Procedures .........................................................74 
9.2.4.2 
Stage 2 Visit (Visits 12 to 16) Procedures .......................................................76 
9.2.5 
Visit 17 Follow-Up Procedures ..........................................................................77 
9.2.6 
Post Study Treatment ..........................................................................................78 
10. EVALUATION, RECORDING AND REPORTING OF AES AND 
SAES ..........................................................................................................................79 
10.1 
Definitions..............................................................................................................79 


 
 
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10.1.1 
Reference Safety Information .............................................................................79 
10.1.2 
Adverse Event .....................................................................................................79 
10.1.3 
Adverse Drug Reaction .......................................................................................79 
10.1.4 
Unexpected AE/ADR .........................................................................................79 
10.1.5 
Serious Adverse Event ........................................................................................79 
10.1.6 
Suspected Unexpected Serious Adverse Reaction..............................................80 
10.2 
AE Descriptors .......................................................................................................80 
10.2.1 
Intensity/Severity Categorisation ........................................................................80 
10.2.2 
Causal Relationship Categorisation ....................................................................81 
10.2.3 
Outcome Categorisation .....................................................................................82 
10.2.4 
Symptoms and Signs of the Disease under Study ..............................................82 
10.2.5 
Clinical Laboratory Evaluations .........................................................................83 
10.2.6 
Abuse, Misuse, Overdose and Medication Error ................................................83 
10.3 
Reporting Procedure for AEs, SAEs and Pregnancy .............................................83 
10.3.1 
Adverse Events ...................................................................................................83 
10.3.2 
Serious Adverse Events ......................................................................................84 
10.3.2.1 
Elective Surgery/Routine Examination............................................................87 
10.3.3 
Pregnancy............................................................................................................87 
11. DSMB PROCEDURES ...........................................................................................89 
12. STATISTICAL ANALYSIS ...................................................................................90 
12.1 
Statistical Methods .................................................................................................90 
12.2 
Sample Size and Power Calculations .....................................................................90 
12.3 
Populations .............................................................................................................90 
12.3.1 
FAS Population ...................................................................................................90 
12.3.2 
PPS Population ...................................................................................................90 
12.3.3 
Safety Population ................................................................................................90 
12.4 
Background and Demographic Characteristics ......................................................91 
12.5 
Study Medication ...................................................................................................91 
12.6 
Concomitant Therapy.............................................................................................91 
12.7 
Efficacy Evaluations ..............................................................................................91 
12.7.1 
Primary................................................................................................................91 
12.7.2 
Secondary............................................................................................................91 
12.8 
Safety Evaluations .................................................................................................92 
12.9 
Other Evaluations...................................................................................................93 
12.9.1 
Patient Reported Palatability and Acceptability .................................................93 
13. STUDY ETHICAL CONSIDERATIONS .............................................................94 
13.1 
Ethical Conduct of the Study .................................................................................94 
13.2 
Informed Consent and Assent ................................................................................94 
13.3 
Institutional Review Board or EC/IEC ..................................................................94 
14. QUALITY CONTROL AND QUALITY ASSURANCE .....................................96 
15. ADMINISTRATIVE PROCEDURES ...................................................................97 
15.1 
Sponsor’s Responsibilities .....................................................................................97 


 
 
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15.1.1 
Study Supplies ....................................................................................................97 
15.1.2 
Insurance .............................................................................................................97 
15.1.3 
Investigator Training...........................................................................................97 
15.1.4 
Study Monitoring ................................................................................................97 
15.2 
Investigator’s Responsibilities ...............................................................................98 
15.2.1 
Reporting and Recording of Data .......................................................................98 
15.2.2 
Source Documentation ........................................................................................98 
15.2.3 
Records Retention ...............................................................................................99 
15.2.4 
Site Documentation.............................................................................................99 
16. PROCEDURE 
FOR 
MODIFICATION 
OF 
PROTOCOL 
OR 
PREMATURE TERMINATION OF THE STUDY ...........................................100 
16.1 
Protocol Waivers, Deviations and Violations ......................................................100 
16.2 
Protocol Amendments ..........................................................................................100 
16.3 
Study Termination ...............................................................................................100 
17. POLICY FOR PUBLICATION AND PRESENTATION OF DATA ..............101 
18. REFERENCES .......................................................................................................102 
 


 
 
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LIST OF TABLES 
Page 
Table 1 
Schedule of Events .....................................................................................15 
Table 2 
Summary of Blood Samples ......................................................................17 
Table 3 
Stage 1 Starting Dose of PA21: Total Daily Dose .....................................35 
Table 4 
PA21 Dosing Regimens .............................................................................35 
Table 5 
Stage 1 Starting Dose and Dosing Regimen of Phoslyra (All Age 
Group) ........................................................................................................35 
Table 6 
Maximum Daily Dose of Phoslyra ............................................................36 
Table 7 
Age Related Safety Limits of Serum Phosphorus......................................36 
Table 8 
Recommended Maximum Oral and/or Enteral Phosphorus Intake 
for Children with CKD ..............................................................................38 
Table 9 
Age Related Safety Limits for Total Calcium ...........................................39 
Table 10 
Minimum Number of Randomised Subjects by Age Group ......................42 
Table 11 
Age Related Serum Phosphorus Targets Post-Randomisation ..................43 
Table 12 
Overview of Formulations .........................................................................52 
Table 13 
Responsibility for Manufacture, Quality Control, Primary 
Packaging and Batch Release ....................................................................52 
Table 14 
Addresses of Drug Product Manufacturers ................................................52 
Table 15 
Composition of PA21 Chewable Tablet ....................................................53 
Table 16 
Composition of PA21 Powder for Oral Suspension ..................................53 
Table 17 
Summary of Quantitative Composition and Function for Phoslyra ..........54 
Table 18 
Dosing of PA21 Powder for Oral Suspension: Subjects Age 0 to 
<1 Year ......................................................................................................56 
Table 19 
Dosing of PA21 Powder for Oral Suspension: Subjects Age ≥1 
Year to <6 Years ........................................................................................56 
Table 20 
Dosing of PA21 Powder for Oral Suspension: Subjects Age ≥6 
Years to <9 Years ......................................................................................56 
Table 21 
Dosing of PA21 Powder for Oral Suspension: Subjects Age ≥9 
Years to <18 Years ....................................................................................57 
Table 22 
Dosing of PA21 Tablet: Subjects Age ≥6 Years to <9 Years ....................57 
Table 23 
Dosing of PA21 Tablet: Subjects Age ≥9 Years to <18 Years ..................58 
Table 24 
Total Daily Dose Phoslyra® (mL/Day) ......................................................58 
Table 25 
Dosing of Phoslyra® ...................................................................................59 
Table 26 
Oral Drugs that Have to be Separated From Phoslyra® .............................64 
Table 27 
Laboratory Assessments ............................................................................69 
Table 28 
Age Related Serum Phosphorus Targets for Washout Period ...................72 


 
 
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Table 29 
Causal Relationship Categories .................................................................81 


 
 
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LIST OF FIGURES 
Page 
Figure 1 
Study Design ..............................................................................................14 
 


 
 
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LIST OF APPENDICES 
Page 
Appendix 1 
Serious Adverse Event Form (Sample)....................................................109 
Appendix 2 
Report on Exposure to Medicines During Pregnancy (Sample) ..............111 
Appendix 3 
Guidelines for Administering Informed Consent ....................................113 
 


 
 
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LIST OF ABBREVIATIONS 
ADI 
Acceptable daily intake 
ADR 
Adverse drug reaction 
AE 
Adverse event 
CKD 
Chronic kidney disease 
CRF 
Case report form 
CRO 
Contract Research Organisation 
DDI 
Drug-drug interaction 
DRI 
Dietary referenced intake 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 
ESRD 
End-stage renal disease 
EU 
European Union 
FAS 
Full analysis set 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice 
HCl 
Hydrochloride 
HD 
Haemodialysis 
HP 
Hyperphosphataemia 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
iPTH 
Intact parathyroid hormone 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
KDOQI 
Kidney Disease Outcomes Quality Initiative 
Kt/V 
K=Dialyser clearance of urea; t=Dialysis time; V=Patient’s total body 
water 
LD 
Low dose 


 
 
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m/m 
Mass fraction 
MD 
Maintenance dose 
NKF 
National Kidney Foundation 
PB 
Phosphate binder 
PD 
Peritoneal dialysis 
PG 
Propylene glycol 
PPS 
Per-protocol set 
SAE 
Serious adverse event 
TEAE 
Treatment-emergent adverse event 
UK 
United Kingdom 
US 
United States 
Vifor Pharma 
Vifor Pharma/Vifor International Ltd. 
WMA 
World Medical Association 
 


 
 
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1. INTRODUCTION AND BACKGROUND 
1.1 
Background of the Disease and Treatment Options 
Hyperphosphataemia (HP) is a common and serious complication in patients with chronic 
kidney disease (CKD), particularly those with end-stage renal disease (ESRD) requiring 
dialysis. In the paediatric population, CKD is most commonly caused by congenital 
anomalies of the kidney and urinary tract such as aplasia/hypoplasia/dysplasia and 
obstructive uropathy. The frequency of such conditions is low. Glomerular diseases of 
various aetiologies, (e.g., polycystic kidneys, pyelonephritis) can also cause CKD, but 
with a lower frequency [1,2,3,4]. HP plays an important role in the pathophysiology of 
major CKD complications for example secondary hyperparathyroidism [5,6,7], renal bone 
disease [8,9] and cardiovascular disease [10,11,12,13], and appears to promote the 
progression of CKD towards ESRD [3]. High levels of serum phosphorus are considered 
to be a risk factor for mortality, morbidity and hospitalisation in patients with ESRD. 
[14,15,16,17]. Complications most relevant to the paediatric population are renal bone 
disease, also called renal osteodystrophy (sometimes referred to as mineral bone disease), 
cardiovascular disease and growth failure [18-22].  
In 2011, in 14 European countries, the prevalence of dialysis and transplantation in the 
age group 0-19 years was 2,098 patients [23]. The incidence gradually increases after the 
age of 5 years, reaching a maximum in adolescents. In the US, 751 prevalent cases of 
ESRD were reported in 2010 in patients aged 0-19. Thirty-eight per cent receive a 
transplant in the first year of being on the transplant list [24]. Again, the incidence 
increases with age. A study on the epidemiology of CKD conducted in several Latin 
American countries showed a wide variation in incidence that ranged from 2.8 to 15.8 
new cases per million of the age related population [25]. CKD is a major health problem 
in Southeast Asia where the true prevalence is unknown but estimates suggest that it may 
be more than reported in Western societies. The majority of the affected individuals are 
young, in the most productive years of their lives [26]. Malaysia is the only country in 
Southeast Asia with a national registry [27]. According to the European Paediatric 
Dialysis Working Group, HP has been observed in children at glomerular filtration rate 
<40 mL/min/1.73 m2, and is almost always present in children on dialysis [28].  
Phosphorus concentrations vary with age, with the normal range declining from birth to 
adult levels. The concentrations are higher in children than in adults, since phosphorus is 
necessary for growth. Phosphorus levels defining HP vary with age. In adults, HP is 
defined as a fasting serum phosphorus concentration >1.8 mmol/L (5.5 mg/dL) [29], 
whereas in children HP is characterised by a level of serum phosphorus above the upper 
normal limit for an age group [30]. 
Transplantation is the preferred treatment in the paediatric population, and dialysis is used 
for the relatively limited period of time waiting for the transplant, or in patients not 
qualifying for renal transplantation [3,31]. However, the time interval waiting for 
transplantation is variable. Kovalski et al, 2007 [32] reported that more than 75% of 


 
 
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children require chronic dialysis while awaiting transplantation, with waiting periods 
varying between a few months and several years.  
HP cannot be satisfactorily controlled by dietary restriction alone in these patients. In 
children protein restriction was shown not to be effective in slowing progression of CKD 
and is generally not recommended due to the concern of adverse outcomes on growth and 
development [2,33]. In addition, dialysis is not particularly effective in removing 
phosphate (as phosphates are largely stored intracellularly after gastrointestinal (GI) 
absorption), therefore it is necessary to employ therapeutic means of binding phosphate to 
reduce dietary uptake. 
A number of phosphate binders (PBs) are currently available for treating HP in adults 
with chronic renal failure and/or dialysis (haemodialysis (HD), peritoneal dialysis (PD)). 
The use of PBs for treatment of HP in paediatric patients with advanced CKD is 
widespread [28,34,35,36,37]. Although the active substances are not approved in 
paediatrics for this indication, National Kidney Foundation (NKF) Kidney Disease 
Outcomes Quality Initiative (KDOQI) Guidelines and the UK National Institute for 
Health and Clinical Excellence recommend use of PBs in children [35,38]. These 
guidelines recommend calcium-based PBs as the first choice, in addition to dietary 
management. Dosing instructions for the paediatric population are included for some 
calcium carbonate PBs [39,40]. To date, there is experience with the use of 
calcium-containing phosphate adsorbents in paediatric patients [41,42], although their use 
is associated with the risk of hypercalcaemia. Calcium salts (carbonate, citrate, acetate) 
can significantly reduce (but not completely prevent) the uptake of phosphate into the 
blood [43]. None of the newer aluminium-free, calcium-free PBs (sevelamer or 
lanthanum carbonate) are approved for use in the paediatric population. To date clinical 
investigations have been conducted with results available on 18 and 15 patients treated 
with sevelamer hydrochloride (HCl) in 2 studies [44,45]. 
In adults, although widely used [46], calcium salts are limited by the development of 
hypercalcaemia, which has been reported to occur in over 50% of CKD patients on HD 
[47]. Furthermore, calcium salts exacerbate hypercalcaemia caused by resorption of 
calcium from the bones, particularly in patients receiving active Vitamin D metabolites 
(which increase intestinal calcium absorption) or when bone turnover is low [48]. In 
conjunction with raised phosphorus levels, this may contribute to vascular calcification 
and arterial and coronary sclerosis [10,11,12,49]. For this reason it has been suggested 
that calcium-based PBs should be avoided in many, if not most, patients who are 
undergoing dialysis [50]. Use of calcium salts may also result in over suppression of 
parathyroid hormone [49]. Aluminium salts are less often used and should be avoided 
because of toxicity due to aluminium absorption which may lead to Vitamin D-resistant 
osteomalacia and various neurological problems including encephalopathy and dementia 
[51,52]. Newer products include a cationic polymer (sevelamer HCl, sevelamer 
carbonate) and lanthanum carbonate. Sevelamer is a non-absorbable, cationic polymer 
capable of reversibly binding anions such as phosphate [53,54]. It is effective in reducing 


 
 
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phosphorus levels [9], but has a relatively high pill burden, requires swallowing of large 
tablets without chewing, and can lead to GI problems [55,56], all of which in turn 
potentially lead to compliance problems, thereby reducing efficacy. Lanthanum carbonate 
is another PB which appears to be well tolerated and has a reduced pill burden compared 
to sevelamer [57,58]; however, low but measurable absorption of lanthanum has been 
observed [59,60], raising potential toxicity concerns.  
Due to the clinical limitations of the available phosphate adsorbents, there is a therapeutic 
need to develop a phosphate adsorbent which is free from aluminium and unlikely to 
induce hypercalcaemia and has thus less potential for hypercalcaemic events. Hence, an 
improved PB with a lower pill burden, better safety and tolerability profile, and improved 
compliance could contribute to better control of serum phosphorus in both adult and 
paediatric patients with CKD. 
Vifor Pharma has developed a new non calcium-based, oral iron containing PB, PA21 
(sucroferric oxyhydroxide), for therapeutic use in the control of serum phosphorus levels 
in patients with CKD undergoing dialysis [61]. The PA21 drug substance is practically 
insoluble and possesses a high phosphate adsorption capacity in combination with a low 
iron release. Following oral administration, PA21 adsorbs the dietary phosphate in the GI 
tract, preventing its uptake into the blood, thereby reducing the serum level of 
phosphorus. The phosphate bound to PA21 is subsequently eliminated through the faeces. 
1.2 
Summary of Nonclinical and Clinical Data 
Details regarding the nonclinical and clinical data which support the rationale for the 
indication under investigation can be found in the current PA21 Investigator’s Brochure 
(IB). 
In vitro data show that PA21 has a high, pH-dependant phosphate-binding capacity 
optimised at a pH of 3 to 8 [62]. It exhibits minimal release of iron across the range of pH 
values found in the GI tract. A dose of 500 mg (iron) binds a minimum of phosphate 
corresponding to 105 mg phosphorus under validated laboratory conditions at pH 3 [63]. 
The safety and efficacy of PA21 has been assessed in over 65 nonclinical studies. 
Generally, the nonclinical studies have demonstrated unremarkable findings and do not 
raise potential safety issues in humans. PA21 was shown to be well tolerated in mice, rats, 
dogs, and rabbits at doses exceeding the maximal expected clinical dose for adults and 
children. The only findings of note in the nonclinical programme were findings in 
carcinogenicity studies performed in mice and rats. There was no clear evidence of a 
carcinogenic effect in mice. Mucosal hyperplasia, with diverticulum/cyst formation was 
observed in the colon and caecum of mice after 2 years treatment, but this was considered 
a species-specific effect with no diverticula/cysts seen in long-term studies in rats or dogs. 
In rats, there was a slightly increased incidence of benign C-cell adenoma in the thyroid 
of male rats given the highest dose of PA21. This is thought to be most likely an adaptive 


 
 
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response to the pharmacological effect of the drug, and not clinically relevant. Further 
details of these studies can be found in the current PA21 IB.  
Given the insolubility and degradation characteristics of PA21, and the minimal 
absorption of the active moiety (sucroferric oxyhydroxide) conventional clinical 
pharmacology studies are not possible. The Phase 1 clinical programme has therefore 
focussed on measures for phosphate binding capacity, iron release and resorption, and 
drug-drug interactions (DDIs). 
The Vifor Pharma clinical development programme comprises 1,112 adult subjects 
treated with PA21 in 7 Phase 1 clinical studies with PA21 and 2 pivotal efficacy and 
safety studies (Phase 2 study PA-CL-03A and Phase 3 study PA-CL-05A with its safety 
extension study, PA-CL-05B). A preliminary, Investigator-initiated Phase 1 study has 
also been published [64]. In addition, 2 supportive Phase 3 studies (PA1301, PA1304) 
have been conducted by Vifor’s Japanese partner, Kissei Pharmaceuticals, Co., Ltd. 
Early evidence of the efficacy and safety of PA21 was demonstrated in the initial Phase 1 
studies. In the Phase 1 absorption, distribution, metabolism and elimination study 
Q-24120, a significant reduction in serum phosphorus levels was seen in CKD subjects 
treated with PA21 2,000 mg iron/day for 7 days, but not in healthy subjects. Similarly, no 
significant changes in serum phosphorus were seen in any of the Phase 1 studies 
conducted in healthy subjects, including dose-ranging/dose-escalation tolerability studies 
and DDI studies. Across studies in healthy volunteers, the phosphorus lowering potential 
of PA21 was suggested with a trend towards slightly reduced urinary phosphorus 
excretion. PA21 was well tolerated in these studies with mainly mild GI adverse events 
(AEs) reported (e.g., diarrhoea and discoloured faeces). Furthermore, in Study Q-24120, 
absorption of iron from PA21 was low in CKD patients (e.g., 0.04%) indicating that the 
potential for iron accumulation is expected to be low in CKD patients. 
Efficacy and safety have been further established in 2 pivotal clinical studies: 
PA-CL-03A and PA-CL-05A/PA-CL-05B which included 835 PA21-treated CKD 
patients on dialysis. A rapid reduction in serum phosphorus levels was demonstrated in 
both these studies at doses of ≥1,000 mg iron/day PA21 and was maintained over 
52 weeks in PA-CL-05A/05B. 
Study PA-CL-03A was a 6-week open-label, randomised, active-controlled, dose-ranging 
study (250 to 2,500 mg iron/day PA21) in CKD patients on HD. PA21 doses of 1,000 to 
2,500 mg iron/day were shown to significantly reduce serum phosphorus in a 
dose-dependent manner whereas the 250 mg iron/day low dose (LD) was shown to be 
ineffective. Pair-wise comparisons of the PA21 LD (250 mg iron/day) to each of the 
higher PA21 doses for the primary endpoint (change from baseline in serum phosphorus) 
were statistically significant for the 2,000 mg iron/day and 2,500 mg iron/day dose groups 
in the full analysis set (FAS), and for all of the higher dose groups in the per-protocol set 
(PPS). The 1,000 and 1,500 mg iron/day doses of PA21 showed similar efficacy to 
4.8 g/day of sevelamer HCl (Renagel®). 


 
 
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Study PA-CL-05A was a confirmatory, 27-week, 2-stage, re-randomisation, withdrawal 
study demonstrating maintenance of efficacy and safety of PA21 in CKD patients on HD 
and non-inferiority compared to sevelamer carbonate (Renvela®) in CKD patients on HD 
or PD. In Stage 1, subjects received PA21 (N=707) at a starting dose of 1,000 mg 
iron/day, or sevelamer carbonate (N=348) at a starting dose of 4.8 g/day. (Note: As both 
sevelamer HCl and sevelamer carbonate contain the same active moiety, and are 
therapeutically equivalent, “sevelamer” will be used throughout the remainder of the 
protocol.) 
Dosing of both drugs was titrated to effect, based on the upper limit of the KDOQI target 
serum phosphorus range of 1.13 to 1.78 mmol/L (3.5 to 5.5 mg/dL), after which subjects 
were continued on a maintenance dose (MD) of either PA21 or sevelamer. The maximum 
dose of PA21 administered was 3,000 mg iron/day. 
A rapid reduction in serum phosphorus levels was observed in both treatment groups, and 
at Week 12, PA21 was shown to be non-inferior to sevelamer, with a markedly reduced 
pill burden. Efficacy was maintained through Week 24 (end of Stage 1). In Stage 2, the 
continued effect of the Week 24 MD in subjects on HD was demonstrated in the 3-week 
withdrawal phase in which the PA21 MD (mean of 1,480 mg iron/day (2.9 tablets/day) 
was shown to be superior (p<0.001) to the non-effective LD control (which in this study 
essentially functioned as a placebo control), thereby confirming the long-term efficacy of 
PA21 in lowering serum phosphorus. The effectiveness of PA21 was further supported by 
the Japanese Phase 3 studies. 
The long-term maintenance of treatment effect over 52 weeks was demonstrated in the 
extension study, PA-CL-05B, in which subjects continued treatment with the same PB 
and at the same dose as at the end of Study PA-CL-05A. Minimal changes in serum 
phosphorus levels were observed in both treatment groups, with mean serum phosphorus 
levels remaining controlled at around the upper limit of the KDOQI target range 
(i.e., 1.78 mmol/L (5.5 mg/dL)). Based on subgroup analyses, efficacy was not affected 
by age, gender, race, or dialysis modality (HD or PD). The mean daily dose of PA21 in 
PA-CL-05B was 2,020 mg iron/day (4.0 tablets/day) compared to 8.1 g/day sevelamer 
(10.1 tablets/day). 
Together, the combined studies PA-CL-05A/05B demonstrated the efficacy of PA21 in 
control of serum phosphorus levels, both in initially lowering, and then maintaining, 
serum phosphorus levels through 52 weeks of treatment, and with a reduced pill burden 
compared to sevelamer. Over the combined studies, the mean (median) number of 
tablets/day was 3.3 (3.1) and 8.7 (8.1), for PA21 and sevelamer, respectively. 
PA21 was well tolerated in these pivotal studies at doses of up to 3,000 mg iron/day for 
up to 55 weeks duration. With the exception of common GI events of diarrhoea and 
faeces discolouration, recognised effects of oral compounds containing iron, the overall 
AE profile of PA21 was broadly similar to sevelamer, and consistent with background 
disease in this population of CKD patients on dialysis. 


 
 
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In studies PA-CL-05A/05B combined, treatment-emergent adverse events (TEAEs) of 
diarrhoea were reported in 23.6% of PA21-treated subjects (versus 11.5% of 
sevelamer-treated subjects). The majority of these diarrhoea TEAEs occurred early after 
starting treatment, were mild in severity, and resolved with continued use of PA21. The 
second most common GI TEAE in the PA21 group was discoloured faeces (16.1%). No 
safety concerns were raised by a comprehensive assessment of laboratory tests which 
included electrocardiograms, haematology, and chemistry tests. 
There were no remarkable differences in the incidence of severe AEs, serious adverse 
events (SAEs), or deaths between PA21 and sevelamer groups over 52 weeks of 
treatment. Very few of the severe TEAEs and SAEs were considered related to study 
medications with no differences between groups. Thirty-five (3.3%) subjects died during 
the study/follow-up: 21 (3.0%) in the PA21 treatment group and 14 (4.0%) in the 
sevelamer group. No deaths were considered related to study treatments. 


 
 
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2. RATIONALE 
As the efficacy and safety of PA21 has been confirmed in adult patients with CKD on 
dialysis, the aim of this Phase 3 clinical study is to demonstrate similar efficacy of PA21 
in paediatric and adolescent patients with CKD, and to provide safety and dosing 
information for this patient population. The Phoslyra group provides information for a 
descriptive comparison of PA21 against a commonly used calcium-based phosphate 
binder (calcium acetate). Approximately130 patients (PA21:100 subjects; Phoslyra: 
30 subjects) will be recruited and randomised in a 2-stage study design. 
A Data and Safety Monitoring Board (DSMB) will oversee the study to protect the safety 
of study participants. 
The screening period is up to 4 weeks and the washout period is up to 3 weeks. 
Stage 1 is an open-label, randomised, active-controlled, dose titration of PA21 and 
Phoslyra® for up to 10 weeks. 
Stage 2 is an open-label, long-term safety extension of PA21 and Phoslyra for 24 weeks. 
Follow-up is 14 days after the final on-treatment visit. 
An open-label design has been employed as it is not considered essential or necessary to 
conduct the study in a double-blind fashion to obtain the required safety and efficacy 
data. In addition, a double-dummy design comparing PA21 with Phoslyra would lead to 
an unreasonably high number of doses to be taken by the subjects who typically are 
already taking a large number 
of medications to treat other co-existing 
diseases/morbidities. Dialysis patients have been reported to have one of the highest daily 
medication burdens of any chronic disease state, and in 1 study the median daily pill 
burden was 19 [65]. In addition, the key efficacy parameter - serum phosphorus level - is 
an objective, precise and reproducible blood assay routinely performed in clinical 
laboratories and is not subject to bias as a consequence of the open design. Finally, to 
minimise selection bias, a central global randomisation procedure (using interactive 
response technology (IRT)) will be employed. 
A dose titration scheme is used for both PA21 and Phoslyra since this reflects normal 
clinical practice. In order to protect study participants, controlled starting doses of both 
treatment groups will be administered at the beginning of Stage 1, as detailed in Table 3 
and Table 5. Phoslyra subjects in each age group will all receive either the same mg/kg 
dose or receive an equivalent dose of their previous PB, calcium-based or sevelamer, 
whichever is considered most appropriate by the Investigator. Subjects can have their 
dose titrated for efficacy reasons, provided they have received that dose for a minimum of 
2 weeks. Titration can occur at any time for safety or tolerability reasons. Since many 
factors affect serum phosphorus levels (such as diet and dialysis) doses of PBs have to be 
individualised for each patient. Experience from Vifor Pharma studies in adults show that 
maximum phosphorus lowering effects of PA21 are usually seen within 1-2 weeks of 


 
 
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PA21 treatment. Moreover, in published paediatric trials with various PBs, dose titration 
intervals of 1 to 4 weeks are used [44,45,66,67,68]. 
Table 3 
Stage 1 Starting Dose of PA21: Total Daily Dose 
Age 
PA21 
(mg Iron/Day) 
0 to <1 year 
125 
≥1 year to <6 years 
500 
≥6 years to <9 years 
750 
≥9 years to <18 years 
1,250 
 
In addition, maximum doses per day, plus maximum dose increases and decreases, for 
both treatments (for each age group) will be controlled as detailed in Table 4, Table 5 and 
Table 6. 
Table 4 
PA21 Dosing Regimens 
Age 
PA21 
(mg Iron/Day) 
Dose Increases 
or Decreases 
Maximum 
Dose 
0 to <1 year 
125 or 250 
1,000 
≥1 year to <6 years 
125 or 250 
1,250 
≥6 years to <9 years 
125, 250 or 375 
2,500 
≥9 years to <18 years 
250 or 500 
3,000 
 
Table 5 
Stage 1 Starting Dose and Dosing Regimen of Phoslyra (All Age 
Group) 
Initial Dose 
Dose Increase 
or Decrease 
Maximum Dose 
(up to 35 kg) 
Maximum Dose 
(above 35 kg) 
0.45 mL/kg/d 
0.1 to 0.2 mL/kg/d 
1.25 mL/kg/d 
44 mL/d 
Note: 
Individual doses will be administered in 0.5 mL increments. 


 
 
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Table 6 
Maximum Daily Dose of Phoslyra 
Body 
Weight 
(kg)  
Phoslyra 
Maximum Dose 
mL/day 
Propylene Glycol 
mg/kg/day(1) 
Elemental Ca 
mg/day(2) 
5 
6.0(1) 
24 
202.6 
10 
12.5(1) 
25 
422 
15 
18.5(1) 
25 
624.6 
20 
25(1) 
25 
845 
25 
31.0(1) 
25 
1,046.6 
30 
37.5(1) 
25 
1,267 
35 
43.5(1) 
25 
1,468.6 
40 
44(2) 
22 
1,487.2 
45 
44(2) 
19.6 
1,487.2 
50 
44(2) 
17.6 
1,487.2 
60 
44(2) 
14.7 
1,487.2 
70 
44(2) 
12.6 
1,487.2 
1 Acceptable daily intake of 25 mg/kg/day for propylene glycol. 
2 Limit of the calcium intake (1,500 mg/day). 
 
Table 7 
Age Related Safety Limits of Serum Phosphorus 
Age 
Upper Safety Limit 
Lower Safety Limit 
mmol/L 
mg/dL 
mmol/L 
mg/dL 
0 to <1 year 
2.91 
9.0 
1.62 
5.0 
≥1 year to <6 years 
2.42 
7.5 
1.45 
4.5 
≥6 years to <13 years 
2.26 
7.0 
1.13 
3.5 
>13 years to <18 years 
2.26 
7.0 
0.81 
2.5 
Note: 
Limits calculated as upper limit of normal ±20% based on National Kidney Foundation Kidney Disease Outcomes Quality 
Initiative, 2008. 
 
Throughout the study stopping rules will apply if a subject’s serum phosphorus level 
exceeds, or is below, the safety limits detailed in Table 7 (see Section 5.4). 
A period of 1-3 weeks for the washout period is considered appropriate to allow sufficient 
time for washout of previous PBs before subjects are randomised into Stage 1. HP is an 
asymptomatic condition and its adverse consequences require many years to develop. 
Therefore this short period should not lead to adverse clinical effects. Subjects will 
continue to receive their regular dialysis sessions and will be advised to adhere to their 
phosphate restricted diet; both measures in themselves will limit the rise in serum 
phosphorus levels. Furthermore, a serum phosphorus safety withdrawal limit detailed in 
Table 7 will ensure that subjects do not have excessively high serum phosphorus levels 
during this short period.  
Clinical data to date have shown that PA21 is generally well tolerated in adults and there 
have been no safety signals to indicate that a paediatric study should not be conducted. 


 
 
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Overall, the safety profile of PA21 in the paediatric population is expected to be 
comparable to that in adults, similar to calcium containing PBs and sevelamer, for which 
a similar safety profile between adult and paediatric patients has been shown [8,35,44].  
The starting doses of PA21 have been determined using the known phosphate-binding 
capacity of PA21, and the recommendations of the NKF KDOQI nutrition guidelines for 
children with CKD [69]. The phosphate binding capacity is expressed as mg phosphorus, 
bound by 1 mg of the iron content of PA21. The biochemistry of phosphate binding has 
been well characterised. Results from the nonclinical studies have provided robust 
information allowing calculation of the appropriate dose of PA21 for the investigation of 
the phosphate binding capacity in vivo. PA21 has been shown to bind in vivo 
approximately 0.2 mg of phosphorus for each mg of iron at pH 3.0 (IB). A dose of 
500 mg iron would therefore be expected to bind 100 mg phosphorus. 
In addition to the amount of dietary phosphate to be bound by the starting doses, 
consideration has also been given to clinical experience with PA21. In the Phase 3 studies 
(PA-CL-05A and PA-CL-05B), a maximum dose of 3,000 mg iron/day has been safely 
given to adult patients with CKD, equating to an exposure of approximately 43 mg 
iron/kg (assuming a 70 kg person). It should be noted that the AE profile of PA21 is 
mainly defined by GI events, primarily diarrhoea which are mainly mild and not 
treatment limiting. The proposed starting doses of PA21 are similar or below this 
exposure level. For example, with reference to growth charts (e.g., Centers for Disease 
Control and Prevention growth charts), a baby of approximately 5.0 kg would be exposed 
to approximately 25.0 mg iron/kg of PA21. In the event that the starting dose is not well 
tolerated, the protocol will allow downward titration. 
For Phoslyra, the phosphate binding capacity in vivo of calcium acetate is expected to be 
45 mg of phosphorus bound for each 1 g of calcium acetate [35]. Each 5 mL of Phoslyra 
contains 667 mg calcium acetate (equal to 169 mg calcium i.e., each 1 mL contains 
33.8 mg of calcium). A dose of 6.0 mL of Phoslyra would therefore be expected to bind 
approximately 36 mg phosphorus. 
The starting dose of Phoslyra was selected as 0.45 mL/kg/day, i.e., divided into 3 meals 
per day with approximately 0.15 mL/kg for each meal. The recommended Phoslyra 
starting dose in adults as per Phoslyra package insert is 10 mL with each meal or 
0.14 mL/kg/meal for a 70 kg adult, and most adult patients require 15 mL to 20 mL per 
meal [70] (0.21 to 0.28 mL/kg/meal). This dose range includes the estimated Phoslyra 
dose (0.27 mL/kg/meal) derived from the Pieper publication. On the basis of the 
publication by Pieper and the starting dose in adult patients (0.14 mL/kg/meal for a 70 kg 
adult), an initial paediatric starting dose for the titration stage was as 0.45 mL/kg/day, 
i.e., divided into 3 meals per day with approximately 0.15 mL/kg for each meal. The 
proposed starting doses for both PA21 and Phoslyra are shown in Table 3 and Table 5. 
Pieper et al, 2006 [44] reported that an adequate calcium acetate dose in paediatric 
patients is 110 mg/kg/day with a standard deviation of 44 mg/kg/day. The calcium acetate 


 
 
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concentration in Phoslyra is 133.4 mg/mL; a Phoslyra volume of 0.82 mL contains 
110 mg of calcium acetate. Thus, based on the publication by Pieper, an estimated 
adequate daily dose of Phoslyra would be 0.82 mL/kg/day and assuming 3 meals per day, 
the estimated dose per meal would be 0.27 mL/kg/meal.  
The dietary referenced intake (DRI) of phosphorus in children with CKD is shown in 
Table 8 [69], along with an estimate of the amount of phosphorus required to be bound 
per day in each of the age groups. In hyperphosphataemic children it is recommended that 
the phosphorus intake be limited to ≤80% of the DRI. 
Table 8 
Recommended Maximum Oral and/or Enteral Phosphorus Intake for 
Children with CKD 
Age 
DRI 
(mg/d) 
Recommended Phosphorus Intake (mg/d) 
VFMCRP Estimate PB Required 
to Bind Approx. (mg/day) 
(DRI Minus High PTH/High 
Phosphorus) 
High PTH and 
Normal Phosphorus(1) 
High PTH and 
High Phosphorus(2) 
0-6m 
100 
≤100 
≤80 
20 
7-12m 
275 
≤275 
≤220 
55 
1-3 y 
460 
≤460 
≤370 
90 
4-8 y 
500 
≤500 
≤400 
100 
9-18 y 
1,250 
≤1,250 
≤1,000 
250 
1 ≤100% of the DRI. 
2 ≤80% of the DRI. 
Notes: CKD=Chronic kidney disease; DRI=Dietary referenced intake; PB=Phosphate binder; PTH=Parathyroid hormone; 
VFMCRP=Vifor Fresenius Medical Care Renal Pharma. 
Source: Adapted from Kidney Disease Outcomes Quality Initiative Clinical Practice Guideline for Nutrition in Children with CKD: 
2008 Update [69]. 
 
Vifor Fresenius Medical Care Renal Pharma has estimated the amount of phosphorus 
required to be bound in each of the age groups based on the phosphorus intakes in 
Table 8. In establishing the daily maximum dose for Phoslyra, the maximum daily intake 
of calcium was also taken into consideration. The publication by Pieper et al, 2006 does 
not identify a maximum calcium acetate dose in the paediatric population. However, the 
paediatric KDOQI guidelines for patients with CKD (Stage 5) on dialysis recommend that 
the calcium intake from phosphate binders should be limited to 1,500 mg/day, equivalent 
to 45 mL of Phoslyra. 
As detailed in Table 17, the formulation of Phoslyra consists of propylene glycol (PG) 
USP. The PG concentration of Phoslyra is 20 mg/mL. Propylene glycol (PG) is a clear, 
colourless, water-soluble alcohol (1, 2-propanediol) used as a co-solvent in parenteral and 
non-parenteral pharmaceutical formulations containing active substances that are not 
highly soluble in water. It is also used in cosmetics products and in the food industry as a 
humectant, as a preservative and as a vehicle for flavours in preference to ethanol [71]. 
On the basis of metabolic and toxicological data, the Joint Food and Agriculture 
Organization of the United Nations/World Health Organization Expert Committee on 
Food Additives, International Programme on Chemical Safety, Chemical Safety 


 
 
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Information from Intergovernmental Organizations [72] defined an acceptable daily 
intake (ADI) of 25 mg/kg/day for PG from all sources. (The ADI value is based on the no 
observed effect level in a long-term toxicity study in rats of 2,500 mg/kg body 
weight/day). The ADI of 25 mg/kg/day has been used to evaluate the PG exposure in this 
paediatric study. The PG concentration of Phoslyra is 20 mg/mL. A Phoslyra dose greater 
than 1.25 mL/kg/day would therefore exceed the PG ADI for food products. Based on the 
limit of the calcium intake (1,500 mg/day), and ADI of PG (25 mg/kg/day), the maximum 
Phoslyra dose was determined in Table 5 and Table 6.  
A calcium–based PB (Phoslyra: calcium acetate) has been chosen as an active control to 
provide assay sensitivity and comparison with respect to the serum phosphorus lowering 
effects and AE profile of PA21 against a PB in a drug class commonly used in clinical 
practice. Although calcium acetate is not specifically approved for use in the paediatric 
population it has been chosen as the active comparator since calcium-based PBs are 
considered “gold-standard” for the treatment of HP in the paediatric patients under 
evaluation in this study [35,38]. No formal sample size has been calculated for the 
comparison with Phoslyra. The number of subjects that would be required to demonstrate 
equivalence or non-inferiority of PA21 against an active control would be too high and 
not feasible in a paediatric population. 
In order to reduce the risk of hypercalcaemia and hypocalcaemia, stopping rules will 
apply throughout the study if, a subject’s serum total corrected calcium exceeds, or is 
below the safety limits detailed in Table 9 (see Section 5.4). 
Table 9 
Age Related Safety Limits for Total Calcium 
Age 
Upper Safety Limit 
Lower Safety Limit 
mmol/L 
mg/dL 
mmol/L 
mg/dL 
0 to <1 year 
2.75 
11.0 
<1.9 
<7.6 
≥1 year to <6 years 
2.70 
10.8 
<1.9 
<7.6 
≥6 years to <13 years 
2.60 
10.3 
<1.9 
<7.6 
≥13 years to <18 years 
2.60 
10.2 
<1.9 
<7.6 
Note: 
Upper safety limits based on National Kidney Foundation Kidney Disease Outcomes Quality Initiative Nutrition Guidelines, 
2008. Lower limit based on literature (Paediatric Nephrology, 2nd edition) and personal communication. 
 
A recent study has shown that more frequent dosing of a PB throughout the day is more 
effective than once daily dosing [73]. In this study, subjects will be advised to take their 
treatment 3 times per day, where possible. This dosing regimen will allow more 
flexibility and better spread of drug administration during the day, thus ensuring that 
more meals can be consumed with a study treatment. 
In the Phase 2 and 3 adult studies only subjects undergoing dialysis were studied. This 
study, however, will recruit CKD Stage 4, 5 and 5D paediatric patients. This is considered 
appropriate since all types of patients are essentially similar with respect to causes and 
natural history of their renal failure. In addition, NKF KDOQI Guideline 6 [35] 


 
 
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recommends treatment with PBs for hyperphosphataemic paediatric patients with CKD 
Stages 2-5 and UK National Institute for Health and Clinical Excellence recommends use 
of PBs in hyperphosphataemic paediatric patients with CKD Stages 4-5 [38]. 


 
 
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3. STUDY OBJECTIVES 
3.1 
Primary Objective 
• To evaluate the efficacy of PA21 in reducing serum phosphorus levels in paediatric 
and adolescent subjects with CKD at the end of Stage 1. 
3.2 
Secondary Objectives 
• To evaluate the efficacy of PA21 in maintaining the serum phosphorus lowering 
effects in paediatric and adolescent subjects with CKD at the end of Stage 2. 
• To evaluate the safety of PA21 in paediatric and adolescent subjects with CKD. 
• To evaluate the efficacy of Phoslyra in reducing and maintaining serum phosphorus 
levels in paediatric and adolescent subjects with CKD at the end of Stages 1 and 2. 
• To evaluate the safety of Phoslyra in paediatric and adolescent subjects with CKD. 


 
 
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4. INVESTIGATIONAL PLAN 
4.1 
Overall Study Design 
This is a Phase 3, multicentre, randomised, prospective, open-label controlled study 
performed at global study centres. 
See Study Design (Figure 1) and Schedule of Events (Table 1). 
The study will aim to randomise approximately 130 subjects into the study via IRT. 
The study will also aim to randomise a minimum number of subjects from each age group 
(Table 10). 
Table 10 
Minimum Number of Randomised Subjects by Age Group 
Age 
PA21 
Phoslyra® 
0 to <1 year 
4 
1 
≥1 year to <6 years 
10 
3 
≥6 years to <9 years 
10 
3 
≥9 years to <18 years 
10 
3 
 
Subjects for whom signed and dated informed consent (and, where appropriate/required, 
assent) has been provided will be enrolled in the study and screened. 
The screening period is up to 4 weeks. 
The washout period is up to 3 weeks. 
Stage 1 is an open-label, randomised, active-controlled, dose titration period of PA21 and 
Phoslyra for up to 10 weeks. One hundred subjects will be randomised to receive PA21 
and 30 subjects will be randomised to receive Phoslyra. PA21 subjects will receive PA21 
at a starting dose based on their age, as detailed in Table 3. Phoslyra subjects will receive 
Phoslyra, either at a starting dose as detailed in Table 5, or, if considered more 
appropriate by the Investigator, at an equivalent dose of their previous PB, calcium-based 
or sevelamer. Doses of PA21 or Phoslyra will be increased or decreased as required for 
efficacy (to achieve age specific target serum phosphorus level as indicated in Table 11), 
provided a subject has been receiving that dose for a minimum of 2 weeks, and for safety 
or tolerability reasons at any time. Increases or decreases in dose and maximum doses are 
detailed in Table 4 for PA21, and Table 5 and Table 6 for Phoslyra. From Week 4, once a 
subject achieves the age specific target serum phosphorus level, as indicated in Table 11, 
they can move to Stage 2. 


 
 
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Table 11 
Age Related Serum Phosphorus Targets Post-Randomisation 
Age 
mmol/L 
mg/dL 
0 to <1 year 
1.62-2.52 
5.0-7.8 
≥1 year to <6 years 
1.45-2.10 
4.5-6.5 
≥6 years to <13 years 
1.16-1.87 
3.6-5.8 
≥13 years to <18 years 
0.74-1.45 
2.3-4.5 
Source: National Kidney Foundation Kidney Disease Outcomes Quality Initiative Nutrition Guidelines, 2008. 
 
Stage 2 is an open-label, long-term safety extension for 24 weeks. All subjects will enter 
this safety extension stage. During Stage 2: 
• Subjects will continue on the dose they received at the end of Stage 1, unless a dose 
change is required.  
• All subjects may have their dose titrated for efficacy to achieve age-specific target 
serum phosphorus levels as indicated in Table 11 (provided the subject has taken the 
dose for a minimum of 2 weeks) and safety or tolerability reasons at any time during 
Stage 2. Maximum doses and dose increases/decreases of PA21 and Phoslyra are 
detailed in Table 4, Table 5 and Table 6. 
The follow-up period will be 14 days after end of study treatment. 
The schedule of assessments is provided in the Schedule of Events (Table 1). 
Table 2 (Summary of Blood Samples), details visits where blood samples must be 
analysed by a central laboratory and visits where there is the option of having blood 
samples analysed by a local laboratory. 
Since subjects may become 18 years old during the study, all values quoted in the 
protocol for subjects <18 years will also apply to these subjects. Once a subject is 
18 years old they must provide informed consent, as described in the inclusion criteria 
(Section 5.2). 
The Investigator is responsible for ensuring that consideration is given to the post study 
care of the subject's medical condition. 
There will be an external DSMB for this study. 
Protocol waivers or exemptions are not allowed, with the exception of immediate safety 
concerns. Therefore adherence to the study design requirements, including those specified 
in the Schedule of Events, Table 1 are essential and required for study conduct. 
4.2 
Duration of Subject Participation and Study 
The expected duration of subject participation is a maximum of 43 weeks including up to 
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period; 24 weeks safety extension. All subjects, whether completing the study or 
withdrawn prematurely, will be followed up 14 days after their last study visit. 


 
 
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5. SELECTION AND WITHDRAWAL OF SUBJECTS 
5.1 
Number of Subjects 
For detailed justification of the sample size please refer to Section 12.2. 
Approximately 130 subjects will be randomised into the Stage 1 titration period of this 
study: 100 subjects will receive PA21 and 30 subjects will receive Phoslyra. The 
randomisation into Stage 1 will be stratified by age group with the objective of 
randomising a minimum number of subjects from each age group as detailed in Table 10. 
All eligible subjects will enter Stage 2, the safety extension stage. 
Recruitment will be on a competitive basis. 
No replacement of subjects will be allowed in Stages 1 or 2. 
5.2 
Inclusion Criteria 
Investigators must maintain a screening log of all potential study candidates that includes 
limited information about the potential candidate, date, and outcome of the screening 
process (e.g., enrolled into study, reason for ineligibility, or refused to participate). The 
following inclusion criteria must be met for each subject: 
1. Subjects 0 to <18 years at time of consent. 
2. Subjects with hyperphosphataemia i.e., with serum phosphorus levels indicated in 
Table 28.  
3. Subjects who are PB naïve or have been receiving stable doses of a PB(s) for at least 
1 month prior to screening. Subjects may be on stable doses of a maximum of 2 PBs. 
Subjects who have been receiving PBs will enter an obligatory washout period and 
may be randomised once their serum phosphorus levels are as indicated in Table 28. 
Subjects already receiving a PB but with serum phosphorus levels indicated in 
Table 28 may be eligible for randomisation without a washout period.  
4. Subjects ≥1 year with CKD Stages 4-5 defined by a glomerular filtration rate 
<30 mL/min/1.73 m2 or with CKD Stage 5D receiving adequate maintenance HD or 
PD for at least 2 months prior to screening.  
5. Subjects <1 year must have CKD. 
6. PD subjects must have had 1 month of unchanged PD prescription (volume and 
number of exchanges). Home HD subjects may be included (no nocturnal HD 
(overnight stay at site) will be allowed). 


 
 
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7. Appropriate written informed consent and, where appropriate/required assent, have 
been provided. Written informed consent (and, where appropriate/required, assent) 
must be provided before any study-specific procedures are performed, including 
screening procedures. 
8. Parents/legal guardians and, where appropriate/required, subjects with the ability to 
provide written informed consent, and where appropriate/required, assent, to 
understand the requirements of the study and abide by the study restrictions, and who 
agree to return for the required assessments, in the Investigator’s opinion. 
5.3 
Exclusion Criteria 
1. Subjects with hypercalcaemia at screening as indicated in Table 9. 
2. Subjects with intact parathyroid hormone (iPTH) levels >700 pg/mL at screening. 
3. Subjects who are PB naïve who weigh <5 kg at screening. Subjects receiving stable 
doses of PBs who weigh <6 kg at screening. (In order to comply with maximum blood 
sample volumes in paediatric clinical trials [75]). 
4. Subjects requiring feeding tube sizes ≤6 FR (French catheter scale). 
5. Subjects with planned or expected parathyroidectomy within the next 12 months, in 
the Investigator’s opinion. 
6. Subjects with history of: 
− 
Major GI surgery which, in the Investigator’s opinion, is likely to influence the 
outcome of treatment with PBs. 
− 
Significant GI disorders. 
7. Subjects with estimated life expectancy of less than 12 months. 
8. Subjects with known seropositivity to human immunodeficiency virus. 
9. Subjects with a history of haemochromatosis or other iron accumulation disorders.  
10. Subjects on PD with a history of peritonitis in the last 3 months or ≥3 episodes in the 
last 12 months. 
11. Subjects with hypocalcaemia (serum total corrected calcium <1.9 mmol/L; 
<7.6 mg/dL) at screening. 
12. Subjects with raised alanine aminotransferase or aspartate aminotransferase >3 times 
the upper limit of the normal range based on central laboratory results at screening. 
13. Subjects taking more than 2 PBs concomitantly prior to screening. 


 
 
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14. Subjects taking any prohibited medication(s) (See Section 7.7). 
15. Subject has known hypersensitivity and/or intolerance to any of the active substances 
or to any of the excipients to be administered. 
16. Subject has previously been randomised into this study. 
17. Subject is currently enrolled in or has completed any other investigational device or 
drug study <30 days prior to screening, or is receiving other investigational agent(s). 
18. Subject is pregnant (e.g., positive human chorionic gonadotropin test) or breast 
feeding.  
19. If of child-bearing potential, subject is not using adequate contraceptive precautions. 
Subject must agree to use a highly effective method of birth control during the study 
and for 1 month after the last dose of study medication. Adequate methods of birth 
control are defined as those which result in a low failure rate (i.e., <1% per year) 
when used consistently and correctly such as implants, injectables, combined oral 
contraceptives, some intra-uterine devices, sexual abstinence or vasectomised partner. 
Non-child-bearing potential includes being surgically sterilised at least 6 months prior 
to the study. 
20. Subject has a history of drug or alcohol abuse within 2 years prior to screening. 
21. Subject has a significant medical condition(s) e.g., uncontrolled diabetes, known 
hepatitis B surface antigen positivity and/or hepatitis C virus ribonucleic acid 
positivity or anticipated need for major surgery during the study, or any other kind of 
disorder that may be associated with increased risk to the subject, or may interfere 
with study assessments or outcomes. 
5.4 
Withdrawal of Subjects 
Subjects may voluntarily withdraw, or their parents/legal guardian may withdraw them, 
from study participation at any time without having to provide a reason. Subjects may be 
withdrawn because of the appearance of a new health condition requiring care or 
medications prohibited by the protocol, unacceptable AEs, refusal to continue treatment, 
or at the Investigator’s discretion if it is in the subject’s best interest. 
5.4.1 
Stopping Rules for Serum Phosphorus Levels 
At any time during the study if a subject’s phosphorus level exceeds or is below the safety 
limits indicated in Table 7: 
• The subject’s study medication must be adjusted and the subject must be asked to 
return for a visit 1 week after the value outside the safety limits indicated in Table 7 
was first seen i.e., irrespective of whether this was during Stage 1 or 2. 


 
 
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• At the next visit, 1 week after the value outside the safety limits indicated in Table 7 
was first seen; a blood sample for serum phosphorus will be taken. Once the site 
receives the blood sample result, if the serum phosphorus level is outside the target 
safety limits indicated in Table 7, the Investigator will inform the subject and, where 
appropriate, parent/legal guardian, (either directly or by phone) whether a dose 
increase or a dose decrease of study medication is indicated. The subject must return 
for a visit 1 week after the change in study medication dose. 
• At the next visit, 1 week after the change in study medication dose, a blood sample for 
serum phosphorus will be taken. Once the site has the blood sample result, if the 
subject’s phosphorus level still exceeds or is below the safety limits indicated in 
Table 7 then the subject must be withdrawn from the study. 
In addition, at each of the above visits, if the subject’s phosphorus level exceeds the upper 
safety limit indicated in Table 7, the site must advise the subject and parent/carer 
regarding a low phosphorus diet. 
The subject does not need to be withdrawn if the 2 follow-up results are outside of the 
safety limit, but in the opposite direction (i.e., one too high and one too low). In this 
situation, the subject’s PB dose must be adjusted and the subject must return in 1 week to 
provide a blood sample for serum phosphorus. Once the site has the blood sample result, 
if the subject’s phosphorus level still exceeds or is below the safety limits indicated in 
Table 7, then the subject must be withdrawn from the study. 
5.4.2 
Stopping Rules for Serum Corrected Total Calcium Levels 
At any time during the study, subjects will be withdrawn immediately if their serum 
corrected total calcium level exceeds 3.0 mmol/L (12 mg/dL) or is below 1.63 mmol/L 
(6.5 mg/dL). 
At any time during the study if a subject’s corrected total calcium level exceeds or is 
below the safety limits indicated in Table 9: 
• The subject should receive appropriate rescue intervention and must be asked to 
return for a visit 1 week after the value outside the safety limits indicated in Table 9 
was first seen. 
• At the next visit, 1 week after the value outside the safety limits indicated in Table 9 
was first seen; a blood sample will be taken. Once the site has the blood sample result, 
if the serum corrected total calcium level is outside the target safety limits indicated in 
Table 9, the Investigator will inform the subject and, where appropriate, parent/legal 
guardian, (either directly or by phone) whether a dose increase or a dose decrease in 
rescue medication or an alternative rescue medication is indicated. The subject must 
return for a visit 1 week after the change in rescue medication.  


 
 
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• At the next visit, 1 week after the change in rescue medication, a blood sample will be 
taken. Once the site has the blood sample result, if the subject’s corrected total 
calcium level still exceeds or is below the safety limits indicated in Table 9 then the 
subject must be withdrawn from the study. 
The subject does not need to be withdrawn if the 2 follow-up results are outside of the 
safety limit, but in the opposite direction (i.e., one too high and one too low). In this 
situation, the subject’s rescue medication must be adjusted and the subject must return in 
1 week to provide a blood sample. Once the site has the blood sample result, if the 
subject’s serum corrected total calcium level still exceeds or is below the safety limits 
indicated in Table 9, then the subject must be withdrawn from the study. 
Appropriate rescue intervention for hypercalcaemia may include: 
• Reduce or stop dose of active Vitamin D metabolite. 
• Increase dose of calcimimetic. 
• Reduce calcium content in dialysate. 
• Phoslyra subjects: reduce dose of Phoslyra. 
Appropriate rescue intervention for hypocalcaemia may include: 
• Increase dose of active Vitamin D metabolite. 
• Decrease dose of calcimimetic. 
• Increase calcium content in dialysate. 
5.4.3 
Other Reasons for Withdrawal 
Subjects will also be withdrawn if: 
• It is necessary to add an additional PB to the treatment regimen. 
• They receive a kidney transplant. 
• Dialysis is initiated in pre-dialysis subjects. 
• They become pregnant. Subject must be withdrawn immediately (pregnancy is to be 
recorded with the same timelines as an SAE). In case of pregnancy the procedure 
described in Section 10.3.3 must be followed. 
Any measures taken must be documented by the Investigator in the appropriate sections 
of the subject’s case report form (CRF) and source documentation. 


 
 
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If a subject withdraws from the study at any time either at his or her request, or at his or 
her parents/legal guardian request, or at the Investigator’s discretion, the reason(s) for 
withdrawal must be recorded on the relevant page of the subject’s CRF and source 
documentation. Subjects who are withdrawn from the study prematurely should, if 
possible, undergo all end of study assessments. 
Any subject who has been treated with study medication, whether completing the study or 
withdrawn prematurely, will be followed up 14 days after their last scheduled study visit 
to collect any new AEs and concomitant medications. 
It is vital to obtain follow-up data on any subject withdrawn because of an AE. Every 
effort must be made to undertake protocol-specified safety follow-up procedures (see 
Section 10.3). If a subject is discontinued due to an AE, the event should be followed by 
the Investigator through contact with the subject until resolution or stabilisation has 
occurred. All drug related AEs should be followed until resolution, stabilisation or the 
subject is lost to follow-up and cannot be contacted. If a subject and/or his/her 
parent/legal guardian refuses to continue study procedures, the reason for refusal should 
be fully documented in the subject’s source document and recorded in the study-specific 
CRF. It is the subject’s right to withdraw (and/or his/her parents/legal guardian right to 
withdraw the subject) from the trial without providing a reason. In this case, the source 
documents and the CRF should document the reason for discontinuation as “withdrawal 
of consent” or “withdrawal of assent”. 


 
 
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6. RANDOMISATION PROCEDURES 
6.1 
Randomisation 
All screened subjects must be identifiable throughout the study by a unique subject 
number. The Investigator will maintain a list of these subject numbers and subject names 
to enable records to be found at a later date.  
In Stage 1, at the end of screening or washout (where required), approximately 
130 eligible subjects will be randomised via IRT to either PA21 (100 subjects) or to 
Phoslyra (30 subjects), respectively, and will enter the treatment period. Each subject will 
receive a randomisation number which they will retain for the duration of their 
participation. The randomisation list will be stratified by age group to satisfy the criteria 
described in Section 5.1. Subjects in each age group will receive their allocated dose as 
detailed in Table 3. 
Randomisation will be performed based on a predefined randomisation list. Randomised 
subjects who terminate their study participation for any reason regardless of whether the 
study drug was taken or not, will retain their randomisation number. 
In Stage 2, subjects continue on either PA21 or Phoslyra for a further 24 weeks safety 
extension.  
Details on IRT will be provided in the study documentation 
6.2 
Blinding 
The study is open-label. 
 


 
 
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7. STUDY TREATMENTS 
7.1 
Dosage Forms/Formulation 
All investigational medicinal products used in this study have been manufactured in 
accordance with current Good Manufacturing Practice (GMP) [74]. The study 
formulations are summarised in Table 12. 
Table 12 
Overview of Formulations 
API 
PA21 
PA21 
Phoslyra® 
Dosage form 
Powder for oral 
suspension 
Chewable tablet 
Oral solution 
Appearance 
Red-brown 
powder 
Red-brown 
tablet 
Pale to light greenish-yellow clear liquid 
Dosage 
strengths (mg) 
125, 250, 500 
250, 500 
Each 5 mL contains 667 mg calcium acetate, 
equal to 169 mg (8.45 mEq) calcium 
Primary 
packaging 
CR sachet 
PP tube with CR 
closure 
Amber-coloured, multiple-dose PET bottles 
with a CR closure. 
Notes: API=Active pharmaceutical ingredient; CR=Child-resistant; PET=Polyethylene terephthalate; PP=Polypropylene. 
 
Responsibility for manufacture, quality control, primary packaging and batch release of 
investigational treatment are summarised in Table 13. 
Table 13 
Responsibility for Manufacture, Quality Control, Primary Packaging 
and Batch Release 
API 
PA21 
PA21 
Phoslyra® 
Dosage form 
Powder for oral suspension 
Chewable tablet 
Oral solution 
Manufacture (bulk) 
Patheon 
Catalent 
Lyne Laboratories, Inc. 
Primary packaging 
Patheon 
Catalent 
Lyne Laboratories, Inc. 
Quality control  
Vifor Int. 
Vifor Int. 
Vifor or CMO 
Batch release 
Vifor Int. 
Vifor Int. 
Vifor or CMO 
Notes: API=Active pharmaceutical ingredient; CMO=Clinical Manufacturing Organisation. 
 
Addresses of the drug manufacturers are provided in Table 14. 
Table 14 
Addresses of Drug Product Manufacturers 
Catalent Germany Schorndorf GmbH, Steinbeissstrasse 1 and 2, 73614 Schorndorf, Germany 
Vifor (International) Inc., Rechenstrasse 37, 9014 St. Gallen, Switzerland 
Patheon France S.A.S., 40 Boulevard de Champaret, 38317 Bourgoin-Jallieu, France 
Lyne Laboratories Inc., Brockton, MA 02301, US 
 


 
 
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7.1.1 
PA21 Chewable Tablet 
The composition of PA21 chewable tablets is provided in Table 15.  
Table 15 
Composition of PA21 Chewable Tablet 
Product Code 
 
YT318 
YT326 
 
Component 
Function 
Quantity per 
Tablet 
(mg) 
Quantity per 
Tablet 
(mg) 
Test Method 
PA21-2 drug substance (sucroferric 
oxyhydroxide), corresponding to iron(III) 
Active 
ingredient 
2,500.00(1) 
500.00 
1,250.00(1) 
250.00 
In-house method 
Silica (colloidal, anhydrous) 
Flow aid 
12.49 
6.245 
Ph. Eur./USP/NF 
Woodberry flavour 
Flavour 
40.00 
20.00 
In-house method 
Neohesperidin dihydrochalcone 
Sweetener 
0.01 
0.005 
Ph. Eur. 
Magnesium stearate 
Lubricant 
25.00 
12.50 
Ph. Eur./USP/NF 
Total 
 
2,577.50 
1,288.75 
 
1 Each tablet is adjusted to 500 mg or 250 mg iron, respectively. 
Notes: NF=National Formulary; Ph. Eur.=European Pharmacopoeia; USP=United States Pharmacopeia. 
 
7.1.2 
PA21 Powder for Oral Suspension  
The composition of PA21 powder for oral suspension is provided in Table 16. 
Table 16 
Composition of PA21 Powder for Oral Suspension 
Product Code 
 
ZF001 
ZF002 
ZF003 
 
Component 
Function 
Quantity 
per Sachet 
(mg) 
Quantity 
per Sachet 
(mg) 
Quantity 
per Sachet 
(mg) 
Test Method 
PA21-2 drug substance 
(sucroferric oxyhydroxide), 
corresponding to iron(III) 
Active 
ingredient 
2,500(1) 
500 
1,250(1) 
250 
625(1) 
125 
In-house method 
Maltodextrin 
Filler/binder 
1,180 
590 
295 
Ph. Eur./USP/NF 
Microcrystalline cellulose  
Filler/binder 
200 
100 
50 
Ph. Eur./USP/NF 
Xanthan gum 
Viscosity 
enhancer 
80 
40 
20 
Ph. Eur./USP/NF 
Silica (colloidal, anhydrous) 
Flow aid 
20 
10 
5 
Ph. Eur./USP/NF 
Magnesium stearate(2)  
Lubricant 
20 
10 
5 
Ph. Eur./USP/NF 
Purified water(3) 
Solvent 
– 
– 
– 
Ph. Eur./USP/NF 
Total 
 
4,000 
2,000 
1,000 
 
1 Each sachet is adjusted to 500 mg, 250 mg or 125 mg iron respectively. 
2 Of vegetable origin. 
3 The solvent for granulation is not present in the drug product. 
Notes: NF=National Formulary; Ph. Eur.=European Pharmacopoeia; USP=United States Pharmacopeia. 
 


 
 
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7.1.3 
Phoslyra Oral Solution (Comparator Group) 
The composition of Phoslyra oral solution is provided in Table 17.  
Table 17 
Summary of Quantitative Composition and Function for Phoslyra 
Ingredient 
Concentration per 5 mL 
% w/v 
Function 
Calcium acetate USP 
667.0 mg/5 mL(1) 
13.34(1) 
Active 
Crystalline maltitol NF 
1,000 mg/5 mL 
20 
Sweetener 
Glycerin USP 
250.0 mg/5 mL 
5 
Sweetener 
Propylene glycol USP 
100.0 mg/5 mL 
2 
Solvent 
Magnasweet 110 
125.0 mg/5 mL 
2.5 
Sweetener 
Sucralose NF 
17.5 mg/5 mL 
0.35 
Sweetener 
Methylparaben NF 
10.0 mg/5 mL 
0.2 
Preservative 
Providone K25 USP 
37.5 mg/5 mL 
0.75 
Solubiliser 
Artificial black cherry flavour #825.083 
10.0 mg/5 mL 
0.2 
Flavouring agent 
Menthol flavour, natural #875.017 
10.0 mg/5 mL 
0.2 
Flavouring agent 
Purified water USP 
Qs 5 mL 
 
Solvent 
1 On anhydrous basis. 
Notes: NF=National Formulary; USP=United States Pharmacopeia. 
 
7.1.3.1 
Primary Packaging 
PA21 chewable tablets (dosage strength: 500 mg iron) are stored in polypropylene tubes 
with a child-resistant closure, containing an integral desiccant sleeve (molecular sieve), 
cotton and a polypropylene insert. One tube contains 12 chewable tablets.  
PA21 chewable tablets (dosage strength: 250 mg iron) are stored in polypropylene tubes 
with a child-resistant closure, containing an integral desiccant sleeve (molecular sieve) 
and cotton. One tube contains 24 chewable tablets.  
PA21 powder for oral suspension (all dosage strengths) is stored in child-resistant sachets 
with aluminium as water-vapour barrier. 
Phoslyra solution is stored in multiple-dose polyethylene terephthalate bottles 473 mL 
with a child-resistant closure.  
7.2 
Drug Dosage and Administration 
7.2.1 
Treatment Arms 
The study will aim to randomise a minimum number of subjects from each age group as 
detailed in Table 10. 
Throughout the study subjects randomised to receive PA21 will be provided with the 
most appropriate formulation i.e., either powder for oral suspension (for subjects 
<6 years) or chewable tablet (for subjects ≥6 years). Due to the possibility of a 
125 mg/day increment for dose changes subjects in the 6 to 9 year age group will ideally 


 
 
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receive powder for oral suspension throughout the study. If required, subjects may change 
to the alternative PA21 formulation, but should remain on the same dose. For example, a 
subject may begin treatment with the chewable tablet but at a subsequent study visit 
change to the powder for oral suspension. 
Stage 1 is up to 10-weeks, and is an open-label, randomised, active-controlled, parallel 
group, dose titration period. Subjects will be randomised to receive either PA21 or 
Phoslyra: 
• PA21 subjects will receive PA21 at a starting dose based on their age, as detailed in 
Table 3.  
• Phoslyra subjects will receive Phoslyra, either at a starting dose as detailed in Table 5, 
or, if considered more appropriate by the Investigator, at an equivalent dose of their 
previous PB, calcium-based or sevelamer.  
Dose of PA21 (100 subjects) or Phoslyra (30 subjects) will be increased or decreased as 
required for efficacy (to achieve age specific target serum phosphorus level as indicated 
in Table 11), provided a subject has been receiving that dose for a minimum of 2 weeks, 
and for safety or tolerability reasons at any time. Increases or decreases in dose and 
maximum doses are detailed in Table 4 for PA21, and Table 5 and Table 6 for Phoslyra. 
From Week 4, once a subject achieves the age specific target serum phosphorus level, as 
indicated in Table 11, they can move to Stage 2.  
Stage 2 is a 24-week, open-label, long-term safety extension period. All eligible subjects 
will enter this safety extension stage.  
During Stage 2 all subjects will continue on the dose received at the end of Stage 1, 
unless a dose change is required.  
• For all subjects, doses may be titrated for efficacy (to achieve age specific target 
serum phosphorus levels, see Table 11), provided a subject has been receiving that 
dose for a minimum of 2 weeks, and for safety or tolerability reasons at any time 
during Stage 2. Increases or decreases in dose and maximum doses are detailed in 
Table 4, Table 5 and Table 6. 
Dose adjustments are described in Section 7.6. 
Due to the large variation in feed types, volumes and regimens in the study population the 
protocol is not prescriptive regarding when and how the total daily dose of study drug 
will be administered to subjects. Investigators (in collaboration with dieticians where this 
is local practice) should decide the optimal way to give the total daily dose of study drug 
to individual subjects. This should also be discussed with the parent/legal guardian (and, 
where appropriate, subject). 


 
 
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Dosing tables (Table 18 to Table 25) are provided as a guideline only. Please also refer to 
Stage 1 starting doses (Table 3 and Table 5) and maximum doses per day, plus maximum 
dose increases and decreases (Table 4, Table 5 and Table 6). 
(Note: Main meal(s) refers to meal(s) with the highest phosphate content). 
7.2.1.1 
Dosing of PA21 Powder for Oral Suspension 
Table 18 
Dosing of PA21 Powder for Oral Suspension: Subjects Age 0 to 
<1 Year 
Total Daily Dose PA21 
(mg Iron/Day) 
Powder for Oral Suspension (mg Sachet) 
Main Meal 
Meal 
Meal 
125 
125 across the day 
250 
125 
125 across remaining meals 
375 
125 
125 
125 
500 
250 
125 
125 
625 
250 
250 
125 
750 
250 
250 
250 
875 
250 + 125 
250 
250 
1,000 
250 + 125 
250 + 125 
250 
 
Table 19 
Dosing of PA21 Powder for Oral Suspension: Subjects Age ≥1 Year to 
<6 Years 
Total Daily Dose PA21 
(mg Iron/Day) 
Powder for Oral Suspension (mg Sachet) 
Main Meal 
Meal 
Meal 
500 
250 
125 
125 
625 
250 
250 
125 
750 
250 
250 
250 
875 
250 + 125 
250 
250 
1,000 
250 + 125 
250 + 125 
250 
1,125 
250 + 125 
250 + 125 
250 + 125 
1,250 
500 
250 + 125 
250 + 125 
 
Table 20 
Dosing of PA21 Powder for Oral Suspension: Subjects Age ≥6 Years 
to <9 Years 
Total Daily Dose PA21 
mg Iron/Day) 
Powder for Oral Suspension (mg Sachet) 
Main Meal 
Meal 
Meal 
750 
250 
250 
250 
875 
250 + 125 
250 
250 
1,000 
250 + 125 
250 + 125 
250 
1,125 
250 + 125 
250 + 125 
250 + 125 
1,250 
500 
250 + 125 
250 + 125 
 


 
 
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Table 20 
Dosing of PA21 Powder for Oral Suspension: Subjects Age ≥6 Years 
to <9 Years (Cont’d) 
Total Daily Dose PA21 
mg Iron/Day) 
Powder for Oral Suspension (mg Sachet) 
Main Meal 
Meal 
Meal 
1,375 
500 
500 
250 + 125 
1,500 
500 
500 
500 
1,625 
500 + 125 
500 
500 
1,750 
500 + 125 
500 + 125 
500 
1,875 
500 + 125 
500 + 125 
500 + 125 
2,000 
500 + 250 
500 + 125 
500 + 125 
2,125 
500 + 250 
500 + 250 
500 + 125 
2,250 
500 + 250 
500 + 250 
500 + 250 
2,375 
500 + 500 
500 + 250 
500 + 125 
2,500 
500 + 500 
500 + 250 
500 + 250 
 
Table 21 
Dosing of PA21 Powder for Oral Suspension: Subjects Age ≥9 Years 
to <18 Years 
Total Daily Dose PA21 
(mg Iron/Day) 
Powder for Oral Suspension (mg Sachet) 
Main Meal 
Meal 
Meal 
1,250 
500 
250 + 125 
250 + 125 
1,500 
500 
500 
500 
1,750 
500 + 250 
500 
500 
2,000 
500 + 250 
500 + 250 
500 
2,250 
500 + 250 
500 + 250 
500 + 250 
2,500 
500 + 500 
500 + 250 
500 + 250 
2,750 
500 + 500 
500 + 500 
500 + 250 
3,000 
500 + 500 
500 + 500 
500 + 500 
 
7.2.1.2 
Dosing of PA21 Tablet 
Table 22 
Dosing of PA21 Tablet: Subjects Age ≥6 Years to <9 Years 
Total Daily Dose PA21 
(mg Iron/Day) 
Chewable Tablet (mg) 
Main Meal 
Meal 
Meal 
750 
250 
250 
250 
1,000 
500 
250 
250 
1,250 
500 
500 
250 
1,500 
500 
500 
500 
1,750 
500 + 250 
500 
500 
2,000 
500 + 250 
500 + 250 
500 
2,250 
500 + 250 
500 + 250 
500 + 250 
2,500 
500 + 500 
500 + 250 
500 + 250 
 


 
 
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Table 23 
Dosing of PA21 Tablet: Subjects Age ≥9 Years to <18 Years 
Total Daily Dose PA21 
(mg Iron/Day) 
Chewable Tablet (mg) 
Main Meal 
Meal 
Meal 
1,250 
500 
500 
250 
1,500 
500 
500 
500 
1,750 
500 + 250 
500 
500 
2,000 
500 + 250 
500 + 250 
500 
2,250 
500 + 250 
500 + 250 
500 + 250 
2,500 
500 + 500 
500 + 250 
500 + 250 
2,750 
500 + 500 
500 + 500 
500 + 250 
3,000 
500 + 500 
500 + 500 
500 + 500 
 
7.2.1.3 
Dosing of Phoslyra 
The starting dose of Phoslyra is 0.45 mL/kg/day, equivalent to 0.15 mL/kg/meal, 3 meals 
per day (detailed in Table 5). The dose of Phoslyra will be increased or decreased as 
required to achieve age specific target serum phosphorus level as indicated in Table 11. 
Table 24 provides Phoslyra dose ranges per body weight, the doses take into 
consideration propylene glycol and calcium intakes in Table 6. Individual doses will be 
rounded to 0.5 mL increments to allow accurate measurement, as shown in Table 25. 
Table 24 
Total Daily Dose Phoslyra® (mL/Day) 
Body Weight 
 
Daily Dose Phoslyra (mL/kg/day) 
0.45 
0.55 
0.65 
0.75 
0.85 
0.95 
1.05 
1.15 
1.25 
5 
2.0 
2.5 
3.0 
3.5 
4.0 
4.5 
5.0 
5.5 
6.0 
10 
4.5 
5.5 
6.5 
7.5 
8.5 
9.5 
10.5 
11.5 
12.5 
15 
6.5 
8.0 
9.5 
11.0 
12.5 
14.0 
15.5 
17.0 
18.5 
20 
9 
11 
13 
15 
17 
19 
21 
23 
25 
25 
11.0 
13.5 
16.0 
18.5 
21.0 
23.5 
26.0 
28.5 
31.0 
30 
13.5 
16.5 
19.5 
22.5 
25.5 
28.5 
31.5 
34.5 
37.5 
35 
15.5 
19.0 
22.5 
26.0 
29.5 
33.0 
36.5 
40.0 
43.5 
40 
18 
22 
26 
30 
34 
38 
42 
44(1) 
44(1) 
45 
20.0 
24.5 
29.0 
33.5 
38.0 
42.5 
44(1) 
44(1) 
44(1) 
50 
22.5 
27.5 
32.5 
37.5 
42.5 
44(1) 
44(1) 
44(1) 
44(1) 
60 
27 
33 
39 
44(1) 
44(1) 
44(1) 
44(1) 
44(1) 
44(1) 
70 
31.5 
38.5 
44(1) 
44(1) 
44(1) 
44(1) 
44(1) 
44(1) 
44(1) 
1 Dose adjusted according to Table 5. 
 


 
 
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Table 25 
Dosing of Phoslyra® 
Total Daily Dose Phoslyra (mL/Day) 
Main Meal (mL) 
Meal (mL) 
Meal (mL) 
2.0 
1.0 
0.5 
0.5 
2.5 
1.0 
1.0 
0.5 
3 
1.0 
1.0 
1.0 
3.5 
1.5 
1.0 
1.0 
4 
1.5 
1.5 
1.0 
4.5 
 1.5 
1.5 
1.5 
5 
2.0 
1.5 
1.5 
5.5 
2.0 
2.0 
1.5 
6 
2.0 
2.0 
2.0 
6.5 
2.5 
2.0 
2.0 
7 
2.5 
2.5 
2.0 
7.5 
2.5 
2.5 
2.5 
8 
3.0 
2.5 
2.5 
8.5 
3.0 
3.0 
2.5 
9 
3.0 
3.0 
3.0 
9.5 
3.5 
3.0 
3.0 
10 
3.5 
3.5 
3.0 
11 
4.0 
3.5 
3.5 
12 
4.0 
4.0 
4.0 
13 
4.5 
4.5 
4.0 
14 
5.0 
4.5 
4.5 
15 
5.0 
5.0 
5.0 
16 
55 
5.5 
5.0 
17 
6.0 
5.5 
5.5 
18 
6.0 
6.0 
6.0 
19 
6.5 
6.5 
6.0 
20 
7.0 
6.5 
6.5 
21 
7.0 
7.0 
7.0 
22 
7.5 
7.5 
7.0 
23 
8.0 
7.5 
7.5 
24 
8.0 
8.0 
8.0 
25 
8.5 
85. 
8.0 
26 
9.0 
8.5 
8.5 
27 
9.0 
9.0 
9.0 
28 
9.5 
9.5 
9.0 
29 
10.0 
9.5 
9.5 
30 
10.0 
10.0 
10.0 
31 
10.5 
10.5 
10.0 
32 
11.0 
10.5 
10.5 
33 
11.0 
11.0 
11.0 
 


 
 
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Table 25 
Dosing of Phoslyra® (Cont’d) 
Total Daily Dose Phoslyra (mL/Day) 
Main Meal (mL) 
Meal (mL) 
Meal (mL) 
34 
11.5 
11.5 
11.0 
35 
12.0 
11.5 
11.5 
36 
12.0 
12.0 
12.0 
37 
12.5 
12.5 
12.0 
38 
13.0 
12.5 
12.5 
39 
13.0 
13.0 
13.0 
40 
13.5 
13.5 
13.0 
41 
14.0 
13.5 
13.5 
42 
14.0 
14.0 
14.0 
43 
14.5 
14.5 
14.0 
44 
15.0 
14.5 
14.5 
 
All remaining tablets, sachets and liquid (and any empty containers) dispensed to the 
subject will be returned at each study visit for tablet, sachet and volume of liquid counts 
to check compliance. The Investigator will count the returned tablets, sachets and volume 
of liquid and, taking into account the dose prescribed, will assess the subjects’ 
compliance. 
This tablet and sachet count and volume of liquid will be documented in the CRF and 
source documentation. 
7.2.2 
Dosing and Administration Guidelines 
7.2.2.1 
PA21 – Investigational Treatment 
PA21 tablets will be chewed or crushed. They must not be swallowed whole.  
PA21 powder for oral suspension should be combined with a suitable food/drink prior to 
administration, for example water, apple sauce, nutritional supplements for renal patients 
or infant formula milk in the following approximate volumes: 
• 500 mg iron: 20 mL 
• 250 mg iron: 10-20 mL 
• 125 mg iron: 5-20 mL 
The suspension should be ingested within 30 minutes after being prepared. 
PA21 powder for oral suspension may be given by feeding tube. 
PA21 must not be taken on an empty stomach. The daily dose will be taken orally with 
meals and with no additional water above the amount usually taken by the subject with 
meals. 


 
 
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7.2.2.3 
Phoslyra Oral Solution - Active Control 
Phoslyra should be administered on its own, unless administering by feeding tube when it 
should be combined with a small volume of water and flushed down the feeding tube 
before the feed. 
7.3 
Package and Labelling 
All study medications will be packaged and labelled by Vifor Pharma (or designee) 
according to all local legal requirements and applicable regulatory requirements. All 
packaging and labelling operations will be performed according to GMP and Good 
Clinical Practice (GCP). Containers provided to centres and to subjects will be labelled in 
the appropriate local language. Container label information will be appropriately 
documented in the drug accountability form after the container has been dispensed to the 
subject. 
7.4 
Study Treatment Allocation 
Each eligible subject will be assigned to the treatment arms via a secure IRT. 
7.5 
Site Supply, Storage, Accountability 
7.5.1 
Site Supply 
Once a site has been approved to receive study drug, the site will be supplied with an 
initial stock of PA21 and Phoslyra. The need for drug resupply will be assessed on a 
regular basis taking into account the number of subjects enrolled, and the number of 
subjects in screening at the site. This will be managed via the IRT. 
7.5.2 
Storage 
The Investigator at each site is responsible for the appropriate storage of study drug 
supplies.  
PA21 should be stored in a locked area at 25°C (77°F) with excursions permitted at 0°C 
to 35°C (32 to 95°F).  
The study drug supplies should be protected from moisture. The containers should be 
tightly closed. 
Phoslyra should be stored in a locked area at 25°C (77°F) with excursions permitted at 
15°C to 30°C (59 to 86°F).  
Maintenance of a temperature log is mandatory. The log should be updated by site 
personnel daily whenever possible. This log must be available for review by the Monitor 
during on-site monitoring visits. 


 
 
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7.5.3 
Accountability 
The Investigator at each site is responsible for study drug supplies. The Investigator will 
ensure that adequate records of the receipt, administration and return of the study drug are 
kept and that the study drug is used only for subjects enrolled in the study. All data 
regarding the study drug must be recorded on the relevant forms provided. 
Each study site will maintain a drug inventory/dispensing record for all drugs dispensed 
and returned. At the end of the study, 1 copy of the drug inventory/dispensing record 
should be sent to the Sponsor or designee for the central study file. The original will be 
kept in the site files. 
After completion of the study, or if it is prematurely terminated, all unused materials will 
be returned to the Sponsor or designee. Vifor Pharma’s policy is not to have materials 
destroyed by sites. However, if there are exceptional cases and the study medication is 
destroyed at site, the Investigator will forward the certificate of destruction to the Sponsor 
or designee. The decision to destroy study medication at site must be made by the 
Sponsor or designee.  
7.6 
Drug Dose Modification 
During the study, dose titrations of PA21 or Phoslyra (increases or decreases) will be 
allowed, for efficacy, provided that the subject has received that dose for a minimum 
period of 2 weeks, and safety or tolerability reasons at any time. Blood samples will be 
taken at these visits in order to obtain serum phosphorus values for dose titration 
purposes. If a dose adjustment is indicated i.e., if the serum phosphorus level is outside 
the target serum phosphorus levels detailed in Table 11, the Investigator will inform the 
subject or legal representative (either directly or by phone) whether a dose increase or a 
dose decrease is indicated. Subjects will thereafter follow the new dose regimen. 
Maximum doses of PA21 and Phoslyra and dose increases or decreases permitted are 
detailed in Table 4, Table 5 and Table 6. 
Rules for stopping study drug are detailed in Section 5.4. 
7.6.1 
Procedures for Overdose 
Any instances of hypophosphataemia due to PB overdose should be treated by stopping 
the drug immediately and by standard clinical practice. 
There is no rescue medication for this study. 
7.6.1.1 
PA21 
There are no reports of overdose with PA21 in patients. Since the absorption of iron from 
PA21 is low, the risk of systemic iron toxicity is negligible. Any instances of 
hypophosphataemia due to PB overdose should be treated by stopping the drug 


 
 
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immediately and by standard clinical practice. PA21 will be provided in child-proof 
containers to avoid unintentional ingestion of study medication by children.  
7.6.1.2 
Phoslyra 
Administration of Phoslyra in excess of the appropriate daily dosage may result in 
hypercalcaemia (refer to Section 5.4). Phoslyra will be provided in a child-proof container 
to avoid unintentional ingestion of study medication by children. 
7.7 
Prohibited Therapy and Concomitant Treatment 
Prohibited therapies in this study include the following: 
• Oral calcium supplements. 
• Antacids containing aluminium, calcium or magnesium. 
• PB binders (i.e., PBs in addition to the study medications: PA21 or Phoslyra). 
• Subjects receiving growth hormone who have not been on a stable dose for 2 months. 
• Subjects taking anti-arrhythmic medications for the control of arrhythmias and 
anti-seizure medications for the control of seizure disorders. 
• In subjects randomised to PA21, oral iron products, oral vitamins containing iron and 
other oral iron containing supplements or medications should be discontinued at the 
start of the study. Iron status should then be monitored and iron therapy initiated if 
indicated as part of routine care. If iron therapy is indicated, intravenous iron is the 
preferred formulation. If oral iron is prescribed, however, the subject should be 
instructed to take it between meals and not at the same time as PA21. 
Concomitant medications that have a direct influence on serum phosphorus levels 
(e.g., Vitamin D, Vitamin D analogues and calcimimetics), dietary restrictions 
(e.g., phosphate and calcium intake) and dialysis regimens (e.g., duration of dialysis, 
number of HD sessions per week, number of PD exchanges/day, modality of dialysis, 
calcium concentration) should remain unchanged as far as possible in both the PA21 and 
Phoslyra groups throughout the study in accordance with local clinical practice. This does 
not apply if changes are indicated for safety and tolerability reasons. 
For HD subjects, details of the subject’s dialysis, date, duration and the day of dialysis 
must be documented in the CRF and in the subject’s medical records. As far as possible, 
dialysis parameters should remain stable throughout the study. All changes must be 
documented in the CRF and in the subject’s medical records. 
Any concomitant treatment given for any reason during the course of the study must be 
recorded on the CRF and in the subject’s medical records, including dosage, start and stop 
dates and reason for use. 


 
 
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7.7.1 
PA21 Interactions 
Human DDI studies have shown no interactions with 5 commonly used medications 
(losartan, furosemide, digoxin, warfarin, and omeprazole) in adult healthy subjects. 
Interaction has been observed in in vitro studies with the following drugs: alendronate, 
cephalexin, doxycycline, levothyroxine, atorvastatin. 
Data from clinical studies, however, have shown that PA21 does not affect the lipid 
lowering effects of HMG-CoA (3-hydroxy-3-methyl-glutaryl-CoA) reductase inhibitors 
(e.g., atorvastatin and simvastatin). In addition, clinical studies demonstrated no impact of 
PA21 on iPTH lowering effect of oral Vitamin D analogues. Vitamin D and 
1,25-dihydroxy Vitamin D levels remained unchanged. 
In vitro studies with the following drugs did not show any relevant interaction: 
acetylsalicylic acid, cephalexin, cinacalcet, ciprofloxacin, clopidogrel, enalapril, 
hydrochlorothiazide, metformin, metoprolol, nifedipine, pioglitazone, simvastatin and 
quinidine. 
When administering any medicinal product that is known to interact with iron, the 
medicinal product should be administered at least 1 hour before or 2 hours after PA21. 
7.7.2 
Phoslyra Interactions 
Phoslyra may decrease the bioavailability of tetracyclines, fluroquinolones or 
levothyroxine. When clinically significant drug interactions are expected, separate dosing 
from Phoslyra, or consider monitoring blood levels of drug. 
Table 26 
Oral Drugs that Have to be Separated From Phoslyra® 
 
Dosing Recommendations 
Flouroquinolones 
Take at least 2 hours before or 6 hours after Phoslyra 
Tetracyclines 
Take at least 1 hour before Phoslyra 
Levothyroxine 
Take at least 4 hours before or 4 hours after Phoslyra 
 
Oral Medications Not Listed in the Table 
There are no empirical data on avoiding drug interactions between Phoslyra and most 
concomitant oral drugs. For oral medications where a reduction in the bioavailability of 
that medication would have a clinically significant effect on its safety or efficacy, 
consider separation of the timing of the administration of the 2 drugs. The duration of 
separation depends upon the absorption characteristics of the medication concomitantly 
administered, such as the time to reach peak systemic levels and whether the drug is an 
immediate release or an extended release product. Consider monitoring clinical responses 
or blood levels of concomitant medications that have a narrow therapeutic range. 
 


 
 
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8. RISKS/PRECAUTIONS 
The required procedures in the study are appropriate for paediatric and adolescent 
patients, including blood sampling which will be in line with current guidelines [75]. 
Study subjects will have phosphorus and calcium levels monitored at frequent intervals 
(weekly during the washout stage of the study) see Section 4. The dose will be adjusted at 
regular intervals to optimise serum phosphorus levels (Section 7.2). Stopping rules are in 
place to ensure withdrawal of subjects whose phosphorus or calcium levels are not 
controlled within required limits (Section 5.4). In addition, the study has an external 
DSMB (Section 11). 
8.1 
PA21 – Investigational Treatment 
Details regarding risks and precautions can be found in the current PA21 IB. 
PA21 is indicated for the control of serum phosphorus levels in adult patients with CKD 
on dialysis. 
The only findings of note in the nonclinical programme were positive findings in rodent 
carcinogenicity studies. Administration of PA21 to mice for up to 2 years resulted in a 
dosage-related increase in mucosal epithelial hyperplasia and development of diverticula 
with cysts. There was no clear evidence of a tumourigenic response in male mice and no 
evidence of a tumourigenic response in female mice in this study. These low grade 
proliferative changes in the caecum and colon of mice are considered species specific and 
not considered a clinically relevant risk to humans. Follicular C-cell adenomas of the 
thyroid were seen in the rat study and these were considered likely to represent an 
exaggerated pharmacological response to the effects of PA21 treatment on calcium and 
phosphate homeostasis. Further details can be found in the PA21 IB. 
The effectiveness of PA21 in lowering serum phosphorus levels in adult patients with 
ESRD on dialysis has been confirmed in 2 adequate and well controlled studies 
(PA-CL-03A and PA-CL-05A). A 6 month safety extension study to PA-CL-05A has also 
been completed (PA-CL-05B), thereby providing PA21 exposure data for up to 1 year. 
Throughout the studies in the adult clinical development programme, PA21 was well 
tolerated at the proposed clinical doses. The most frequent patient-reported adverse drug 
reactions (ADRs) were GI AEs, consisting mainly of diarrhoea, faeces discoloured, and 
other mild to moderate GI AEs. 
Diarrhoea occurred in 11.6% of patients in clinical trials (PA-CL-03A, PA-CL-05A and 
PA-CL-05B). In the 55 weeks long-term studies, the majority of these treatment-related 
diarrhoea events were mild (59.8%) and transient, occurred early during treatment 
initiation and led to treatment discontinuation in 3.1% of patients. 


 
 
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PA21 can cause discoloured (black) stools. Discoloured (black) stool may visually mask 
GI bleeding. The usage of a faecal occult blood test will be able to distinguish discoloured 
(black) stools caused by PA21 from those due to a GI bleed. PA21 does not affect guaiac 
based (Haemoccult®) or immunological based (iColo Rectal®, and Hexagon Obti®) faecal 
occult blood tests. 
In combined studies PA-CL-05A/05B, temporary tooth discolouration was reported with 
a higher frequency in the PA21 group compared to the sevelamer group (1.4% versus no 
subjects, respectively). 
The use of PA21 is contraindicated in patients with (1) hypersensitivity to the active 
substance or any of the excipients, and (2) haemochromatosis and any other iron 
accumulation disorders. 
Patients with rare hereditary problems of fructose intolerance, glucose-galactose 
malabsorption or sucrose-isomaltose insufficiency should not take PA21. 
One tablet of PA21 is equivalent to 0.116 bread units (equivalent to approximately 1.4 g 
of carbohydrates). 
No safety concerns were raised by a comprehensive assessment of laboratory tests which 
included electrocardiograms, haematology and chemistry tests in adult subjects.  
Human DDI studies have shown no interactions with 5 commonly used medications 
(losartan, furosemide, digoxin, warfarin, and omeprazole) in adult healthy subjects. Data 
from clinical studies have shown that PA21 does not affect the lipid lowering effects of 
HMG-CoA reductase inhibitors (e.g., atorvastatin and simvastatin). In addition, clinical 
studies demonstrated no impact of PA21 on iPTH lowering effect of oral Vitamin D 
analogues. Vitamin D and 1, 25-dihydroxy Vitamin D levels remained unchanged. When 
administering any medicinal product that is known to interact with iron, the medicinal 
product should be administered at least 1 hour before or 2 hours after PA21. 
The rationale for the PA21 starting dose and age-specific dosing are described in 
Section 2. 
The safety and efficacy of PA21 in children below the age of 18 years has not yet been 
established. 
8.2 
Phoslyra – Active Control 
Details regarding risks and precautions can be found in the current Phoslyra IB. 
Patients with ESRD may develop hypercalcaemia when treated with calcium, including 
calcium acetate (Phoslyra). Avoid the concurrent use of calcium supplements, including 
calcium-based non-prescription antacids, with Phoslyra. An overdose of Phoslyra may 
lead to progressive hypercalcaemia, which may require emergency measures. Therefore, 


 
 
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early in the treatment phase during the dosage adjustment period, monitor serum calcium 
levels regularly. Should hypercalcaemia develop, reduce the Phoslyra dosage or 
discontinue the treatment, depending on the severity of hypercalcaemia. More severe 
hypercalcaemia (calcium >12 mg/dL) is associated with confusion, delirium, stupor and 
coma. Severe hypercalcaemia can be treated by acute HD and discontinuing Phoslyra 
therapy. Mild hypercalcaemia (10.5 to 11.9 mg/dL) may be asymptomatic or manifest as 
constipation, anorexia, nausea, and vomiting. Mild hypercalcaemia is usually controlled 
by reducing the Phoslyra dose or temporarily discontinuing therapy. Decreasing or 
discontinuing Vitamin D therapy is recommended as well. Chronic hypercalcaemia may 
lead to vascular calcification and other soft-tissue calcification. Radiographic evaluation 
of suspected anatomical regions may be helpful in early detection of soft tissue 
calcification. The long-term effect of Phoslyra on the progression of vascular or soft 
tissue calcification has not been determined. Hypercalcaemia (>11 mg/dL) was reported 
in 16% of patients in a 3-month study of a solid dose formulation of calcium acetate; all 
cases resolved upon lowering the dose or discontinuing treatment.  
Phoslyra contains maltitol (1 g per 5 mL) and may induce a laxative effect, especially if 
taken with other products containing maltitol. 
In subjects randomised to Phoslyra, hypercalcaemia may aggravate digitalis toxicity. 
The safety and efficacy of Phoslyra in children below the age of 18 years has not yet been 
established. 


 
 
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9. STUDY PROCEDURES 
9.1 
Description of Study Assessments 
9.1.1 
Laboratory Assessments 
Laboratory assessments are detailed in Table 27. Some laboratory assessments will be 
excluded for subjects <36 months of age, and some will only be collected if the results are 
available from routine clinical management of the subject (see Summary of Blood 
Samples, Table 2). 
Wherever possible, blood samples should be analysed at the central laboratory. 
Specifically, a central laboratory sample for serum phosphorus, calcium and albumin 
should be obtained at the final study visit in Stage 1 if possible. Table 2 gives details of 
those visits at which local laboratory analysis of blood samples is permitted. Standard 
validated methods must be used. Contact details for the central laboratory will be 
provided in the study documentation Laboratory Manual. 
For HD subjects, study visits after washout (or after screening for those subjects not 
requiring washout) will be planned after a maximum interdialytic period of 48 hours. 
Collection of laboratory samples will be completed before dialysis is initiated, using the 
dialysis access. 
Home HD, pre-dialysis and PD subjects will be free to select a weekday for the study 
visits that coincides best with their weekly routine, preferably in the first half of the week. 
All subsequent study visits will be scheduled on the same weekday thereafter, wherever 
possible. Collection of laboratory samples will, where possible, be completed at a 
consistent time for each visit. 
Blood samples for the following efficacy and safety assessments will be drawn in 
accordance with the Summary of Blood Samples, Table 2. 


 
 
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Table 27 
Laboratory Assessments 
Haematology: 
• 
Erythrocytes 
• 
Mean corpuscular 
volume 
• 
Mean corpuscular 
haemoglobin 
• 
Mean corpuscular 
haemoglobin 
concentration 
• 
Haemoglobin 
• 
Haematocrit 
• 
Reticulocyte count 
• 
White blood cells 
• 
White blood cell 
differential (% and 
absolute value) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Platelets 
• 
Leukocytes 
Clinical 
Chemistry: 
• 
Phosphorus 
• 
Calcium (total, corrected)  
• 
Intact parathyroid hormone 
• 
Creatinine 
• 
Glucose 
• 
Triglycerides 
• 
Total protein 
• 
Albumin 
• 
Urea 
• 
Uric acid 
• 
Total bilirubin 
• 
Total cholesterol (differentiated in 
high density lipoproteins and low 
density lipoproteins) 
• 
Creatine phosphokinase 
• 
C-reactive protein 
• 
Bicarbonate 
• 
Sodium 
• 
Potassium 
• 
Chloride 
Coagulation:(1) 
• 
Activated partial 
thromboplastin time 
• 
Prothrombin time 
Clinical 
Chemistry: 
Liver 
Enzymes: 
• 
Alkaline phosphatase 
• 
Aspartate transaminase 
• 
Alanine transaminase 
• 
Lactate dehydrogenase 
• 
Gamma-glutamyl transpeptidase 
Iron Status 
Parameters: 
• 
Iron 
• 
Ferritin(2) 
• 
Transferrin 
• 
Transferrin saturation 
Vitamins:(2) 
• 
A 
• 
25(OH)D 
• 
1,25(OH)2D(1) 
• 
E 
• 
K 
Bone Markers:(2) • 
Carboxyterminal cross-linking telopeptide of bone collagen 
• 
Tartrate-resistant acid phosphatase 5b 
• 
Bone-specific alkaline phosphatase 
• 
Osteocalcin 
• 
Fibroblast growth factor 23 
1 These assessments will only be collected if taken as part of the routine clinical management of the subjects. 
2 These assessments will be excluded in subjects <36 months of age (but will be collected if available from routine clinical 
assessment). 
 
Samples for bone marker assessment will be obtained and may be stored (frozen) for later 
analysis. 


 
 
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The total amount of blood (including efficacy endpoints) that will be collected during the 
study from an individual subject will comply with current paediatric guidelines [75]. Over 
a period of approximately 41 weeks the amount of blood taken will be up to 
approximately 53.5 mL for subjects <36 months and up to approximately 78.2 mL for 
subjects ≥36 months of age. In addition, female subjects of child bearing potential will 
have approximately 3 x 1.5 mL pregnancy tests. The exact volume will depend on, for 
example, how many visits the subject has during Stage 1, whether the subject requires 
washout visits and the techniques/tubes used to collect blood. 
Serum pregnancy tests in females of child-bearing potential will be performed by the 
central laboratory. Positive pregnancy tests will be repeated 2 weeks later, to check for 
false positive results. 
For details on whether laboratory abnormalities should be reported as AEs and on the 
follow-up required in such cases, see Section 10.2.5. 
9.1.2 
Physical Examinations 
Physical examinations will be performed in accordance with the Schedule of Events, 
Table 1. 
Body systems to be assessed as part of the physical examination will include general 
appearance, head (eyes, ears, nose, and throat), cardiovascular, respiratory, abdomen, 
musculoskeletal, neurological, lymph nodes, and skin. 
Body weight and height will be measured as part of the physical examinations and, in 
addition, in accordance with the Schedule of Events, Table 1. 
9.1.3 
Vital Signs 
The following vital signs will be measured in accordance with the Schedule of Events, 
Table 1. 
• Resting blood pressure (systolic and diastolic) 
• Resting heart rate 
• Body temperature (°C; oral, otic or axillary) 
Blood pressure and heart rate will be measured using age-appropriate equipment. 
9.1.4 
Patient Reported Palatability and Acceptability Assessments 
Patient reported palatability and acceptability assessments will be performed in 
accordance with the Schedule of Events, Table 1. 
Age-appropriate assessments will be used based on already-established and standardised 
versions of the combined facial hedonic facial and 10 cm visual analogue scale. Site staff 


 
 
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will be trained to give standardised, age-appropriate, brief, clear instructions to the 
subjects or, where appropriate, the parents/carers. 
9.1.5 
Dialysis Parameters 
Dialysis parameters will be recorded in accordance with the Schedule of Events, Table 1. 
As far as possible, dialysis parameters should remain stable throughout the study. All 
changes must be documented in the CRF and in the subject’s medical records. 
For HD subjects, the following parameters must be documented in the CRF and in the 
subject’s medical records at each visit: date, duration of dialysis and the day of dialysis.  
Kt/V will only be recorded by the Investigator where these data are collected as part of 
the routine management of the subject. 
9.1.6 
Diet 
Investigators will discuss and advise on the subject’s diet at every visit.  
9.2 
Schedule of Assessments 
For a detailed schedule of visits and assessments (including visit windows) please refer to 
the Schedule of Events, Table 1. 
9.2.1 
Screening Visit (Visit 1) Procedures 
No study related assessments will be performed until signed and dated informed consent 
(and, where applicable/required, assent) has been provided for the subject.  
Subjects for whom signed and dated informed consent (and, where applicable/required, 
assent) has been provided will be enrolled in the study and screened. By signing and 
dating the informed consent form (ICF), the parent/legal guardian (and by signing the 
assent form where applicable/required, the subject) consent for a possible participation in 
screening, washout (where applicable), Stages 1 and 2 and follow-up of this clinical trial. 
As far as possible, all assessments (except for palatability and acceptability assessment 
and physical examinations) should be completed prior to dialysis sessions. Subjects 
previously taking PBs who are eligible for inclusion will continue into the washout phase. 
Subjects previously taking PBs but with serum phosphorus levels indicated in Table 28 
may be randomised without a washout period when the results from the screening visit 
are available for assessment of study eligibility.  
Subjects who are PB naïve and whose serum phosphorus levels values are as indicated in 
Table 28 will be eligible for randomisation when the results from the screening visit are 
available for assessment of study eligibility. In centre HD subjects must be randomised 
after a maximum interdialytic period of 48 hours, once qualifying screening results are 
received. Home HD, pre-dialysis and PD subjects should be randomised as soon as 
feasible after qualifying screening results are received, and preferably within 4 days. 


 
 
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Table 28 
Age Related Serum Phosphorus Targets for Washout Period 
Age 
mmol/L 
mg/dL 
0 to <6 months 
>2.62 
>8.1 
≥6 months to <1 year 
>2.29 
>7.1 
≥1 year to <6 years 
>2.02 
>6.3 
≥6 years to <13 years 
>1.77 
>5.5 
≥13 years to <18 years 
>1.36 
>4.2 
Note: 
Adapted from National Kidney Foundation Kidney Disease Outcomes Quality Initiative Nutrition Guidelines, 2008 and 
personal communication. 
 
During the screening visit the following procedures will be undertaken: 
• Informed consent 
• Inclusion/exclusion criteria review to confirm eligibility 
• Demography 
• Medical/surgical history 
• Prior medication history 
• Physical examination 
• Height and body weight 
• Vital signs 
• Blood sample 
• Confirmation of screening using IRT 
• Dialysis parameters 
• Dialysis parameters for Kt/V (when available from routine clinical assessment) 
• Adverse events 
• Concomitant medication 
• Discuss and advise on the subject’s diet 
9.2.2 
Washout Visit (Visits 2 to 4) Procedures 
For subjects taking PBs, the washout period cannot begin until the results from the 
screening visit are available for assessment of study eligibility. The dose of previous PB 
treatment must remain stable until the subject, or their parent/legal guardian, is contacted 


 
 
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by the site. Subjects who are eligible for inclusion (or their parent/legal guardian) will 
then be contacted by the site and asked to stop taking their current PBs. The subject will 
then undergo a washout from their previous PBs for up to 3 weeks. Serum phosphorus 
levels will be monitored weekly up to 3 weeks of washout. At the end of the first week of 
the washout period subjects whose serum phosphorus levels have risen to those detailed 
in Table 28 will be eligible for randomisation and enter the treatment period. 
Subjects who have serum phosphorus levels below those detailed in Table 28 at this time 
can continue in the washout period for an additional 2 weeks. As soon as their serum 
phosphorus levels have risen to those detailed in Table 28 they can be randomised into 
the treatment period. In centre HD subjects must be randomised after a maximum 
interdialytic period of 48 hours, once qualifying screening results are received. Home 
HD, pre-dialysis and PD subjects should be randomised as soon as feasible after 
qualifying results are received, and preferably within 4 days. If, after 3 weeks of washout, 
the serum phosphorus remains below those detailed in Table 28 the subject is not eligible 
for randomisation. 
During the washout visits the following procedures will be undertaken: 
• Blood sample 
• Call to IRT 
• Dialysis parameters 
• Dialysis parameters for Kt/V (when available from routine clinical assessment) 
• Adverse events 
• Concomitant medications 
• Discuss and advise on the subject’s diet 
9.2.3 
Baseline Visit (Visit 5) Procedures 
• Inclusion/exclusion criteria review to confirm eligibility 
• Height and body weight 
• Vital signs 
• Blood sample 
• Call to IRT: randomisation into Stage 1 
• Dispense subject identification card 


 
 
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• Dialysis parameters 
• Dialysis parameters for Kt/V (when available from routine clinical assessment) 
• Dispense study medication 
• Adverse events 
• Concomitant medication 
• Discuss and advise on the subject’s diet 
9.2.4 
Treatment Visit (Visits 6 to 16) Procedures 
For in centre HD subjects study visits must be planned after a maximum interdialytic 
period of 48 hours and on the same day and same session each week, as far as possible. 
Collection of laboratory samples and completion of all other procedures required by the 
protocol, except the physical examination and the patient reported palatability and 
acceptability will be completed before dialysis is initiated. 
Subjects who are on home HD, pre-dialysis or on PD will be free to select a weekday for 
the study visits that coincides best with their weekly routine, preferably in the first half of 
the week. All subsequent study visits will be scheduled on the same weekday thereafter, 
wherever possible. For these subjects, where possible, all laboratory samples and other 
procedures required by the protocol will be taken at a consistent time for each visit. 
AEs and concomitant medication will be recorded prior to the conduct of other study 
assessments at each visit. 
For dosing and dose titration procedures see Section 7. 
9.2.4.1 
Stage 1 Visit (Visits 6 to 11) Procedures 
9.2.4.1.1 
Visit 6 Procedures 
During Visit 6 the following procedures will be undertaken: 
• Call to IRT 
• Dialysis parameters 
• Dialysis parameters for Kt/V (when available from routine clinical assessment) 
• Dispense study medication 
• Returned study medication count 
• Adverse events 


 
 
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• Concomitant medication 
• Discuss and advise on the subject’s diet 
9.2.4.1.2 
Visits 7, 9 and 10 Procedures 
Subjects attending site Visits 7, 9 and 10 will undergo the following procedures: 
• Blood sample 
• Call to IRT 
• Dialysis parameters 
• Dialysis parameters for Kt/V (when available from routine clinical assessment) 
• From Visit 8, subjects can move to Stage 2 if they have been on a stable dose of study 
drug for a minimum of 2 weeks 
• Dispense study medication 
• Returned study medication count 
• Adverse events 
• Concomitant medication 
• Discuss and advise on the subject’s diet 
9.2.4.1.3 
Visits 8 and 11 Procedures 
During Visits 8 and 11 the following procedures will be undertaken: 
• Height and body weight 
• Vital signs 
• Blood sample 
• Call to IRT 
• Dialysis parameters 
• Dialysis parameters for Kt/V (when available from routine clinical assessment) 
• From Visit 8, subjects can move to Stage 2 if they have been on a stable dose of study 
drug for a minimum of 2 weeks 


 
 
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• Dispense study medication 
• Returned study medication count 
• Visit 8 only: patient reported palatability and acceptability 
• Adverse events 
• Concomitant medication 
• Discuss and advise on the subject’s diet 
9.2.4.2 
Stage 2 Visit (Visits 12 to 16) Procedures 
9.2.4.2.1 
Visit 12 and 14 Procedures 
During Visit 12 and 14 the following procedures will be undertaken: 
• Visits 12 only: physical examination 
• Height and body weight 
• Vital signs 
• Blood sample 
• Call to IRT 
• Dialysis parameters 
• Dialysis parameters for Kt/V (when available from routine clinical assessment) 
• Dispense study medication 
• Returned study medication count 
• Adverse events 
• Concomitant medication 
• Discuss and advise on the subject’s diet 
9.2.4.2.2 
Visit 13 and 15 Procedures 
During Visits 13 and 15 the following procedures will be undertaken: 
• Blood sample 
• Call to IRT 


 
 
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• Dialysis parameters 
• Dialysis parameters for Kt/V (when available from routine clinical assessment) 
• Dispense study medication 
• Returned study medication count 
• Adverse events 
• Concomitant medication 
• Discuss and advise on the subject’s diet 
9.2.4.2.3 
Visit 16 End of Study (or Early Discontinuation) Procedures 
On completion of the study or early discontinuation/withdrawal, the following procedures 
will be undertaken. See also Section 5.4, for further information on withdrawal 
procedures and criteria. 
• Physical examination 
• Height and body weight 
• Vital signs 
• Blood sample  
• Call to IRT: confirmation of subject completion/discontinuation 
• Dialysis parameters and dietary habits 
• Dialysis parameters for Kt/V (when available from routine clinical assessment) 
• Returned study medication count 
• Patient reported palatability and acceptability 
• Adverse events 
• Concomitant medication 
• Discuss and advise on the subject’s diet 
9.2.5 
Visit 17 Follow-Up Procedures 
All subjects, whether completing the study or who have withdrawn prematurely, will be 
followed up 14 days after their last study visit to collect any new AEs and concomitant 


 
 
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medications. This visit may be conducted by telephone call or as an in-clinic visit. If the 
Investigator has not seen the subject at a clinic visit at the end of the reporting period, the 
Investigator must attempt 2 telephone calls to the subject, and if there is no response, a 
registered letter will be mailed, with return receipt requested. 
See Section 10.3.1 and Section 10.3.2 for instructions on follow-up of AEs, SAEs and 
pregnancies. 
9.2.6 
Post Study Treatment 
The Investigator is responsible for ensuring that consideration is given to the appropriate 
post study care of the subject's medical condition. 


 
 
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10. EVALUATION, RECORDING AND REPORTING OF AES AND 
SAES 
10.1 Definitions 
10.1.1 Reference Safety Information 
The Reference Safety Information is a document covering information relating to safety, 
indications, dosing, pharmacology, warnings, precautions, contraindications and other 
information concerning the product. As a minimum, it contains the Company Core Safety 
Information, which consists of the information on Contraindications, Warnings and 
Precautions, Use in Special Populations, Undesirable Effects and Overdose from the 
Company Core Data Sheet. 
In the context of this study, for both PA21 and Phoslyra the Reference Safety Information 
is the current version of the IB. 
10.1.2 Adverse Event 
Any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to 
the medicinal (investigational) product. 
10.1.3 Adverse Drug Reaction 
In the pre-approval clinical experience with a new medical product or its new usages, 
particularly as the therapeutic dose(s) may not be established, all noxious and unintended 
responses to a medicinal product related to any dose should be considered ADRs. This 
definition also covers medication errors and uses outside what is foreseen in the protocol, 
including misuse and abuse of the product. The phrase “responses to a medicinal product” 
means that a causal relationship between a medicinal product and an AE is at least a 
reasonable possibility, i.e., the relationship cannot be ruled out.  
10.1.4 Unexpected AE/ADR 
An AE/ADR, the nature (i.e., specificity/seriousness/outcome/frequency) or severity of 
which is not consistent with the applicable product information (IB for both PA21 and 
Phoslyra). 
10.1.5 Serious Adverse Event 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death 


 
 
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• Is life-threatening (the term life-threatening in the definition of serious refers to an 
event in which the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe) 
• Requires inpatient hospitalisation or prolongation of existing hospitalisation (unless 
elective surgery (a planned, non-emergency medical procedure)) 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is an important medical event (i.e., medically significant) 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalisation but may jeopardise the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These events should also be considered as serious. 
Conversely, some hospitalisations, particularly those which are the result of elective or 
previously scheduled surgery for pre-existing conditions should not automatically be 
classed as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair or kidney transplant surgery would not be classed as an SAE. Previously scheduled 
hospitalisations must be documented in the subject’s source documents before the 
parents/legal guardian signs the ICF and the subject, where appropriate/required, signs the 
assent form. Any worsening of a pre-existing medical condition or any new medical 
condition that meets the above SAE criteria should be considered as an SAE. 
Any suspected transmission of any infectious agent via a medicinal product should be 
considered as an important medical event (i.e., medically significant) and therefore 
documented as an SAE. 
The Investigator is encouraged to discuss with the Sponsor, or designee, any AEs for 
which the issue of seriousness is unclear or questionable. 
10.1.6 Suspected Unexpected Serious Adverse Reaction 
Any ADR that is both serious and unexpected (per the Reference Safety Information) 
that, based on the opinion of the Investigator or Sponsor, or designee, is felt to have a 
reasonable suspected causal relationship to a medicinal product. 
10.2 AE Descriptors 
10.2.1 Intensity/Severity Categorisation 
The term severe is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); however the event itself may be of 


 
 
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relatively minor medical significance (such as severe headache). This is not the same as 
serious, which is based on subject/event outcome or action criteria usually associated with 
events that pose a threat to a subject’s life or functioning. Seriousness (not severity) 
serves as a guide for defining regulatory reporting obligations. 
In general, the intensity of a particular AE to be recorded is the worst intensity 
experienced by the subject during the course of the event. The medical assessment of 
intensity will be determined by using the following definitions: 
Mild: 
The AE is easily tolerated and does not interfere with usual activity. 
Moderate: 
The AE interferes with daily activity, but the subject is still able to 
function.  
Severe: 
The AE is incapacitating and the subject is unable to work or complete 
usual activity. 
10.2.2 Causal Relationship Categorisation 
An Investigator who is qualified in medicine must make the determination of relationship 
to investigational product for each AE and SAE. The Investigator should decide whether, 
in his or her medical judgement, there is a reasonable possibility that the event may have 
been caused by the investigational product. If there is no valid reason for suggesting a 
relationship, then the AE/SAE should be classified as unrelated or unlikely related. 
Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting a 
cause-and-effect relationship between the investigational product and the occurrence of 
the AE/SAE, then the AE/SAE should be considered certainly, probably/likely, or 
possibly related.  
For additional guidance refer to Table 29. 
Table 29 
Causal Relationship Categories 
Term 
Relationship 
Definition 
Certain 
Yes 
• 
Event or laboratory test abnormality, with plausible time relationship to 
drug intake 
• 
Cannot be explained by disease or other drugs 
• 
Response to withdrawal plausible (pharmacologically, pathologically) 
• 
Event definitive pharmacologically or phenomenologically (i.e., an 
objective 
and 
specific 
medical 
disorder 
or 
a 
recognised 
pharmacological phenomenon) 
• 
Rechallenge satisfactory, if necessary 
 


 
 
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Table 29 
Causal Relationship Categories (Cont’d) 
Term 
Relationship 
Definition 
Probable/likely 
Yes 
• 
Event or laboratory test abnormality, with reasonable time relationship 
to drug intake 
• 
Unlikely to be attributed to disease or other drugs 
• 
Response to withdrawal clinically reasonable 
• 
Rechallenge not required 
Possible 
Yes 
• 
Event or laboratory test abnormality, with reasonable time relationship 
to drug intake 
• 
Could also be explained by disease or other drugs 
• 
Information on drug withdrawal may be lacking or unclear 
Unlikely 
No 
• 
Event or laboratory test abnormality, with a time to drug intake that 
makes a relationship improbable (but not impossible) 
• 
Disease or other drugs provide plausible explanations 
Unrelated 
No 
• 
Event or laboratory test abnormality which is clearly related to 
circumstances not connected with the drug intake. 
 
If the causal relationship between an AE/SAE and the investigational product is 
determined to be “certainly, probably/likely, or possibly related”, the event will be 
considered to be related to the investigational product for the purposes of expedited 
regulatory reporting. In circumstances where the Investigator has not provided his/her 
assessment about the relationship, the event will be considered as related and will qualify 
for expedited regulatory reporting 
10.2.3 Outcome Categorisation 
Outcome may be classified as: recovered/resolved; recovering/resolving, not 
recovered/not resolved/ongoing, recovered/resolved with sequelae; fatal; or unknown (if 
follow-up is not possible).  
If the outcome of an SAE is reported as recovered/resolved with sequelae, the 
Investigator should specify the kind of sequelae on the SAE form. If the outcome of an 
SAE is reported as unknown, the Investigator should specify (on the SAE form) the 
rationale why unknown was selected. 
10.2.4 Symptoms and Signs of the Disease under Study 
Symptoms of the disease under study should not be classed as AEs as long as they are 
within the normal day-to-day fluctuation of the disease. 
Worsening of the symptoms however, should be recorded as an AE, and clearly marked 
as worsening. 


 
 
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10.2.5 Clinical Laboratory Evaluations 
A change in the value of a safety laboratory investigation can represent an AE if the 
change is clinically relevant or if, during treatment with the investigational product, a 
shift of a parameter is observed from a normal value to a pathological value, or a further 
worsening of an already pathological value. When evaluating such changes, the extent of 
deviation from the reference range, the duration until return to the reference range, either 
while continuing treatment or after the end of treatment with the investigational product, 
and the range of variation of the respective parameter within its reference range, must be 
taken into consideration. 
If, at the end of the treatment phase, there are pathological laboratory values which were 
not present at baseline, further clinical or laboratory investigations should be performed 
until the values return to within reference range or until a plausible explanation 
(e.g., concomitant disease) is found for the pathological laboratory values. 
The Investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a laboratory parameter is clinically significant and therefore 
represents an AE. If the Investigator considers such an AE as serious (e.g., medically 
significant event fulfilling criteria per Section 10.1.5) it must be reported as an SAE. 
At the end of the study period, all pathological laboratory findings/values diagnosed 
throughout the treatment period should be reviewed by the Investigator to provide a final 
clinical assessment in view of the dynamic of laboratory changes/abnormalities. 
10.2.6 Abuse, Misuse, Overdose and Medication Error 
All special events such as study medication abuse, misuse, overdose and medication 
errors have to be documented in the subject’s CRF and source documents. If any abuse, 
misuse, overdose, or medication errors lead to an SAE (see Section 10.1.5), then the event 
has to be reported per standard guidelines. 
10.3 Reporting Procedure for AEs, SAEs and Pregnancy 
10.3.1 Adverse Events 
All AEs either observed by the Investigator or one of his/her medical collaborators, or 
reported by the subject spontaneously, or in response to a direct question, will be noted in 
the AE section of the subject's CRF and source documentation. This applies to all AEs 
regardless of presumed relationship to the study treatment, including the investigational 
product, active comparator and no treatment period (e.g., screening and washout periods). 
AEs leading to discontinuation of study treatment should also be collected. 
If any AE is reported, the date of onset, relationship to study medication or treatment, any 
action taken, date of resolution (or the fact that it is still continuing or has become 
chronic), outcome, and whether the AE is serious or not will be recorded. Where possible, 


 
 
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the Investigator should report a diagnosis rather than signs and symptoms or abnormal 
laboratory values. 
The AE reporting/recording period begins at the time the ICF (and where 
required/appropriate, assent) is signed. The AE reporting/recording period ends at the last 
study/follow up visit.  
All AEs persisting at the time of study completion will be followed by the Investigator 
through contact with the subject until resolution or stabilisation, or the subject is lost to 
follow-up and cannot be contacted. The outcome must be documented in the subject’s 
source documents. 
If the subject reports an AE, it is the Investigator’s responsibility to acquire sufficient 
information in order to assess causality. This may require additional laboratory testing, 
physical examinations, telephone contacts, etc.  
In order to avoid bias in eliciting AEs, subjects, where appropriate/required, and their 
parents/legal guardian should be asked a non-leading question, such as “How are you/is 
the subject feeling?” It is also important to question the subject, where 
appropriate/required, and their parents/legal guardian in a non-leading way about changes 
in the subject’s health or concomitant medication usage since their last visit. This 
information should be collected prior to completion of assessments at all study visits. In 
addition, any symptoms/conditions reported during assessments and deemed to be 
clinically significant by the Investigator will be assessed as AEs. 
As GI AEs (e.g., nausea, vomiting, diarrhoea, constipation and dyspepsia) are associated 
with the use of all phosphate binders, it should be ensured that all occurrences of GI 
events are appropriately reported. 
10.3.2 Serious Adverse Events 
The occurrence of an SAE must be immediately reported to Vifor Pharma or designee, 
within 24 hours of awareness by facsimile, email or telephone.  
A safety contact sheet will be provided by the Sponsor, or designee, to the Investigator 
(prior to first subject providing informed consent) detailing all applicable contact 
information. This will be kept up to date with any changes being provided to the 
Investigator immediately. 
The detailed SAE reporting procedures will be provided in the study documentation (SAE 
Processing and Reporting Plan). The SAE should be reported using the Vifor Pharma, or 
designee, SAE report form provided by Vifor Pharma, or designee (see Appendix 1). The 
Investigator must complete, sign and date the SAE pages, and verify the accuracy of the 
information recorded on the SAE pages with the corresponding AE CRF page(s) and 
source documents. The Vifor Pharma, or designee, SAE report form must be completed in 


 
 
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capital letters, in medical terms, in English and to the best extent possible given the time 
constraints.  
Where possible, the Investigator should report a diagnosis rather than signs and 
symptoms. In case of a fatal outcome, the Investigator should provide a working 
diagnosis (event which caused outcome, e.g., death due to fatal myocardial infarction) 
instead of reporting only death; an autopsy report should be provided where possible.  
Where the SAE report form cannot be transmitted due to technical problems, the 
Investigator must inform Vifor Pharma, or designee, about the SAE by phone. As soon as 
technical problems are resolved, the Investigator will send a copy of the SAE report form 
to the Vifor Pharma, or designee.  
All SAEs (regardless of relationship to investigational product) will be reported from the 
time the informed consent (and where required/appropriate, assent) is signed until 30 days 
following the last study visit (including the follow-up visit if applicable) or until 30 days 
after last study drug administration, whichever is longer. No formal study visit is required 
but the Investigator must report any SAEs that occur during this period using the SAE 
form. If the Investigator has not seen the subject at a clinic visit at the end of the reporting 
period, the Investigator must attempt 2 telephone calls to the subject to inquire about 
SAEs, and if there is no response, a registered letter will be mailed, with return receipt 
requested. SAEs starting before first administration of study drug must be identified as 
such on the CRF and source documentation. 
A death occurring during the study or which comes to the attention of the Investigator 
within 30 days after the last study visit (including the follow-up visit if applicable) or 
until 30 days after the last study drug administration, whichever is longer, whether 
considered treatment-related or not, must be reported to Vifor Pharma, or designee, using 
the Vifor Pharma, or designee, SAE form. Preliminary reports will be followed by 
detailed descriptions which will include copies of hospital case reports, autopsy 
reports/certificates and other documents when requested and applicable. 
Contact information for reporting of SAEs will be provided in the study documentation 
(SAE Processing and Reporting Plan). 
The onset date of the AE is defined as the onset of signs and symptoms or a change from 
baseline. The onset date of the SAE is defined as the date the signs and 
symptoms/diagnosis became serious, i.e., met at least 1 of the International Conference on 
Harmonisation (ICH)) criteria for serious. The resolution date of the SAE is defined as 
when the symptoms resolve (subject recovering), or the event is considered chronic 
(e.g., sequelae) or stable, and/or if the seriousness criteria are no longer applicable. 
Serious AEs that are ongoing at the time of death are considered unresolved.  
All recorded SAEs, regardless of relationship to investigational product, will be followed 
up until resolution, stabilisation, or the subject is lost to follow-up and cannot be 


 
 
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contacted. In circumstances where the Investigator is unable to make contact with the 
subject (or his/her relatives/legal guardian), the Investigator must provide a written 
statement (recorded in the subject’s source documents) to Vifor Pharma, or designee, 
confirming that the subject is lost to follow-up.  
At a minimum the following should be provided at the time of the initial SAE report: 
• Study name and/or number 
• Subject number, age and gender/sex 
• SAE description (including onset date of the SAE, outcome and reason for it being 
considered serious) 
• Relationship to investigational product (i.e., causality) 
• Name of the investigational product (including drug dose and administration dates) 
• Investigator name and address 
• Name of the reporter (including site name or number and country), and, 
• Dated signature of the Investigator or Sub-/Co-Investigator 
Additional follow-up information, if required or available, must be faxed immediately 
(within 24 hours of awareness) following Investigator (or site) awareness of the 
information. The follow-up information must be completed on a Vifor Pharma, or 
designee, SAE report form (marked follow-up) and placed with the original in the 
appropriate section of the study file. 
Preliminary reports will be followed by detailed descriptions which will include copies of 
hospital case reports, autopsy reports/certificates (in case of death) and other documents 
when requested and applicable. 
The Investigator is encouraged to discuss with Contract Research Organisation 
(CRO)/Sponsor any AEs for which the issue of seriousness is unclear or questionable. 
Vifor Pharma, or designee, is responsible for expedited reporting to the relevant 
Regulatory Authorities, to Investigators and to local and central Institutional Review 
Board/Ethics Committee/Independent Ethics Committee (IRB/EC/IEC) as per local 
regulations. 
Any SAE considered to have a causal relationship (i.e., related) to the investigational 
product and discovered by the Investigator at any time after the study should be reported. 
A rationale for the assessment of a causal relationship must be provided by the 
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information that is obtained after database lock of the clinical database will be 
documented only in the safety database.  
Additional detail regarding SAE reporting is available in the SAE Processing and 
Reporting Plan, which will be provided in the study documentation. 
10.3.2.1 
Elective Surgery/Routine Examination 
Elective surgery (a pre-planned, non-emergency medical procedure) and in-patient 
routine examination for a pre-existing condition do not qualify as SAEs but must be 
recorded in the subject’s source documents. However, AEs which occur during the 
elective hospitalisation will need to be collected and reported. 
10.3.3 Pregnancy 
When a female subject becomes pregnant during the study and study treatment has been 
administered to the subject, the outcome of the pregnancy needs to be monitored and the 
safety of the mother and unborn child need to be safeguarded (as per protocol, pregnancy 
is an exclusion criteria). Therefore, the outcome of all such pregnancies (including normal 
births) must be followed up and documented, even if the subject was withdrawn from the 
study.  
Women of child-bearing potential should have a negative serum pregnancy test prior to 
randomisation. Study medication should not be initiated by the Investigator until a report 
of a negative pregnancy test has been obtained. 
Subjects with CKD may experience false positive results in serum pregnancy tests. 
Women with a positive pregnancy test at screening will be withdrawn from the study and 
can be rescreened about 2 weeks later if subsequent test is negative. Women who have a 
positive pregnancy test during the study will be withdrawn from the study immediately, 
and the procedures for withdrawal will be completed (see Section 5.4). Positive 
pregnancy tests during the study will be repeated 2 weeks later, in order to eliminate false 
positive results. 
Effective contraception must be used (in sexually mature male and female subjects) 
before beginning study medication, during study dosing, and for 30 days following 
discontinuation of study medication even when there has been a history of infertility, 
unless due to hysterectomy. A reliable form of contraception (i.e., with a failure rate of 
<1% per year) must be used unless abstinence is the chosen method or subject has been 
surgically sterilised. Please refer to the exclusion/inclusion criteria (Section 5) for 
additional information. 
A female subject must immediately inform the Investigator if she becomes pregnant 
during the study and be instructed to stop taking study medication. The Investigator 
should counsel the subject and discuss the risks of continuing with the pregnancy and the 
possible effects on the foetus.  


 
 
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The Investigator/Sponsor, or designee, is responsible for monitoring the subject and 
pregnancy outcome. Every effort should be made to gather information regarding the 
pregnancy outcome until 90 days postpartum (or otherwise as appropriate). It will be the 
responsibility of the Sponsor, or designee, together with the appropriate support of the 
Investigator, to obtain this information.  
Any report of pregnancy recorded for any female subject should be reported to Vifor 
Pharma, or designee, within the same timelines as SAE reporting, i.e., immediately 
(within 24 hours of awareness). The Investigator should complete a Vifor Pharma, or 
designee, Report on Exposure to Medicines during Pregnancy form (see Appendix 2) and 
forward to Vifor Pharma, or designee. Complications of pregnancy such as abortion 
(spontaneous or induced), premature birth or congenital abnormality are considered SAEs 
and should be reported using the Vifor Pharma, or designee, SAE report form.  
All pregnancies occurring in a female subject within 30 days after discontinuation of 
investigational product should be reported within the same timelines as SAE reporting to 
Vifor Pharma, or designee. 


 
 
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11. DSMB PROCEDURES 
A DSMB will be constituted to protect the safety of study participants. A DSMB is a 
group of independent experts external to a study assessing the progress, safety data and, if 
needed, critical efficacy endpoints of a clinical study. The DSMB will be composed of 
clinicians with expertise in relevant clinical specialties and at least 1 biostatistician 
knowledgeable about statistical methods for clinical trials and sequential analysis of trial 
data.  
The DSMB will receive CRF data in the form of tables and listings. The data should 
include, but is not limited to, demographics, subject enrolment, baseline characteristics, 
AE data, SAE data (by severity and causality), laboratory data, dose adjustments, protocol 
adherence, and subject withdrawals. The DSMB will evaluate participant benefit versus 
risk. In addition the DSMB will monitor external factors relevant to the trial, for example 
scientific and therapeutic developments that may affect participant safety. Based on the 
observed benefits or adverse effects, the DSMB will make recommendations to the 
Sponsor concerning continuation, termination or modifications of the trial. 
The Sponsor will establish a charter document explaining the working procedures for the 
DSMB. 


 
 
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12. STATISTICAL ANALYSIS 
12.1 Statistical Methods 
All statistical analyses will be performed using SAS Version 9.2 or later (SAS Institute 
Inc. SAS/STAT, Cary, NC, US). Detailed methodology (including handling of missing 
data, data from subjects receiving a kidney transplant and data from subjects moving from 
pre-dialysis to dialysis) for summary and statistical analyses of the data collected in this 
trial will be documented and finalised prior to study completion. A general description of 
the planned methods is provided below.  
12.2 Sample Size and Power Calculations 
In the PA21 treatment group, assuming a mean change in serum phosphorus levels from 
baseline to end of Stage 1 of 1.2 mg/dL, a standard deviation for the change of 2.0 and to 
further allow for an approximate drop-out rate of 30%, 100 randomised subjects will 
provide more than 90% power. 
The sample size estimation is based on conservative values from the Phase 3 study, and 
performed using nQuery Version 6.0. 
One hundred subjects should also be sufficient to provide robust safety and dosing 
information for PA21 in the paediatric and adolescent patients with CKD.  
12.3 Populations 
12.3.1 FAS Population 
The FAS population will consist of all subjects who satisfy the following criteria: 
• Randomised to treatment at Stage 1 
• Received at least 1 dose of randomised treatment 
• Had at least 1 post-baseline assessment of the efficacy endpoint (serum phosphorus) 
• The FAS will be analysed based on the treatment to which the subject was 
randomised. 
12.3.2 PPS Population 
The PPS population consists of all subjects who, in addition to the FAS criteria, had no 
major protocol violations. 
12.3.3 Safety Population 
The safety population consists of all randomised subjects who have taken at least 1 dose 
of study medication. The subjects in this group will be analysed based on the treatment 
they received.  


 
 
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12.4 Background and Demographic Characteristics 
Demographic and baseline disease characteristics will be summarised and compared 
between the PA21 and Phoslyra groups. 
12.5 Study Medication 
The total amount of drug given will be calculated for each subject and will be compared 
to the amount expected to be given for each subject. Treatment compliance will be 
calculated for each subject and summarised by treatment group. 
Results will be summarised by means of descriptive statistics (n, mean, standard 
deviation, median, minimum and maximum) and frequency tables, stratified by treatment 
group. 
12.6 Concomitant Therapy 
Concomitant medications will be categorised according to a standard dictionary (World 
Health Organization Anatomical Therapeutic Chemical Drug Reference List classification 
– the version will be provided in the study report). Counts and percentages of subject use 
for each medication will be computed and summarised by treatment group. 
12.7 Efficacy Evaluations 
12.7.1 Primary 
The primary efficacy analysis will be performed on the change in serum phosphorus 
levels from baseline to the end of Stage 1 in the PA21 and group. The change from 
baseline in the PA21 group will be analysed for the subjects of the FAS, using a paired 
t-test. The changes from baseline will also be summarised descriptively. 
Analyses will generally be based on the results from the central laboratory. Depending on 
availability of data, the change from baseline may be computed using pre- and 
post-treatment values from the local laboratory. Summary of Blood Samples (see 
Table 2). 
12.7.2 Secondary 
Additional secondary efficacy endpoints that will be analysed include: 
• Change in serum phosphorus from baseline in the Phoslyra group at the end of 
Stage 1. 
• Change in serum phosphorus from baseline in PA21 and Phoslyra groups at the end of 
Stage 2. 
• Serum phosphorus values at each visit during Stage 1and 2. 


 
 
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• Percentage of subjects in each period during which the subject has serum phosphorus 
levels in the age dependent target ranges at each visit. 
• Percentage of subjects with serum phosphorus within the normal range for the age 
dependent target range at each visit. 
The secondary efficacy endpoints will be summarised by visits, and changes from 
baseline will be analysed with descriptive statistics. 
12.8 Safety Evaluations 
Primary safety endpoint: 
• AE profile  
• Percentage of withdrawals due to AEs 
Secondary safety endpoints: 
• Serum total corrected calcium at each time point and change from baseline 
• Percentage of subjects that develop at least 1 episode of sustained hypercalcaemia 
during study participation (confirmed by repeat sample 1 week later; see 
Section 5.4.2) 
• Serum total corrected calcium-phosphorus product at each time point and change 
from baseline 
• Serum iPTH levels at each time point and change from baseline 
• Routine biochemical/haematological laboratory tests 
AEs, laboratory values, vital signs and other safety parameters will be summarised. AEs 
of special interest will be summarised separately. Descriptive comparisons will be made 
for changes from baseline where appropriate.  
AEs will be coded using the latest available version of the Medical Dictionary for 
Regulatory Activities, the version of which will be provided in the Clinical Study Report. 
AEs will be summarised by system organ class and preferred term for the incidence and 
prevalence of the AEs. SAEs, SAEs that led to death and (S)AEs that led to withdrawal 
will also be summarised and listed.  
Only AEs and concomitant medications which started on or after written and dated 
informed consent have been provided (and, where appropriate/required, assent) will be 
summarised for this study. All AE summaries will be done for all of the subjects in a 


 
 
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treatment group combined and by the maximum dose received during the trial. All AEs 
will be listed. 
12.9 Other Evaluations 
12.9.1 Patient Reported Palatability and Acceptability 
Patient reported palatability and acceptability assessments will be summarised by 
treatment group.  


 
 
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13. STUDY ETHICAL CONSIDERATIONS 
13.1 Ethical Conduct of the Study 
The study will be conducted according to the principles of the World Medical 
Association’s (WMA) Declaration of Helsinki (as amended by the 64th WMA General 
Assembly, Fortaleza, Brazil, October 2013) [76], and the ICH guidelines for GCP [77]. 
Vifor Pharma, or designee, will ensure that the study complies with all local, federal or 
country regulatory requirements.  
The Investigator must ensure the anonymity of all subjects participating in the study. 
Each subject will be assigned a unique subject number and this should be used on all 
forms associated with the subject’s documents or samples that will be supplied to the 
Sponsor or any party completing testing on behalf of the Sponsor (e.g., blood for central 
laboratory assessments).  
All anonymous data remains the property of Vifor Pharma. 
13.2 Informed Consent and Assent 
The ICF used for the study must comply with the Declaration of Helsinki, federal 
regulations, and ICH guidelines; and must have been approved by the appropriate 
IRB/EC/IEC prior to use. The age-appropriate assent forms must comply with all relevant 
regulations for the centre and must also have also been approved by the appropriate 
IRB/EC/IEC prior to use. The Investigator or an authorised associate must explain orally 
and in writing the nature of the study and the treatment in such a manner that the subject, 
where appropriate/required, and their parent/legal guardian are aware of potential benefits 
and risks. Subjects, where appropriate/required, and their parent/legal guardian must also 
be informed that participation is voluntary and that the subject may withdraw, or be 
withdrawn by their parents/legal guardian, from the study at any time, without prejudice. 
Subjects and their parent/legal guardian must be provided sufficient time to consider 
participation, including discussion with other family members prior to signing the ICF, 
and, where applicable, assent. Documentation of the discussion and the date of informed 
consent, and where applicable assent, must be recorded in the source documentation. 
Subjects, 
parents/legal 
guardian 
must 
give 
informed 
consent 
(and 
where 
appropriate/required, subjects must give assent) in writing. 
A guideline on how to administer informed consent, is attached in Appendix 3 and should 
be followed by all site staff administering informed consent to subject’s parents/legal 
guardian (and where appropriate/required, subjects), when an equivalent process is not 
available at the site. 
13.3 Institutional Review Board or EC/IEC 
The protocol, any protocol amendments, consent and assent forms for the proposed 
clinical study and any other documents required by the local IRB/EC/IEC must be 
submitted by the Investigator for review and approval to the IRB/EC/IEC. The 


 
 
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Investigator must also ensure that the IRB/EC/IEC reviews the progress of the study on a 
regular basis and, if necessary, renews its approval of the study on an annual basis. A 
copy of the approval letter must be forwarded to Vifor Pharma or designee before the 
study is implemented. 


 
 
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14. QUALITY CONTROL AND QUALITY ASSURANCE 
The Investigator must ensure that all trial related site source data, study related documents 
and reports will be available, and that the provision of direct access for monitoring and 
auditing by Vifor Pharma or its designees will be permitted. In addition, the Investigator 
must ensure that all trial related site source data, study related documents and reports will 
be made available for inspection by the appropriate Regulatory Authority and review by 
the IRB/EC/IEC. 
Accurate and reliable data collection will be assured by verification and cross-check of 
the CRFs against the Investigator’s records by the Study Monitor (source document 
verification), and the maintenance of a drug dispensing log by the Investigator. The data 
collected will be entered (electronic data capture) into the study database and will be 
verified by the Monitor. A comprehensive validation check program will verify the data 
and queries will be generated for resolution by the Investigator. Throughout the study, 
Vifor Pharma or its designee may review data as deemed necessary. 


 
 
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15. ADMINISTRATIVE PROCEDURES 
15.1 Sponsor’s Responsibilities 
15.1.1 Study Supplies 
Sites will be provisioned with supplies required to manage this study. This will include 
but not be limited to:  
• Investigator file(s) (for filing of all study related documentation) 
• Kits for collection, storage and transportation of applicable samples required for 
central laboratories. This will also include all applicable guidelines and contact details 
• Contact list of all relevant study personnel 
• Documentation and directions for use of relevant study questionnaires 
• Access to electronic CRF and completion guidelines 
• Access to IRT and user guidelines 
• Study Reference Manual 
• All study forms (e.g., SAE, pregnancy, drug accountability, etc.) 
15.1.2 Insurance 
Vifor Pharma confirms that it carries liability insurance which protects non-employee 
physicians or Investigators against claims for which they may become liable as a result of 
damages caused by Vifor Pharma products used in clinical studies. Insurance coverage is 
not extended to damages that the Investigators or third parties may suffer by reason of 
acts of commission or omission on the part of such Investigators or third parties and that 
are not in accordance with accepted common medical practices (lege artis procedures). 
Vifor Pharma will reimburse the subject for all study-related injuries provided that the 
injury does not arise from the subject’s misuse of the study drug or failure to follow the 
Investigator’s instructions. 
15.1.3 Investigator Training 
All Investigators and their study personnel will receive training regarding the study 
procedures and GCP/regulations specific to the conduct of clinical trials. This training 
will take place prior to enrolment of the first subject at the study centre.  
15.1.4 Study Monitoring 
The study will be monitored by representatives of Vifor Pharma, or designee, which may 
include a CRO and/or partner company. 


 
 
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It is understood that the responsible Vifor Pharma Monitor (or designee) will contact and 
visit the Investigator regularly and will be allowed, on request, to inspect the various 
records of the trial (CRFs and other pertinent data) provided that subject confidentiality is 
maintained in accordance with local requirements. 
It will be the Monitor's responsibility to inspect the CRFs at frequent regular intervals 
throughout the study, to verify adherence to the protocol and the completeness, 
consistency and accuracy of the data being entered on them. The Monitor must have 
access to laboratory test reports and other subject records needed to verify the entries on 
the CRF. The Investigator (or his/her deputy) agrees to co-operate with the Monitor to 
ensure that any problems detected in the course of these monitoring visits are resolved. 
15.2 Investigator’s Responsibilities 
15.2.1 Reporting and Recording of Data 
All required study data must be entered in the CRF created for the study. Training on the 
system will be provided to all sites, including instructions on how to address missing data, 
corrections, query procedures and electronic signatures. Only individuals who are 
identified on the authorised signature page may enter/correct data in the CRF. For those 
subjects who withdraw before completion of the study, all available efficacy and safety 
data must be entered in the CRF. Incomplete or inconsistent data on the CRF will result in 
data queries addressed to the Investigator for resolution. 
15.2.2 Source Documentation 
All data for the study must be available in source documentation. The Investigator must 
maintain adequate and accurate source documents upon which case reports for each 
subject are based. They are to be separate and distinct from CRFs. These records should 
include detailed notes on: 
• The medical history prior to participation in the study 
• The basic identifying information, such as demographics, that link the subject’s 
source documents with the CRFs 
• The results of all diagnostic tests performed, diagnoses made, therapy provided and 
any other data on the condition of the subject 
• The subject’s exposure to study treatment 
• All AEs 
• The subject’s exposure to any concomitant therapy (including date and quantity 
dispensed) 
• All relevant observations and data on the condition of the subject throughout the study 


 
 
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• The oral and written communication with the subject’s parent/legal guardian and, 
where appropriate/required, the subject regarding the study treatment (including the 
risks and benefits of the study). The date of informed consent, and where applicable 
assent, must be recorded in the source documentation. 
15.2.3 Records Retention 
The Investigator must arrange for the retention of all study documentation (such as CRF 
data, research files, and master files) for the duration specified in their respective site 
contract or as specified by the applicable Regulatory Authority, whichever is longer. The 
Sponsor will inform the Investigator in writing when files can be destroyed. Archived 
data may be held on microfiche or electronic record, provided that a back-up copy exists 
and that a hard copy can be generated if required. 
The Investigator must inform Vifor Pharma or designee immediately if any documents 
are lost, to be transferred to a different facility, or to be transferred to a different owner. 
15.2.4 Site Documentation 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified. 


 
 
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16. PROCEDURE FOR MODIFICATION OF PROTOCOL OR 
PREMATURE TERMINATION OF THE STUDY 
16.1 Protocol Waivers, Deviations and Violations 
Protocol waivers shall not be permitted except where necessary to eliminate an immediate 
hazard to subjects. 
Deviations from the protocol including violations of inclusion/exclusion criteria will be 
assessed as minor or major on a case-by-case basis. The criteria describing the 
deviation(s) and how they will be handled will be documented. 
16.2 Protocol Amendments 
Protocol amendments, except where necessary to eliminate an immediate hazard to 
subjects, must be made only with the prior approval of Vifor Pharma. Each applicable 
Regulatory Authority/IRB/EC/IEC will review and approve amendments prior to their 
implementation. Regulatory Authority/IRB/EC/IEC approval need not be obtained prior 
to removal of an immediate hazard to subjects. 
16.3 Study Termination 
Vifor Pharma reserves the right to terminate the study in its entirety or at a site at any 
time. Reasons for termination may include (but are not limited to) unsatisfactory subject 
enrolment with respect to quality and/or quantity, site is unable to comply with the 
requirements of the protocol or GCP, or data recording is inaccurate and/or incomplete. 
In terminating the study, Vifor Pharma and the Investigator will assure that adequate 
consideration is given to the protection of the subject’s interests. Both parties will arrange 
the procedures on an individual basis after review and consultation and in accordance 
with the study contract. 


 
 
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17. POLICY FOR PUBLICATION AND PRESENTATION OF DATA 
Vifor Pharma is committed to the timely communication of data from clinical research 
trials, following the Pharmaceutical Research and Manufacturers of America principles 
[78]. Where possible, authorship will be agreed at the beginning of the study. The authors 
will form a publication committee and this committee will propose and develop 
appropriate scientific manuscripts or abstracts from the study data. Investigators may not 
present or publish partial or complete study results individually. Any manuscript or 
abstract proposed by the Investigators must be reviewed and approved in writing by Vifor 
Pharma before submission for publication. Names of all Investigators participating in the 
study will be included in the publication. 
The publication committee for a study will comprise of authors selected in adherence 
with the International Committee of Medical Journal Editors criteria [79] for authorship. 
That is, all authors must meet each of the following 3 criteria: 
1. Substantial contribution to conception and design or acquisition of data, or analysis 
and interpretation of data 
2. Drafted the article or revised it critically for important intellectual content 
3. Approved the final version for publication 
Members of the study steering committee generally fulfil the authorship criteria through 
their involvement in protocol design and review, monitoring of and sometimes direct 
involvement with recruitment, and thus they will usually be part of the publication 
committee. If studies are multicentre, it may be appropriate to assign group authorship.  
In addition, certain Vifor Pharma employees involved in the design and conception of the 
protocol, study management and data analysis and interpretation are qualified authors and 
will be included in the publication committee e.g., the lead physician, statistician and 
study project manager or their equivalents. 


 
 
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18. REFERENCES 
1. 
van der Heijden BJ, van Dijk PCW, Verrier-Jones K, Jager KJ, Briggs JD. Renal 
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2. 
Vogt BA, Avner ED. Acute renal failure. In: Kliegman RM, Jenson HB, Behrman 
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3. 
Warady BA, Chadha V. Chronic kidney disease in children: the global 
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4. 
Fivush B, Jabs K, Neu A, Sullivan K, Feld L, Kohaut E, et al. Chronic renal 
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5. 
Combe C, Aparicio M. Phosphorus and protein restriction and parathyroid 
function in chronic renal failure. Kidney Int. 1994;46:1381-6.  
6. 
Lopez-Hilker S, Dusso AS, Rapp NS, Martin KJ, Slatopolsky E. Phosphorus 
restriction reverses hyperparathyroidism in uremia independent of changes in 
calcium and calcitriol. Am J Physiol. 1990;259:F432-7. 
7. 
NKF KDOQI Guidelines. KDOQI Clinical practice guidelines for bone 
metabolism and disease in chronic kidney disease. Clinical practice guidelines. 
Guideline 4. Restriction of dietary phosphorus in patients with CKD [Internet]. 
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8. 
Lederer E, Ouseph R, Nayak V. Hyperphosphatemia. MedScape eMedicine 
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9. 
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10. 
Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of serum 
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11. 
Block GA. Control of serum phosphorus: implications for coronary artery 
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12. 
Kanbay M, Goldsmith D, Akcay A, Covic A. Phosphate - the silent stealthy 
cardiorenal culprit in all stages of chronic kidney disease: a systematic review. 
Blood Purif. 2009;27:220-30. 


 
 
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13. 
Litwin M, Wühl E, Jourdan C, Trelewicz J, Niemirska A, Fahr K, et al. Altered 
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14. 
Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D, et al. Coronary-
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15. 
Levey AS, Eckardt K-U, Tsukamoto Y, Levin A, Coresh J, Rossert J, et al. 
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16. 
The Renal Association, Royal College of Physicians. Chronic kidney disease in 
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17. 
Saran R, Bragg-Gresham JL, Rayner HC, Goodkin DA, Keen ML, Van Dijk PC, 
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18. 
Chesney RW. Bone structure, growth, and hormonal regulation In: Kliegman RM, 
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19. 
Oh J, Wunsch R, Turzer M, Bahner M, Raggi P, Querfeld U, et al. Advanced 
coronary and carotid arteriopathy in young adults with childhood-onset chronic 
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20. 
Shroff R, Ledermann S. Long-term outcome of chronic dialysis in children. 
Pediatr Nephrol. 2007. 12 p. 
21. 
Chesney RW, Brewer E, Moxey-Mims M, Watkins S, Furth SL, Harmon WE, et 
al. Report of an NIH task force on research priorities in chronic kidney disease in 
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22. 
Rashid R, Neill E, Maxwell H, Ahmed SF. Growth and body composition in 
children with chronic kidney disease. Br J Nutr. 2007;97:232-8. 
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ERA-EDTA Registry: ERA-EDTA Registry 2011 Annual Report. Academic 
Medical Center, Department of Medical Informatics, Amsterdam (The 
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25. 
Harambat J, van Stralen KJ, Kim JJ, Tizard EJ. Epidemiology of chronic kidney 
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26. 
Jha V. Current status of chronic kidney disease care in southeast Asia. Semin 
Nephrol. 2009 Sep;29(5):487-96.  


 
 
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27. 
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failure: European guidelines. Pediatr Nephrol. 2006;21:151-9. 
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Bringhurst FR, Demay MB, Krane SM, Kronenberg HM. Bone and mineral 
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30. 
National Kidney Foundation. KDOQI clinical practice guidelines for bone 
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Target serum phosphorus levels. [Internet]. National Kidney Foundation; 2005 
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Groothoff JW. Long-term outcomes of children with end-stage renal disease. 
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33. 
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of growth and nutritional status in children on chronic peritoneal dialysis. 2008. 
35. 
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metabolism and disease in children with chronic kidney disease. Guideline 6. Use 
of phosphate binders in CKD. [Internet]. National Kidney Foundation; 2005 [cited 
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children with chronic kidney disease according to KDOQI. Kidney Int. 
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37. 
North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS). 
2011 Annual Dialysis Report. 2011. Available from: https://web.emmes.com/ 
study/ped/annlrept/annualrept2011.pdf.  


 
 
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38. 
NICE Clinical Guideline 157. Hyperphosphataemia in chronic kidney disease. 
Management of hyperphosphataemia in patients with stage 4 or 5 chronic kidney 
disease. Mar 2013. Available from: http://www.guidance.nic.org.uk/cg157. 
39. 
Calcichew® 500 mg chewable tablets. SmPC. Takeda UK Ltd. Buckinghamshire, 
UK. 
2014 
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Available 
from: 
http://www.medicines.org.uk/emc/ 
medicine/28505/SPC/Calcichew+500mg+Chewable+Tablets/. 
40. 
Adcal® Summary of Product Characteristics. ProStrakan Limited, Scotland, UK. 
2008.  
41. 
Alon U, Davidai G, Bentur L, Berant M, Better OS. Oral calcium carbonate as 
phosphate-binder in infants and children with chronic renal failure. Mineral 
Electrolyte Metab. 1986;12:320-5. 
42. 
Salusky IB, Coburn JW, Foley J, Nelson P, Fine RN. Effects of oral calcium 
carbonate on control of serum phosphorus and changes in plasma aluminum levels 
after discontinuation of aluminium containing gels in children receiving dialysis. J 
Pediatr. 1986 May;108(5 Part 1):767-70. 
43. 
PhosLo® gelcaps (calcium acetate) Package Insert. Fresenius Medical Care North 
America, Waltham, MA. 2007. Available from: http://www.fmcna.com/fmcna/ 
idcplg?IdcService=GET_FILE&allowInterrupt=1&RevisionSelectionMethod=Lat
estReleased&Rendition=Primary&dDocName=LINK_100048295 
44. 
Pieper A-K, Haffner D, Hoppe B, Dittrich K, Offner G, Bonzel K-E, et al. A 
randomized crossover trial comparing sevelamer with calcium acetate in children 
with CKD. Am J Kidney Dis. 2006 Apr;47(4):625-35. 
45. 
Salusky IB, Goodman WG, Sahney S, Gales B, Perilloux A, Wang H-J, et al. 
Sevelamer controls parathyroid hormone-induced bone disease as efficiently as 
calcium carbonate without increasing serum calcium levels during therapy with 
active vitamin D sterols. J Am Soc Nephrol. 2005;16:2501-8. 
46. 
Elseviers M, De Vos J-Y. The Research Board of EDTNA/ERCA. The use of 
phosphate binders: data from contributors to the European practice database. J 
Ren Care. 2009;35 Suppl 1:14-8. 
47. 
Schaefer K, Umlauf E, von Herrath D. Reduced risk of hypercalcemia for 
hemodialysis patients by administering calcitriol at night. Am J Kidney Dis. 1992 
May;19(5):460-4. 
48. 
Meric F, Yap P, Bia MJ. Etiology of hypercalcemia in hemodialysis patients on 
calcium carbonate therapy. Am J Kidney Dis. 1990 Nov;16(5):459-64. 
49. 
London GM, Marty C, Marchais SJ, Guerin AP, Metivier F, de Vernejoul M-C. 
Arterial calcifications and bone histomorphometry in end-stage renal disease. J 
Am Soc Nephrol. 2004;15:1943-51. 
50. 
Moe SM, Chertow GM. The case against calcium-based phosphate binders. Clin J 
Am Soc Nephrol. 2006;1:697-703.  


 
 
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51. 
Wills MR, Savory J. Aluminium poisoning: dialysis encephalopathy, 
osteomalacia, and anaemia. Lancet. 1983 Jul 2:29-34. 
52. 
Alfrey AC, LeGendre GR, Kaehny WD. The dialysis encephalopathy syndrome. 
Possible aluminium intoxication. N Engl J Med. 1976 Jan 22;294(4):184-8. 
53. 
Chertow GM, Burke SK, Lazarus JM, Stenzel KH, Wombolt D, Goldberg D, et al. 
Poly[allylamine hydrochloride] (RenaGel): a noncalcemic phosphate binder for 
the treatment of hyperphosphatemia in chronic renal failure. Am J Kidney Dis. 
1997 Jan;29(1):66-71. 
54. 
Burke SK, Slatopolsky EA, Goldberg DI. RenaGel®, a novel calcium- and 
aluminium-free phosphate binder, inhibits phosphate absorption in normal 
volunteers. Nephrol Dial Transplant. 1997;12:1640-4. 
55. 
Renagel® 800 mg film-coated tablets. SmPC. Sanofi, Surrey, UK. 2011 Dec. 
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Renagel+800+mg+film-coated+tablets/. 
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Renvela® 800 mg film-coated tablets. SmPC. Sanofi, Surrey, UK. 2014 Mar. 
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Renvela+800+mg+film+coated+tablets/. 
57. 
Fosrenol® SmPC 2013 Available from: http://www.medicines.org.uk/emc/ 
medicine/19617/SPC/Fosrenol+500mg%2c+750mg+%26+1000mg+chewable+ 
tablets/ 
58. 
Mohammed IA, Hutchison AJ. Phosphate binding therapy in dialysis patients: 
focus on lanthanum carbonate. Ther Clin Risk Manag. 2008;4(5):887-93. 
59. 
Pennick M, Dennis K, Damment SJP. Absolute bioavailability and disposition of 
lanthanum in healthy human subjects administered lanthanum carbonate. J Clin 
Pharmacol. 2006;46:738-46. 
60. 
Damment SJP, Pennick M. Clinical pharmacokinetics of the phosphate binder 
lanthanum carbonate. Clin Pharmacokinet. 2008;47(9):553-63. 
61. 
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hyperphosphatemia in chronic kidney disease. Clin Nephrol. 2010 Jul;74(1):4-11. 
62. 
Geisser P, Philipp E. Adsorbent for phosphate from an aqueous medium, 
production and use of said adsorbent. United States Patent. Patent No.: US 
6,174,442 B1. 2001 Jan 16. 
63. 
Wilhelm M, Gaillard S, Rakov V, Funk F. The iron-based phosphate binder PA21 
has potent phosphate binding capacity and minimal iron release across a 
physiological pH range in vitro. Clin Nephrol. 2014;81(4):251-8. 
64. 
Hergesell O, Ritz E. Stabilized polynuclear iron hydroxide is an efficient oral 
phosphate binder in uraemic patients. Nephrol Dial Transplant. 1999;14:863-7. 


 
 
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65. 
Chiu YW, Teitelbaum I, Misra M, de Leon EM, Adzize T, Mehrotra R. Pill 
burden, adherence, hyperphosphatemia, and quality of life in maintenance dialysis 
patients. Clin J Am Soc Nephrol. 2009;4:1089-96. 
66. 
Wesseling-Perry K, Harkins GC, Wang HJ, Sahney S, Gales B, Elashoff RM, et 
al. Response of different PTH assays to therapy with sevelamer or CaCO3 and 
active vitamin D sterols. Pediatr Nephrol. 2009 Jul;24(7):1355-61. Epub 2009 
Mar 20. 
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Wallot M, Bonzel KE, Winter A, Geörger B, Lettgen B, Bald M. Calcium acetate 
versus calcium carbonate as oral phosphate binder in pediatric and adolescent 
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Mahdavi H, Kuizon BD, Gales B, Wang HJ, Elashoff RM, Salusky IB. Sevelamer 
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71. 
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A randomized, parallel, open-label study to compare once-daily sevelamer 
carbonate powder dosing with thrice-daily sevelamer hydrochloride tablet dosing 
in CKD patients on hemodialysis. Am J Kidney Dis. 2010 Feb;55(2):307-15. 
74. 
EC.Europa.eu [Internet]. Belgium: EudraLex: The rules governing medicinal 
products in the European Union. Volume 4 EU Guidelines to good manufacturing 
practice medicinal products for human and veterinary use. Annex 13: 
Investigational medicinal products; 2010. Available from: http://ec.europa.eu/ 
health/documents/eudralex/vol-4/index_en.htmThe Rules Governing Medicinal 
Products in the European Union; Volume 4; EU Guidelines to Good 
Manufacturing Practice Medicinal Products for Human and Veterinary Use; 
Annex 13: Investigational Medicinal Products; 2010. 


 
 
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75. 
Ethical Considerations for Clinical Trials on Medicinal Products Conducted with 
the Paediatric Population. Recommendations of the ad hoc group for development 
of implementing guidelines for Directive 2001/20/EC relating to good clinical 
practice in the conduct of clinical trials on medicinal products for human use. 
2008 
76. 
World Medical Association Declaration of Helsinki. Ethical principles for medical 
research involving human subjects. October 2013. 
77. 
EMEA European Medicines Agency. ICH Topic E6(R1): Guideline for good 
clinical practice. Final guidance. 2002 Jul. Report No.: CPMP/ICH/135/95. 
78. 
PhRMA principles and guidelines: public disclosure of clinical trial results. 
Pharmaceutical Research and Manufacturers of America [Internet]. 2009 [cited 
2009]. Available from: http://www.phrma.org/principles_and_guidelines. 
79. 
International Committee of Medical Journal Editors [Internet]. Uniform 
requirements for manuscripts submitted to biomedical journals: writing and 
editing for biomedical publication [updated 2008 Oct]. Available from: 
http://www.icmje.org. 
 


                                                     FOR 107: SAE REPORT 
FORM 
VIFOR (Int.) ONLY: Coding number:__________________
©Vifor Pharma - FINAL 
Confidential 
Page 1 of 2 
1    Vifor Study:  
      CRO No. :  
      EudraCT No.:  
Initial Report        
Follow-up Report 
Follow-up Number:______ 
Date of Report :                                                    
(dd/mmm/yyyy)

Year of birth:                                  If unknown, age at onset:                                 Gender:  Male      
                               (yyyy)                                                       (Years)                                    Female  
Patient No.:                                                       
                    Screening No.:    Random No.:      Weight: ______ kg     Height: _______ cm     Hb Value _____ mg/dl
                                                                                                                                             (at Baseline) 

Treatment drug:        VIFOR DRUG            COMPARATOR                  PLACEBO                 
Total calculated dose: _______ mg 
First Application of Study Drug:                                            Last Application of Study Drug: 
                                                          (dd/mmm/yyyy)                                                                     (dd/mmm/yyyy) 
Most recent Application of Study Drug before onset of SAE:  
                                                                                                            (dd/mmm/yyy) 
Dilution: _____________                            Duration of infusion: ____________  
Total dose of study drug until start of event: ________ mg 
Will study drug treatment be continued?      No,   If no: Why was study drug stopped?       ______________ 
                                                              Yes,  If yes: Date of next drug administration:______________
Next originally planned date of drug administration if it is different from the date above: _________________ 

Serious Adverse Event Term: 
______________________________________________________________________________________________

Event start date:                                                  Event stop date:                                                  OR  ongoing 
                                   (dd/mmm/yyyy)                                                    (dd/mmm/yyyy)      

( incl. signs, symptoms, most important reaction(s), diagnosis, relevant tests, relevant lab data) 

Please attach a copy of  Prior and Concomitant Medication and Medical and Surgical History CRF page. 
 - Please continue on next page - 
Study Medication 
SAE
Information 
SAE Description 
Event 
Verbatim 
  
   
    
Patient information 
  
   
  
 
 
Concomitant 
Drugs 
and Diseases
  
   
    
      
  
   
    
$SSHQGL[6HULRXV$GYHUVH(YHQW)RUP6DPSOH
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22 September 2015
Confidential
Page 109 of 114


©Vifor Pharma - FINAL 
Confidential 
Page 2 of 2 
Page 2 of:              Initial Report                     Follow-up Report                      Patient No.:                                                       

SAE treatment medication given ?   No   Yes  
If yes, provide medication number(s) of attached CRF: ______________________________________________ 
Non-drug treatment, specify: ___________________________________________________________________ 
Withdrawal from study due to event  Yes 
                                                            No 

 Recovered without sequelae      Recovered with sequelae
 Not yet recovered      Death          Unknown 

 Death, date:                                                                         Autopsy:  No   Yes   
                                    (dd/mmm/yyyy)
    Cause of death: ________________________________   If yes, please attach a copy of the autopsy report 
 Life-threatening  
 Persistent or significant disability/incapacity 
 Inpatient hospitalization..from                                               to 
 Prolongation of existing inpatient hospitalisation                 (dd/mmm/yyyy)                  (dd/mmm/yyyy) 
 Congenital anomaly/birth defect 
 Important medical event  
Premature births will be considered SAEs up to gestational week 35. 

Which one of the following best describes the role of the investigational product in causing this SAE?: 
Certain  
Probable/Likely  
Possible  
Unlikely  
Unrelated  
 
  
Please describe reason for your opinion: _________________________________________________________ 
__________________________________________________________________________________________ 
__________________________________________________________________________________________ 

 Mild 
 Moderate 
 Severe

Reporters Name, Profession (speciality): _______________________________________________________ 
Name & Address of Institution: ______________________________________________________________
Phone/Fax: ______________________________________________________________________________ 
Signature of Reporter: _________________________  Date:                                              (dd/mmm/yyyy)
Site Number:                   Investigators Name (if different form Reporters Name):_______________________ 
Date report received:                                                     (dd/mmm/yyyy)
Name Recipient:        ______________________________________ 
Signature Recipient:  __________________________________________
Causality 
Assessment 
VIFOR  
ONLY 
Intensity
Reporter 
Identifier 
SAE category 
Action Taken 
Outcome 
Velphoro Protocol PA-CL-PED-01 Version 2.0
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                FOR GDS 171: PREGNANCY REPORT V01 
©Vifor Pharma - FINAL 
Confidential 
Page 1 of 2 
REPORT ON EXPOSURE TO MEDICINES DURING PREGNANCY Part 1 
Name of Vifor Drug (Trade name / IMP):
      
Clinical Trial Protocol Identifier (if applicable): 

Patients Initials / No: 

Country: 

Local Reference No: 

Details of Mother and Pregnancy 
Date / Year of Birth:  
//     
Age: 
   
Occupation: 
      
(dd/mmm/yyyy)
Previous Pregnancy 
Yes
        No 
Total  no. of  pregnancies: 
   
Normal Deliveries: 
   
Abortions (Spontaneous ): 
   
Abortions (performed): 
   
Relevant Medical History:
(including pregnancy risk factors,  Pre-eclampsia, 
eclampsia, smoking, alcohol, environmental & occupational 
exposures etc.) 
      
Relevant Family History:    
(hereditary diseases e.g. hypertension, diabetes)  
      
Current Pregnancy 
First day of Last Menstruation: 
//     
Expected Delivery Date: 
//     
(dd/mmm/yyyy) 
(dd/mmm/yyyy) 
Gestational age of foetus (specify at time of exposure / time of reporting) : 
      
Ultrasound performed? Yes  
  No 
If yes, findings if any: 
      
Any complications, infections or illnesses during pregnancy?    Yes  
        No  
If yes, elaborate: 
      
Drug Exposure during Pregnancy
Mother 
/Father 
Exposure 
Suspect 
Drug/ 
Concomitant 
medication 
Product 
Name
(Trade / 
IMP)
Batch no. 
Total 
Daily 
Dose 
(Units) 
Therapy
Start date 
Therapy
Stop date 
Indication 
for use 
Route of 
application 
(oral, 
infusion,
injection)
      
      
     
      
      

      
      
      
      
     
      
      

      
      
      
      
     
      
      

      
      
      
      
     
      
      

      
      
 
Place, Date (dd/mmm/yyyy) 
 
 
 Name/ Signature/Stamp of Reporter 
$SSHQGL[5HSRUWRQ([SRVXUHWR0HGLFLQHV'XULQJ3UHJQDQF\6DPSOH
Velphoro Protocol PA-CL-PED-01 Version 2.0
22 September 2015
Confidential
Page 111 of 114


                FOR GDS 171: PREGNANCY REPORT V01 
©Vifor Pharma - FINAL 
Confidential 
Page 2 of 2 
REPORT ON EXPOSURE TO MEDICINES DURING PREGNANCY Part 2 
Information on Outcome of Pregnancy 
Name of Vifor Drug (Trade name/IMP):
      
Clinical Trial Protocol Identifier (if applicable): 

Patients Initials / No: 
      
Country: 
      
Local Reference No: 
      
Outcome of Pregnancy 
Full Term                              Normal delivery or Caesarean: 
      
Premature Birth                    If premature birth, gestational age:       
weeks 
Spontaneous Miscarriage 
Elective termination             Medical Reason?  
  Yes       
 No 
If yes, specify: 
      
Details / Comments (if any): 
      
Healthy Baby                                                     
Multiple Births 
Sick Baby (e.g. Birth trauma, infection etc.)  
Congenital anomaly or Birth defect 
Still Birth 
Date of Birth
//     
Sex    
 Male      
 Female      
(dd/mmm/yyyy)
Size:
      
Weight:        
APGAR scores, if provided (Birth/5/10 mins.) 
      
Details / Comments (if any): 
      
Please comment on any abnormal condition or occurrence regarding outcome of pregnancy and/or birth/delivery. 
      
Is there a suspicion that adverse outcome of pregnancy is related to exposure to Product? 
   
  Yes       
 No
Please elaborate: 
      
 
Place, Date (dd/mmm/yyyy) 
 
 
 Name/ Signature/Stamp of Reporter 
Please always send both Part I and Part II of the form to safety.VIT@viforpharma.com
or fax to: +0041 58851 8659
Velphoro Protocol PA-CL-PED-01 Version 2.0
22 September 2015
Confidential
Page 112 of 114


Administrating Informed Consent 
Version 1.0 
©Vifor Pharma 
Page 1 of 2 
These guidelines apply to all study site personnel administrating informed consent to 
a potential subject or their legally acceptable representative, which must be done 
prior to conducting any study related functions, including verifying eligibility. 
These guidelines are to be used when your site IRB does not provide you with an 
equivalent documented consent process; or when your site does not have an 
equivalent written process (like an SOP). 
1. Present the potential subject or legally acceptable representative with:
 
The most up-to-date version of the IRB/REB/EC  approved informed consent form (ICF)  
 
The Subject Information Sheet (PIS) (if any) 
2. Explain the following to the potential subject:
 
That the trial involves research 
 
The purpose of the trial 
 
The trial treatments, procedures to be followed and (if randomized) the probability of each 
treatment 
 
Alternative procedures or treatment that may be available 
 
The subjects responsibilities 
 
All aspects of the trial which are experimental 
 
Reasonably foreseeable risks 
 
Reasonably expected benefits 
 
Compensation and/or treatment available in the event of trial-related injury 
 
Anticipated payment to the subject, and expenses (if applicable) 
 
The subjects participation is voluntary; the subject may withdraw consent at anytime. In the 
USA and whenever possible the withdrawal of consent must be done in writing. 
 
Monitor(s), auditor(s) and the IRB/EC and Regulatory Authorities may be allowed direct 
access to the subjects medical records. 
 
Records identifying the subject will be kept confidential 
 
If any information becomes available which may be relevant to the subjects willingness to 
continue in the trial, he/she should be informed in a timely manner 
 
The person(s) to contact for further information regarding the trial and the subjects rights 
 
The foreseeable circumstances and/or reasons whereby the subject may be withdrawn from 
the trial 
 
The foreseeable circumstances and/or reasons whereby the trial may be terminated 
 
The expected duration of the subjects participation in the trial 
 
The approximate number of subjects in the trial 
3. Throughout the process, ensure that:
 
The potential subject is not coerced or unduly influenced to participate in the trial 
$SSHQGL[*XLGHOLQHVIRU$GPLQLVWHULQJ,QIRUPHG&RQVHQW
Velphoro Protocol PA-CL-PED-01 Version 2.0
22 September 2015
Confidential
Page 113 of 114


Administrating Informed Consent 
Version 1.0 
©Vifor Pharma 
Page 2 of 2 
 
There is ample opportunity and time for the subject to ask questions and to receive 
satisfactory answers. 
 
If the subject (or representative) is unable to read, an impartial witness is present during the 
entire consent discussion. By signing the consent form, the witness confirms that the trial was 
fully explained and verbal consent willingly given. 
 
The consent form is signed and dated by the subject (or representative), the person 
explaining the study and the witness (if applicable). 
 
The subject (or representative) receives a copy of the signed and dated consent form and all 
other written subject information. 
IT IS THE PRINCIPAL INVESTIGATOR'S RESPONSIBILITY TO DOCUMENT THIS 
PROCESS
4. Tips on documentation of  the informed consent process

There should be a "contextual" statement in the source document to show exactly how and 
when IC was administered - including the time (even if it is on the ICF).  
Velphoro Protocol PA-CL-PED-01 Version 2.0
22 September 2015
Confidential
Page 114 of 114

SAP_001.pdf: 
Confidentiality 
This document is confidential and proprietary property of Vifor Pharma and to be used only as authorized by Vifor 
Pharma.  No part is to be reproduced, disclosed to others, or quoted without prior written authorization from Vifor 
Pharma 
STATISTICAL ANALYSIS PLAN 
Protocol PA-CL-PED-01 
An Open-label, Randomised, Active-controlled, Parallel 
Group, Multicentre, Phase 3 Study to Investigate the Safety 
and Efficacy of PA21 (Velphoro®) and Calcium Acetate 
(Phoslyra®) in Paediatric and Adolescent CKD Patients with 
Hyperphosphataemia 
Protocol Number: 
(Version Date) 
PA-CL-PED-01 
22 September 2015 
Name of Test Drug: 
PA21 
Phase: 
3 
Methodology: 
Randomised, Open-Label, Active-controlled, Parallel 
Group, Multicentre Study 
Sponsor: 
Vifor Fresenius Medical Care Renal Pharma France 
100-101 Terrasse Boieldieu 
 Tour Franklin La Défense 8 
 92042 Paris La Défense Cedex 
 France 
 
Sponsor Representative: 
 
Statistician 
 
 
Document Date: 
20 March 2019 
Document Version: 
Final Version 3.0 
 
PPD


 
SAP SIGNATURE PAGE 
Protocol Title: 
An Open-label, Randomised, Active-controlled, Parallel 
Group, Multicentre, Phase 3 Study to Investigate the Safety 
and Efficacy of PA21 (Velphoro®) and Calcium Acetate 
(Phoslyra®) in Paediatric and Adolescent CKD Patients with 
Hyperphosphataemia 
Sponsor: 
Vifor Fresenius Medical Care Renal Pharma France 
100-101 Terrasse Boieldieu 
Tour Franklin La Défense 8 
92042 Paris La Défense Cedex 
France 
Protocol Number: 
PA-CL-PED-01 
Document Date/Version: 
20 March 2019 / Final Version 3.0 
Cytel, Inc. Author: 
Cytel, Inc. 
Route de Prébois, 20-ICC, 
1215 Geneva 15, Switzerland  
 
Signature:_
______ 
Date:_____
______ 
 
 
PPD
PPD


Vifor Fresenius Medical Care Renal Pharma 
Protocol PA-CL-PED-01 
22 SEP 2015 
 
CONFIDENTIAL 
Sponsor Approval 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein.  I agree that the planned statistical analyses are 
appropriate for this study, are in accordance with the study objectives, and are consistent with the 
statistical methodology described in the protocol, clinical development plan, and all applicable 
regulatory guidances and guidelines. 
I have discussed any questions I have regarding the contents of this document with the 
biostatistical author. 
I also understand that any subsequent changes to the planned statistical analyses, as described 
herein, may have a regulatory impact and/or result in timeline adjustments.  All changes to the 
planned analyses will be described in the clinical study report (CSR). 
Sponsor Signatory: 
Trial Statistician 
VFMCRP 
Flughofstrasse 61   
8152 Glattbrugg 
Switzerland 
 
Signatu
________ 
Date:_
________ 
 
cal Expert  
VFMCRP 
Flughofstrasse 61   
8152 Glattbrugg 
Switzerland 
 
Signature:
_______ 
Date:____
_______ 
 
Head of Biometric 
VFMCRP 
Flughofstrasse 61   
8152 Glattbrugg 
Switzerland 
 
Signature:_
___________ 
Date:_____
___________ 
 
Head Global Clinical 
VFMCRP 
Flughofstrasse 61   
8152 Glattbrugg 
Switzerland 
 
Signature:_____
_______ 
Date:_________
_______ 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Vifor Fresenius Medical Care Renal Pharma 
Protocol PA-CL-PED-01 
22 SEP 2015 
 
CONFIDENTIAL 
4
TABLE OF CONTENTS 
Section 
Page 
1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS .......................................... 10 
1.1. 
Introduction ........................................................................................................ 10 
1.2. 
Objectives of Statistical Analysis ...................................................................... 10 
2. 
STUDY DESIGN ............................................................................................................ 12 
2.1. 
Synopsis of Study Design ................................................................................... 12 
2.2. 
Randomisation Methodology ............................................................................ 12 
2.3. 
Stopping Rules and Unblinding ........................................................................ 13 
2.4. 
Study Procedures ............................................................................................... 13 
2.5. 
Efficacy, Pharmacokinetic, and Safety Variables ........................................... 16 
2.5.1. 
Efficacy Variables................................................................................. 16 
2.5.2. 
Pharmacokinetic Variables ................................................................... 17 
2.5.3. 
Safety Variables .................................................................................... 17 
2.5.4. 
Other Variables ..................................................................................... 18 
3. 
SUBJECT POPULATIONS .......................................................................................... 19 
3.1. 
Population Definitions ....................................................................................... 19 
3.2. 
Protocol Violations ............................................................................................. 19 
4. 
STATISTICAL METHODS ......................................................................................... 21 
4.1. 
Sample Size Justification ................................................................................... 21 
4.2. 
General Statistical Methods and Data Handling ............................................ 21 
4.2.1. 
General Methods ................................................................................... 21 
4.2.2. 
Computing Environment....................................................................... 22 
4.2.3. 
Methods of Pooling Data ...................................................................... 22 
4.2.4. 
Adjustments for Covariates .................................................................. 22 
4.2.5. 
Multiple Comparisons/Multiplicity ...................................................... 22 
4.2.6. 
Subpopulations...................................................................................... 22 
4.2.7. 
Withdrawals, Dropouts, Loss to Follow-up .......................................... 22 
4.2.8. 
Missing, Unused, and Spurious Data .................................................... 22 
4.2.9. 
Visit Windows ...................................................................................... 25 
4.3. 
Interim Analyses ................................................................................................ 26 
4.4. 
Subject Disposition............................................................................................. 26 


Vifor Fresenius Medical Care Renal Pharma 
Protocol PA-CL-PED-01 
22 SEP 2015 
 
CONFIDENTIAL 
5
Section 
Page 
4.5. 
Demographic and Baseline Characteristics ..................................................... 27 
4.5.1. 
Demographics ....................................................................................... 27 
4.5.2. 
Baseline Disease Characteristics .......................................................... 27 
4.5.3. 
Medical History .................................................................................... 27 
4.5.4. 
Surgery History ..................................................................................... 27 
4.6. 
Exposure to Study Drug .................................................................................... 27 
4.7. 
Efficacy Evaluation ............................................................................................ 31 
4.7.1. 
Primary Efficacy Endpoint ................................................................... 31 
4.7.2. 
Secondary Efficacy Endpoints .............................................................. 32 
4.8. 
Pharmacokinetic Evaluations ........................................................................... 32 
4.9. 
Safety Analyses ................................................................................................... 32 
4.9.1. 
Primary Safety Endpoint: Adverse Events ........................................... 32 
4.9.2. 
Secondary Safety Endpoints ................................................................. 35 
4.9.3. 
Laboratory Data .................................................................................... 36 
4.9.4. 
Vital Signs and Physical Examinations ................................................ 39 
4.9.5. 
Electrocardiogram ................................................................................. 39 
4.9.6. 
Prior and Concomitant Medications ..................................................... 39 
4.9.7. 
Subject Reported Palatability and Acceptability .................................. 39 
5. 
CHANGES TO PLANNED ANALYSES .................................................................... 40 
6. 
REFERENCES ............................................................................................................... 42 
7. 
CLINICAL STUDY REPORT APPENDICES ........................................................... 43 
7.1. 
Statistical Tables to be generated ..................................................................... 43 
7.2. 
Data Listings to be Generated .......................................................................... 51 
7.3. 
Figures to be Generated .................................................................................... 53 
 
 
 
 


Vifor Fresenius Medical Care Renal Pharma 
Protocol PA-CL-PED-01 
22 SEP 2015 
 
CONFIDENTIAL 
6
LIST OF IN-TEXT TABLES 
Table 
Page 
Table 1 
Minimum Number of Randomised Subjects by Age Group ............................................ 13 
Table 2 
Schedule of Assessments ................................................................................................. 14 
Table 3 
Schedule of Blood Samples ............................................................................................. 15 
Table 4 
Age Related Serum Phosphorus Targets Post-Randomisation ........................................ 16 
Table 5 
Age Related Normal Range of Serum Phosphorus .......................................................... 17 
Table 6 
Age Related Safety Limits of Total Calcium ................................................................... 18 
Table 7 
Approximate transformation from millimetres to millilitres to be used for 
Phoslyra compliance derivation ....................................................................................... 30 
Table 8 
Adverse Event of special interest definition .................................................................... 34 
Table 9 
List of Maximum daily dose prescribed by treatment ..................................................... 34 
Table 10 
List of Laboratory Parameters ......................................................................................... 38 
Table 11 
eGFR formula by age and gender categories ................................................................... 39 
 


Vifor Fresenius Medical Care Renal Pharma 
Protocol PA-CL-PED-01 
22 SEP 2015 
 
CONFIDENTIAL 
7
ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse events 
ATC 
BLQ 
Anatomic Therapeutic Chemical 
Below Limit of Quantification 
BMI 
Body mass index 
BP 
Blood pressure 
CDC 
Centers for Disease Control 
CI 
Confidence interval 
CKD 
Chronic kidney disease 
CRF 
Case report form 
CSR 
Clinical study report 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case report form  
eGFR 
Estimated glomerular filtration rate 
ESRD 
End-stage renal disease 
FAS 
Full analysis set 
HP 
Hyperphosphataemia 
ICH 
International Conference on Harmonisation 
iPTH 
IxRS 
LOQ 
Intact parathyroid hormone 
Interactive Voice/Web Response System 
Limit of Quantification 
MedDRA 
N/A 
Medical Dictionary for Regulatory Activities 
Not Applicable 
PB 
Phosphate binder 
PPS 
Per-protocol set 
PT 
Preferred term 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS®  
Statistical Analysis System 
SMQ 
Standardised MedDRA Query 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
TSAT 
UIBC 
Transferrin saturation 
Unsaturated iron binding capacity 
WHO 
World Health Organisation 


Vifor Fresenius Medical Care Renal Pharma 
Protocol PA-CL-PED-01 
22 SEP 2015 
 
CONFIDENTIAL 
8
DOCUMENT HISTORY 
 
Version 
Date 
Modification 
Final v1.0 
27-DEC-2018 
N/A 
Final v2.0 
13-FEB-2019 
- Typo corrected in abbreviations section on ATC. N/A added. 
- Tables 4, 5 and 6: Last category extended to include 18 years. 
Indeed, we may have subjects enrolled at less than 18, but aged of 18 
years during the study. Footnote added. 
- Section 3.2: missing compliance added on the first programmable 
protocol violation. 
- Section 4.2.6: Last category for the age at randomisation extended to 
include 18 years. Indeed, we may have subjects enrolled at less than 
18, but aged of 18 years at the time of randomisation. 
- Sections 4.2.8.1 and 4.2.8.2: Precisions added on the derived analysis 
visits (applying windowing as defined in section 4.2.9) to be used. 
- Section 4.2.8.4: Imputation rule added if value > X for laboratory 
parameters. 
- Section 4.2.9: Column “Analysis visit” added to be consistent with 
the reference in sections 4.2.8.1 and 4.2.8.2. Precisions added on the 
CRF visits to be used to derive “End of stage 1” and “End of stage 2” 
for safety analysis, and the fact that the last non missing assessment 
collected in each period will be reported under “End of Stage 1” and 
“End of Stage 2”. 
- Section 4.6: Details added on the compliance calculation for Stage 1 
and Stage 2. 
- Section 4.7: details added regarding conversion factor to convert 
mmol/L into mg/dL for serum phosphorus. 
- Section 4.9.1: Slashes removed from System/Organ/Class in order to 
be system organ class. Addition of AE table by SOC and PT, and by 
age. 
- Section 4.9.2: details added for the derivation of an episode of 
sustained hypercalcaemia. 
- Section 4.9.3: Formula added to derive Transferrin Saturation (%) 
laboratory parameter. Unsaturated Iron Binding Capacity parameter 
added in Table 10. 
- Section 4.9.4: BMI parameter added in the descriptive table. 
- Section 7.1: Numbering updated in AE section due to duplicate 
numbering. Addition of 2 tables related to Serum total corrected 
calcium (Table 14.4.3.1 and 14.4.4.1), numbering updated on the 
Calcium-Phosphorus product tables. Addition of 2 tables related to 
TEAE by SOC and PT, and by Age (Table 14.3.1.30 and 14.3.1.31). 
- Section 7.2: Addition of listing 16.1.6.2: Listing of patients receiving 
test drug(s)/investigational product(s) from specific batches, where 
more than one batch was used. Numbering updated on Listing 16.1.6.2 
to become Listing 16.1.6.3. 
Final v3.0 
20-MAR-2019 
- Addition of updates detailed in the SAP Addendum dated of 22 
February 2019:  


Vifor Fresenius Medical Care Renal Pharma 
Protocol PA-CL-PED-01 
22 SEP 2015 
 
CONFIDENTIAL 
9
 
Section 4.2.8.5: imputation of missing or partial dates on 
disease history 
 
Section 4.6: addition of new exposure to study drug tables by 
age group 
 
Section 4.9.1: (a) addition of a new listing of AEs occurring in 
patients randomized but not treated; (b) in the tables by SOC 
and PT and by time of onset, the denominator is the number of 
patients at risk at the beginning of the period (excluding those 
who have withdrawn or completed). 
 
Section 4.9.3:  
(a) TSAT will not be derived and presented;  
(b) In Table 11, last age category for the eGFR formula 
extended to include 18 years. Indeed, we may have subjects 
enrolled at less than 18, but aged of 18 years during the time 
of the study;  
(c) For the shift tables, a list of parameters has been added for 
which we will not produce shift tables due to normal ranges 
not available. 
 
Sections 7.1 and 7.2: new tables and listing added per the 
above updates. 
- Section 4.4: addition of the early termination and reasons table by 
age group. 
- Section 4.6:  
(a) Addition of exposure to PA21 drug tables during Stage 1, Stage 2 
and overall by gender, by region and by formulation (tablets only, 
sachets only, both);  
(b) Addition of details regarding exposure variables for patients with 
all dispensed tablets/sachets or bottles unused, reported as lost and no 
tablets/sachets or bottles returned dates. 
- Section 4.7.1: addition of change from baseline sP in PA21 Group – 
end of stage 1 table (FAS population) by formulation, by serum 
phosphorus at baseline according to the age related normal range 
(Above vs. within + below), and by age group*serum phosphorus at 
baseline according to the age related normal range (first age group will 
be excluded as no subject in). 
- Section 4.9.1:  
(a) In the tables by SOC and PT and by age group, the denominator is 
the number of patients in each age group.  
(b) Removal of the additional listing of AEs occurring in patients 
randomized but not treated  
-Sections 7.1 and 7.2: new tables added or listing removed per the 
above updates. 
 
 


Vifor Fresenius Medical Care Renal Pharma 
Protocol PA-CL-PED-01 
22 SEP 2015 
 
CONFIDENTIAL 
10
1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS 
1.1. 
Introduction 
Hyperphosphataemia (HP) is a common and serious complication in subjects with chronic 
kidney disease (CKD), particularly those with end-stage renal disease (ESRD) requiring dialysis. 
In the paediatric population, CKD is most commonly caused by congenital anomalies of the 
kidney and urinary tract such as aplasia/hypoplasia/dysplasia and obstructive uropathy. The 
frequency of such conditions is low. Glomerular diseases of various aetiologies, (e.g., polycystic 
kidneys, pyelonephritis) can also cause CKD, but with a lower frequency. HP plays an important 
role in the pathophysiology of major CKD complications for example secondary 
hyperparathyroidism, renal bone disease and cardiovascular disease, and appears to promote the 
progression of CKD towards ESRD. High levels of serum phosphorus are considered to be a risk 
factor for mortality, morbidity and hospitalisation in patients with ESRD. 
Complications most relevant to the paediatric population are renal bone disease, also called renal 
osteodystrophy (sometimes referred to as mineral bone disease), cardiovascular disease and 
growth failure. 
As the efficacy and safety of PA21 has been confirmed in adult subjects with CKD on dialysis, 
the aim of this Phase 3 clinical study is to demonstrate similar efficacy of PA21 in paediatric and 
adolescent subjects with CKD, and to provide safety and dosing information for this subject 
population. The Phoslyra group provides information for a descriptive comparison of PA21 
against a commonly used calcium-based phosphate binder (calcium acetate).  
This Statistical Analysis Plan (SAP) has been developed for the final analyses of protocol PA-
CL-PED-01 (Version 2.0, 22 September 2015), prior to final database lock. It outlines the 
efficacy and safety analyses, including tables, listings, and graphical presentations to be included 
in the Clinical Study Report (CSR). A complete draft SAP has been developed and approved by 
the sponsor statistician before any significant accumulation of data.  
1.2. 
Objectives of Statistical Analysis 
The primary objective of this study is: 
 To evaluate the efficacy of PA21 in reducing serum phosphorus levels in paediatric and 
adolescent subjects with CKD at the end of Stage 1. 
The secondary objectives of this study are: 
 To evaluate the efficacy of PA21 in maintaining the serum phosphorus lowering effects 
in paediatric and adolescent subjects with CKD at the end of Stage 2. 
 To evaluate the safety of PA21 in paediatric and adolescent subjects with CKD. 
 To evaluate the efficacy of Phoslyra in reducing and maintaining serum phosphorus 
levels in paediatric and adolescent subjects with CKD at the end of Stages 1 and 2. 
 To evaluate the safety of Phoslyra in paediatric and adolescent subjects with CKD. 
This SAP is designed to outline the methods to be used in the analysis of study data in order to 
answer the study objectives as defined above. Populations for analysis, data handling rules, 
statistical methods, and formats for data presentation are provided. The statistical analyses and 


Vifor Fresenius Medical Care Renal Pharma 
Protocol PA-CL-PED-01 
22 SEP 2015 
 
CONFIDENTIAL 
11 
summary tabulations described in this SAP will provide the basis for the results sections of the 
clinical study report (CSR) for this trial. 


Vifor Fresenius Medical Care Renal Pharma 
Protocol PA-CL-PED-01 
22 SEP 2015 
 
CONFIDENTIAL 
12 
2. 
STUDY DESIGN 
2.1. 
Synopsis of Study Design 
This study is a prospective, open-label, randomised, active-controlled, parallel group, 
multicenter, phase 3 study investigating the safety and efficacy of PA21 (Velphoro®) and 
calcium 
acetate 
(Phoslyra®) 
in 
paediatric 
and 
adolescent 
CKD 
subjects 
with 
hyperphosphataemia. 
Approximately 130 subjects will be randomised to either PA21 (approximately 100 subjects) or 
to Phoslyra (approximately 30 subjects) with age as stratification factor. 
Throughout the study, subjects randomised to receive PA21 will be provided with the most 
appropriate formulation i.e., either powder for oral suspension (for subjects <6 years) or 
chewable tablet (for subjects ≥6 years). For Phoslyra, only oral solution will be dispensed. 
The study will consist of a maximum of 43 weeks including a screening period, a washout 
period, a treatment period split into 2 stages, and a follow-up period. Screening should be up to 4 
weeks. The washout period should be of 1-3 weeks to allow sufficient time for washout of 
previous Phosphate Binders (PBs). Of note, subjects already receiving a PB but with age related 
serum phosphorus levels (Table H of the protocol) may be eligible for randomisation without a 
washout period. Treatment period will be split in 2 stages: 
 Stage 1 is a dose titration period of PA21 and Phoslyra for up to 10 weeks. PA21 subjects 
will receive PA21 at a starting dose based on their age, as detailed in Table 3 from 
protocol. Phoslyra subjects will receive Phoslyra, either at a starting dose as detailed in 
Table 5 from protocol, or, if considered more appropriate by the Investigator, at an 
equivalent dose of their previous PB, calcium-based or sevelamer. Doses of PA21 or 
Phoslyra will be increased or decreased as required for efficacy (to achieve age specific 
target serum phosphorus level as indicated in Table 11 from protocol), provided a subject 
has been receiving that dose for a minimum of 2 weeks, and for safety or tolerability 
reasons at any time. Increases or decreases in dose and maximum doses are detailed in 
Table 4 from protocol for PA21, and Table 5 and Table 6 from protocol for Phoslyra. 
From Week 4, once a subject achieves the age specific target serum phosphorus level, as 
indicated in Table 11 from protocol, they can move to Stage 2. 
 Stage 2 is a long-term safety extension of PA21 and Phoslyra for 24 weeks. All subjects 
will enter this safety extension and will continue on the dose they received at end of stage 
1, unless a dose change is required. All subjects may have their dose titrated for efficacy 
to achieve age-specific target serum phosphorus levels and safety or tolerability reasons 
at any time during Stage 2. 
All subjects, whether completing the study or withdrawn prematurely, will be followed up 14 
days after their last study visit. 
A Data and Safety Monitoring Board (DSMB) will review regularly the safety data to protect the 
safety of study participants. 
2.2. 
Randomisation Methodology 
Approximately 130 subjects will be randomised via interactive response technology to either 
receive PA21 (approximately 100 subjects) or to Phoslyra (approximately 30 subjects). 


Vifor Fresenius Medical Care Renal Pharma 
Protocol PA-CL-PED-01 
22 SEP 2015 
 
CONFIDENTIAL 
13 
The randomisation will be stratified by age group and will also aim to randomise at least the 
minimum number of subjects from each age group as outlines in Table A from study protocol 
synopsis and as shown in Table 1 below: 
 
Table 1 
Minimum Number of Randomised Subjects by Age Group 
Age 
PA21 
Phoslyra 
0 to <1year 
4 
1 
≥1 year to <6 years 
10 
3 
≥6 years to <9 years 
10 
3 
≥9 years to <18 years 
10 
3 
 
2.3. 
Stopping Rules and Unblinding 
The study will be conducted in an open-label manner. However, the sponsor will not receive any 
IxRS data or data summarised by treatment groups before the database lock in order to preserve 
the integrity of the trial. In particular during the DSMB meeting, the sponsor will not attend the 
closed session of the meeting where data splitted by treatment could be presented. 
2.4. 
Study Procedures 
The schedule of assessments and blood samples, as outlined in the Tables 1 and 2 from study 
protocol, is provided in Table 2 and Table 3 below. 


Vifor Fresenius Medical Care Renal Pharma 
Protocol PA-CL-PED-01 
22 SEP 2015 
 
CONFIDENTIAL 
14 
Table 2 
Schedule of Assessments 
 


Vifor Fresenius Medical Care Renal Pharma 
Protocol PA-CL-PED-01 
22 SEP 2015 
 
CONFIDENTIAL 
15 
Table 3 
Schedule of Blood Samples 


Vifor Fresenius Medical Care Renal Pharma 
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2.5. 
Efficacy, Pharmacokinetic, and Safety Variables 
2.5.1. 
Efficacy Variables 
2.5.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change in serum phosphorus levels from baseline to the end 
of Stage 1 in PA21 group. It is based on central laboratory data; in case of missing data, the 
change from baseline will be computed using pre- and post-treatment values from the local 
laboratory (see Section 4.2.8). 
2.5.1.2. 
Secondary Efficacy Endpoints 
The following secondary endpoints based on central laboratory measurement are planned for 
analysis: 
 Change in serum phosphorus levels from baseline to the end of Stage 1 in Phoslyra group 
 Change in serum phosphorus levels from baseline to the end of Stage 2 in both groups 
In case of missing central laboratory data, the change from baseline will be computed using pre- 
and post-treatment values from the local laboratory (see Section 4.2.8). 
The following secondary endpoints based on both central and local laboratory measurements are 
planned for analysis: 
 Serum phosphorus values at each visit during Stages 1 and 2 
 Percentage of subjects with serum phosphorus level in the age related target range (Table 
D from the study protocol synopsis; Table 4 below) at each visit. 
 Percentage of subjects with serum phosphorus level within the age related normal range 
(Table 5) at each visit. 
Table 4 
Age Related Serum Phosphorus Targets Post-Randomisation 
Age 
mmol/L 
mg/dL 
0 to <1 year 
1.62-2.52 
5.0-7.8 
≥1 year to <6 years 
1.45-2.10 
4.5-6.5 
≥6 years to <13 years 
1.16-1.87 
3.6-5.8 
≥13 years to ≤18 years 
0.74-1.45 
2.3-4.5 
Note: This table comes from National Kidney Foundation Kidney Disease Outcomes Quality Initiative Nutrition Guidelines, 
2008, and was slightly modified to include 18 year in the last category. 
 
 
 


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Table 5 
Age Related Normal Range of Serum Phosphorus 
Age 
mmol/L  
mg/dL  
 
Lower Limit 
Upper Limit 
Lower Limit 
Upper Limit 
0 to <1year 
1.36 
2.62 
4.2 
8.1 
≥1 year to <6 years 
1.03 
1.97 
3.2 
6.1 
≥6 years to <9 years 
1.03 
1.97 
3.2 
6.1 
≥9 years to <10 years 
1.03 
1.97 
3.2 
6.1 
≥10 years to <15 years 
1.00 
1.94 
3.1 
6.0 
≥15 years to ≤18 years 
0.71 
1.65 
2.2 
5.1 
Note: This table comes from Covance central laboratory normal range, and was slightly modified to include 18 year in the last 
category. 
2.5.2. 
Pharmacokinetic Variables 
Not applicable. 
2.5.3. 
Safety Variables 
2.5.3.1. 
Primary Safety Endpoint 
The primary safety endpoint is the AE profile, and percentage of treatment withdrawals due to 
AEs (treatment withdrawals due to AEs information will be retrieved from the Treatment 
Termination eCRF page). 
2.5.3.2. 
Secondary Safety Endpoints 
The following safety secondary endpoints are planned for analysis: 
 Serum total corrected calcium at each time point and change from baseline 
 Percentage of subjects who develop at least 1 episode of sustained hypercalcaemia 
(defined as total calcium value>upper safety limit from Table 6 (Table J from the study 
protocol synopsis) confirmed by repeat sample 1 week later) after start of treatment 
 Serum total corrected calcium-phosphorus product at each time point and change from 
baseline, where serum total corrected calcium-phosphorus product correspond to the 
product of serum total calcium and Phosphorus, expressed in mmol2/L2 (serum total 
calcium and Phosphorus units must be the same). 
 Serum iPTH levels at each time point and change from baseline 
 Routine biochemical/haematological laboratory tests (blood iron parameters, Vitamin D 
parameters and bone markers) 
 Vital signs 
 
 


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Table 6 
Age Related Safety Limits of Total Calcium 
Age 
Upper Safety Limit 
Lower Safety Limit 
 
mmol/L 
mg/dL 
mmol/L 
mg/dL 
0 to <1year 
2.75 
11.0 
<1.9 
<7.6 
≥1 year to <6 years 
2.70 
10.8 
<1.9 
<7.6 
≥6 years to <13 years 
2.60 
10.3 
<1.9 
<7.6 
≥13 years to ≤18 years 
2.60 
10.2 
<1.9 
<7.6 
Note: Upper safety limits were based on National Kidney Foundation Kidney Disease Outcomes Quality Initiative Nutrition 
Guidelines, 2008. Lower limit were based on literature (Paediatric Nephrology, 2nd edition) and personal communication. Both 
limits were slightly modified to include 18 year in the last category. 
2.5.3.3. 
Other Safety Endpoints 
Safety assessments performed during the study including physical examinations. 
2.5.4. 
Other Variables 
2.5.4.1. 
Subject Reported Palatability and Acceptability 
Age-appropriate assessments will be used based on already-established and standardised versions 
of the combined facial/hedonic and 10 cm visual analogue scale. 


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3. 
SUBJECT POPULATIONS 
3.1. 
Population Definitions 
The following subject populations will be evaluated and used for presentation and analysis of the 
data: 
 Full Analysis Set (FAS) Population: all subjects randomised to treatment at Stage 1, 
who received at least one dose of randomised treatment and who had at least one post-
baseline assessment of the efficacy endpoint (serum phosphorus level). FAS population 
will be analysed according to treatment randomised. This population will be analysed for 
the protocol deviations, demographics and baseline characteristics, medical history and 
efficacy endpoints. 
 Per Protocol Set (PPS) Population: all subjects in the FAS population who had no 
statistical major protocol violations. This population will be analysed for the 
demographics and baseline characteristics, medical history as well as for the primary and 
secondary efficacy endpoints 
 Safety Population: all subjects who have taken at least one dose of study medication. 
Safety population will be analysed according to treatment received. 
 Stage 2 Safety Population: all subjects who have taken at least one dose of study 
medication during stage 2. 
If a subject switches from a treatment to the other by mistake, then other safety populations will 
be created to report the adverse events under each received treatment. 
The FAS Population is the primary population for the analysis of efficacy parameters. A subset 
of efficacy parameters will be evaluated for the PPS Population. The Safety Population is the 
population for the analysis of safety endpoints. If a subject switches from a treatment to the other 
by mistake, further adverse events summary tables will be generated using additional safety 
populations.   
3.2. 
Protocol Violations 
The sponsor trial statistician with the Clinical Research Manager and the Clinical Trial Manager 
using the SAP and the final and consolidated versions of the Important and Non-important 
Protocol Deviations Designation and Escalation files (produced by Covance) will produce a 
protocol deviation criteria list to review, assess all protocol deviations (programmable deviations 
and deviations captured by the CRA) and classify as major deviations those which lead to 
exclusion of a subject’s data from the PPS Population.  
Covance will be responsible to review programmable PDs listing provided by Cytel on a 
quarterly basis and reconcile them to produce the final protocol deviation file (formatted as a 
Microsoft Excel file). This file will include the Important and Non-important Protocol 
Deviations Designation and Escalation lists as well as the programmable PDs. The protocol 
deviation file reconciled by Covance will include subject number, deviation code and a 
description of the protocol deviation.  
The protocol deviation criteria list provided by the sponsor will specify the list of all protocol 
deviations and for each deviation a deviation code, and will identify whether or not the deviation 


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may warrant exclusion from the PPS Population. The final and reconciled protocol deviation file 
provided by Covance will be sent to the sponsor.  
The sponsor will be in charge to review, update this file with the information coming from 
protocol deviation criteria list and send back to Cytel. This final file will be reviewed during the 
blinded data review meeting and finalised prior to hard database lock.  
The major protocol deviations are as follows: 
 Subject with insufficient compliance, i.e. missing, <70% or >120% during stage 1 or 
stage 2,  (programmatically derived) 
 Randomized subjects not fulfilling inclusion criterion number 2 on Hyperphosphatemia 
values (according to age) before randomisation (programmatically derived) 
 Subjects with no baseline serum phosphorus value (programmatically derived) 
 Subject with End of stage 1 visit date outside of allowed visit windows (section 4.2.9) 
(programmatically derived) 
 Incorrect study treatment (not compliant with the IxRS randomisation) given to the 
subject (programmatically derived) 
 Subjects who received both PA21 and Phoslyra (programmatically derived) 
 Subject was randomised but did not meet inclusion criterion 4 or 5 (programmatically 
derived). 
 Subject was randomised but met exclusion criterion 1, 2, 11 or 12 (programmatically 
derived). 
 ICF not signed or signed by parents/guardian after randomisation date and if child is 7 or 
older, assent not obtained or obtained after randomisation date (programmatically 
derived). 
 Other from deviations identified during the study which may lead to classification of 
“Major” as per clinical judgment during the blinded Data Review Meeting. If these 
deviations could not be programmatically derived, then an excel file will be provided by 
the sponsor with the corresponding major deviation information. 
 
All protocol deviations will be presented in the data listings. 


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4. 
STATISTICAL METHODS 
4.1. 
Sample Size Justification 
In the PA21 treatment group, assuming a mean change in serum phosphorus levels from baseline 
to end of Stage 1 of 1.2 mg/dL, a standard deviation for the change of 2.0 and to further allow for 
an approximate drop-out rate of 30%, 100 randomised subjects will provide more than 90% 
power. 
The sample size estimation is based on conservative values from the Phase 3 study, and 
performed using nQuery Version 6.0. 
One hundred subjects should also be sufficient to provide robust safety and dosing information 
for PA21 in the paediatric and adolescent subjects with CKD. 
4.2. 
General Statistical Methods and Data Handling 
4.2.1. 
General Methods 
All outputs will be incorporated into rtf files, sorted and labelled according to the International 
Conference on Harmonisation (ICH) recommendations, and formatted to the appropriate page 
size(s). 
For all outputs, the order and labelling of the treatment groups will be maintained as shown 
below:  
1. PA21 
2. Phoslyra  
A ‘Total’ column will be used in all the outputs, which will present a total over both treatment 
groups, with the exception of exposure data where data will be presented separately for each 
drug. 
Tabulations will be produced for appropriate demographic, baseline, efficacy and safety 
parameters. For categorical variables, summary tabulations of the number and missing 
observations as well as the number and percentage within each category of the parameter will be 
presented. For continuous variables, the number and missing observations, mean, median, 
standard deviation, Q1, Q3, minimum, and maximum values will be presented. 
For the laboratory parameters, the number of the decimal places (dp) will be determined using 
the following rules based on the number of dp from the raw data: 
- 
mean, median, q1 and q3 = raw + 1 
- 
sd = raw + 2 
- 
Min and max = raw 
Formal statistical hypothesis testing will be performed on the primary endpoint only with test 
conducted at the 2-sided, 0.05 level of significance. Summary statistics will be presented, as well 
as confidence intervals on selected parameters, as described in the sections below. Some other 
statistical tests within each group may be performed for the secondary efficacy endpoints 
depending on the observed clinical differences. 
Baseline will be defined as the latest measurement collected prior to first dose of study treatment. 


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Stage 1 data will be defined as all data collected until the last visit in the titration phase (prior to 
visit 12 and when “Yes” is responded to the question “Will subject enter the Stage 2 Safety 
Extension period after the current visit?”). Of note, if subject withdrew during stage 1 (i.e. no 
stage 2 initiated), visit 16 will be considered as part of stage 1.  
Stage 2 data will be defined as all data collected from the day after the last visit in the titration 
phase. 
Both local and central laboratory data will be reported using SI units, unless otherwise specify.  
4.2.2. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software (Version 9.4 
or later), unless otherwise noted. Medical History and adverse events will be coding using 
MedDRA (version 19.1 or later). Concomitant medications will be coded using World Health 
Organisation (WHO) Drug Dictionary (version June 2016 or later).  
4.2.3. 
Methods of Pooling Data 
Not applicable to the present study. 
4.2.4. 
Adjustments for Covariates 
The primary and secondary efficacy endpoints including change in serum phosphorus levels 
from baseline will be analysed through a linear mixed model with baseline serum phosphorus 
value, age (in categories) at randomisation, region and gender as covariates.  
4.2.5. 
Multiple Comparisons/Multiplicity 
Multiplicity is not of concern for this study with a single primary efficacy endpoint. 
4.2.6. 
Subpopulations 
The following subgroups will be considered: 
 Age at randomisation: 0 to <2 year/ ≥2 year to <6 years/ ≥6 years to <12 years/ ≥12 years 
to ≤18 years 
 Gender: Male/Female 
 Region: Europe/Rest of the World/United States 
Europe and Rest of the World maybe pooled under Non-US if Rest of the World represents a low 
number of subjects (e.g. less than 5% of the overall Safety Population). 
In case of imbalance between treatment groups regarding baseline characteristics, other subgroup 
analyses may be performed. 
4.2.7. 
Withdrawals, Dropouts, Loss to Follow-up 
Subjects who withdrew from the study were not to be replaced. 
4.2.8. 
Missing, Unused, and Spurious Data 
All data recorded on the CRF will be included in data listings that will accompany the clinical 
study report. 


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In general there will be no imputation of missing data. There are a few exceptions where data 
imputation will be implemented see paragraph below. 
4.2.8.1. 
Primary endpoint and secondary efficacy endpoints related to change in serum 
phosphorus levels from baseline to the end of Stage 1 
To compute the change from baseline in serum phosphorus at end of stage 1, the laboratory 
values post-baseline and at baseline should be from the same source (i.e. either both central or 
both local). In addition, the following steps will be followed regarding the value to be considered 
at end of stage 1 for serum phosphorus: 
 Step 1: Take central laboratory value at Visit 11 (visit n) if available. 
 Step 2: If central laboratory value at Visit 11 is not available, then the central laboratory 
value at the previous visit, if available, is to be used. The previous visit to be called visit 
(n-1) will be the latest visit between Visit 16 (if subject early withdrew during stage 1) 
and Visit 10. 
 Step 3: If central laboratory value at visit (n-1), as defined above, is not available, if local 
laboratory values at Visit (n-1) and at baseline are both available for the subject, then 
local laboratory value at Visit (n-1) is to be used. 
 Step 4: If local laboratory value at Visit (n-1) is not available or if local laboratory value 
at baseline is not available, then the central laboratory value at visit (n-2) will be 
considered. 
 Step 5: Repeat step 3 considering Visit (n-2) 
 Step 6: Repeat step 3 and 4 considering visit (n-3),  
o until visit 1 for PB naive subjects  
o until visit 2 for subjects on PB 
Note: “Visit 11”, “Visit 16” and more generally “Visit x” will refer to the derived analysis visits 
(applying windowing as defined in section 4.2.9). 
4.2.8.2. 
Secondary efficacy endpoints related to change in serum phosphorus levels from 
baseline to the end of Stage 2 
To compute the change from baseline in serum phosphorus at end of stage 2, the laboratory 
values post-baseline and at baseline should be from the same source (i.e. either both central or 
both local). In addition, the following steps will be followed regarding the value to be considered 
at end of stage 2 for serum phosphorus. Of note Visit 16 will be taken into account only if 
subject did not early withdraw during stage 1: 
 Step 1: Take central laboratory value at Visit 16 (visit n) if available. 
 Step 2: If central laboratory value at Visit 16 is not available then the central laboratory 
value at the previous visit, Visit (n-1) (i.e. visit 15), is to be used, if available. 
 Step 3: If central laboratory value at Visit (n-1) is not available, if local laboratory values 
at Visit (n-1) and at baseline are both available for the subject, then local laboratory value 
at Visit (n-1) is to be used. 


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 Step 4: if local laboratory value at Visit (n-1) or local baseline are not available, central 
laboratory value at Visit (n-2) is to be used. 
 Step 5: Repeat step 3 considering Visit (n-2) 
 Step 6: Repeat step 4 and 5 for Visit (n-3), until Visit 12 
Note: “Visit 16”, “Visit 15” and more generally “Visit x” will refer to the derived analysis visits 
(applying windowing as defined in section 4.2.9). 
4.2.8.3. 
Glomerular Filtration Rate 
For subjects on dialysis values of glomerular filtration rate will not be deemed interpretable. 
Therefore all eGFR values for subjects on dialysis at screening as well as eGFR values after 
dialysis for subjects requiring dialysis for the first time during the study will not be part of the 
summary statistics over time of eGFR, they will be listed only. 
4.2.8.4. 
Laboratory parameters 
Clinical laboratory values as “<X” where X is the numerical value of the limit of quantification 
(LOQ) established by the laboratory will be imputed by LOQ/2 for summaries in the tables. 
Clinical laboratory values as “>X” where X is the numerical value of the limit of quantification 
(LOQ) established by the laboratory will be imputed by LOQ for summaries in the tables. 
Laboratory data below the lower limit of quantification (BLQ) should be labelled as such in the 
data listings.  
4.2.8.5. 
Missing and partially missing dates  
For identification of AEs as treatment-emergent, partial or missing dates for adverse events will 
be imputed as follows: 
 Incomplete start date: if the day and month are missing and year is the same as first drug 
administration, or if only the day is missing and month and year are the same as first drug 
administration then the start date will be replaced by the minimum between first drug 
administration and AE resolution date. In all other cases the missing start day or start month 
will be replaced by 01. 
 Complete missing start date: the start date will be replaced by the minimum between first 
drug administration and AE resolution date. 
 Incomplete stop dates (Month and year available or only year available): these dates will be 
imputed to the last day of the corresponding month, or the last day of the corresponding year 
if not resulting in a date later than the date of subject's death. In the latter case the date of 
death will be used to impute the incomplete stop date. In all other cases the incomplete stop 
date will not be imputed. 
For medications and procedures, imputation of missing or partial dates will be done to identify 
concomitant medications and procedures as follows: 


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 If the start date of the medication/procedure is unknown (i.e. complete missing date), the 
worst-case scenario will be assumed. The medication/procedure will be considered as both a 
prior medication/procedure and a concomitant medication/procedure (i.e. the medication will 
be assumed to start on January, 1st 2016). 
 If the month and the day of the start date of the medication/procedure are missing, the month 
and the day will be imputed to January, 1st of the year specified. 
 If the day of the start date of the medication/procedure is missing, the day will be imputed to 
the first day of the month specified. 
 If the end date is unknown (i.e. missing), the date will be kept as missing however the 
medication/procedure will be considered concomitant. 
 If the month and the day of the end date of the medication/procedure are missing, the month 
and the day will be imputed to December, 31st of the year specified. 
 If the day of the end date of the medication/procedure is missing, the day will be imputed to 
the last day of the month specified. 
For disease history, imputation of missing or partial dates (date of onset of CKD and date of first 
dialysis) will be done as follows: 
 If the month and the day of the date are missing, the month and the day will be imputed to 
January, 1st of the year specified. 
 If the day of the date is missing, the day will be imputed to the first day of the month 
specified. 
 In case of missing date, no imputation will be performed. 
No other dates will be imputed. 
The original incomplete, missing or partial dates will be presented in the listings, not the imputed 
dates. 
4.2.9. 
Visit Windows 
The below windowing will be applied for summary tables with descriptive statistics over time, 
label of the visit will be derived as below.  
 
 
Analysis visit 
Week number 
Windowing 
 
Visit 5 
Day 1 (Baseline) Stage 1 
Day 1 (Visit 5) 
 
Visit 6 
Week 1 - Stage 1 
Day 8 (+/- 3 days) 
 
Visit 7 
Week 2 - Stage 1 
Day 15 (+/- 3 days) 
 
Visit 8 
Week 4 - Stage 1  
Day 29 (+/- 3 days) 
 
Visit 9 
Week 6 - Stage 1 
Day 43 (+/- 3 days) 


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Visit 10 
Week 8 - Stage 1 
Day 57 (+/- 3 days) 
 
Visit 11 
Week 10 - Stage 1 
Day 71 (+/- 7 days) 
 
N/A 
Day 1 (Baseline) Stage 2 
Day 1 (last visit in the titration phase + 1) 
 
Visit 12 
Week 4 - Stage 2 
Day 29 (+/- 3 days) 
 
Visit 13 
Week 8 - Stage 2 
Day 57 (+/- 3 days) 
 
Visit 14 
Week 12 - Stage 2 
Day 85 (+/- 3 days) 
 
Visit 15 
Week 18 - Stage 2 
Day 127 (+/- 7 days) 
 
Visit 16 
Week 24 - Stage 2 
Day 169 (+/- 7 days) 
If several values are falling into the same time window then the nearest value compared to the 
pre-defined week window as per protocol will be considered for efficacy and safety, if they are 
still 2 or more values then the first one in time among the nearest value will be considered. In 
case of 2 values at the same time (planned visit and unscheduled one), then the planned visit will 
be considered. 
In addition, visit 11 or earlier (visit when “Yes” is responded to the question “Will subject enter 
the Stage 2 Safety Extension period after the current visit?”) and visit 16 or earlier data will be 
reported with the corresponding label in the summary tables "End of Stage 1" and "End of Stage 
2", respectively. If subject withdrew during stage 1, visit 16 will be displayed with the 
corresponding label in the summary tables "End of Stage 1".  
For "End of Stage 1" and "End of Stage 2" reported visits of the safety analyses, the original 
visits (as collected in the EDC system and not derived) will be used. The last non missing 
assessment collected in each period will be reported under “End of Stage 1” and “End of Stage 
2”. 
4.3. 
Interim Analyses 
No interim analysis is planned for this study. A DSMB will review regularly the safety data to 
protect the safety of study participants. The procedures and analyses provided to DSMB are 
described in the DSMB Charter document. 
4.4. 
Subject Disposition 
Number of subjects treated at each site, country and region will be tabulated by treatment group 
and overall. A study populations table will describe the different populations used for analysis 
(FAS, PPS, Safety Population and Stage 2 Safety Population). 
Subject disposition will be tabulated and will include the number of subjects randomised in Stage 
1, the number of subjects treated, the number of subjects who enter the Stage 2, the number of 
subjects who completed the study, the number who withdrew prior to completing the treatment 
overall, during stage 1 and during stage 2, and reason(s) for withdrawal. The number of subjects 
who withdrew prior to completing the treatment overall, during stage 1 and during stage 2, and 
reason(s) for withdrawal will be also provided by age group. Summary data will be presented by 
treatment group and overall.  
A by-subject listing of treatment completion information, including the reason for premature 
treatment withdrawal, if applicable, will be presented. 


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4.5. 
Demographic and Baseline Characteristics 
Baseline, demographic, medical history and surgery history information will be summarised for 
the safety, Stage 2 safety, FAS and PPS Populations by treatment group and overall using 
descriptive statistics. No formal statistical comparisons will be performed. 
Demographics and baseline disease characteristics will also be summarised by subgroups (age, 
gender, and region) for the safety, Stage 2 safety, FAS and PPS Populations. 
Demographic and baseline data will be provided in data listings. 
4.5.1. 
Demographics  
Summary statistics will be provided for age at randomisation (years) as continuous and 
categorical variables (section 4.2.6; the 0 to <2 year category will be divided in two categories: 0 
to <1 year and 1 to <2 year) and below), sex, race, ethnicity, region, baseline height (cm), 
baseline weight (kg), and baseline body mass index (BMI; kg/m2). 
The following age categories will be considered: 
 New borns (0-27 days) 
 Infants and toddlers (28 days-23 months) 
 Children (2-11 years) 
 Adolescents (12-17 years) 
 Adults (18-64 years) 
4.5.2. 
Baseline Disease Characteristics  
Summary statistics will be provided for baseline disease characteristics including reason or cause 
of CKD, CKD stage, time since onset of CKD (years), time since first dialysis (years), baseline 
type of dialysis (haemodialysis, peritoneal dialysis, none), PB naïve (yes/no), Washout period 
needed (yes/no), baseline serum phosphorus (central laboratory in both Standard and 
Conventional units). 
Time since onset of CKD (years) will be derived as: (date of informed consent - date of onset of 
CKD +1)/365.25 
Time since first dialysis (year) will be derived as: (date of informed consent - date of first 
dialysis +1)/365.25 
4.5.3. 
Medical History  
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 
version 19.1 or later) and displayed in tables and listings using System Organ Class (SOC) and 
Preferred Term. 
4.5.4. 
Surgery History  
Surgery history will be displayed in listing only. 
4.6. 
Exposure to Study Drug 
Exposure to study drug will be summarised for each drug separately and for stage 1, stage 2 and 
overall study using descriptive statistics. Summary tables will be generated on the Safety 
Population for stage 1 and overall study exposure and on the Stage 2 Safety Population for stage 
2 exposure data. They will include: 


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 For PA21 drug:   
o total number of tablets(1) taken / total number of sachets taken,  
o actual average daily number of tablets(1) taken / actual average daily number of 
sachets taken  
o actual average daily dosage (mg),  
o prescribed average daily dosage (mg),  
o duration of  exposure (weeks),  
o compliance  
o maximum prescribed daily dose, 
o and reason of dose change. 
 For Phoslyra drug:  
o actual average daily dosage (mL),  
o prescribed average daily dosage (mL),  
o duration of exposure (weeks),  
o compliance, 
o maximum prescribed daily dose, 
o and reason of dose change. 
(1)  Note: Tablets may have different strengths. 
These tables for the PA21 group will be repeated by age group at randomisation, by gender, by 
region and by formulation (tablets only/sachets only/both).  
The total and actual average daily number of tablets/sachets taken will be defined as 
 For PA21 Drug:  
Number of tablets/sachets dispensed – sum(Number of tablets/sachets returned or lost) 
The actual average daily number of tablets/sachets taken will be defined as: 
Total number of tablets/sachets taken / (last date of administration - start date of administration + 
1) 
The average daily dosage (g or mL) will be defined as 
 For PA21 Drug: 
(Total number of tablets/sachets taken × strength in g PA21) / (last date of administration - start 
date of administration + 1) 
 For Phoslyra Drug: 
(Total content of bottles taken) / (last date of administration - start date of administration + 1) 
 
The prescribed average daily dosage (mg or mL) will be defined as: 


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∑n
i=1 (end date - start date of administration(i) +1) * Prescribed Total Daily dosage of administration(i)  
__________________________________________________________________ 
                   last date administration - start date of administration + 1 
i being the ith subject's administration and n the last subject's administration, i will be 
incremented from 1 until n by 1. 
All subject's administrations will be considered for the overall study prescribed average daily 
dosage, whereas only subject's administration during the stage 1 or during the stage 2 will be 
considered for the prescribed average daily dosage for the stage 1 and for the stage 2, 
respectively. 
Duration of exposure (days) for stage 1 will be defined as: (date of last administration in stage 1 
(i.e. last administration until the last visit in the titration phase) – date of first administration in 
stage 1+1). 
Duration of exposure (days) for stage 2 will be defined as: (date of last administration in stage 2– 
date of first administration in stage 2 (i.e. from the day after the last visit in the titration phase) 
+1). 
Overall duration of exposure (days) will be defined as: (date of last administration in the study – 
date of first administration in stage 1+1). 
Overall compliance (%) will be defined as:  
 For PA21 drug: [[total number of mg corresponding to sachets/tablets dispensed - (total 
number of mg corresponding to unused sachets/tablets returned + total number of mg 
corresponding to unused sachets/tablets reported as lost)]/ total prescribed dose (in 
mg)]*100, where the total number of mg corresponds to the number of sachets/tablets * 
the dosage of the corresponding sachets/tablets and the total prescribed dose corresponds 
to ∑n
i=1 (end date - start date of administration(i) +1) * Prescribed Total Daily dosage of 
administration(i) (in mg) as defined earlier. The prescribed total daily dosage (in mg) from 
the PA21 dosing eCRF page will be considered. 
 For Phoslyra drug:[[473* total number of bottles dispensed - (473* total number of 
unused bottles  + 473* total number of bottles  reported as lost +  sum of mL left from the 
total number of partially used bottles returned)] / total prescribed dose (in mL)]*100, 
where the total prescribed dose corresponds to ∑n
i=1 (end date - start date of 
administration(i) +1) * Prescribed dose of administration(i) (in mL/day) as defined earlier. 
The prescribed dose (in mL/day) from the Phoslyra dosing eCRF page will be considered. 
Of note for the partially used bottles, eCRF collect only millimetres left, the information 
from table 7 will be used to convert approximately the millimetres to millilitres. Each 
bottle will be assumed to contain 473mL, i.e. 139 millimetres. In case no kit/bottle is 
returned or all kits/bottles are declared as lost, the compliance will be considered as 
missing. 
For patients with all dispensed tablets/sachets or bottles unused, reported as lost and no 
tablets/sachets or bottles returned dates, all exposure variables listed above excluding exposure 
durations and prescribed daily dose variables (maximum, average); and compliance will be set to 
missing. 


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For subjects who did not enter into Stage 2: all the records from the “Dispensation/Compliance” 
CRF Form will be assigned into Stage 1. 
For subjects who entered into Stage 2: all the records from the “Dispensation/Compliance” CRF 
Form with a dispensed date < End of Stage 1 date -3 days will be assigned into Stage 1; the other 
records will be assigned into Stage 2. 
 
Table 7 
Approximate transformation from millimetres to millilitres to be used for 
Phoslyra compliance derivation 
Phoslyra Bottle 
Millimetres (mm) 
Millilitres (mL) 
139 
473 
130 
448 
120 
411 
110 
375 
100 
339 
90 
303 
80 
268 
70 
234 
60 
200 
50 
166 
40 
130 
30 
94 
20 
59 
10 
24 
1 
1 
Linear interpolation will be used for millimetres not listed in table 7. The following formula will 
be applied: 
mL= mL0+ (mm-mm0) * [ (mL1-mL0)/(mm1-mm0)] 
Where   
 mm is the observed value in millimetres for which approximate transformation in 
millilitres needs to be derived 
 mL is the approximate transformation of mm in millilitres 
 mm0 is the lower value in millimetres from table 7 compared to mm 
 mm1 is the upper value in millimetres from table 7 compared to mm 
 mL0 is the known value in millilitres (from table 7) for mm0  
 mL1 is the known value in millilitres (from table 7) for mm1 
Compliance (%) will be derived based on the sachets/tablets/bottles returned, reported as lost and 
dispensed and total prescribed dose during the stage considered.  


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All exposure data will be listed including the overall maximum dose prescribed (unit/day), 
overall maximum dose prescribed (unit/kg/day) and overall maximum dose received 
(unit/kg/day). In case subjects received both PA21 and Phoslyra during the study, one listing will 
be generated to display the list of subjects in that situation. 
4.7. 
Efficacy Evaluation 
Efficacy analysis will be conducted using the FAS and PPS Populations as outlined below. 
All results related to serum phosphorus will be expressed in both mmol/L and mg/dL units. 
Standard units (mmol/L) from the laboratory file sent by the external vendor will be used to 
derive the unit in mg/dL using the following conversion factor: ×3.096, starting from the 
standardized result. 
4.7.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change in serum phosphorus levels from baseline to the end 
of Stage 1 (i.e. considering the last available value in stage 1) in PA21 group. It is based on 
central laboratory data; in case of missing data regarding central laboratory data, local laboratory 
measurements are used (please refer to Section 4.2.8.1 for the imputation to be applied). 
The change from baseline in the PA21 group will be analysed using a linear mixed model with 
treatment, baseline serum phosphorus, age (in categories) at randomisation, region and gender as 
fixed effects. Summary statistics with the estimate of the adjusted mean change from baseline 
and its 95%CI as well as the corresponding p-value from the t-test will also be provided. 
The SAS code used for the linear mixed model will be as below:  
proc mixed data=input method=type3; 
class treatment age region gender; 
model chg_end_stage1=treatment age region gender baseline / ddfm=KENWARDROGER solution; 
lsmeans treatment / CL alpha=0.05; 
where treatment=’PA21’; 
ods output lsmeans=lsm1; 
run; 
The primary efficacy analysis will be repeated on the FAS by the following subgroups: 
- 
Formulation (tablets only/sachets only/both) 
- 
Serum phosphorus at baseline according to the age related normal range (above, within + 
below; see Table 5) 
- 
Age group at randomisation (0-<2, 2-<6, 6-<12, 12-<=18) * Serum phosphorus at 
baseline according to the age related normal range (above, within + below; see Table 5). 
In case of no subject in an age group, this category will not be displayed. 
Sensitivity analyses will include a repeat of the primary analysis on the FAS population based on 
observed data from the central laboratory only (with no imputation by local laboratory data).  
Homogeneity of the results of the primary endpoint will be investigated on the FAS population 
by displaying summary statistics of change from baseline with the estimate of the adjusted mean 
change from baseline and its 95%CI for the following subgroups using the same linear mixed 
model as above: 


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 By age group at randomisation 
 By gender 
 By region 
4.7.2. 
Secondary Efficacy Endpoints 
For the following secondary endpoints, summary statistics with 95%CIs for the mean change 
will be provided by treatment group using the same linear mixed model as for the primary 
efficacy endpoint: 
 Change in serum phosphorus levels from baseline to the end of Stage 1 in Phoslyra group 
 Change in serum phosphorus levels from baseline to the end of Stage 2 in both groups 
The above secondary endpoints are based on central laboratory data; in case of missing data 
regarding central laboratory data, local laboratory measurements are used (please refer to 
Sections 4.2.8.1 and 4.2.8.2 for the imputation to be applied). 
Serum phosphorus values over time will be summarised by treatment group using descriptive 
statistics based both on central and on local laboratory measurements, separately.   
Box plots will be generated for the change in serum phosphorus levels from baseline for each 
treatment arm to the end of Stage 1 and to the end of Stage 2 on the FAS and PPS Populations. 
In addition, plots will be provided with one curve for each treatment arm representing the mean 
change (±standard error of the mean (SEM)) from baseline in serum phosphorus levels at each 
time point to the end of Stage 1 and to the end of Stage 2 for the FAS and PPS Populations. 
For the following secondary endpoints based on both central and local laboratory measurements, 
number and percentage calculated using the number of subjects with non-missing serum 
phosphorus level as denominators with corresponding exact 95%CIs will be provided by 
treatment group: 
 Subjects with serum phosphorus level within the age related target range at each visit 
 Subjects with serum phosphorus level within the age related normal range at each visit. 
4.8. 
Pharmacokinetic Evaluations 
Not applicable. 
4.9. 
Safety Analyses 
Safety analyses will be conducted using the Safety Population. 
4.9.1. 
Primary Safety Endpoint: Adverse Events 
Adverse events will be coded using MedDRA and displayed in tables and listings using System 
Organ Class (SOC) and Preferred Term. 
Analyses of adverse events will be performed for those events that are considered treatment 
emergent, where treatment emergent is defined as any adverse event with onset after the 
administration of study medication through the end of the study or any event that was present at 
baseline but worsened in intensity.   


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Adverse events are summarised by subject incidence rates, therefore, in any tabulation, a subject 
contributes only once to the count for a given adverse event (SOC or preferred term using the 
worst severity and the strongest relationship). The number of events will be reported as well in 
the summary tables. Multiple occurrences of the same TEAE in one subject during the same 
treatment in the trial will be counted as multiple events in the frequency counts for adverse 
events.  
All TEAE summaries will be generated by treatment group and for both periods cumulatively, 
i.e. until end of stage 1 and until end of stage 2. 
 
An overview of adverse events will be presented and will include the number and percentage of 
patients as well as the number of events with at least one:  
• 
Treatment-emergent adverse events 
• 
Treatment-related treatment-emergent adverse events  
• 
Serious treatment-emergent adverse events 
• 
Treatment-emergent adverse events leading to study drug discontinuation 
• 
Treatment-emergent adverse events leading to Death 
• 
Severe treatment-emergent adverse events 
 
This table will be also repeated for any treatment-emergent adverse event of special interest 
(listed in Table 8 below). The overall summary of TEAEs will be also repeated by treatment 
group and overall maximum dose prescribed (see Table 9) during the trial. Results of the TEAE 
analysis by overall maximum dose prescribed may be confounded as the dose prescribed 
depends on the age. Therefore, a summary table with descriptive statistics for age will be 
provided for each overall maximum dose prescribed category by treatment. 
 
The number and percentage of subjects as well as the number of events with the following 
adverse events will be presented by SOC and PT: 
 with any treatment-emergent adverse event,  
 with any treatment-emergent adverse events by causality assessed by the Investigator 
(related, unrelated),  
 with any treatment-emergent adverse events by intensity assessed by investigator (mild, 
moderate, severe),  
 with any treatment-emergent adverse events by age at randomisation (0-<2, 2-<6, 6-<12, 
12-<=18). The denominator will be the number of patients in each age group category,  
 with any treatment-emergent adverse event of special interest (listed in Table 8 below),  
 with any serious treatment-emergent adverse event,  
 with any serious treatment-related treatment-emergent adverse event,  
 with any serious treatment-emergent adverse event that led to death,  
 with any non-serious treatment-emergent adverse event,  
 with any treatment-emergent adverse events that led to study drug discontinuation,   
 and with any treatment-emergent adverse events started <4 weeks (<1 weeks, 1-<2 weeks 
and 2-<4 weeks will also be presented for more granularity), 4 to <12 weeks, 12 to <24 
weeks, ≥24 weeks. The denominator is the number of patients at risk at the beginning of 


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the period (excluding those who have withdrawn or completed); i.e. in the category 2-<4 
weeks, the denominator will include patients at risk/active at week 2. 
 
Related events include Events with Certain or Probably/Likely or Possible as causality assessed 
by the investigator. Unrelated events include unlikely or unrelated as causality assessed by the 
investigator. 
 
Table 8 
Adverse Event of special interest definition 
 
Events of special interest 
MedDRA 
Diarrhoea 
MedDRA PT:  
-Diarrhoea 
Potential of iron accumulation 
MedDRA PT:  
-Cardiac iron overload 
-Haemochromatosis 
-Haemosiderosis 
-Hereditary haemochromatosis 
-Hepatic siderosis 
-Iron overload 
-Pulmonary haemosiderosis 
-Superficial siderosis of central nervous system 
Masking of GI bleeding due to 
discoloured stool 
MedDRA PT:  
-Faeces discoloured 
MedDRA SMQs:  
-SMQ GI haemorrhage 
Events, which could be linked to 
(deficiencies in) growth and 
skeletal development and review 
of bone markers 
SOC: Musculoskeletal and connective tissue disorder 
-HLT: Bone disorders NEC (from HLGT Bone disorders (excl 
congenital and fractures)) 
-HLT: Metabolic bone disorders NEC (from HLGT Bone disorders 
(excl congenital and fractures)) 
-HLGT: Fractures 
 
SOC: Metabolism and nutrition disorders 
-HLT: Bone metabolism disorders (HLGT: Bone, calcium, 
magnesium and phosphorus metabolism disorders) 
-HLT: Calcium metabolism disorders (HLGT: Bone, calcium, 
magnesium and phosphorus metabolism disorders) 
 
The maximum dose prescribed during the trial to be considered for each treatment is listed 
below: 
 
Table 9 
List of Maximum daily dose prescribed by treatment 
PA21 
(g PA21/day) 
Phoslyra 
(mL/day) 
≤2.5 
<15 
]2.5-5.0] 
[15-25[ 


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]5.0-7.5] 
[25-35[ 
]7.5-10.0] 
[35-44[ 
]10.0-12.5] 
≥44 
]12.5-15.0] 
 
 
 
Conversion between both units for PA21 (mg Iron and g PA21) will be obtained using the below 
table: 
PA21 Dose (Units) 
mg iron 
g PA21 
Number of  
Tablets 
(using   
1 tablet=2.5g PA21) 
250 
1.25 
0.5 
500 
2.5 
1 
750 
3.75 
1.5 
1000 
5.0 
2 
1500 
7.5 
3 
1750 
8.75 
3.5 
2000 
10.0 
4 
2250 
11.25 
4.5 
2500 
12.5 
5 
3000 
15.0 
6 
 
In these tabulations, each subject will contribute only once (i.e., the most related occurrence or 
the most severe occurrence) to each of the incidence rates in the descriptive analysis, regardless 
of the number of episodes. 
No formal hypothesis-testing analysis of adverse events incidence rates will be performed. 
If a subject switches from a treatment to the other by mistake, then further summary tables will 
be generated to display for each treatment the adverse events reported under each received 
treatment. 
All adverse events (treatment-emergent adverse events or non-treatment-emergent adverse 
events) occurring on study will be listed in subject data listings. 
By-subject listings also will be provided for the following: subject deaths; serious adverse 
events; adverse events leading to study drug withdrawal; most common SOC based on PA21 
total; adverse events of special interest. 
If a subject switches from a treatment to the other by mistake, then further by-subject listings for 
adverse events will be provided, one by treatment.  
4.9.2. 
Secondary Safety Endpoints 
For serum total corrected calcium and serum total corrected calcium-phosphorus product 
expressed in mmol/L and mmol2/L2 respectively, absolute value and change from baseline value 


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based on both central and local laboratory data, separately, will be described at each time point 
by treatment group.  
For serum intact parathyroid hormone (iPTH) levels, absolute value and change from baseline 
value based on central laboratory data will be described at each time point by treatment group 
and will be expressed in both pmol/L and ng/mL units. 
Percentage of subjects who develop at least 1 episode of sustained hypercalcaemia (defined as 
total calcium value>upper safety limit from Table 6 confirmed by repeat sample 1 week later) 
after start of treatment will be provided by treatment group. All the records from the local and 
central laboratories including scheduled and unscheduled visits will be taken into account. 
Patient will be considered as having an episode of sustained hypercalcaemia if two consecutive 
assessments separated by 6 days or more have calcium value greater than the upper limit of 
safety. 
4.9.3. 
Laboratory Data 
Clinical laboratory values will be expressed using SI units.  
The actual value and change from baseline will be summarised for each clinical laboratory 
parameter at each time point by treatment group based on central laboratory measurements. For 
serum phosphorus, calcium (total and corrected) and albumin chemistry parameters, both central 
and local laboratory summary tables will be provided. 
Shift tables from baseline to each post-baseline visit will be produced using the low/normal/high 
classification based on laboratory reference ranges. 
The normal ranges of some parameters from the central laboratory data are only available for the 
age group above or equal to 18 years and not from 0 to 17yrs; therefore shift tables will not 
produce for the below parameters due to missing normal ranges. Only Actual Values and 
Changes Over Time tables and listings will be presented. 
 Ferritin 
 Osteocalcin 
 Transferrin 
 Vitamin A 
 Vitamin E 
 
Vitamin K 
 Intact parathyroid hormone  
 Fibroblast growth factor 23  
 Tartrate-resistant acid phosphatase 5b 
 Atypical lymphocytes and Lymphocytes atypical/leukocytes 
 
All laboratory data will be provided in data listings. 
A subset listing will be presented for all abnormal laboratory values. 
 


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Table 10 
List of Laboratory Parameters 
Category 
Parameters 
Haematology 
Erythrocytes, Mean corpuscular volume, Mean corpuscular haemoglobin 
Mean corpuscular haemoglobin concentration, Haemoglobin, Haematocrit 
Reticulocyte count, White blood cells, White blood cell differential (% 
and absolute value), Neutrophils, Eosinophils, Basophils, Lymphocytes, 
Monocytes, Platelets  
Chemistry 
Calcium (total, corrected), Intact parathyroid hormone (only shift tables as 
already summarised as part of the secondary safety endpoints), Creatinine, 
Glucose, Triglycerides, Total protein, Albumin, Urea, Uric acid, Total 
bilirubin, Total cholesterol (differential in high density lipoproteins and 
low density lipoproteins), Creatine phosphokinase, C-reactive protein, 
Bicarbonate, Sodium, Potassium, Chloride 
Chemistry – Liver 
Enzymes 
Alkaline phosphatase, Aspartate transaminase, Alanine transaminase, 
Lactate dehydrogenase, Gamma-glutamyl transpeptidase 
Iron Status 
Parameters 
Iron, Ferritin, Transferrin, Unsaturated Iron Binding Capacity, Transferrin 
saturation 
Vitamins 
A, 25(OH)D, 1,25(OH)2D, E, K 
Bone Markers 
Carboxyterminal cross-linking telopeptide of bone collagen,  
Tartrate-resistant acid phosphatase 5b, Bone-specific alkaline phosphatase, 
Osteocalcin, Fibroblast growth factor 23 
 
 
In addition, the actual value will be summarised for eGFR (estimated Glomerular Filtration Rate) 
at each time point by treatment group based on central laboratory measurements for subjects not 
on dialysis at screening. For subjects not on dialysis at screening but requiring dialysis for the 
first time during the study, only eGFR values before dialysis will be part of the summary table. 
All eGFR values will be listed and for subjects on dialysis, values of glomerular filtration rate 
will not be deemed interpretable and therefore will be flagged. For subjects on dialysis at 
screening, all eGFR values will be flagged. For subjects not on dialysis at screening but requiring 
dialysis for the first time during the study, eGFR values after dialysis will be flagged.  
Glomerular Filtration Rate will be estimated through creatinine clearance paediatric Schwartz 
(2009) formula and it will be available at each timepoint it is possible to derive it as depending 
on height and serum creatinine. Age at each timepoint from Central Laboratory file will be used. 
If not available, age from CRF data at the same visit will be used, and in case of missing data, 
imputation will be done as follows: 
- 
If visit date is missing, age will be left as missing, so eGFR will not be calculated 
- 
If visit date is available, then calculate the duration in days between the last visit with an 
available age and the visit with a missing age (visit y date – visit x date + 1), and if this 
duration <= 365 days then imputed age will be the age at the previous visit, else impute 
with age (years) at previous visit + 1. 
Please refer to Table 11 for the formula to be used. 
 


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Table 11 
eGFR formula by age and gender categories 
Category 
eGFR Formula 
Unit 
< 1 year 
(0.45 * Height (cm))/ (serum creatinine (umol/L) * 0.01131) 
mL/min/1.73m2 
1 - <13 years 
(0.55 * Height (cm))/ (serum creatinine (umol/L) * 0.01131) 
mL/min/1.73m2 
Females 13- ≤18 years 
(0.55 * Height (cm))/ (serum creatinine (umol/L) * 0.01131) 
mL/min/1.73m2 
Males  13- ≤18 years 
(0.70 * Height (cm))/ (serum creatinine (umol/L) * 0.01131) 
mL/min/1.73m2 
 
4.9.4. 
Vital Signs and Physical Examinations 
The actual value and change from baseline will be summarised for each vital signs (height, 
weight, BMI, resting blood pressure, resting heart rate and temperature) parameter at each time 
point by treatment group. The vital signs will also be summarised by age categories at 
randomisation within treatment group. 
As the temperature can be taken using different modes (Oral, Otic or Axillary), then it will not be 
presented in the summary statistics when the mode at Week x is different from the mode at 
Baseline and then the change from baseline will not be derived in that case. All values will be 
presented in the listing. 
So for the temperature, summary by mode will be presented. 
By-subject listings of vital sign measurements will be presented in data listings. 
For physical examination, shift table from baseline to each time point will be presented. All 
physical examination findings will be presented in a data listing. 
4.9.5. 
Electrocardiogram 
Not applicable. 
4.9.6. 
Prior and Concomitant Medications 
A concomitant medication is defined as any medication/therapy with an end date on or after the 
date of the first drug administration of study drug or missing (medication assumed to be 
ongoing). 
A prior medication is defined as any medication with an end date prior to the date of the first 
administration of study drug.  
Prior and concomitant medications will be coded using the WHO Drug Dictionary. Results will 
be tabulated by Anatomic Therapeutic Chemical (ATC) Level 2, Level 4) and Preferred Term. 
All medications will be presented in a data listing, with a flag identifying them as prior or 
concomitant medications. 
Type of dialysis (haemodialysis, peritoneal dialysis, none) will be summarised at each visit. All 
data related to dialysis will be listed.  
4.9.7. 
Subject Reported Palatability and Acceptability 
Subject reported palatability and acceptability results will be summarised at each time point. By-
subject listings of visual analogue scale measurements will be presented in a data listing. 


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5. 
CHANGES TO PLANNED ANALYSES 
To take into consideration covariate factors for the evaluation of the primary endpoint, baseline 
serum phosphorus, age (in categories) at randomisation, region and gender, a mixed model will 
be used in replacement to the paired t-test mentioned in the protocol. 
 
Following discussions and agreements with PDCO and FDA, the following new age 
classification at randomisation will be used for the outputs: 0 to <1 year/ ≥1 year to <6 years/ ≥6 
years to <12 years/ ≥12 years to <18 years. 
 
Due to difficulties in the recruitment of patients below 9 years of age, PDCO agreed to reduce 
required minimum numbers of recruited patients as follows: 
At least 60 subjects must be randomised into PA21 group and the following number of subjects 
from each age group as detailed below: 
• Less than 1 year: no minimum number of randomised patients 
• From 1 to less than 6 years: at least 5 patients on PA21 
• From 6 to less than 12 years: at least 10 patients on PA21 
• From 12 to less than 18 years: at least 10 patients on PA21 
• Phoslyra arm: no minimum number of randomised patients. 
Furthermore, FDA agreed that a partial waiver of PREA study requirements in patients less than 
2 years of age can be justified on the basis that necessary studies are impossible or highly 
impracticable. The Agency also believes that it may be possible to generalize the findings in 
older paediatric patients down to younger patients greater than 2 years of age, indicating that the 
study can be completed without the need to recruit originally required minimum numbers of 
patients below 9 years of age. 
 
Following PDCO advice from the Modification Summary Report Day 30 (EMA/170421/2018), 
the Sponsor plans to include additional comparison with an external control from paediatric 
study SVCARB07609 (EudraCT No. 2011-002329-23), conducted with sevelamer carbonate 
[Fathallah-Shaykh S. et al, 2018] where appropriate. This Phase II study is a 2-week, 
randomized, placebo-controlled, fixed dose period followed by a 6-month, single-arm, open-
label, dose titration period study to investigate the efficacy and safety of sevelamer carbonate in 
hyperphosphatemic paediatric patients with CKD. The Sponsor selected this external control 
from available studies on the hyperphosphatemic paediatric patients with CKD due to the large 
sample size and the results of this paediatric study supported the extension of the indication for 
sevelamer to paediatric patients in the EU [EMA/271022/2016 and EMA/352101/2017]. 
However, due to differences in the design of the studies, there will be limitations to this 
comparison approach.  
Descriptive comparison of safety endpoints, including AE profile, using publicly available data 
from the SVCARB07609 trial is foreseen and will be summarised in a separate report supporting 
the main conclusions from the PA-CL-PED-01 study. 
 


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According to the clinical study protocol the following iron status parameters have to be assessed: 
Iron, Ferritin, Transferrin and Transferrin saturation (TSAT). The iron parameters assessed 
during the conduct of study PA-CL-PED-01 are: Iron, Ferritin, Transferrin and Unsaturated Iron 
Binding Capacity (UIBC).  
Unsaturated iron binding capacity (UIBC) is a surrogate marker of TSAT and has been reported 
to identify 100% of iron overloaded patients and 95% of patients with normal iron stores. The 
UIBC is therefore a reliable method. 
The use of UIBC instead of TSAT is estimated to have no impact on the reliability of safety 
assessments in this clinical study and on the conclusions of the analysis. Therefore, TSAT will 
not be derived and presented. A Note to File at Vifor was created. 
 
 


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6. 
REFERENCES 
 
EMA/271022/2016: Assessment report for paediatric studies submitted according to Article 46 
of the Regulation (EC) No 1901/2006, 1 April 2016. 
 
EMA/352101/2017: EPAR - Assessment report – Variation Type II, 18 May 2017. 
 
Fathallah-Shaykh S, Drozdz D, Flynn J, Jenkins R, Wesseling-Perry K,  et al. Efficacy and safety 
of sevelamer carbonate in hyperphosphatemic pediatric patients with chronic kidney disease. 
Pediatr Nephrol (2018) 33: 325. 
 
International Conference on Harmonisation (ICH) E3. (ICH E3: Structure and content of Clinical 
Study Reports, dated 30 November 1995) 
 
Schwartz GJ and Work DF. Measurement and estimation of GFR in children and adolescents. J 
Am Soc Nephrol. 2009; Nov; 4(11): 1832–1843 
 
 


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7. 
CLINICAL STUDY REPORT APPENDICES 
7.1. 
Statistical Tables to be generated 
Table 14.1.1 
Subject Enrolment (Safety Population) 
Table 14.1.2 
Study Population (Safety Population) 
Table 14.1.3.1 
Subject Disposition (All Enrolled Subjects) 
Table 14.1.3.2 
Early Termination and Reason (Safety Population) 
Table 14.1.3.2.1 
Early Termination and Reason, by Age (Safety Population) 
Table 14.1.3.3 
Major Protocol Deviations (FAS Population) 
Table 14.1.4.1 
Demographic Characteristics (Safety Population) 
Table 14.1.4.2 
Demographic Characteristics (Stage 2 Safety Population) 
Table 14.1.4.3 
Demographic Characteristics (FAS Population) 
Table 14.1.4.4 
Demographic Characteristics (PPS Population) 
Table 14.1.4.5 
Demographic Characteristics, by Age (Safety Population) 
Table 14.1.4.6 
Demographic Characteristics, by Age (Stage 2 Safety Population) 
Table 14.1.4.7 
Demographic Characteristics, by Age (FAS Population) 
Table 14.1.4.8 
Demographic Characteristics, by Age (PPS Population) 
Table 14.1.4.9 
Demographic Characteristics, by Gender (Safety Population) 
Table 14.1.4.10 
Demographic Characteristics, by Gender (Stage 2 Safety Population) 
Table 14.1.4.11 
Demographic Characteristics, by Gender (FAS Population) 
Table 14.1.4.12 
Demographic Characteristics, by Gender (PPS Population) 
Table 14.1.4.13 
Demographic Characteristics, by Region (Safety Population) 
Table 14.1.4.14 
Demographic Characteristics, by Region (Stage 2 Safety Population) 
Table 14.1.4.15 
Demographic Characteristics, by Region (FAS Population) 
Table 14.1.4.16 
Demographic Characteristics, by Region (PPS Population) 
Table 14.1.5.1 
Baseline Disease Characteristics (Safety Population) 


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Table 14.1.5.2 
Baseline Disease Characteristics (Stage 2 Safety Population) 
Table 14.1.5.3 
Baseline Disease Characteristics (FAS Population) 
Table 14.1.5.4 
Baseline Disease Characteristics (PPS Population) 
Table 14.1.5.5 
Baseline Disease Characteristics, by Age (Safety Population) 
Table 14.1.5.6 
Baseline Disease Characteristics, by Age (Stage 2 Safety Population) 
Table 14.1.5.7 
Baseline Disease Characteristics, by Age (FAS Population) 
Table 14.1.5.8 
Baseline Disease Characteristics, by Age (PPS Population) 
Table 14.1.5.9 
Baseline Disease Characteristics, by Gender (Safety Population) 
Table 14.1.5.10 
Baseline Disease Characteristics, by Gender (Stage 2 Safety Population) 
Table 14.1.5.11 
Baseline Disease Characteristics, by Gender (FAS Population) 
Table 14.1.5.12 
Baseline Disease Characteristics, by Gender (PPS Population) 
Table 14.1.5.13 
Baseline Disease Characteristics, by Region (Safety Population) 
Table 14.1.5.14 
Baseline Disease Characteristics, by Region (Stage 2 Safety Population) 
Table 14.1.5.15 
Baseline Disease Characteristics, by Region (FAS Population) 
Table 14.1.5.16 
Baseline Disease Characteristics, by Region (PPS Population) 
Table 14.1.6.1 
Medical History (Safety Population) 
Table 14.1.6.2 
Medical History (Stage 2 Safety Population) 
Table 14.1.6.3 
Medical History (FAS Population) 
Table 14.1.6.4 
Medical History (PPS Population) 
Table 14.1.7.1 
Prior Medications (Safety Population) 
Table 14.1.8.1 
Exposure to PA21 Drug - Stage 1 and Overall Study  (Safety 
Population) 
Table 14.1.8.1.1 
Exposure to PA21 Drug, by Age - Stage 1 and Overall Study  (Safety 
Population) 
Table 14.1.8.1.2 
Exposure to PA21 Drug, by Gender - Stage 1 and Overall Study  (Safety 
Population) 


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Table 14.1.8.1.3 
Exposure to PA21 Drug, by Region - Stage 1 and Overall Study  (Safety 
Population) 
Table 14.1.8.1.4 
Exposure to PA21 Drug, by Formulation - Stage 1 and Overall Study  
(Safety Population) 
Table 14.1.8.2 
Exposure to PA21 Drug - Stage 2 (Stage 2 Safety Population) 
Table 14.1.8.2.1 
Exposure to PA21 Drug, by Age - Stage 2  (Safety Population) 
Table 14.1.8.2.2 
Exposure to PA21 Drug, by Gender - Stage 2  (Safety Population) 
Table 14.1.8.2.3 
Exposure to PA21 Drug, by Region - Stage 2  (Safety Population) 
Table 14.1.8.2.4 
Exposure to PA21 Drug, by Formulation - Stage 2  (Safety Population) 
Table 14.1.8.3 
Exposure to Phoslyra Drug - Stage 1 and Overall Study  (Safety 
Population) 
Table 14.1.8.3.1 
Exposure to Phoslyra Drug, by Age - Stage 1 and Overall Study  (Safety 
Population) 
Table 14.1.8.4 
Exposure to Phoslyra Drug - Stage 2 (Stage 2 Safety Population) 
Table 14.1.8.4.1 
Exposure to Phoslyra Drug, by Age - Stage 2  (Safety Population) 
Table 14.1.8.5 
Dose Changes with PA21 Drug - Stage 1 and Overall Study  (Safety 
Population) 
Table 14.1.8.6 
Dose Changes with PA21 Drug - Stage 2 (Stage 2 Safety Population) 
Table 14.1.8.7 
Dose Changes with Phoslyra Drug - Stage 1 and Overall Study (Safety 
Population) 
Table 14.1.8.8 
Dose Changes with Phoslyra Drug - Stage 2 (Stage 2 Safety Population) 
Table 14.1.8.9 
Age at Randomisation by Maximum Dose Prescribed Category (Safety 
Population) 
Table 14.2.1.1 
Change in Serum Phosphorus Level from Baseline to End of Stage 1 in 
PA21 Group (FAS Population) 
Table 14.2.1.2 
Change in Serum Phosphorus Level from Baseline to End of Stage 1 in 
PA21 Group (PPS Population) 
Table 14.2.1.3 
Change in Serum Phosphorus Level from Baseline to End of Stage 1 in 
PA21 Group without Imputation (FAS Population) 


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Table 14.2.1.4 
Change in Serum Phosphorus Level from Baseline to End of Stage 1 in 
PA21 Group by Age (FAS Population) 
Table 14.2.1.5 
Change in Serum Phosphorus Level from Baseline to End of Stage 1 in 
PA21 Group by Gender (FAS Population) 
Table 14.2.1.6 
Change in Serum Phosphorus Level from Baseline to End of Stage 1 in 
PA21 Group by Region (FAS Population) 
Table 14.2.1.7 
Change in Serum Phosphorus Level from Baseline to End of Stage 1 in 
PA21 Group by Formulation (FAS Population) 
Table 14.2.1.8 
Change in Serum Phosphorus Level from Baseline to End of Stage 1 in 
PA21 Group by Serum Phosphorus at Baseline According to Age 
Related Normal Range (FAS Population) 
Table 14.2.1.9 
Change in Serum Phosphorus Level from Baseline to End of Stage 1 in 
PA21 Group by Age and Serum Phosphorus at Baseline According to 
Age Related Normal Range (FAS Population) 
Table 14.2.2.1 
Change in Serum Phosphorus Level from Baseline to End of Stage 1 in 
Phoslyra Group (FAS Population) 
Table 14.2.2.2 
Change in Serum Phosphorus Level from Baseline to End of Stage 1 in 
Phoslyra Group (PPS Population) 
Table 14.2.3.1 
Change in Serum Phosphorus Level from Baseline to End of Stage 2 
(FAS Population) 
Table 14.2.3.2 
Change in Serum Phosphorus Level from Baseline to End of Stage 2 
(PPS Population) 
Table 14.2.4.1 
Serum Phosphorus Level over Time - Central Laboratory Measurement 
(FAS Population) 
Table 14.2.4.2 
Serum Phosphorus Level over Time - Central Laboratory Measurement 
(PPS Population) 
Table 14.2.4.3 
Serum Phosphorus Level over Time - Local Laboratory Measurement 
(FAS Population) 
Table 14.2.4.4 
Serum Phosphorus Level over Time - Local Laboratory Measurement 
(PPS Population) 
Table 14.2.5.1 
Serum Phosphorus Level over Time according to the Age Related 
Target Range - Central Laboratory Measurement (FAS Population) 
Table 14.2.5.2 
Serum Phosphorus Level over Time according to the Age Related 


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Target Range - Local Laboratory Measurement (FAS Population) 
Table 14.2.5.3 
Serum Phosphorus Level over Time according to the Age Related 
Target Range - Central Laboratory Measurement (PPS Population) 
Table 14.2.5.4 
Serum Phosphorus Level over Time according to the Age Related 
Target Range - Local Laboratory Measurement (PPS Population) 
Table 14.2.6.1 
Serum Phosphorus Level over Time according to the Age Related 
Normal Range - Central Laboratory Measurement (FAS Population) 
Table 14.2.6.2 
Serum Phosphorus Level over Time according to the Age Related 
Normal Range - Local Laboratory Measurement (FAS Population) 
Table 14.2.6.3 
Serum Phosphorus Level over Time according to the Age Related 
Normal Range - Central Laboratory Measurement (PPS Population) 
Table 14.2.6.4 
Serum Phosphorus Level over Time according to the Age Related 
Normal Range - Local Laboratory Measurement (PPS Population) 
Table 14.3.1.1 
Overview of Treatment-Emergent Adverse Events - Until End of Stage 
1 (Safety Population) 
Table 14.3.1.2 
Overview of Treatment-Emergent Adverse Events - Until End of Stage 
2 (Safety Population) 
Table 14.3.1.3 
Overview of Treatment-Emergent Adverse Events of Special Interest - 
Until End of Stage 1 (Safety Population) 
Table 14.3.1.4 
Overview of Treatment-Emergent Adverse Events of Special Interest - 
Until End of Stage 2 (Safety Population) 
Table 14.3.1.5 
Overview of Treatment-Emergent Adverse Events by Maximum Dose 
Prescribed (Safety Population) 
Table 14.3.1.6 
Treatment-Emergent Adverse Events by MedDRA System Organ Class 
and Preferred Term - Until End of Stage 1 (Safety Population) 
Table 14.3.1.7 
Treatment-Emergent Adverse Events by MedDRA System Organ Class 
and Preferred Term - Until End of Stage 2 (Safety Population) 
Table 14.3.1.8 
Serious Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term - Until End of Stage 1 (Safety 
Population) 
Table 14.3.1.9 
Serious Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term - Until End of Stage 2 (Safety 
Population) 


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Table 14.3.1.10 
Non-serious Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term - Until End of Stage 1 (Safety 
Population) 
Table 14.3.1.11 
Non-serious Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term - Until End of Stage 2 (Safety 
Population) 
Table 14.3.1.12 
Treatment-Emergent Adverse Events Related to Study Drug by 
MedDRA System Organ Class and Preferred Term - Until End of Stage 
1 (Safety Population) 
Table 14.3.1.13 
Treatment-Emergent Adverse Events Related to Study Drug by 
MedDRA System Organ Class and Preferred Term - Until End of Stage 
2 (Safety Population) 
Table 14.3.1.14 
Serious Treatment-Emergent Adverse Events Related to Study Drug by 
MedDRA System Organ Class and Preferred Term - Until End of Stage 
1 (Safety Population) 
Table 14.3.1.15 
Serious Treatment-Emergent Adverse Events Related to Study Drug by 
MedDRA System Organ Class and Preferred Term - Until End of Stage 
2 (Safety Population) 
Table 14.3.1.16 
Serious Treatment-Emergent Adverse Events that Led to Death by 
MedDRA System Organ Class and Preferred Term - Until End of Stage 
1 (Safety Population) 
Table 14.3.1.17 
Serious Treatment-Emergent Adverse Events that Led to Death by 
MedDRA System Organ Class and Preferred Term - Until End of Stage 
2 (Safety Population) 
Table 14.3.1.18 
Treatment-Emergent Adverse Events that Led to Study Drug 
Withdrawal by MedDRA System Organ Class and Preferred Term - 
Until End of Stage 1 (Safety Population) 
Table 14.3.1.19 
Treatment-Emergent Adverse Events that Led to Study Drug 
Withdrawal by MedDRA System Organ Class and Preferred Term - 
Until End of Stage 2 (Safety Population) 
Table 14.3.1.20 
Treatment-Emergent Adverse Events of Special Interest by MedDRA 
System Organ Class and Preferred Term - Until End of Stage 1 (Safety 
Population) 
Table 14.3.1.21 
Treatment-Emergent Adverse Events of Special Interest by MedDRA 
System Organ Class and Preferred Term - Until End of Stage 2 (Safety 
Population) 


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Table 14.3.1.22 
Treatment-Emergent Adverse Events by Maximum Intensity by 
MedDRA System Organ Class and Preferred Term - Until End of Stage 
1 (Safety Population) 
Table 14.3.1.23 
Treatment-Emergent Adverse Events by Maximum Intensity by 
MedDRA System Organ Class and Preferred Term - Until End of Stage 
2 (Safety Population) 
Table 14.3.1.24 
Treatment-Emergent Adverse Events by Causality by MedDRA System 
Organ Class and Preferred Term - Until End of Stage 1 (Safety 
Population) 
Table 14.3.1.25 
Treatment-Emergent Adverse Events by Causality by MedDRA System 
Organ Class and Preferred Term - Until End of Stage 2 (Safety 
Population) 
Table 14.3.1.26 
Treatment-Emergent Adverse Events by Time of Onset by MedDRA 
System Organ Class and Preferred Term - Until End of Stage 1 (Safety 
Population) 
Table 14.3.1.27 
Treatment-Emergent Adverse Events by Time of Onset by MedDRA 
System Organ Class and Preferred Term - Until End of Stage 2 (Safety 
Population) 
Table 14.3.1.28 
Overview of Treatment-Emergent Adverse Events by Age - Until End 
of Stage 1 (Safety Population) 
Table 14.3.1.29 
Overview of Treatment-Emergent Adverse Events by Age - Until End 
of Stage 2 (Safety Population) 
Table 14.3.1.30 
Treatment-Emergent Adverse Events by Age by MedDRA System 
Organ Class and Preferred Term - Until End of Stage 1 (Safety 
Population) 
Table 14.3.1.31 
Treatment-Emergent Adverse Events by Age by MedDRA System 
Organ Class and Preferred Term - Until End of Stage 2 (Safety 
Population) 
Table 14.4.1 
Serum Phosphorus Level Over Time - Central Laboratory Measurement 
(Safety Population) 
Table 14.4.2 
Serum Phosphorus Level Over Time - Local Laboratory Measurement 
(Safety Population) 
Table 14.4.3.1 
Serum Total Corrected Calcium: Actual Values and Changes Over Time 
- Central Laboratory Measurement (Safety Population) 
Table 14.4.3.2 
Serum Total Corrected Calcium-Phosphorus Product: Actual Values and 


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Changes Over Time - Central Laboratory Measurement (Safety 
Population) 
Table 14.4.4.1 
Serum Total Corrected Calcium: Actual Values and Changes Over Time 
- Local Laboratory Measurement (Safety Population) 
Table 14.4.4.2 
Serum Total Corrected Calcium-Phosphorus Product: Actual Values and 
Changes Over Time - Local Laboratory Measurement (Safety 
Population) 
Table 14.4.5 
Serum Intact Parathyroid Hormone: Actual Values and Changes Over 
Time - Central Laboratory Measurement (Safety Population) 
Table 14.4.6 
Sustained Hypercalcaemia (Safety Population) 
Table 14.4.7.1 
Clinical Laboratories – Haematology: Actual Values and Changes Over 
Time - Central Laboratory Measurement (Safety Population) 
Table 14.4.7.2 
Clinical Laboratories – Chemistry: Actual Values and Changes Over 
Time - Central Laboratory Measurement (Safety Population) 
Table 14.4.7.3 
Clinical Laboratories - Chemistry: Actual Values and Changes Over 
Time - Local Laboratory Measurement (Safety Population) 
Table 14.4.7.4 
Clinical Laboratories - Chemistry – Liver Enzymes: Actual Values and 
Changes Over Time - Central Laboratory Measurement (Safety 
Population) 
Table 14.4.7.5 
Clinical Laboratories - estimated Glomerular Filtration Rate: Actual 
Values Over Time - Central Laboratory Measurement (Safety 
Population) 
Table 14.4.7.6 
Clinical Laboratories – Iron Status Parameters: Actual Values and 
Changes Over Time - Central Laboratory Measurement (Safety 
Population) 
Table 14.4.7.7 
Clinical Laboratories – Vitamins: Actual Values and Changes Over 
Time - Central Laboratory Measurement (Safety Population) 
Table 14.4.7.8 
Clinical Laboratories – Bone Markers: Actual Values and Changes Over 
Time - Central Laboratory Measurement (Safety Population) 
Table 14.4.8.1 
Clinical Laboratories - Haematology: Shift Table from Baseline to each 
Post-Baseline Value by timepoint (Safety Population) 
Table 14.4.8.2 
Clinical Laboratories - Chemistry: Shift Table from Baseline to each 
Post-Baseline Value by timepoint (Safety Population) 


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Table 14.4.8.3 
Clinical Laboratories – Chemistry - Liver Enzymes: Shift Table from 
Baseline to each Post-Baseline Value by timepoint (Safety Population) 
Table 14.4.8.4 
Clinical Laboratories – Iron Status Parameters: Shift Table from 
Baseline to each Post-Baseline Value by timepoint (Safety Population) 
Table 14.4.8.5 
Clinical Laboratories – Vitamins: Shift Table from Baseline to each 
Post-Baseline Value by timepoint (Safety Population) 
Table 14.4.8.6 
Clinical Laboratories – Bone Markers: Shift Table from Baseline to 
each Post-Baseline Value by timepoint (Safety Population) 
Table 14.4.9.1 
Vital Signs: Actual Values and Changes over Time (Safety Population) 
Table 14.4.9.2 
Vital Signs: Actual Values and Changes over Time, by Age (Safety 
Population) 
Table 14.4.10 
Physical Examination (Safety Population) 
Table 14.4.11 
Concomitant Medications (Safety Population) 
Table 14.4.12 
Dialysis Type over Time (Safety Population) 
Table 14.4.13 
Subject Reported Palatability and Acceptability over Time (Safety 
Population) 
7.2. 
Data Listings to be Generated 
Listing 16.1.6.1.A 
Investigational Product(s) Received for PA21 Dosing (Safety 
Population) 
Listing 16.1.6.1.B 
Investigational Product(s) Received for Phoslyra Dosing (Safety 
Population) 
Listing 16.1.6.2 
Listing of Patients Receiving Test Drug(s)/Investigational Product(s) 
From Specific Batches, Where More Than One Batch Was Used 
Listing 16.1.6.3 
Listing of Subjects Receiving Study Drug Different than the One 
Assigned in at least One of the Administration (Safety Population) 
Listing 16.1.7 
Randomisation Data  (Safety Population) 
Listing 16.2.1 
Subject Disposition and Treatment Termination (Safety Population) 
Listing 16.2.2.1 
Inclusion/Exclusion Criteria Not Met (Safety Population) 


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Listing 16.2.2.2 
Protocol Deviations (Safety Population) 
Listing 16.2.3 
Subjects Excluded from Efficacy Analysis (Safety Population) 
Listing 16.2.4.1 
Demographic Data (Safety Population) 
Listing 16.2.4.2 
Baseline Disease Characteristics (Safety Population) 
Listing 16.2.4.3 
Medical History (Safety Population) 
Listing 16.2.4.4 
Surgery History (Safety Population) 
Listing 16.2.5.1.A 
Dosing Information – PA21 Drug (Safety Population) 
Listing 16.2.5.1.B 
Dosing Information – Phoslyra Drug (Safety Population) 
Listing 16.2.5.2 
Compliance and Exposure to Study Drug (Safety Population) 
Listing 16.2.6.1 
Change in Serum Phosphorus Levels from Baseline to End of Stage 
1 (Safety Population) 
Listing 16.2.6.2 
Change in Serum Phosphorus Levels from Baseline to End of Stage 
2 (Safety Population) 
Listing 16.2.6.3 
Serum Phosphorus Levels (Safety Population)  
Listing 16.2.7.1 
All Adverse Events (Safety Population) 
Listing 16.2.7.2 
Deaths (Safety Population) 
Listing 16.2.7.3 
Serious Adverse Events (Safety Population) 
Listing 16.2.7.4 
Adverse Events Leading to Study Drug Withdrawal (Safety 
Population) 
Listing 16.2.7.5 
Adverse Events in Most Common SOC Observed (Safety 
Population) 
Listing 16.2.7.6 
Adverse Events of Special Interest (Safety Population) 
Listing 16.2.8.1 
Laboratory Results: Haematology (Safety Population) 
Listing 16.2.8.2 
Laboratory Results: Chemistry (Safety Population) 
Listing 16.2.8.3 
Laboratory Results: estimated Glomerular Filtration Rate (Safety 


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Population) 
Listing 16.2.8.4 
Laboratory Results: Chemistry – Liver Enzymes (Safety Population) 
Listing 16.2.8.5 
Laboratory Results: Iron Status Parameters (Safety Population) 
Listing 16.2.8.6 
Laboratory Results: Vitamins (Safety Population) 
Listing 16.2.8.7 
Laboratory Results: Bone Markers (Safety Population) 
 Listing 16.2.8.8 
 Abnormal Laboratory Values (Safety Population) 
Listing 16.2.8.9 
Pregnancy Test Results (Safety Population) 
Listing 16.2.9.1 
Vital Signs (Safety Population) 
Listing 16.2.9.2 
Physical Examination  (Safety Population) 
Listing 16.2.9.3 
Prior and Concomitant Medications (Safety Population) 
Listing 16.2.9.4 
Haemodialysis (Safety Population) 
Listing 16.2.9.5 
Peritoneal Dialysis Parameters (Safety Population) 
Listing 16.2.9.6 
Subject Reported Palatability and Acceptability(Safety Population) 
7.3. 
Figures to be Generated 
Figure 14.2.1.1 
Change in Serum Phosphorus Levels from Baseline to End of Stage 
1 (FAS Population) 
Figure 14.2.1.2 
Change in Serum Phosphorus Levels from Baseline to End of Stage 
1 (PPS Population) 
Figure 14.2.1.3 
Change in Serum Phosphorus Levels from Baseline to End of Stage 
2 (FAS Population) 
Figure 14.2.1.4 
Change in Serum Phosphorus Levels from Baseline to End of Stage 
2 (PPS Population) 
Figure 14.2.2.1 
Mean Change (±SEM) from Baseline in Serum Phosphorus Levels to 
End of Stage 1 (FAS Population) 
Figure 14.2.2.2 
Mean Change (±SEM) from Baseline in Serum Phosphorus Levels to 
End of Stage 1 (PPS Population) 


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Figure 14.2.2.3 
Mean Change (±SEM) from Baseline in Serum Phosphorus Levels to 
End of Stage 2 (FAS Population) 
Figure 14.2.2.4 
Mean Change (±SEM) from Baseline in Serum Phosphorus Levels to 
End of Stage 2 (PPS Population)