Clinical trial NCT03001011
Conditions: Hyperphosphatemia
Sponsor: Sanofi
Start date: 2017-06-07; Completion date: 2019-08-16
Enrollment: 202 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

To demonstrate efficacy of Renvela tablets in the reduction of serum phosphorus in hyperphosphatemia in participants with chronic kidney disease not on dialysis.

Secondary Objectives:

To document the efficacy of Renvela tablets in the reduction of serum lipids (total cholesterol and low-density lipoprotein cholesterol \[LDL-C\]).

To document the efficacy of Renvela tablets in the reduction of calcium-phosphorus product.

To document the efficacy of Renvela tablets in the reduction of intact parathyroid hormone (iPTH).

To document the efficacy of Renvela tablets in proportion of participants reaching the target serum phosphorus level 4.6 milligrams per decilitre (mg/dL) (1.47 millimoles per litre \[mmol/L\], inclusive).

To evaluate safety of Renvela tablets.

Detailed description:
The total duration of study period per participant was up to 14 weeks.

Arms: arm 1: Participants received placebo (for Renvela) orally 3 times per day (TID) for up to 8 weeks. One to five tablets were taken with meals, as directed by physician and were titrated (up to a maximum of 15 tablets per day) to reach a target goal of serum phosphorus less than or equal to (\<=) 4.6 mg/dL (\<=1.49 mmol/L). arm 2: Participants received Renvela orally TID for up to 8 weeks. One to five tablets were taken with meals, as directed by physician and were titrated (up to a maximum of 15 tablets per day) to reach a target goal of serum phosphorus \<=4.6 mg/dL (\<=1.49 mmol/L).
Interventions: intervention 1: Placebo intervention 2: Sevelamer Carbonate (GZ419831)
Intervention descriptions: intervention 1: Pharmaceutical form: tablet

Route of administration: oral intervention 2: Pharmaceutical form: tablet

Route of administration: oral

Protocol documents:
Prot_000.pdf: 
 
 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
 
According to template: QSD-003152 VERSION N°3.0 (04-FEB-2016) 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL NO. 02 
 
COMPOUND: Renvela® /sevelamer carbonate/GZ419831  
A randomized, double blind, parallel group study for assessing the efficacy and 
safety of Renvela® tablets for the treatment of hyperphosphatemia in patients with 
chronic kidney disease not on dialysis versus placebo (RECOVER Study)  
STUDY NUMBER: EFC14011 
STUDY NAME: RECOVER Study 
VERSION DATE / STATUS: Approval date (13-Apr-2018) / Approved 
Protocol Amendment 02 
Version number: 1 (electronic 1.0) 
Date : 13-Apr-2018 
Amended Clinical Trial  Protocol 01 
Version number: 1 (electronic 1.0) 
Date : 13-Dec-2017 
Protocol Amendment 01 
Version number: 1 (electronic 1.0) 
Date : 13-Dec-2017 
Clinical Trial Protocol 
Version number: 1 (electronic 1.0) 
Date : 07-Nov-2014 
EudraCT 
Not applicable 
IND Number(s) 
Not applicable 
Version Number: 
1  
WHO universal trial number 
U1111-1161-9850 
Date: 
13-Apr-2018 
Total number of pages: 
69 
 
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NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
  
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
 
Company: 
Address: 
 
 
 
 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
  
 
 
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CLINICAL TRIAL SUMMARY 
COMPOUND: 
Renvela®/sevelamer 
carbonate/GZ419831 
STUDY No: EFC14011  
STUDY NAME : RECOVER Study 
TITLE 
A randomized, double blind, parallel group study for assessing the efficacy and 
safety of Renvela® tablets for the treatment of hyperphosphatemia in patients 
with chronic kidney disease not on dialysis versus placebo 
INVESTIGATOR/TRIAL LOCATION 
China only 
PHASE OF DEVELOPMENT 
III 
STUDY OBJECTIVE(S) 
 
Primary Objective 
x 
The primary objective of this study is to demonstrate efficacy of 
Renvela® tablets in the reduction of serum phosphorus in 
hyperphosphatemia in patients with chronic kidney disease (CKD) not 
on dialysis. 
Secondary Objective(s) 
x 
To document the efficacy of Renvela tablets in the reduction of serum 
lipids (total cholesterol and low-density lipoprotein cholesterol 
[LDL-C]). 
x 
To document the efficacy of Renvela tablets in the reduction of 
calcium-phosphorus product. 
x 
To document the efficacy of Renvela tablets in the reduction of intact 
parathyroid hormone (iPTH). 
x 
To document the efficacy of Renvela tablets in proportion of patients 
reaching the target serum phosphorus level (4.6 mg/dL [1.49 mmol/L], 
inclusive). 
x 
To evaluate safety of Renvela tablets. 
STUDY DESIGN 
This is a randomized, double blind, parallel group, dose titration study to 
evaluate efficacy and safety of Renvela tablets versus placebo. This study is 
divided into 3 periods: Screening Period (for patients who are not on phosphate 
binder[s] at Screening Visit 1, the Screening Period is up to 10 days; for patients 
who are on phosphate binder[s] at Screening Visit 1, a 2-week Washout period 
is needed before Post-Washout Screening Visit 1a [The time window of V1 and 
V1a is up to 10 days, respectively. However, the total time window of V1 and 
V1a should not exceed 14 days to ensure the total duration of screening period 
is up to 4 weeks), Treatment Period (8 weeks) and Post-treatment Period 
(2 weeks). 
Hyperphosphatemia patients with CKD not on dialysis will be screened for 
eligibility. Eligible patients will be randomized 1:1 to Renvela tablets or placebo 
arm. Stratification factor is screening serum phosphorus (5.5 - 6.0 mg/dL [1.78 
– 1.94 mmol/L] and >6.0 mg/dL [1.94 mmol/L]). For eligible patients who are not 
taking phosphate binder(s) at screening visit, serum phosphorus at V1 will be 
used for stratification. For eligible patients who are taking phosphate binder(s) at 
screening visit, serum phosphorus at V1a will be used for stratification. 
STUDY POPULATION  
Main selection criteria 
Chronic kidney disease has been defined according to the criteria: 
1. 
Kidney damage 3 months, as defined by structural or functional 
abnormalities of the kidney, with or without decreased Glomerular 
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Filtration Rate (GFR), manifest by either: 
x 
Pathological abnormalities; or 
x 
Markers of kidney damage, including abnormalities in the composition 
of the blood or urine, or abnormalities in imaging tests. 
2. 
GFR <60 mL/min/1.73 m2 for 3 months, with or without kidney 
damage.  
Inclusion Criteria: 
I 01. 
Patients with chronic kidney disease who have not been on dialysis, 
and are not expected to begin dialysis, or renal transplantation in the 
next 4 months from the Screening Visit. 
I 02. 
Have serum phosphorus measurement 5.5 mg/dL (1.78 mmol/L) at 
Screening Visit (if patients are not on phosphate binder[s] at Screening 
Visit) OR at the end of Washout Period (if patients are on phosphate 
binder[s] at Screening Visit). 
I 03. 
Have the following laboratory measurements at Screening Visit: 
x 
25-hydroxy vitamin D 5 ng/mL  
x 
iPTH 800 pg/mL. 
I 04. 
Signed written informed consent.  
Exclusion Criteria : 
E 01. 
Men or women below 18 years of age. 
E 02. 
Is not of the level of understanding and willingness to cooperate with 
all visits and procedures, as described in the study protocol. 
E 03. 
Not yet received CKD diet education before Screening Visit. 
E 04. 
Not willing and not able to avoid changes to diet during the study. 
E 05. 
Not willing or not able to maintain screening doses of lipid lowering 
medication, 1, 25 dihydroxy vitamin D, and/or cinacalcet for the 
duration of the study, except for safety reasons. 
E 06. 
Not willing or not able to avoid antacids and phosphate binders 
containing aluminium, magnesium, calcium or lanthanum for the 
duration of the study unless prescribed as an evening calcium 
supplement. 
E 07. 
Have participated in any other investigational drug studies within 
30 days or 5 half-lives, whichever is longer, prior to Screening Visit. 
E 08. 
Have known hypersensitivity to sevelamer or any constituents of 
Renvela tablets. 
E 09. 
Have bowel obstruction, active dysphagia, swallowing disorder, a 
predisposition to or current bowel obstruction, ileus, or severe 
gastrointestinal motility disorders including severe constipation. 
E 10. 
Using or plan to use anti-arrhythmic or anti-seizure medications for 
arrhythmia or seizure disorders. 
E 11. 
Is pregnant or breast-feeding. 
E 12. 
If the patient is female, and of childbearing potential (such as pre-
menopausal and not surgically sterile, postmenopausal women who 
are amenorrheic for less than12 months), is not willing to use an 
effective contraceptive method throughout the study. 
E 13. 
Have any condition, which in the opinion of the investigator would 
prohibit the patient’s inclusion in the study. 
  
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Total expected number of patients 
Expected number of sites: 
Approximately 202 patients will be randomized. 
Approximately 20-40 sites will join this study. 
STUDY TREATMENT(s) 
 
Investigational medicinal product(s) 
Formulation 
Renvela® (sevelamer carbonate) or matching placebo 
800 mg/tablet 
Route(s) of administration 
Taken orally with meal 
Dose regimen 
The starting dose of the study treatment is 1 tablet (if serum phosphorus is 
between 5.5 – 7.5 mg/dL [inclusive] at screening) or 2 tablets (if serum 
phosphorus is >7.5 mg/dL at screening) of Renvela or placebo 3 times per day 
(TID) with meals. For eligible patients who are not taking phosphate binder(s) at 
screening visit, serum phosphorus at V1 will be used for determination of the 
starting dose. For eligible patients who are taking phosphate binder(s) at 
screening visit, serum phosphorus at V1a will be used. 
In order to adjust the deviation of starting dose based on phosphorus at 
screening, after the phosphorus result at V2 is received from the central 
laboratory, a dose adjustment phone call at V2a (as soon as possible once 
serum phosphorus at V2 is available) will be made by the investigator to instruct 
patients to adjust their IMP starting dose, if dose adjustment is needed. The 
adjusted dose at V2a is 1 tablet (if serum phosphorus is 7.5 mg/dL at V2) or 
2 tablets (if serum phosphorus is >7.5 mg/dL at V2) of Renvela or placebo 
3 times per day (TID) with meals.  
During the Treatment Period, patients return to the investigative site every 
2 weeks. Samples for laboratory measurements are collected at each site visit. 
After the results are received from the central laboratory, the serum phosphorus 
results are evaluated. If the serum phosphorus is 4.6 mg/dL (1.49 mmol/L), 
the patient is to be instructed by the investigator to increase their study 
treatment dose by 1 tablet TID with meals. If the serum phosphorus is 
<2.7 mg/dL (<0.87 mmol/L), the patient is to be instructed by the investigator to 
decrease their study treatment dose by 1 tablet TID with meals. Therefore, the 
potential maximal dose could be up to 15 tablets a day. 
At the End of Treatment Period, study treatment is stopped and patients will be 
followed up for 2 weeks. 
Noninvestigational medicinal 
product(s) (if applicable) 
Native Vitamin D  
Formulation 
Drops 
Route(s) of administration 
Taken orally  
Dose regimen 
400 IU/day 
ENDPOINT(S) 
 
Primary Endpoint: 
The change from baseline in serum phosphorus level at Week 8 
Secondary Endpoint(s): 
x 
The change from baseline in total cholesterol at Week 8 
x 
The change from baseline in LDL-C at Week 8 
x 
The change from baseline in calcium-phosphorus product at Week 8 
x 
The change from baseline in iPTH level at Week 8 
x 
Percentage of patients reaching the target serum phosphorus level 
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(4.6 mg/dL [1.49 mmol/L], inclusive) at Week 8 
x 
The change from baseline in serum phosphorus level at Week 4 
Safety Endpoint(s): 
x 
Proportion of patients with adverse events 
x 
Clinically significant changes in vital signs and clinical laboratory 
parameters 
ASSESSMENT SCHEDULE 
V1 (Week -1.5 [Day -10 to Day -1] for patients not on phosphate binder[s]; 
Week -4 [Day-28 to Day -19] for patients on phosphate binder[s]): Screening 
Visit. 
V1a (Week -1.5 [Day -10 to Day -1] for patients on phosphate binder[s]): 
Post-Washout Visit for patients on phosphate binder(s) at Screening Visit. 
V2 (Day 1): Randomization; first Renvela or placebo tablets administration; 
baseline.  
V2a (phone call visit): Patients will be contacted by phone if adjustment of the 
starting dose of IMP based on serum phosphorus level at V2 is needed. 
V3 (Week 2), V4 (Week 4) and V5 (Week 6): Efficacy and safety assessments. 
V3a, V4a and V5a (phone call visits): Patients will be contacted by phone if dose 
titration based on serum phosphorus level of V3, V4 and V5 is needed. 
V6 (Week 8): End of treatment, last Renvela or placebo tablets administration. 
V7 (Week 10): Follow up visit. 
For all visits (except phone call visits), a time frame of ±3 days is acceptable 
using Day 1 as reference.  
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
To detect a difference of 1 mg/dL in the change from baseline in serum 
phosphorus between Renvela and placebo at Week 8, 86 patients per arm will 
provide the power of 90% assuming the common standard deviation is 2 mg/dL 
(based on data observed in prior study SVCARB03808) with a 2-sided test at 
the 5% significance level. With expected dropout rate of 15%, the final total 
sample size will be 202 patients (101 patients in each arm). 
Analysis Population: 
x 
Modified Intention To Treat (mITT) population: The mITT population 
consists of all patients who are randomized, receive at least one dose 
of investigational medicinal product (IMP), and have both a baseline 
assessment and at least one post-baseline assessment of phosphorus 
measure. 
x 
Safety population: The safety population consists of all randomized 
patients who receive at least one dose of IMP. 
Primary Analysis: 
The primary efficacy variable (the change from baseline in serum phosphorus at 
Week 8) will be compared between Renvela and placebo using stratified 
Wilcoxon rank sum tests considering randomization strata (screening serum 
phosphorus [5.5 – 6.0 mg/dL or >6.0 mg/dL]).  
Analysis of secondary endpoints 
Change in total cholesterol, LDL-C, calcium-phosphorus product, iPTH and 
percentage of patients reaching the target serum phosphorus level (4.6 mg/dL 
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[1.49 mmol/L], inclusive) at Week 8, and change in serum phosphorus at 
Week 4 will be analyzed using stratified Wilcoxon rank sum tests using 
randomization strata (screening serum phosphorus [5.5 – 6.0 mg/dL or 
>6.0 mg/dL]). 
Percentage of patients reaching the target serum phosphorus level will be 
compared by treatment assignment (Renvela or placebo) using a 
Cochran-Mantel-Haensel method stratified by randomization strata (screening 
serum phosphorus [5.5 – 6.0 mg/dL or >6.0 mg/dL]), the odds ratio and 95% 
confidence intervals will be calculated. 
DURATION OF STUDY PERIOD (per 
patient)  
Study duration is up to 14 weeks. 
x 
Screening Period is up to 4 weeks (a 2-week Washout Period is only 
applicable to eligible patients taking phosphate binder[s] at Screening 
Visit); 
x 
Treatment Period is 8 week; 
x 
Post-treatment Period is 2 weeks. 
STUDY COMMITTEES 
Steering Committee:  
 Yes    
 No 
Data Monitoring Committee: 
 Yes    
 No 
Adjudication Committee:  
 Yes    
 No 
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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
 
x 
R=Randomization 
x 
Screening criteria: 
 
CKD patients not on dialysis 
 
Serum phosphorus level 5.5 mg/dL (1.78 mmol/L) 
x 
Stratification factor, at the time of randomization, is screening serum phosphorus (5.5 – 6.0 mg/dL [1.78 – 1.94 mmol/L] and >6.0 mg/dL [1.94 mmol/L]). For eligible patients who are not taking phosphate 
binder(s) at screening visit, serum phosphorus at V1 will be used for stratification. For eligible patients who are taking phosphate binder(s) at screening visit, serum phosphorus at V1a will be used for 
stratification. 
x 
Assessment of the primary efficacy (change from baseline in serum phosphorus level) endpoint is at Week 8. 
x 
Wash out period is only for patients on phosphate binder(s) at screening. Patients not on phosphate binder(s) would proceed directly to the start of the 8-week treatment period (Day 1). 
x 
During the Treatment Period, patients return to the investigative site every 2 weeks. Samples for laboratory measurements are collected at each site visit. After the results are received from the central 
laboratory, the serum phosphorus results are evaluated. Investigator will be informed by the IVRS/IWRS for dose titration. If the serum phosphorus is 4.6 mg/dL (1.49 mmol/L), the patient is to be 
instructed by the investigator to increase their study treatment dose by 1 tablet TID with meals. If the serum phosphorus is <2.7 mg/dL (<0.87 mmol/L), the patient is to be instructed by the investigator to 
decrease their study treatment dose by 1 tablet TID with meals.  
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c Chemistry panel at Visits 2 and 6/End of Treatment: Calcium (adjusted for albumin), albumin, calcium-phosphorus product, chloride, bicarbonate, uric acid, sodium, potassium, glucose, blood urea nitrogen, liver 
function tests (ALT and AST) and creatinine. According to the discretion of the Investigator for safety concern, the relevant laboratory parameters (eg, serum potassium) can be tested at any scheduled visit or 
unscheduled visit if necessary. 
d Chemistry panel at Visits 3, 4, and 5: Calcium (adjusted for albumin), albumin, calcium-phosphorus product, chloride, and bicarbonate. 
e Lipid panel includes total cholesterol, LDL-C, HDL-C, non-HDL-C and triglycerides. 
f 
After the phosphorus result at V2 is received from the central laboratory, a dose adjustment phone call at V2a (as soon as possible once V2 serum phosphorus is available) will be made by the investigator to 
instruct patients to adjust their starting IMP dosage, if dose adjustment is needed. The adjusted dose is 1 tablet (if serum phosphorus is 7.5 mg/dL at V2) or 2 tablets (if serum phosphorus is >7.5 mg/dL at V2) of 
Renvela or placebo 3 times per day (TID) with meals. A confirmation phone call (a second phone call, in addition to the dose adjustment phone call) will be made a working day after dose adjusting phone call, in 
order to remind patients their correct dosage. 
g If dose titration is required, a dose titration phone call will be made by the investigator to patients as soon as possible once serum phosphorus result is available. A confirmation phone call (a second phone call, in 
addition to the dose titration phone call) will be made a working day after dose titration phone call (a total of two phone calls), in order to remind subjects their correct dosage. However, no phone calls will be 
required if dose titration is not required. 
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2 
TABLE OF CONTENTS 
 
1 
FLOW CHARTS...............................................................................................................................8 
1.1 
GRAPHICAL STUDY DESIGN ........................................................................................................8 
1.2 
STUDY FLOW CHART ....................................................................................................................9 
2 
TABLE OF CONTENTS ................................................................................................................13 
3 
LIST OF ABBREVIATIONS ..........................................................................................................18 
4 
INTRODUCTION AND RATIONALE.............................................................................................19 
5 
STUDY OBJECTIVES ...................................................................................................................22 
5.1 
PRIMARY.......................................................................................................................................22 
5.2 
SECONDARY ................................................................................................................................22 
6 
STUDY DESIGN ............................................................................................................................23 
6.1 
DESCRIPTION OF THE PROTOCOL...........................................................................................23 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................24 
6.2.1 
Duration of study participation for each patient .............................................................................24 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................24 
6.3 
INTERIM ANALYSIS......................................................................................................................25 
6.4 
STUDY COMMITTEE ....................................................................................................................25 
7 
SELECTION OF PATIENTS..........................................................................................................26 
7.1 
INCLUSION CRITERIA..................................................................................................................26 
7.2 
EXCLUSION CRITERIA ................................................................................................................26 
7.2.1 
Exclusion criteria related to study methodology ............................................................................26 
7.2.2 
Exclusion criteria related to the current knowledge of Sanofi compound......................................27 
7.2.3 
Additional exclusion criteria during or at the end of screening or washout period before 
randomization.................................................................................................................................28 
8 
STUDY TREATMENTS .................................................................................................................29 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ..........................................................................29 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) ..................................................................29 
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8.3 
BLINDING PROCEDURES............................................................................................................29 
8.3.1 
Methods of blinding........................................................................................................................29 
8.3.2 
Randomization code breaking during the study.............................................................................30 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................30 
8.5 
PACKAGING AND LABELING ......................................................................................................31 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................31 
8.7 
RESPONSIBILITIES ......................................................................................................................31 
8.7.1 
Treatment accountability and compliance......................................................................................32 
8.7.2 
Return and/or destruction of treatments ........................................................................................32 
8.8 
CONCOMITANT MEDICATION.....................................................................................................32 
8.8.1 
Prohibited concomitant medications ..............................................................................................33 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................34 
9.1 
PRIMARY ENDPOINT ...................................................................................................................34 
9.2 
SECONDARY ENDPOINTS ..........................................................................................................34 
9.3 
SAFETY ENDPOINTS ...................................................................................................................34 
9.3.1 
Adverse events ..............................................................................................................................35 
9.3.2 
Laboratory safety variables............................................................................................................35 
9.3.3 
Vital signs.......................................................................................................................................35 
10 
STUDY PROCEDURES ................................................................................................................36 
10.1 
VISIT SCHEDULE..........................................................................................................................36 
10.1.1 
Screening Period............................................................................................................................37 
10.1.1.1 Screening Visit (Visit 1/Week -4 /Day -28 up to -19 for patients on phosphate binder[s] and 
Visit 1/Week -1.5/Day -10 to -1 for patients not on phosphate binder[s])......................................37 
10.1.1.2 Post-Washout visit (Visit 1a/Week -1.5/Day -10 to -1)...................................................................38 
10.1.2 
Double-Blind Treatment Period (Study Site Visits)........................................................................39 
10.1.2.1 Randomization Visit (Visit 2/Week 0/Day 1) ..................................................................................39 
10.1.2.2 Visit 2a: Phone Call Visit................................................................................................................40 
10.1.2.3 Visit 3/Week 2, Visit 4/Week 4 and Visit 5/Week 6 (Day 15, 29 and 43 ± 3).................................40 
10.1.2.4 Visit 3a/Visit 4a/Visit 5a: Phone Call Visits ....................................................................................41 
10.1.2.5 Visit 6/Week 8 (Day 57 ± 3): End of Treatment Visit .....................................................................41 
10.1.3 
Post-Treatment Period...................................................................................................................41 
10.1.3.1 Follow-Up Visit (Visit 7/ Week 10/ Day 71 ± 3) ..............................................................................41 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................42 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................43 
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10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) ...........................43 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ...........................43 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................43 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................44 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................44 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................45 
10.4.1 
Definitions of adverse events.........................................................................................................45 
10.4.1.1 Adverse event ................................................................................................................................45 
10.4.1.2 Serious adverse event ...................................................................................................................45 
10.4.1.3 Adverse event of special interest...................................................................................................46 
10.4.2 
General guidelines for reporting adverse events ...........................................................................47 
10.4.3 
Instructions for reporting serious adverse events ..........................................................................47 
10.4.4 
Guidelines for reporting adverse events of special interest...........................................................48 
10.4.5 
Guidelines for management of specific laboratory abnormalities ..................................................48 
10.5 
OBLIGATIONS OF THE SPONSOR .............................................................................................49 
10.6 
SAFETY INSTRUCTIONS .............................................................................................................49 
10.7 
ADVERSE EVENTS MONITORING..............................................................................................49 
11 
STATISTICAL CONSIDERATIONS..............................................................................................50 
11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................50 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................50 
11.3 
ANALYSIS POPULATIONS...........................................................................................................51 
11.3.1 
Efficacy populations .......................................................................................................................51 
11.3.1.1 Modified intent-to-treat population .................................................................................................51 
11.3.2 
Safety population ...........................................................................................................................51 
11.4 
STATISTICAL METHODS .............................................................................................................51 
11.4.1 
Extent of study treatment exposure and compliance.....................................................................51 
11.4.1.1 Extent of investigational medicinal product exposure....................................................................51 
11.4.1.2 Compliance ....................................................................................................................................51 
11.4.2 
Analyses of efficacy endpoints.......................................................................................................52 
11.4.2.1 Analysis of primary efficacy endpoint(s) ........................................................................................52 
11.4.2.2 Analyses of secondary efficacy endpoints.....................................................................................52 
11.4.2.3 Multiplicity considerations ..............................................................................................................53 
11.4.3 
Analyses of safety data..................................................................................................................53 
11.4.3.1 Adverse events ..............................................................................................................................54 
11.4.3.2 Laboratory data and vital signs......................................................................................................54 
11.5 
INTERIM ANALYSIS......................................................................................................................54 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................55 
12.1 
ETHICAL AND REGULATORY STANDARDS ..............................................................................55 
12.2 
INFORMED CONSENT .................................................................................................................55 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) ..............55 
13 
STUDY MONITORING...................................................................................................................57 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).......................................................................57 
13.2 
RESPONSIBILITIES OF THE SPONSOR.....................................................................................57 
13.3 
SOURCE DOCUMENT REQUIREMENTS....................................................................................57 
13.4 
USE AND COMPLETION OF ELECTRONIC CASE REPORT FORMS (E-CRFS) AND 
ADDITIONAL REQUEST ...............................................................................................................58 
13.5 
USE OF COMPUTERIZED SYSTEMS..........................................................................................58 
14 
ADDITIONAL REQUIREMENTS...................................................................................................59 
14.1 
CURRICULUM VITAE....................................................................................................................59 
14.2 
RECORD RETENTION IN STUDY SITES ....................................................................................59 
14.3 
CONFIDENTIALITY .......................................................................................................................59 
14.4 
PROPERTY RIGHTS.....................................................................................................................60 
14.5 
DATA PROTECTION.....................................................................................................................60 
14.6 
INSURANCE COMPENSATION....................................................................................................60 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES .................................60 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................61 
14.8.1 
By the Sponsor...............................................................................................................................61 
14.8.2 
By the Investigator .........................................................................................................................61 
14.9 
CLINICAL TRIAL RESULTS ..........................................................................................................62 
14.10 
PUBLICATIONS AND COMMUNICATIONS .................................................................................62 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ..........................................................................63 
16 
BIBLIOGRAPHIC REFERENCES.................................................................................................64 
17 
APPENDICES................................................................................................................................66 
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APPENDIX A 
GUIDANCE FOR THE FOLLOW-UP OF LABORATORY ABNORMALITIES BY 
SANOFI..........................................................................................................................................66 
 
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3 
LIST OF ABBREVIATIONS 
 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
AST: 
aspartate aminotransferase 
BP: 
blood pressure 
BUN: 
blood urea nitrogen  
CBC: 
complete blood count 
CFDA: 
China Food and Drug Administration 
CKD: 
Chronic Kidney Disease 
CKD-MBD: 
Chronic Kidney Disease - Mineral and Bone Disorder 
DBTP: 
double blind treatment period 
DRF: 
Discrepancy Resolution Form  
e-CRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration rate 
EMA: 
European Medicine Agency 
GCP: 
good clinical practice 
GFR: 
Glomerular Filtration Rate 
HDL-C: 
high-density lipoprotein cholesterol 
HLGT: 
high level group term  
HLT: 
high level term  
HR: 
heart rate 
IMP: 
investigational medicinal product  
iPTH: 
intact parathyroid hormone 
IVRS: 
interactive voice response system 
IWRS: 
interactive web response system  
KDIGO: 
Kidney Disease Improving Global Outcomes  
LDL-C: 
low-density lipoprotein cholesterol 
LLT: 
lowest level term  
LOCF: 
Last Observation Carried Forward 
MedDRA: 
Medical Dictionary for Regulatory Activities  
mITT: 
Modified Intention To Treat  
non-HDL-C: 
non-high-density lipoprotein cholesterol 
PCSA: 
potentially clinically significant abnormality 
PT: 
preferred term  
PTH: 
parathyroid hormone  
SAP: 
statistical analysis plan 
SD: 
standard deviation  
SOC: 
system organ class  
TEAE: 
treatment emergent adverse event 
TID: 
3 times per day  
ULN: 
upper limit of normal range 
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4 
INTRODUCTION AND RATIONALE 
Chronic kidney disease (CKD) is a progressive disease in which over time the filtering capacity of 
the kidney gradually diminishes until renal replacement therapy is required. Based on a recently 
published, and also the first China cross-sectional survey, prevalence of CKD in China is 10.8%, 
which accounts for approximately 119.5 million patients (1). This estimated prevalence of CKD 
in China is similar to that reported for United States (10%) and Japan (13%) (2, 3). The Kidney 
Disease Improving Global Outcomes (KDIGO) recognizes the causal role of hyperphosphatemia 
and secondary hyperparathyroidism in Chronic Kidney Disease-Mineral and Bone Disorder 
(CKD-MBD), and its relation to increased morbidity and mortality (4). Hyperphosphatemia is an 
independent risk factor for cardiovascular mortality and all-cause mortality in CKD patients (5). 
Hyperphosphatemia directly stimulates parathyroid hormone (PTH) secretion. It also reduces 
serum calcium level, which in turn stimulates PTH secretion. High PTH reduces tubular 
reabsorption of phosphorus and returns serum phosphorus toward normal. It increases bone 
turnover, enhances bone resorption, and releases calcium and phosphorus into the circulation, 
causing hypercalcemia and aggravating hyperphosphatemia. High phosphate results in inhibition 
of 1E-hydroxylase and then contributing to vitamin D deficiency. In CKD, high PTH, high 
phosphorus, low calcium levels, and vitamin D deficiency are all part of the disturbed mineral 
metabolism that is a common complication of these patients.  
CKD is classified (Stages 1-5) on the basis of the presence of kidney damage and the glomerular 
filtration rate (GFR). Hyperphosphatemia manifests prior to CKD Stage 5. Thus, there is an 
opportunity via phosphate binder therapy to provide therapeutic benefit to CKD patients prior to 
dialysis. The approach of identifying and treating early CKD is recommended by multiple clinical 
guidelines (4). 
Renvela®, sevelamer carbonate, a non-absorbed, calcium free phosphate binder, is developed as a 
pharmaceutical alternate to sevelamer hydrochloride. Sevelamer carbonate is an anion exchange 
resin with the same polymeric structure as sevelamer hydrochloride where carbonate is an 
alternative counterion to chloride. Replacement of the counterion with carbonate provides alkali 
supplementation to CKD patients who typically develop metabolic acidosis as a result of 
underlying kidney insufficiency. While the counterions differ for the two salts, the polymer itself, 
the active moiety responsible for binding of phosphate, is the same.  
The multiple groups in sevelamer carbonate become protonated in the stomach, and thus 
positively charged, and bind negatively charged ions in the intestine such as phosphate that are 
liberated during the digestive process. Phosphate sequestered by the polymer is not absorbed into 
the blood, but passes through the intestine and is excreted in the feces (4).  
Renvela tablet is approved by China Food and Drug Administration (CFDA) in June 2013 to 
control hyperphosphatemia in CKD patients on dialysis based on SVCARB03808 study (6). This 
randomized, double-blind, dose-titration study compared Renvela with placebo over 8 weeks’ 
duration in Chinese CKD patients on haemodialysis. Patients were required to be using 
calcium-based binders prior to study start. In all, 205 patients were randomized (Renvela, n = 135; 
placebo, n = 70). The mean serum phosphorus decreased significantly in patients treated with 
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Renvela (change -2.14 ±1.98 mg/dL) but remained persistently elevated with placebo 
(change -0.19 ±1.76 mg/dL, P <0.0001). When compared with placebo, Renvela treatment 
resulted in statistically significant greater mean reductions from baseline in serum total cholesterol 
(-17.1% versus -3.3%). Renvela was well tolerated with 96% adherence compared with 97% 
adherence in the placebo arm. Overall, adverse events experienced by patients in Renvela and 
placebo treatment groups were similar and consistent with their underlying renal disease.  
In Europe, Renvela is approved to treat hyperphosphatemia in not-on-dialysis population based on 
SVCARB00105 (7). This was an open-label, dosage-titration study. Patients with serum 
phosphorus 5.5 mg/dL were enrolled (n = 46). Renvela was administered for 8 weeks. The 
primary efficacy parameter was the change from baseline in serum phosphorus. Renvela treatment 
resulted in a statistically significant decrease in mean serum phosphorus levels from baseline to 
end of treatment. A total of 75% of patients with CKD Stage 4 and 70% of patients with CKD 
Stage 5 achieved the target serum phosphorus (2.7 ~ 4.6 mg/dL) at the end of treatment. 
Sevelamer carbonate was well tolerated in this population.  
Giving sevelamer’s mode of action, Renvela should be taken three times a day with meals. No 
separate dose-response studies were performed with Renvela to be used in pre-dialysis CKD 
patients, or CKD patients on dialysis. The dose was based on the titrated dose of sevelamer 
hydrochloride obtained during the run-in period (GD3-163-201 and SVCARB00205) or the 
highest starting dose of sevelamer hydrochloride (GD3-199-301). The starting dose of sevelamer 
hydrochloride ranges from 2.4 g/day to 4.8 g/day, and is titrated at regular intervals based on 
serum phosphorus levels until an acceptable serum phosphorus level is reached (8). Based on 
totality of Renvela and sevelamer hydrochloride registration study data, the recommended starting 
dose of Renvela is 2.4 g/day to 4.8 g/day with meals depending on serum phosphorus level. With 
Renvela immediate effect on phosphorus absorption in intestine, it is expected that 
pharmacodynamic steady state is reached fairly quickly. In addition, hyperphosphatemia in CKD 
patients not on dialysis is not a therapeutic emergency. Considering both, it is decided to titrate 
dose with an interval of 2 weeks from administrative convenience aspect. In CKD patients on 
dialysis, the maximum dose studied was 14 g of Renvela as in United States and European Union 
label (9, 10). There is not yet approved drug covers not-on-dialysis population in China. This 
China registration study is designed to evaluate the benefits and risks of Renvela tablet to control 
hyperphosphatemia in CKD patients not on dialysis. 
Patient population selection for this study is partially based on SVCARB00105. Therefore CKD 
patients not on dialysis with serum phosphorus 5.5 mg/dL are the target population (7). Target 
serum phosphorus level follows China Society of Nephrology recommendation (>4.5 mg/dL) (11). 
Due to a possible effect on the absorption of vitamin D, a fat-soluble vitamin, “patient with 
25-hydroxy vitamin D 5 ng/mL” will be one of the eligibility criteria.  In addition, previous 
studies had shown to have favorable effects on the lipid profile. Nevertheless, we endeavor 
patients continue their screening doses of lipid lowering medication, 1, 25-dihydroxy vitamin D, 
and/or cinacalcet for the duration of the study as in SVCARB00105 study. 
Duration of screening is up to 4 weeks. For patients who are not taking phosphate binder(s) at 
screening visit, up to 10 days Screening Period is allowed for central laboratory to report serum 
phosphorus, intact parathyroid hormone (iPTH) and 25-hydroxy vitamin D levels. For the ones 
who are taking phosphate binder(s), a 2-week Washout is to allow effect of previous phosphate 
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binder(s) subside before testing baseline serum phosphorus. The 8-week Treatment Period is set to 
allow Renvela reaches stable and full serum phosphorus reduction (6, 7, 12, 13, 14, 15).  
Evidence model utilized in KDIGO CKD–MBD Guideline regards serum phosphorus as an 
appropriate laboratory surrogate outcome (4). This viewpoint and precedence from European 
Medicine Agency (EMA) would support using serum phosphorus control as the primary endpoint.  
Placebo is considered as an appropriate control as giving no phosphate binder is indicated to treat 
hyperphosphatemia in CKD pre-dialysis patients in China. Even calcium carbonate and calcium 
acetate are used in clinical as phosphate binders, there is no well-designed randomized control 
trials assessing carbonate phosphate binders’ efficacy and safety in not-on-dialysis population. 
Calcium-based phosphate binders do not meet the requirement of a suitable active comparator 
treatment as indicated in ICH E9 Section 3.3.2 and ICH E10 2.4.1. 
Objective of this study is to obtain new indication of Renvela in China. Per China regulation, 
efficacy and safety in a minimum of 200 Chinese patients (100 patients in each arm) is required. 
This gives a power of 90% for detecting a difference of 1 mg/dL in serum phosphorus. Based on 
recent meta-analysis of serum level of phosphorus and risk of death and cardiovascular disease in 
CKD population, all-cause mortality and cardiovascular mortality increased 18% and 10%, 
respectively, for every 1 mg/dL increase in serum phosphorus (5). This is hence considered 
clinically relevant. 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
x 
The primary objective of this study is to demonstrate efficacy of Renvela tablets in the 
reduction of serum phosphorus in hyperphosphatemia in patients with CKD not on 
dialysis. 
5.2 
SECONDARY 
x 
To document the efficacy of Renvela tablets in the reduction of serum lipids (total 
cholesterol and low-density lipoprotein cholesterol [LDL-C]). 
x 
To document the efficacy of Renvela tablets in the reduction of calcium-phosphorus 
product. 
x 
To document the efficacy of Renvela tablets in the reduction of iPTH. 
x 
To document the efficacy of Renvela tablets in proportion of patients reaching the target 
serum phosphorus level (4.6 mg/dL [1.49 mmol/L], inclusive). 
x 
To evaluate safety of Renvela tablets. 
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6 
STUDY DESIGN 
This is a phase III, multi-center, randomized, double blind, placebo-controlled, balanced 
(1:1, Renvela:placebo), parallel-group study to evaluate the efficacy and safety of Renvela versus 
placebo in hyperphosphatemic CKD patients not on dialysis in China.  
Eligible patients who are taking phosphate binder(s) at screening visit will enter a 2-week 
phosphate binder washout period before V1a.  Eligible patients who are not taking phosphate 
binder(s) at screening visit will proceed directly to the start of the 8-week treatment period 
(Day 1).  
Randomization will be stratified according to screening serum phosphorus (5.5 – 6.0 mg/dL 
[1.78 – 1.94 mmol/L] and >6.0 mg/dL [1.94 mmol/L]). For eligible patients who are not taking 
phosphate binder(s) at screening visit, serum phosphorus at V1 will be used for stratification. For 
eligible patients who are taking phosphate binder(s) at screening visit, serum phosphorus at V1a 
will be used for stratification. After randomization, patients will receive double-blind study 
treatment (either Renvela or placebo) over a period of 8 weeks. 
Patients will be followed for 2 weeks after the last visit of the Double Blinded Treatment Period 
(DBTP). 
6.1 
DESCRIPTION OF THE PROTOCOL 
The study consists of 3 periods: screening, double-blind treatment, and follow up. 
x 
Screening period – up to 4 weeks in duration, including a washout period during which 
eligible patients who are taking phosphate binder(s) at screening visit will enter a 2-week 
phosphate binder washout period. Eligible patients who are not taking phosphate binder(s) 
at screening visit will proceed directly to the start of the 8-week treatment period as soon 
as possible once the central laboratory results are received (Day 1).  
x 
Double-blind treatment period – A randomized, double-blind study treatment period of 
8 weeks. The first administration of the investigational medicinal product (IMP) during the 
double-blind period will be done at the site on the day of randomization (Week 0 
[D1] -V2) and as soon as possible after the contact with interactive voice response system 
(IVRS)/interactive web response system (IWRS) for randomization into the study.  
After randomization: 
- 
1 (if serum phosphorus is between 5.5 – 7.5 mg/dL [inclusive] at screening) tablet of 
Renvela or placebo will be taken orally 3 times per day (TID) with meals 
or  
- 
2 (if serum phosphorus is >7.5 mg/dL at screening) tablets of Renvela or placebo will 
be taken orally TID with meals. 
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For eligible patients who are not taking phosphate binder(s) at screening visit, serum 
phosphorus at V1 will be used for determination of the starting dose. For eligible 
patients who are taking phosphate binder(s) at screening visit, serum phosphorus at 
V1a will be used. 
In order to adjust the deviation of starting dose based on phosphorus at screening, after 
the phosphorus result at V2 is received from the central laboratory, a dose adjustment 
phone call at V2a (as soon as possible once serum phosphorus at V2 is available) will 
be made by the investigator to instruct patients to adjust their IMP starting dose, if 
dose adjustment is needed. The adjusted dose at V2a is 1 tablet (if serum phosphorus is 
7.5 mg/dL at V2) or 2 tablets (if serum phosphorus is >7.5 mg/dL at V2) of Renvela 
or placebo 3 times per day (TID) with meals.  
During the Treatment Period, patients return to the investigative site every 2 weeks. 
Samples for laboratory measurements are collected at each site visit. After the results 
are received from the central laboratory, the serum phosphorus results are evaluated. 
Investigator will be informed by the IVRS/IWRS for dose titration. If the serum 
phosphorus is 4.6 mg/dL (1.49 mmol/L), the patient is to be instructed by the 
investigator to increase their study treatment dose by 1 tablet TID with meals. If the 
serum phosphorus is <2.7 mg/dL (<0.87 mmol/L), the patient is to be instructed by the 
investigator to decrease their study treatment dose by 1 tablet TID with meals.  
x 
Post-treatment period – A period of 2 weeks after the end of the DBTP. 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
The study duration includes a screening period of up to 4 weeks, an 8-week DBTP for efficacy 
and safety assessment, and a 2-week post-treatment period for all patients after the last visit of the 
DBTP. 
Thus, the study duration per patient is about 14 weeks (up to 4 weeks screening + 8 weeks DBTP 
+ 2 weeks follow-up). The 2-weeks washout period is only applicable to eligible patients taking 
phosphate binder(s) at screening visit. 
Patients who experience an ongoing SAE or an Adverse Event of Special Interest (AESI), at the 
pre-specified study end-date, should be followed until resolution, stabilization or death, and 
related data will be collected. 
6.2.2 Determination of end of clinical trial (all patients) 
The end of the study is defined as being the last patient last on site visit as scheduled by protocol. 
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6.3 
INTERIM ANALYSIS 
No interim analysis is planned. 
6.4 
STUDY COMMITTEE 
The Steering Committee is composed of hospital-based clinicians (experts in the field of renal, 
and/or nephrologist) with clinical and methodological expertise, working in collaboration with 
Sponsor based scientists. The Steering Committee provides scientific opinions and advice related 
to the conduct, results analysis, and publication strategy for this study to Sanofi and investigators. 
Among its responsibilities, the Steering Committee may/will review blinded study status reports 
from the Sponsor. The Steering Committee members and Sponsor based scientists will participate 
in face-to-face meetings at regular intervals throughout the study and/or in regularly scheduled 
teleconferences. 
Detailed activities and responsibilities of the Steering Committee are described in the Steering 
Committee charter. 
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7 
SELECTION OF PATIENTS 
Chronic kidney disease has been defined according to the criteria: 
1. Kidney damage 3 months, as defined by structural or functional abnormalities of the 
kidney, with or without decreased GFR, manifest by either: 
x 
Pathological abnormalities; or 
x 
Markers of kidney damage, including abnormalities in the composition of the blood or 
urine, or abnormalities in imaging tests. 
2. GFR <60 mL/min/1.73 m2 for 3 months, with or without kidney damage.  
7.1 
INCLUSION CRITERIA 
I 01. Patients with CKD who have not been on dialysis, and are not expected to begin dialysis, 
or renal transplantation in the next 4 months from the Screening Visit. 
I 02. Have serum phosphorus measurement 5.5 mg/dL (1.78 mmol/L) at Screening Visit (if 
patients are not on phosphate binder[s] at Screening Visit) OR at the end of Washout 
Period (if patients are on phosphate binder[s] at Screening Visit). 
I 03. Have the following laboratory measurements at Screening Visit: 
x 
25-hydroxy vitamin D 5 ng/mL 
x 
iPTH 800 pg/mL. 
I 04. Signed written informed consent. 
7.2 
EXCLUSION CRITERIA 
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following 4 subsections:  
7.2.1 Exclusion criteria related to study methodology 
E 01. Men or women below 18 years of age. 
E 02. Any technical/administrative reason that makes it impossible to randomize the patient in 
the study. 
E 03. Is not of the level of understanding and willingness to cooperate with all visits and 
procedures, as described in the study protocol. 
E 04. Not yet received CKD diet education before Screening Visit. 
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E 05. Not willing and not able to avoid changes to diet during the study. 
E 06. Not willing or not able to maintain screening doses of lipid lowering medication, 1, 25 
dihydroxy vitamin D, and/or cinacalcet for the duration of the study, except for safety 
reasons. 
E 07. Not willing or not able to avoid antacids and phosphate binders containing aluminium, 
magnesium, calcium or lanthanum for the duration of the study unless prescribed as an 
evening calcium supplement. 
E 08. Have participated in any other investigational drug studies within 30 days or 5 half-lives, 
whichever is longer, prior to Screening Visit. 
E 09. Conditions/situations such as: 
x 
Patient is the Investigator or any Subinvestigator, research assistant, pharmacist, study 
coordinator, other staff or relative thereof directly involved in the conduct of the protocol. 
x 
Uncooperative or any condition that could make the patient potentially non-compliant to 
the study procedures (for example, patients cannot be contacted by phones as required in 
phone call visits). 
x 
Evidence of active malignancy. 
x 
Not on stable medical condition (for example, but not limited to, active ethanol or drug 
abuse [tobacco use acceptable]; documented poorly controlled diabetes mellitus, poorly 
controlled hypertension, active vasculitis, HIV infection), or has any clinically significant 
medical conditions. 
7.2.2 Exclusion criteria related to the current knowledge of Sanofi compound  
E 10. Have known hypersensitivity to sevelamer or any constituents of Renvela tablets. 
E 11. Have bowel obstruction, active dysphagia, swallowing disorder, a predisposition to or 
current bowel obstruction, ileus, or severe gastrointestinal motility disorders including 
severe constipation.  
E 12. Using or plan to use anti-arrhythmic or anti-seizure medications for arrhythmia or seizure 
disorders. 
E 13. Is pregnant or breast-feeding. 
E 14. If the patient is female, and of childbearing potential (such as pre-menopausal and not 
surgically sterile, postmenopausal women who are amenorrheic for less than12 months), is 
not willing to use an effective contraceptive method throughout the study.  
E 15. Have any condition, which in the opinion of the investigator would prohibit the patient’s 
inclusion in the study. 
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7.2.3 Additional exclusion criteria during or at the end of screening or washout period 
before randomization 
E 16. Patient who has withdrawn consent before randomization (starting from signed informed 
consent form). 
E 17. Have serum phosphorus measurement <5.5 mg/dL (1.78 mmol/L) at Screening Visit (if 
patients are not on phosphate binder[s] at Screening Visit) OR at the end of Washout 
Period (if patients are on phosphate binder[s] at Screening Visit). 
Re-screening:  
Patients who are screened and failed to fulfill the inclusion or exclusion criteria could be 
re-screened if their screening central lab results are as follows:  
x 
serum phosphorus levels >4.6 mg/dL (1.49 mmol/L) 
Re-screen is not advised within 1 month of the prior screening attempt. All patients re-screened 
must sign a consent form prior to any re-screening activities taking place. The number of 
re-screening attempts will be limited to two. Careful consideration is necessary as to the 
appropriateness of multiple re-screening attempts. Patients should only be re-screened if their 
condition has progressed such that the treating physician believes that they may now be eligible 
and the patient is a willing participant. Patients who fail screening following wash out from their 
usual phosphate binder(s) may be prescribed these again at the physician’s discretion. However 
the dose should be considered to be stabilized by the investigator prior to re-screening.  
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
Investigational medicinal product is either Renvela or placebo for Renvela. Renvela (sevelamer 
carbonate) is chemically known as poly (allylamine-co-N,N’-diallyl-1,3-diamino-2-hydroxypropane), 
carbonate salt. It is a polymeric anion exchange resin where the amines in the polymer exist in a 
protonated form and bind to negatively charged phosphates. The 800 mg tablet contains the active 
ingredient sevelamer carbonate and the inactive ingredients are hypromellose, diacetylated 
monoglyceride, microcrystalline cellulose, zinc stearate, and sodium chloride. Renvela or placebo 
for Renvela will be supplied as a white to off white tablet with no imprinting. Sevelamer 
carbonate tablets and/or matching placebo tablets (IMP) will be supplied in bottles containing 
180 tablets. 
All study medication will be taken orally three times per day with meals from randomization visit 
to end of treatment visit (8 weeks in total). Sufficient liquid should be taken to ensure the tablets 
clear the oral cavity and esophagus. Patients will be instructed not to bite, chew, mix with food, or 
dissolve tablets in water prior to dosing. Patients will be instructed to take the study medication 
with meal. One to five tablets of IMP taken orally three times per day with meals as directed by 
physician titrated to reach a target goal of serum phosphorus 4.6 mg/dL (1.49 mmol/L). Please 
refer to Section 6.1 for dose titration. The potential maximal dose could be up to 15 tablets a day. 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) 
Native vitamin D will be supplied by the Sponsor centrally as the noninvestigational medicinal 
product (NIMP). Patients will be supplemented with a daily dose of 400 IU of native vitamin D to 
be taken orally by drops at bedtime to minimize the effects of dietary absorption of vitamin D that 
may occur with treatment of sevelamer carbonate.  
8.3 
BLINDING PROCEDURES 
8.3.1 Methods of blinding 
Renvela and placebo for Renvela will be provided in identically matched tablet and packaged 
identically which includes labeling to protect the blind. 
Each double-blind treatment kit will be labeled with treatment kit number. The treatment kit 
numbers will be obtained by the Investigator at the time of patient randomization and subsequent 
patient visits scheduled via the IVRS/IWRS that will be available 24 hours-a-day, 7 days-a-week. 
In accordance with the double-blind design, study patients, Investigators and study site personnel 
will remain blinded to study treatment and will not have access to the randomization (treatment 
codes) except under circumstances described in Section 8.3.2.  
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8.3.2 Randomization code breaking during the study 
In case of an adverse event (AE), the code should only be broken in circumstances when 
knowledge of the IMP is required for treating the patient. If possible, a contact should be initiated 
with the Monitoring Team/Medical Monitor before breaking the code. All calls will be 
documented by the Monitoring Team as appropriate to include date and time of the call, name of 
the person contacted within the Monitoring Team, patient identification, documentation of the 
request, and decision for unblinding or not.  
Code breaking can be performed at any time by using the proper module of the IVRS/IWRS 
and/or by calling any other phone number provided by the Sponsor for that purpose. If the blind is 
broken, the Investigator should document the date, time of day, reason for code breaking and 
report this information (or “relevant information as required by”) on the appropriate page of the 
electronic-Case Report Form (e-CRF). 
Note that when documenting the reason for unblinding, the Investigator must not provide any 
detail regarding the nature of the IMP. The Investigator should not divulge IMP detail to the 
Sponsor’s representative or to any staff members until database closure. Furthermore, when 
completing forms (eg, AEs, SAEs), the study treatment should not be disclosed on the forms. 
The code-breaking can also be performed by contacting the “24 hour alert system”; but this 
system should be used in very exceptional cases only (ie, unavailability of a centralized treatment 
allocation system or inability to contact Investigator and/or site staff). However, the preferred 
option is to unblind using a centralized treatment allocation system. The Investigators will be 
informed by the clinical monitoring team about the availability of the local code-breaking details 
(through an emergency centralized 24 hour telephone system for use with emergency scientific 
and medical services [e-SMS]). A patient card, including the relevant “24 hour alert system” 
telephone number will be provided to every patient who will participate in the study. 
Unblinding may also be performed by the Sponsor for some SAEs that are both related and 
unexpected in order to conform to regulatory reporting requirements. 
If the code is broken, the patient must withdraw from IMP administration. 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP 
The randomized treatment kit number list is generated centrally by Sanofi. The IMPs (Renvela or 
placebo kit) are packaged in accordance with this list. Both the randomization and treatment kit 
lists will be loaded into the centralized treatment allocation system. 
Patients will be randomized to receive either placebo or Renvela during the double-blind study 
treatment period using a ratio 1:1. Randomization will be stratified according to screening serum 
phosphorus level [5.5 - 6.0 mg/dL or >6.0 mg/dL]. For eligible patients who are not taking 
phosphate binder(s) at screening visit, serum phosphorus at V1 will be used for stratification. For 
eligible patients who are taking phosphate binder(s) at screening visit, serum phosphorus at V1a 
will be used for stratification. 
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The treatment kit numbers will be allocated using the IVRS/IWRS on randomization visit (Day 1, 
Week 0), and then at Week 2, Week 4 and Week 6 as resupply visits, and at unscheduled visits, if 
needed. 
Before randomizing a patient, the Investigator or designee will have to contact the IVRS/IWRS.  
A randomized patient is defined as a patient who is registered and assigned with a treatment kit 
number from the IVRS/IWRS, as documented from its log file. A patient cannot be randomized 
more than once in the study. If a treatment is used without contacting the IVRS/IWRS patient will 
be considered as not randomized and withdrawn from the study. 
Two types of centralized treatment allocation system will be used, the IVRS and the IWRS, 
depending on the choice of the site. 
Details of the IVRS/IWRS procedures will be provided to sites in the IVRS/IWRS site manual. 
8.5 
PACKAGING AND LABELING 
Packaging is in accordance with the administration schedule. The content of the labeling is in 
accordance with the local regulatory specifications and requirements. 
In order to protect the blind, IMP kits will have the same look and therefore will be labeled with a 
double-blind label. 
8.6 
STORAGE CONDITIONS AND SHELF LIFE 
Investigators or other authorized persons (eg, pharmacists) are responsible for storing the IMP in a 
secure and safe place in accordance with local regulations, labeling specifications, policies, and 
procedures.  
Control of IMP storage conditions, especially control of temperature and information on in-use 
stability and instructions for handling the Sanofi compound should be managed according to the 
rules provided by the Sponsor. 
8.7 
RESPONSIBILITIES 
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor and in accordance with applicable regulatory requirements. 
All IMP will be dispensed in accordance with the Investigator’s prescription and it is the 
Investigator’s responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
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Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) should be promptly notified to the 
Sponsor. Some deficiencies may be recorded through a complaint procedure. 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party, allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
8.7.1 Treatment accountability and compliance 
IMP administration data will be recorded by the patients onto a patient’s diary. 
Measures taken to ensure and document IMP compliance and accountability are described below: 
x 
The Investigator or designee will obtain via IVRS/IWRS the treatment kit numbers and 
he/she will dispense the treatment kits to the patient. 
x 
The accountability is to be performed at Visits 3, 4, 5 and 6 (Days 15, 29, 43 and 57). The 
unused treatment should be returned by the patient to such visits for accountability 
purposes. 
x 
The Investigator or designee will complete the corresponding treatment log form from 
patient’s diary. 
x 
The Investigator/study coordinator will enter data in the appropriate e-CRF pages, 
according to data recorded in the treatment log form.  
x 
The monitor will check the data consistency between e-CRF pages, treatment log forms 
using patient’s diary, and returned unused treatment. 
8.7.2 Return and/or destruction of treatments 
All partially used or unused treatment kits will be retrieved by the Sponsor or destroyed at study 
site. A detailed treatment log of the returned IMP will be established with the Investigator (or the 
pharmacist) and countersigned by the Investigator and the monitoring team. 
A detailed treatment log of the destroyed IMP will be established with the Investigator (or the 
pharmacist) and countersigned by the Investigator and the monitoring team. The Investigator will 
not destroy the unused IMP unless the Sponsor provides written authorization.  
8.8 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly to the study 
(from Screening Visit until Follow-Up visit).  
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All medications taken by the patient within 30 days of Screening Visit until study completion will 
be recorded in the patient’s e-CRF. Patients will not consume calcium, aluminum, or magnesium 
containing antacids and phosphate binders throughout the duration of the study unless prescribed 
as an evening calcium supplement. 
Should serum calcium (adjusted for albumin) fall below normal during the study, the investigator 
will return the serum calcium (adjusted for albumin) level to within the normal range by 
prescribing an evening calcium supplement to be taken at bedtime. 
If the patient is on lipid lowering medication, 1, 25 dihydroxy Vitamin D, and/or cinacalcet 
therapy, the investigator will maintain the patient on the dose recorded at Screening Visit for the 
duration of the study, except for safety reasons.  
To minimize the effects of dietary absorption of vitamin D that may occur with treatment with 
sevelamer carbonate, patients will be supplemented with a daily dose of 400 IU of the native form 
of this vitamin to be taken at bedtime away from the dose of sevelamer carbonate. This 
supplement should be given in addition to any ongoing active vitamin D therapy routinely 
prescribed. 
8.8.1 Prohibited concomitant medications 
Forbidden concomitant medications from the initial Screening Visit until the Follow-Up visit 
include the following: 
x 
Anti-arrhythmic and anti-epileptics for arrhythmia or seizure disorders. 
x 
Antacids and phosphate binders containing aluminium, magnesium, calcium or lanthanum 
for the duration of the study unless prescribed as an evening calcium supplement. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
PRIMARY ENDPOINT 
The primary endpoint is the change from baseline in serum phosphorus level at Week 8. 
The baseline of serum phosphorus value will be the last serum phosphorus level obtained before 
the first double-blind IMP dosing. 
The serum phosphorus at Week 8 will be the serum phosphorus level obtained within the Week 8 
analysis window. 
All serum phosphorus values (scheduled or unscheduled) may be used to provide a value for the 
primary endpoint if appropriate according to above definition. The analysis window used to 
allocate a time point to a measurement will be defined in the Statistical Analysis Plan (SAP). 
9.2 
SECONDARY ENDPOINTS 
x 
The change from baseline in total cholesterol at Week 8 
x 
The change from baseline in LDL-C at Week 8 
x 
The change from baseline in calcium-phosphorus product at Week 8 
x 
The change from baseline in iPTH level at Week 8 
x 
Percentage of patients reaching the target serum phosphorus level (4.6 mg/dL 
[1.49 mmol/L], inclusive) at Week 8 
x 
The change from baseline in serum phosphorus level at Week 4 
9.3 
SAFETY ENDPOINTS 
x 
Proportion of patients with adverse events 
x 
Clinically significant changes in vital signs and clinical laboratory parameters 
Observation period 
The observation of safety data will be as follows: 
x 
Pre-treatment period: The pre-treatment observation period is defined from the signed 
informed consent up to the first dose of double-blind IMP. 
x 
Treatment Emergent Adverse Event (TEAE) period: The TEAE observation period is 
defined as the time from the first dose of double-blind IMP to the last dose of double-blind 
IMP+3 days. 
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x 
Post-treatment period: The post-treatment observation period is defined as the time 
starting the day after the end of the TEAE period up to the end of the study (see definition 
in Section 6.2.1). 
9.3.1 Adverse events 
All AEs diagnosed by the Investigator will be reported and described. 
All AEs will be coded to a “Lowest level term (LLT)”, “Preferred term (PT)”, “High level term 
(HLT)”, “High level group term (HLGT)” and associated primary “System organ class (SOC)” 
using the version of Medical dictionary for regulatory activities (MedDRA) currently at Sanofi at 
the time of the considered database lock.  
Refer to Section 10.4 to Section 10.7 for details. 
9.3.2 Laboratory safety variables 
The clinical laboratory data consist of hematology (complete blood count [CBC], differential, 
platelet and prothrombin time), chemistry (serum phosphorus, calcium [adjusted for albumin], 
albumin, calcium-phosphorus product, chloride, bicarbonate, uric acid, sodium, potassium, 
glucose, blood urea nitrogen [BUN], alanine aminotransferase [ALT], aspartate aminotransferase 
[AST], creatinine), and lipid panel (total cholesterol, LDL-C, high-density lipoprotein cholesterol 
[HDL-C], non-high-density lipoprotein cholesterol [non-HDL-C] and triglycerides).  
Clinical laboratory values will be analyzed after conversion into standard international units. 
International units will be used in all listings and tables. 
9.3.3 Vital signs 
Vital signs include: heart rate (HR), systolic blood pressure (BP) and diastolic BP, and body 
temperature in sitting position. 
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10 
STUDY PROCEDURES 
10.1 
VISIT SCHEDULE 
For all visits after Day 1/Week 0 (randomization visit), a timeframe of ±3 days will be allowed.  
For all visits after Day 1/Week 0 (randomization visit), if one visit date is changed, then the next 
visit should take place according to the original schedule as outlined Section 1.2. 
Laboratory tests:  
The laboratory data are collected in accordance with the study schedule in Section 1.2: 
x 
Hematology 
x 
Chemistry  
x 
Serum pregnancy test 
NOTE: Any clinically relevant abnormal laboratory value should be immediately rechecked for 
confirmation before making any decision for the concerned patient. It should be documented as an 
AE/SAE as applicable. Please also refer to Section 10.4.  
According to the discretion of the Investigator for safety concern, the relevant laboratory 
parameters (eg, serum potassium) can be tested at any scheduled visit or unscheduled visit if 
necessary. 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix A. 
Physical examination:  
A general physical examination should be performed at the time points indicated in the study 
flowchart in Section 1.2. If a new clinically significant abnormality or worsening from baseline is 
detected after randomization, then an AE should be reported and the patient should be considered 
for further clinical investigations and/or specialist consultation as per the Investigator’s medical 
judgment. 
Blood pressure / heart rate: 
Blood pressure should be measured in sitting position under standardized conditions, 
approximately at the same time of the day, on the same arm, with the same apparatus (after the 
patient has rested comfortably in sitting position for at least five minutes). Values are to be 
recorded in the e-CRF; both systolic BP and diastolic BP should be recorded. At the first 
Screening Visit, BP should be measured in both arms. The arm with the highest diastolic pressure 
will be determined at this visit, and BP should be measured on this arm throughout the study. This 
highest value will be recorded in the e-CRF. 
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Heart rate will be measured at the time of the measurement of BP. 
NOTE: in case of high BP values at Screening Visit, the Investigator is responsible for the 
optimization of the patient’s treatment to achieve BP targets as defined by local guidelines.  
Body weight and height 
Body weight should be obtained with the patient wearing undergarments or very light clothing 
and no shoes, and with an empty bladder. The same scale should be used throughout the study. 
The use of calibrated balance scales is recommended, if possible. Self-reported weights are not 
acceptable; patients must not read the scales themselves. 
Height needs to be measured as self-reported heights are not acceptable. 
10.1.1 Screening Period 
The screening period will take place up to 4 weeks or 28 days (and as short as possible, upon 
receipt of laboratory eligibility criteria) prior to randomization/Day 1 visit. Eligible patients who 
are taking phosphate binder(s) at Screening Visit will enter a 2-week phosphate binder washout 
period. Eligible patients who are not taking phosphate binder(s) at screening visit will proceed to 
the start of the 8-week treatment period (Day 1).  
10.1.1.1 Screening Visit (Visit 1/Week -4 /Day -28 up to -19 for patients on phosphate 
binder[s] and Visit 1/Week -1.5/Day -10 to -1 for patients not on phosphate 
binder[s]) 
x 
Complete informed consent - the patient will receive complete information about the study 
both verbally and in writing. Written informed consent for the study must be obtained 
prior to any study-related investigations. 
x 
Assess inclusion/exclusion criteria. 
x 
Obtain patient demography – age and gender. 
x 
Obtain medical history (including menopausal status) and renal history. 
x 
Document prior medication (prescription and non-prescription medication) history within 
the last 30 days, especially for phosphate binder(s) treatment. 
x 
Record concomitant medication (prescription and non-prescription medication). 
x 
Physical examination.  
x 
Take vital signs including HR, BP and body temperature. 
x 
Get body weight and height measurements. 
x 
Contact IVRS/IWRS for notification of Screening Visit. Patient number will be allocated 
by the IVRS/IWRS. This patient number is composed of a 12-digit number containing the 
3-digit country code, the 4-digit center code and the 5-digit patient chronological number 
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(the 5-digit patient chronological number is 00001 for the first patient screened in a center, 
00002 for the second patient screened in the same center). 
x 
Collect AEs from this point onward:  
All AEs and SAEs will be collected from the time of informed consent signature and throughout 
the study until the post Follow-Up visit. 
x 
Obtain blood sample for: 
- 
Hematology: CBC, differential, platelet and prothrombin time. 
- 
Chemistry: calcium (adjusted for albumin), albumin, calcium-phosphorus product, 
chloride, bicarbonate and creatinine. 
- 
Serum phosphorus. 
- 
Serum iPTH. 
- 
Serum 25-hydroxy vitamin D. 
- 
Serum pregnancy test (women of childbearing potential only). 
- 
Calculate and record estimated Glomerular Filtration Rate (eGFR) based upon 
screening values using Modification of Diet in Renal Disease (MDRD) formula:  
eGFR (mL/min/1.73 m2) = 175 x (serum creatinine [mg/dL])-1.154 x (Age [years])-0.203 x 
(0.742, if female) 
x 
Inform patient who are taking phosphate binder(s) to discontinue their current phosphate 
binder(s) for 2 weeks (washout period). These patients will return for their V1a (Day -10 
to -1). 
x 
An appointment will be given for the next visit. 
10.1.1.2 Post-Washout visit (Visit 1a/Week -1.5/Day -10 to -1) 
This visit is only applied for patients taking phosphate binder(s) at screening visit. 
x 
Assess inclusion/exclusion criteria. 
x 
Collect AEs. 
x 
Record concomitant medication (prescription and non-prescription medication).  
x 
Obtain blood sample for: 
- 
Chemistry: serum phosphorus. 
x 
An appointment will be given for the next visit. 
Note: For patients on phosphate binder(s), the time window of V1 and V1a is up to 10 days, 
respectively. However, the total time window of V1 and V1a should not exceed 14 days to ensure 
the screening period is up to 4 weeks, including a wash out period which should be 2 weeks 
(14 days). 
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10.1.2 Double-Blind Treatment Period (Study Site Visits) 
10.1.2.1 Randomization Visit (Visit 2/Week 0/Day 1) 
x 
Assess Inclusion/Exclusion Criteria. 
x 
Physical examination.  
x 
Take vital signs including HR, BP and body temperature. 
x 
Get body weight measurements. 
x 
Collect AEs.  
x 
Record concomitant medication (prescription and non-prescription medication).  
x 
Obtain blood sample for: 
- 
Hematology: CBC, differential, platelet and prothrombin time. 
- 
Chemistry: calcium (adjusted for albumin), albumin, calcium-phosphorus product, 
chloride, bicarbonate, uric acid, sodium, potassium, glucose, BUN, liver function tests 
(ALT and AST), creatinine. 
- 
Serum phosphorus. 
- 
Lipid panel: total cholesterol, LDL-C, HDL-C, non-HDL-C and triglycerides. 
- 
Serum iPTH. 
x 
If the patient is confirmed eligible, the Investigator will start the next study procedures: 
- 
IVRS/IWRS contact for randomization and allocation of a 7-digit treatment kit 
numbers according to the randomization list. Investigators should never allocate a 
treatment kit number to a patient without contacting IVRS/IWRS. 
x 
Double-blind IMP kits dispensation as per treatment kit numbers provided by IVRS/IWRS 
along with schedule reminder.  
x 
The first double-blind IMP administration will take place at the study site, but only after 
the collection of the blood samples and after the assessment of all evaluations planned at 
that visit.  
x 
Instruct the patient to maintain the prescribed dose of IMP including taking daily dose of 
400 IU of native vitamin D. 
x 
The patient diary should be given and instructions on its completion should be reviewed. 
x 
Reminders 
- 
An appointment will be given for the next study site visit. 
- 
Patient to bring the diary, at the next study site visit. 
- 
Patient to bring unused treatment at the next study site visit. 
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10.1.2.2 Visit 2a: Phone Call Visit 
After the phosphorus result at V2 is received from the central laboratory, a dose adjustment phone 
call at V2a (as soon as possible once V2 serum phosphorus is available) will be made by the 
investigator to instruct patients to adjust their starting IMP dosage, if dose adjustment is needed. 
The adjusted dose is 1 tablet (if serum phosphorus is 7.5 mg/dL at V2) or 2 tablets (if serum 
phosphorus is >7.5 mg/dL at V2) of Renvela or placebo 3 times per day (TID) with meals. A 
confirmation phone call (a second phone call, in addition to the dose adjustment phone call) will 
be made a working day after dose adjusting phone call, in order to remind patients their correct 
dosage. 
10.1.2.3 Visit 3/Week 2, Visit 4/Week 4 and Visit 5/Week 6 (Day 15, 29 and 43 ± 3)   
x 
Physical examination.  
x 
Take vital signs including HR, BP and body temperature. 
x 
Get body weight measurements.   
x 
Collect AEs. 
x 
Record concomitant medication (prescription and non-prescription medication.  
x 
Data collection on IMP administration and IMP compliance check by review of diary and 
unused treatment. 
x 
Obtain blood sample for: 
- 
Chemistry: calcium (adjusted for albumin), albumin, calcium-phosphorus product, 
chloride, and bicarbonate. 
- 
Serum phosphorus. 
- 
Serum iPTH. 
x 
Return the bottle (s) and any unused treatment to the site; dispense enough additional IMP 
for 2 weeks treatment. 
x 
Instruct the patient to maintain the prescribed dose of IMP including taking daily dose of 
400 IU of native vitamin D. 
x 
Once the central laboratory results are available for Visit 3, 4 and 5, Investigator will be 
informed by the IVRS/IWRS for dose titration. If the serum phosphorus is 4.6 mg/dL 
(1.49 mmol/L), the patient is to be instructed by the investigator to increase their study 
treatment dose by 1 x 800 mg tablet TID with meals. If the serum phosphorus is 
<2.7 mg/dL (<0.87 mmol/L), the patient is to be instructed by the investigator to decrease 
their study treatment dose by 1 x 800 mg tablet TID with meals.  
x 
Reminders 
- 
An appointment will be given for the next study site visit. 
- 
Patient to bring the diary at the next study site visit.   
- 
Patient to bring unused treatment at the next study site visit.  
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10.1.2.4 Visit 3a/Visit 4a/Visit 5a: Phone Call Visits 
x 
If dose titration is required, a dose titration phone call will be made by the investigator to 
patients as soon as possible once serum phosphorus result is available. A confirmation 
phone call (a second phone call, in addition to the dose titration phone call) will be made a 
working day after dose titration phone call, in order to remind subjects their correct dosage. 
x 
Instruct the patient to maintain the prescribed dose of IMP including taking daily dose of 
400 IU of native vitamin D. 
10.1.2.5 Visit 6/Week 8 (Day 57 ± 3): End of Treatment Visit 
x 
Physical examination.  
x 
Take vital signs including HR, BP and body temperature. 
x 
Get body weight measurements.   
x 
Collect AEs. 
x 
Record concomitant medication (prescription and non-prescription medication).  
x 
IVRS/IWRS contact to document the end of treatment. 
x 
Data collection on IMP administration and IMP compliance check by review of diary and 
treatment kit accountability. 
x 
Obtain blood sample for: 
- 
Hematology: CBC, differential, platelet and prothrombin time. 
- 
Chemistry: calcium (adjusted for albumin), albumin, calcium-phosphorus product, 
chloride, bicarbonate, uric acid, sodium, potassium, glucose, BUN, liver function tests 
(ALT and AST), creatinine. 
- 
Serum phosphorus. 
- 
Lipid panel: total cholesterol, LDL-C, HDL-C, non-HDL-C and triglycerides. 
- 
Serum iPTH. 
x 
Instruct patients to refrain from taking any phosphate binder(s). 
x 
Reminders 
- 
An appointment will be given for the next study site visit. 
10.1.3 Post-Treatment Period  
10.1.3.1 Follow-Up Visit (Visit 7/ Week 10/ Day 71 ± 3) 
x 
Collect AEs. 
x 
Record concomitant medication (prescription and non-prescription medication).  
x 
IVRS/IWRS contact to document the end of study. 
x 
Instruct patients to return to their previous phosphate binder(s) (if applicable). 
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x 
Obtain blood sample for: 
Only in case of clinically relevant abnormal values for these parameters at the end of 
treatment visit will the following be obtained at this visit: 
- 
Hematology: CBC, differential, platelet and prothrombin time. 
- 
Chemistry: calcium (adjusted for albumin), albumin, calcium-phosphorus product, 
chloride, bicarbonate, uric acid, sodium, potassium, glucose, BUN, liver function tests 
(ALT and AST), creatinine. 
- 
Serum phosphorus.  
- 
Lipid panel: total cholesterol, LDL-C, HDL-C, non-HDL-C and triglycerides. 
10.2 
DEFINITION OF SOURCE DATA 
Evaluations that are reported in the e-CRF must be supported by appropriately signed identified 
source documentation related but not limited to the following: 
x 
Agreement, date, and signature of informed consent mentioning the study identification. 
x 
Patient identification, last participation in a clinical trial, medical history, associated 
diseases, and data related to the studied pathology. 
x 
Contraception methods for women of childbearing potential. 
x 
Previous and concomitant medication. 
x 
Study identification. 
x 
Treatment number, dates of administration. 
x 
Dates of visits and assessments including the examination report. 
x 
Vital signs, height, body weight. 
x 
Emailed central lab reports (dated and signed by the Principal Investigator or 
Subinvestigator). 
x 
IVRS/IWRS confirmation email (screening, screen failure, training kit allocation, 
randomization, treatment reallocation, discontinuation, end of DBTP, end of study, 
unblinding if applicable). 
x 
AEs and follow-up: 
- 
In case of SAE, the site should file in the source document at least copies of the 
hospitalization reports and any relevant examination reports documenting the 
follow-up of the SAE. 
x 
Date of premature study discontinuation (if any) and reason. 
Source documentation may be found in the following: 
x 
Patient’s identity. 
x 
Medical history. 
x 
Hospital records. 
x 
Nursing notes. 
x 
Physician’s notes. 
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10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION  
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporarily; permanent IMP discontinuation should be 
a last resort. Any IMP discontinuation should be fully documented in the e-CRF. In any case, the 
patient should remain in the study as long as possible. 
x 
Pregnancy in female participant will lead to definitive treatment discontinuation in all 
cases.  
10.3.1 Temporary treatment discontinuation with investigational medicinal product(s) 
Temporary treatment discontinuation may be considered by the Investigator because of suspected 
AEs. Reinitiation of treatment with the IMP will be done under close and appropriate clinical/and 
or laboratory monitoring once the Investigator will have considered according to his/her best 
medical judgment that the responsibility of the IMP(s) in the occurrence of the concerned event 
was unlikely and if the selection criteria for the study are still met (refer to Section 7.1 and 
Section 7.2). 
For all temporary treatment discontinuations, duration should be recorded by the Investigator in 
the appropriate pages of the e-CRF.  
10.3.2 Permanent treatment discontinuation with investigational medicinal product(s) 
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator or the patient not to re-expose the patient to the IMP at 
any time. 
10.3.3 List of criteria for permanent treatment discontinuation 
The patients may withdraw from treatment with the IMP if they decide to do so, at any time and 
irrespective of the reason, or this may be the Investigator’s decision. All efforts should be made to 
document the reasons for treatment discontinuation and this should be documented in the e-CRF. 
Patients should discontinue the IMP for the following reasons: 
x 
Pregnancy, intention for pregnancy, or no longer with effective contraceptive method of 
birth control (females only). 
x 
Serious adverse event (or non-serious but severe in intensity) of hypersensitivity reaction 
considered related to IMP. 
x 
At patient request. 
x 
If, in the Investigator's opinion, continuation with the administration of the IMP would be 
detrimental to the patient's well-being. 
x 
Intercurrent condition that requires discontinuation of the IMP (eg, laboratory 
abnormalities, please refer to decision tree Appendix A). 
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x 
At the specific request of the Sponsor. 
x 
Any code breaking requested by the Investigator. 
x 
Patient receives double-blind treatment prior to randomization.  
In addition, if the patient requires dialysis (hemodialysis or peritoneal dialysis) or is admitted for 
renal transplantation at any time, he or she must be withdrawn.  
10.3.4 Handling of patients after permanent treatment discontinuation 
Patients will be followed-up according to the study procedures as specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
If possible, and after the permanent discontinuation of treatment, the patients will be assessed 
using the procedure normally planned for the last dosing day with the IMP. 
If applicable, instruct patient to resume their previous phosphate binder(s). 
All cases of permanent treatment discontinuation should be recorded by the Investigator in the 
appropriate pages of the e-CRF when considered as confirmed. The investigator will retrieve any 
unused treatment and instruct the patient to resume their phosphate binder(s), if applicable. 
10.3.5 Procedure and consequence for patient withdrawal from study  
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason. If possible, the patients are assessed using the procedure 
normally planned for the end-of-study visit. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
e-CRF and in the patient’s medical records (with, in this medical records, at least date of 
withdrawal and reason for) when considered as confirmed. 
For patients who fail to return to the site, the Investigator should make the best effort to recontact 
the patient (eg, contacting patient’s family or private physician, reviewing available registries or 
health care databases), and to determine his/her health status, including at least his/her vital status. 
Attempts to contact such patients must be documented in the patient’s records (eg, times and dates 
of attempted telephone contact, receipt for sending a registered letter). 
Patients who have withdrawn from the study cannot be rerandomized (treated) in the study. Their 
inclusion and treatment numbers must not be reused.  
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10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.4.1 Definitions of adverse events  
10.4.1.1 Adverse event 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
10.4.1.2 Serious adverse event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
x 
Results in death, or 
x 
Is life-threatening, or 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient 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 were more severe. 
x 
Requires inpatient hospitalization or prolongation of existing hospitalization, or 
x 
Results in persistent or significant disability/incapacity, or 
x 
Is a congenital anomaly/birth defect 
x 
Is a medically important event 
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 hospitalization but may jeopardize the 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above. 
Note: The following list of medically important events is intended to serve as a guideline for 
determining which condition has to be considered as a medically important event. The list is 
not intended to be exhaustive: 
- 
Intensive treatment in an emergency room or at home for: 
a) Allergic bronchospasm  
b) Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc),  
c) Convulsions (seizures, epilepsy, epileptic fit, absence seizures, etc). 
- 
Development of drug dependence or drug abuse 
- 
ALT >3 x upper limit of normal range (ULN) + total bilirubin >2 x ULN or 
asymptomatic ALT increase >10 x ULN 
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- 
Suicide attempt or any event suggestive of suicidality 
- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling) 
- 
Bullous cutaneous eruptions 
- 
Cancers diagnosed during the study or aggravated during the study (only if judged 
unusual/significant by the Investigators in oncology studies) 
- 
Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study 
(only if judged unusual/significant by the Investigators in studies assessing specifically 
the effect of a study drug on these diseases). 
10.4.1.3 Adverse event of special interest 
An AESI is an AE (serious or non-serious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor is required. Such events may require further investigation in order to 
characterize and understand them. Adverse events of special interest may be added or removed 
during a study by protocol amendment. Please see Section 10.4.4 and Appendix A for additional 
information.  
x 
Pregnancy of a female subject entered in a study as well as pregnancy occurring in a 
female partner of a male subject entered in a study with IMP 
- 
Pregnancy occurring in a female patient entered in the clinical trial or in a female 
partner of a male patient entered in the clinical trial. It will be qualified as an SAE only 
if it fulfills one of the seriousness criteria (see Section 10.4.1.2) 
- 
In the event of pregnancy in a female participant, IMP should be discontinued. 
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined. 
x 
Symptomatic overdose (serious or non-serious) with IMP/NIMP 
- 
An overdose (accidental or intentional) with the IMP/NIMP is an event suspected by 
the Investigator or spontaneously notified by the patient (not based on systematic pills 
count). Renvela is a non-absorbed drug, thus it is not possible to define a symptomatic 
overdose prospectively. However, the investigator may use his or her judgment to 
report an event that he or she considers to be a symptomatic overdose using the 
corresponding screens in the e-CRF using the Term “Symptomatic OVERDOSE 
(accidental [or intentional])”. The patient should be monitored and appropriate 
symptomatic treatment instituted. 
The circumstances of the overdose should be clearly specified in the verbatim. 
Of note, asymptomatic overdose has to be reported as a standard AE. 
x 
Increase in alanine transaminase (ALT) (see the “Increase in ALT” flow chart in Appendix A 
of the protocol).  
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10.4.2 General guidelines for reporting adverse events 
x 
All AEs, regardless of seriousness or relationship to IMP/NIMP, spanning from the 
signature of the informed consent form until the end of the study as defined by the 
protocol for that patient, are to be recorded on the corresponding page(s) or screen(s) of 
the e-CRF. 
x 
Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. 
The Investigator should specify the date of onset, intensity, action taken with respect to 
IMP, corrective treatment/therapy given, additional investigations performed, outcome, 
and his/her opinion as to whether there is a reasonable possibility that the AE was caused 
by the IMP or by the study procedure(s).  
x 
The Investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until progression has been 
stabilized, or until death, in order to ensure the safety of the patients. This may imply that 
observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the monitoring team up to as noticed by the Sponsor. 
When treatment is prematurely discontinued, the patient’s observations will continue until 
the end of the study as defined by the protocol for that patient. 
x 
Laboratory or vital signs abnormalities are to be recorded as AEs only if:  
- 
Symptomatic and/or  
- 
Requiring either corrective treatment or consultation, and/or  
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI 
Instructions for AE reporting are summarized in Table 1.  
10.4.3 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator must immediately: 
x 
ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the e-CRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the e-CRF or after a standard delay. 
x 
SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
team whose name, fax number, and email address appear on the clinical trial protocol. 
Care should be taken to ensure that the patient's identity is protected and the patient's 
identifiers in the clinical trial are properly mentioned on any copy of a source document 
provided to the Sponsor. For laboratory results, include the laboratory normal ranges. 
x 
All further data updates should be recorded in the e-CRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc) should be sent (by fax or e-mail) to the monitoring team 
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within 24 hours of knowledge of the SAE. In addition, every effort should be made to 
further document any SAE that is fatal or life threatening within a week (7 days) of the 
initial notification. 
x 
A back-up plan (using a paper CRF process) is available and should be used when the 
e-CRF system does not work. 
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team. 
10.4.4 Guidelines for reporting adverse events of special interest   
For AESIs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.4.3, even if not fulfilling a seriousness criterion, 
using the corresponding screens in the e-CRF. 
Instructions for AE reporting are summarized in Table 1. 
10.4.5 Guidelines for management of specific laboratory abnormalities 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix A.  
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices.  
x 
Neutropenia 
x 
Thrombocytopenia 
x 
Suspicion of rhabdomyolysis 
x 
Increase in ALT 
NOTE: Increase in ALT can be considered as AESIs (see Section 10.4.1.3) 
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Table 1 - Summary of adverse event reporting instructions 
Case Report Form completion 
Event category 
Reporting 
timeframe 
Specific events in this 
category 
AE 
form 
Safety Comple-
mentary Form 
Other 
specific 
forms 
Adverse Event 
(non-SAE, non-AESI) 
Routine 
Any AE that is not SAE or AESI 
Yes 
No 
No 
Serious Adverse Event 
(non-AESI or AESI) 
Expedited (within 
24 hours) 
Any AE meeting seriousness criterion 
per Section 10.4.1.2 
Yes 
Yes 
No 
Adverse Event of 
Special Interest  
Expedited (within 
24 hours) 
Pregnancy 
Yes 
Yes 
Yes 
 
 
Symptomatic overdose 
Yes 
Yes 
No 
 
 
ALT3 ULN (if baseline ALT<ULN) and 
ALT2 x baseline (if baseline ALTULN) 
Yes 
Yes 
Yes 
 
10.5 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
x 
All SAEs that are both unexpected and at least reasonably related to the IMP (SUSAR), to 
the regulatory authorities, IECs/IRBs as appropriate and to the Investigators. 
x 
All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
In this study, some AEs are considered related to the underlying condition and thus will not be 
considered unexpected (please refer to the IB). 
Any other AE not listed as an expected event in the Investigator’s Brochure or in this protocol 
will be considered unexpected. 
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 
10.6 
SAFETY INSTRUCTIONS 
x 
No specific safety instructions required in relation to the clinical trial.  
10.7 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final clinical study report. 
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11 
STATISTICAL CONSIDERATIONS 
11.1 
DETERMINATION OF SAMPLE SIZE 
The sample size calculations are based on the primary efficacy variable of serum phosphorus 
change from baseline to Week 8, with the following assumptions:  
x 
A common standard deviation (SD) of 2 mg/dL, which is assumed based on the data from 
previous trials  
x 
A 1 mg/dL mean difference between test and placebo in change from baseline in serum 
phosphorus 
x 
A t-test at a 2-sided 5% significance level with 90% power 
x 
Expected dropout rate = 15%. 
Based on the above assumptions, 101 patients per arm are needed for this study. Calculations 
were made using nQuery Advisor 7.0. 
11.2 
DISPOSITION OF PATIENTS 
Screened patients are defined as any patient who met the inclusion criteria and signed the 
informed consent.  
Randomized patients consist of all patients, who have been allocated a treatment kit by 
IVRS/IWRS, and regardless of whether the treatment kit was used or not. 
Patients treated without being randomized will not be considered as randomized and will not be 
included in any efficacy population. 
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population. The safety experience associated with any later 
randomization will be assessed separately. 
The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be in the safety population. 
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11.3 
ANALYSIS POPULATIONS 
11.3.1 Efficacy populations 
11.3.1.1 Modified intent-to-treat population 
Modified Intention To Treat (mITT) population: The mITT population consists of all patients who 
are randomized, receive at least one dose of IMP, and have both a baseline assessment and at least 
one post-baseline assessment of phosphorus measure. 
11.3.2 Safety population 
Safety population: The safety population consists of all randomized patients who receive at least 
one dose of IMP.  
In addition:  
x 
Nonrandomized but treated patients with IMP will not be part of the safety population, but 
their safety data will be presented separately.  
x 
Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized. 
x 
For patients receiving more than 1 study treatment during the trial, the treatment group 
allocation for as-treated analysis will be in Renvela group. 
11.4 
STATISTICAL METHODS 
11.4.1 Extent of study treatment exposure and compliance 
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual treatment received within the safety population. 
11.4.1.1 Extent of investigational medicinal product exposure 
Duration of IMP exposure is defined as:  last dose date – first dose date + 1 day, regardless of 
unplanned intermittent discontinuations.   
11.4.1.2 Compliance  
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data.  
Treatment compliance, average dose, final dose and highest dose will be summarized 
descriptively (N, Mean, SD, Median, Min, and Max). The percentage of patients with compliance 
is <80% will be summarized. In addition, number and percentage of patients with at least 1 
above-planned dosing administration will be given, as well as the number and percentage of 
patients with 0, (0, 20%], and >20% under-planned dosing administrations. 
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11.4.2 Analyses of efficacy endpoints 
11.4.2.1 Analysis of primary efficacy endpoint(s) 
The change from baseline in serum phosphorus at Week 8 as defined in Section 9.1 will be 
compared between the Renvela group to the placebo group in the mITT population using stratified 
Wilcoxon rank sum tests considering randomization strata (screening serum phosphorus 
[5.5 - 6.0 mg/dL or >6.0 mg/dL]). The statistical test will be two-sided tests at a nominal 5% 
significance level. 
If a patient discontinues the treatment prematurely or does not have serum phosphorus value at 
Week 8, the last post-baseline on-treatment serum phosphorus measurement during the 8-week 
double-blind period will be used for the calculation of Week 8 (Last Observation Carried Forward 
[LOCF] procedure). 
11.4.2.2 Analyses of secondary efficacy endpoints 
The secondary efficacy variables are: 
x 
The change from baseline in total cholesterol at Week 8 
x 
The change from baseline in LDL-C at Week 8 
x 
The change from baseline in calcium-phosphorus product at Week 8 
x 
The change from baseline in iPTH level at Week 8 
x 
Percentage of patients reaching the target serum phosphorus level (4.6 mg/dL 
[1.49 mmol/L], inclusive) at Week 8 
x 
The change from baseline in serum phosphorus level at Week 4  
All secondary endpoints will be analyzed using the mITT population.  
Descriptive statistics (number, mean, SD, median, Q1, Q3, minimum, and maximum) will be 
provided by treatment for all continuous secondary variables at the scheduled visits. 
All continuous secondary efficacy variables, ie, the change from baseline in serum lipids (total 
cholesterol and LDL-C), calcium-phosphorus product at Week 8, iPTH at Week 8 and serum 
phosphorus at Week 4 will be analyzed using stratified Wilcoxon rank sum tests using 
randomization strata (screening serum phosphorus [5.5 – 6.0 mg/dL or >6.0 mg/dL]), the same 
test described in Section 11.4.2.1. The same procedure for handling missing assessments/early 
discontinuation will also be applied as for the primary variable. 
Percentage of patients reaching the target serum phosphorus level will be compared by treatment 
assignment (Renvela or placebo) using a Cochran-Mantel-Haensel method stratified by 
randomization strata (screening serum phosphorus [5.5 – 6.0 mg/dL or >6.0 mg/dL]), the odds 
ratio and 95% confidence intervals will be calculated. 
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11.4.2.3 Multiplicity considerations 
In order to handle multiple key endpoints, the overall type-I error will be controlled by the use of 
a fixed sequence approach. Statistical significance of the primary parameter at the 0.05 alpha level 
is required before drawing inferential conclusions about first secondary endpoint (refer to order of 
list in Section 9.2). Inferential conclusions about successive secondary endpoints require 
statistical significance of the prior one. 
This fixed hierarchical approach will ensure a strong control of the overall type-I error rate at the 
0.05 level.  
No further adjustments will be made for other secondary endpoints, for which p-values will be 
provided for descriptive purpose only (no claim). 
11.4.3 Analyses of safety data 
The summary of safety results will be presented by treatment group. No formal inferential testing 
will be performed. Summaries will be descriptive in nature. 
All safety analyses will be performed on the Safety population using the following common rules: 
x 
The baseline value is defined generally as the last available value before first dose 
administration. 
The following definitions will be applied to laboratory parameters and vital signs. 
x 
The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests and vital signs.  
x 
PCSA criteria will determine which patients had at least 1 PCSA during the on-treatment 
period, taking into account all evaluations performed during the on-treatment period, 
including unscheduled or repeated evaluations. The number of all such patients will be the 
numerator for the on-treatment PCSA percentage. 
The observation period will be divided into three segments: pre-treatment, on-treatment and 
post-treatment 
x 
The pre-treatment period is defined as the time between the date of the informed consent 
and the start of study medication.  
x 
The on-treatment period is defined as the time from the first dose of study medication up 
to 3 days after the last dose of study medication administration. 
x 
The post-treatment period is defined as the time starting 4 days after last dose of study 
medication administration (after the on-treatment period) to the end of the study.   
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11.4.3.1 Adverse events 
Adverse event incidence tables will present by SOC (sorted by internationally agreed order), 
HLGT, HLT and PT sorted in alphabetical order for each treatment group, the number (n) and 
percentage (%) of patients experiencing an AE. Multiple occurrences of the same event in the 
same patient will be counted only once in the tables within a treatment phase. The denominator 
for computation of percentages is the safety population within each treatment group. 
Adverse event incidence table will be provided by treatment group for all types of TEAEs: all 
TEAEs, all treatment emergent AESI (defined with a PT or a prespecified grouping), all treatment 
emergent SAEs and all TEAEs leading to permanent treatment discontinuation. 
Death:  
The following deaths summaries will be generated: 
x 
Number (%) of patients who died by study period (TEAE, on-study) and reasons for death 
summarized on the safety population by treatment received. 
x 
Death in nonrandomized patients or randomized and not treated patients. 
x 
TEAE leading to death (death as an outcome on the AE CRF page as reported by the 
Investigator) by primary SOC , HLGT, HLT and PT showing number (%) of patients 
sorted by internationally agreed order of SOC and alphabetic order of HLGT, HLT, and 
PT.  
11.4.3.2 Laboratory data and vital signs 
The summary statistics of all laboratory variables, all vital signs parameters will be calculated for 
each visit, and last value assessed during the treatment period and presented by treatment group.  
The incidence of PCSAs at any time during the TEAE period (on-treatment PCSAs) will be 
summarized by treatment group whatever the baseline level and/or according to the following 
baseline categories: 
x 
Normal/missing 
x 
Abnormal according to PCSA criterion or criteria 
For laboratory parameters for which PCSA criterion is not defined, similar table(s) using the 
normal range could be provided. 
11.5 
INTERIM ANALYSIS 
No interim analysis is planned. 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 
ETHICAL AND REGULATORY STANDARDS 
This clinical trial will be conducted by the Sponsor, the Investigator, delegated Investigator staff 
and Subinvestigator, in accordance with the principles laid down by the 18th World Medical 
Assembly (Helsinki, 1964) and all applicable amendments laid down by the World Medical 
Assemblies, and the ICH guidelines for good clinical practice (GCP), all applicable laws, rules 
and regulations. 
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with Sanofi public disclosure commitments.  
12.2 
INFORMED CONSENT 
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient of all 
pertinent aspects of the clinical trial including the written information giving approval/favorable 
opinion by the Ethics Committee (IRB/IEC). All participants should be informed to the fullest 
extent possible about the study, in language and terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the written informed consent form should be 
signed, name filled in and personally dated by the patient or by the patient’s legally acceptable 
representative, and by the person who conducted the informed consent discussion. A copy of the 
signed and dated written informed consent form will be provided to the patient.  
The informed consent form used by the Investigator for obtaining the patient's informed consent 
must be reviewed and approved by the Sponsor prior to submission to the appropriate Ethics 
Committee (IRB/IEC) for approval/favorable opinion. 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) 
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the appropriate IRB/IEC, and is required to forward to the respective other party  a 
copy of the written and dated approval/favorable opinion signed by the Chairman with IRB/IEC 
composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, informed consent form, Investigator’s Brochure, Investigator’s 
curriculum vitae [CV], etc) and the date of the review should be clearly stated on the written 
(IRB/IEC) approval/favorable opinion. 
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IMP will not be released at the study site and the Investigator will not start the study before the 
written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the IRB/IEC before implementation, unless the change is necessary to eliminate an 
immediate hazard to the patients, in which case the IRB/IEC should be informed as soon as 
possible. It should also be informed of any event likely to affect the safety of patients or the 
continued conduct of the clinical trial, in particular any change in safety. All updates to the 
Investigator’s Brochure will be sent to the IRB/IEC. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial.  
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13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the e-CRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Subinvestigators shall be appointed and listed in a timely manner. The 
Subinvestigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR 
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the e-CRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, IMP allocation, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use and quality of 
data. 
13.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH GCP, the monitoring team must check the e-CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the e-CRF. The informed 
consent form will include a statement by which the patient allows the Sponsor’s duly authorized 
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personnel, the Ethics Committee (IRB/IEC), and the regulatory authorities to have direct access to 
original medical records which support the data on the e-CRFs (eg, patient's medical file, 
appointment books, original laboratory records, etc). These personnel, bound by professional 
secrecy, must maintain the confidentiality of all personal identity or personal medical information 
(according to confidentiality and personal data protection rules). 
13.4 
USE AND COMPLETION OF ELECTRONIC CASE REPORT FORMS (E-CRFS) AND 
ADDITIONAL REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate e-CRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All e-CRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. 
Should a correction be made, the corrected information will be entered in the e-CRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor as soon as they are entered in the e-CRF. 
The computerized handling of the data by the Sponsor may generate additional requests (DRF) to 
which the Investigator is obliged to respond by confirming or modifying the data questioned. The 
requests with their responses will be managed through the e-CRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor and Investigator study files. 
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14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Subinvestigator will be signed, dated and provided to the Sponsor prior to 
the beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES 
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee.  
14.3 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the e-CRFs, the Investigator’s Brochure and the 
results obtained during the course of the clinical trial, is confidential, prior to the publication of 
results. The Investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
Ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical trial. 
The Investigator and the Subinvestigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
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14.4 
PROPERTY RIGHTS 
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff/Subinvestigator not to 
mention any information or the Product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Subinvestigators shall provide all assistance 
required by the Sponsor, at the Sponsor’s expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
DATA PROTECTION 
x 
The patient’s personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations; 
x 
When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
x 
The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations. 
14.6 
INSURANCE COMPENSATION 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship.  This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document.  
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 
For the purpose of ensuring compliance with the clinical trial protocol, Good Clinical Practice and 
applicable regulatory requirements, the Investigator should permit auditing by or on the behalf of 
the Sponsor and inspection by regulatory authorities. 
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The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.8.1 By the Sponsor  
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
x 
The information on the product leads to doubt as to the benefit/risk ratio; 
x 
Patient enrollment is unsatisfactory; 
x 
The Investigator has received from the Sponsor all IMP, means and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon; 
x 
Non-compliance of the Investigator or Subinvestigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP; 
x 
The total number of patients are included earlier than expected; 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
14.8.2 By the Investigator 
The Investigator may terminate his/her participation upon thirty (30) days’ prior written notice if 
the study site or the Investigator for any reason becomes unable to perform or complete the 
clinical trial.  
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In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS 
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway or 
planned within twelve (12) months of the completion of this study at all sites, the Investigator 
shall have the right to publish or present independently the results of this study in agreement with 
other Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of 
any such presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication. In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights.  
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes of the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) 
to clinical trial patients, or when the change(s) involves only logistical or administrative aspects of 
the trial. Any change agreed upon will be recorded in writing, the written amendment will be 
signed by the Investigator and by the Sponsor and the signed amendment will be filed with this 
clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be re-collected if 
necessary. 
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16 
BIBLIOGRAPHIC REFERENCES 
1. Zhang L, Wang F, Wang L, Wang W, Liu B, Liu J, et al. Prevalence of chronic kidney disease 
in China: a cross-sectional survey. Lancet. 2012 Mar 3;379(9818):815-22. 
2. Imai E, Horio M, Watanabe T, Iseki K, Yamagata K, Hara S, et al. Prevalence of chronic 
kidney disease in the Japanese general population. Clin Exp Nephrol. 2009 Dec;13(6):621-30. 
3. Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, et al. Prevalence of chronic 
kidney disease in the United States. JAMA. 2007 Nov 7;298(17):2038-47. 
4. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO 
clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic 
Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl. 2009 
Aug;(113):S1-130. 
5. Palmer SC, Hayen A, Macaskill P, Pellegrini F, Craig JC, Elder GJ, et al. Serum levels of 
phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease 
in individuals with chronic kidney disease: a systematic review and meta-analysis. JAMA. 
2011 Mar 16;305(11):1119-27. 
6. Chen N, Wu X, Ding X, Mei C, Fu P, Jiang G, et al. Sevelamer carbonate lowers serum 
phosphorus effectively in haemodialysis patients: a randomized, double-blind, 
placebocontrolled, dose-titration study. Nephrol Dial Transplant. 2014 Jan;29(1):152-60. 
7. Ketteler M, Rix M, Fan S, Pritchard N, Oestergaard O, Chasan-Taber S, et al. Efficacy and 
tolerability of sevelamer carbonate in hyperphosphatemic patients who have chronic kidney 
disease and are not on dialysis. Clin J Am Soc Nephrol. 2008 Jul;3(4):1125-30. 
8. Perry CM, Plosker GL. Sevelamer carbonate: a review in hyperphosphataemia in adults with 
chronic kidney disease. Drugs. 2014 May;74(7):771-92. 
9. Renvela EARP Summary for the public (2009 June). Available at: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Summary_for_the_public/human/000993/WC500052613.pdf. Retrieved June 2014. 
10. US FDA Renvela Label Information (2011 June). Available 
at:http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_
ApprovalHistory#labelinfo. Retrieved June 2014. 
11. Guidance for Diagnosis and Treatment of Mineral and Bone Disorder in Chronic Kidney 
Disease (2013 December). Available 
at:http://www.csnchina.org/uploadfiles/img/file/20131202/20131202150017091709.pdf. 
Retrieved June 2014. 
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12. Bleyer AJ, Burke SK, Dillon M, Garrett B, Kant KS, Lynch D, et al. A comparison of the 
calcium-free phosphate binder sevelamer hydrochloride with calcium acetate in the treatment 
of hyperphosphatemia in hemodialysis patients. Am J Kidney Dis. 1999 Apr;33(4):694-701. 
13. Slatopolsky EA, Burke SK, Dillon MA. RenaGel, a nonabsorbed calcium- and aluminum-free 
phosphate binder, lowers serum phosphorus and parathyroid hormone. The RenaGel Study 
Group. Kidney Int. 1999 Jan;55(1):299-307. 
14. Wilkes BM, Reiner D, Kern M, Burke S. Simultaneous lowering of serum phosphate and 
LDL-cholesterol by sevelamer hydrochloride (RenaGel) in dialysis patients. Clin Nephrol. 
1998 Dec;50(6):381-6. 
15. Braun J, Asmus HG, Holzer H, Brunkhorst R, Krause R, Schulz W, et al. Long-term 
comparison of a calcium-free phosphate binder and calcium carbonate--phosphorus 
metabolism and cardiovascular calcification. Clin Nephrol. 2004 Aug;62(2):104-15. 
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NOTE: ALT 3 ULN (IF BASELINE ALT < ULN) OR ALT 2 TIMES THE BASELINE VALUE (IF BASELINE ALT  ULN) 
SHOULD BE NOTIFIED WITHIN 24 HOURS TO THE MONITORING TEAM (SEE SECTIONS 10.4.1.3 AND 10.4.5). IN 
ADDITION, IF ALT <3 ULN MEETS A SERIOUSNESS CRITERION, THE EVENT SHOULD BE NOTIFIED WITHIN 
24 HOURS TO THE MONITORING TEAM 
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SAP_001.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-002643 VERSION 7.0 (20-FEB-2019)
Page 1
STATISTICAL ANALYSIS PLAN
A randomized, double blind, parallel group study for assessing the efficacy and
safety of Renvela® tablets for the treatment of hyperphosphatemia in patients with
chronic kidney disease not on dialysis versus placebo (RECOVER Study)
GZ419831-EFC14011
Renvela® /sevelamer carbonate
STATISTICIAN:
DATE OF ISSUE: 17-Sep-2019
Total number of pages:
38
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Statistical Analysis Plan
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN ...................................................................................................................1 
TABLE OF CONTENTS..................................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................................................................4 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................5 
1.1 
STUDY DESIGN AND RANDOMIZATION ......................................................................................5 
1.2 
OBJECTIVES...................................................................................................................................5 
1.2.1 
Primary objectives............................................................................................................................5 
1.2.2 
Secondary objectives.......................................................................................................................5 
1.3 
DETERMINATION OF SAMPLE SIZE.............................................................................................5 
1.4 
STUDY PLAN...................................................................................................................................6 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL..................................6 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN .......................7 
2 
STATISTICAL AND ANALYTICAL PROCEDURES ......................................................................8 
2.1 
ANALYSIS ENDPOINTS .................................................................................................................8 
2.1.1 
Demographic and baseline characteristics ......................................................................................8 
2.1.2 
Prior or concomitant medications.....................................................................................................9 
2.1.3 
Efficacy endpoints............................................................................................................................9 
2.1.3.1 
Primary efficacy endpoint(s) ............................................................................................................9 
2.1.3.2 
Secondary efficacy endpoint(s)......................................................................................................10 
2.1.4 
Safety endpoints ............................................................................................................................10 
2.1.4.1 
Adverse events variables...............................................................................................................10 
2.1.4.2 
Deaths............................................................................................................................................12 
2.1.4.3 
Laboratory safety variables............................................................................................................12 
2.1.4.4 
Vital signs variables .......................................................................................................................12 
2.2 
DISPOSITION OF PATIENTS .......................................................................................................12 
2.2.1 
Randomization and drug dispensing irregularities.........................................................................14 
2.3 
ANALYSIS POPULATIONS...........................................................................................................14 
2.3.1 
Efficacy populations .......................................................................................................................15 
2.3.1.1 
Modified intent-to-treat population .................................................................................................15 
2.3.2 
Safety population ...........................................................................................................................15 
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2.4 
STATISTICAL METHODS .............................................................................................................15 
2.4.1 
Demographics and baseline characteristics ..................................................................................15 
2.4.2 
Prior or concomitant medications...................................................................................................16 
2.4.3 
Extent of investigational medicinal product exposure and compliance .........................................16 
2.4.3.1 
Extent of investigational medicinal product exposure....................................................................16 
2.4.3.2 
Compliance ....................................................................................................................................17 
2.4.4 
Analyses of efficacy endpoints.......................................................................................................18 
2.4.4.1 
Analysis of primary efficacy endpoint.............................................................................................18 
2.4.4.1.1 Primary efficacy analysis ...............................................................................................................18 
2.4.4.1.2 Sensitivity analysis of primary efficacy endpoint............................................................................18 
2.4.4.1.3 Subgroup analysis..........................................................................................................................18 
2.4.4.2 
Analyses of secondary efficacy endpoints.....................................................................................19 
2.4.4.3 
Multiplicity issues ...........................................................................................................................19 
2.4.5 
Analyses of safety data..................................................................................................................20 
2.4.5.1 
Analyses of adverse events ...........................................................................................................21 
2.4.5.2 
Deaths............................................................................................................................................22 
2.4.5.3 
Analyses of laboratory variables ....................................................................................................23 
2.4.5.4 
Analyses of vital sign variables ......................................................................................................23 
2.5 
DATA HANDLING CONVENTIONS ..............................................................................................23 
2.5.1 
Data handling conventions for secondary efficacy variables .........................................................23 
2.5.2 
Missing data...................................................................................................................................23 
2.5.3 
Windows for time points.................................................................................................................25 
2.5.4 
Unscheduled visits .........................................................................................................................26 
2.5.5 
Pooling of centers for statistical analyses......................................................................................26 
3 
INTERIM ANALYSIS .....................................................................................................................27 
4 
DATABASE LOCK........................................................................................................................28 
5 
SOFTWARE DOCUMENTATION .................................................................................................29 
6 
REFERENCES...............................................................................................................................30 
7 
LIST OF APPENDICES.................................................................................................................31 
APPENDIX A POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA .........................32 
APPENDIX B SUMMARY OF STATISTICAL ANALYSES ...........................................................................37 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
ATC: 
anatomic category 
BP: 
blood pressure 
CKD: 
Chronic Kidney Disease 
DBTP: 
double blind treatment period 
eCRF: 
electronic case report form 
HLGT: 
high level group term 
HLT: 
high level term 
HR: 
heart rate 
IMP: 
investigational medicinal product 
iPTH: 
intact parathyroid hormone 
IVRS: 
interactive voice response system 
IWRS: 
interactive web response system 
LDL-C: 
low density lipoprotein cholesterol 
LLT: 
Low level term 
LOCF: 
last observation carried forward 
MedDRA: 
Medical Dictionary for Regulatory Activities 
mITT: 
modified Intent To Treat 
PCSA: 
potentially clinically significant abnormality 
PT: 
preferred term 
Q1: 
first quartile 
Q3: 
third quartile 
SAE: 
serious adverse event 
SD: 
standard deviation 
SOC: 
system organ class 
TEAE: 
treatment emergent adverse event 
TID: 
3 times per day 
 
 
 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN AND RANDOMIZATION  
This is a phase III, multi-center, randomized, double blind, placebo-controlled, balanced (1:1, 
Renvela: placebo), parallel-group study to evaluate the efficacy and safety of Renvela versus 
placebo in hyperphosphatemic CKD patients not on dialysis in China. 
Eligible patients who are taking a phosphate binder at screening visit will enter a 2-week 
phosphate binder washout period. Eligible patients who are not taking a phosphate binder at 
screening visit will proceed directly to the start of the 8-week treatment period (Day 1). 
Randomization will be stratified according to baseline serum phosphorus (Ӌ5.5 – 6.0 mg/dL 
[1.78 – 1.94 mmol/L] and >6.0 mg/dL [1.94 mmol/L]). After randomization, patients will receive 
double-blind study treatment (either Renvela or placebo) over a period of 8 weeks. 
Patients will be followed for 2 weeks after the last visit of the Double Blinded Treatment Period 
(DBTP). 
1.2 
OBJECTIVES  
1.2.1 Primary objectives  
The primary objective of this study is to demonstrate efficacy of Renvela tablets in the reduction 
of serum phosphorus in hyperphosphatemia in patients with CKD not on dialysis. 
1.2.2 Secondary objectives  
The secondary objectives are: 
x To document the efficacy of Renvela tablets in the reduction of serum lipids (total 
cholesterol and low-density lipoprotein cholesterol [LDL-C]). 
x To document the efficacy of Renvela tablets in the reduction of calcium-phosphorus 
product. 
x To document the efficacy of Renvela tablets in the reduction of iPTH. 
x To document the efficacy of Renvela tablets in proportion of patients reaching the target 
serum phosphorus level (4.6 mg/dL [1.49 mmol/L], inclusive). 
x To evaluate safety of Renvela tablets. 
1.3 
DETERMINATION OF SAMPLE SIZE  
The sample size calculations are based on the primary efficacy variable of serum phosphorus 
change from baseline to Week 8, with the following assumptions: 
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x A common standard deviation (SD) of 2 mg/dL, which is assumed based on the data from 
previous trials 
x A 1 mg/dL mean difference between test and placebo in change from baseline in serum 
phosphorus 
x A t-test at a 2-sided 5% significance level with 90% power 
x Expected dropout rate = 15%. 
Based on the above assumptions, 101 patients per arm are needed for this study. Calculations 
were made using nQuery Advisor 7.0. 
1.4 
STUDY PLAN  
The following figure presents the graphical study design: 
 
x 
R=Randomization 
x 
Screening criteria: 
- 
CKD patients not on dialysis 
- 
Serum phosphorus level ≥5.5 mg/dL (1.78 mmol/L) 
x 
Stratification factor, at the time of randomization, is screening serum phosphorus (≥5.5 – 6.0 mg/dL [1.78 – 1.94 mmol/L] and >6.0 
mg/dL [1.94 mmol/L]). For eligible patients who are not taking phosphate binder(s) at screening visit, serum phosphorus at V1 will be 
used for stratification. For eligible patients who are taking phosphate binder(s) at screening visit, serum phosphorus at V1a will be 
used for stratification. 
x 
Assessment of the primary efficacy (change from baseline in serum phosphorus level) endpoint is at Week 8. 
x 
Wash out period is only for patients on phosphate binder(s) at screening. Patients not on phosphate binder(s) would proceed directly 
to the start of the 8-week treatment period (Day 1). 
x 
During the Treatment Period, patients return to the investigative site every 2 weeks. Samples for laboratory measurements are 
collected at each site visit. After the results are received from the central laboratory, the serum phosphorus results are evaluated. 
Investigator will be informed by the IVRS/IWRS for dose titration. If the serum phosphorus is ≥4.6 mg/dL (≥1.49 mmol/L), the patient 
is to be instructed by the investigator to increase their study treatment dose by 1 tablet TID with meals. If the serum phosphorus is 
<2.7 mg/dL (<0.87 mmol/L), the patient is to be instructed by the investigator to decrease their study treatment dose by 1 tablet TID 
with meals. 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
There are no major changes to the protocol statistical section. 
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The first patient was screened on 7 Jun 2016. The first patient was randomized on 21 July 2016. 
There are no planned interim analyses. 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN  
Not applicable. 
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2
STATISTICAL AND ANALYTICAL PROCEDURES
2.1
ANALYSIS ENDPOINTS
2.1.1
Demographic and baseline characteristics
The baseline value is defined as the last available value obtained up to the date and time of the 
first double-blind investigational medicinal product (IMP) administration. For patients 
randomized and not treated, the baseline value is defined as the last available value obtained up to 
the date and time of randomization.
All baseline safety and efficacy parameters (apart from those listed below) are presented along 
with summary statistics in the safety and efficacy sections (Section 2.4.4 and Section 2.4.5).
Demographic characteristics
Demographics and baseline characteristics will be listed and summarized by treatment group and
overall for randomized patients. Standard descriptive statistics will be presented for the following
continuous variables:
x
age (years) 
x
weight (kg);
x
height (cm);
x
body mass index [BMI] (kg/m2) [calculated as (weight/height2) where weight is in kg and 
height is in m];
The total counts and percentages of patients will be presented for the categorical variables of:
x
age group (years) : <45, Ӌ45 to <65, Ӌ65 to <75, and Ӌ75 years; and <65, and Ӌ65 years.
x
gender (Male, Female);
x
race (Asian, other).
x
Alcohol use within 12 months.
Disease characteristics at baseline  
Disease characteristics at baseline will be listed and summarized by treatment group and overall 
for randomized patients. Standard descriptive statistics will be presented for eGFR and total 
counts and percentages of patient will be presented for the CKD stage at baseline.
Medical and Renal history
Medical and renal history findings at Screening will be tabulated overall and by treatment group
for randomized patients, including any past and/or concomitant diseases or past surgeries, primary 
cause of chronic kidney disease (CKD) and parathyroid gland resection.
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2.1.2
Prior or concomitant medications
As specified in the protocol, all medications and therapies taken by the patient from 30 days prior 
to the signing of the informed consent through the end of the study will be recorded.
Medications will be coded to anatomic therapeutic class (ATC) term and generic name using the 
World Health Organization (WHO) Drug dictionary using the latest version at the date of DBL.
Tables will be sorted first by alphabetical ATC and then by descending frequency of generic name 
within ATC based on the prevalence across all treatment groups. The highest ATC level for each 
medication will be used for summary. Multiple records of the same drug (based on generic name) 
used by a patient are counted once within a drug class and within a generic name.
Prior medications will be summarized, both overall and by treatment group for the Safety Set, by 
ATC and generic name for all medications.
Prior medications are defined as follows:
x
Prior medications include any medications that were used within 30 days of screening visit
and prior to the date of first dose of study drug.
Concomitant medications will be summarized by treatment group for the Safety
Set, by ATC and generic name for all medications. 
Concomitant medications are defined as follows:
x
Concomitant medications include any medications used between study drug start and end 
of study.
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5.
2.1.3
Efficacy endpoints
2.1.3.1
Primary efficacy endpoint(s)
The primary endpoint is the change from baseline in serum phosphorus level at Week 8.
The baseline of serum phosphorus value will be the last serum phosphorus level obtained before 
the first double-blind IMP dosing.
The serum phosphorus at Week 8 will be the serum phosphorus level obtained within the Week 8
analysis window.
All serum phosphorus values (scheduled or unscheduled) may be used to provide a value for the
primary endpoint if appropriate according to above definition. The analysis window used to
allocate a time point to a measurement is defined in Section 2.5.3.
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2.1.3.2 Secondary efficacy endpoint(s)  
The secondary efficacy endpoints are: 
x The change from baseline in total cholesterol at Week 8 
x The change from baseline in LDL-C at Week 8 
x The change from baseline in calcium-phosphorus product at Week 8 
x The change from baseline in iPTH level at Week 8 
x Percentage of patients reaching the target serum phosphorus level (4.6 mg/dL 
[1.49 mmol/L], inclusive) at Week 8 
x The change from baseline in serum phosphorus level at Week 4. 
2.1.4 Safety endpoints  
The safety analysis will be based on the reported adverse events (AEs) and other safety 
information, such as clinical laboratory data and vital signs.  
Observation period  
The observation of safety data will be as follows: 
x Pre-treatment period: The pre-treatment observation period is defined from the signed 
informed consent up to the first dose of double-blind IMP. 
x Treatment Emergent Adverse Event (TEAE) period: The TEAE observation period is 
defined as the time from the first dose of double-blind IMP to the last dose of double-blind 
IMP+3 days. 
x Post-treatment period: The post-treatment observation period is defined as the time 
starting the day after the end of the TEAE period up to the end of the study (see definition 
in Protocol Section 6.2.1). 
2.1.4.1 Adverse events variables  
All adverse events (including serious adverse events [SAE], and  AEs of special interest) will be 
coded to a lower-level term (LLT), preferred term (PT), high-level term (HLT), high-level group 
term (HLGT), and associated primary system organ class (SOC) using the version of Medical 
Dictionary for Regulatory Activities (MedDRA) currently in effect at Sanofi at the time of 
database lock. 
Record the occurrence of adverse events (including serious adverse events and AEs of special 
interest) from the time of signed informed consent until the end of the study. 
Adverse event observation period 
Pre-treatment adverse events are adverse events that developed or worsened or became serious 
from the signed informed consent date up to first administration of the IMP. 
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Treatment-emergent adverse events (TEAE) are adverse events that developed or worsened or 
became serious during the treatment period. 
Post-treatment adverse events are adverse events that developed or worsened or became serious 
during the post-treatment period 
Serious adverse event 
A serious adverse event (SAE) is any untoward medical occurrence that: 
x Results in death, or 
x Is life-threatening, or 
Note: The term Ȕlife-threateningȕ in the definition of Ȕseriousȕ refers to an event in 
which the patient 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 were more severe. 
x Requires inpatient hospitalization or prolongation of existing hospitalization, or 
x Results in persistent or significant disability/incapacity, or 
x Is a congenital anomaly/birth defect 
x Is a medically important event 
Adverse event of special interest 
An AESI is an AE (serious or non-serious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor is required. Such events may require further investigation in order to 
characterize and understand them.  
x Pregnancy of a female subject entered in a study as well as pregnancy occurring in a 
female partner of a male subject entered in a study with IMP 
- 
Pregnancy occurring in a female patient entered in the clinical trial or in a female 
partner of a male patient entered in the clinical trial. It will be qualified as an SAE only 
if it fulfills one of the seriousness criteria 
- 
In the event of pregnancy in a female participant, IMP should be discontinued. 
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined. 
x Symptomatic overdose (serious or non-serious) with IMP/NIMP 
- 
An overdose (accidental or intentional) with the IMP/NIMP is an event suspected by 
the Investigator or spontaneously notified by the patient (not based on systematic pills 
count). Renvela is a non-absorbed drug, thus it is not possible to define a symptomatic 
overdose prospectively.  However, the investigator may use his or her judgment to 
report an event that he or she considers to be a symptomatic overdose using the 
corresponding screens in the e-CRF using the Term ȔSymptomatic OVERDOSE 
(accidental [or intentional])ȕ. The patient should be monitored and appropriate 
symptomatic treatment instituted. The circumstances of the overdose should be clearly 
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specified in the verbatim. Of note, asymptomatic overdose has to be reported as a 
standard AE. 
x Increase in alanine transaminase (ALT) (see the ĀIncrease in ALTā flow chart in 
Appendix A of the protocol). 
2.1.4.2 Deaths  
The deaths observation period are defined as below.  
x Death on-study:  deaths occurring during the on-study observation period (defined as the 
time from start of treatment until the end of the study) 
x Death on-treatment:  deaths occurring during the treatment-emergent adverse event period  
2.1.4.3 Laboratory safety variables  
The clinical laboratory data consist of hematology (complete blood count [CBC], differential, 
platelet and prothrombin time), chemistry (serum phosphorus, calcium [adjusted for albumin], 
albumin, calcium-phosphorus product, chloride, bicarbonate, uric acid, sodium, potassium, 
glucose, blood urea nitrogen [BUN], alanine aminotransferase [ALT], aspartate aminotransferase 
[AST], creatinine), and lipid panel (total cholesterol, LDL-C, high-density lipoprotein cholesterol 
[HDL-C], non-high-density lipoprotein cholesterol [non-HDL-C] and triglycerides). Laboratory 
variables which are defined as efficacy variables will not be included in the safety analysis. 
Clinical laboratory values after conversion will be analyzed into standard international units and 
international units will be used in all listings and tables. 
Blood samples for clinical laboratories will be taken at Visit 1 (Week -4), Visit 2 (Week 0), Visit 
3 (Week 2), Visit 4 (Week 4), Visit 5 (Week 6), Visit 6 (Week 8) and/or early termination unless 
otherwise specified.   
2.1.4.4 Vital signs variables  
Vital signs include: heart rate (HR), systolic blood pressure (BP) and diastolic BP, and body 
temperature in sitting position. 
2.2 
DISPOSITION OF PATIENTS  
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Screened patients are defined as any patients who met the inclusion criteria and signed the 
informed consent.   
Randomized patients consist of all patients with a signed informed consent form who have had a 
treatment kit number allocated and recorded in the IRT database, regardless of whether the 
treatment kit was used. 
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For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population. The safety experience associated with any later 
randomization will be assessed separately.
The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be in the safety population.
For patient study status, the total number of patients in each of the following categories will be 
presented in the clinical study report using a flowchart diagram or summary table:
x
Screened patients;
x
Screen failure patients and reasons for screen failure;
x
Nonrandomized but treated patients, if any;
x
Randomized patients;
x
Randomized but not treated patients;
x
Randomized and treated patients;
x
Patients who did not complete the study treatment period as per protocol;
x
Patients who discontinued study treatment by main reason for permanent treatment 
discontinuation (For the case of treatment discontinuation due to adverse event which is 
provided in CRF by investigators, medical expert will conduct a blinded review on the 
adverse event or pre-specify a rule to distinguish the “adverse event” or “CKD worsening 
underwent dialysis” before database lock);
x
Status at last study contact.
For all categories of patients (except for the screened and nonrandomized categories) percentages 
will be calculated using the number of randomized patients as the denominator divided by the 
number of exposed patients.
Reasons for treatment discontinuation will be supplied in tables giving numbers and percentages 
by treatment group.  
All critical or major deviations potentially impacting efficacy analyses, randomization, and 
drug-dispensing irregularities, and other major or critical deviations will be summarized in tables 
giving numbers and percentages of deviations by treatment group.
Additionally, the analysis populations for safety, efficacy will be summarized in a table by 
number of patients on the randomized population:
x
Randomized population
x
Efficacy population: modified intent-to-treat (mITT) population
x
Safety population
Definitions of the study population are provided in Section 2.3.
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2.2.1 Randomization and drug dispensing irregularities  
Randomization and drug-dispensing irregularities occur whenever: 
1. A randomization is not in accordance with the protocol-defined randomization method, 
such as a) an ineligible patient is randomized, b) a patient is randomized based on an 
incorrect stratum, c) a patient is randomized twice, or d) in a dynamic randomization 
scheme the treatment assignment is, in fact, not random, due to a computer program error.  
 
OR 
2. A patient is dispensed an IMP kit not allocated by the protocol-defined randomization, 
such as a) a patient at any time in the study is dispensed a different treatment kit than as 
randomized (which may or may not contain the correct-as-randomized IMP), or b) a 
nonrandomized patient is treated with IMP reserved for randomized patients. 
Randomization and drug-dispensing irregularities will be monitored throughout the study and 
reviewed on an ongoing basis.  
All randomization and drug-dispensing irregularities will be documented in the clinical study 
report.  If the number of irregularities is large enough to make a tabular summary useful, the 
irregularities will be categorized and summarized among randomized patients (number and 
percentages).  Nonrandomized, treated patients will be described separately.  
Randomization and drug-dispensing irregularities to be prospectively identified include but are 
not limited to:  
Randomization and drug allocation irregularities 
Kit dispensation without IRT transaction 
Erroneous kit dispensation 
Kit not available 
Randomization by error 
Patient randomized twice 
Stratification error 
2.3 
ANALYSIS POPULATIONS  
Patients treated without being randomized will not be considered randomized and will not be 
included in any efficacy population.   
Patients who are dispensed study drug without calling the IRT or before calling the IRT are 
considered nonrandomized patients.  They are excluded from any population for analysis, 
including safety.  However, if these patients experienced any significant safety event, they should 
be documented separately in the clinical study report. 
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2.3.1
Efficacy populations
The primary efficacy analysis population will be the mITT population.
2.3.1.1
Modified intent-to-treat population
Modified Intent-to-treat (mITT) population: The mITT population consists of all patients who are 
randomized, receive at least one dose of IMP, and have both a baseline assessment and at least 
one post-baseline assessment of phosphorus measure.
2.3.2
Safety population
Safety population: The safety population consists of all randomized patients who receive at least 
one dose of IMP.
In addition:
x
Nonrandomized but treated patients with IMP will not be part of the safety population, but 
their safety data will be presented separately.
x
Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized.
x
For patients receiving more than 1 study treatment during the trial, the treatment group 
allocation for as-treated analysis will be in Renvela group.
2.4
STATISTICAL METHODS
2.4.1
Demographics and baseline characteristics
Continuous data will be summarized using the number of available data, mean, standard 
deviation (SD), median, minimum, and maximum for each treatment group. First quartile (Q1)
and third quartile (Q3) will be provided for baseline serum phosphorus. Categorical and ordinal 
data will be summarized using the number and percentage of patients in each treatment group. 
Parameters will be summarized on the randomized population and analyzed by the treatment 
group to which they were randomized. In the randomized population, parameters will also be 
summarized within each randomization stratum as per IVRS.
Parameters described in Section 2.1.1 will be summarized by treatment group and overall 
treatment groups using descriptive statistics. 
All reported patientÿs medical and surgical history will be presented by primary SOC and PT.
The tables will be sorted by SOC internationally agreed order and decreasing frequency of PT 
based on the overall incidence across treatment groups. In addition all medical history of specific
interest (see Section 2.1.1) will be presented by treatment group.
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2.4.2
Prior or concomitant medications
The prior and concomitant medications will be presented for the safety population. 
Medications will be summarized by treatment group according to the WHO-DD dictionary, 
considering the first digit of the anatomic category (ATC) class (anatomic category) and the first 3
digits of the ATC class (therapeutic category). A given medication may be classified in more than 
1 ATC class. All ATC codes corresponding to a medication will be summarized, and patients will 
be counted once in each ATC category (anatomic or therapeutic) linked to the medication.
Therefore patients may be counted several times for the same medication. 
The table for prior medications and concomitant medications will be presented by anatomic 
category, therapeutic category and generic medication name, sorted by decreasing frequency of 
ATC and generic medication name based on the overall incidence in Renvela group. In case of 
equal frequency regarding ATCs (anatomic, therapeutic categories or generic medication name),
alphabetical order will be used.
The use of concomitant Native Vitamin D will be summarized by treatment group.
2.4.3
Extent of investigational medicinal product exposure and compliance
The extent of IMP exposure and compliance will be assessed and summarized by actual treatment 
within the safety population (Section 2.3.2).
2.4.3.1
Extent of investigational medicinal product exposure
The extent of IMP exposure will be assessed by the duration of IMP exposure, and actual dose 
information.
Duration of IMP exposure is defined as last dose date – first dose date + 1 day, regardless of 
unplanned intermittent discontinuations (see Section 2.5.2 for calculation in case of missing or 
incomplete data). Non-integer values will be rounded to 1 decimal place.
Duration of IMP exposure will be summarized using number, mean, SD, median, minimum, and 
maximum. In addition, the durations of treatment exposure will be summarized the percentage of 
patients according to the following categories: ≤2 weeks, >2weeks and ≤4 weeks, >4weeks and 
≤6 weeks, >6weeks and ≤8 weeks, and >8 weeks.
Titration
The number and percentage of patients with an up-titration or down-titration in the Renvela group 
will be described. Patients with a titration are defined as titrated patients according to IVRS/IWRS 
Week 3a, 4a and 5a, transaction with at least 1 tablet IMP intake afterwards.
Dose information will be assessed by the following variables:
x
The actual dose received is defined as total IMP dose intake.
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x
The intended dose is defined as the intended dose according to the initial dose level 
adjustment and intended dose titration due to phosphorus level or adverse events.
Dose information including average dose, final dose and highest dose will be summarized 
descriptively (number, mean, SD, median, Q1:Q3, minimum, and maximum).
2.4.3.2
Compliance
A given administration will be considered noncompliant if the patient did not take the planned
dose of treatment as required by the protocol.  No imputation will be made for patients with 
missing or incomplete data. 
1) Planned dose according to serum phosphorous level per protocol:
Planned dose at visit i= planned daily dose per serum phosphorus level at visit i * duration of the 
planned dose at visit i
Planned daily dose per phosphorus level at visit i = planned daily dose adjusted per serum 
phosphorus level at visit i based on intended dose before serum phosphorus sampling at visit i
Duration of planned dose at visit i = date of next phone call visit (visit (i+1)a) - date of phone call 
visit soon after the serum phosphorus sample (visit ia)
Given no phone call visit for visit i or visit i+1, the projected dose start or end date will be the 
serum phosphorous sampling date +3 days.
z
If the first dosing visit of visit 2, planned dose at visit 2= planned starting daily dose per serum 
phosphorus level at screening * (date of visit 2a - first dose date) + planned daily dose per 
serum phosphorus level at visit 2 * (date of visit 3a - date of visit 2a)
z
For the last scheduled dosing visit, taking visit 5 as an example, planned dose at visit 5= planned 
daily dose per serum phosphorus level at visit 5 * [last dose date - date of last phone call visit 
(visit 5a)]
2) Compliance rate = cumulative actual dose during study / (sum of planned dose per serum 
phosphorous level for all visits across study) *100%
Treatment compliance will be summarized descriptively as quantitative variables (number,
mean, SD, median, minimum, and maximum). The percentage of patients whose compliance is 
<80% will be summarized.
Cases of overdose will constitute adverse events and will be listed as such. More generally, 
dosing irregularities will be listed in Section 2.2.1.
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2.4.4
Analyses of efficacy endpoints
2.4.4.1
Analysis of primary efficacy endpoint
2.4.4.1.1 Primary efficacy analysis
The change from baseline in serum phosphorus at Week 8 as defined in Section 2.1.3.1 will be
compared between the Renvela group to the placebo group in the mITT population using stratified
Wilcoxon rank sum tests considering randomization strata (screening serum phosphorus
[Ӌ5.5 - 6.0 mg/dL or >6.0 mg/dL]). The statistical test will be two-sided tests at a nominal 5%
significance level.
If a patient discontinues the treatment prematurely or does not have serum phosphorus value at
Week 8, the last post-baseline on-treatment serum phosphorus measurement during the 8-week
double-blind period will be used for the calculation of Week 8 (Last Observation Carried Forward
[LOCF] procedure). 
2.4.4.1.2 Sensitivity analysis of primary efficacy endpoint
The following sensitivity analyses will be performed for the primary endpoint.
An analysis of covariance (ANCOVA) with the missing data imputed by LOCF will be performed 
on the primary efficacy variable. The model will include treatment (Renvela or placebo) and 
screen serum phosphorus class (Ӌ5.5 - 6.0 mg/dL [1.78 - 1.94 mmol/L] or >6.0 mg/dL [1.94 
mmol/L]) and baseline serum phosphorus level as covariates. The adjusted mean difference of
primary endpoint between two treatment groups will be provided as well as the 95% confidence 
interval and P-value.
The Markov Chain Monte Carlo (MCMC) method for multiple imputation will be used to account 
for missing values in change from baseline in serum phosphorus at Week 8. The imputation model 
will include baseline serum phosphorus level and all serum phosphorus level at all post-baseline
visits stratified by treatment group and screen serum phosphorus class. The seed used for these 
imputations will be 14011. A minimum value of 0 will be specified in order to avoid negative 
imputed Phosphorus level. 
Missing value in serum phosphorus will be imputed 100 times to generate 100 data sets with 
complete serum phosphorus values at Week 8. The change from baseline will be derived from 
observed and imputed serum phosphorus values. The completed data sets will be analyzed using 
an ANCOVA model with treatment groups, screen serum phosphorus class and baseline serum 
phosphorus level as covariates. The results from the 100 analyses will be combined using SAS 
PROC MIANALYZE.
2.4.4.1.3 Subgroup analysis
Subgroup analysis of primary endpoint will be conducted for exploratory purpose. The subgroup 
analysis include: 
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x
Screening serum phosphorus level (Ӌ5.5 - 6.0 mg/dL [1.78 - 1.94 mmol/L] or >6.0 mg/dL
[1.94 mmol/L])
x
Age (quartiles)
x
Baseline eGFR (quartiles)
x
Main cause of CKD (diabetes, hypertension and glomerulonephritis)
x
Average daily dose (quartiles) 
x
Average daily dose (quartiles) * Screening serum phosphorus level (Ӌ5.5 - 6.0 mg/dL
[1.78 - 1.94 mmol/L] or >6.0 mg/dL [1.94 mmol/L])
x
Screening serum phosphorus level (ӊ7.5 mg/dL[2.42mmol/L] or >7.5
mg/dL[>2.42mmol/L])
2.4.4.2
Analyses of secondary efficacy endpoints
All secondary endpoints will be analyzed using the mITT population.
Descriptive statistics (number, mean, SD, median, Q1, Q3, minimum, and maximum) will be 
provided by treatment for all continuous secondary variables at the scheduled visits.
All continuous secondary efficacy variables, ie, the change from baseline in serum lipids (total 
cholesterol and LDL-C), calcium-phosphorus product at Week 8, iPTH at Week 8 and serum 
phosphorus at Week 4 will be analyzed using the same test described in Section 2.4.4.1.1. For 
total cholesterol and LDL-C, sensitivity analysis of multiple imputation will not be applied. The 
same procedure for handling missing assessments/early discontinuation will also be applied as for 
the primary variable.
Proportion of patients reaching the target serum phosphorus level at Week 8 will be compared by 
treatment assignment (Renvela or placebo) using a Cochran-Mantel-Haensel method stratified by 
randomization strata (screening serum phosphorus: Ӌ5.5 - 6.0 mg/dL [1.78 - 1.94 mmol/L] or >6.0 
mg/dL [1.94 mmol/L]), the proportion difference between Renvela and placebo group and 95% 
confidence intervals will be calculated.
2.4.4.3
Multiplicity issues
In order to handle multiple key endpoints, the overall type-I error will be controlled by the use of 
a fixed sequence approach. Statistical significance of the primary parameter at the 0.05 alpha level 
is required before drawing inferential conclusions about first secondary endpoint. Inferential 
conclusions about successive secondary endpoints require statistical significance of the prior one.
The statistical inference order is as follows:
x
The change from baseline in serum phosphorus at Week 8 
x
The change from baseline in total cholesterol at Week 8
x
The change from baseline in LDL-C at Week 8
x
The change from baseline in calcium-phosphorus product at Week 8
x
The change from baseline in iPTH level at Week 8
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x
Percentage of patients reaching the target serum phosphorus level (4.6 mg/dL 
[1.49 mmol/L], inclusive) at Week 8
x
The change from baseline in serum phosphorus level at Week 4
This fixed hierarchical approach will ensure a strong control of the overall type-I error rate at the
0.05 level. No further adjustments will be made for other secondary endpoints, for which p-values 
will be provided for descriptive purpose only (no claim).
2.4.5
Analyses of safety data
The summary of safety results will be presented by treatment group. No formal inferential testing 
will be performed. Summaries will be descriptive in nature.
General common rules
All safety analyses will be performed on the safety population as defined in Section 2.3.2, unless
otherwise specified, using the following common rules:
x
Safety data in patients who do not belong to the safety population (eg, exposed but not 
randomized) will be listed separately.
x
The baseline value is defined as last available value obtained up to the date and time of the
first double-blind IMP administration, except other specified.
x
The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests, vital signs, and ECG (see 0). In case the threshold defined in the PCSA 
list for a given lab parameter is below the ULN, the following PCSA criterion will be used 
for the PCSA analysis: >PCSA threshold or > ULN (if ULN Ӌ PCSA threshold).
x
PCSA criteria will determine which patients had at least 1 PCSA during the treatment-
emergent adverse event period, taking into account all evaluations performed during the 
treatment-emergent adverse event period, including nonscheduled or repeated evaluations.  
The number of all such patients will be the numerator for the on-treatment PCSA 
percentage.
x
The treatment-emergent PCSA denominator by group for a given parameter will be based 
on the number of patients assessed for that given parameter in the treatment-emergent 
adverse event period by treatment group on the safety population.
All measurements, scheduled or unscheduled, will be assigned to analysis windows defined in 
Section 2.5.3, Table 2 in order to provide an assessment for Week 2 to Week 8 time points.
x
For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results and change from baseline values by 
visit and treatment group. Summaries will also be provided for the last on-treatment value. 
The last on-treatment value is defined as the value collected at the same day/time of the 
last administration of IMP. If this value is missing, this endpoint value will be the closest 
value prior to the last dose intake.  
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2.4.5.1
Analyses of adverse events
Generalities
The primary focus of adverse event (AE) reporting will be on treatment-emergent adverse events
(TEAEs). Pre-treatment and post-treatment adverse events will be described separately. 
If an adverse event date/time of onset (occurrence, worsening, or becoming serious) is incomplete, 
an imputation algorithm will be used to classify the adverse event as pre-treatment, treatment-
emergent, or post-treatment. The algorithm for imputing date/time of onset will be conservative 
and will classify an adverse event as treatment emergent unless there is definitive information to 
determine it is pre-treatment or post-treatment. Details on classification of adverse events with
missing or partial onset dates are provided in Section 2.5.2.
Adverse event incidence tables will present by SOC, HLGT, HLT, and PT, sorted in alphabetical 
order for each treatment group, the number (n) and percentage (%) of patients experiencing an 
adverse event. Multiple occurrences of the same event in the same patient will be counted only 
once in the tables within a treatment phase. The denominator for computation of percentages is 
the safety population within each treatment group.
Sorting within tables ensures the same presentation for the set of all adverse events within the 
observation period (pre-treatment, treatment-emergent, and post-treatment). For that purpose, the 
table of all treatment-emergent adverse events presented by SOC and PT sorted by the 
internationally agreed SOC order and decreasing frequency of PTs within SOCs will define the 
presentation order for all other tables unless otherwise specified. Sorting will be based on results 
for the experimental treatment arm. The tables of AEs by SOC, HLGT, HLT, and PT will be 
sorted by the SOC internationally agreed order and the other levels (HLGT, HLT, and PT) will be 
presented in alphabetical order, unless otherwise specified.
Analysis of all treatment-emergent adverse events
The following treatment-emergent adverse event summaries will be generated for the safety 
population.
x
Overview of treatment-emergent adverse events, summarizing number (%) of patients 
with any
-
Treatment-emergent adverse event
-
Serious treatment-emergent adverse event
-
Treatment-emergent adverse event leading to death
-
Treatment-emergent adverse event leading to permanent treatment discontinuation
x
All treatment-emergent adverse event by primary SOC, HLGT, HLT, and PT, showing 
number (%) of patients with at least 1 treatment-emergent adverse event sorted by the 
SOC internationally agreed order. 
x
All treatment-emergent adverse events by primary SOC and PT, showing the number (%) 
of patients with at least 1 treatment-emergent adverse event.
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x All treatment-emergent adverse events related to IMP by primary SOC and PT, showing 
the number (%) of patients with at least 1 treatment-emergent adverse event, sorted by the 
internationally agreed SOC order.  
x All treatment-emergent adverse events by maximal severity, presented by primary SOC 
and PT, showing the number (%) of patients with at least 1 treatment-emergent adverse 
event by severity (i.e., mild, moderate, or severe), sorted by the sorting order defined 
above. 
Analysis of all treatment emergent serious adverse event(s) 
x All treatment-emergent serious adverse events by primary SOC and PT, showing the 
number (%) of patients with at least 1 serious treatment-emergent adverse event. 
x All treatment-emergent serious adverse events related to IMP, by primary SOC and PT, 
showing the number (%) of patients with at least 1 treatment-emergent serious adverse 
event, sorted by the internationally agreed SOC order.   
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
x All treatment-emergent adverse events leading to treatment discontinuation, by primary 
SOC and PT, showing the number (%) of patients sorted by the internationally agreed 
SOC order.   
x All treatment-emergent adverse events related to IMP leading to treatment discontinuation, 
by primary SOC and PT, showing the number (%) of patients sorted by the internationally 
agreed SOC order.   
Analysis of all treatment-emergent adverse event(s) of special interest 
x All treatment-emergent adverse events of special interest, by primary SOC and PT, 
showing the number (%) of patients sorted by the internationally agreed SOC order.   
Analysis of pre-treatment and post-treatment adverse events 
x All pre-treatment AEs by primary SOC and PT, sorted by the internationally agreed SOC 
order and decreasing incidence of PTs (in the Renvela group) within each SOC. 
x All post-treatment AEs by primary SOC and PT, sorted by the internationally agreed SOC 
order and decreasing incidence of PTs (in the Renvela group) within each SOC. 
2.4.5.2 Deaths  
The following summaries of deaths will be generated for the safety population. 
x Number (%) of patients who died by study period (on-study, on TEAE period, post-study) 
and reasons for death if collected in the death report form. 
x Deaths in nonrandomized patients or randomized but not treated patients. 
x Treatment-emergent adverse events leading to death (death as an outcome on the adverse 
event case report form page as reported by the Investigator) by primary SOC , HLGT, 
HLT, and PT showing number (%) of patients sorted by internationally agreed SOC order, 
with HLGT, HLT, and PT presented in alphabetical order within each SOC.  
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2.4.5.3
Analyses of laboratory variables
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all laboratory variables (central laboratory values and changes from baseline) will 
be calculated for each visit or study assessment (baseline, each post baseline time point, last on-
treatment) by treatment group.  This section will be organized by biological function as specified 
in Section 2.1.4.3.
The incidence of PCSAs (list provided in 0) at any time during the treatment-emergent adverse 
event period will be summarized by biological function and treatment group whatever the baseline 
level and/or according to the following baseline status categories: 
x
Normal/missing
x
Abnormal according to PCSA criterion 
For parameters for which no PCSA criteria are defined, similar table(s) using the normal range 
will be provided.
2.4.5.4
Analyses of vital sign variables
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all vital signs variables (central laboratory values and changes from baseline) will 
be calculated for each visit or study assessment (baseline, each post-baseline time point, last on-
treatment) by treatment group.  
The incidence of PCSAs at any time during the treatment-emergent adverse event period will be 
summarized by treatment group irrespective of the baseline level and according to the following 
baseline status categories: 
x
Normal/missing
x
Abnormal according to PCSA criterion or criteria
2.5
DATA HANDLING CONVENTIONS
2.5.1
Data handling conventions for secondary efficacy variables
See Section 2.4.4.2 Analysis of secondary endpoints.
2.5.2
Missing data
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified. When relevant, the number of patients with missing data 
is presented.
Handling of missing/partial dates for medical history
Time from diagnosis of chronic kidney disease or resection (years) = (Date of informed consent –
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Date of diagnosis*) / 365.25. 
*In case the day of diagnosis would be missing, it will be imputed as to 01. In case the month of 
diagnosis would be missing, it will be imputed as 01JANUARY if the year of diagnosis equals the 
year of informed consent; it will be imputed as 01JULY if the year of diagnosis does not equal the 
year of informed consent. 
 
Handling of baseline definition if time of first double-blind administration or time of 
assessment at Week 0 visit is missing 
If the time of the first double-blind administration or time assessment at Week 0 visit is missing 
then the baseline value is defined as the last available value obtained before or on the day of the 
first double-blind IMP administration. 
Handling of computation of treatment duration and compliance if investigational medicinal 
product end of treatment date is missing 
For the calculation of the treatment duration, the date of the last dose of IMP is equal to the date 
of last administration reported on the end-of-treatment case report form page.  If this date is 
missing, the exposure duration should be left as missing.  
The last dose intake should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 
Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed.  If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior and concomitant medication. 
Handling of adverse events when date and time of first investigational medicinal product 
administration is missing 
When the date and time of the first IMP administration is missing, all adverse events that occurred 
on or after the day of randomization should be considered as treatment-emergent adverse events.  
The exposure duration should be kept as missing. 
The last dose intake should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 
Handling of missing assessment of relationship of adverse events to investigational medicinal 
product  
If the assessment of the relationship to IMP is missing, then the relationship to IMP has to be 
assumed and the adverse event considered as such in the frequency tables of possibly related 
adverse events, but no imputation should be done at the data level. 
Handling of missing severity of adverse events 
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If the severity is missing for 1 of the treatment-emergent occurrences of an adverse event, the 
maximal severity on the remaining occurrences will be considered.  If the severity is missing for 
all the occurrences, a “missing” category will be added in the summary table. 
Handling of potentially clinically significant abnormalities  
If a patient has a missing baseline he will be grouped in the category “normal/missing at 
baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; e.g., for eosinophils the PCSA is > 0.5 GIGA/L or >ULN 
if ULN Ӌ0.5 GIGA/L.  When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values.  
2.5.3 Windows for time points  
Data analyzed by time point (including efficacy, laboratory safety data, and vital signs) will be 
summarized using the analysis windows given in Table 2. These analysis windows will be 
applicable for all analyses, and they are defined to provide more homogeneous data for time 
point-specific analyses. 
Table 1 - Analysis windows definition  
Time point 
Targeted study day 
Analysis window in study days 
Week 2 
15 
2 to 22 
Week 4 
29 
23 to 36 
Week 6 
43 
37 to 50 
Week 8 
57 
51 to 64 
Follow-up 
71 
65 ~ 
 
For the case multiple visit dates fall into the same analysis window, the one close to the targeted 
study day is applied. In case of two visit dates are equally close to targeted date, the original 
record of visit will be applied. For the Week 8, the analysis visit should use the one close to the 
last IMP dose intake.  
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2.5.4 Unscheduled visits  
For efficacy, safety laboratory data, and vital signs, unscheduled visit measurements may be used 
to provide a measurement for a time point, a baseline, a last or a worst value, if appropriate 
according to their definitions. The measurements may also be used to determine abnormal/PCSA. 
2.5.5 Pooling of centers for statistical analyses  
Not applicable. 
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3 
INTERIM ANALYSIS  
Not applicable. 
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4 
DATABASE LOCK  
The database is planned to be locked 5 weeks after last patient last visit. 
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5 
SOFTWARE DOCUMENTATION  
All summaries and statistical analyses will be generated using SAS version 9.2 or higher. 
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6 
REFERENCES  
 
Not applicable. 
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7
LIST OF APPENDICES
Appendix A:
Potentially clinically significant abnormalities (PCSA) criteria
Appendix B:
Summary of statistical analyses 
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Appendix A Potentially clinically significant abnormalities criteria  
 
Parameter 
PCSA 
Comments 
Clinical Chemistry 
ALT 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be 
expressed in ULN, not in IU/L.  
Concept paper on DILI – FDA 
draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows 
following one mentioning zero 
can be deleted. 
AST 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be 
expressed in ULN, not in IU/L.  
Concept paper on DILI – FDA 
draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows 
following one mentioning zero 
can be deleted. 
Alkaline Phosphatase 
>1.5 ULN 
Enzymes activities must be 
expressed in ULN, not in IU/L. 
Concept paper on DILI – FDA 
draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Total Bilirubin 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in 
μmol/L or mg/L. Categories are 
cumulative. 
Concept paper on DILI – FDA 
draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Conjugated Bilirubin 
>35% Total Bilirubin and TBILI>1.5 ULN 
Conjugated bilirubin dosed on a 
case-by-case basis. 
ALT and Total Bilirubin 
ALT>3 ULN and TBILI>2 ULN 
Concept paper on DILI – FDA 
draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
To be counted within a same 
treatment phase, whatever the 
interval between measurement. 
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Parameter 
PCSA 
Comments 
CPK 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows 
following one mentioning zero 
can be deleted. 
CLcr (mL/min) 
(Estimated creatinine clearance 
based on the Cokcroft-Gault 
equation)  
<15 (end stage renal disease) 
Ӌ15 - <30 (severe decrease in GFR) 
Ӌ30 - < 60 (moderate decrease in GFR) 
Ӌ60 - <90 (mild decrease in GFR) 
Ӌ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with 
impaired renal function-study 
design, data analysis, and impact 
on dosing and labeling 
eGFR (mL/min/1.73m2) 
(Estimate of GFR based on an 
MDRD equation)  
 
<15 (end stage renal disease) 
Ӌ15 - <30 (severe decrease in GFR) 
Ӌ30 - <60 (moderate decrease in GFR) 
Ӌ60 - <90 (mild decrease in GFR) 
Ӌ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with 
impaired renal function-study 
design, data analysis, and impact 
on dosing and labeling 
Creatinine 
Ӌ150 ȣmol/L (Adults) 
Ӌ30% change from baseline 
Ӌ100% change from baseline 
Benichou C., 1994. 
 
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L 
<120 μmol/L  
Harrison- Principles of internal 
Medicine 17th Ed., 2008. 
Blood Urea Nitrogen 
Ӌ17 mmol/L 
 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
Sodium 
ӊ129 mmol/L 
Ӌ160 mmol/L 
 
Potassium 
<3 mmol/L 
Ӌ5.5 mmol/L 
FDA Feb 2005. 
Total Cholesterol 
Ӌ7.74 mmol/L  
Threshold for therapeutic 
intervention. 
Triglycerides 
Ӌ4.6 mmol/L 
Threshold for therapeutic 
intervention. 
Lipasemia 
Ӌ3 ULN 
 
Amylasemia 
Ӌ3 ULN 
 
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Parameter 
PCSA 
Comments 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
ӊ3.9 mmol/L and <LLN 
Ӌ11.1 mmol/L (unfasted); Ӌ7 mmol/L (fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>8% 
 
Albumin 
ӊ25 g/L 
 
CRP 
>2 ULN or >10 mg/L (if ULN not provided) 
 FDA Sept 2005. 
Hematology 
WBC 
<3.0 Giga/L (Non-Black); <2.0 Giga/L (Black) 
Ӌ16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no 
differential count available. 
Lymphocytes 
>4.0 Giga/L 
 
Neutrophils 
<1.5 Giga/L (Non-Black);<1.0 Giga/L (Black) 
International Consensus meeting 
on drug-induced blood cytopenias, 
1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L 
 
Basophils 
>0.1 Giga/L 
 
Eosinophils 
>0.5 Giga/L or >ULN (if ULNӋ0.5 Giga/L) 
Harrison- Principles of internal 
Medicine 17th Ed., 2008. 
Hemoglobin 
ӊ115 g/L (Male); ӊ95 g/L (Female) 
Ӌ185 g/L (Male); Ӌ165 g/L (Female) 
 
Decrease from Baseline Ӌ20 g/L 
Criteria based upon decrease from 
baseline are more relevant than 
based on absolute value. Other 
categories for decrease from 
baseline can be used (Ӌ30 g/L, Ӌ
40 g/L, Ӌ50 g/L). 
Hematocrit 
ӊ0.37 v/v (Male) ; ӊ0.32 v/v (Female) 
Ӌ0.55 v/v (Male) ; Ӌ0.5 v/v (Female) 
 
RBC 
Ӌ6 Tera/L 
Unless specifically required for 
particular drug development, the 
analysis is redundant with that of 
Hb. 
Otherwise, consider FDA criteria. 
Platelets 
<100 Giga/L 
Ӌ700 Giga/L 
International Consensus meeting 
on drug-induced blood cytopenias, 
1991. 
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Parameter 
PCSA 
Comments 
Urinalysis 
pH 
ӊ4.6 
Ӌ8 
 
Vital signs 
HR 
ӊ50 bpm and decrease from baseline Ӌ20 bpm 
Ӌ120 bpm and increase from baselineӋ20 bpm 
To be applied for all positions 
(including missing) except 
STANDING. 
SBP 
ӊ95 mmHg and decrease from baseline Ӌ
20mmHg 
Ӌ160 mmHg and increase from baseline Ӌ20 
mmHg 
To be applied for all positions 
(including missing) except 
STANDING. 
DBP 
ӊ45 mmHg and decrease from baseline Ӌ10 
mmHg 
Ӌ110 mmHg and increase from baseline Ӌ10 
mmHg 
To be applied for all positions 
(including missing) except 
STANDING. 
Orthostatic Hypotension 
Orthostatic SDB 
Orthostatic DBP 
 
 
ӊ-20 mmHg 
ӊ-10 mmHg 
 
Weight 
Ӌ5% increase from baseline  
Ӌ5% decrease from baseline 
FDA Feb 2007. 
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Parameter 
PCSA 
Comments 
ECG 
Ref.: ICH E14 guidance (2005) 
and E14 Q&A (2012), and 
Cardiac Safety Research 
Consortium White Paper on PR 
and QRS (Nada et al. Am Heart J. 
2013; 165(4) : 489-500) 
HR 
<50 bpm 
<50 bpm and decrease from baseline Ӌ20 bpm 
<40 bpm 
<40 bpm and decrease from baseline Ӌ20 bpm 
<30 bpm 
<30 bpm and decrease from baseline Ӌ20 bpm 
 
>90 bpm 
>90 bpm and increase from baseline Ӌ20bpm 
>100 bpm  
>100 bpm and increase from baseline Ӌ20bpm 
>120 bpm  
>120 bpm and increase from baseline Ӌ20 bpm 
Categories are cumulative 
 
 
 
 
 
 
Categories are cumulative 
 
PR 
>200 ms 
>200 ms and increase from baseline Ӌ25% 
> 220 ms 
>220 ms and increase from baseline Ӌ25% 
> 240 ms 
> 240 ms and increase from baseline Ӌ25% 
Categories are cumulative 
 
QRS 
>110 ms 
>110 msec and increase from baseline Ӌ25% 
>120 ms 
>120 ms and increase from baseline Ӌ25% 
Categories are cumulative 
QT 
>500 ms 
 
QTc 
 
Absolute values (ms) 
 
 
>450 ms 
>480 ms 
>500 ms 
 
Increase from baseline 
Increase from baseline ]30-60] ms 
Increase from baseline >60 ms 
To be applied to any kind of QT 
correction formula.  
Absolute values categories are 
cumulative 
 
QTc >480 ms and 'QTc>60 ms 
are the 2 PCSA categories to be 
identified in individual 
subjects/patients listings. 
 
 
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Appendix B Summary of statistical analyses  
 
EFFICACY ANALYSIS 
Endpoint 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
Primary endpoint 
Serum Phosphorus Level 
Change from baseline at 
Week 8 
mITT 
Stratified Wilcoxon rank sum tests 
ANCOVA 
Multiple Imputation 
Yes 
No 
Secondary endpoints 
Total cholesterol change 
from baseline at Week 8 
mITT 
Stratified Wilcoxon rank sum test 
ANCOVA 
No 
No 
LDL-Cat change from 
baseline at Week 8 
mITT 
Stratified Wilcoxon rank sum test 
ANCOVA 
No 
No 
Calcium-phosphorus 
product change from 
baseline at Week 8 
mITT 
Stratified Wilcoxon rank sum test 
ANCOVA 
Multiple Imputation 
No 
No 
iPTH level change from 
baseline at Week 8 
mITT 
Stratified Wilcoxon rank sum test 
ANCOVA 
Multiple Imputation 
No 
No 
Serum Phosphorus level 
change from baseline at 
Week 4 
mITT 
Stratified Wilcoxon rank sum test 
ANCOVA 
Multiple Imputation 
No 
No 
Percentage of patients 
reaching target serum 
phosphorus level at Week 8 
mITT 
Cochran-Mantel-Haensel Method 
Yes 
Multiple Imputation 
No 
No 
 
 
 
 
 
 
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SAFETY ANALYSES 
Endpoint 
Analysis 
population 
Primary analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
Adverse events 
Safety 
Follow safety guidelines 
No 
No 
No 
Deaths 
Safety 
Follow safety guidelines 
No 
No 
No 
Laboratory safety 
Safety 
Follow safety guidelines 
No 
No 
No 
Vital signs 
Safety 
Follow safety guidelines 
No 
No 
No 
 
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