Clinical trial NCT01696279
Conditions: Chronic Kidney Disease Hyperphosphatemia
Sponsor: Shire
Start date: 2013-02-15; Completion date: 2018-11-16
Enrollment: 63 participants; Allocation: NON_RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to summarize the percentage of participants achieving age-specific Kidney Disease Outcomes Quality Initiative (KDOQI) targets for serum phosphorus in hyperphosphatemic children and adolescents with chronic kidney disease (CKD) who are on dialysis, following 8 weeks of treatment with lanthanum carbonate.

Detailed description:

Arms: arm 1: Participants will receive lanthanum carbonate orally at a total daily dose of 1500 mg to 3000 mg divided and mixed equally between in three meals. arm 2: Participants will receive calcium carbonate orally at a total daily dose adjusted as appropriate, until the target serum phosphorus level is achieved or until a maximum daily dose of 6500 mg is reached.
Interventions: intervention 1: Lanthanum Carbonate intervention 2: Calcium Carbonate
Intervention descriptions: intervention 1: Lanthanum Carbonate 1500 mg to 3000 mg powder will be administered orally. intervention 2: Calcium carbonate will be administered orally at a total daily dose based on standard clinical practice. The total daily dose may be adjusted as appropriate, until the target serum phosphorus level is achieved or until a maximum daily dose of 6500 mg is reached.

Protocol documents:
Prot_000.pdf: 














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Protocol SPD405-207
18 Oct 2016 
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES...........................................................................................................3
EMERGENCY CONTACT INFORMATION................................................................................8
PRODUCT QUALITY COMPLAINTS..........................................................................................9
TABLE OF CONTENTS...............................................................................................................10
LIST OF TABLES.........................................................................................................................14
LIST OF FIGURES .......................................................................................................................14
LIST OF APPENDICES................................................................................................................14
ABBREVIATIONS .......................................................................................................................15
DEFINITIONS...............................................................................................................................17
STUDY SYNOPSIS ......................................................................................................................21
STUDY SCHEDULE(S) ...............................................................................................................29
1.
BACKGROUND INFORMATION.......................................................................................38
1.1
Condition Background and Current Treatment........................................................38
1.2
Product Background.................................................................................................38
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................38
2.1
Rationale for the Study.............................................................................................38
2.2
Study Objectives ......................................................................................................39
2.2.1
Primary Objective..................................................................................................39
2.2.2
Secondary Objectives.............................................................................................39
3.
STUDY DESIGN ...................................................................................................................40
3.1
Study Design ............................................................................................................40
3.2
Number and Type of Subjects..................................................................................43
3.3
Investigational Product.............................................................................................43
3.4
Sites and Regions .....................................................................................................44
4.
STUDY POPULATION.........................................................................................................44
4.1
Inclusion Criteria......................................................................................................44
4.2
Exclusion Criteria.....................................................................................................44
4.3
Reproductive Potential .............................................................................................45
4.4
Restrictions...............................................................................................................45
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................47
5.1
Prior Treatment ........................................................................................................47
5.2
Concomitant Treatment............................................................................................47


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6.
INVESTIGATIONAL PRODUCT ........................................................................................48
6.1
Identity of Investigational Product...........................................................................48
6.2
Administration of Investigational Product(s)...........................................................48
6.2.1
Dosing....................................................................................................................48
6.2.2
Blinding the Treatment Assignment......................................................................50
6.2.3
Allocation of Subjects to Treatment ......................................................................50
6.2.4
Unblinding the Treatment Assignment..................................................................50
6.3
Labelling, Packaging, Storage, and Handling..........................................................50
6.3.1
Labelling ................................................................................................................50
6.3.2
Packaging...............................................................................................................51
6.3.3
Storage ...................................................................................................................51
6.3.4
Handling.................................................................................................................52
6.4
Investigational Product Quality Complaints ............................................................52
6.5
Drug Accountability.................................................................................................52
6.6
Subject Compliance..................................................................................................53
7.
STUDY PROCEDURES........................................................................................................53
7.1
Study Schedule.........................................................................................................53
7.1.1
Screening Period....................................................................................................53
7.1.1.1
Part 1: Screening Visit Part 1 (Visit 1.0, Week -5).......................................53
7.1.1.2
Part 2a: Screening Visit (Visit 2.0; Week 0).................................................54
7.1.1.3
Part 2b: Screening Visit (Visit 1.0; Week 0) ................................................55
7.1.1.4
Washout (W1)...............................................................................................56
7.1.2
Treatment Period....................................................................................................57
7.1.2.1
Part 1: Visit 1.1/ Week -5 to -1 (3 Days)....................................................57
7.1.2.2
Part 2a: Visits 2.1-2.3 (Weeks 2, 4, and 6; 3 Days)....................................57
7.1.2.3
Part 2a: Visit 2.4 (Week 8; 3 Days)............................................................58
7.1.2.4
Part 2a: Washout (W2)..................................................................................58
7.1.2.5
Part 2a: Visits 2.5-2.7 (Weeks 10, 12, and 14, Nominally; 3 Days)...........59
7.1.2.6
Part 2a: Final Visit (Visit 2.8; Week 16 Nominally; 3 Days).....................59
7.1.2.7
Part 2b: Visits 2.1-2.3 (Weeks 2, 4, and 6; Nominally; 3 Days) ................59
7.1.2.8
Part 2b: Final Visit (Visit 2.4; Week 8; Nominally; 3 Days) .....................60
7.1.2.9
Part 3 (Visits 3.0-3.4: Weeks 20, 24, 28, 32, and 36; 1 Week for Part 
2a; Weeks 12, 16, 20, 24, and 28 for Part 2b)........................................60
7.1.2.10 End of Part 3 (Visit 3.5: Week 40/ End of Study for Part 2a; Week 
32/End of Study for Part 2b; 1 Week)..................................................61
7.1.3
Follow-up Period ...................................................................................................61
7.1.4
Additional Care of Subjects After the Study .........................................................61
7.2
Study Evaluations and Procedures ...........................................................................61


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7.2.1
Demographic and Other Baseline Characteristics .................................................61
7.2.2
Efficacy..................................................................................................................61
7.2.3
Safety .....................................................................................................................62
7.2.3.1
Medical and Medication History ..................................................................62
7.2.3.2
Physical Examination....................................................................................62
7.2.3.3
Adverse Event Collection .............................................................................62
7.2.3.4
Vital Signs.....................................................................................................62
7.2.3.5
Clinical Laboratory Evaluations ...................................................................62
7.2.3.6
Pregnancy Test..............................................................................................64
7.2.3.7
Electrocardiogram.........................................................................................64
7.2.4
Others.....................................................................................................................64
7.2.4.1
Clinical Pharmacology Assessments ............................................................64
7.2.4.2
Pharmacodynamic Assessments ...................................................................65
7.2.4.3
Quality of Life Assessments.........................................................................65
7.2.4.4
Health Outcomes Assessments .....................................................................65
7.2.5
Volume of Blood to be Drawn From Each Subject...............................................65
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................66
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................66
8.1.1
Severity Categorization..........................................................................................66
8.1.2
Relationship Categorization...................................................................................67
8.1.3
Outcome Categorization ........................................................................................67
8.1.4
Symptoms of the Disease Under Study .................................................................67
8.1.5
Clinical Laboratory Evaluations ............................................................................68
8.1.6
Pregnancy...............................................................................................................68
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................68
8.2
Serious Adverse Event Procedures ..........................................................................69
8.2.1
Reference Safety Information................................................................................69
8.2.2
Reporting Procedures.............................................................................................69
8.2.3
Serious Adverse Event Definition .........................................................................70
8.2.4
Serious Adverse Event Collection Timeframe ......................................................70
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................70
8.2.6
Fatal Outcome........................................................................................................71
8.2.7
Regulatory Agency, Institutional Review Board, Independent Ethics 
Committee, and Site Reporting..............................................................................71
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................71
9.1
Data Collection.........................................................................................................71
9.2
Clinical Data Management.......................................................................................72
9.3
Statistical Analysis Process......................................................................................72


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9.4
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......72
9.5
Selection of Subjects to be Included in the Analyses...............................................72
9.6
Subject Disposition ..................................................................................................73
9.7
Demographic and Baseline Characteristics..............................................................74
9.8
Investigational Product Exposure.............................................................................74
9.9
Prior and Concomitant Medication ..........................................................................74
9.10
Efficacy Analyses.....................................................................................................75
9.10.1 Primary Efficacy Variable .....................................................................................75
9.10.2 Secondary Variables ..............................................................................................75
9.10.3 Tertiary Efficacy Variables....................................................................................76
9.11
Safety Analyses........................................................................................................76
9.12
Other Analyses .........................................................................................................76
9.12.1 Pharmacokinetic Analyses.....................................................................................76
9.13
Sample Size Calculation and Power Considerations................................................77
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................78
10.1
Sponsor’s Responsibilities .......................................................................................78
10.1.1 Good Clinical Practice Compliance.......................................................................78
10.1.2 Indemnity/Liability and Insurance.........................................................................78
10.1.3 Public Posting of Study Information......................................................................78
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Independent Ethics Committees......................78
10.1.5 Study Suspension, Termination, and Completion..................................................79
10.2
Investigator’s Responsibilities .................................................................................79
10.2.1 Good Clinical Practice Compliance.......................................................................79
10.2.2 Protocol Adherence and Investigator Agreement..................................................79
10.2.3 Documentation and Retention of Records.............................................................80
10.2.3.1 Case Report Forms........................................................................................80
10.2.3.2 Recording, Access, and Retention of Source Data and Study Documents...80
10.2.3.3 Audit/Inspection............................................................................................81
10.2.3.4 Financial Disclosure......................................................................................81
10.3
Ethical Considerations..............................................................................................81
10.3.1 Informed Consent...................................................................................................81
10.3.2 Institutional Review Board or Independent Ethics Committee .............................82
10.4
Privacy and Confidentiality......................................................................................82
10.5
Publication Policy ....................................................................................................83
11. REFERENCES .......................................................................................................................85
12. APPENDICES ........................................................................................................................86


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CONFIDENTIAL
Page 14
Protocol SPD405-207
18 Oct 2016 
LIST OF TABLES
Table 1:  Schedule of Assessments for Part 1, Part 2a (Treatment Periods 1 and 2), and 
Part 3..............................................................................................................29
Table 2:  Detailed Schedule of Assessments for Visit 1.1 in Part 1 ........................................34
Table 3:  Schedule of Assessments for Part 2b and Part 3.......................................................35
Table 4:  Common Excluded Treatments and Washout Period...............................................47
Table 5:  Volume of Blood to be Drawn From Each Subject..................................................65
LIST OF FIGURES
Figure 1:
Study Design Flow Chart- Part 1, Part 2a (Treatment Periods 1 and 2) 
and Part 3.......................................................................................................42
Figure 2:
Study Design Flow Chart- Part 2b and Part 3 ...............................................43
LIST OF APPENDICES
APPENDIX 1 Protocol History .............................................................................................86
APPENDIX 2 Guidelines for Phosphorus and Calcium......................................................101


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Protocol SPD405-207
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ABBREVIATIONS
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine transaminase (SGPT)
AST
aspartate transaminase (SGOT)
AUC
area under the curve
AUC0-t
area under the plasma concentration-time curve from time zero to the time 
of the last quantifiable concentration
CFR
Code of Federal Regulations
CKD
chronic kidney disease
Cmax
maximum plasma concentration
CRF
case report form
CRO
Contract Research Organization
ECG
electrocardiogram
EOS
End of Study
EU
European Union
FAS
Full Analysis Set
FGF-23
fibroblast growth factor 23
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
KDOQI
Kidney Disease Outcomes Quality Initiative
LAR
legally authorized representative
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
PP
Per-protocol
PTH
parathyroid hormone
RBC
red blood cell
SAE
serious adverse event
SCS
Safety Completer Set
t½
apparent terminal-phase disposition half-life


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Protocol SPD405-207
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TEAE
treatment-emergent adverse event
TRAP
tartrate-resistant acid phosphatase
WBC
white blood cell
z
apparent terminal-phase disposition rate constant


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CONFIDENTIAL
Page 17
Protocol SPD405-207
18 Oct 2016 
DEFINITIONS
Term
Definition
Abuse
Persistent or sporadic intentional intake of investigational product 
when used for a non-medical purpose (eg, to alter one’s state of 
consciousness or get high) in a manner that may be detrimental to 
the individual and/or society.
Adverse Event
Any untoward medical occurrence in a clinical investigation 
subject administered a pharmaceutical product and that does not 
necessarily have a causal relationship with this treatment.  An 
adverse event (AE) can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.
Adverse Event Relationship
Related:
The temporal relationship between the event and the 
administration of the investigational product is compelling and/or 
follows a known or suspected response pattern to that product, 
and the event cannot be explained by the subject’s medical 
condition, other therapies, or accident.
Not Related:
The event can be readily explained by other factors such as the 
subject’s underlying medical condition, concomitant therapy, or 
accident and no plausible temporal or biologic relationship exists 
between the investigational product and the event.
Adverse Event Severity
Mild:
A type of AE that is usually transient and may 
require only minimal treatment or therapeutic 
intervention.  The event does not generally 
interfere with usual activities of daily living.
Moderate:
A type of AE that is usually alleviated with 
specific therapeutic intervention.  The event 
interferes with usual activities of daily living, 
causing discomfort but poses no significant or 
permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of 
daily living, or significantly affects clinical status, 
or may require intensive therapeutic intervention.


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Protocol SPD405-207
18 Oct 2016 
Term
Definition
Baseline
Baseline is the last assessment prior to the first dose of 
investigational product in each treatment period.
Investigational Product
A pharmaceutical form of an active ingredient or placebo being 
tested or used as a reference in a clinical (ie, human) study.  
Investigational product also includes biologics, medical devices, 
and ‘Investigational Medicinal Product’ (IMP) as referenced in 
the European Communities (EC) Directive 2001/20/EC.  It 
includes a product with a marketing authorization (ie, marketed 
product) when:

Used or assembled (eg, formulated, packaged) in a way 
different from the approved form,

Used for an unapproved indication, or

Used to gain further information about an approved use.
Medication Error
An error made in prescribing, dispensing, administration, and/or 
use of an investigational product.  For studies, medication errors 
are reportable to the Sponsor only as defined in this protocol (see 
Section 8.1.7).
Misuse
Intentional use of investigational product other than as directed or 
indicated at any dose (Note: this includes a situation where the 
investigational product is not used as directed at the dose 
prescribed by the protocol).
Overdose
Intentional or unintentional intake of a dose of an investigational 
product exceeding a pre-specified total daily dose of 3000mg of 
lanthanum or 6500mg calcium.
Primary Completion Date
The date that the final subject was examined or received an 
intervention for the purposes of final collection of data for the 
primary outcome (Last Subject Last Visit in most cases).  Note:  
This date is used to ascertain timing for study results posting.
Product Quality Complaint
Any communication received which suggests that the quality or 
performance of a Shire marketed product or investigational 
product does not meet expectations or that the product did not 
meet the specifications defined in the regulatory applications/
licenses/marketing authorizations for the product.
Examples (but not limited to):

Wrong product (label and contents are different products)

Correct product but wrong strength


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Page 19
Protocol SPD405-207
18 Oct 2016 
Term
Definition

Product contamination

Product mix (“rogues” within a pack)

Counterfeit or deliberately tampered-with product within the 
distribution chain

Label or leaflet missing information, or providing misleading 
information

Missing label on primary packaging

Inadequate/faulty closure

Empty capsule

Overfilled capsule

Bottle fill shortage or overage

Vial fill shortage or overage

Broken/chipped tablets

Broken/damaged capsules

Broken/cracked vial
Screen Failure
A subject who has given informed consent and failed to meet the 
inclusion and/or meet at least 1 of the exclusion criteria and/or has 
not been randomized or administered investigational product(s) as 
defined by the protocol.
Serious Adverse Event
Any untoward medical occurrence (whether considered to be 
related to investigational product or not) that at any dose:

Results in death

Is life-threatening

Requires inpatient hospitalization or prolongation of existing 
hospitalization

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event.  Note: Important medical 
events that may not result in death, be life-threatening, or 
require hospitalisation may be considered a serious adverse 
event (SAE) when, based upon appropriate medical judgment, 
they may jeopardise the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this 
definition.  Examples of such medical events include allergic 


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CONFIDENTIAL
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Protocol SPD405-207
18 Oct 2016 
Term
Definition
bronchospasm requiring intensive treatment in an emergency 
room or at home; blood dyscrasias or convulsions that do not 
result in inpatient hospitalisation; or the development of drug 
dependency or drug abuse.  
Study Completion Date
Last Subject Last Visit (or last dose) including the follow-up 
period as defined in the protocol for the LAST site OR in other
words, the latest site completion date for the protocol.  This date 
determines the timing for the Clinical Study Report and 
notification timelines for competent authorities (as required).


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PPD


Shire
CONFIDENTIAL
Page 22
Protocol SPD405-207
18 Oct 2016 
months of treatment with lanthanum carbonate in children and adolescents aged 10 years to <18 years (Parts 2 
and 3 of the study combined).
7.
To investigate biochemical markers of bone metabolism including bone alkaline phosphatase (ALP), tartrate-
resistant acid phosphatase (TRAP), osteocalcin, fibroblast growth factor 23 (FGF-23), parathyroid hormone 
(PTH), sclerostin and fetuin-A in children and adolescents aged 10 years to <18 years with CKD who are on 
dialysis.
8.
To investigate growth in children and adolescents aged 10 years to <18 years with CKD who are on dialysis.
Rationale:
Lanthanum carbonate is a phosphate binding medication indicated for the control of hyperphosphatemia in adult 
patients with end-stage renal disease receiving dialysis, as well as adult CKD patients not on dialysis with serum 
phosphorus 5.5mg/dL (1.78mmol/L).  Currently, there are no data on lanthanum carbonate in pediatric patients.  
The data from this study will provide pharmacokinetic, safety and efficacy information in this population compared 
to a standard calcium-based phosphate binder.
Investigational products, dose, and mode of administration:
Lanthanum carbonate oral powder packaged in 250mg sachets and calcium carbonate as 500mg tables.  
Part 1: An age-appropriate single dose of lanthanum carbonate oral powder will be given following breakfast. 
Part 2a, Treatment Period 1: Calcium carbonate will be orally administered either alone or mixed with food, the 
total daily dose will be based on standard clinical practice in order to achieve or maintain serum phosphorus levels 
in accordance with KDOQI age guidelines.  
Part 2a, Treatment Period 2:  Lanthanum carbonate oral powder will be administered mixed with food; the total 
daily dose will be divided between meals, and will be titrated, as appropriate to achieve or maintain serum 
phosphorus levels in accordance with KDOQI age guidelines or until a maximum daily dose of 3000mg is 
reached. 
Part 2b:  Lanthanum carbonate oral powder will be administered mixed with food; the total daily dose will be 
divided between meals, and will be titrated, as appropriate to achieve or maintain serum phosphorus levels in 
accordance with KDOQI age guidelines or until a maximum daily dose of 3000mg is reached. 
Part 3: Lanthanum carbonate oral powder will be administered mixed with food.  The dosage of lanthanum 
carbonate will be determined by the Investigator based on serum phosphorus levels taken at each study visit up to 
a maximum dose of 3000mg/day.


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CONFIDENTIAL
Page 23
Protocol SPD405-207
18 Oct 2016 
Methodology:
This is a 3-part study:

Part 1: Single-dose pharmacokinetic assessments of lanthanum carbonate in at least 8 subjects. Part 1 is 
complete and an interim clinical study report interpreting and summarizing the data is available.

Part 2a: Open-label, active comparator crossover period. Subjects participating in Part 1 will begin Part 2 
immediately following the completion of the pharmacokinetic assessments. Subjects not participating in Part 1 
will enter Part 2a. During Part 2a, all subjects will receive calcium carbonate for the first 8 weeks (Treatment 
Period 1), followed by treatment with lanthanum carbonate for 8 weeks (Treatment Period 2). If needed, there 
will be a washout period up to 3 weeks between treatment with calcium carbonate (Treatment Period 1) and 
lanthanum carbonate (Treatment Period 2). No new subjects will be enrolled in Part 2a under Version 6.0 of the 
protocol.

Part 2b: Open-label treatment period. Part 2b is modified Part 2a, where subjects will receive treatment with 
lanthanum carbonate only for 8 weeks. All new subjects will be enrolled in Part 2b only under Version 6.0 of 
the protocol.

Part 3: Subjects in Part 2a (including subjects in Treatment Period 1/calcium carbonate treatment arm who 
discontinued due to hypercalcemia; refer to Section 6.2.1, Dosing, Hypercalcemia) and Part 2b may continue to 
receive open-label lanthanum carbonate for up to 6 additional months of therapy.
Screening: 
There will be a 2-week screening period during which eligibility will be determined.  Subjects who are eligible to 
participate will enter a washout period of up to 3 weeks if the phosphorus level is not above KDOQI required levels.  
During the washout period the existing phosphate binder treatment will be discontinued until phosphate levels have 
risen above 6.0mg/dL (1.94mmol/L) in subjects aged under 12 years or >5.5mg/dL (1.78mmol/L) in subjects aged 
over 12 years.  At the end of the washout period, subjects will be assessed for inclusion in the study based on their 
serum phosphorus levels.  
Treatment Period: 
Part 1.  At least 8 subjects will undergo pharmacokinetic sampling following a single dose of lanthanum carbonate 
in order to assess the plasma concentration-time relationship of lanthanum carbonate.  At the completion of the 
pharmacokinetic assessment period, these subjects will enter Part 2 of the study.
Part 2a. Subjects who meet eligibility criteria and who are not participating in Part 1 will be enrolled into Part 2a 
(Treatment Period 1) and will receive calcium carbonate for the first 8 weeks. At the completion of the first 8 weeks 
of Part 2a, if required subjects will enter a washout period of up to 3 weeks duration and will then cross over to Part 
2a to receive lanthanum carbonate treatment for 8 weeks (Treatment Period 2). No new subjects will be enrolled in 
Part 2a under Version 6.0 of the protocol.
Part 2b. Subjects who meet eligibility will be enrolled into Part 2b and will receive lanthanum carbonate treatment 
for 8 weeks. All new subjects will be enrolled in Part 2b only under Version 6.0 of the protocol.
Part 3. At the conclusion of Part 2 (2a and 2b), subjects may continue to receive open-label lanthanum carbonate for 
up to 6 additional months of therapy (including subjects who participated in Part 2a, Treatment Period 1/calcium 
carbonate treatment arm, but who discontinued due to hypercalcemia; refer to Section 6.2.1, Dosing, 
Hypercalcemia). 
Dosing information: 
Part 1: Lanthanum carbonate oral powder will be administered in the morning following breakfast on the day after 
receiving dialysis treatment.
Subjects aged between 10 and 12 years will receive a dose of 500mg lanthanum (as lanthanum carbonate hydrate; 
SPD405) and subjects aged 12 years and over will receive 1000mg lanthanum (as lanthanum carbonate hydrate; 
SPD405).


Shire
CONFIDENTIAL
Page 24
Protocol SPD405-207
18 Oct 2016 
Part 2a, Treatment Period 1: Calcium carbonate may be started at the dose taken by the subject prior to starting 
the study or equivalent. For new subjects dosing will be based on standard clinical practice and the dose will be 
titrated 2-weekly as appropriate, until the target serum phosphorus level is achieved, or until a maximum daily dose 
of 6500mg is reached.  Once serum phosphorus control is achieved, the dose of calcium carbonate will be 
maintained until the end of the 8-week calcium carbonate treatment period. 
Part 2a, Treatment Period 2: At the end of the first 8-week treatment period of Part 2a (ie, Treatment Period 1), all 
subjects will begin 8 weeks of treatment with lanthanum carbonate following a washout period of 3 weeks, or until 
phosphorus level is above KDOQI required levels, whichever is sooner.  Lanthanum carbonate will be mixed with 
food and given 3 times a day.  If the subject has only 2 meals a day the lanthanum carbonate dose will split equally 
across the 2 meals with a single dose not exceeding 1000mg.  The starting total daily dose of lanthanum carbonate is 
1500mg for all subjects.  The total daily dose will be titrated 2-weekly, as appropriate, until the target serum 
phosphorus level is achieved, or until a maximum daily dose of 3000mg is reached.  Once serum phosphorus control 
is achieved or the maximum dose is reached, the dose of lanthanum carbonate will be maintained until the end of the 
8-week treatment period. No new subjects will be enrolled in Part 2a under Version 6.0 of the protocol.
Part 2b: Subjects will begin 8 weeks of treatment with lanthanum carbonate. Lanthanum carbonate will be mixed 
with food and given 3 times a day. If the subject has only 2 meals a day the lanthanum carbonate dose will split 
equally across the 2 meals with a single dose not exceeding 1000mg. The starting total daily dose of lanthanum 
carbonate is 1500mg for all subjects. The total daily dose will be titrated 2-weekly, as appropriate, until the target 
serum phosphorus level is achieved, or until a maximum daily dose of 3000mg is reached. Once serum phosphorus 
control is achieved or the maximum dose is reached, the dose of lanthanum carbonate will be maintained until the 
end of the 8-week treatment period. All new subjects will be enrolled in Part 2b only under Version 6.0 of the 
protocol.
Part 3: Subjects who complete participation in Part 2 (2a or 2b) may continue to receive lanthanum carbonate for an 
additional 6 months (including subjects who participated in Part 2a, Treatment Period 1/calcium carbonate treatment 
arm, but who discontinued due to hypercalcemia). The dosage of lanthanum carbonate will be determined by the 
Investigator based on serum phosphate levels taken at each study visit up to a maximum dose of 3000mg/day. 
Safety Follow-up:  A safety follow-up telephone call will be made to all subjects or their parent/legally authorized 
representative (LAR) 7-14 days following the last dose.  In the event of early discontinuation due to kidney 
transplantation, the safety follow-up call will be 30±7 days from the last dose.
Inclusion and exclusion criteria:
Inclusion Criteria:
1.
Aged 10 years to <18 years of age at the time of consent. 
2.
Subject or parent/LAR understand and are able, willing, and likely to fully comply with the study procedures 
and restrictions defined in this protocol. 
3.
Male, or non-pregnant, non-lactating female who agrees to comply with any applicable contraceptive 
requirements of the protocol. 
4.
Established CKD, on dialysis, and requires treatment for hyperphosphatemia with a phosphate binder. 
5.
Serum phosphorus levels after a washout period of up to 3 weeks as follows:

Age <12 years:  Serum phosphorus >6.0mg/dL (1.94mmol/L)

Age 12 years and older:  Serum phosphorus >5.5mg/dL (1.78mmol/L)
6.
Ability to provide written, signed, and dated (personally or via an LAR) informed consent/and assent, as 
applicable, to participate in the study. 


Shire
CONFIDENTIAL
Page 25
Protocol SPD405-207
18 Oct 2016 
Exclusion Criteria:
Subjects are excluded from the study if any of the following criteria are met.
1.
Current or recurrent disease (eg, cardiovascular, liver, unstable and uncontrolled gastrointestinal, malignancy, 
or other conditions) other than CKD or end-stage renal disease that could affect the action, absorption or 
disposition of the investigational product, or clinical or laboratory assessments.
2.
Current or relevant history of physical or psychiatric illness, any medical disorder (except for CKD or end-
stage renal disease and related co-morbidities) that may require treatment or make the subject unlikely to 
fully complete the study, or any condition that presents undue risk from the investigational product or 
procedures.
3.
Unable to eat semi-solid foods or on Total Enteral Alimentation.
4.
Known or suspected intolerance or hypersensitivity to the investigational product(s), closely related 
compounds, or any of the stated ingredients.
5.
History of alcohol or other substance abuse within the last year.
6.
Current use of any medication (including over-the-counter, herbal, or homeopathic preparations) that could 
affect (improve or worsen) the condition being studied, or could affect the action, absorption, or disposition 
of the investigational product(s), or clinical or laboratory assessment.
7.
Weight and age of subject are outside of local applicable criteria for blood sample volume limits.
8.
Use of another investigational product within 30 days prior to receiving the first dose of investigational 
product.
Maximum duration of subject involvement in the study:

Planned duration of screening period: Up to 2 weeks if washout not required, otherwise up to 5 weeks

Planned duration of enrollment period: 64 months

Planned duration of treatment period:  Part 1 - 48 hours, Part 2a - 16 weeks (+ up to 3 weeks for washout 
between treatments) or Part 2b - 8 weeks, Part 3 - up to 6 months

Planned duration of follow-up: 7-14 days or 30 ± 7 days in case of kidney transplantation
Endpoints and statistical analysis:  
Primary Efficacy Measure:

The percentage of subjects achieving age-specific KDOQI targets for serum phosphate level following 
8-weeks of treatment with lanthanum carbonate will be descriptively summarized. The KDOQI serum 
phosphorus targets are defined as:
-
Adolescents aged ≥12-<18 years: ≤5.5mg/dL (1.78mmol/L)
-
Children aged 10 years -<12 years: ≤6.0mg/dL (1.94mmol/L)
Secondary Measures:

The percentage of subjects with serum phosphorus levels below the age-specific KDOQI targets following 
8 weeks of treatment with calcium carbonate followed by 8 weeks of treatment with lanthanum carbonate, 
will be descriptively summarized. The KDOQI serum phosphorus targets are defined as:
-
Adolescents aged ≥12-<18 years: ≤5.5mg/dL (1.78mmol/L)
-
Children aged 10 years -<12 years: ≤6.0mg/dL (1.94mmol/L)

Changes from baseline in serum phosphorus, calcium and calcium-phosphorus product in 
hyperphosphatemic children and adolescents with CKD who are on dialysis, following treatment with 


Shire
CONFIDENTIAL
Page 26
Protocol SPD405-207
18 Oct 2016 
lanthanum carbonate for 8 weeks.

Changes from baseline in serum phosphorus, calcium and calcium-phosphorus product in 
hyperphosphatemic children and adolescents with CKD who are on dialysis, following treatment with 
calcium carbonate for 8 weeks and lanthanum carbonate for 8 weeks. 

Change from baseline in serum phosphorus, calcium and calcium-phosphorus product levels at the last visit 
of each 8-week treatment period during Part 2 and monthly during the 6-month extension phase (Part 3).

Biochemical bone markers: bone ALP, osteocalcin, TRAP, FGF-23, PTH, sclerostin and fetuin-A before 
and after each treatment period in Part 2, and at the end of Part 3.

Height and weight at:
o
Visits 2.0, 2.4, 2.8, and 3.5 (Parts 2a and 3)
o
Visits 1.0, 2.4, and 3.5 (Parts 2b and 3).
Safety Assessments:
Safety will be assessed by the collection of adverse events (AEs), vital signs, physical examinations, and clinical 
laboratory tests (chemistry and hematology).
Pharmacokinetics:
Blood samples for pharmacokinetic evaluation will be collected during all 3 study periods (Parts 1, 2, and 3).  
Plasma lanthanum concentrations will be determined by a previously validated method utilizing inductively coupled 
plasma mass spectrometry.
Part 1.  Blood samples for determination of single-dose lanthanum pharmacokinetics will be collected pre-dose and 
at 3, 5, 6, 8, 12, 24, and 48 hours after dosing.  Plasma lanthanum concentrations will be analyzed by 
non-compartmental methods to determine pharmacokinetic parameters including, but not limited to, AUC0-t, area 
under the plasma concentration-time curve from time zero to 48 hours (AUC0-48), Cmax, time to Cmax, and, if 
appropriate, apparent terminal half-life (t1/2) and apparent terminal-phase disposition rate constant (λz) and area 
under the plasma concentration-time curve from time zero to infinity (AUC0-).  
Summary statistics (number of observations, mean, standard deviation, coefficient of variation, median, maximum, 
minimum, and geometric mean) will be determined for all pharmacokinetic parameters.
Part 2 (Part 2a (Treatment Period 2) and Part 2b) and Part 3. Pharmacokinetics will be evaluated during lanthanum 
carbonate dosing using a sparse sampling approach. Blood samples (at least 2 per subject) for pharmacokinetic 
assessments will be collected during Parts 2a (Treatment Period 2), 2b and 3 from defined time-windows (to be 
selected from: 0-2 hours, 2-4 hours and 4-6 hours, after the first dose/meal of the day, so as to cover the full dosing 
interval). Plasma concentration-time data for Parts 2a (Treatment Period 2), 2b and 3 will be combined with those 
from Part 1 and subjected to population pharmacokinetic analysis using NONMEM software to determine estimates 
of steady-state systemic exposure (Cmax, Cmin [minimum plasma concentration], and area under the plasma 
concentration-time curve at steady-state) and relationships of systemic exposure to dose and to safety findings 
explored if appropriate.
STATISTICAL METHODS
Analysis Populations
Screened Set – The set of subjects who have signed informed consent.
Enrolled Set – Subjects who have signed informed consent and have begun some study procedures (eg, dispensed 
investigational product, current drug has been withdrawn).
Safety Analysis Set 1 – Enrolled subjects who have taken 1 dose of investigational product in Part 1 and who have 
completed at least 1 follow-up safety assessment.
Safety Analysis Set 2 – Enrolled subjects who have taken 1 dose of investigational product in Part 2 or Part 3 and 
who have completed at least 1 follow-up safety assessment. 


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CONFIDENTIAL
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Protocol SPD405-207
18 Oct 2016 
It is noted that safety assessments from the period when a subject is exposed to calcium carbonate will be 
summarized for calcium carbonate treatment. Safety assessments from the period when a subject is exposed to 
lanthanum carbonate will be summarized for lanthanum carbonate treatment.  
Safety Completer Set (SCS) – Subjects who receive at least 8 weeks of lanthanum carbonate treatment from either 
Part 2 or Part 3 of the study. 
Full Analysis Set (FAS) – Subjects who have taken at least 1 dose of investigational product and who have at least 
1 phosphate assessment during Part 2 or Part 3.
Per-protocol Set 1 (PP1) – Subjects in the Full Analysis Set who complete 8 weeks of calcium carbonate treatment 
followed by 8 weeks of lanthanum carbonate treatment and who have serum phosphate assessment data available to 
allow summarizing the percentage of subjects achieving age-specific KDOQI target. Only subjects who have serum 
phosphate levels equal to or above the age-specific KDOQI targets at study entry and between the calcium carbonate 
treatment and lanthanum carbonate treatment at Visit 2.4 will be included in this set.
Per-protocol Set 2 (PP2) – Subjects in the Full Analysis Set who complete 8 weeks of treatment with lanthanum 
carbonate and who have serum phosphate assessment data available to allow summarizing the percentage of subjects 
achieving age-specific KDOQI target. Subjects who have serum phosphate levels equal to or above the age-specific 
KDOQI targets prior to the start of lanthanum carbonate treatment will be included in this set.
Pharmacokinetic Set 1 - Subjects in the Safety Analysis Set 1 for whom the primary pharmacokinetic data are 
considered sufficient and interpretable.  Subjects in Part 1 who vomited may be excluded from Pharmacokinetic Set 
1.
Pharmacokinetic Set 2 - Subjects in Safety Analysis Sets 1 or 2 for whom the primary pharmacokinetic data are 
considered sufficient and interpretable will be included in Pharmacokinetic Set 2. 
Efficacy Analyses
The FAS and PP2 Sets will be used for the primary endpoint analyses. 
For the primary endpoint, the percentage of subjects achieving age-specific KDOQI targets for serum phosphate
level after 8 weeks of lanthanum carbonate treatment will be calculated along with a 95% confidence interval. The 
FAS and PP2 Sets will be used for this summarization.
The FAS, PP1, and PP2 Sets will be used for the secondary efficacy endpoint analyses.
For the secondary endpoint, the percentage of subjects achieving age-specific KDOQI targets after 8 weeks of 
calcium carbonate treatment followed by 8 weeks of lanthanum carbonate will be calculated along with a 95% 
confidence interval, separately, for each treatment arm. 
For the long-term assessment, efficacy and safety variables will be summarized using the FAS and Safety Analysis 
Set 2 respectively, for each visit using descriptive statistics as follows:

For continuous data: number of observations, mean, standard deviation, standard error, minimum, 
maximum, median, and 95% confidence interval

For categorical data: number of observations and percentages. 
Safety Analyses
All safety variables will be summarized using the defined Safety Analysis Sets. Summaries will be presented by 
treatment group and overall.
The number of events, incidence, and percentage of treatment emergent AEs (TEAEs) will be calculated overall, by 
system organ class, and by preferred term.  Treatment-emergent AEs will be further summarized by age group, 
severity and relationship to investigational product.  Adverse events related to investigational product, AEs leading 
to withdrawal, SAEs, and deaths will be summarized/listed. Clinical laboratory tests, vital signs, and ECG findings 


Shire
CONFIDENTIAL
Page 28
Protocol SPD405-207
18 Oct 2016 
will be summarized.  Potentially clinically important findings will also be summarized or listed.
Expected Number of Subjects:
Pharmacokinetic Assessment
From Study LAM-IV-111, the meanstandard deviation AUC0-t was 3.0992.888ng hr/mL and Cmax was 
0.2960.177ng hr/mL for a 1000mg single dose of lanthanum carbonate. Assuming the standard deviations from 
Study LAM-IV-111, a sample size of 8 subjects will have 80% assurance that the 2-sided 95% confidence interval 
for the AUC0-t will be no wider than 2.86ng.hr/mL and 80% assurance that 2-sided 95% confidence interval for 
Cmax is no wider than 0.18ng /mL.
Efficacy – Percentage of Subjects Achieving KDOQI Target for Serum Phosphorus
Originally, the sample size of at least 50 subjects for the PP set had been chosen based on practical considerations 
and on agreement with the Paediatric Committee of the European Medicines Agency.  In order to obtain a PP Set of 
50 subjects, a sample size of approximately 72 subjects were to be enrolled in Part 2.  This assumed 70% of the 
subjects are eligible for the PP Set.  This sample size has 81% power to show that the lower limit of the 95% 
confidence interval for the difference (LC – CC) in the percentage of subjects achieving serum phosphorus target is 
above the non-inferiority margin of -18%.  
However, given the extreme difficulty in recruiting enough subjects to obtain at least 50 subjects for the PP set for 
the assessment of non-inferiority, serious consideration had to be given to adjust the sample size and focus of the 
study to safety, in order to complete it. The sample size has been adjusted to include at least 35 subjects, who 
complete 8 weeks of treatment with lanthanum carbonate and are assessable for the primary endpoint. This study is 
still useful in collecting information, where there is a void, regarding the use of lanthanum carbonate in the pediatric 
population. 
Safety – Investigation of the Safety profile in hyperphosphatemic children and adolescents with CKD on 
dialysis treated with lanthanum carbonate.
A sample size of 35 subjects is necessary in order to observe at least one event with a true event rate of 5% at a 
probability of 83.4%.


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CONFIDENTIAL
Page 29
Protocol SPD405-207
18 Oct 2016 
STUDY SCHEDULE(S)
Table 1:  Schedule of Assessments for Part 1, Part 2a (Treatment Periods 1 and 2), and Part 3
Part 1
Subjects who enrol into Part 
1 will omit the first washout 
in Part 2
(Visit window ±3 days)
Part 2a
(Visit window ±3 days)
Part 3
(Visit window 
±1 week)
Visit
1.0
Washout 
W1j
1.1a
2.0b
Washout
W1j
2.1
2.2-
2.3
2.4
Washout
W2j
2.5-
2.7
2.8
3.0-
3.4
3.5/End 
of Studyc
Safety 
Follow-up 
callk
Week 
–5
-4 to -1
-4 to -
1
0
0-3
weeks 
duration
2d
4, 6d
8d
0-3 week
duration
10, 
12, 
14d
16d
20, 
24, 
28, 
32, 36 
40d
41-42d
Informed consent


In/exclusion criteria


j
Medical and renal 
history


Demographics


12-lead ECG




Physical examination




Vital signs, height  
and weight








Shire
CONFIDENTIAL
Page 30
Protocol SPD405-207
18 Oct 2016 
Table 1:  Schedule of Assessments for Part 1, Part 2a (Treatment Periods 1 and 2), and Part 3
Part 1
Subjects who enrol into Part 
1 will omit the first washout 
in Part 2
(Visit window ±3 days)
Part 2a
(Visit window ±3 days)
Part 3
(Visit window 
±1 week)
Visit
1.0
Washout 
W1j
1.1a
2.0b
Washout
W1j
2.1
2.2-
2.3
2.4
Washout
W2j
2.5-
2.7
2.8
3.0-
3.4
3.5/End 
of Studyc
Safety 
Follow-up 
callk
Week 
–5
-4 to -1
-4 to -
1
0
0-3
weeks 
duration
2d
4, 6d
8d
0-3 week
duration
10, 
12, 
14d
16d
20, 
24, 
28, 
32, 36 
40d
41-42d
Local laboratory testsf








Central laboratory 
phosphate 
confirmation



Biochemistry 





Hematology



Biochemical bone 
markers 





Pregnancy test (where 
applicable)



Lanthanum 
pharmacokinetics

g  
h


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Protocol SPD405-207
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Table 1:  Schedule of Assessments for Part 1, Part 2a (Treatment Periods 1 and 2), and Part 3
Part 1
Subjects who enrol into Part 
1 will omit the first washout 
in Part 2
(Visit window ±3 days)
Part 2a
(Visit window ±3 days)
Part 3
(Visit window 
±1 week)
Visit
1.0
Washout 
W1j
1.1a
2.0b
Washout
W1j
2.1
2.2-
2.3
2.4
Washout
W2j
2.5-
2.7
2.8
3.0-
3.4
3.5/End 
of Studyc
Safety 
Follow-up 
callk
Week 
–5
-4 to -1
-4 to -
1
0
0-3
weeks 
duration
2d
4, 6d
8d
0-3 week
duration
10, 
12, 
14d
16d
20, 
24, 
28, 
32, 36 
40d
41-42d
Investigational 
product dispensed

e
e





i

Investigational 
product collected







Dose adjustment (as 
needed) and 
compliance







Record adverse events














Record concomitant 
medication














Dialysis adequacy









Confirmation of 
dietary advice









a Visit 1.1 should be scheduled for the day after dialysis.  See Table 2 for a detailed schedule of assessments.


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Protocol SPD405-207
18 Oct 2016 
Table 1:  Schedule of Assessments for Part 1, Part 2a (Treatment Periods 1 and 2), and Part 3
Part 1
Subjects who enrol into Part 
1 will omit the first washout 
in Part 2
(Visit window ±3 days)
Part 2a
(Visit window ±3 days)
Part 3
(Visit window 
±1 week)
Visit
1.0
Washout 
W1j
1.1a
2.0b
Washout
W1j
2.1
2.2-
2.3
2.4
Washout
W2j
2.5-
2.7
2.8
3.0-
3.4
3.5/End 
of Studyc
Safety 
Follow-up 
callk
Week 
–5
-4 to -1
-4 to -
1
0
0-3
weeks 
duration
2d
4, 6d
8d
0-3 week
duration
10, 
12, 
14d
16d
20, 
24, 
28, 
32, 36 
40d
41-42d
b For subjects who have completed Part 1, laboratory and other assessments can be completed from Visit 1.0, no further blood samples are required.  A consent form to participate 
in Part 2a must be signed.
c Assessments scheduled for Visit 3.5 should also be carried out at the time of discontinuation for all subjects who withdraw from the study early or as close as possible to the time 
of discontinuation.  These assessments are not required for subjects post-transplantation, however a safety follow-up call is required.
d Visit weeks may be variable depending on duration of washout (+3 weeks).
e Investigational product will be dispensed at Visit 2.0 if eligible, however if a washout is required then investigational product will be dispensed at visit W1.
f Local laboratory assessments for phosphorus, serum calcium, and calcium phosphorus product in Parts 1 and 2 are for titration purposes, as required, and will not be analyzed; 
data from Visits 3.0-3.4 will be collected and assessed.
g Visit 2.6 only; Each subject will have at least 2 samples taken for pharmacokinetic assessment.  These should be taken during defined time windows (to be selected from: 0-2 
hours, 2-4 hours and 4-6 hours, after the first dose/meal of the day).  Note:  If the sampling is not done at Visit 2.6, blood sampling for pharmacokinetics must be taken at an 
alternative visit during Part 2.
h Visit 3.3 only; Each subject will have at least 2 samples taken for pharmacokinetic assessment.  These should be taken during defined time windows (to be selected from: 0-2 
hours, 2-4 hours and 4-6 hours, after the first dose/meal of the day).  Note:  If the sampling is not done at Visit 3.3, blood sampling for pharmacokinetics must be taken at an 
alternative visit during Part 3.
i For subjects entering Part 3 only.
j Only for subjects completing the washout.


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Protocol SPD405-207
18 Oct 2016 
Table 1:  Schedule of Assessments for Part 1, Part 2a (Treatment Periods 1 and 2), and Part 3
Part 1
Subjects who enrol into Part 
1 will omit the first washout 
in Part 2
(Visit window ±3 days)
Part 2a
(Visit window ±3 days)
Part 3
(Visit window 
±1 week)
Visit
1.0
Washout 
W1j
1.1a
2.0b
Washout
W1j
2.1
2.2-
2.3
2.4
Washout
W2j
2.5-
2.7
2.8
3.0-
3.4
3.5/End 
of Studyc
Safety 
Follow-up 
callk
Week 
–5
-4 to -1
-4 to -
1
0
0-3
weeks 
duration
2d
4, 6d
8d
0-3 week
duration
10, 
12, 
14d
16d
20, 
24, 
28, 
32, 36 
40d
41-42d
k Safety follow-up call to be made 7-14 days following last dose of investigational product.  For subjects discontinued due to kidney transplantation, the safety follow up call to be 
made 30 ± 7 days from the last dose.


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Protocol SPD405-207
18 Oct 2016 
Table 2:  Detailed Schedule of Assessments for Visit 1.1 in Part 1 
Hour (in relation to dosing 
time)
Pre-dose
0
3
5
6
8
12
24
48
Physical examination 
a
Vital signs (blood pressure and 
pulse)b


a
Lanthanum carbonate single 
dose

Pharmacokinetic blood 
samplingc








Record adverse events 









Record concomitant 
medications









a An attempt to perform these assessments and procedures should be made for any subject who withdraws or is removed early 
from the study, as well as those subjects completing the 48 hour period.
b Vital signs will be taken within 15 minutes of nominal dosing time. 
c The samples should be drawn within 5 minutes of the nominal in the first 4 hours after taking the investigational product, 
15 minutes up to 24 hours after taking the investigational product and within 60 minutes thereafter.


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Protocol SPD405-207
18 Oct 2016 
Table 3:  Schedule of Assessments for Part 2b and Part 3
Part 2b
(Visit window ±3 days)
Part 3
(Visit window ±1 week)
Visit
1.0a
Washout
W1b
2.1-2.3
2.4
3.0-3.4
3.5/End of 
Studyc
Safety 
Follow-up 
callj
Week 
0
0-3
weeks duration
2, 4, 6d
8 d
12, 16, 20, 
24, 28 
32d
33-34d
Informed consent

In/exclusion criteria

b
Medical and renal 
history

Demographics

12-lead ECG



Physical 
examination


Vital signs, height 
and weight



Local laboratory 
testse




Central laboratory 
phosphate 
confirmation

Biochemistry 



Hematology


Biochemical bone 
markers 





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Shire
CONFIDENTIAL 
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Protocol SPD405-207
18 Oct 2016 
Table 3:  Schedule of Assessments for Part 2b and Part 3
Part 2b
(Visit window ±3 days)
Part 3
(Visit window ±1 week)
Visit
1.0a
Washout
W1b
2.1-2.3
2.4
3.0-3.4
3.5/End of 
Studyc
Safety 
Follow-up 
callj
Week 
0
0-3
weeks duration
2, 4, 6d
8 d
12, 16, 20, 
24, 28 
32d
33-34d
d Visit weeks may be variable depending on duration of washout (+3 weeks).
e Local laboratory assessments for phosphorus in Part 2b are for titration purposes, as required, and will not be analyzed; data from Visits 3.0-3.4 will be collected and assessed.
f Visit 2.2 only; Each subject will have at least 2 samples taken for pharmacokinetic assessment. These should be taken during defined time windows (to be selected from: 0-2 
hours, 2-4 hours and 4-6 hours, after the first dose/meal of the day). Note: If the sampling is not done at Visit 2.2, blood sampling for pharmacokinetics must be taken at an 
alternative visit during Part 2b.
g Visit 3.3 only; Each subject will have at least 2 samples taken for pharmacokinetic assessment. These should be taken during defined time windows (to be selected from: 0-2 
hours, 2-4 hours and 4-6 hours, after the first dose/meal of the day). Note: If the sampling is not done at Visit 3.3, blood sampling for pharmacokinetics must be taken at an 
alternative visit during Part 3.
h Investigational product will be dispensed at Visit 1.0 if eligible, however if a washout is required then investigational product will be dispensed at visit W1.
i For subjects entering Part 3 only.
j Safety follow-up call to be made 7-14 days following last dose of investigational product. For subjects discontinued due to kidney transplantation, the safety follow up call to be 
made 30 ± 7 days from the last dose.


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Protocol SPD405-207
18 Oct 2016 
1.
BACKGROUND INFORMATION
1.1
Condition Background and Current Treatment 
Chronic kidney disease
Lanthanum carbonate has been developed as a phosphate-binding agent for the treatment of 
hyperphosphatemia associated with chronic kidney disease (CKD).  Control of serum phosphate 
levels is fundamental in the management of CKD, which leads to progressive decline in the 
kidney’s ability to excrete phosphate, produce active vitamin D (calcitrol), and maintain calcium 
homeostasis.
CKD is associated with complex metabolic, bone and vasculature abnormalities that together 
encompass a syndrome defined in 2006 as CKD-mineral and bone disorder (Moe et al. 2006).  
Hyperphosphatemia and secondary hyperparathyroidism are implicated as central components in 
CKD- mineral and bone disorder.  
The pathophysiological consequences of positive phosphate balance and hyperphosphatemia 
include hyperparathyroidism and the associated renal osteodystrophy.  Hyperphosphatemia and 
hyperparathyroidism in CKD is a vicious cycle with serious consequences.  The associated high 
turnover bone disease manifests with bone pain, bone fracture, bone deformity, osteopenia, 
myopathy, arthritis, resistance to erythropoietin due to marrow fibrosis, growth failure in 
children, and extraskeletal calcification.
Serum phosphorus levels vary depending on age (Kidney Disease Outcomes Quality Initiative 
[KDOQI] Guideline 4, 2005).
A limited number of clinical studies have been conducted in the pediatric population with 
phosphate binders (Pieper et al. 2006; Alon et al. 1986; Clark et al. 1989; Mahdavi et al. 2003; 
Salusky et al. 2005).  Currently the only such products with an approved indication in children 
are calcium-based binders and aluminium hydroxide.  
1.2
Product Background
Lanthanum carbonate contains lanthanum carbonate hydrate, an inorganic salt with the chemical 
formula LA2(CO3)3.4H20.  Lanthanum carbonate is a phosphate binder. 
Always refer to the latest version of the SPD405 Investigator’s Brochure (IB) for the most 
accurate and current information regarding the efficacy and safety of SPD405.
2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
The European guideline on prevention and treatment of renal osteodystrophy in children with 
chronic renal failure recommends calcium-based phosphate binders as first-line treatment for
hyperphosphatemia and calcium-free binders in cases of hypercalcemia (Klaus et al. 2006).  
Aluminium and sevelamer are included in this latter category.  Aluminium use is not 


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CONFIDENTIAL
Page 39
Protocol SPD405-207
18 Oct 2016 
recommended because of known toxicities to bone and central nervous system and sevelamer is 
not licensed for use in children.  Lanthanum carbonate is also a calcium-free binder but no 
clinical studies have been conducted in children.  
This study is intended to provide pharmacokinetic, safety and efficacy data on lanthanum 
carbonate in pediatric patients as compared to a standard calcium-based phosphate binder.
2.2
Study Objectives
2.2.1
Primary Objective
To summarize the percentage of subjects achieving age-specific Kidney Disease Outcomes 
Quality Initiative (KDOQI) targets for serum phosphorus in hyperphosphatemic children and
adolescents with chronic kidney disease (CKD) who are on dialysis, following 8 weeks of 
treatment with lanthanum carbonate.
2.2.2
Secondary Objectives
1. To investigate the safety profile in hyperphosphatemic children and adolescents with CKD 
on dialysis treated with calcium carbonate and/or lanthanum carbonate.
2. To summarize the percentage of subjects achieving KDOQI targets for serum phosphorus in 
hyperphosphatemic children and adolescents with CKD who are on dialysis following 
treatment with calcium carbonate for 8 weeks and lanthanum carbonate for 8 weeks.
3. To assess mean changes from baseline in serum phosphorus, calcium and calcium-
phosphorus product in hyperphosphatemic children and adolescents with CKD who are on 
dialysis, following treatment with lanthanum carbonate for 8 weeks.
4. To summarize mean changes from baseline in serum phosphorus, calcium and calcium-
phosphorus product in hyperphosphatemic children and adolescents with CKD who are on 
dialysis, following treatment with calcium carbonate for 8 weeks and lanthanum carbonate 
for 8 weeks.
5. To describe the pharmacokinetics (maximum plasma concentration [Cmax] and area under the 
plasma concentration-time curve from time zero to the time of the last quantifiable 
concentration [AUC0-t]; body-weight-normalized) of lanthanum carbonate in 
hyperphosphatemic children and adolescents aged 10 years to <18 years with CKD who are 
on dialysis, after a single dose of lanthanum carbonate oral powder formulation is 
administered (Part 1 of the study).
6. To investigate the efficacy (serum phosphorus, calcium, and calcium-phosphorus product) 
and safety of up to 8 months of treatment with lanthanum carbonate in children and 
adolescents aged 10 years to <18 years (Parts 2 and 3 of the study combined).
7. To investigate biochemical markers of bone metabolism including bone alkaline phosphatase 
(ALP), tartrate-resistant acid phosphatase (TRAP), osteocalcin, fibroblast growth factor 23 
(FGF-23), parathyroid hormone (PTH), sclerostin and fetuin-A in children and adolescents 
aged 10 years to <18 years with CKD who are on dialysis.


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CONFIDENTIAL
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Protocol SPD405-207
18 Oct 2016 
8. To investigate growth in children and adolescents aged 10 years to <18 years with CKD who
are on dialysis.
3.
STUDY DESIGN
3.1
Study Design
This 3-part study has been approved by the Paediatric Committee of the European Medicines 
Agency as part of the Paediatric Investigational Plan for lanthanum carbonate.  Pharmacokinetic 
data will be collected during the study as there are currently no data on lanthanum carbonate in 
pediatric patients under the age of 18 years.  The data from this study will be evaluated against 
historical systemic exposure data in adults.  The pharmacokinetic assessment is combined with 
the efficacy and safety sections to reduce the number of studies to be performed and to ease 
subject enrollment.
Part 1: Single-dose, pharmacokinetic assessment 
This part of the study was a single-dose pharmacokinetic assessment of lanthanum carbonate in 
at least 8 subjects. There was a 2-week screening period during which eligibility was determined 
for Part 1.  Subjects who were eligible to participate entered a washout period of up to 3 weeks if 
the phosphorus level was not above KDOQI required levels.  During the washout period the 
existing phosphate binder treatment was discontinued until phosphate levels had risen above 
6.0mg/dL (1.94mmol/L) in subjects aged under 12 years or >5.5mg/dL (1.78mmol/L) in subjects 
aged over 12 years.  At the end of the washout period, subjects were assessed for inclusion in the 
study based on their serum phosphorus levels.  
Subjects participating in Part 1 could begin Part 2a immediately following the completion of the 
pharmacokinetic assessments. Subjects not participating in Part 1 entered Part 2a after screening 
at Visit 2/Week 0 (see Table 1).
Part 1 is complete and an interim clinical study report interpreting and summarizing the data is 
available.
Part 2a: Open-label, active comparator crossover period
Originally, the design of Part 2 of Study SPD405-207 was a crossover non-inferiority one to 
allow a formal comparison of the efficacy of lanthanum carbonate with calcium carbonate. It was 
a single-sequence design (8 weeks of calcium carbonate followed by 8 weeks of lanthanum 
carbonate) to minimize disruption to the subjects. The comparator calcium carbonate was 
selected to meet the comparator criteria outlined by Pediatric Committee of the European 
Medicines Agency. Since the originally proposed study included only 1 sequence (calcium 
carbonate for the 1st treatment period and lanthanum carbonate for the 2nd treatment period) 
blinding was not applicable, thus the study was open-label. As shown in the study schematic in 
Figure 1, all subjects were to receive lanthanum carbonate in period 2 of the crossover and had 
the option to continue on to Part 3 of the study on the same treatment for up to 6 months. If 
needed, there was a washout period for up to 3 weeks between treatment with calcium carbonate 
(Treatment Period 1) and lanthanum carbonate (Treatment Period 2). Subjects who discontinued 
calcium carbonate treatment period/Treatment Period 1 due to hypercalcemia in Part 2 of the 


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CONFIDENTIAL
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Protocol SPD405-207
18 Oct 2016 
originally proposed study could also continue to Part 3 to receive lanthanum carbonate treatment 
(see Section 4.4.1 and Section 6.2.1 [Dosing, Hypercalcemia]) for up to 6 additional months. 
No new subject will be enrolled in Part 2a under Version 6.0 of the protocol.
Part 2b: 8-week lanthanum carbonate treatment
Given the extreme difficulty in recruiting enough subjects to obtain the originally proposed 
sample size of 50 subjects required for the Per-protocol Set for a cross-over non-inferiority 
study, the active comparator (calcium carbonate) treatment arm was removed (see Part 2a) in 
Part 2b; serious consideration had to be given to adjust the sample size and focus of the study to 
safety, in order to complete it.  The sample size has been adjusted to include at least 35 subjects 
who will complete 8 weeks of treatment with lanthanum carbonate and will be assessable for the 
primary endpoint. As shown in the study schematic in Figure 2, eligible subjects will be enrolled 
in Part 2b after screening at Visit 1/Week 0 (see Table 3) to receive 8 weeks of lanthanum 
carbonate treatment only under Version 6.0 of the protocol. Subjects in Part 2b will have the 
option to continue on to Part 3 of the study on the same treatment for up to 6 additional months.
Part 3: 6-month lanthanum carbonate treatment
Subjects in Part 2a (including subjects in Treatment Period 1/calcium carbonate treatment arm 
who discontinued due to hypercalcemia; see Section 4.4.1 and Section 6.2.1 [Dosing, 
Hypercalcemia]) and Part 2b may continue to receive open-label lanthanum carbonate for up to 6 
additional months of therapy.
The doses selected for Part 1 of the study were those that were suggested for use in children in 
clinical practice and those in Part 2 are based on known phosphate binder values for maintaining 
phosphate level balance.


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Protocol SPD405-207
18 Oct 2016 
Figure 1:
Study Design Flow Chart- Part 1, Part 2a (Treatment Periods 1 and 2) and 
Part 3
Note: The schematic in Figure 1 is applicable to the originally proposed open-label cross over study design.




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Protocol SPD405-207
18 Oct 2016 
Part 2a only (see Table 1). Under Version 6.0 of the protocol, only lanthanum carbonate will be 
administered for 8 weeks of treatment in Part 2b (see Table 3).
3.4
Sites and Regions
Up to 36 sites are expected to participate in this study, from European Union, Russian 
Federation, and Republic of Turkey.
4.
STUDY POPULATION
4.1
Inclusion Criteria
The subject cannot be enrolled in the study before all of the following inclusion criteria
(including test results) are met.
1. Aged 10 years to <18 years of age at the time of consent. 
2. Subject or parent/legally authorized representative (LAR) understand and are able, willing, 
and likely to fully comply with the study procedures and restrictions defined in this protocol. 
3. Male, or non-pregnant, non-lactating female who agrees to comply with any applicable 
contraceptive requirements of the protocol. 
4. Established CKD, on dialysis, and requires treatment for hyperphosphatemia with a 
phosphate binder. 
5. Serum phosphorus levels after a washout period of up to 3 weeks as follows:

Age <12 years:  Serum phosphorus >6.0mg/dL (1.94mmol/L)

Age 12 years and older:  Serum phosphorus >5.5mg/dL (1.78mmol/L)
6. Ability to provide written, signed and dated (personally or via an LAR) informed consent/and 
assent, as applicable, to participate in the study. 
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met. 
1. Current or recurrent disease (eg, cardiovascular, liver, unstable and uncontrolled 
gastrointestinal, malignancy, or other conditions) other than CKD or end-stage renal disease 
that could affect the action, absorption or disposition of the investigational product, or 
clinical or laboratory assessments.
2. Current or relevant history of physical or psychiatric illness, any medical disorder (except for 
CKD or end-stage renal disease and related co-morbidities) that may require treatment or 
make the subject unlikely to fully complete the study, or any condition that presents undue 
risk from the investigational product or procedures.
3. Unable to eat semi-solid foods or on Total Enteral Alimentation.
4. Known or suspected intolerance or hypersensitivity to the investigational product(s), closely 
related compounds, or any of the stated ingredients.


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Protocol SPD405-207
18 Oct 2016 
5. History of alcohol or other substance abuse within the last year.
6. Current use of any medication (including over-the-counter, herbal, or homeopathic 
preparations) that could affect (improve or worsen) the condition being studied, or could 
affect the action, absorption, or disposition of the investigational product(s), or clinical or 
laboratory assessment.
7. Weight and age of subject are outside of local applicable criteria for blood sample volume 
limits.
8. Use of another investigational product within 30 days prior to receiving the first dose of 
investigational product.
4.3
Reproductive Potential
All females must have a negative serum beta human chorionic gonadotropin pregnancy test at 
Visit 1.0 and/or Visit 2.0.  Females must abstain from sexual activity that could result in 
pregnancy or agree to use acceptable methods of contraception.
Condoms should be used with the following acceptable contraceptives:  
Intrauterine devices 
Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring).
Other acceptable contraception methods are:
Double barrier methods (eg, condoms and diaphragms with spermicidal gel or foam).
Sexually active females should have been using an acceptable form of contraception for at least 4 
weeks prior to enrollment.  All females must be advised to use acceptable contraceptives 
throughout the study period and for 30 days following the last dose of investigational product.  If 
hormonal contraceptives are used they should be administered according to the package insert.  
Females who are not currently sexually active must agree to use acceptable contraception, as 
defined above, if they become sexually active during the period of the study and 30 days 
following the last dose of investigational product.  
4.3.1
Restrictions
None.
4.4
Withdrawal of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution.  The Investigator or Sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety).  The withdrawal of a 
subject from investigational product by the Investigator should be discussed where possible with 
the Medical Monitor before the subject stops investigational product.
If investigational product is permanently discontinued, regardless of the reason, the final 
evaluations are to be performed as completely as possible.  Whenever possible, all discontinued 
subjects should also undergo the protocol-specified follow-up.  Comments (spontaneous or 


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elicited) or complaints made by the subject must be recorded in the source documents.  The 
reason for termination, date of stopping investigational product, and the total amount of 
investigational product taken must be recorded on the case report form (CRF) and source 
documents.
4.4.1
Subject Stopping Criteria
Subjects must be removed from study if any 1 or more of the following events occur:
Violation of inclusion/exclusion criteria at study entry
Taking another non-study phosphate binder (on either calcium carbonate and lanthanum 
carbonate arms) rather than the investigational product during the study
Kidney transplant during the study.  Subjects should be followed 30±7 days post-transplant
Pregnancy
Serum phosphorus rises above 10.0mg/dL (3.23mmol/L) during the study (however this 
does not apply during the washout periods)
Calcium level rises to >11.5mg/dL (2.88mmol/L) during the first treatment period of Part 
2a (calcium carbonate). Subjects may continue to Part 3 but must complete all procedures 
for Visit 2.4 prior to commencing Part 3.
See APPENDIX 2 for guidelines on phosphorus and calcium levels.
4.4.2
Reasons for Discontinuation
The reason for withdrawal must be determined by the Investigator and recorded in the subject’s 
medical record and on the CRF.  If a subject is withdrawn for more than 1 reason, each reason 
should be documented in the source document and the most clinically relevant reason should be 
entered on the CRF.
If an adverse event (AE) is a reason for discontinuation, then “adverse event” must be recorded 
as the reason for discontinuation on the CRF.
Reasons for discontinuation include but are not limited to: 
Death 
Withdrawal by subject
Lost to follow-up
Lack of efficacy 
Physician decision
Pregnancy
Kidney transplant
Other (must be specified. eg, met stopping 1 or more stopping criteria).


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Reasons for possible discontinuation (to be determined by Sponsor and Investigator discussion) 
include but are not limited to:
Adverse event
Protocol violation
Non-compliance with study drug
Progressive disease.
4.4.3
Subjects ‘Lost to Follow-up” Prior to Last Scheduled Visit
At least 3 documented attempts must be made to contact any subject lost to follow-up at any time 
point prior to the last scheduled contact (office visit or telephone contact). One of these 
documented attempts must include a written communication sent to the subject’s last known 
address via courier or mail (with an acknowledgement of receipt request) asking that they return 
any unused investigational product and return to the site for final safety evaluations.
5.
PRIOR AND CONCOMITANT TREATMENT
5.1
Prior Treatment
Prior treatment includes all treatment (including over-the-counter, herbal treatments, vitamins, 
non-pharmacological treatment such as psychotherapy as appropriate), received within 30 days
of, and discontinued prior to, the date of first dose of investigational product.  Prior treatment 
information must be recorded on the appropriate CRF page.
Subjects taking growth hormone must have started their treatment at least 2 months prior to Visit 
1.0 (Part 1, Table 1 or Part 2b and 3, Table 3) or Visit 2.0 (Part 2a and 3, Table 1).
Treatment with proton pump inhibitors must be initiated at least 4 weeks prior to Visit 1.0 (Part 
1, Table 1 or Part 2b and 3, Table 3) or Visit 2.0 (Part 2a and 3, Table 1).
Table 4 details the washout period for common prior treatments and highlights excluded 
medications. 
Table 4:  Common Excluded Treatments and Washout Period
Treatment
Washout
Examples (if applicable)
Cinacalcet hydrochloride
Up to 3 weeksa
MIMPARA
Sevelamer hydrochloride
Up to 3 weeksa
RENAGEL, RENVELA
a Until phosphate levels are <6.0mg/dL (1.94mmol/L) for subjects under 12 years or <5.5mg/dL (1.78mmol/L) for subjects aged 
12 years and over
5.2
Concomitant Treatment 
Concomitant treatment taken between the dates of the first and last dose of investigational 
product, inclusive, must be listed on the appropriate CRF page.


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Treatments not listed in Table 4 above are considered allowable. 
Subjects who require treatment with Vitamin D analogues should maintain a stable dose 
throughout the study unless modification is required due to hypercalcaemia as specified in 
Section 6.2.1.  Vitamin D therapy including dose, unit, route, regimen, indication and dates of 
use, and the calcium concentration of the dialysate will also be recorded in the CRF. 
Treatment with cinacalcet hydrochloride, or with compounds containing phosphate or 
magnesium, aluminum, or calcium that are used as a phosphate binder are prohibited during the 
study.
Contraceptives for females should be taken at least 4 weeks prior to enrollment and continued 
throughout the duration of the study and for 30 days following the last dose of investigational 
product.
6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is lanthanum carbonate, which will be provided in 250mg sachets in powder 
form.  Additional information is provided in the current SPD405 IB and Summary of Product 
Characteristics.
The reference/comparator product in Part 2a is calcium carbonate which is provided in 500mg 
tablet form.  Additional information is provided in the Summary of Product Characteristics. 
6.2
Administration of Investigational Product(s)
6.2.1
Dosing
Both calcium carbonate tablets and lanthanum carbonate powder are to be taken orally.
Part 1: Lanthanum carbonate oral powder will be administered in the morning following 
breakfast at Visit 1.1, which is the day after dialysis treatment.
Subjects aged between 10-12 years will receive a single dose of 500mg lanthanum (as lanthanum 
carbonate hydrate; SPD405) and subjects aged >12 years will receive a single 1000mg dose of 
lanthanum (as lanthanum carbonate hydrate; SPD405).
Part 2a, Treatment Period 1: Calcium carbonate may be started at the dose taken by the subject 
prior to starting the study or equivalent.  For new subjects, dosing will be based on standard 
clinical practice.  The total daily dose may be adjusted as appropriate, until the target serum 
phosphorus level is achieved or until a maximum daily dose of 6500mg is reached.  Once serum 
phosphorus control is achieved, the dose of calcium carbonate will be maintained until the end of 
the 8-week calcium carbonate treatment period. 
Investigational product will be dispensed at Visit 2.0 if eligible, however if a washout is required 
then investigational product will be dispensed at visit W1.


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Part 2a, Treatment Period 2: At the end of the first 8-week treatment period of Part 2a, all 
subjects will begin 8 weeks of treatment with lanthanum carbonate following a washout period 
of up to 3 weeks if necessary (see Section 7.1.2.4).  Subjects reaching a level of phosphorus 
equal to or greater than the age-appropriate KDOQI guidance (aged under 12 years: serum 
phosphorus >6.0mg/dL [1.94mmol/L] and aged 12 years and older:  serum phosphorus 
>5.5mg/dL [1.78mmol/L]) will be withdrawn from washout and commence treatment with 
lanthanum carbonate.
Lanthanum carbonate will be started at a total daily dose of 1500mg mixed into meals for all 
subjects.  Lanthanum carbonate will be mixed with food and given 3 times a day.  If the subject 
has only 2 meals a day the lanthanum carbonate dose will split equally across the 2 meals with a 
single dose not exceeding 1000mg.  The total daily dose will be titrated as appropriate, until the 
target serum phosphorus level is achieved in accordance with KDOQI age guidelines or until a 
maximum daily dose of 3000mg is reached.  Once serum phosphorus control is achieved, the 
dose of lanthanum carbonate will be maintained until the end of the 8-week lanthanum carbonate 
treatment period. 
Part 2b: Eligible subjects will begin 8 weeks of treatment with lanthanum carbonate if they have 
phosphate levels equal to or greater than the age appropriate KDOQI guidance (serum 
phosphorus >6.0mg/dL [1.94mmol/L] for subjects aged under 12 years; >5.5mg/dL 
[1.78mmol/L] for subjects aged 12 years and older) at Visit 1, Week 0. Eligible subjects with 
serum phosphate levels below the age appropriate KDOQI guidance at Visit 1, Week 0 will enter 
a washout period (W1) of up to 3 weeks (see Table 3). 
Lanthanum carbonate will be mixed with food and given 3 times a day. If the subject has only 2 
meals a day the lanthanum carbonate dose will split equally across the 2 meals with a single dose 
not exceeding 1000mg. The starting total daily dose of lanthanum carbonate is 1500mg for all 
subjects. The total daily dose will be titrated 2-weekly, as appropriate, until the target serum 
phosphorus level is achieved, or until a maximum daily dose of 3000mg is reached. Once serum 
phosphorus control is achieved or the maximum dose is reached, the dose of lanthanum 
carbonate will be maintained until the end of the 8-week treatment period. All new subjects will 
be enrolled in Part 2b only under Version 6.0 of the protocol.
Part 3: Subjects who complete participation in Part 2 (2a or 2b) may continue to receive 
lanthanum carbonate for an additional 6 months (including subjects who participated in Part 2a, 
Treatment Period 1/calcium carbonate treatment arm, but who discontinued due to 
hypercalcemia). The dosage of lanthanum carbonate will be determined by the Investigator based 
on serum phosphate levels taken at each study visit up to a maximum dose of 3000mg/day.
Hypophosphatemia During Parts 2 and 3
(See APPENDIX 2 for guidelines on phosphate and calcium level management.)
If the serum phosphate is <4mg/dL (1.29mmol/L) for adolescents aged 12-18 years, or 
<4.5mg/dL (1.45mmol/L) for subjects aged 10 years to <12 years, we advise that the Investigator 
monitor the phosphate levels carefully and consider reducing the binder dose by 25% depending 
on the rate at which the phosphorus is falling when prior laboratory testing is reviewed. 


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If the serum phosphate is <3.5mg/dL (1.13mmol/L) for adolescents aged 12-18 years, or 
<4mg/dL (1.29mmol/L) for subjects aged 10 years to <12 years, the binder should be stopped 
and serum phosphate levels monitored closely.
The binder should be resumed at 50% of the prior dose when the serum phosphorus is >4mg/dL 
(1.29mmol/L) for adolescents, and >4.5mg/dL (1.45mmol/L) for subjects aged 10 years to <12 
years.
Hypocalcemia During Parts 2 and 3
Subjects whose serum levels of corrected total calcium are below the lower limit (<8.8mg/dL 
[2.20mmol/L]) should receive therapy to increase serum calcium levels.  This must be taken 
between meals and/or at bedtime. 
Hypercalcemia
If hypercalcaemia (serum calcium >10.2mg/dL (2.54mmol/L) develops during administration of 
calcium carbonate in Part 2a (Treatment Period 1) of the study, active vitamin D sterols should 
be decreased by 50%, the dose of calcium carbonate should be decreased by 25%, and the 
subject should be monitored.  If after 2 weeks hypercalcemia persists, active vitamin D sterols 
should be stopped.  If after another 2 weeks from onset of hypercalcemia it persists, the subject 
should be withdrawn from Part 2a.  If the Investigator believes there are no contraindications and 
the subject is willing to continue, the subject can start Part 3.
If hypercalcemia (serum calcium >10.2mg/dL (2.54mmol/L) develops during administration of 
lanthanum carbonate, active vitamin D sterols should be decreased by 50%.  If after 2 weeks 
hypercalcemia persists, active vitamin D sterols should be stopped until required.
6.2.2
Blinding the Treatment Assignment
Not Applicable. 
6.2.3
Allocation of Subjects to Treatment 
This is an open-label study.  Subject numbers are assigned to all subjects as they consent to take 
part in the study.  Within each site (numbered uniquely within a protocol), this number is 
assigned to subjects according to the sequence of presentation for study participation.  
6.2.4
Unblinding the Treatment Assignment
Not Applicable.
6.3
Labelling, Packaging, Storage, and Handling
6.3.1
Labelling
All investigational product is labelled with a minimum of the protocol number, medication 
identification number, dosage form (including product name and quantity in pack), directions for 
use, storage conditions, expiry date (if applicable), batch number and/or packaging reference, the 
statements ‘For clinical trial use only’ and ‘Keep out of reach of children’, and the Sponsor's 


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name and address.  Any additional labelling requirements for participating countries and/or 
controlled substances will also be included on the label.
Space is allocated on the label so that the site representative can record a unique subject 
identifier and initials.
Additional labels may, on a case-by-case basis, be applied to the investigational product in order 
to satisfy local or institutional requirements, but must not:

Contradict the clinical study label

Obscure the clinical study label

Identify the study subject by name.
Additional labels may not be added without the Sponsor’s prior full agreement.
6.3.2
Packaging
Lanthanum carbonate is packaged in the following labelled containers: cartons containing 50 of 
the 250mg sachets.
Calcium carbonate is supplied in a white high-density polyethylene bottle with a white round cap 
with a plastic ring pull seal, containing 100 tablets.
Changes to Sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the Sponsor.
6.3.3
Storage
The Investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location.  Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.  Investigational products are 
distributed by the pharmacy or nominated member of the study team.  The pharmacist/nominated 
team member will enter the unique subject identifier on the investigational product bottle/carton 
labels as they are distributed.
Investigational product must be stored in accordance with labelled storage conditions.  
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range.  The Investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device, such as a calibrated chart recorder, or by 
manual means, such that both minimum and maximum thermometric values over a specific time 
period can be recorded and retrieved as required.  Such a device (ie, certified Min/Max 
Thermometer) would require manual resetting upon each recording.  The Sponsor must be 
notified upon discovery of any excursion from the established range.  Temperature excursions 
will require site investigation as to cause and remediation.  The Sponsor will determine the 
ultimate impact of excursions on the investigational product and will provide supportive 


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documentation as necessary.  Under no circumstances should product be dispensed to subjects 
until the impact is determined and product is deemed appropriate for use by Sponsor.
6.3.4
Handling
There are no special investigational product handling instructions.
6.4
Investigational Product Quality Complaints
Investigators are required to report investigational product quality complaints to Shire within 24 
hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products).
6.5
Drug Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects.  The Investigator or designee will acknowledge 
receipt of the investigational product documenting shipment content and condition.  Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section. 
The Investigator has overall responsibility for administering/dispensing investigational product.  
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the 
Investigator.  This delegation must be documented in the applicable study delegation of authority 
form.
The Investigator or his/her designee (as documented by the Investigator in the applicable study 
delegation of authority form) will dispense the investigational product only to subjects included 
in this study following the procedures set out in the study protocol.  Each subject will be given 
only the investigational product carrying his/her treatment assignment.  All dispensing will be 
documented on the CRFs and/or other investigational product record.  The Investigator is 
responsible for assuring the retrieval of all study supplies from subjects.  
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
Sponsor.  If such transfer is authorized by the Sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The Sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the Sponsor, all unused stock, subject-returned 
investigational product, and empty/used investigational product packaging are to be sent to a 
nominated contractor on behalf of the Sponsor.  Investigational products being returned to the 


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Sponsor’s-designated contractors must be counted and verified by clinical site personnel and the 
Sponsor (or designated Contract Research Organization; CRO).  For unused supplies where the 
original supplied tamper-evident feature is verified as intact, the tamper-evident feature must not 
be broken and the labelled amount is to be documented in lieu of counting.  All certificates of 
delivery/drug receipts should be signed by the site representative to confirm contents of 
shipment.  Shipment return forms, when used, must be signed prior to shipment from the site.  
Returned investigational products must be packed in a tamper-evident manner to ensure product 
integrity.  Contact the Sponsor for authorisation to return any investigational product prior to 
shipment.  Shipment of all returned investigational product must comply with local, state, and 
national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned.  All investigational products 
must be accounted for and all discrepancies investigated and documented to the Sponsor’s 
satisfaction. 
6.6
Subject Compliance
Subjects must be instructed to bring their unused investigational product and empty/used 
investigational product packaging to every visit.  Drug accountability must be assessed at the 
container/packaging level for unused investigational product that is contained within the original 
tamper-evident sealed container (eg, bottles, cartons) or at the individual count level for opened 
containers/packaging.  The pharmacist/nominated person will record details on the drug 
accountability form.
At each visit the investigational product dispensed at the previous visit will be counted, 
compliance calculated and the container returned to the subject until exhausted.
7.
STUDY PROCEDURES
7.1
Study Schedule
See Table 1 and Table 3 for study procedures.
7.1.1
Screening Period
7.1.1.1
Part 1: Screening Visit Part 1 (Visit 1.0, Week -5)
The Investigator or designee will obtain written informed consent/assent from the subject/LAR 
prior to any study-related procedures being performed. 
Each subject will be assigned a 7-digit number using the unique site number and the order of the 
subject as they present eg, the first subject at Site 101 would be 101-0001, the second 101-0002.

All inclusion/exclusion criteria will be assessed and demographic characteristics recorded.

Significant medical and renal history (in the Investigators’ opinions) will be recorded.

A full physical examination as well as height, weight, and vital signs will be performed.


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
A 12-lead electrocardiogram (ECG) will be undertaken to exclude any underlying cardiac 
diseases.

Blood samples will be taken for biochemistry, hematology, and biochemical bone markers.

All females will undergo a serum pregnancy test.

All concomitant medication and ongoing AEs will be recorded.

Confirmation of dialysis adequacy and dietary advice will be made.
If all criteria are met except the phosphate level, the subject will enter the washout period for 
Part 1. 
A screen failure will be considered to be a subject who has given informed consent and failed to 
meet the inclusion and/or meet at least 1 of the exclusion criteria and has not been administered 
investigational product(s) as defined by the protocol. 
Subjects cannot be re-screened once they have been designated as a screen failure.
7.1.1.2
Part 2a: Screening Visit (Visit 2.0; Week 0)
The Investigator or designee will obtain written informed consent/assent from the subject/LAR 
prior to any study-related procedures being performed, irrespective of whether the subject has 
already completed Part 1 of the study. 
Subjects who have completed Part 1 do not need to have a further blood sample taken and all of 
the study information itemized below can be obtained from their Visit 1.0 assessments.  Upon 
completion of Visit 2.0, these subjects will enter Visit 2.1.
Each subject will be assigned a unique 7-digit number in the order that they present in the clinic, 
regardless if they start at Part 1 or Part 2 of the study eg, the first subject at Site 001 would be 
001-0001, the second 001-0002. 

All inclusion/exclusion criteria will be assessed and demographic characteristics recorded 
(Version 5.0 of the protocol).

Eligibility can be based on local laboratory results; however blood samples must be 
submitted to the central laboratory to obtain central laboratory results.  Phosphorus 
levels and serum pregnancy results must be taken from samples within 7 days of 
planned enrollment, and PTH samples must be taken within 3 months of planned 
enrollment. 

Significant medical and renal history (in the Investigator’s opinion) will be recorded, 
including the last assessment of glomerular filtration rate taken from the medical record.

A full physical examination including height, weight, and vital signs will be performed.

A 12-lead ECG will be undertaken to exclude any underlying cardiac diseases.

Blood samples will be taken for biochemistry, hematology and biochemical bone markers.

All females will undergo a serum pregnancy test.


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
All concomitant medication and ongoing AEs will be recorded.

Confirmation of dialysis adequacy and dietary advice will be made.

Investigational product will be dispensed to subjects who do not require a washout and 
have already reached a level of phosphorus equal to or greater than the age appropriate 
KDOQI guidance (aged under 12 years: serum phosphorus >6.0mg/dL [1.94mmol/L] and 
aged 12 years and older:  serum phosphorus >5.5mg/dL [1.78mmol/L]).  If a subject has 
started calcium carbonate based on local laboratory results, the subject will be allowed to 
continue in the study even if central laboratory results do not agree.
7.1.1.3
Part 2b: Screening Visit (Visit 1.0; Week 0)
The Investigator or designee will obtain written informed consent/assent from the subject/LAR 
prior to any study-related procedures being performed. Upon completion of Visit 1.0 for Part 2b, 
these subjects will enter Visit 2.1. All new eligible subjects will directly enter Part 2b under 
Version 6.0 of the protocol.
Each subject will be assigned a unique 7-digit number in the order that they present in the clinic, 
eg, the first subject at Site 001 would be 001-0001, the second 001-0002. 

All inclusion/exclusion criteria will be assessed and demographic characteristics recorded 
(Version 6.0 of the protocol).

Eligibility can be based on local laboratory results; however blood samples must be 
submitted to the central laboratory to obtain central laboratory results. Phosphorus 
levels and serum pregnancy results must be taken from samples within 7 days of 
planned enrollment, and PTH samples must be taken within 3 months of planned 
enrollment. 

Significant medical and renal history (in the Investigator’s opinion) will be recorded, 
including the last assessment of glomerular filtration rate taken from the medical record.

A full physical examination including height, weight, and vital signs will be performed.

A 12-lead ECG will be undertaken to exclude any underlying cardiac diseases.

Blood samples will be taken for biochemistry, hematology and biochemical bone markers.

All females will undergo a serum pregnancy test.

All concomitant medication and ongoing AEs will be recorded.

Confirmation of dialysis adequacy and dietary advice will be made.

Investigational product will be dispensed to subjects who have a level of serum phosphorus 
equal to or greater than the age appropriate KDOQI guidance (aged under 12 years: serum 
phosphorus >6.0mg/dL [1.94mmol/L] and aged 12 years and older:  serum phosphorus 
>5.5mg/dL [1.78mmol/L]).

If all criteria are met except the phosphate level, the subject will enter the washout period 
W1 for Part 2b.


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7.1.1.4
Washout (W1) 
Part 1 (between Visits 1.0 and 1.1)
Subjects must stop taking any phosphate binder medication for up to 3 weeks prior to the first 
dose of investigational product if their phosphate levels are <6.0mg/dL (1.94mmol/L) for 
subjects under 12 years or <5.5mg/dL (1.78mmol/L) for subjects aged 12 years and over.
If a subject under 12 years already has phosphate levels >6.0mg/dL (1.94mmol/L) or >5.5mg/dL 
(1.78mmol/L) for subjects aged 12 years and older, the subject may proceed directly to the next 
part of the study (Visit 1.1).  If a subject has started lanthanum carbonate based on local 
laboratory results, the subject will be allowed to continue in the study even if central laboratory 
results do not agree.
Blood sample(s) will be taken locally during the washout period to ensure the phosphorus 
reaches the KDOQI required level.  When reached the phosphate level should be confirmed by 
taking a sample (between 0.1-0.7mL depending on each country’s specific requirements) which 
will be analyzed by the central laboratory.  However study medication can be dispensed based on 
the local laboratory result.
Any AEs or changes to concomitant medication will be recorded.
Part 2a (between Visits 2.0 and 2.1) and Part 2b (between Visit 1.0 and 2.1)
Subjects must stop taking any phosphate binder medication for up to 3 weeks prior to the first 
dose of investigational product if their phosphate levels are <6.0mg/dL (1.94mmol/L) for 
subjects under 12 years or <5.5mg/dL (1.78mmol/L) for subjects aged 12 years and over.
If a subject aged under 12 years already has phosphate levels >6.0mg/dL (1.94mmol/L) or 
>5.5mg/dL (1.78mmol/L) for subjects aged 12 years and older, the subject may proceed directly 
to the next part of the study (Visit 2.1).  If a subject has started calcium carbonate or lanthanum 
carbonate based on local laboratory results, the subject will be allowed to continue in the study 
even if central laboratory results do not agree.
If phosphate levels reach >6.0mg/dL (1.94mmol/L) for subjects aged under 12 years or 
>5.5mg/dL (1.78mmol/L) for subjects aged 12 years and older during the washout, the subject 
will be withdrawn from washout and start the next part of the study (Visit 2.1).  
Blood sample(s) will be taken locally during the washout period to ensure the phosphorus 
reaches the KDOQI required level.  When reached, the phosphate level should be confirmed by 
taking a sample (between 0.1-0.7mL depending on each country’s specific requirements) which 
will be analyzed by the central laboratory.  However subjects can be enrolled based on the local 
laboratory result.
Any AEs or changes to concomitant medication will be recorded.
Subjects who have participated in Part 1 do not need to have a washout prior to entering Part 2 
(not applicable to part 2b).


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Subjects who have completed the washout (W1) and have phosphate levels equal to or greater 
than the age appropriate KDOQI guidance (serum phosphorus >6.0mg/dL [1.94mmol/L] for 
subjects aged under 12 years; >5.5mg/dL [1.78mmol/L] for subjects aged 12 years and older) 
will:

Part 2a: Be dispensed calcium carbonate at either the dose taken by the subject prior to 
starting the study or at a dose determined by the Investigator for new subjects based on 
standard clinical practice.

Part 2b: Be dispensed lanthanum carbonate with the starting total daily dose as 1500mg for 
all subjects. The total daily dose will be titrated 2-weekly, as appropriate, until the target 
serum phosphorus level is achieved, or until a maximum daily dose of 3000mg is reached.

Have any AEs that occurred since the last visit recorded.

Have a review of any concomitant medication taken since the last visit undertaken and 
changes recorded.
7.1.2
Treatment Period
7.1.2.1
Part 1: Visit 1.1/ Week -5 to -1 (3 Days)
Visit 1.1 should be scheduled on the day after dialysis.  See Table 2 for a detailed schedule of 
assessments for this visit.

Subjects aged between 10 and 12 years will receive a single dose of 500mg lanthanum (as 
lanthanum carbonate hydrate) and subjects aged 12 years and over will receive a single 
1000mg dose lanthanum (as lanthanum carbonate hydrate; SPD405).

Blood samples for pharmacokinetic analyses will be taken pre-dose and at 3, 5, 6, 8, 12, 
24, and 48 hours after dosing.

Vital signs (blood pressure and pulse) will be recorded pre-dose, and at 24 and 48 hours 
after dosing.

A physical examination will be done at 48 hours post-dose.

Adverse events and changes to concomitant medication will be recorded.
7.1.2.2
Part 2a: Visits 2.1-2.3 (Weeks 2, 4, and 6; 3 Days)

Subjects will attend the clinic every 2 weeks for scheduled study visits, starting from the 
first dose of investigational product

Phosphate and calcium levels will be measured locally for titration purposes.

The investigational product dispensed at the previous visit will be counted, compliance 
calculated and the container returned to the subject until exhausted. If necessary, a new 
container of investigational product will be dispensed.

The dose of calcium carbonate will be adjusted as required at each visit.

Any AEs that occurred since the last visit will be recorded.


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
A review of any concomitant medication taken since the last visit will be undertaken and 
changes recorded.

Confirmation of dialysis adequacy and dietary advice will be made.
7.1.2.3
Part 2a: Visit 2.4 (Week 8; 3 Days)

Vital signs, height, and weight will be measured.

Blood samples will be taken for biochemistry, and biochemical bone markers.

Investigational product will be collected and drug accountability performed.

Any AEs that occurred since the last visit will be recorded.

A review of any concomitant medication taken since the last visit will be performed and 
changes recorded.

Confirmation of dialysis adequacy and dietary advice will be made. 

If phosphate levels remain >6.0mg/dL (1.94mmol/L) for subjects aged under 12 years or 
>5.5mg/dL (1.78mmol/L) for subjects aged 12 years and older, the subject may be 
dispensed lanthanum carbonate at a total daily dose of 1500mg to be taken with meals.  If 
phosphate levels are below these levels the subject must enter a washout period of up to 
3 weeks or until the targeted levels are reached, whichever is earliest.  If a subject has 
started lanthanum carbonate based on local laboratory results, the subject will be allowed 
to continue the study even if central laboratory results do not agree. 
7.1.2.4
Part 2a: Washout (W2)
Subjects will be asked to stop taking calcium carbonate and will not be taking a phosphate 
binder, for up to 3 weeks or until phosphate levels, to be measured locally, of >6.0mg/dL 
(1.94mmol/L) for subjects aged under 12 years or >5.5mg/dL (1.78mmol/L) for subjects aged 12 
years and older are reached, whichever is sooner. The phosphate level should be confirmed by 
taking a sample (between 0.1-0.7mL depending on each country’s specific requirements) which 
will be analyzed by the central laboratory. If a subject has started lanthanum carbonate based on 
local laboratory results, the subject will be allowed to continue the study even if central 
laboratory results do not agree.
Any AEs or changes to concomitant medication will be recorded.
Subjects who complete the 3-week washout (W2) will be dispensed lanthanum carbonate at a 
starting daily dose of 1500mg to be taken with meals.
Subjects whose phosphate levels do not rise above 6.0mg/dL (1.94mmol/L) for subjects aged 
under 12 years or >5.5mg/dL (1.78mmol/L) for subjects aged 12 years and older during the 
washout period may be dispensed lanthanum carbonate for Part 3 at a daily dose determined by 
the Investigator based on serum phosphorus levels taken at each study visit up to a maximum 
daily dose of 3000mg which will be taken with meals. 
If phosphate levels do not reach the required levels then the subject cannot enter the second 
treatment period of Part 2, however they can proceed to Part 3.


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7.1.2.5
Part 2a: Visits 2.5-2.7 (Weeks 10, 12, and 14, Nominally; 3 Days)

Subjects will attend the clinic every 2 weeks for scheduled study visits.

At Visit 2.6 only, blood samples will be taken to measure lanthanum pharmacokinetics (2 
samples to be selected from: 0-2 hours, 2-4 hours, or 4-6 hours).  Note:  If the sampling is 
not done at Visit 2.6, blood sampling for pharmacokinetics must be taken at an alternative 
visit during Part 2.

Phosphate levels will be measured locally at Visits 2.5, 2.6 and 2.7 only, for titration 
purposes.

The investigational product dispensed at the previous visit will be counted, compliance 
calculated and the container returned to the subject until exhausted. If necessary, a new 
container of investigational product will be dispensed.

The dose of lanthanum carbonate will be adjusted and dispensed as required.

Any AEs that occurred since the last visit will be recorded.

A review of any concomitant medication taken since the last visit will be undertaken and 
changes recorded.

Confirmation of dialysis adequacy and dietary advice will be made.
7.1.2.6
Part 2a: Final Visit (Visit 2.8; Week 16 Nominally; 3 Days)

A 12-lead ECG will be performed.

Vital signs, height and weight will be measured.

Blood samples will be taken for biochemistry, and biochemical bone markers.

Any unused lanthanum carbonate will be collected and drug accountability performed

Any AEs that occurred since the last visit will be recorded.

A review of any concomitant medication taken since the last visit will be performed and 
changes recorded.

Confirmation of dialysis adequacy and dietary advice will be made.

For subjects entering Part 3, lanthanum carbonate will be dispensed at a dose determined 
by the Investigator based on serum phosphorus levels taken at each study visit up to a 
maximum dose of 3000mg/day.
7.1.2.7
Part 2b: Visits 2.1-2.3 (Weeks 2, 4, and 6; Nominally; 3 Days)

Subjects will attend the clinic every 2 weeks for scheduled study visits, starting from the 
first dose of investigational product.

At Visit 2.2 only, blood samples will be taken to measure lanthanum pharmacokinetics (2 
samples to be selected from: 0-2 hours, 2-4 hours, or 4-6 hours).  Note:  If the sampling is 
not done at Visit 2.2, blood sampling for pharmacokinetics must be taken at an alternative 
visit during Part 2b.


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
Phosphate levels will be measured locally at Visits 2.1, 2.2 and 2.3 only, for titration 
purposes.

The investigational product dispensed at the previous visit will be counted, compliance 
calculated and the container returned to the subject until exhausted. If necessary, a new 
container of investigational product will be dispensed.

The dose of lanthanum carbonate will be adjusted and dispensed as required.

Any AEs that occurred since the last visit will be recorded.

A review of any concomitant medication taken since the last visit will be undertaken and 
changes recorded.

Confirmation of dialysis adequacy and dietary advice will be made.
7.1.2.8
Part 2b: Final Visit (Visit 2.4; Week 8; Nominally; 3 Days)

A 12-lead ECG will be performed.

Vital signs, height and weight will be measured.

Blood samples will be taken for biochemistry, and biochemical bone markers.

Any unused lanthanum carbonate will be collected and drug accountability performed.

Any AEs that occurred since the last visit will be recorded.

A review of any concomitant medication taken since the last visit will be performed and 
changes recorded.

Confirmation of dialysis adequacy and dietary advice will be made.

For subjects entering Part 3, lanthanum carbonate will be dispensed at a dose determined 
by the Investigator based on serum phosphorus levels taken at each study visit up to a 
maximum dose of 3000mg/day.
7.1.2.9
Part 3 (Visits 3.0-3.4: Weeks 20, 24, 28, 32, and 36; 1 Week for Part 2a; 
Weeks 12, 16, 20, 24, and 28 for Part 2b)

Subjects who have successfully completed Part 2 of the study will continue to be dispensed 
lanthanum carbonate for a further 6 months.

Subjects will attend the clinic once every month for scheduled study visits.

At Visits 3.0-3.4 the local lab results for serum calcium, serum phosphorus, and calcium 
phosphorus product will be taken for analysis.

At Visit 3.3 only, blood samples will be taken to measure lanthanum pharmacokinetics (2 
samples to be selected from: pre dose to 2 hours, 2-4 hours, and 4-6 hours).  Note:  If the 
sampling is not done at Visit 3.3, blood sampling for pharmacokinetics must be taken at an 
alternative visit during Part 3.

The dose of lanthanum carbonate will be adjusted and dispensed as required and any 
unused lanthanum carbonate will be collected, and drug accountability performed.

Any AEs that occurred since the last visit will be recorded.


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
A review of any concomitant medication taken since the last visit will be undertaken and 
changes recorded.

Confirmation of dialysis adequacy and dietary advice will be made.
7.1.2.10
End of Part 3 (Visit 3.5: Week 40/ End of Study for Part 2a; Week 32/End 
of Study for Part 2b; 1 Week)

A full physical examination including vital signs, weight and height will be carried out.

12-lead ECG will be performed.

Blood samples will be taken for biochemistry, hematology, and biochemical bone markers.

All females will undergo a serum pregnancy test.

All AEs and concomitant medication will be recorded.

Confirmation of dialysis adequacy and dietary advice will be made.

The primary reason for withdrawal will be recorded, if applicable.

All returned study medication will be counted and recorded, and compliance calculated.

An End of Study (EOS) Visit should be performed for all subjects in the study, including 
those subjects who discontinue early.
7.1.3
Follow-up Period 
The safety follow-up call for this protocol is 7-14 days following last dose of investigational 
product (Table 1 and Table 3).  Subjects who discontinue due to kidney transplantation, will 
have their safety follow-up call after 30±7 days from the last dose.
The telephone call is initiated by the site staff to query for serious adverse events (SAEs), AEs, 
and concomitant treatments.
7.1.4
Additional Care of Subjects After the Study
Not Applicable.
7.2
Study Evaluations and Procedures
7.2.1
Demographic and Other Baseline Characteristics
Patient demographic details, medical history, vital signs, including height, weight, physical 
examination, biochemistry, hematology, serum pregnancy test, type of dialysis (hemodialysis or 
peritoneal), vitamin D levels, and concomitant medication data will be obtained at Visit 1.0 (Part 
1, Table 1 or Part 2b and 3,Table 3) or Visit 2.0 (Part 2a and 3,Table 1).
7.2.2
Efficacy
The primary efficacy endpoint is the percentage of subjects achieving age-specific KDOQI 
targets for serum phosphate level following 8 weeks of treatment with lanthanum carbonate.


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The KDOQI serum phosphate targets are defined as:

Adolescents aged ≥12-18 years: ≤5.5mg/dL (1.78mmol/L)

Children aged 10 years to <12years: ≤6.0mg/dL (1.94mmol/L)
The secondary efficacy endpoints will be evaluated by analysis of, phosphorus PTH, ALP, bone 
ALP, osteocalcin, TRAP, FGF-23, sclerostin and fetuin-A taken from blood samples at Visits 
2.0, 2.4, 2.8 and 3.5 for Part 2a (see Table 1) and at Visits 1.0, 2.4, and 3.5 for Part 2b (see Table 
3).
7.2.3
Safety
7.2.3.1
Medical and Medication History
Medical and renal history will be recorded.
7.2.3.2
Physical Examination 
Abnormalities identified at Visit 1.0 (see Table 1 and Table 3) or Visit 2.0 (see Table 1), will be 
documented in the subject’s source documents and on the medical history CRF. Changes after 
these visits will be captured as AEs on the AE CRF page, as deemed by the Investigator.
7.2.3.3
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”).  
Adverse events are collected from the time informed consent is signed.
7.2.3.4
Vital Signs
Blood pressure should be determined by cuff (using the same method, the same arm, and in the 
same position throughout the study).  Any clinically significant deviations from baseline vital 
signs which are deemed clinically significant in the opinion of the Investigator are recorded as an 
AE.
Height and weight will be measured as part of the vital signs assessments.
7.2.3.5
Clinical Laboratory Evaluations
The name and address of the each clinical laboratory used in this study will be maintained in the 
Investigator’s files at each site.
All clinical laboratory assays will be performed according to the laboratory’s normal procedures.  
Reference ranges are supplied by the laboratory and used to assess the clinical laboratory data for 
clinical significance and out-of-range pathological changes.  The Investigator should assess out-
of-range clinical laboratory values for clinical significance, indicating if the value(s) is/are not 
clinically significant or clinically significant.  Abnormal clinical laboratory values, which are 
unexpected or not explained by the subject’s clinical condition may be, at the discretion of the 
Investigator or Sponsor, repeated until confirmed, explained, or resolved as soon as possible.  


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The following clinical laboratory assessments will be performed: 
Biochemistry
Blood samples (approximately 4.0mL) for biochemistry will be taken according to the Schedule 
of Assessments (see Table 1 and Table 3).  The following parameters will be assessed:
Sodium
Aspartate aminotransferase (AST)
Potassium
Alanine aminotransferase (ALT)
Calcium
Alkaline phosphatase (ALP)
Urea
Gamma glutamyl transferase (GGT)
Creatinine
Total bilirubin
Albumin
Magnesium
Total protein
Serum phosphorus
25-hydroxy Vitamin Da, 
a 25-hydroxy Vitamin D will be measured at baseline and EOS only
Changes from baseline will be recorded as an AE if clinically relevant.
Hematology
Blood samples (approximately 500µL) for hematology will be taken according to the Schedule
of Assessments (see Table 1 and Table 3).  The following parameters will be assessed:
Hemoglobin
Mean corpuscular hemoglobin (MCH)
Hematocrit
Mean corpuscular hemoglobin concentration (MCHC)
Red blood cells
White blood cell count – total and differential 
Mean corpuscular volume (MCV)
Platelet count
Changes from baseline will be recorded as an AE if clinically relevant.
Biochemical Bone Markers
Blood samples (approximately 3.0mL) for biochemical bone markers will be taken according to 
the Schedule of Assessments (see Table 1 and Table 3).  The following parameters will be 
assessed:


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TRAP
FGF-23
Osteocalcin
Bone ALP
PTHa
Sclerostin
Fetuin- A
Changes from baseline will be recorded as an AE if clinically relevant.
7.2.3.6
Pregnancy Test 
A serum pregnancy test is performed on all female subjects  at Visit 1.0, and/or Visit 2.0, and at 
the final visit (Visit 3.5), or if pregnancy is suspected, or on withdrawal of the subject from the 
study (see Table 1 and Table 3).
7.2.3.7
Electrocardiogram 
An ECG will be carried out at Visit 1.0, at Visits 2.0, 2.8 and 3.5/EOS for Part 2a (see Table 1), 
and at Visits 1.0, 2.4, and 3.5/EOS for Part 2b (see Table 3).
The ECG must be assessed by either a cardiac specialist or by a study physician who is trained to 
perform this assessment.
7.2.4
Others 
7.2.4.1
Clinical Pharmacology Assessments
Blood Sampling for Lanthanum Pharmacokinetic Evaluation
Actual pharmacokinetic blood sample collection times relative to the time of dosing will be 
monitored.  The Sponsor's expectation is that the Investigator will ensure that every effort is 
made to collect all pharmacokinetic blood samples at the precise protocol-scheduled time.  
Blood samples (1mL each) for pharmacokinetic evaluation will be collected during all 3 study 
periods (Parts 1, 2 [2a and 2b], and 3). 
Part 1.  Blood samples for determination of single-dose lanthanum pharmacokinetics will be 
collected at pre-dose and at 3, 5, 6, 8, 12, 24, and 48 hours after dosing.  
Part 2 (2a or 2b) and Part 3.  Pharmacokinetics will be evaluated during lanthanum carbonate 
dosing using a sparse sampling approach.  Blood samples (at least 2 per subject) for 
pharmacokinetic assessments will be collected during Parts 2 (2a or 2b) and 3 in defined time 
windows (to be selected from: 0-2 hours, 2-4 hours and 4-6 hours after the first dose/meal of the 
day, so as to cover the full dosing interval).  
The actual time that the sample was taken will be recorded; it should be within 5 minutes of the 
nominal in the first 4 hours after taking the investigational product, 15 minutes up to 24 hours 
after taking the investigational product (Parts 1, 2, and 3), and within 60 minutes thereafter 
(Part 1 only). 


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Samples drawn outside these parameters will be considered a protocol deviation.
7.2.4.2
Pharmacodynamic Assessments
Not Applicable.
7.2.4.3
Quality of Life Assessments
Not Applicable.
7.2.4.4
Health Outcomes Assessments
Not Applicable.
7.2.5
Volume of Blood to be Drawn From Each Subject
Table 5:  Volume of Blood to be Drawn From Each Subject
Assessment
Sample Volume (mL)
Number of 
Samples
Maximum Total 
Volume (mL)
Pharmacokinetic samples
1.0a
12
12.0
Safety
Biochemistry with -HCGa
4.0
4
16.0
Hematology
0.5
2
1.0
Biochemical bone markers
3.0
4
12.0
Centrally confirmed phosphateb
0.1-0.7c
2
1.4
Total mL
42.4
HCG=human chorionic gonadotropin
a -HCG testing for all female subjects will be analyzed from the biochemistry samples so no additional blood volume is required
b Only for those subjects who require confirmation of their phosphate levels from the central laboratory, during the washout 
periods
c Volume will vary according to country
In the originally proposed study, it was expected that approximately 41.0mL of blood will be 
taken from all subjects, regardless of sex; a maximum of 42.4mL of blood will be taken from 
those subjects who require confirmation of their phosphate levels during both washouts in Part 2 
(41.7mL if they only require confirmation during 1 of the washouts). 
Under Version 6.0 of the protocol, subjects will enter Part 2b, after screening at Visit 1.0/Week 0 
for this part, for 8 weeks of lanthanum carbonate treatment only. They will undergo assessments 
for Part 2b and 3 as presented in Table 3. It is expected that approximately 34mL of blood will 
be taken from all subjects, regardless of sex.
Note: The above amount of blood to be taken for each assessment is an estimate.  The amount of 
blood to be taken may vary according to the instructions provided by the manufacturer or 
laboratory for an individual assessment.  However, the total volume drawn over the course of the 
study should be approximately 41.0mL (maximum of 42.4mL).  When more than 1 blood 


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assessment is to be done at the time point/period, if they require the same type of tube, the 
assessments may be combined.  
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An Adverse Event (AE) is any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (International Conference on Harmonisation [ICH] Guidance E2A 1995).  
All AEs should be captured on the AE CRF. 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3 and are to be recorded on the appropriate AE pages in the CRF and 
in source documents.  Where possible, a diagnosis, rather than a list of symptoms, should be 
recorded.  If a diagnosis has not been made, then each symptom should be listed individually.  In
addition to untoward AEs, unexpected benefits outside the investigational product indication 
should also be captured on the AE CRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), an outcome is reached, stabilization (the Investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained regardless of whether the subject is still participating in the study.  When appropriate, 
medical tests and examinations are performed so that resolution of event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity.  An event that changes in severity should be captured as a new 
event.  Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate CRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention.  The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.


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Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A Physician/Investigator must make the assessment of relationship to investigational product for 
each AE.  The Investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product.  If 
there is no valid reason for suggesting a relationship, then the AE should be classified as ‘not 
related’.  Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered ‘related’.  The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship
Definition
Related
Yes
The temporal relationship between the event and the administration of 
the investigational product is compelling and/or follows a known or 
suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
No
The event can be readily explained by other factors such as the 
subject’s underlying medical condition, concomitant therapy, or 
accident and no plausible temporal or biologic relationship exists 
between the investigational product and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF.  Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae 

Recovering/Resolving

Unknown
8.1.4
Symptoms of the Disease Under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease.  However, significant 
worsening of the symptoms should be recorded as an AE.


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8.1.5
Clinical Laboratory Evaluations
A change in the value of a clinical laboratory investigation can represent an AE if the change is 
clinically relevant or if, during treatment with the investigational product, a shift of a parameter 
is observed from a normal value to an abnormal value, or a further worsening of an already 
abnormal value.  When evaluating such changes, the extent of deviation from the reference 
range, the duration until return to the reference range, either while continuing treatment or after 
the end of treatment with the investigational product, and the range of variation of the respective 
parameter within its reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory values which were not 
present at baseline, further clinical or laboratory investigations should be performed until the 
values return to within the reference range or until a plausible explanation (eg, concomitant 
disease) is found for the abnormal clinical laboratory values.
The Investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory parameter is clinically significant and therefore 
represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.3.
Any report of pregnancy for any female study participant must be reported within 24 hours to the 
Shire Pharmacovigilance Department using the Shire Pharmaceuticals Investigational and 
Marketed Products Pregnancy Report Form.  The female study participant must be withdrawn 
from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant.  It is the responsibility of the Investigator to obtain this information 
within 30 calendar days after the initial notification and approximately 30 calendar days 
post-partum. 
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Pharmaceuticals Clinical Trial Serious 
Adverse Event Form.  Note:  An elective abortion is not considered an SAE.
In addition to the above, if the Investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Pharmaceuticals Clinical Trial Serious Adverse 
Event Form as well as the Shire Pharmaceuticals Investigational and Marketed Products 
Pregnancy Report Form.  The test date of the first positive serum/urine human chorionic 
gonadotropin test or ultrasound result will determine the pregnancy onset date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the Sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 


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in Section 8.2.  Note: The 24 hours reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society. 

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol). 

Overdose – Intentional or unintentional intake of a dose of an investigational product 
exceeding a pre-specified total daily dose of 3000mg of lanthanum and 6500mg of 
calcium.  

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product.  For studies, medication errors are reportable to the Sponsor 
only as defined below.
Cases of subjects missing doses of product are not considered reportable as medication errors.  
Medication errors should be collected/reported for all products under investigation.  The 
administration and/or use of the unassigned treatment is always reportable as a medication error.  
The administration and/or use of an expired product should be considered as a reportable 
medication error. 
All investigational product provided to pediatric subjects should be supervised by the 
parent/LAR/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for lanthanum carbonate for this study is the current 
SPD405 IB which the Sponsor has provided under separate cover to all Investigators, and the 
Summary of Product Characteristics.
The reference for safety information for the comparator/reference product in this study (calcium 
carbonate) is the Summary of Product Characteristics which the Sponsor has provided under 
separate cover to all Investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the Investigator to the Shire 
Pharmacovigilance Department within 24 hours of the first awareness of the event. Note: The 24 
hours reporting requirement for SAEs does not apply to reports of abuse, misuse, overdose, or 
medication errors (see Section 8.1.7) unless they result in an SAE. 
The Investigator must complete, sign, and date the Shire Pharmaceuticals Clinical Trial Serious 
Adverse Event Form and verify the accuracy of the information recorded on the form with the 


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corresponding source documents (Note:  Source documents are not to be sent unless requested) 
and fax or e-mail the form to the Shire Pharmacovigilance Department. 
8.2.3
Serious Adverse Event Definition
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to be 
related to investigational product or not) that at any dose:

Results in death

Is life-threatening
NOTE: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event; Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardise the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition.  Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse.  
Hospitalizations, which are the result of elective or previously scheduled surgery for pre-existing 
conditions, which have not worsened after initiation of treatment, should not be classified as 
SAEs.  For example, an admission for a previously scheduled ventral hernia repair would not be 
classified as an SAE.
However, complication(s) resulting from a hospitalization for an elective or previously scheduled 
surgery that meets serious criteria must be reported as SAE(s).
8.2.4
Serious Adverse Event Collection Timeframe
All SAEs (regardless of relationship to study) are collected from the time the subject signs 
informed consent until the defined follow-up period stated in Section 7.1.3, and must be reported 
to the Shire Pharmacovigilance Department within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
Investigator at any interval after the study has completed must be reported to the Shire 
Pharmacovigilance Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria.  The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 


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event is considered chronic.  In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject prior to study entry or leading up 
to the onset date of the SAE or following the resolution date of the SAE, must be recorded as an 
AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date.  
For all other events ongoing at time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, the 
action taken with the investigational product should be recorded as “dose not changed” or “not 
applicable” (if the subject never received investigational product).
8.2.7
Regulatory Agency, Institutional Review Board, Independent Ethics 
Committee, and Site Reporting
The Sponsor and the Clinical CRO are responsible for notifying the relevant regulatory 
authorities and European Union (EU) central Independent Ethics Committees (IECs) of related, 
unexpected SAEs.
In addition the Sponsor and the Clinical CRO are responsible for notifying active sites of all 
related, unexpected SAEs occurring during all interventional studies across the SPD405 
program.  
The Investigator is responsible for notifying the local Institutional Review Board (IRB), local 
IEC, or the relevant local regulatory authority of all SAEs that occur at his or her site as required.  
9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The Investigators’ authorized site personnel must enter the information required by the protocol 
on the CRF.  A study monitor will visit each site in accordance with the monitoring plan and 
review the CRF data against the source data for completeness and accuracy.  Discrepancies 
between source data and data entered on the CRF will be addressed by qualified site personnel.  
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel.  Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the Investigator’s Meeting.  It is expected that site personnel will complete the CRF 
entry within 5 business days of the subject’s visit.


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9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management plan.  
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures.  Data queries requiring clarification are 
to be communicated to the site for resolution.  Only authorized personnel will make corrections 
to the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process
Details regarding the statistical methods and definitions will be provided in the statistical 
analysis plan. 
To preserve the integrity of the statistical analysis and study conclusions, the statistical plan will 
be finalized prior to database lock.
PRA International will perform all pre-defined statistical analyses after the database is locked.  
Statistical analyses of efficacy and safety data will be performed using Version 9.1 or higher of 
SAS(SAS Institute, Cary, NC 27513).
All data will be summarized overall.
9.4
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
No formal interim analysis is planned for this study. However, descriptive analyses of efficacy 
and safety data will be provided in Q4 2014 to assist with regulatory interactions if the 
recruitment targets have not been met.  Adaptive design has not been selected for this study and 
there will not be a Data Monitoring Committee.
9.5
Selection of Subjects to be Included in the Analyses
Screened Set – The set of subjects who have signed informed consent.
Enrolled Set – Subjects who have signed informed consent and have begun some study 
procedures (eg, dispensed investigational product, current drug has been withdrawn).
Safety Analysis Set 1 – Enrolled subjects who have taken 1 dose of investigational product in 
Part 1 and who have completed at least 1 follow-up safety assessment.
Safety Analysis Set 2 – Enrolled subjects who have taken 1 dose of investigational product in 
Part 2 or Part 3 and who have completed at least 1 follow-up safety assessment. 
It is noted that safety assessments from the period when a subject is exposed to calcium 
carbonate will be summarized for calcium carbonate treatment. Safety assessments from the 


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period when a subject is exposed to lanthanum carbonate will be summarized for lanthanum 
carbonate treatment.  
Safety Completer Set (SCS) – Subjects who receive at least 8 weeks of lanthanum carbonate 
treatment from either Part 2 or Part 3 of the study. 
Full Analysis Set (FAS)–Subjects who have taken at least 1 dose of investigational product and 
who have at least 1 phosphate assessment during Part 2 or Part 3.
Per-protocol Set 1 (PP1) – Subjects in the Full Analysis Set who complete 8 weeks of calcium 
carbonate treatment followed by 8 weeks of lanthanum carbonate treatment and who have serum 
phosphate assessment data available to allow summarizing the percentage of subjects achieving 
age-specific KDOQI target. Only subjects who have serum phosphate levels equal to or above 
the age-specific KDOQI targets at study entry and between the calcium carbonate treatment and 
lanthanum carbonate treatment at Visit 2.4 will be included in this set.
Per-protocol Set 2 (PP2) – Subjects in the Full Analysis Set who complete 8 weeks of treatment 
with lanthanum carbonate and who have serum phosphate assessment data available to allow 
summarizing the percentage of subjects achieving age-specific KDOQI target. Subjects who 
have serum phosphate levels equal to or above the age-specific KDOQI targets prior to the start 
of lanthanum carbonate treatment will be included in this set.
Pharmacokinetic Set 1 - Subjects in the Safety Analysis Set 1 for whom the primary 
pharmacokinetic data are considered sufficient and interpretable.  Subjects in Part 1 who vomited 
may be excluded from Pharmacokinetic Set 1.
Pharmacokinetic Set 2 - Subjects in Safety Analysis Sets 1 or 2 for whom the primary 
pharmacokinetic data are considered sufficient and interpretable will be included in 
Pharmacokinetic Set 2. 
9.6
Subject Disposition
Part 1: Subjects who are in each applicable analysis set, as well as those subjects who complete 
Part 1, and those subjects who prematurely discontinue from Part 1 will be summarized using 
descriptive statistics.  In addition, for subjects who prematurely discontinue from Part 1 of the 
study, the reasons for discontinuation will be summarized.  
Part 2 (2a and 2b): All subjects from Safety Analysis Set 2 (including those who entered the 
study in Part 2b) who are in each applicable analysis set, as well as those subjects who complete 
Part 2, those subjects who prematurely discontinue from Part 2, and those subjects who entered 
Part 3 will be summarized by treatment group using descriptive statistics.  In addition, for 
subjects who prematurely discontinue from Part 2, the reasons for discontinuation will be 
summarized by treatment group.  Subjects who entered Part 3 due to hypercalcemia in Part 2 will 
also be summarized.
Part 2a (Treatment Period 2), Part 2b, and Part 3 Combined (lanthanum carbonate only):  
All subjects from Safety Analysis Set 2 who are in each applicable analysis set, as well as those 
subjects who complete the study, and those subjects who prematurely discontinue from the study 


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will be summarized using descriptive statistics.  In addition, for subjects who prematurely 
discontinue, the reasons for discontinuation will be summarized.  
9.7
Demographic and Baseline Characteristics
Descriptive summaries of demographic and baseline characteristics will be presented separately 
for Pharmacokinetic Set 1 and for Pharmacokinetic Set 2. Part 1 will be summarized using the 
Safety Analysis Set 1. Part 2 will be summarized by treatment group using Safety Analysis Set 2, 
the FAS, the PP1, the PP2 for lanthanum carbonate treatment only (Part 2a, Treatment Period 2 
and Part 2b), and the SCS for 8 weeks of lanthanum carbonate treatment only in Parts 2 and 3 
combined.
Continuous variables such as subject age, weight, height, and body mass index will be 
summarized using number of observations, mean, standard deviation, median, minimum, and 
maximum values.  Categorical variables such as subject sex and race will be summarized using 
number of observations and percentages for each category.  
Medical history will be listed.
9.8
Investigational Product Exposure 
Data regarding exposure to lanthanum carbonate in Part 1 will be listed for Safety Analysis Set 
1.
Part 2: Summary statistics for the duration of exposure to investigational product in Part 2 will 
be presented by treatment group for Safety Analysis Set 2.  Compliance rates will be summarized 
by treatment. 
Part 2 and 3 Combined (lanthanum carbonate only): Summary statistics for the duration of 
exposure to investigational product will be presented for the SCS and the Safety Analysis Set 2.  
Compliance rates will be summarized.  
9.9
Prior and Concomitant Medication
Prior and concomitant medications will be coded using the World Health Organization drug 
dictionary (WHODRUG/2006QA or newer version).  
Prior medications in Part 1 and Part 2 for Safety Analysis Set 1 and Safety Analysis Set 2, 
respectively, will be summarized by preferred drug name.  Concomitant medications in Part 2 for 
Safety Analysis Set 2 will be summarized by preferred drug name and treatment group.  
Concomitant medications to the lanthanum carbonate treatment in Part 1, using Safety Analysis 
Set 1, and in Part 2 and Part 3 combined, using the Safety Analysis Set 2 and the SCS, will be 
summarized by preferred drug name.  


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9.10
Efficacy Analyses
9.10.1
Primary Efficacy Variable
The primary efficacy variable for the study is the percentage of subjects achieving age-specific 
KDOQI targets for serum phosphate level following 8-weeks of lanthanum carbonate treatment.
The KDOQI serum phosphorus targets are defined as:
-
Adolescents aged 12-<18 years:   5.5mg/dL (1.78mmol/L)
-
Children aged 10 years -<12 years:   6.0mg/dL (1.94mmol/L)
For the primary endpoint, the percentage of subjects achieving age-specific KDOQI targets for 
serum phosphate levels after 8 weeks of lanthanum carbonate treatment will be descriptively 
summarized and calculated along with a 95% confidence interval. The FAS and PP2 Sets will be 
used for this descriptive summarization. Serum phosphate levels tested at a central laboratory 
will be used for the analysis. In the case of missing central laboratory data, local laboratory data 
will be used.
Handling of missing data rules will be described in the statistical analysis plan.
9.10.2
Secondary Variables
The secondary analyses will be carried out using the analysis populations of FAS, PP1, and PP2.
Secondary variables are:

The percentage of subjects with serum phosphorus levels below the age-specific KDOQI 
targets following 8 weeks of treatment with calcium carbonate followed by 8 weeks of 
treatment with lanthanum carbonate will be descriptively summarized and will be calculated 
along with a 95% confidence interval, separately, for each treatment arm. The FAS and PP1 
Sets will be used for this summarization. The KDOQI serum phosphorus targets are defined 
as:
-
Adolescents aged ≥12-<18 years: ≤5.5mg/dL (1.78mmol/L)
-
Children aged 10 years -<12 years: ≤6.0mg/dL (1.94mmol/L)

Changes from baseline in serum phosphorus, calcium and calcium-phosphorus product in 
hyperphosphatemic children and adolescents with CKD who are on dialysis, following 
treatment with lanthanum carbonate for 8 weeks.

Changes from baseline in serum phosphorus, calcium and calcium-phosphorus product in 
hyperphosphatemic children and adolescents with CKD who are on dialysis, following 
treatment with calcium carbonate for 8 weeks and lanthanum carbonate for 8 weeks. 

Change from baseline in serum phosphorus, calcium and calcium-phosphorus product levels 
at the last visit of each 8-week treatment period during Part 2 and monthly during the 6-
month extension phase (Part 3).

Biochemical bone markers: bone ALP, osteocalcin, TRAP, FGF-23, PTH, sclerostin and 
fetuin-A before and after each treatment period in Part 2, and at the end of Part 3.


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
Height and weight at:
o
Visits 2.0, 2.4, 2.8, and 3.5 (Parts 2a and 3)
o
Visits 1.0, 2.4, and 3.5 (Parts 2b and 3).
For the long-term assessment, efficacy and safety variables will be summarized using the Safety 
Analysis Set 2 for each visit using descriptive statistics as follows:

For continuous data: number of observations, mean, standard deviation, standard error, 
minimum, maximum, median, and 95% confidence interval

For categorical data: number of observations and percentages. 
Summary statistics (number of observations, mean, standard deviation, coefficient of variation, 
median, minimum, maximum and geometric mean) will be determined for all pharmacokinetic 
parameters.
9.10.3
Tertiary Efficacy Variables
Not Applicable. 
9.11
Safety Analyses
All safety variables will be summarized using the defined Safety Analysis Sets (Safety Analysis 
Set 1, Safety Analysis Set 2, and SCS; see Section 9.5). Summaries will be presented by 
treatment group and overall. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities, Version 
13.0.  
The number of events, incidence, and percentage of treatment-emergent adverse events (TEAEs 
will be calculated overall, by system organ class, and by preferred term.  Treatment-emergent 
AEs will be further summarized by age group, severity and relationship to investigational 
product.  Adverse events related to investigational product, AEs leading to withdrawal, SAEs, 
and deaths will be summarized/listed.  Clinical laboratory tests, vital signs, and ECG findings 
will be summarized.  Potentially clinically important findings will also be summarized or listed.
9.12
Other Analyses
9.12.1
Pharmacokinetic Analyses
Part 1
Plasma lanthanum concentrations will be analyzed by non-compartmental methods to determine 
pharmacokinetic parameters including, but not limited to, area under the plasma concentration-
time curve from time zero to the time of the last quantifiable concentration (AUC0-t), area under 
the plasma concentration-time curve from time zero to 48 hours (AUC0-48), Cmax, time to Cmax,
and, if appropriate,  apparent terminal half-life (t½) and apparent terminal-phase disposition rate 
constant (λz) and area under the plasma concentration-time curve from time zero to infinity 
(AUC0-).  


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Summary statistics (number of observations, mean, standard deviation, coefficient of variation, 
median, minimum, maximum, and geometric mean) will be determined for all pharmacokinetic 
parameters. 
Parts 2 and 3
Plasma concentration-time data for Part 2a (Treatment Period 2), Part 2b, and Part 3 will be 
combined with those from Part 1 and subjected to population pharmacokinetic analysis using 
NONMEM to determine estimates of steady-state systemic exposure (Cmax, minimum plasma 
concentration [Cmin] and area under the plasma concentration-time curve [AUC] at steady-state)
and relationships of systemic exposure to dose and to safety findings explored if appropriate.
9.13
Sample Size Calculation and Power Considerations
Part 1 (Pharmacokinetic Assessment)
From Study LAM-IV-111, the meanstandard deviation AUC0-t was 3.0992.888ng.hr/mL and 
Cmax was 0.2960.177ng.hr/mL for a 1000mg single dose of lanthanum carbonate in subjects 
with renal failure who were receiving dialysis. Assuming the standard deviations from Study 
LAM-IV-111, a sample size of 8 subjects will have 80% assurance that the 2-sided 95% 
confidence interval for the AUC0-t will be no wider than 2.86ng.hr/mL and 80% assurance that 
2-sided 95% confidence interval for Cmax is no wider than 0.18ng.hr/mL.
Parts 2 and 3 (Efficacy – Percentage of Subjects Achieving KDOQI Target for Serum
Phosphorus)
Originally, the sample size of at least 50 subjects for the PP set had been chosen based on 
practical considerations and on agreement with the Paediatric Committee of the European 
Medicines Agency.  In order to obtain a PP Set of 50 subjects, a sample size of approximately 72 
subjects were to be enrolled in Part 2.  This assumed 70% of the subjects are eligible for the PP 
Set.  This sample size has 81% power to show that the lower limit of the 95% confidence interval 
for the difference (LC – CC) in the percentage of subjects achieving serum phosphorus target is 
above the non-inferiority margin of -18%.  
However, given the extreme difficulty in recruiting enough subjects to obtain at least 50 subjects 
for the PP set for the assessment of non-inferiority, serious consideration had to be given to 
adjust the sample size and focus of the study to safety, in order to complete it. The sample size 
has been adjusted to include at least 35 subjects, who complete 8 weeks of treatment with 
lanthanum carbonate and are assessable for the primary endpoint. This study is still useful in 
collecting information, where there is a void, regarding the use of lanthanum in the pediatric 
population. 
For the investigation of safety profile in hyperphosphatemic children and adolescents with CKD 
on dialysis treated with lanthanum carbonate, a sample size of 35 subjects is necessary in order 
to observe at least one event with a true event rate of 5% at a probability of 83.4%.


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10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements.  
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations and ICH Good Clinical Practice (GCP) Guideline E6 (1996) and 
EU Directive 2001/20/EC.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the Sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
inter/national government regulations and guidelines.  Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The Sponsor ensures that Local Regulatory Authority requirements are met before the start of the 
study. The Sponsor (or a nominated designee) is responsible for the preparation, submission, 
and confirmation of receipt of any Regulatory Authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The Sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines.  If appropriate, a copy of the Indemnity document is 
supplied to the Investigator before study initiation, per local country guidelines.
The Sponsor ensures that suitable clinical study insurance coverage is in place prior to the start 
of the study.  An insurance certificate is supplied to the CRO as necessary.
10.1.3
Public Posting of Study Information
The Sponsor is responsible for posting appropriate study information on applicable websites.  
Information included in clinical study registries may include participating Investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Independent Ethics Committees
The Sponsor will provide a summary of the Clinical Study Report within 1 year of the end of the 
study completion date to the competent authority of the Member State(s) concerned as required 
by regulatory requirement(s) and to comply with the Community guideline on GCP.  The 
Sponsor will provide the IECs with a copy of the same summary.


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10.1.5
Study Suspension, Termination, and Completion
The Sponsor may suspend or terminate the study or part of the study at any time for any reason.  
If the study is suspended or terminated, the Sponsor will ensure that applicable regulatory 
agencies and IRBs/IECs are notified as appropriate.  Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
The Sponsor will make an EOS declaration to the relevant competent authority as required by 
Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The Investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC and applicable regulatory requirements and guidelines.
It is the Investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study.  The 
Investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The Investigator will maintain a list of appropriately qualified persons to whom the Investigator 
has delegated significant study-related tasks.  Curriculum vitae for Investigators and 
sub-investigators are provided to the study Sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the Investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A Coordinating Principal Investigator is appointed to review the final Clinical Study Report for 
multi-site studies.  Agreement with the final Clinical Study Report is documented by the signed 
and dated signature of the Coordinating Principal Investigator (multi-site study), in compliance 
with Directive 2001/83/EC as amended by Directive 2003/63/EC and ICH Guidance E3 (1995). 
10.2.2
Protocol Adherence and Investigator Agreement
The Investigator and any co-investigators must adhere to the protocol as detailed in this 
document.  The Investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria.  Investigators are required to sign an Investigator Agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the Investigator suspends or terminates the study at their site, the Investigator will promptly 
inform the Sponsor and the IRB/IEC and provide them with a detailed written explanation.  The 
Investigator will also return all investigational product, containers, and other study materials to 
the Sponsor. Upon study completion, the Investigator will provide the Sponsor, IRB/IEC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.


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Communication with local IRBs/IECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the Sponsor, applicable CRO, Investigator, or for 
multi-site studies, the Coordinating Principle Investigator according to national provisions and 
will be documented in the Investigator Agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
Case Report Forms are supplied by the CRO and should be handled in accordance with 
instructions from the Sponsor.
The Investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation.  Case Report Forms must be 
completed by the Investigator or designee as stated in the site delegation log. 
All data will have separate source documentation; no data will be recorded directly onto the 
CRF.
All data sent to the Sponsor must be endorsed by the Investigator. 
The Clinical Research Associate/Study Monitor will verify the contents against the source data 
per the Monitoring Plan.  If the data are unclear or contradictory, queries are sent for corrections 
or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file and original clinical laboratory reports, and histology reports.  All key data 
must be recorded in the subject’s medical records.
All key data must be recorded in the subject’s medical records.
The Investigator must permit authorized representatives of the Sponsor, the respective national, 
local, or foreign regulatory authorities, the IRB/IEC, and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The Clinical Research Associate/Study Monitor (and auditors, IRB/IEC or regulatory inspectors) 
may check the CRF entries against the source documents.  The consent form includes a statement 
by which the subject agrees to the monitor/auditor from the Sponsor or its representatives, 
national or local regulatory authorities, or the IRB/IEC having access to source data (eg, 
subject’s medical file, appointment books, original laboratory reports, X-rays etc).  Non-study 
site personnel will not disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the United States 
Food and Drug Administration, European Medicines Agency, UK Medicines and Healthcare 
products Regulatory Agency) or an auditor).


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Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the Sponsor.  
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the United States Food and Drug 
Administration (as well as other United States national and local regulatory authorities), the 
European Medicines Agency, the Medicines and Healthcare Products Regulatory Agency, other 
regulatory authorities, the Sponsor or its representatives, and the IRB/IEC for each site.
10.2.3.4
Financial Disclosure
The Investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the value of the compensation for conducting the study could be influenced by the 
outcome of the study.  The following information is collected: any significant payments from the 
Sponsor or subsidiaries such as a grant to fund ongoing research, compensation in the form of 
equipment, retainer for ongoing consultation or honoraria; any proprietary interest in 
investigational product; any significant equity interest in the Sponsor or subsidiaries as defined 
in 21 CFR 54 2(b) (1998).
In consideration of participation in the study, the Sponsor pays the Investigator or nominated 
payee the sums set out in the payment schedule attached to the Investigator agreement.
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the Investigator to obtain written informed consent, and assent where 
applicable, from all study subjects prior to any study-related procedures including screening 
assessments.  All consent and assent documentation must be in accordance with applicable 
regulations and GCP.  Each subject or the subject’s LAR as applicable is requested to sign the 
Subject Informed Consent Form or a certified translation, if applicable after the subject has 
received and read (or been read) the written subject information and received an explanation of 
what the study involves, including but not limited to: the objectives, potential benefits and risk, 
inconveniences, and the subject’s rights and responsibilities.  A copy of the informed consent 
and assent documentation (ie, a complete set of subject information sheets and fully executed 
signature pages) must be given to the subject or the subject’s LAR as applicable.  If applicable, it 
is provided in a certified translation of the local language.  Signed consent/assent forms must 
remain in each subject’s study file and must be available for verification at any time.
Site personnel should document parent/LAR/caregiver teaching and understanding within the 
source documents for safe, responsible storage and administration of investigational product to 
the study subject.
The Principal Investigator provides the Sponsor with a copy of the consent form (and assent 
form where applicable) which was reviewed by the IRB/IEC and which received their favourable 
opinion/approval.  A copy of the IRB/IEC’s written favourable opinion/approval of these 
documents must be provided to the Sponsor, prior to the start of the study unless it is agreed to 


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and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (ie, Sponsor or Coordinating Principal Investigator) is responsible for this 
action.  Additionally, if the IRB/IEC requires modification of the sample Subject Information 
and Consent document provided by the Sponsor, the documentation supporting this requirement 
must be provided to the Sponsor.
10.3.2
Institutional Review Board or Independent Ethics Committee
For sites outside the EU, it is the responsibility of the Investigator to submit this protocol, the 
informed consent document (approved by the Sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/IEC for review, and all 
must be approved prior to site initiation.
For sites within the EU, the applicant for an IEC opinion can be the Sponsor, the Investigator, or 
for multi-site studies the Coordinating Principal Investigator or Sponsor, according to national 
provisions.
Responsibility for coordinating with IRBs/IECs is defined in the Investigator Agreement.
Prior to implementing changes in the study, the Sponsor and the IRB/IEC must approve any 
revisions of any revised informed consent documents and amendments to the protocol unless 
there is a subject safety issue.
Investigational product supplies will not be released until the Sponsor has received written 
IRB/IEC approval of and copies of revised documents.
For sites outside the EU, the Investigator is responsible for keeping the IRB/IEC appraised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; for sites within the EU, this can be done by the Sponsor, the Investigator or for multi-site 
studies the Coordinating Principal Investigator, according to national provisions.  The 
Investigator must also keep the local IRB/IEC informed of any serious and significant AEs.
10.4
Privacy and Confidentiality
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the Sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, 
in addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the Sponsor; third parties with whom the Sponsor may develop, register, or 
market lanthanum carbonate; national or local regulatory authorities; and the IRB(s)/IEC(s) 
which gave approval for the study to proceed.  The Sponsor and/or its representatives accessing 
the records and data will take all reasonable precautions in accordance with applicable laws, 
regulations, and guidelines to maintain the confidentiality of subjects' identities.


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Subjects are assigned a unique identifying number.  However, their initials and date of birth may 
also be collected and used to assist the Sponsor to verify the accuracy of the data, for example, to 
confirm that laboratory results have been assigned to the correct subject.
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded.  They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted.  The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire. The purpose of the 
publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, 
joint or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.


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If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to 
a journal for publication by the sponsor within an 18-month period after conclusion, 
abandonment, or termination of the study at all sites, or after the sponsor confirms there shall be 
no multicenter study publication of the study results, an investigator may individually publish the 
study results from the specific site in accordance with this section. The investigator must, 
however, acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.


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11.
REFERENCES
Alon U, Davidai G, Bentur L, Berant M, Better OS 1986. Oral calcium carbonate as phosphate-
binder in infants and children with chronic renal failure. Miner Electrolyte Metab; 12(5-6): 320-
25.
Clark AG, Oner A, Ward G, Turner C, Rigden SP, Haycock GB et al. 1989.  Safety and efficacy 
of calcium carbonate in children with chronic renal failure.  Nephrol Dial Transplant; 4(6): 539-
44.
KDOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Children With 
Chronic Kidney Disease, Guideline 4 2005. Target Phosphorus Levels.
Klaus G, Watson A, Edefonti A, Fischbach M, Rönnholm K, Schaefer F et al. 2006.  Prevention 
and treatment of renal osteodystrophy in children on chronic renal failure: European guidelines. 
Pediatr Nephrol; 21(2): 151–59.
Mahdavi H, Kuizon BD, Gales B, Wang HJ, Elashoff RM, Salusky IB 2003.  Sevelamer 
hydrochloride: an effective phosphate binder in dialyzed children.  Pediatr Nephrol; 18(12): 
1260–64.
Moe S, Drüeke T, Cunningham J, Goodman W, Martin K, Olgaard K et al. 2006.  Definition, 
evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: 
Improving Global Outcomes (KDIGO).  Kidney Int; 69(11):1945–53.
Pieper AK, Haffner D, Hoppe B, Dittrich K, Offner G, Bonzel KE et al. 2006.  A Randomized 
Crossover Trial Comparing Sevelamer With Calcium Acetate in Children With CKD.  Am J 
Kidney Dis; 47(4): 625-35.
Salusky IB, Goodman WG, Sahney S, Gales B, Perilloux A, Wang HJ et al. 2005.  Sevelamer 
controls parathyroid hormone-induced bone disease as efficiently as calcium carbonate without 
increasing serum calcium levels during therapy with active vitamin D sterols.  J Am Soc 
Nephrol; 16(8): 2501–08.
































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APPENDIX 2 GUIDELINES FOR PHOSPHORUS AND CALCIUM 
The following guidelines summarize the requirements for each parameter during the study.
Parameter
Value
Age Range (Years)
Action
Phosphate
<4.0mg/dL (1.29mmol/L)
12 to <18 
Monitor phosphate levels 
carefully and consider
reducing the binder dose 
by 25% depending on the 
rate at which phosphate is 
falling.
<4.5mg/dL (1.45mmol/L)
10 to <12
Phosphate
<3.5mg/dL (1.13mmol/L)
12 to <18
Binder should be stopped 
and phosphate levels 
monitored closely.
The binder should be 
resumed at 50% of the 
prior dose when 
phosphate levels are 
>4.0mg/dL 
(1.29mmol/L).
Phosphate
<4.0mg/dL (1.29mmol/L)
10 to <12
Binder should be stopped 
and phosphate levels 
monitored closely.
The binder should be 
resumed at 50% of the 
prior dose when 
phosphate levels are 
>4.5mg/dL 
(1.45mmol/L).
Phosphate
>10.0mg/dL 
(3.23mmol/L) except 
during washout periods
10 to <18
Discontinue subject.
Calcium
<8.8mg/dL (2.20mmol/L)
10 to <18
Subject should receive 
therapy to increase 
calcium levels.
Calcium
>10.2mg/dL 
(2.54mmol/L) during Part 
2 Treatment Period 1
10 to <18
Active vitamin D sterols 
should be decreased by 
50%, calcium carbonate 
decreased by 25% and the 
subjects should be 
monitored.
If after 2 weeks 
hypercalcaemia persists, 
active vitamin D sterols 
should be stopped.
If after another 2 weeks it 
persists the subject should 
be withdrawn from Part 2 
and may continue to 
Part 3.
Calcium 
>10.2mg/dL 
10 to <18
Active vitamin D sterols 


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Parameter
Value
Age Range (Years)
Action
(2.54mmol/L) during 
lanthanum carbonate 
treatment 
should be decreased by 
50%, calcium carbonate 
decreased by 25% and the 
subjects should be 
monitored.
If after 2 weeks 
hypercalcaemia persists, 
active vitamin D sterols 
should be stopped.
Calcium
>11.5mg/dL 
(2.88mmol/L) during first 
treatment period of Part 2 
10 to <18
Discontinue subject from 
Part 2, and proceed to 
Part 3.

SAP_001.pdf: 




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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................ 3 
LIST OF TABLES ...................................................................................................................... 6 
ABBREVIATIONS .................................................................................................................... 7 
1. 
INTRODUCTION .......................................................................................................... 8 
2. 
STUDY DESIGN ........................................................................................................... 9 
2.1 
General Study Design ..................................................................................................... 9 
2.2 
Randomization .............................................................................................................. 12 
2.3 
Blinding ........................................................................................................................ 12 
2.4 
Schedule of Assessments .............................................................................................. 12 
STUDY SCHEDULE(S) .......................................................................................................... 13 
2.5 
Determination of Sample Size ...................................................................................... 21 
2.6 
Multiplicity Adjustments for Type I Error Control ...................................................... 21 
3. 
OBJECTIVES ............................................................................................................... 22 
3.1.1 
Primary Objectives ................................................................................................. 22 
3.1.2 
Secondary Objectives ............................................................................................. 22 
4. 
SUBJECT POPULATION SETS ................................................................................. 23 
4.1 
Screened Set ................................................................................................................. 23 
4.2 
Enrolled Set .................................................................................................................. 23 
4.3 
Safety Analysis Sets ..................................................................................................... 23 
4.3.1 
Safety Analysis Set 1 (SAS1) ....................................................................................... 23 
4.3.2 
Safety Analysis Set 2 (SAS2) ....................................................................................... 23 
4.3.3 
Safety Completer Set (SCS) ......................................................................................... 23 
4.4 
Full Analysis Set (FAS) ................................................................................................ 23 
4.5 
Per-protocol Set 1 (PP1) ............................................................................................... 23 
4.6 
Per-protocol Set 2 (PP2) ............................................................................................... 24 
4.7 
Pharmacokinetic Sets (PK Sets) ................................................................................... 24 
4.7.1 
Pharmacokinetic Set 1 .................................................................................................. 24 
4.7.2 
Pharmacokinetic Set 2 .................................................................................................. 24 
5. 
SUBJECT DISPOSITION ............................................................................................ 25 
6. 
PROTOCOL DEVIATIONS ........................................................................................ 27 
7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ....................... 28 


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8. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ............................. 30 
8.1 
Exposure to Investigational Product ............................................................................. 30 
8.2 
Measurement of Treatment Compliance ...................................................................... 30 
9. 
PRIOR AND CONCOMITANT MEDICATION ........................................................ 32 
10. 
EFFICACY ANALYSES ............................................................................................. 34 
10.1 
Primary Efficacy Endpoint(s) and Analysis ................................................................. 34 
10.2 
Key Secondary Efficacy Endpoint(s) and Analysis ..................................................... 34 
10.3 
Other Secondary Efficacy Endpoint(s) and Analysis ................................................... 34 
10.4 
Exploratory Efficacy Endpoint(s) and Analyses .......................................................... 36 
11. 
SAFETY ANALYSES ................................................................................................. 37 
11.1 
Adverse Events ............................................................................................................. 37 
11.2 
Clinical Laboratory Variables ...................................................................................... 38 
11.3 
Vital Signs .................................................................................................................... 40 
11.4 
Electrocardiogram (ECG) ............................................................................................. 40 
11.5 
Other Safety Variables .................................................................................................. 41 
12. 
CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES.. 42 
12.1 
Pharmacokinetics Population (and Pharmacodynamic Population, if applicable) ....... 42 
12.2 
Pharmacokinetic Methods ............................................................................................ 42 
12.2.1 Concentration Data ....................................................................................................... 42 
12.2.2 Handling BLQ Values .................................................................................................. 42 
12.2.3 Pharmacokinetic Parameters ......................................................................................... 42 
12.3 
Statistical Analysis of Pharmacokinetic Data ............................................................... 43 
12.4 
Pharmacodynamic Methods ......................................................................................... 44 
12.5 
Statistical Analysis of Pharmacodynamic Data (if applicable) .................................... 44 
12.6 
Analyses of Pharmacokinetic/Pharmacodynamic Relationships (If applicable) .......... 44 
12.7 
Changes in the Pharmacokinetic or Statistical Methods from Those stated in the 
Protocol ......................................................................................................................... 44 
12.8 
Pharmacokinetic References ......................................................................................... 44 
12.9 
Table of Contents for Pharmacokinetic Figures, Tables, and Listings ......................... 44 
13. 
OTHER ANALYSES ................................................................................................... 46 
14. 
INTERIM ANALYSIS ................................................................................................. 47 
15. 
DATA MONITORING/REVIEW COMMITTEE ....................................................... 48 
16. 
COMPUTER METHODS ............................................................................................ 49 


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17. 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ....................................... 50 
18. 
DATA HANDLING CONVENTIONS ........................................................................ 51 
18.1 
General Data Reporting Conventions ........................................................................... 51 
18.2 
Derived Efficacy Endpoints .......................................................................................... 51 
18.3 
Repeated or Unscheduled Assessments of Safety Parameters ..................................... 51 
18.4 
Missing Date of Investigational Product ...................................................................... 51 
18.5 
Missing Date Information for Prior or Concomitant Medications ............................... 51 
18.5.1 Incomplete Start Date............................................................................................. 51 
18.5.2 Incomplete Stop Date ............................................................................................. 52 
18.6 
Missing Date Information for Adverse Events ............................................................. 53 
18.6.1 Incomplete Start Date............................................................................................. 53 
18.6.2 Incomplete Stop Date ............................................................................................. 53 
18.7 
Missing Severity Assessment for Adverse Events ....................................................... 53 
18.8 
Missing Relationship to Investigation Product for Adverse Events ............................. 53 
18.9 
Character Values of Clinical Laboratory Variables ..................................................... 53 
19. 
REFERENCES ............................................................................................................. 54 
20. 
TABLE OF CONTENTS FOR TABLES, FIGURES AND LISTINGS ..................... 55 
21. 
APPENDIX .................................................................................................................. 67 
21.1 
Evaluable Subject Determination Plan ......................................................................... 67 


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LIST OF TABLES 
Table 1:  Schedule of Assessments for Part 1, Part 2a (Treatment Periods 1 and 2), and Part 
3 .............................................................................................................................. 13 
Table 2:  Detailed Schedule of Assessments for Visit 1.1 in Part 1 ......................................... 17 
Table 3:  Schedule of Assessments for Part 2b and Part 3 ........................................................ 18 
Table 4:  Data for Evaluable Subject Determination ................ Error! Bookmark not defined. 


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ABBREVIATIONS 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC0-t  
area under the plasma concentration-time curve from time zero to the time 
of the last quantifiable concentration 
CC 
calcium carbonate 
CKD 
chronic kidney disease 
Cmax 
maximum plasma concentration 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
end of study 
FAS 
Full Analysis Set 
FGF-23 
fibroblast growth factor 23 
GGT 
gamma glutamyl transferase 
IP 
investigational product 
KDOQI 
Kidney Disease Outcomes Quality Initiative 
LC 
lanthanum carbonate 
MCH 
mean corpuscular haemoglobin 
MCHC 
mean corpuscular haemoglobin concentration 
MCV 
mean corpuscular volume 
PK 
pharmacokinetic 
PP 
per-protocol 
PTH 
parathyroid hormone 
SAE 
serious adverse event 
SOC 
system organ class 
SAP 
statistical analysis plan 
TEAE 
treatment-emergent adverse event 
TRAP 
tartrate-resistant acid phosphatase 
WHO 
World Health Organisation 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the statistical 
analyses of efficacy, safety, and pharmacokinetic data as described in the final study protocol 
version 6.0 dated 18 Oct 2016 incorporating most recent amendment #5. Specifications for 
tables, figures, and listings are contained in a separate document.  


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2. 
STUDY DESIGN  
2.1 
General Study Design 
This study has been approved by the Paediatric Committee of the European Medicines Agency 
as part of the Paediatric Investigational Plan for lanthanum carbonate. Pharmacokinetic (PK) 
data will be collected during the study as there are currently no data on lanthanum carbonate in 
paediatric subjects under the age of 18 years. The data from this study will be evaluated against 
historical systemic exposure data in adults, in a separate document.  The pharmacokinetic 
assessment is combined with the efficacy and safety sections to reduce the number of studies to 
be performed and to ease subject enrolment. 
Part 1: Single-dose, pharmacokinetic assessment  
This part of the study was a single-dose pharmacokinetic assessment of lanthanum carbonate in 
at least 8 subjects. There was a 2-week screening period during which eligibility was determined 
for Part 1.  Subjects who were eligible to participate entered a washout period of up to 3 weeks if 
the phosphorus level was not above Kidney Disease Outcomes Quality Initiative (KDOQI) 
required levels.  During the washout period the existing phosphate binder treatment was 
discontinued until phosphate levels had risen above 6.0mg/dL (1.94mmol/L) in subjects aged 
under 12 years or >5.5mg/dL (1.78mmol/L) in subjects aged over 12 years.  At the end of the 
washout period, subjects were assessed for inclusion in the study based on their serum 
phosphorus levels.   
Subjects participating in Part 1 could begin Part 2a immediately following the completion of the 
pharmacokinetic assessments. Subjects not participating in Part 1 entered Part 2a after screening 
at Visit 2/Week 0 (see Table 1:  Schedule of Assessments for Part 1, Part 2a (Treatment Periods 
1 and 2), and Part 3).  
Part 1 is complete and an interim clinical study report interpreting and summarizing the data for 
the first 10 subjects in Part 1 is available.  
Part 2a: Open-label, active comparator crossover period 
Originally, the design of Part 2 of Study SPD405-207 was a crossover non-inferiority one to 
allow a formal comparison of the efficacy of lanthanum carbonate with calcium carbonate. It was 
a single sequence design (8 weeks of calcium carbonate followed by 8 weeks of lanthanum 
carbonate) to minimize disruption to the subjects. The comparator calcium carbonate was 
selected to meet the comparator criteria outlined by Paediatric Committee of the European 
Medicines Agency. Since the originally proposed study included only 1 sequence (calcium 
carbonate for the 1st treatment period and lanthanum carbonate for the 2nd treatment period) 
blinding was not applicable, thus the study was open-label. As shown in the study schematic in 
Figure 1: 
Study Design Flow Chart- Part 1, Part 2a (Treatment Periods 1 and 2) and 
Part 3Figure 1, all subjects were to receive lanthanum carbonate in part 2, period 2 of the 
crossover and had the option to continue on to Part 3 of the study on the same treatment, ie, 
lanthanum carbonate for up to 6 months. If needed, there was a washout period for up to 3 weeks 
between treatment with calcium carbonate (Part 2, Treatment Period 1) and lanthanum carbonate 


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(Part 2, Treatment Period 2). Subjects who discontinued calcium carbonate treatment 
period/Treatment Period 1 due to hypercalcemia in Part 2 of the originally proposed study could 
also continue to Part 3 to receive lanthanum carbonate treatment (see Protocol Version 6.0 
(Amendment 5), Section 4.5.1 [Subject Stopping Criteria] and Section 6.2.1 [Dosing, 
Hypercalcemia]) for up to 6 additional months.  
Following Version 6.0 (Amendment 5), Part 2 is amended to enrol subjects to receive lanthanum 
carbonate treatment only. The calcium carbonate treatment followed by lanthanum carbonate 
treatment is referred to as Part 2a in protocol Version 6 (Amendment 5). Subjects to be enrolled 
under Version 6 (Amendment 5), of protocol will enter/be enrolled directly into Part 2b, which is 
8 weeks of lanthanum treatment only. 
Part 2b: 8-week lanthanum carbonate treatment 
Given the extreme difficulty in recruiting enough subjects to obtain the originally proposed 
sample size of 50 subjects required for the Per-protocol Set for a cross-over non-inferiority 
study, the active comparator (calcium carbonate) treatment arm was removed (see Part 2a) in 
Part 2b; serious consideration had to be given to adjust the sample size and focus of the study to 
safety, in order to complete it. The sample size has been adjusted to include at least 32 subjects 
who will complete 8 weeks of treatment with lanthanum carbonate and will be assessable for the 
primary endpoint. As shown in the study schematic in Figure 2 eligible subjects will be enrolled 
in Part 2b after screening at Visit 1/Week 0 (see Table 3) to receive 8 weeks of lanthanum 
carbonate treatment only under Version 6.0 of the protocol. Subjects in Part 2b will have the 
option to continue on to Part 3 of the study on the same treatment for up to 6 additional months.  
Part 3: 6-month lanthanum carbonate treatment 
Subjects in Part 2a (including subjects in Treatment Period 1/calcium carbonate treatment arm 
who discontinued due to hypercalcemia; see Protocol Version 6.0 (Amendment 5), Section 4.5.1 
[Subject Stopping Criteria] and Section 6.2.1 [Dosing, Hypercalcemia]) and Part 2b may 
continue to receive open-label lanthanum carbonate for up to 6 additional months of therapy. 
The doses selected for Part 1 of the study were those that were suggested for use in children in 
clinical practice and those in Part 2 are based on known phosphate binder values for maintaining 
phosphate level balance. 
 


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Figure 1: Study Design Flow Chart- Part 1, Part 2a (Treatment Periods 1 and 2) and 
Part 3 
 
Note: The schematic in Figure 1 is applicable to the originally proposed open-label cross over study design.  
 




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STUDY SCHEDULE(S) 
Table 1:  Schedule of Assessments for Part 1, Part 2a (Treatment Periods 1 and 2), and Part 3 
 
Part 1 
Subjects who enrol into 
Part 1 will omit the first 
washout in Part 2 
(Visit window ±3 days) 
Part 2a 
(Visit window ±3 days) 
Part 3 
(Visit window 
±1 week) 
 
Visit 
1.0 
Washout 
W1j 
1.1a 
2.0b 
Washout 
W1j 
2.1 
2.2-
2.3 
2.4 
Washout 
W2j 
2.5-
2.7 
2.8 
3.0-
3.4 
3.5/End 
of Studyc 
Safety 
Follow-up 
callk 
Week  
–5 
-4 to -1 
-4 to -
1 
0 
0-3 
weeks 
duration 
2d 
4, 
6d 
8d 
0-3 week 
duration 
10, 
12, 
14d 
16d 
20, 
24, 
28, 
32, 
36  
40d 
41-42d 
Informed consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In/exclusion criteria 
 
 
 
 
j 
 
 
 
 
 
 
 
 
 
Medical and renal history 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs, height and weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Local laboratory testsf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central laboratory phosphate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1:  Schedule of Assessments for Part 1, Part 2a (Treatment Periods 1 and 2), and Part 3 
 
Part 1 
Subjects who enrol into 
Part 1 will omit the first 
washout in Part 2 
(Visit window ±3 days) 
Part 2a 
(Visit window ±3 days) 
Part 3 
(Visit window 
±1 week) 
 
Visit 
1.0 
Washout 
W1j 
1.1a 
2.0b 
Washout 
W1j 
2.1 
2.2-
2.3 
2.4 
Washout 
W2j 
2.5-
2.7 
2.8 
3.0-
3.4 
3.5/End 
of Studyc 
Safety 
Follow-up 
callk 
Week  
–5 
-4 to -1 
-4 to -
1 
0 
0-3 
weeks 
duration 
2d 
4, 
6d 
8d 
0-3 week 
duration 
10, 
12, 
14d 
16d 
20, 
24, 
28, 
32, 
36  
40d 
41-42d 
confirmation 
Biochemistry  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biochemical bone markers  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (where 
applicable) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lanthanum pharmacokinetics 
 
 
 
 
 
 
 
 
 
g   
 
h 
 
 
Investigational product dispensed 
 
 
 
e 
e 
 
 
 
 
 
i 
 
 
 
Investigational product collected 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose adjustment (as needed) and 
compliance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record concomitant medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1:  Schedule of Assessments for Part 1, Part 2a (Treatment Periods 1 and 2), and Part 3 
 
Part 1 
Subjects who enrol into 
Part 1 will omit the first 
washout in Part 2 
(Visit window ±3 days) 
Part 2a 
(Visit window ±3 days) 
Part 3 
(Visit window 
±1 week) 
 
Visit 
1.0 
Washout 
W1j 
1.1a 
2.0b 
Washout 
W1j 
2.1 
2.2-
2.3 
2.4 
Washout 
W2j 
2.5-
2.7 
2.8 
3.0-
3.4 
3.5/End 
of Studyc 
Safety 
Follow-up 
callk 
Week  
–5 
-4 to -1 
-4 to -
1 
0 
0-3 
weeks 
duration 
2d 
4, 
6d 
8d 
0-3 week 
duration 
10, 
12, 
14d 
16d 
20, 
24, 
28, 
32, 
36  
40d 
41-42d 
Dialysis adequacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of dietary advice 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Visit 1.1 should be scheduled for the day after dialysis.  See Table 2 for a detailed schedule of assessments. 
b For subjects who have completed Part 1, laboratory and other assessments can be completed from Visit 1.0, no further blood samples are required.  A consent form to participate in Part 
2a must be signed. 
c Assessments scheduled for Visit 3.5 should also be carried out at the time of discontinuation for all subjects who withdraw from the study early or as close as possible to the time of 
discontinuation.  These assessments are not required for subjects post-transplantation, however a safety follow-up call is required. 
d Visit weeks may be variable depending on duration of washout (+3 weeks). 
e Investigational product will be dispensed at Visit 2.0 if eligible, however if a washout is required then investigational product will be dispensed at visit W1. 
f Local laboratory assessments for phosphorus, serum calcium, and calcium phosphorus product in Parts 1 and 2 are for titration purposes, as required, and will not be analyzed; data from 
Visits 3.0-3.4 will be collected and assessed. 
g Visit 2.6 only; Each subject will have at least 2 samples taken for pharmacokinetic assessment.  These should be taken during defined time windows (to be selected from: 0-2 hours, 2-4 
hours and 4-6 hours, after the first dose/meal of the day).  Note: If the sampling is not done at Visit 2.6, blood sampling for pharmacokinetics must be taken at an alternative visit during 
Part 2. 
h Visit 3.3 only; Each subject will have at least 2 samples taken for pharmacokinetic assessment.  These should be taken during defined time windows (to be selected from: 0-2 hours, 2-4 
hours and 4-6 hours, after the first dose/meal of the day).  Note:  If the sampling is not done at Visit 3.3, blood sampling for pharmacokinetics must be taken at an alternative visit during 
Part 3. 


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Table 1:  Schedule of Assessments for Part 1, Part 2a (Treatment Periods 1 and 2), and Part 3 
 
Part 1 
Subjects who enrol into 
Part 1 will omit the first 
washout in Part 2 
(Visit window ±3 days) 
Part 2a 
(Visit window ±3 days) 
Part 3 
(Visit window 
±1 week) 
 
Visit 
1.0 
Washout 
W1j 
1.1a 
2.0b 
Washout 
W1j 
2.1 
2.2-
2.3 
2.4 
Washout 
W2j 
2.5-
2.7 
2.8 
3.0-
3.4 
3.5/End 
of Studyc 
Safety 
Follow-up 
callk 
Week  
–5 
-4 to -1 
-4 to -
1 
0 
0-3 
weeks 
duration 
2d 
4, 
6d 
8d 
0-3 week 
duration 
10, 
12, 
14d 
16d 
20, 
24, 
28, 
32, 
36  
40d 
41-42d 
i For subjects entering Part 3 only. 
j Only for subjects completing the washout. 
k Safety follow-up call to be made 7-14 days following last dose of investigational product.  For subjects discontinued due to kidney transplantation, the safety follow up call to be made 
30 ± 7 days from the last dose.  
 
 
 
 
 


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Table 2:  Detailed Schedule of Assessments for Visit 1.1 in Part 1  
Hour (in relation to dosing time) 
Pre-dose 
0 
3 
5 
6 
8 
12 
24 
48 
Physical examination  
 
 
 
 
 
 
 
 
a 
Vital signs (blood pressure and pulse)b 
 
 
 
 
 
 
 
 
a 
Lanthanum carbonate single dose 
 
 
 
 
 
 
 
 
 
Pharmacokinetic blood samplingc 
 
 
 
 
 
 
 
 
 
Record adverse events  
 
 
 
 
 
 
 
 
 
Record concomitant medications 
 
 
 
 
 
 
 
 
 
a An attempt to perform these assessments and procedures should be made for any subject who withdraws or is removed early from the study, as well as those subjects completing 
the 48 hour period 
b Vital signs will be taken within 15 minutes of nominal dosing time.  
c The samples should be drawn within ±5 minutes of the nominal in the first 4 hours after taking the investigational product, ±15 minutes up to 24 hours after taking the 
investigational product and within ±60 minutes thereafter. 


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Table 3:  Schedule of Assessments for Part 2b and Part 3 
 
Part 2b 
(Visit window ±3 days) 
Part 3 
(Visit window ±1 week) 
 
Visit 
1.0a 
Washout 
W1b 
2.1-2.3 
2.4 
3.0-3.4 
3.5/End of 
Studyc 
Safety 
Follow-up 
callj 
Week  
0 
0-3 
weeks duration 
2, 4, 6d 
8 d 
12, 16, 20, 
24, 28  
32d 
33-34d 
Informed consent 
 
 
 
 
 
 
 
In/exclusion criteria 
 
b 
 
 
 
 
 
Medical and renal 
history 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
12-lead ECG 
 
 
 
 
 
 
 
Physical 
examination 
 
 
 
 
 
 
 
Vital signs, height 
and weight 
 
 
 
 
 
 
 
Local laboratory 
testse 
 
 
 
 
 
 
 
Central laboratory 
phosphate 
confirmation 
 
 
 
 
 
 
 
Biochemistry  
 
 
 
 
 
 
 
Hematology 
 
 
 
 
 
 
 


S hire  
C O N FI D E N TI A L  
1 4 Fe br uar y 2 0 1 9  
Pr ot oc ol S P D 4 0 5 - 2 0 7 
  
Versi o n 3. 0 
Pa ge 1 9 of 7 0 
T a ble 3 :  Sc he d ule of Assess me nts f or P a rt 2 b a n d P art 3 
 
P art 2 b  
( Visit wi n d o w ± 3 d a ys) 
P art 3  
( Visit wi n d o w ± 1 w ee k ) 
 
Visit  
1. 0 a  
W as h o ut  
W 1
b  
2. 1 -2. 3  
2 . 4 
3. 0 -3. 4  
3. 5/ E n d of 
St u d y c 
S afet y 
F oll o w -u p 
c all j 
Wee k  
0 
0- 3 
w ee k s d ur ati o n 
2, 4, 6 d  
8  d  
1 2, 1 6, 2 0, 
2 4, 2 8  
3 2 d  
3 3 -3 4 d  
Bi oc he mical b o ne 
mar kers  
 
 
 
 
 
 
 
Pre g na nc y test 
( w here a p plica ble) 
 
 
 
 
 
 
 
La nt ha n u m 
p har mac o ki netics  
 
�

f  
 

g 
 
 
I n vesti gati o nal 
pr o d uct dis pe nse d  

h 

h 
 

i 
 
 
 
I n vesti gati o nal 
pr o d uct c ollecte d  
 
 
 
 
 
 
 
D ose a dj ust me nt (as 
nee de d) a n d 
c o m plia nce  
 
 
 
 

 

 
 
Rec or d a d verse 
e ve nts  
 
 
 
 
 
 
 
 
Rec or d c o nc o mita nt 
me dicati o n  
 
 
 
 
 
 
 
Dial ysis a de q uac y  
 
 
 
 
 
 
 
C o nfir mati o n of 
dietar y a d vice  
 
 
 
 
 
 
 


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Table 3:  Schedule of Assessments for Part 2b and Part 3 
 
Part 2b 
(Visit window ±3 days) 
Part 3 
(Visit window ±1 week) 
 
Visit 
1.0a 
Washout 
W1b 
2.1-2.3 
2.4 
3.0-3.4 
3.5/End of 
Studyc 
Safety 
Follow-up 
callj 
Week  
0 
0-3 
weeks duration 
2, 4, 6d 
8 d 
12, 16, 20, 
24, 28  
32d 
33-34d 
a A consent form to participate in Part 2b must be signed. 
b Only for subjects completing washout. 
c Assessments scheduled for Visit 3.5 should also be carried out at the time of discontinuation for all subjects who withdraw from the study early or as close as  possible to the 
time of discontinuation.  These assessments are not required for subjects post-transplantation; however a safety follow-up call is required. 
d Visit weeks may be variable depending on duration of washout (+3 weeks). 
e Local laboratory assessments for phosphorus in Part 2b are for titration purposes, as required, and will not be analyzed; data from Visits 3.0-3.4 will be collected and 
assessed. 
f Visit 2.2 only; Each subject will have at least 2 samples taken for pharmacokinetic assessment. These should be taken during defined time windows (to be selected from: 0-2 
hours, 2-4 hours and 4-6 hours, after the first dose/meal of the day). Note: If the sampling is not done at Visit 2.2, blood sampling for pharmacokinetics must be taken at an 
alternative visit during Part 2b. 
g Visit 3 3 only; Each subject will have at least 2 samples taken for pharmacokinetic assessment. These should be taken during defined time windows (to be selected from: 
0-2 hours, 2-4 hours and 4-6 hours, after the first dose/meal of the day). Note: If the sampling is not done at Visit 3.3, blood sampling for pharmacokinetics must be taken at 
an alternative visit during Part 3. 
h Investigational product will be dispensed at Visit 1.0 if eligible, however if a washout is required then investigational product will be dispensed at visit W1. 
i For subjects entering Part 3 only. 
j Safety follow-up call to be made 7-14 days following last dose of investigational product. For subjects discontinued due to kidney transplantation, the safety follow up call 
to be made 30 ± 7 days from the last dose. 


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2.5 
Determination of Sample Size 
Part 1 (Pharmacokinetic Assessment) 
From Study LAM-IV-111, the mean±standard deviation AUC0-t was 3.099±2.888ng.hr/mL and 
Cmax was 0.296±0.177ng.hr/mL for a 1000mg single dose of lanthanum carbonate in subjects 
with renal failure who were receiving dialysis.  Assuming the standard deviations from Study 
LAM-IV-111, a sample size of 8 subjects will have 80% assurance that the 2-sided 95% 
confidence interval for the AUC0-t will be no wider than ±2.86ng.hr/mL and 80% assurance that 
2-sided 95% confidence interval for Cmax is no wider than ±0.18ng.hr/mL. 
Parts 2 and 3 [Efficacy – Percentage of Subjects Achieving Kidney Disease Outcome 
Quality Initiative (KDOQI) Target for Serum Phosphorus] 
Originally, the sample size of at least 50 subjects for the PP set had been chosen based on 
practical considerations and on agreement with the Paediatric Committee of the European 
Medicines Agency.  In order to obtain a PP Set of 50 subjects, a sample size of approximately 72 
subjects were to be enrolled in Part 2. This assumed 70% of the subjects are eligible for the PP 
Set.  This sample size has 81% power to show that the lower limit of the 95% confidence interval 
for the difference (LC – CC) in the percentage of subjects achieving serum phosphorus target is 
above the non-inferiority margin of -18%. 
 
However, given the extreme difficulty in recruiting enough subjects to obtain at least 50 subjects 
for the PP set for the assessment of non-inferiority, serious consideration had to be given to 
adjust the sample size and focus of the study to safety, in order to complete it. The sample size 
has been adjusted to include at least 32 subjects, who complete 8 weeks of treatment with 
lanthanum carbonate and are assessable for the primary endpoint.  This study is still useful in 
collecting information, where there is a void, regarding the use of lanthanum in the paediatric 
population.  
 
For the investigation of safety profile in hyperphosphatemic children and adolescents with 
chronic kidney disease (CKD) on dialysis treated with lanthanum carbonate, a sample size of 32 
subjects is necessary in order to observe at least one event with a true event rate of 5% at a 
probability of 80.6%. 
2.6 
Multiplicity Adjustments for Type I Error Control 
There is a single primary objective that specifies summarization of the percentage of subjects 
achieving age-specific KDOQI targets for serum phosphorus in hyperphosphatemic children and 
adolescents with CKD who are on dialysis, following 8 weeks of treatment with lanthanum 
carbonate. Consequently, no adjustment for multiplicity is required.   
  


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3. 
OBJECTIVES 
3.1.1 
Primary Objectives 
To summarize the percentage of subjects achieving age-specific Kidney Disease Outcomes 
Quality Initiative (KDOQI) targets for serum phosphorus in hyperphosphatemic children and 
adolescents with chronic kidney disease (CKD) who are on dialysis, following 8 weeks of 
treatment with lanthanum carbonate. 
3.1.2 
 Secondary Objectives 
1. To investigate the safety profile in hyperphosphatemic children and adolescents with CKD 
on dialysis treated with calcium carbonate and/or lanthanum carbonate.  
2. To summarize the percentage of subjects achieving KDOQI targets for serum phosphorus 
in hyperphosphatemic children and adolescents with CKD who are on dialysis following 
treatment with calcium carbonate for 8 weeks and lanthanum carbonate for 8 weeks. 
3. To assess mean changes from baseline in serum phosphorus, calcium and calcium-
phosphorus product in hyperphosphatemic children and adolescents with CKD who are on 
dialysis, following treatment with lanthanum carbonate for 8 weeks.  
4. To summarize mean changes from baseline in serum phosphorus, calcium and calcium-
phosphorus product in hyperphosphatemic children and adolescents with CKD who are on 
dialysis, following treatment with calcium carbonate for 8 weeks and lanthanum carbonate 
for 8 weeks. 
5. To describe the pharmacokinetics (maximum plasma concentration [Cmax] and area under 
the plasma concentration-time curve from time zero to the time of the last quantifiable 
concentration 
[AUC0-t]; 
body 
weight-normalized) 
of 
lanthanum 
carbonate 
in 
hyperphosphatemic children and adolescents aged 10 years to <18 years with CKD who 
are on dialysis, after a single dose of lanthanum carbonate oral powder formulation is 
administered (Part 1 of the study). 
6. To investigate the efficacy (serum phosphorus, calcium, and calcium phosphorus product) 
and safety of up to 8 months of treatment with lanthanum carbonate in children and 
adolescents aged 10 years to <18 years (Parts 2 and 3 of the study combined).  
7. To investigate biochemical markers of bone metabolism including bone alkaline 
phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP), osteocalcin, fibroblast 
growth factor 23 (FGF-23), parathyroid hormone (PTH), sclerostin and fetuin-A in 
children and adolescents aged 10 years to <18 years with CKD who are on dialysis.  
8. To investigate growth in children and adolescents aged 10 years to <18 years with CKD 
who are on dialysis and weight. 
 


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4. 
SUBJECT POPULATION SETS 
4.1 
Screened Set  
The Screened Set is defined as the set of subjects who have signed informed consent. 
4.2 
Enrolled Set 
The Enrolled Set is defined as subjects who have signed informed consent and have begun some 
study procedures (eg, dispensed investigational product, current drug has been withdrawn). 
4.3 
Safety Analysis Sets 
4.3.1 
Safety Analysis Set 1 (SAS1)  
Safety Analysis Set 1 is defined as enrolled subjects who have taken 1 dose of investigational 
product in Part 1 and who have completed at least 1 follow-up safety assessment.  
4.3.2 
Safety Analysis Set 2 (SAS2) 
Safety Analysis Set 2 is defined as enrolled subjects who have taken 1 dose of investigational 
product in Part 2 or Part 3 and who have completed at least 1 follow-up safety assessment.  
It is noted that safety assessments from the period when a subject is exposed to calcium 
carbonate will be summarized for calcium carbonate treatment and will include events occurring 
during calcium carbonate therapy prior to receiving lanthanum carbonate or going off study. 
Safety assessments from the period when a subject is exposed to lanthanum carbonate will be 
summarized for lanthanum carbonate treatment.  
4.3.3 
Safety Completer Set (SCS) 
The Safety Completer Set is defined as subjects who receive at least 8 weeks of lanthanum 
carbonate treatment from either Part 2 or Part 3 of the study.  
4.4 
Full Analysis Set (FAS) 
The Full Analysis Set is defined as subjects who have taken at least 1 dose of investigational 
product and who have at least 1 phosphate assessment during Part 2 or Part 3. 
4.5 
Per-protocol Set 1 (PP1)  
Per-protocol Set 1 is defined as subjects in the Full Analysis Set who complete 8 weeks of 
calcium carbonate treatment followed by 8 weeks of lanthanum carbonate treatment and who 
have serum phosphate assessment data available to allow summarizing the percentage of subjects 
achieving age-specific KDOQI target. Only subjects who have serum phosphate levels above the 
age-specific KDOQI targets at study entry and between the calcium carbonate treatment and 
lanthanum carbonate treatment at Visit 2.4 or the visits during washout will be included in this 


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set. Further details are described in the Evaluable Subjects Determination Plan which can be 
found in Section 21. 
4.6 
Per-protocol Set 2 (PP2) 
Per-protocol Set 2 is defined as subjects in the Full Analysis Set who complete 8 weeks of 
treatment with lanthanum carbonate and who have serum phosphate assessment data available to 
allow summarizing the percentage of subjects achieving age-specific KDOQI target. Subjects 
who have serum phosphate levels above the age-specific KDOQI targets prior to the start of 
lanthanum carbonate treatment will be included in this set. Further details are described in the 
Evaluable Subjects Determination Plan which can be found in Section 21. 
Subjects who experienced hypophosphatemia, that lead to temporary interruption or 
discontinuation of treatment before the 8-week phosphate assessment, are considered compliant 
with the 8 week treatment requirement (as treatment dosed per-protocol, Section 6.2.1) and can 
thus be included in the PP2, PP1, and SCS analysis populations. 
In previous versions of the protocol, a Per-protocol (PP) Set, defined as consisting “… of all 
Subjects in the FAS who complete Part 2 (ie, subjects who have a visit 2.8 serum phosphorus 
assessment) and do not have any pre-defined major protocol deviations that may affect the 
primary efficacy variable” was the only analysis set created to summarize efficacy endpoints.  
Following Protocol Version 6.0 (Amendment 5), two PP sets: PP1 and PP2 were defined. 
4.7 
Pharmacokinetic Sets (PK Sets) 
4.7.1 
Pharmacokinetic Set 1 
The Pharmacokinetic Set 1 is defined in Section 12.1. 
4.7.2 
Pharmacokinetic Set 2 
The Pharmacokinetic Set 2 is defined in Section 12.1. 


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5. 
SUBJECT DISPOSITION 
Part 1: A summary table will be produced for all subjects showing the number of subjects 
screened and enrolled, in addition to the number and proportion of subjects in the Safety 
Analysis Set 1, subjects who completed Part 1, subjects who prematurely discontinued from Part 
1 (also split by reason for withdrawal) and subjects who entered Part 2 (Table 1.1.1.1). This 
summary table will also be presented by age group (≥ 10 to <12 years, ≥12 to <18 years). (Table 
1.1.1.2) 
Part 2 (2a and 2b):  
A summary table will be produced by treatment group, showing the number and proportion of 
subjects in the Safety Analysis Set 2 (including those who entered the study in Part 2b), subjects 
who completed Part 2, subjects who prematurely discontinued from Part 2 (also split by reason 
for withdrawal), subjects who entered Part 3 (prematurely or otherwise), including those who 
entered Part 3 due to hypercalcaemia during treatment with calcium carbonate in Part 2 (a), 
subjects in the FAS, PP1, PP2 and subjects in the SCS Set. (Table 1.1.2.1) This summary table 
will also be presented by age group (≥ 10 to <12 years, ≥12 to <18 years). (Table 1.1.2.2) 
Part 2a (Treatment Period 2), Part 2b and Part 3 Combined (Lanthanum Carbonate only): 
A summary table will be produced showing the number and proportion of subjects in Safety 
Analysis Set 2 who completed the study, who entered Part 3 due to hypercalcaemia during 
treatment with calcium carbonate in Part 2a (Treatment Period 1), subjects in the FAS, PP2, SCS 
Set and subjects who prematurely discontinued from the study (also split by reason for 
withdrawal). (Table 1.1.3.1) This summary table will also be presented by age group (≥ 10 to 
<12 years, ≥12 to <18 years). (Table 1.1.3.2) 
An enrolment summary will be presented by site, and by country, showing the first day of 
consent, and the last study completion/withdrawal date among all Enrolled Subjects, the duration 
of enrolment (in days) [calculated as (last date of contact for any subject at that site - the first 
date of informed consent for any subject at that site + 1)], and the number of subjects enrolled 
and in each subject population set. The number and proportion of subjects enrolled in total, by 
site, and by country will be summarised. For individual sites, the site location and primary 
investigator’s name will also be presented. (Table 1.1.4) 
A listing of all Screen Failures (ie, subjects who gave informed consent and failed to meet the 
inclusion and/or met at least 1 of the exclusion criteria and were not administered IP(s) as 
defined by the protocol) will be presented along with reasons for screen fail and details of any 
adverse events (AEs).  
A listing of subject disposition (Listing 1.1) will be provided for all Enrolled Subjects, including 
the date of informed consent/assent, date of first dose and date of last dose for each part of the 
study (Part 1, Part 2, and Part 3) and each treatment group, accordingly (Part 2a: Calcium 
Carbonate, Part2a: Lanthanum Carbonate), date of completion/discontinuation, and whether the 
subject completed the study. Details of early terminations will also be listed for all Enrolled 
Subjects including the date of informed consent/assent, date of first dose and date of last dose for 
the part of the study (Part 1, Part 2, or Part 3) and treatment group, accordingly (Part 2a: Calcium 


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Carbonate, Part 2a: Lanthanum Carbonate or Part 2b: Lanthanum Carbonate) in which the 
subject withdrew, date of termination, duration of exposure (days), and primary reason for 
discontinuation as recorded on the termination page in the eCRF. (Listing 1.2) A listing of study 
analysis set classifications will be provided for all Enrolled Subjects specifying whether each 
subject was part of the defined analysis sets of Section 4, or not. (Listing 1.3) 


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6. 
PROTOCOL DEVIATIONS 
Part 1: A summary of the number (and percentage) of all Safety Analysis Set 1 with any 
protocol deviations, as well as the categories of deviations, will be provided overall and by site. 
(Table 1.5.1) 
Part 2: A summary of the number (and percentage) of subjects in the Safety Analysis Set 2 with 
any protocol deviations, as well as the categories of deviations, will be provided overall and by 
site for each treatment group. (Table 1.5.2) 
Part 2 and 3 combined (Lanthanum Carbonate only): A summary of the number (and 
percentage) of subjects in the Safety Analysis Set 2 and SCS with any protocol deviations, as 
well as the categories of deviations, will be provided overall and by site. (Table 1.5.3, Table 
1.5.4) 
Protocol deviation data will be listed for all enrolled subjects. (Listing 2.1.1) 
Evaluable subjects for the PP1 and PP2 Sets will be listed for the Full Analysis Set. (Listing 
2.1.2) 
 


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7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Part 1: Descriptive summaries will be presented for Lanthanum Carbonate for the Safety 
Analysis Set 1 (Table 1.2.1.1.1) and presented by age group (≥ 10 to <12 years, ≥12 to <18 
years). (Table 1.2.1.1.2) 
Part 2: Descriptive summaries will be presented by treatment group for the Safety Analysis Set 
2, the FAS, the PP1, the PP2 for lanthanum carbonate treatment only (Part 2a, Treatment Period 
2 and Part 2b) additionally presented by age group (≥ 10 to <12 years, ≥12 to <18 years) (Table 
1.2.1.2.1 to Table 1.2.1.4.2 and Table 1.2.1.5.1 and Table 1.2.1.5.2, respectively). 
Part 2 and 3 Combined (Lanthanum Carbonate only): Descriptive summaries will be 
presented for Lanthanum Carbonate for the SCS for 8 weeks of lanthanum carbonate treatment 
only, (Table 1.2.1.6.1) additionally presented by age group (≥ 10 to <12 years, ≥12 to <18 
years). (Table 1.2.1.6.2) 
Pharmacokinetic Set 1: Descriptive summaries will be presented for PK Set 1 (Table 
1.2.1.7.1), and additionally presented by age group (≥ 10 to <12 years, ≥12 to <18 years). (Table 
1.2.1.7.2) 
Pharmacokinetic Set 2: Descriptive summaries will be presented for PK Set 2 (Table 
1.2.1.7.3), and additionally presented by age group (≥ 10 to <12 years, ≥12 to <18 years). (Table 
1.2.1.7.4) 
The following demographic characteristics will be summarised in the following order in the 
tables: age (years), age group (categorical: <10 years, ≥ 10 to <12 years, ≥12 to <18 years and 
≥18 years), sex, ethnicity, race, weight (kg), height (cm) and Body Mass Index (kg/m2). 
Continuous variables such as subject age, weight, and height will be summarised using number 
of observations, mean, standard deviation, median, minimum, and maximum values. Categorical 
variables such as the subject’s sex, ethnicity, and race will be summarised using number of 
observations and percentages for each category.  Please note that age will only be calculated 
when the date of birth is not partial.  Age will be calculated as the difference between date of 
birth and date of informed consent or assent, which is usually signed at the beginning of the 
Screening Period. 
Renal history will be summarised for each of the Safety Analysis Sets (Safety Analysis Set 1, 
Safety Analysis Set 2 and the SCS) for each Part of the study (Table 1.2.2.1 [Part 1], Table 
1.2.2.2 [Part 2], Table 1.2.2.3 [Part 2 and 3 combined]), including the number and proportion 
of subjects who have each of the primary and secondary renal disease diagnoses stated in the 
eCRF, subjects who have haemodialysis and peritoneal dialysis and the categorical calcium 
concentrate (mmol/L) of the dialysate currently used for the subjects. In addition, summary 
statistics (n, mean, standard deviation, minimum, median, and maximum) for the time since first 
dialysis (calculated as the difference between date of first dialysis and date of informed consent 
or assent, truncated to years) will be presented. 
A listing of demographic and other baseline characteristics will be provided for all Enrolled 
Subjects. (Listing 4.1) 


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Renal history and diagnosis information including primary renal disease diagnosis, secondary 
renal disease diagnosis, date of first dialysis, type of dialysis, and the current calcium 
concentration of the dialysate the subject is using will also be listed for all Enrolled Subjects. 
(Listing 4.2) 
Medical history including verbatim term, date of onset, and date resolved (or whether it was 
ongoing) will be listed for all Enrolled Subjects. (Listing 4.3) 


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8. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
8.1 
Exposure to Investigational Product  
Exposure to IP will be summarised in terms of treatment duration for Parts 2 and 3, which is 
calculated as the number of days from the date of first dose of IP taken to the date of the last 
dose of IP taken within the respective part of the study, inclusively.  
Part 1: Data regarding study drug exposure during Part 1 will be listed for the Safety Analysis 
Set 1, including treatment start date, treatment start time, and dose per administration (mg). 
(Listing 5.1.1) For the Safety Analysis Set 2, summary statistics (n, mean, standard deviation, 
minimum, median, and maximum) for the total daily dose (mg/day), and length of exposure 
(days) will be presented by treatment group where total dose is defined as the sum of the doses 
within a treatment group and total daily dose is defined as the total dose / total days of dosing. In 
addition, total exposure (person-years and a summary of the number (and percentage) of subjects 
who fall within the categories of ≤1 week, >1-2 weeks, >2-3 weeks, >3-4 weeks, >4-5 weeks, 
>5-6 weeks, >6-7 weeks, >7-8 weeks, and >8 weeks, for the length of exposure will be presented 
by treatment group. Total exposure (person-years) will be the total number of days of IP (last 
dose – first dose + 1) summed over all subjects within a treatment group divided by 365.25 days. 
(Table 4.1.1; Listing 5.1.2) 
Part 2 and 3 Combined (Lanthanum carbonate only): For the Safety Analysis Set 2 and SCS, 
summary statistics (n, mean, standard deviation, minimum, median, and maximum) for the total 
daily dose (mg/day), and length of exposure (days) will be presented. In addition, total exposure 
(person-years) and a summary of the number (and percentage) of subjects whose length of 
exposure fall within specified categories (≤1 week, >1-4 weeks, >4-8 weeks, >8-12 weeks, >12-
16 weeks, >16-20 weeks, >20-24 weeks, >24-28 weeks, >28-32 weeks, and >32 weeks) will be 
presented. (Table 4.1.2 and Table 4.1.3) 
Data regarding study drug exposure during Part 2 and 3 will be listed for the Safety Analysis Set 
2 and SCS, including date of first dose, treatment, total daily dose (mg), and date of last dose. In 
addition the date the IP was returned from the previous visit, the amount of IP returned, the 
amount of IP taken, as well as the date the IP was dispensed, and the amount of IP dispensed, 
will also be listed by timepoint. (Listing 5.1.2 and Listing 5.1.3, respectively) 
8.2 
 Measurement of Treatment Compliance 
Investigational Product dosing compliance for a specified period is defined as the total number of 
sachets/tablets actually taken by a subject during that period divided by the number of 
sachets/tablets expected to be taken during the same period multiplied by 100. The total number 
of sachets/tablets actually taken is calculated by the total number of sachets/tablets dispensed 
minus the number of sachets/tablets returned. The number of sachets/tablets expected to be taken 
for a specified period is calculated as the number of days in that period multiplied by the number 
of sachets/tablets to be taken per day during that period. Within the summary tables of IP 
exposure, a summary of the number (and percentage) of subjects who fall within the compliance 
categories of <60%, 60% - 120%, and >120% will be presented. Exposure in Part 2 will be 
summarized by treatment group for Safety Analysis Set 2 (Table 4.1.1); Lanthanum Carbonate 


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exposure in Part 2 and 3 combined will be summarized for the Safety Analysis Set 2 and SCS 
(Table 4.1.2 and Table 4.1.3, respectively).  Subject compliance within Part 1, Part 2 only and 
within Part 2 and 3 combined will be listed within the IP accountability listing by treatment 
group. (Listing 5.1.1, Listing 5.1.2, Listing 5.1.3) 


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9. 
PRIOR AND CONCOMITANT MEDICATION  
Presently, version 2013Sep01_DD (Basic) of the World Health Organization (WHO) drug 
dictionary, is being used to classify prior and concomitant medications by therapeutic class. 
However, nearer to the conclusion of data collection, a decision will be made as to the most 
desirable dictionary to use. 
Prior medications will be presented for Part 1 (Table 1.3.1) and Part 2 (Table 1.3.2) and defined 
as any medication with a start date prior to the date of first IP intake in the relevant Part of the 
study, irrespective of when they stopped (for more specifics please see Protocol Section 5.1). 
Concomitant medication usage will be summarised by the number and proportion of subjects 
receiving each medication within each preferred term for the Safety Analysis Set 1, Safety 
Analysis Set 2 and the SCS. 
Part 1: Concomitant medications in Part 1 are defined as any medication with a start date prior 
to Part 1 and continuing on to 2 days after the day of IP in Part 1. Concomitant medication usage 
will be summarised by the number and proportion of subjects receiving each medication within 
each preferred term for the Safety Analysis Set 1. Multiple medication usage by a subject in the 
same category will be counted only once. (Table 1.3.3) 
Part 2: Concomitant medication in Part 2 of the study is defined as any medication with a start 
date prior to Part 2 and continuing after the first dose of IP in Part 2, or with a start date between 
the dates of the first and last doses of IP in Part 2, inclusive. Any medication with a start date 
after the date of the last dose of IP in Part 2 will not be considered a concomitant 
medication in Part 2. In the case of missing or partially missing start or stop dates for 
concomitant medications, if the information available could only lead to the medication being 
considered as starting on or after the first dose of IP in Part 2 and on or before the last dose date 
in Part 2 then it will be considered concomitant in Part 2. Concomitant medications will be listed 
and summarised by preferred drug name and treatment group. Concomitant medication usage 
will be summarised by the number and proportion of subjects in each treatment group receiving 
each medication within each preferred term for the Safety Analysis Set 2. Multiple medication 
usage by a subject in the same category will be counted only once. (Table 1.3.4, Table 1.3.5) 
Part 2 and 3 combined (Lanthanum carbonate only): Concomitant medications in Part 2 and 
3 combined are defined as any medication with a start date prior to and continuing after the first 
dose of lanthanum carbonate in Part 2 or 3, or with a start date between the dates of the first and 
last doses of lanthanum carbonate (inclusive) within Part 2 and 3 combined.  Any medication 
with a start date after the date of the last dose of lanthanum carbonate in Part 2 and 3 combined 
will not be considered a concomitant medication in Part 2 and 3 combined.  In the case of 
missing or partially missing start or stop medication dates, if with the available information one 
could only conclude that a medication started on or after the first dose of lanthanum carbonate in 
Part 2 or 3, and on or before the last dose of lanthanum carbonate in Part 2 and 3 combined, then 
the medication will be considered concomitant in Part 2 and 3 combined. Concomitant 
medications will be listed and summarised by preferred drug name.  Concomitant medication 
usage will be summarised by the number and proportion of subjects receiving each medication 
within each preferred term for the Safety Analysis Set 2 and the SCS.  Multiple medication usage 
by a subject in the same category will be counted only once. (Tables 1.3.6 and Table 1.3.7) 


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All prior and concomitant medications will be listed (Listing 4.4) including medication name, 
preferred drug name, the total daily dose (and units), route, frequency, indication, start date of 
medication, stop date of medication (or whether ongoing), classification of prior and 
concomitant, and if it was a concomitant medication; whether it was a vitamin D therapy, growth 
hormone, or proton pump inhibitor.   


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10. 
EFFICACY ANALYSES 
Efficacy analyses will be based on the PP2, PP1and FAS Sets. Generally, Baseline, for all 
efficacy analyses, is defined as the last assessment prior to the first dose of IP. A detailed 
description of Baseline, for the study, for treatment groups in Parts 2 and 3, can be found in the 
TLG shells, Appendix 2.  
All confidence intervals will be 2-sided 95% confidence intervals.  
10.1 
Primary Efficacy Endpoint(s) and Analysis   
The primary efficacy variable for the study is the percentage of subjects achieving age specific 
KDOQI targets for serum phosphate level following 8 weeks of lanthanum carbonate treatment. 
The KDOQI serum phosphorus targets are defined as: 
- 
Adolescents aged ≥12-<18 years:  ≤ 5.5mg/dL (1.78mmol/L) 
- 
Children aged 10 years -<12 years: ≤6.0mg/dL (1.94mmol/L) 
For the primary endpoint, the percentage of subjects achieving age-specific KDOQI targets for 
serum phosphate levels after 8 weeks of lanthanum carbonate treatment will be descriptively 
summarized and calculated along with an exact (Clopper-Pearson) 95% confidence interval. PP2 
will be the primary analysis population and will be used for this descriptive summarization. 
Serum phosphate levels tested at a central laboratory will be used for the analysis. In the case of 
missing central laboratory data, local laboratory data will be used. Please note that serum 
phosphorous assessments must come from a homogeneous source ie, from either central or local 
laboratory for baseline and following weeks 8 of lanthanum treatment, respectively, within 
subject (Table 3.1.1.1 and Table 3.1.1.2). KDOQI Serum Phosphorous Target Achievement will 
be listed (Listing 6.1). 
10.2 
Key Secondary Efficacy Endpoint(s) and Analysis  
Not applicable. 
10.3 
Other Secondary Efficacy Endpoint(s) and Analysis 
The secondary analyses will be carried out using the analysis populations of FAS, PP1, and/or 
PP2. 
Secondary variables are: 
• The percentage of subjects with serum phosphorus levels at or below the age-specific 
KDOQI targets following 8 weeks of treatment with calcium carbonate followed by 8 weeks 
of treatment with lanthanum carbonate will be descriptively summarized similarly as for the 
primary efficacy variable, however, this will be performed for each treatment arm. The PP1 
and FAS will be used for this summarization. (Table 3.1.2.1 and Table 3.1.2.2) The KDOQI 
serum phosphorus targets are defined above.  


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• Changes from baseline in serum phosphorus, calcium and calcium-phosphorus product in 
hyperphosphatemic children and adolescents with CKD who are on dialysis, following 
treatment with lanthanum carbonate for 8 weeks.  The PP2 and FAS will be used for this 
summarization (Table 3.1.4.1 to Table 3.1.4.6) [Part 2 and 3 combined]. 
• Changes from baseline in serum phosphorus, calcium and calcium-phosphorus product in 
hyperphosphatemic children and adolescents with CKD who are on dialysis, following 
treatment with calcium carbonate for 8 weeks and lanthanum carbonate for 8 weeks. The PP1 
and FAS Set will be used for this summarization (Table 3.1.3.1 to Table 3.1.3.6) [Part 2]. 
• Change from baseline in serum phosphorus, calcium and calcium-phosphorus product levels 
at the last visit of 8-week treatment period during Part 2 and monthly during the 6-month 
extension phase (Part 3). The PP2 and FAS Sets will be used for this summarization (Table 
3.1.4.1 to Table 3.1.4.6) [Part 2 and 3 combined]. 
• Biochemical bone markers: bone ALP, osteocalcin, TRAP, FGF-23, PTH, sclerostin and 
fetuin-A before and after each treatment period in Part 2, and at the end of Part 3 (Tables 
3.1.5.1 to 3.1.5.14 [Part 2a and 3], Tables 3.2.5.1 to 3.2.5.14 [Part 2b and 3]) will be 
summarized for PP1 and FAS and PP2 and FAS, respectively. 
• Height and Weight at: 
o Visits 2.0, 2.4, 2.8, and 3.5 (Parts 2a and 3): (PP1 and FAS Sets) 
o Visits 1.0, 2.4, and 3.5 (Parts 2b and 3). (PP2 and FAS Sets) 
(Tables 3.1.6.1 to 3.1.6.4, Tables 3.1.7.1 to 3.1.7.4, respectively). 
• Number and percentage of subjects with serum phosphorus levels at the age-specific KDOQI 
targets by week of treatment with lanthanum carbonate for PP2 and FAS (Tables 3.1.8.1 to 
3.1.8.2, respectively). 
 
All secondary variables will be summarised using descriptive statistics as follows: 
• For continuous data: number of observations, mean, standard deviation, standard error, 
median, minimum, maximum values and 95% confidence interval (normal approximation) of 
the mean. 
• For categorical data: number of observations and percentages. 
All secondary efficacy endpoints will be summarised using both an appropriate PP Set (for the 
endpoint) and the FAS. Serum phosphorus, calcium, and calcium-phosphorus product will be 
summarized for Part 2 by treatment and weeks of administration of treatment, and for Part 2 and 
3 combined for lanthanum carbonate only by weeks of treatment with lanthanum carbonate. For 
summaries by week of treatment, +/-1 week will be used to assign values to a timepoint ie, Week 
8 will include 7-9 weeks of exposure. If more than 1 value for a subject falls into one window, 
then the value closest to the planned visit will be included in the summary, ie, if we have a value 
on day 51 and a value on day 57, the day 57 value will be used in the Week 8 summary. If two 
values are equidistance from the timepoint then the higher value will be used for analysis, 
assuming worst case. 


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All other secondary endpoints will be summarized by scheduled assessment.  
It is stated in the protocol that local laboratory assessments for phosphorus, serum calcium, and 
calcium phosphorus product in Parts 1 and 2 are for titration purposes, as required, and will not 
be analyzed; data from Visits 3.0-3.4 will be collected and analysed. However, it should be 
clarified that in the case of missing central laboratory data, local laboratory data will be used, as 
appropriate. For example, in the case of the change from baseline to an assessment following 8 
weeks of an IP, both assessments (baseline and following 8 weeks of treatment) must be from 
either the central or the local lab.       
Bar charts will be provided for the mean change from baseline in Part 2 by treatment group for 
serum phosphorus, (Figure 3.1.3.1) calcium (Figure 3.1.3.2,), and calcium-phosphorus product 
(Figure 3.1.3.3) for the PP1 Set.  
The mean change from baseline in Part 2 and 3 combined by weeks of treatment with lanthanum 
carbonate will also be graphically presented, via line graph for serum phosphorus, calcium, and 
calcium-phosphorus product for the following Analysis Populations: PP2, FAS Sets. (Figures 
3.1.4.1 to 3.1.4.6) 
10.4 
Exploratory Efficacy Endpoint(s) and Analyses  
Not applicable. 


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11. 
SAFETY ANALYSES 
For scheduled assessment all safety variables for Part 1 will be summarised using the Safety 
Analysis Set 1; Safety variables for Parts 2 and 3 will be summarised using the Safety Analysis 
Set 2 and SCS (where applicable). Safety variables include AEs, clinical laboratory variables, 
vital signs, and electrocardiogram (ECG) variables. For each safety variable, the last value 
collected before the first dose of IP will be used as baseline for all analyses of that safety 
variable. Additionally, a detailed description of Baseline, for treatment groups in Parts 2 and 3, 
can be found in the TLG shells, Appendix 2.  
11.1 
Adverse Events  
Onset day of an AE is calculated as (start date of the AE - date of the first dose of IP) + 1. AEs 
will be classified into system organ class (SOC) and preferred term (PT) using Version 16.1, of 
MedDRA, to be determined closer to the conclusion of data collection.  
An AE that occurs during the study will be considered a treatment emergent AE (TEAE) if it has 
a start date on or after the first dose of IP. TEAEs will be allocated to Part 1, Part 2, or Part 3, 
based on the onset date of the AE relative to the date and Part of the most recently administered 
IP. If an AE occurred more than 3 weeks after the date of the most recent IP, it will not be 
considered a TEAE. In the case of increases in severity, if there is more than 1 reference AE with 
the same preferred term then the AE with the greatest severity will be used as the benchmark for 
comparison to the AEs occurring in each Part of the study.  
Part 1: An overall summary (Table 4.2.1.1) and summary by age group (Table 4.2.1.2) of the 
number of subjects in Safety Analysis Set 1 with TEAEs in Part 1 will be presented, including 
the number and proportion of subjects with any TEAEs, serious TEAEs, TEAEs related to 
lanthanum carbonate, TEAEs leading to study withdrawal, and TEAEs leading to death. The 
number of events, incidence, and percentage of TEAEs will be presented by SOC, and by 
preferred term (Table 4.2.2.1); by SOC, preferred term, and maximum severity (Table 4.3.1.1); 
and by SOC, preferred term, and relationship to lanthanum carbonate (Table 4.3.2.1). Similar 
summaries by SOC and preferred term will be produced for SAEs (Table 4.4.1.1), for deaths 
(Table 4.4.2.1), and for TEAEs leading to study withdrawal (Table 4.4.3.1). AEs (Listing 7.1), 
SAEs (Listing 7.2), AEs related to lanthanum carbonate (Listing 7.3), AEs leading to study 
withdrawal (Listing 7.4), and deaths (Listing 7.5) will be listed. AEs related to bone disease 
(preferred terms: adynamic bone disease and long bone fracture) are of special interest and will 
be summarised by SOC and preferred term (Tables 4.5.1.1 and 4.5.2.1) and listed separately 
(Listing 7.6). 
Part 2: An overall summary (Table 4.2.1.3) and summary by age group (Table 4.2.1.4) of the 
number of subjects in Safety Analysis Set 2 with TEAEs in Part 2 will be presented, including 
the number and proportion of subjects with any TEAEs, serious TEAEs, TEAEs related to IP, 
TEAEs leading to study withdrawal, and TEAEs leading to death. The number of events, 
incidence, and percentage of TEAEs in each treatment group will be presented by SOC and 
preferred term (Table 4.2.2.2); by SOC, preferred term, and maximum severity (Table 4.3.1.2); 
and by SOC, preferred term, and relationship to IP (Table 4.3.2.2). Similar summaries by SOC 
and preferred term will be produced for SAEs (Table 4.4.1.2), for deaths (Table 4.4.2.2), and for 


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TEAEs leading to study withdrawal (Table 4.4.3.2). AEs, AEs related to IP, SAEs, AEs leading 
to study withdrawal, and deaths will be listed (Listing 7.1, Listing 7.3, Listing 7.4 and Listing 
7.5). TEAEs related to bone disease (preferred terms: adynamic bone disease and long bone 
fracture) are of special interest and will be summarised by SOC and preferred term for Part 2 
(Tables 4.5.1.2 and 4.5.2.2) and listed separately (Listing 7.6). 
Part 2 and 3 combined (lanthanum carbonate only): An overall summary (Tables 4.2.1.5 and 
4.2.1.7) and summary by age group (Tables 4.2.1.6 and 4.2.1.8) of the number of subjects in 
Safety Analysis Set 2 and SCS with TEAEs in Part 2 and 3 combined will be presented. The 
number of events, incidence, and percentage of TEAEs will be presented by SOC by preferred 
term (Tables 4.2.2.3 and 4.2.2.4); by SOC, preferred term, and maximum severity (Tables 
4.3.1.3 and 4.3.1.4); and by SOC, preferred term, and relationship to lanthanum carbonate 
(Tables 4.3.2.3 and 4.3.2.4). Similar summaries by SOC and preferred term will be produced for 
SAEs (Tables 4.4.1.3 and 4.4.1.4), for deaths (Tables 4.4.2.3 and 4.4.2.4), and for TEAEs 
leading to study withdrawal (Tables 4.4.3.3 and 4.4.3.4). AEs, AEs related to lanthanum 
carbonate, SAEs, AEs leading to study withdrawal, and deaths will be listed (refer to listings 
noted above). TEAEs related to bone disease (preferred terms: adynamic bone disease and long 
bone fracture) are of special interest and will be presented by SOC and preferred term in Table 
4.5.1.3 and Table 4.5.1.4 and by sex and age group in Table 4.5.2.3 and 4.5.2.4 and will be 
listed separately. (Listing 7.6) 
Only Part 2 will be summarised by treatment group (Calcium Carbonate and Lanthanum 
Carbonate) for the Safety Analysis Set 2 population summary. 
11.2 
Clinical Laboratory Variables 
Clinical laboratory data (biochemistry, haematology, and biochemical bone markers) will be 
summarised by parameter and visit for Part 1 for the Safety Analysis Set 1 (Tables 4.6.1.1, 
4.6.1.2 and 4.6.1.3, respectively). 
Clinical laboratory data (biochemistry, haematology, and biochemical bone markers) will be 
summarised by parameter, visit and treatment group for Part 2 and 3 for the Safety Analysis Set 
2 (Tables 4.6.2.1, 4.6.2.2 and 4.6.2.3, respectively). Additionally, summarization will also be 
performed by parameter and visit for Lanthanum Carbonate for Parts 2 and 3 for the SCS 
(Tables 4.6.2.4, 4.6.2.5 and 4.6.2.6, respectively).  
Descriptive statistics (n, mean, standard deviation, minimum, median, and maximum) for clinical 
laboratory values (in SI units) and changes from baseline at each assessment time point as well 
as shift tables (in terms of abnormality: low, normal, and high) from baseline to each visit for 
quantitative variables will be presented for the following clinical laboratory variables for Part 2 
and 3 for the Safety Analysis Set 2 (Tables 4.6.3.1, 4.6.3.2, 4.6.3.3) and SCS (Tables 4.6.3.4, 
4.6.3.5 and 4.6.3.6).  


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Biochemistry 
 
Blood samples (approximately 4.0mL) for biochemistry will be taken according to the Schedule 
of Assessments (see Table 1 and Table 3). The following parameters will be assessed: 
Sodium 
Alanine aminotransferase (ALT) 
Potassium 
ALP 
Calcium 
Gamma glutamyl transferase (GGT) 
Urea 
Total bilirubin 
Creatinine 
Magnesium 
Albumin 
Serum phosphorus 
Total protein 
25-hydroxy Vitamin Da 
Aspartate aminotransferase (AST) 
 
a 25-hydroxy Vitamin D will be measured at baseline and End of Study (EOS) only. 
 
Haematology 
 
Blood samples (approximately 500µL) for haematology will be taken according to the Schedule 
of Assessments (see Table 1 and Table 3). The following parameters will be assessed: 
Haemoglobin 
Mean corpuscular haemoglobin (MCH) 
Haematocrit 
Mean corpuscular haemoglobin concentration 
(MCHC) 
Red blood cells 
White blood cell count – total and differential  
Mean corpuscular volume (MCV) 
Platelet count 
 
 
 


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Biochemical Bone Markers 
 
Blood samples (approximately 3.0mL) for biochemical bone markers will be taken according to 
the Schedule of Assessments (see Table 1 and Table 3). The following parameters will be 
assessed: 
Tartrate-resistant acid phosphatase 
Bone ALP 
Osteocalcin 
Sclerostin 
Fetuin- A 
PTH 
FGF-23 
 
 
Normal ranges for all clinical laboratory data parameters (biochemistry, haematology, and 
biochemical bone markers) will be listed (Tables 4.6.5.1, 4.6.5.2 and 4.6.5.3, respectively). 
All clinical laboratory data including serum pregnancy test results will be listed (Listings 8.1.1 
[clinical laboratory sample collection and results for pregnancy]  
and Listing 8.1.2 [clinical laboratory test results]). 
11.3 
Vital Signs 
Vital signs data [height (cm), weight (kg), pulse (beats/min), systolic blood pressure (mmHg), 
and diastolic blood pressure (mmHg)] will be summarised by visit and by timepoint (for 
Visit 1.1); by Lanthanum Carbonate for Part 1 (Table 4.7.1), by treatment group for Part 2 and 3, 
for Lanthanum Carbonate only for Part 2 and 3 for the Safety Analysis Set 2 (Table 4.7.2 and 
Table 4.7.3, respectively) and for Lanthanum Carbonate only for Part 2 and 3 for the SCS 
(Table 4.7.4).  Baseline is defined as the last assessment prior to the first dose of IP.  A detailed 
description of Baseline, for the study, for treatment groups in Parts 2 and 3, can be found in the 
TLG shells, Appendix 2.  
Descriptive statistics (n, mean, standard deviation, minimum, median, and maximum) for vital 
sign variables and their changes from baseline at each post-baseline visit will be presented. 
All vital signs data will be listed (Listing 8.2.1). 
11.4 
Electrocardiogram (ECG) 
ECG interpretation will be summarised by visit for Lanthanum Carbonate only for Parts 2a and 3 
combined and Parts 2b and 3 combined for the Safety Analysis Set 2 (Table 4.8.1 and Table 
4.8.2, respectively) and the SCS (Table 4.8.3 and Table 4.8.4, respectively). A shift table (in 
terms of clinical significance: normal, abnormal not clinically significant, and abnormal 
clinically significant) from baseline to each visit for qualitative ECG results will be presented for 
Lanthanum Carbonate only for Parts 2a and 3 combined and Parts 2b and 3 combined for the 
Safety Analysis Set 2 (Table 4.8.5 and Table 4.8.6, respectively) and for the SCS (Table 4.8.7 
and Table 4.8.8, respectively). 
ECG Investigator interpretations will be listed (Listing 8.3.1). 


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11.5 
Other Safety Variables 
No other safety assessments/variables are planned for this study. 


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12. 
CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC 
ANALYSES 
12.1 
Pharmacokinetics Population (and Pharmacodynamic Population, if applicable) 
Pharmacokinetic Set 1 - Subjects in the Safety Analysis Set 1 who have at least 1 measurable 
post-dose plasma concentration of Lanthanum Carbonate.  Subjects in Part 1 who vomited may 
be excluded from Pharmacokinetic Set 1. 
Pharmacokinetic Set 2 - Subjects in Safety Analysis Sets 1 or 2 who have at least 1 measurable 
post-dose plasma concentration of Lanthanum Carbonate will be included in Pharmacokinetic 
Set 2. 
12.2 
Pharmacokinetic Methods 
12.2.1 
Concentration Data 
Plasma lanthanum concentrations will be measured using Inductively Coupled Plasma Mass 
Spectrometry. 
12.2.2 
Handling BLQ Values 
The following procedures will be used for plasma concentrations below the lower limit of 
quantification (LLOQ) (reported as not quantifiable [NQ]):   
• Plasma samples that are BLQ are reported as zero on the data listings. 
• Samples that are BLQ are treated as zero in the calculation of summary statistics (eg 
mean, SD, etc.) for the plasma concentrations at individual time points. 
• Mean concentrations are reported as zero if all values are BLQ, and no descriptive 
statistics are reported. If the calculated mean (± SD) concentration is less than the LLOQ, 
the value will be reported as calculated. The mean values derived using these conventions 
will be used to create the mean plasma concentration versus time plots. 
• For calculation of area under the plasma concentration curve (AUC), BLQ values are set 
equal to zero in the dataset loaded into WinNonlin for pharmacokinetic analysis. 
WinNonlin uses the zero values that occur before the first time point with a concentration 
greater than LLOQ, but WinNonlin excludes the zero values from the AUC calculation 
for all later time points. 
12.2.3 
Pharmacokinetic Parameters 
Part 1 
The PK analysis for Part 1 will be conducted by the Clinical Pharmacology and 
Pharmacokinetics Department of Shire Pharmaceuticals or its designee using WinNonlin 
Phoenix version 6.2 or higher (Pharsight Corporation, Mountain View, California, USA). 


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PK parameters will be determined from the plasma concentration-time data for lanthanum by 
non-compartmental analysis. All calculations will be based on actual sampling times.   
The PK parameters will include, but not be limited to: 
• 
Cmax 
Maximum concentration occurring at tmax  
• 
tmax 
Time of maximum observed concentration sampled during a dosing 
 
interval  
• 
AUC0-∞ 
Area under the curve extrapolated to infinity, calculated using the observed 
 
value of the last non-zero concentration 
• 
AUClast 
Area under the curve from the time of dosing to the last measurable 
 
concentration 
• 
AUC0-48 
Area under the curve over the interval from dosing to 48 hours post-dose 
• 
t½ 
Terminal half-life 
• 
λz  
First order rate constant associated with the terminal (log-linear) portion of 
 
the curve 
• 
CL/F 
Total body clearance for extravascular  administration 
divided 
by 
the 
 
fraction of dose absorbed 
• 
Vz/F 
Volume of distribution associated with the terminal slope following 
 
extravascular administration divided by the fraction of dose absorbed. 
 
Parts 2 and 3 
The PK analysis for Parts 2 and 3 will be conducted by a vendor that specializes in population 
PK analysis.  
Plasma concentration-time data for Part 2 treatment period 2, and Part 3 will be combined with 
those from Part 1 and subjected to population PK analysis using NONMEM to determine 
estimates of steady-state systemic exposure (Cmax, minimum plasma concentration and area 
under the plasma concentration-time curve at steady-state) and relationships of systemic 
exposure to dose and to safety findings explored if appropriate. 
12.3 
Statistical Analysis of Pharmacokinetic Data 
All of the PK analyses for Part 1 will be performed using the Pharmacokinetic Set 1. All of the 
PK analyses for Parts 2 and 3 will be performed using the Pharmacokinetic Set 2.   
Summary statistics (number of observations, mean, standard deviation, coefficient of variation, 
median, maximum, minimum, and geometric mean) will be determined for all pharmacokinetic 
parameters by age group for Part 1. Plasma concentrations at each nominal sampling time will 
also be summarized by age group for Part 1 using descriptive statistics (number of observations, 
mean, standard deviation, coefficient of variation, median, maximum, and minimum).  


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12.4 
Pharmacodynamic Methods 
Not Applicable.  
12.5 
Statistical Analysis of Pharmacodynamic Data (if applicable) 
Not Applicable.  
12.6 
Analyses of Pharmacokinetic/Pharmacodynamic Relationships (If applicable) 
Not Applicable.  
12.7 
Changes in the Pharmacokinetic or Statistical Methods from Those stated in the 
Protocol 
The definition of the Pharmacokinetic Set 1 and Pharmacokinetic Set 2 appears as follows in 
Protocol Version 6.0 (Amendment 5): 
Pharmacokinetic Set 1 - Subjects in the Safety Analysis Set 1 for whom the primary 
pharmacokinetic data are considered sufficient and interpretable. Subjects in Part 1 who vomited 
may be excluded from Pharmacokinetic Set 1. 
Pharmacokinetic Set 2 - Subjects in Safety Analysis Sets 1 or 2 for whom the primary PK data 
are considered sufficient and interpretable will be included in Pharmacokinetic Set 2 
The definition of Pharmacokinetic Set 1 and Pharmacokinetic Set 2 appears as the following in 
the present SAP for simplification and as a result of standardization of these definitions across 
studies within Shire: 
Pharmacokinetic Set 1 - Subjects in the Safety Analysis Set 1 who have at least 1 measurable 
post-dose plasma concentration of Lanthanum Carbonate. Subjects in Part 1who vomited may be 
excluded from Pharmacokinetic Set 1. 
Pharmacokinetic Set 2 - Subjects in Safety Analysis Sets 1 or 2 who have at least 1 measurable 
post-dose plasma concentration of Lanthanum Carbonate will be included in Pharmacokinetic 
Set 2.  
12.8 
Pharmacokinetic References 
Not Applicable.  
12.9 
Table of Contents for Pharmacokinetic Figures, Tables, and Listings 
Formats and numbering of the tables, listings and figures will be finalized prior to the completion 
of the Clinical Study Report. No revision to this document is required for changes which do not 
affect the statistical or PK methods, definitions, or rules defined in this document. 
In the event that a limited number of samples yield measurable concentrations, the PK tables, 
listings and figures will be generated as deemed appropriate. No revision of this document will 


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be required. 
 
 
 
TABLES 
PK Tables will be provided by Clinical Pharmacology and Pharmacokinetics Department of 
Shire Pharmaceuticals or its’ designee, as overseen by the pharmacology group. 
LISTINGS 
PK Listings will be provided by Clinical Pharmacology and Pharmacokinetics Department of 
Shire Pharmaceuticals or its’ designee, as overseen by the pharmacology group. 
FIGURES 
Pharmacokinetic Figures 
PK Figures will be provided by Clinical Pharmacology and Pharmacokinetics Department of 
Shire Pharmaceuticals or its’ designee, as overseen by the pharmacology group. 


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13. 
OTHER ANALYSES  
Not applicable. 
 


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14. 
INTERIM ANALYSIS  
No formal interim analysis is planned for this study. However, a descriptive analysis of efficacy 
and safety data was produced in Q4 2014 to assist with regulatory interactions as recruitment 
targets had not been met.  


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15. 
DATA MONITORING/REVIEW COMMITTEE  
Not applicable. 
 


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16. 
COMPUTER METHODS  
PRA International will perform all pre-defined statistical analyses after the database is locked. 
Statistical analyses of efficacy and safety data will be performed using Version 9.1 or higher of 
SAS (SAS Institute, Cary, NC 27513).  


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17. 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
The following changes to the analyses as outlined in the Protocol Version 6.0 (Amendment 5), 
18 Oct 2016 were as follows: 
• Subject Disposition for Part 2 (2a and 2b) was proposed to be presented by Treatment 
group.  However, the presentation will be presented by Parts 2a and 2b.  
• The Safety Analysis Set 2 was redefined to include Part 3 (long-term safety); therefore, 
removed Safety Analysis Set 3 and added Safety Completer Set (SCS) to include subjects 
who received 8 weeks of lanthanum carbonate treatment from Part 2 or Part 3 of the 
study as a result of and in response to discussions with PDCO. 
• An inconsistency in wording exists between the protocol Synopsis (under the Efficacy 
Analysis section on pages 29 and 30) and protocol Section 9.10.2 (Secondary Variables, 
page 80). The Synopsis wording states “For the long-term assessment, efficacy and safety 
variables will be summarized using the FAS and SAS2, respectively…” whereas the 
wording in Section 9.10.2 states “For the long-term assessment, efficacy and safety 
variables will be summarized using the Safety Analysis Set 2 for each visit using 
descriptive statistics…”. The wording will no longer appear in the text, but the SAP will 
more closely follow what appears in the protocol Synopsis and summarize long-term 
variables using the FAS analysis population. 
The definitions of the FAS and SAS2 are identical except for a subsequent required 
assessment (ie, at least 1 phosphate assessment or the completion of at least 1 follow-up 
safety assessment, respectively). It is unlikely that a subject would complete a follow-up 
safety assessment without also having at least 1 phosphate assessment. As a result, if 
there is a difference in the size or quality between these 2 analysis populations it would 
be negligible and hence no impact on the summaries that will be provided.     
• The age group categories that will summarized within the Demographic and Baseline 
Characteristics tables has been updated from 2 categories (ie, <12 years and ≥12 years) to 
4 categories (<10 years, ≥ 10 to <12 years, ≥12 to <18 years and ≥ 18 years) to account 
for the ages of all subjects who participated in the study across various versions of the 
protocol and age group categories that appear in the most recent and up-to-date CRF.  
• The age group categories that will be summarized for the “by Age” summary tables for 
Subject Disposition, Demographic and Baseline Characteristics and Adverse Events have 
been clarified and now explicitly align with the age groups upon which the primary and 
secondary endpoints are analysed (≥ 10 to <12 years and  ≥12 to <18 years vs. <12 years 
and  ≥12 years).  
• The study will enrol at least 32 (rather than 35) subjects who complete 8 weeks of 
treatment with lanthanum carbonate and are assessable for the primary endpoint.  
• The definitions of PP1 and PP2 will only include subjects who have serum phosphate 
levels above the age-specific KDOQI target (rather than equal to or above). 


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18. 
DATA HANDLING CONVENTIONS 
18.1 
General Data Reporting Conventions 
Continuous variables will be summarised using the following descriptive statistics: n, mean, 
median, standard deviation, minimum, maximum. Categorical and count variables will be 
summarised by the number of subjects (n) and the percent of subjects in each category. 
Percentages will be presented as whole numbers.  
See Shire Standards for rules on the number of decimal places to present data and p-values.  
18.2 
Derived Efficacy Endpoints  
Not applicable. 
18.3 
Repeated or Unscheduled Assessments of Safety Parameters  
If a subject has repeated assessments before the start of IP, then the results from the final 
assessment made prior to the start of IP will be used as baseline. If end of study assessments are 
repeated or unscheduled, the last post-baseline assessment will be used as the end of study 
assessment for generating descriptive statistics.  
18.4 
Missing Date of Investigational Product  
When the date of the last dose of IP is missing for a subject in any Part of the study, all efforts 
should be made to obtain the date from the investigator. If it is still missing after all efforts, then 
the last visit date when IP was returned will be used in the calculation of treatment duration.  
18.5 
Missing Date Information for Prior or Concomitant Medications  
For prior or concomitant medications, incomplete (ie, partially missing) start date and/or stop 
date will be imputed. When the start date and the stop date are both incomplete for a subject, 
impute the start date first.  
18.5.1 
Incomplete Start Date  
The following rules will be applied to impute the missing numerical fields. If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date. 
Missing day and month 
• 
If the year of the incomplete start date is the same as the year of the date of the first dose of 
IP, then the day and month of the date of the first dose of IP will be assigned to the 
missing fields. 
• 
If the year of the incomplete start date is before the year of the date of the first dose of IP, 
then December 31 will be assigned to the missing fields 
• 
If the year of the incomplete start date is after the year of the date of the first dose of IP, 


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then 01 January will be assigned to the missing fields. 
 
Missing month only 
• 
The day will be treated as missing and both month and day will be replaced according to 
the above procedure. 
Missing day only 
• 
If the month and year of the incomplete start date are the same as the month and year of the 
date of the first dose of IP, then the day of the date of the first dose of IP will be assigned 
to the missing day 
• 
If either the year is before the year of the date of the first dose of IP or if both years are the 
same but the month is before the month of the date of the first dose of IP, then the last day 
of the month will be assigned to the missing day 
• 
If either the year is after the year of the date of the first dose of IP or if both years are the 
same but the month is after the month of the date of the first dose of IP, then the first day 
of the month will be assigned to the missing day.  
18.5.2 
Incomplete Stop Date  
The following rules will be applied to impute the missing numerical fields. If the date of the last 
dose of IP is missing, then replace it with the last visit date. If the imputed stop date is before the 
start date (imputed or non-imputed start date), then the imputed stop date will be equal to the 
start date. 
Missing day and month 
• 
If the year of the incomplete stop date is the same as the year as of the date of the last dose 
of IP, then the day and month of the date of the last dose of IP will be assigned to the 
missing fields 
• 
If the year of the incomplete stop date is before the year of the date of the last dose of IP, 
then 31 December will be assigned to the missing fields 
• 
If the year of the incomplete stop date is after the year of the date of the last dose of IP, 
then 01 January will be assigned to the missing fields. 
Missing month only 
• 
The day will be treated as missing and both month and day will be replaced according to 
the above procedure. 
Missing day only 
• 
If the month and year of the incomplete stop date are the same as the month and year of the 
date of the last dose of IP, then the day of the date of the last dose of IP will be assigned to 
the missing day 
• 
If either the year is before the year of the date of the last dose of IP or if both years are the 
same but the month is before the month of the date of the last dose of IP, then the last day 
of the month will be assigned to the missing day 
• 
If either the year is after the year of the last dose of IP or if both years are the same but the 


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month is after the month of the date of the last dose of IP, then the first day of the month 
will be assigned to the missing day. 
18.6 
Missing Date Information for Adverse Events  
For AEs, the default is to only impute incomplete (ie, partially missing) start dates. Incomplete 
stop dates may also be imputed when calculation of the duration of an AE is required per the 
protocol. If imputation of an incomplete stop date is required, and both the start date and the stop 
date are incomplete for a subject, impute the start date first. 
18.6.1 
Incomplete Start Date  
Follow same rules as in Section 18.5.1. 
18.6.2 
Incomplete Stop Date  
When required per the protocol, follow the same rules as in Section 18.5.2.  
18.7 
Missing Severity Assessment for Adverse Events 
If severity is missing for an AE starting prior to the date of the first dose of IP, then a severity of 
“Mild” will be assigned. If the severity is missing for an AE starting on or after the date of the 
first dose of IP, then a severity of “Severe” will be assigned. The imputed values for severity 
assessment will be used for incidence summaries, while the actual values will be used in data 
listings. 
18.8 
Missing Relationship to Investigation Product for Adverse Events 
If the relationship to IP is missing for an AE starting on or after the date of the first dose of IP, a 
causality of “Related” will be assigned. The imputed values for relationship to double-blind IP 
will be used for incidence summaries, while the actual values will be presented in data listings. 
18.9 
Character Values of Clinical Laboratory Variables  
If the reported value of a clinical laboratory endpoint cannot be used in a statistical analysis due 
to, for example, that a character string is reported for a numerical endpoint, the appropriately 
determined coded value will be used in the statistical analysis. However, the actual values as 
reported in the database will be presented in data listings. Coding of special character values will 
be determined before the database lock. 


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19. 
REFERENCES 
None 


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20. 
TABLE OF CONTENTS FOR TABLES, FIGURES AND LISTINGS 
Table 
Title 
Shire 
Std 
1.1.1.1 
Disposition in Part 1 (Safety Analysis Set 1 – Subjects Taking 
Lanthanum Carbonate) 
 
Y 
1.1.1.2 
Disposition in Part 1 by Age Group (Safety Analysis Set 1 – 
Subjects Taking Lanthanum Carbonate) 
Y 
1.1.2.1 
Disposition in Part 2 (Part 2a and Part 2b) (Safety Analysis Set 2) 
Y 
1.1.2.2 
Disposition in Part 2 (Part 2a and Part 2b) by Age Group (Safety 
Analysis Set 2) 
Y 
1.1.3.1 
Disposition in Part 2a (Treatment period 2), Part 2b and Part 3 
Combined (Lanthanum Carbonate Only) (Safety Analysis Set 2 – 
Subjects Taking Lanthanum Carbonate) 
Y 
1.1.3.2 
Disposition in Part 2a (Treatment period 2), Part 2b and Part 3 
Combined (Lanthanum Carbonate Only) by Age Group (Safety 
Analysis Set 2 – Subjects Taking Lanthanum Carbonate) 
Y 
1.1.4 
Enrolment Duration by Site and Country (Enrolled Set) 
Y 
1.2.1.1.1 
Demographic and Baseline Characteristics in Part 1 (Safety 
Analysis Set 1) 
Y 
1.2.1.1.2 
Demographic and Baseline Characteristics in Part 1 by Age Group 
(Safety Analysis Set 1) 
Y 
1.2.1.2.1 
Demographic and Baseline Characteristics in Part 2 (Part 2a and 
Part 2b) by Treatment Group (Safety Analysis Set 2) 
Y 
1.2.1.2.2 
Demographic and Baseline Characteristics in Part 2 (Part 2a and 
Part 2b) by Treatment and Age Group (Safety Analysis Set 2) 
Y 
1.2.1. 3.1 
Demographic and Baseline Characteristics in Part 2 (Part 2a and 
Part 2b) by Treatment Group (Full Analysis Set) 
Y 
1.2.1.3.2 
Demographic and Baseline Characteristics in Part 2 (Part 2a and 
Part 2b) by Treatment and Age Group (Full Analysis Set) 
Y 
1.2.1.4.1 
Demographic and Baseline Characteristics in Part 2 (Part 2a and 
Part 2b) by Treatment Group (Per-protocol Set 1) 
Y 
1.2.1.4.2 
Demographic and Baseline Characteristics in Part 2 (Part 2a and 
Part 2b) by Treatment and Age Group (Per-protocol Set 1) 
Y 
1.2.1.5.1 
Demographic and Baseline Characteristics in Part 2 (Part 2a and 
Part 2b) (Lanthanum Carbonate only) (Per-protocol Set 2) 
Y 
1.2.1.5.2 
Demographic and Baseline Characteristics in Part 2 (Part 2a and 
Part 2b) (Lanthanum Carbonate only) by Age Group (Per-protocol 
Set 2) 
Y 
1.2.1.6.1 
Demographic and Baseline Characteristics in Part 2 and 3 
Combined (Safety Completer Set) 
Y 
1.2.1.6.2 
Demographic and Baseline Characteristics in Part 2 and 3 
Combined by Age Group (Safety Completer Set – Subjects Taking 
Lanthanum Carbonate) 
Y 
1.2.1.7.1 
Demographic and Baseline Characteristics (Pharmacokinetic Set 1) Y 


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Table 
Title 
Shire 
Std 
1.2.1.7.2 
Demographic and Baseline Characteristics by Age Group 
(Pharmacokinetic Set 1) 
 
1.2.1.7.3 
Demographic and Baseline Characteristics (Pharmacokinetic Set 2) Y 
1.2.1.7.4 
Demographic and Baseline Characteristics by Age Group 
(Pharmacokinetic Set 2) 
 
1.2.2.1 
Renal History in Part 1 (Safety Analysis Set 1) 
Y 
1.2.2.2 
Renal History in Part 2 (Part 2a and Part 2b) (Safety Analysis Set 
2) 
Y 
1.2.2.3 
Renal History in Part 2 and Part 3 Combined (Safety Completer 2) 
Y 
1.3.1 
Prior Medications in Part 1 (Safety Analysis Set 1) 
Y 
1.3.2 
Prior Medications in Part 2 (Part 2a and Part 2b) (Safety Analysis 
Set 2) 
Y 
1.3.3   
Concomitant Medications in Part 1 (Safety Analysis Set 1) 
Y 
1.3.4   
Concomitant Medications in Part 2 (Part 2a and Part 2b) (Safety 
Analysis Set 2) 
Y 
1.3.5   
Concomitant Medications in Part 2 (Part 2a and Part 2b) by 
Treatment Group (Safety Analysis Set 2) 
Y 
1.3.6   
Concomitant Medications in Part 2 and 3 Combined (Lanthanum 
Carbonate only) (Safety Analysis Set 2) 
Y 
1.3.7   
Concomitant Medications in Part 2 and 3 Combined (Lanthanum 
Carbonate only) (Safety Completer Set)  
Y 
1.5.1 
Protocol Deviations in Part 1 by Site (Safety Analysis Set 1 – 
Subjects Taking Lanthanum Carbonate) 
Y 
1.5.2 
Protocol Deviations in Part 2 (Part 2a and Part 2b) by Site and 
Treatment Group (Safety Analysis Set 2) 
Y 
1.5.3 
Protocol Deviations in Part 2 and 3 (Lanthanum Carbonate only) 
Combined by Site (Safety Analysis Set 2) 
Y 
1.5.4 
Protocol Deviations in Part 2 and 3 (Lanthanum Carbonate only) 
Combined by Site (Safety Completer Set) 
Y 
3.1.1.1 
Summary of Percentage of Subjects achieving Age-specific 
KDOQI Serum Phosphorous Target following 8-weeks of 
Lanthanum Carbonate Treatment (Per-Protocol Set 2 – Subjects 
Taking Lanthanum Carbonate) 
Y 
3.1.1.2 
Summary of Percentage of Subjects achieving Age-specific 
KDOQI Serum Phosphorous Target following 8-weeks of 
Lanthanum Carbonate Treatment (Full Analysis Set) 
Y 
3.1.2.1 
Summary of Percentage of Subjects achieving Age-specific 
KDOQI Serum Phosphorous Target following 8-weeks of 
Treatment by Treatment Group (Per-Protocol Set 1) 
Y 
3.1.2.2 
Summary of Percentage of Subjects achieving Age-specific 
KDOQI Serum Phosphorous Target following 8-weeks of 
Treatment by Treatment Group (Full Analysis Set) 
Y 


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Table 
Title 
Shire 
Std 
3.1.3.1 
 Summary and Analysis of Change from Baseline in Serum 
Phosphorous in Part 2 (Part 2a and Part 2b) by Treatment Group 
(Per-protocol Set 1) 
Y 
3.1.3.2 
Summary and Analysis of Change from Baseline in Calcium in 
Part 2 by Treatment Group (Per-protocol Set 1) 
Y 
3.1.3.3 
Summary and Analysis of Change from Baseline in Calcium-
Phosphorous Product in Part 2 (Part 2a and Part 2b) by Treatment 
Group (Per-protocol Set 1) 
Y 
3.1.3.4 
 Summary and Analysis of Change from Baseline in Serum 
Phosphorous in Part 2 (Part 2a and Part 2b) by Treatment Group 
(Full Analysis Set) 
Y 
3.1.3.5 
Summary and Analysis of Change from Baseline in Calcium in 
Part 2 by Treatment Group (Full Analysis Set) 
Y 
3.1.3.6 
Summary and Analysis of Change from Baseline in Calcium-
Phosphorous Product in Part 2 (Part 2a and Part 2b) by Treatment 
Group (Full Analysis Set) 
Y 
3.1.4.1 
Summary of Change from Baseline in Serum Phosphorous in Part 
2 and 3 Combined by Weeks of Treatment with Lanthanum 
Carbonate (Per-protocol Set 2) 
Y 
3.1.4.2 
Summary and Analysis of Change from Baseline in Serum 
Phosphorous in Part 2 and 3 Combined by Weeks of Treatment  
with Lanthanum Carbonate (Full Analysis Set) 
Y 
3.1.4.3 
Summary and Analysis of Change from Baseline in Calcium in 
Part 2 and 3 Combined by Weeks of Treatment with Lanthanum 
Carbonate (Per-protocol Set 2) 
Y 
3.1.4.4 
Summary and Analysis of Change from Baseline in Calcium in 
Part 2 and 3 Combined by Weeks of Treatment with Lanthanum 
Carbonate (Full Analysis Set)  
Y 
3.1.4.5 
Summary and Analysis of Change from Baseline in Calcium-
Phosphorous Product in Part 2 and 3 Combined by Weeks of 
Treatment with Lanthanum Carbonate (Per-protocol Set 2) 
Y 
3.1.4.6 
Summary and Analysis of Change from Baseline in Calcium-
Phosphorous Product in Part 2 and 3 Combined by Weeks of 
Treatment with Lanthanum Carbonate (Full Analysis Set) 
Y 
3.1.5.1 
Summary of Change from Baseline in Bone Alkaline Phosphatase 
in Part 2 and 3 Combined by Treatment Group (Parts 2a and 3) 
(Per-protocol Set 1) 
Y 
3.1.5.2 
Summary of Change from Baseline in Bone Alkaline Phosphatase 
in Part 2 and 3 Combined by Treatment Group (Parts 2a and 3) 
(Full Analysis Set) 
Y 
3.1.5.3 
Summary of Change from Baseline in Osteocalcin in Part 2 and 3 
Combined by Treatment Group (Parts 2a and 3) (Per-protocol Set 
1) 
Y 


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Table 
Title 
Shire 
Std 
3.1.5.4 
Summary of Change from Baseline in Osteocalcin in Part 2 and 3 
Combined by Treatment Group (Parts 2a and 3) (Full Analysis Set) 
Y 
3.1.5.5 
Summary of Change from Baseline in Tartrate-Resistant Acid 
Phosphatase in Part 2 and 3 Combined by Treatment Group (Parts 
2a and 3) (Per-protocol Set 1) 
Y 
3.1.5.6 
Summary of Change from Baseline in Tartrate-Resistant Acid 
Phosphatase in Part 2 and 3 Combined by Treatment Group (Parts 
2a and 3) (Full Analysis Set) 
Y 
3.1.5.7 
Summary of Change from Baseline in Fibroblast Growth Factor-23 
in Part 2 and 3 Combined by Treatment Group (Parts 2a and 3) 
(Per-protocol Set 1) 
Y 
3.1.5.8 
Summary of Change from Baseline in Fibroblast Growth Factor-23 
in Part 2 and 3 Combined by Treatment Group (Parts 2a and 3) 
(Full Analysis Set) 
Y 
3.1.5.9 
Summary of Change from Baseline in Parathyroid Hormone in Part 
2 and 3 Combined by Treatment Group (Parts 2a and 3) (Per-
protocol Set 1) 
Y 
3.1.5.10 
Summary of Change from Baseline in Parathyroid Hormone in Part 
2 and 3 Combined by Treatment Group (Parts 2a and 3) (Full 
Analysis Set) 
Y 
3.1.5.11 
Summary of Change from Baseline in Sclerostin in Part 2 and 3 
Combined by Treatment Group (Parts 2a and 3) (Per-protocol Set 
1) 
Y 
3.1.5.12 
Summary of Change from Baseline in Sclerostin in Part 2 and 3 
Combined by Treatment Group (Parts 2a and 3) (Full Analysis Set) 
Y 
3.1.5.13 
Summary of Change from Baseline in Fetuin-A in Part 2 and 3 
Combined by Treatment Group (Parts 2a and 3) (Per-protocol Set 
1) 
Y 
3.1.5.14 
Summary of Change from Baseline in Fetuin-A in Part 2 and 3 
Combined by Treatment Group (Parts 2a and 3) (Full Analysis Set) 
Y 
3.2.5.1 
Summary of Change from Baseline in Bone Alkaline Phosphatase 
in Part 2 and 3 Combined for Lanthanum Carbonate (Parts 2b and 
3) (Per-protocol Set 2) 
Y 
3.2.5.2 
Summary of Change from Baseline in Bone Alkaline Phosphatase 
in Part 2 and 3 Combined for Lanthanum Carbonate (Parts 2b and 
3) (Full Analysis Set) 
Y 
3.2.5.3 
Summary of Change from Baseline in Osteocalcin in Part 2 and 3 
Combined for Lanthanum Carbonate (Parts 2b and 3) (Per-protocol 
Set 2) 
Y 
3.2.5.4 
Summary of Change from Baseline in Osteocalcin in Part 2 and 3 
Combined for Lanthanum Carbonate (Parts 2b and 3) (Full 
Analysis Set) 
Y 


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Table 
Title 
Shire 
Std 
3.2.5.5 
Summary of Change from Baseline in Tartrate-Resistant Acid 
Phosphatase in Part 2 and 3 Combined for Lanthanum Carbonate 
(Parts 2b and 3) (Per-protocol Set 2) 
Y 
3.2.5.6 
Summary of Change from Baseline in Tartrate-Resistant Acid 
Phosphatase in Part 2 and 3 Combined for Lanthanum Carbonate 
(Parts 2b and 3) (Full Analysis Set) 
Y 
3.2.5.7 
Summary of Change from Baseline in Fibroblast Growth Factor-23 
in Part 2 and 3 Combined for Lanthanum Carbonate (Parts 2b and 
3) (Per-protocol Set 2) 
Y 
3.2.5.8 
Summary of Change from Baseline in Fibroblast Growth Factor-23 
in Part 2 and 3 Combined for Lanthanum Carbonate (Parts 2b and 
3) (Full Analysis Set) 
Y 
3.2.5.9 
Summary of Change from Baseline in Parathyroid Hormone in Part 
2 and 3 Combined for Lanthanum Carbonate (Parts 2b and 3) (Per-
protocol Set 2) 
Y 
3.2.5.10 
Summary of Change from Baseline in Parathyroid Hormone in Part 
2 and 3 Combined for Lanthanum Carbonate (Parts 2b and 3) (Full 
Analysis Set) 
Y 
3.2.5.11 
Summary of Change from Baseline in Sclerostin in Part 2 and 3 
Combined for Lanthanum Carbonate (Parts 2b and 3) (Per-protocol 
Set 2) 
Y 
3.2.5.12 
Summary of Change from Baseline in Sclerostin in Part 2 and 3 
Combined for Lanthanum Carbonate (Parts 2b and 3) (Full 
Analysis Set) 
Y 
3.2.5.13 
Summary of Change from Baseline in Fetuin-A in Part 2 and 3 
Combined for Lanthanum Carbonate (Parts 2b and 3) (Per-protocol 
Set 2) 
Y 
3.2.5.14 
Summary of Change from Baseline in Fetuin-A in Part 2 and 3 
Combined for Lanthanum Carbonate (Parts 2b and 3) (Full 
Analysis Set) 
Y 
3.1.6.1 
Summary of Change from Baseline in Height (cm) in Part 2 and 3 
Combined by Treatment Group (Parts 2a and 3) (Per-protocol Set 
1) 
Y 
3.1.6.2 
Summary of Change from Baseline in Height (cm) in Part 2 and 3 
Combined by Treatment Group (Parts 2a and 3) (Full Analysis Set) 
Y 
3.1.6.3 
Summary of Change from Baseline in Weight (kg) in Part 2 and 3 
Combined by Treatment Group (Parts 2a and 3) (Per-protocol Set 
1) 
Y 
3.1.6.4 
Summary of Change from Baseline in Weight (kg) in Part 2 and 3 
Combined by Treatment Group (Parts 2a and 3) (Full Analysis Set) 
Y 
3.1.7.1 
Summary of Change from Baseline in Height (cm) in Part 2 and 3 
Combined for Lanthanum Carbonate (Parts 2b and 3) (Per-protocol 
Set 2) 
Y 


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Table 
Title 
Shire 
Std 
3.1.7.2 
Summary of Change from Baseline in Height (cm) in Part 2 and 3 
Combined for Lanthanum Carbonate (Parts 2b and 3) (Full 
Analysis Set)  
Y 
3.1.7.3 
Summary of Change from Baseline in Weight (kg) in Part 2 and 3 
Combined for Lanthanum Carbonate (Parts 2b and 3) (Per-protocol 
Set 2) 
Y 
3.1.7.4 
Summary of Change from Baseline in Weight (kg) in Part 2 and 3 
Combined for Lanthanum Carbonate (Parts 2b and 3) (Full 
Analysis Set) 
Y 
3.1.8.1 
Summary of Percentage of Subjects achieving Age-specific 
KDOQI Serum Phosphorous Target by Weeks of Treatment with 
Lanthanum Carbonate (Per-protocol Set 2) 
 
3.1.8.2 
Summary of Percentage of Subjects achieving Age-specific 
KDOQI Serum Phosphorous Target by Weeks of Treatment with 
Lanthanum Carbonate (Full Analysis Set) 
 
4.1.1 
Investigational Product Exposure in Part 2 (Part 2a and Part 2b) by 
Treatment Group (Safety Analysis Set 2) 
Y 
4.1.2 
Investigational Product Exposure in Part 2 and 3 Combined 
(Lanthanum Carbonate only) (Safety Analysis Set 2) 
Y 
4.1.3 
Investigational Product Exposure in Part 2 and 3 Combined 
(Lanthanum Carbonate only) (Safety Completer Set) 
Y 
4.2.1.1 
Overall Treatment-emergent Adverse Events (TEAEs) in Part 1 
(Safety Analysis Set 1 – Subjects Taking Lanthanum Carbonate) 
Y 
4.2.1.2 
Overall Treatment-emergent Adverse Events (TEAEs) in Part 1 by 
Age Group (Safety Analysis Set 1 – Subjects Taking Lanthanum 
Carbonate) 
Y 
4.2.1.3 
Overall Treatment-emergent Adverse Events (TEAEs) in Part 2 
(Part 2a and Part 2b) by Treatment Group (Safety Analysis Set 2) 
Y 
4.2.1.4 
Overall Treatment-emergent Adverse Events (TEAEs) in Part 2 
(Part 2a and Part 2b) by Treatment and Age Group (Safety 
Analysis Set 2) 
Y 
4.2.1.5 
Overall Treatment-emergent Adverse Events (TEAEs) in Part 2 
and 3 Combined for Lanthanum Carbonate (Safety Analysis Set 2 
– Subjects Taking Lanthanum Carbonate) 
Y 
4.2.1.6 
Overall Treatment-emergent Adverse Events (TEAEs) in Part 2 
and 3 Combined by Age Group (Safety Analysis Set 2 – Subjects 
Taking Lanthanum Carbonate) 
Y 
4.2.1.7 
Overall Treatment-emergent Adverse Events (TEAEs) in Part 2 
and 3 Combined (Safety Completer Set – Subjects Taking 
Lanthanum Carbonate) 
Y 
4.2.1.8 
Overall Treatment-emergent Adverse Events (TEAEs) in Part 2 
and 3 Combined by Age Group (Safety Completer Set – Subjects 
Taking Lanthanum Carbonate) 
Y 


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Table 
Title 
Shire 
Std 
4.2.2.1 
Treatment-emergent Adverse Events by System Organ Class and 
Preferred Term in Part 1 (Safety Analysis Set 1 – Subjects Taking 
Lanthanum Carbonate) 
Y 
4.2.2.2 
Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and Treatment Group in Part 2 (Part 2a and Part 
2b) (Safety Analysis Set 2) 
Y 
4.2.2.3 
Treatment-emergent Adverse Events by System Organ Class and 
Preferred Term in Part 2 and 3 Combined for Lanthanum 
Carbonate (Safety Analysis Set 2 – Subjects Taking Lanthanum 
Carbonate) 
Y 
4.2.2.4 
Treatment-emergent Adverse Events by System Organ Class and 
Preferred Term in Part 2 and 3 Combined for Lanthanum 
Carbonate (Safety Completer Set – Subjects Taking Lanthanum 
Carbonate) 
Y 
4.3.1.1 
Treatment-emergent Adverse Events by Maximum Severity, 
System Organ Class and Preferred Term in Part 1 (Safety Analysis 
Set 1 – Subjects Taking Lanthanum Carbonate) 
Y 
4.3.1.2 
Treatment-emergent Adverse Events by Maximum Severity, 
System Organ Class, Preferred Term and Treatment Group in Part 
2 (Part 2a and Part 2b) (Safety Analysis Set 2) 
Y 
4.3.1.3 
Treatment-emergent Adverse Events by Maximum Severity, 
System Organ Class and Preferred Term in Part 2 and 3 Combined 
for Lanthanum Carbonate (Safety Analysis Set 2 – Subjects Taking 
Lanthanum Carbonate)) 
Y 
4.3.1.4 
Treatment-emergent Adverse Events by Maximum Severity, 
System Organ Class and Preferred Term in Part 2 and 3 Combined 
for Lanthanum Carbonate (Safety Completer Set – Subjects Taking 
Lanthanum Carbonate) 
Y 
4.3.2.1 
Treatment-emergent Adverse Events Considered Related to 
Investigational Product by System Organ Class and Preferred Term 
in Part 1 (Safety Analysis Set 1 – Subjects Taking Lanthanum 
Carbonate) 
Y 
4.3.2.2 
Treatment-emergent Adverse Events Considered Related to 
Investigational Product by System Organ Class, Preferred Term 
and Treatment Group in Part 2 (Part 2a and Part 2b) (Safety 
Analysis Set 2) 
Y 
4.3.2.3 
Treatment-emergent Adverse Events Considered Related to 
Investigational Product by System Organ Class and Preferred Term 
in Part 2 and 3 Combined for Lanthanum Carbonate (Safety 
Analysis Set 2 – Subjects Taking Lanthanum Carbonate) 
Y 
4.3.2.4 
Treatment-emergent Adverse Events Considered Related to 
Investigational Product by System Organ Class and Preferred Term 
in Part 2 and 3 Combined for Lanthanum Carbonate (Safety 
Completer Set – Subjects Taking Lanthanum Carbonate)  
Y 


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Table 
Title 
Shire 
Std 
4.4.1.1 
Treatment-emergent Serious Adverse Events by System Organ 
Class and Preferred Term in Part 1 (Safety Analysis Set 1 – 
Subjects Taking Lanthanum Carbonate) 
Y 
4.4.1.2 
Treatment-emergent Serious Adverse Events by System Organ 
Class, Preferred Term and Treatment Group in Part 2 (Part 2a and 
Part 2b) (Safety Analysis Set 2) 
Y 
4.4.1.3 
Treatment-emergent Serious Adverse Events by System Organ 
Class and Preferred Term in Part 2 and 3 Combined for Lanthanum 
Carbonate (Safety Analysis Set 2 – Subjects Taking Lanthanum 
Carbonate) 
Y 
4.4.1.4 
Treatment-emergent Serious Adverse Events by System Organ 
Class and Preferred Term in Part 2 and 3 Combined for Lanthanum 
Carbonate (Safety Completer Set – Subjects Taking Lanthanum 
Carbonate) 
Y 
4.4.2.1 
Deaths by System Organ Class and Preferred Term in Part 1 
(Safety Analysis Set 1 – Subjects Taking Lanthanum Carbonate) 
Y 
4.4.2.2 
Deaths by System Organ Class, Preferred Term and Treatment 
Group in Part 2 (Part 2a and Part 2b) (Safety Analysis Set 2) 
Y 
4.4.2.3 
Deaths by System Organ Class and Preferred Term in Part 2 and 3 
Combined for Lanthanum Carbonate (Safety Analysis Set 2 – 
Subjects Taking Lanthanum Carbonate) 
Y 
4.4.2.4 
Deaths by System Organ Class and Preferred Term in Part 2 and 3 
Combined for Lanthanum Carbonate (Safety Completer Set – 
Subjects Taking Lanthanum Carbonate) 
Y 
4.4.3.1 
Treatment-emergent Adverse Events leading to study withdrawal 
by System Organ Class and Preferred Term in Part 1 (Safety 
Analysis Set 1 – Subjects Taking Lanthanum Carbonate) 
Y 
4.4.3.2 
Treatment-emergent Adverse Events leading to study withdrawal 
by System Organ Class, Preferred Term and Treatment Group in 
Part 2 (Part 2a and Part 2b) (Safety Analysis Set 2) 
Y 
4.4.3.3 
Treatment-emergent Adverse Events leading to study withdrawal 
by System Organ Class and Preferred Term in Part 2 and 3 
Combined for Lanthanum Carbonate (Safety Analysis Set 2 – 
Subjects Taking Lanthanum Carbonate) 
Y 
4.4.3.4 
Treatment-emergent Adverse Events leading to study withdrawal 
by System Organ Class and Preferred Term in Part 2 and 3 
Combined for Lanthanum Carbonate (Safety Completer Set – 
Subjects Taking Lanthanum Carbonate) 
Y 
4.5.1.1 
Treatment-emergent Bone Disease Adverse Events of Special 
Interest by System Organ Class and Preferred Term in Part 1 
(Safety Analysis Set 1 – Subjects Taking Lanthanum Carbonate) 
Y 
4.5.1.2 
Treatment-emergent Bone Disease Adverse Events of Special 
Interest by System Organ Class, Preferred Term and Treatment 
Group in Part 2 (Part 2a and Part 2b) (Safety Analysis Set 2) 
Y 


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Table 
Title 
Shire 
Std 
4.5.1.3 
Treatment-emergent Bone Disease Adverse Events of Special 
Interest by System Organ Class, Preferred Term in Part 2 and 3 
Combined for Lanthanum Carbonate (Safety Analysis Set 2 – 
Subjects Taking Lanthanum Carbonate) 
Y 
4.5.1.4 
Treatment-emergent Bone Disease Adverse Events of Special 
Interest by System Organ Class, Preferred Term in Part 2 and 3 
Combined for Lanthanum Carbonate (Safety Completer Set – 
Subjects Taking Lanthanum Carbonate) 
Y 
4.5.2.1 
Treatment-emergent Bone Disease Adverse Events of Special 
Interest by Sex and Age Group in Part 1 (Safety Analysis Set 1) 
Y 
4.5.2.2 
Treatment-emergent Bone Disease Adverse Events of Special 
Interest by Sex and Age Group and Treatment Group in Part 2 
(Part 2a and Part 2b) (Safety Analysis Set 2) 
Y 
4.5.2.3 
Treatment-emergent Bone Disease Adverse Events of Special 
Interest by Sex and Age Group in Part 2 and 3 Combined for 
Lanthanum Carbonate (Safety Analysis Set 2 – Subjects Taking 
Lanthanum Carbonate) 
Y 
4.5.2.4 
Treatment-emergent Bone Disease Adverse Events of Special 
Interest by Sex and Age Group in Part 2 and 3 Combined for 
Lanthanum Carbonate (Safety Completer Set – Subjects Taking 
Lanthanum Carbonate) 
Y 
4.6.1.1 
Quantitative Clinical Laboratory Results in Part 1: Biochemistry 
(Safety Analysis Set 1 – Subjects Taking Lanthanum Carbonate) 
Y 
4.6.1.2 
Quantitative Clinical Laboratory Results in Part 1: Haematology 
(Safety Analysis Set 1 – Subjects Taking Lanthanum Carbonate) 
Y 
4.6.1.3 
Quantitative Clinical Laboratory Results in Part 1: Biochemical 
Bone Markers (Safety Analysis Set 1 – Subjects Taking 
Lanthanum Carbonate) 
Y 
4.6.2.1 
Quantitative Clinical Laboratory Results in Part 2 and 3 Combined 
by Treatment Group: Biochemistry (Safety Analysis Set 2) 
Y 
4.6.2.2 
Quantitative Clinical Laboratory Results in Part 2 and 3 Combined 
by Treatment Group: Haematology (Safety Analysis Set 2) 
Y 
4.6.2.3 
Quantitative Clinical Laboratory Results in Part 2 and 3 Combined 
by Treatment Group: Biochemical Bone Markers (Safety Analysis 
Set 2) 
Y 
4.6.2.4 
Quantitative Clinical Laboratory Results in Part 2 and 3 Combined 
by Treatment Group for Lanthanum Carbonate: Biochemistry 
(Safety Completer Set – Subjects Taking Lanthanum Carbonate) 
Y 
4.6.2.5 
Quantitative Clinical Laboratory Results in Part 2 and 3 Combined 
by Treatment Group for Lanthanum Carbonate: Haematology 
(Safety Completer Set – Subjects Taking Lanthanum Carbonate) 
Y 


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Table 
Title 
Shire 
Std 
4.6.2.6 
Quantitative Clinical Laboratory Results in Part 2 and 3 Combined 
by Treatment Group for Lanthanum Carbonate: Biochemical Bone 
Markers (Safety Completer Set – Subjects Taking Lanthanum 
Carbonate) 
Y 
4.6.3.1 
Shift from Baseline in Clinical Laboratory Results in Part 2 and 3 
Combined by Treatment Group: Biochemistry (Safety Analysis Set 
2) 
Y 
4.6.3.2 
Shift from Baseline in Clinical Laboratory Results in Part 2 and 3 
Combined by Treatment Group: Haematology (Safety Analysis Set 
2) 
Y 
4.6.3.3   
Shift from Baseline in Clinical Laboratory Results in Part 2 and 3 
Combined by Treatment Group: Biochemical Bone Markers 
(Safety Analysis Set 2) 
Y 
4.6.4.1 
Normal Ranges: Biochemistry 
Y 
4.6.4.2 
Normal Ranges: Haematology 
Y 
4.6.4.3 
Normal Ranges: Biochemical Bone Markers 
Y 
4.7.1 
Actual Values and Change from Baseline in Vital Signs in Part 1 
(Safety Analysis Set 1 – Subjects Taking Lanthanum Carbonate) 
Y 
4.7.2 
Actual Values and Change from Baseline in Vital Signs in Part 2 
and 3 Combined by Treatment Group (Safety Analysis Set 2) 
Y 
4.7.3 
Actual Values and Change from Baseline in Vital Signs in Part 2 
and 3 Combined for Lanthanum Carbonate (Safety Analysis Set 2 
– Subjects Taking Lanthanum Carbonate) 
Y 
4.7.4 
Actual Values and Change from Baseline in Vital Signs in Part 2 
and 3 Combined for Lanthanum Carbonate (Safety Completer Set 
– Subjects Taking Lanthanum Carbonate) 
Y 
4.8.1 
ECG Interpretation in Part 2 and 3 Combined by Timepoint for 
Lanthanum Carbonate only (Parts 2a and 3) (Safety Analysis Set 2)  
Y 
4.8.2 
ECG Interpretation in Part 2 and 3 Combined by Timepoint for 
Lanthanum Carbonate only (Parts 2b and 3) (Safety Analysis Set 
2) 
Y 
4.8.3 
ECG Interpretation in Part 2 and 3 Combined by Timepoint for 
Lanthanum Carbonate only (Parts 2a and 3) (Safety Completer Set)  
Y 
4.8.4 
ECG Interpretation in Part 2 and 3 Combined by Timepoint for 
Lanthanum Carbonate only (Parts 2b and 3) (Safety Completer Set) 
Y 
4.8.5 
Shift from Baseline to Post-Baseline Timepoint in Qualitative ECG 
Results in Part 2 and 3 Combined for Lanthanum Carbonate only 
(Parts 2a and 3) (Safety Analysis Set 2) 
Y 
4.8.6 
Shift from Baseline to Post-Baseline Timepoint in Qualitative ECG 
Results in Part 2 and 3 Combined for Lanthanum Carbonate only 
(Parts 2b and 3) (Safety Analysis Set 2) 
Y 


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Table 
Title 
Shire 
Std 
4.8.7 
Shift from Baseline to Post-Baseline Timepoint in Qualitative ECG 
Results in Part 2 and 3 Combined for Lanthanum Carbonate only 
(Parts 2a and 3) (Safety Completer Set) 
Y 
4.8.8 
Shift from Baseline to Post-Baseline Timepoint in Qualitative ECG 
Results in Part 2 and 3 Combined for Lanthanum Carbonate only 
(Parts 2b and 3) (Safety Completer Set) 
Y 
 
Figure 
Title 
Shire 
Std 
3.1.3.1 
Bar Chart of Mean Change from Baseline and 95% CI for Serum 
Phosphorous after 8-weeks of Treatment in Part 2 (Part 2a and Part 
2b) by Treatment Group (Per-protocol Set 1) 
 
3.1.3.2 
Bar Chart of Mean Change from Baseline and 95% CI for Calcium 
after 8-weeks of Treatment in Part 2 (Part 2a and Part 2b) by 
Treatment Group (Per-protocol Set 1) 
 
3.1.3.3 
Bar Chart of Mean Change from Baseline and 95% CI for 
Calcium-Phosphorous Product after 8-weeks of Treatment in Part 2 
(Part 2a and Part 2b) by Treatment Group (Per-protocol Set 1) 
 
3.1.4.1 
Line Graph of Mean Change from Baseline and 95% CI in Serum 
Phosphorous in Part 2 and 3 Combined by Weeks of Treatment 
with Lanthanum Carbonate (Per-protocol Set 2) 
 
3.1.4.2 
Line Graph of Mean Change from Baseline and 95% CI in Serum 
Phosphorous in Part 2 and 3 Combined by Weeks of Treatment 
with Lanthanum Carbonate (Full Analysis Set) 
 
3.1.4.3 
Line Graph of Mean Change from Baseline and 95% CI in 
Calcium in Part 2 and 3 Combined by Weeks of Treatment with 
Lanthanum Carbonate (Per-protocol Set 2) 
 
3.1.4.4 
Line Graph of Mean Change from Baseline and 95% CI in 
Calcium in Part 2 and 3 Combined by Weeks of Treatment with 
Lanthanum Carbonate (Full Analysis Set) 
 
3.1.4.5 
Line Graph of Mean Change from Baseline and 95% CI in 
Calcium-Phosphorous Product in Part 2 and 3 Combined by Weeks 
of Treatment with Lanthanum Carbonate (Per-protocol Set 2) 
 
3.1.4.6 
Line Graph of Mean Change from Baseline and 95% CI in 
Calcium-Phosphorous Product in Part 2 and 3 Combined by Weeks 
of Treatment with Lanthanum Carbonate (Full Analysis Set) 
 
 
Listing 
Title 
Shire 
Std 
 
Listing of Subject Data for Screen Failures 
Y 
1.1 
Subject Disposition (Enrolled Set) 
Y 
1.2 
Subjects Who Terminated from the Study (Enrolled Set) 
Y 


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Listing 
Title 
Shire 
Std 
1.3 
Study Analysis Set Classification (Enrolled Set) 
Y 
2.1.1 
Listing of Protocol Deviations (Enrolled Set) 
Y 
2.1.2 
Listing of Evaluable Subjects (Full Analysis Set) 
 
4.1 
Subject Demographic and Baseline Characteristics (Enrolled 
Subjects) 
Y 
4.2 
Renal History (Enrolled Subjects) 
Y 
4.3 
Medical History (Enrolled Set) 
Y 
4.4 
Prior and Concomitant Medications (Enrolled Set) 
Y 
5.1.1 
Investigational Product Accountability in Part 1 (Safety Analysis 
Set 1) 
Y 
5.1.2 
Investigational Product Accountability in Part 2 and 3 Combined 
(Safety Analysis Set 2) 
Y 
5.1.3 
Investigational Product Exposure in Part 2 and 3 Combined (Safety 
Completer Set) 
Y 
5.2 
Pharmacokinetic Blood Draw Times (Enrolled Set) 
Y 
6.1 
KDOQI Serum Phosphorous Target Achievement (Enrolled Set) 
Y 
7.1 
Adverse Events (Enrolled Set) 
Y 
7.2 
Serious Adverse Events (Enrolled Set) 
Y 
7.3 
Adverse Events Related to Investigational Product (Enrolled Set) 
Y 
7.4 
Adverse Events Leading to Study Withdrawal (Enrolled Set) 
Y 
7.5 
Adverse Events Leading to Death (Enrolled Set) 
Y 
7.6 
Subjects Reporting Bone Disease Treatment-emergent Adverse 
Events (Enrolled Set) 
Y 
8.1.1 
Clinical Laboratory Sample Collection and Results for Pregnancy 
(Enrolled Set) 
Y 
8.1.2 
Clinical Laboratory Test Results (Enrolled Set) 
Y 
8.2.1 
Vital Signs (Enrolled Set) 
Y 
8.3.1 
12-lead ECG Investigator’s Interpretation (Enrolled Set) 
Y 
 


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21. 
APPENDIX 
21.1 
Evaluable Subject Determination Plan 
1. Definition of Evaluable Subject in Per-Protocol Analysis Set 2 for Primary Endpoint 
Assessment 
 
For the purposes of the primary endpoint assessment, at least 32 subjects, who complete 8 weeks 
of treatment with lanthanum carbonate and are assessable for baseline and 8 weeks serum 
phosphate level, will be required. Approximately 65 subjects may be enrolled to acquire at least 
32 evaluable subjects. In order to prevent over enrolment, subjects’ evaluability status will be 
assessed and confirmation of achieving at least 32 evaluable subjects will be performed.  
The criteria that subjects must meet to determine eligibility include: 
• Aged 10 years to <18 years of age at the time of consent 
• Confirmed serum phosphorus level drawn prior to commencing Lanthanum therapy in 
Part 2 or Part 3 of the clinical trial (Baseline Phosphorus) 
o Subjects who participated in Part 2a and received calcium carbonate, baseline 
serum phosphorus must be drawn after a washout period of up to 3 weeks 
• Baseline serum phosphorus levels above KDOQI recommendations: 
o Age <12 years: Serum phosphorus >6.0mg/dL (1.94mmol/L) 
o Age ≥12 years and older: Serum phosphorus >5.5mg/dL (1.78mmol/L) 
• Demonstration of 8 weeks of Lanthanum therapy 
• Confirmed serum phosphorus level after 8 weeks of Lanthanum therapy 
• Both baseline and 8 weeks serum phosphorus levels are assessed at the same lab (central 
or local lab) 
• Subjects, who received lanthanum carbonate therapy in part 2 or part 3 but did not 
receive 8 weeks of continuous treatment because of temporary dose interruption due to 
hypophosphatemia (protocol Appendix 2: guidelines for phosphorus and calcium levels), 
will be considered evaluable, if they satisfy other criteria mentioned above (eg baseline 
phosphate > KDOQI target). 
1.1   Data Variable Requirements 
 
I. 
Subject Age 
 
Age is calculated using Informed Consent Date minus Birth date. However, birth date may 
not be available in all cases (due to subject privacy concerns). When instead of birth date 
only birth year is entered in the clinical database, age will be imputed using June 30th of the 
year of birth. However, if the age falls below 10 years old or over 18 years old and inclusion 
criteria number 01 is met, we will consider the age-categories to confirm whether the age-
criterion was met. KDOQI Target: Created based on age condition:  


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• If DM.AGE <12 years, then KDOQI Target = 1.94mmol/L 
• If DM.AGE ≥12 years, then KDOQI Target = 1.78mmol/L 
 
II. 
First Lanthanum Carbonate Medication  
Time of First Exposure to Treatment (Lanthanum Carbonate) in either Part 2 or Part 3 of the 
study. 
III. 
Baseline Phosphate Level: 
Procedural Steps:  
i) Obtain the baseline lab visit (from central lab) for each individual subject and choose 
the lab visit that is closest to the first lanthanum carbonate administration date; and 
ii) Obtain the baseline lab visit (from local lab, whenever available) for each individual 
subject and choose the lab visit that is closest to the first lanthanum carbonate 
administration date.  This data will be used further when there is no central lab 
baseline Phosphate result (see below)l lab result. 
 
IV. 
Post 8-week Phosphate Level: 
 
i) Subset week 8 central lab data from Part 2 or Part 3 central lab data, selecting the on-
treatment record closest to target day 56/week 8 (with +/-7 days window). Target day 
is created using the first dose of Lanthanum in Part 2 or Part 3 (if Part 2 first 
Lanthanum dose is missing). 
ii)  Subset week 8 local lab data from Part 2 or Part 3 local lab data, select the on-
treatment record closest to target day 56/week 8 (with +/-7 days window). Target day 
is created using the first dose of Lanthanum in Part 2 or Part 3 (if Part 2 first 
Lanthanum dose is missing). 
iii) For subjects who experienced hypophosphatemia, that lead to temporary interruption 
or discontinuation of treatment before the 8 weeks phosphate assessment they will be 
considered compliant with the 8 weeks treatment requirement.  
In the case of missing central lab data, local lab data will be used.  Serum phosphorous 
assessments must come from a homogeneous source ie, from either central or local lab for 
baseline and following weeks 8 of lanthanum treatment, respectively, within subject.  
If baseline phosphorus value from central lab is available and above the KDOQI criteria, but the 
central lab 8-week value is missing, then local lab data (baseline and day 56/week 8 phosphorus 
results) can be used.   
NB. Both the baseline and day 56/week 8 phosphorus results must come from a single source 
(both central or both local).  


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If baseline phosphorus value from central lab is available and not above the KDOQI criteria, then 
the subject is not evaluable even if the subject has local lab values for both baseline and 8-week 
and the baseline value satisfies KDOQI criteria. Evaluability based on local lab is assessed only 
if central laboratory data is missing. 
1.2 Data Sources for Assessment of Evaluability 
 
Evaluability Assessment will be performed on the subject level analysis data set (one record per 
subject) created through the steps described in section V.  
Evaluability is determined if the following conditions are met 
1. If subject is not a screen failure 
2. Baseline Phosphate data is not missing, and baseline phosphate is ≥ KDOQI Target 
3. Week 8 Phosphate data is not missing  
OR 
Phosphate value missing at Week 8, but early termination shows hypophosphatemia 
(Protocol Appendix 2: guidelines for phosphorus and calcium levels). 
2. Definition of Evaluable Subjects in Per-Protocol Analysis Set 1 for Primary 
Endpoint Assessment 
 
Evaluable subjects in per-protocol 1 population will be defined similar to evaluable subject in 
per-protocol 2 population, see above, with subjects meeting the following criteria to be deemed 
eligible for the per-protocol 1 population: 
• Aged 10 years to <18 years of age at the time of consent 
• Confirmed serum phosphorus level at study entry and between the calcium carbonate 
treatment and lanthanum carbonate treatment at Visit 2.4 or unscheduled visits in part 2 
(Baseline Phosphorus) 
o Subjects who participated in Part 2a and received calcium carbonate, baseline 
serum phosphorus must be drawn after a washout period of up to 3 weeks 
• Baseline serum phosphorus levels above KDOQI recommendations: 
o Age <12 years: Serum phosphorus >6.0mg/dL (1.94mmol/L) 
o Age ≥12 years and older: Serum phosphorus >5.5mg/dL (1.78mmol/L) 
• Demonstration of 8 weeks of Calcium Carbonate therapy followed by 8 weeks of 
Lanthanum therapy 
• Confirmed serum phosphorus level after 8 weeks of Calcium Carbonate therapy followed 
by 8 weeks of Lanthanum therapy 
• Both baseline and 8 weeks serum phosphorus levels are assessed at the same lab (central 
or local lab) 


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14 February 2019 
Protocol SPD405-207 
 
Version 3.0 
Page 70 of 70 
• Subjects, who received Calcium Carbonate and Lanthanum Carbonate therapy in part 2 
or part 3 but did not receive 8 weeks of continuous treatment because of temporary dose 
interruption due to hypophosphatemia (protocol Appendix 2: guidelines for phosphorus 
and calcium levels), will be considered evaluable, if they qualify other criteria mentioned 
above (eg baseline phosphate > KDOQI target).