Clinical trial NCT03258762
Conditions: Toxoplasmosis
Keywords: Japanese Caucasian pharmacokinetics pyrimethamine toxoplasmosis
Sponsor: GlaxoSmithKline
Start date: 2017-09-25; Completion date: 2017-11-19
Enrollment: 14 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Pyrimethamine in combination with a sulphonamide is known to be effective in the treatment of toxoplasmosis. However, Pyrimethamine has not been approved by the Japanese regulatory body (Pharmaceutical and Medical Devices Agency \[PMDA\]/ Ministry of Health, Labor and Welfare \[MHLW\]). The pharmacokinetics (PK) of Pyrimethamine has been investigated following administration of Sulfadoxine/Pyrimethamine tablet in healthy Japanese subjects. However, the study did not provide sufficient information for approval of Pyrimethamine in Japan; hence, PMDA has requested confirmation of the PK of Pyrimethamine in another PK study in Japanese and Caucasian healthy subjects. This study will be a single centre, open-label, parallel-group, single oral dose study to evaluate the PK, safety and tolerability of Pyrimethamine in healthy Japanese and Caucasian male subjects. Subjects will undergo a screening visit within 30 days prior to first dose of the study drug. On Day 1, subjects will be administered a single oral dose of pyrimethamine 50 milligrams (mg) along with calcium folinate 15 mg after an overnight fast of at least 10 hours. Subjects will continue to receive calcium folinate once daily until Day 8 of the treatment period. Blood sampling for PK analysis and safety assessments will be performed prior to dosing and over 22 days after dosing. Each subject will participate in the study for approximately 2 months from screening to follow-up.

Detailed description:

Arms: arm 1: Healthy Japanese male subjects will receive a single oral dose of Pyrimethamine 50 mg in the fasted state co-administered with calcium folinate 15 mg on Day 1. Oral calcium folinate will be administered once daily until Day 8. Blood samples for PK analysis will be collected prior to administering first dose of Pyrimethamine and over 22 days post dose. Each subject will participate in the study for a duration of approximately 2 months from screening to follow-up. arm 2: Healthy Caucasian male subjects will receive a single oral dose of Pyrimethamine 50 mg in the fasted state co-administered with calcium folinate 15 mg on Day 1. Oral calcium folinate will be administered once daily until Day 8. Blood samples for PK analysis will be collected prior to administering first dose of Pyrimethamine and over 22 days post dose. Each subject will participate in the study for a duration of approximately 2 months from screening to follow-up.
Interventions: intervention 1: Pyrimethamine intervention 2: Calcium folinate
Intervention descriptions: intervention 1: Pyrimethamine will be available as 25 mg tablets. Subjects will be orally administered two pyrimethamine tablets on Day 1 in a fasted condition with 240 mL of water. intervention 2: Calcium folinate will be available as 5 mg tablets. Subjects will be orally administered three calcium folinate tablets on Day 1 along with pyrimethamine followed by once daily administration of calcium folinate until Day 8. Each administration will be with 240 mL water.

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE
Protocol Title: A single centre, open-label, parallel-group, single oral dose study to 
evaluate the pharmacokinetics, safety and tolerability of Pyrimethamine in healthy 
Japanese and Caucasian male subjects
Protocol Number: 204678
Short Title: Phase I study of Pyrimethamine in healthy Japanese and Caucasian Subjects
Compound Number:
GR99352
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information:
GlaxoSmithKline K.K. 
6-15, Sendagaya 4-chome Shibuya-ku,
Tokyo 151-8566 
Japan
Regulatory Agency Identifying Number(s): N/A
Approval Date: 19-JULY-2017
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.
Unauthorised copying or use of this information is prohibited.
PPD


PPD
PPD
PPD


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TABLE OF CONTENTS
PAGE
1.
SYNOPSIS...............................................................................................................5
2.
SCHEDULE OF ACTIVITIES (SOA).........................................................................7
3.
INTRODUCTION......................................................................................................8
3.1.
Study Rationale ............................................................................................8
3.2.
Background ..................................................................................................8
3.3.
Benefit/Risk Assessment ..............................................................................9
3.3.1.
Risk Assessment ...........................................................................9
3.3.2.
Benefit Assessment.....................................................................10
3.3.3.
Overall Benefit: Risk Conclusion..................................................10
4.
OBJECTIVES AND ENDPOINTS...........................................................................11
5.
STUDY DESIGN ....................................................................................................11
5.1.
Overall Design ............................................................................................11
5.2.
Number of Participants ...............................................................................11
5.3.
Participant and Study Completion...............................................................12
5.4.
Scientific Rationale for Study Design ..........................................................12
5.5.
Dose Justification........................................................................................13
6.
STUDY POPULATION...........................................................................................13
6.1.
Inclusion Criteria.........................................................................................14
6.2.
Exclusion Criteria........................................................................................14
6.3.
Lifestyle Restrictions...................................................................................16
6.3.1.
Meals and Dietary Restrictions ....................................................16
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................16
6.3.3.
Activity .........................................................................................17
6.4.
Screen Failures...........................................................................................17
7.
TREATMENTS.......................................................................................................17
7.1.
Treatments Administered............................................................................18
7.2.
Dose Modification .......................................................................................18
7.3.
Method of Treatment Assignment ...............................................................18
7.4.
Blinding.......................................................................................................18
7.5.
Preparation/Handling/Storage/Accountability..............................................18
7.6.
Treatment Compliance................................................................................19
7.7.
Concomitant Therapy..................................................................................19
7.8.
Treatment after the End of the Study ..........................................................20
8.
DISCONTINUATION CRITERIA.............................................................................20
8.1.
Discontinuation of Study Treatment ............................................................20
8.1.1.
Liver Chemistry Stopping Criteria ................................................20
8.1.2.
QTc Stopping Criteria ..................................................................21
8.2.
Withdrawal from the Study..........................................................................21
8.3.
Lost to Follow-Up........................................................................................21
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................22
9.1.
Adverse Events...........................................................................................22


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9.1.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................22
9.1.2.
Method of Detecting AEs and SAEs.............................................23
9.1.3.
Follow-up of AEs and SAEs.........................................................23
9.1.4.
Regulatory Reporting Requirements for SAEs .............................23
9.1.5.
Pregnancy ...................................................................................24
9.2.
Treatment of Overdose...............................................................................24
9.3.
Safety Assessments ...................................................................................24
9.3.1.
Physical Examinations.................................................................24
9.3.2.
Vital Signs....................................................................................24
9.3.3.
Electrocardiograms......................................................................25
9.3.4.
Clinical Safety Laboratory Assessments ......................................25
9.4.
Pharmacokinetics .......................................................................................25
10. STATISTICAL CONSIDERATIONS........................................................................26
10.1.
Sample Size Determination ........................................................................26
10.1.1.
Sample Size Assumptions ...........................................................26
10.1.2.
Sample Size Sensitivity................................................................26
10.2.
Populations for Analyses ............................................................................26
10.3.
Statistical Analyses.....................................................................................27
10.3.1.
Safety Analyses...........................................................................27
10.3.2.
Pharmacokinetic Analyses...........................................................27
10.3.3.
Interim Analyses ..........................................................................28
11. REFERENCES.......................................................................................................29
12. APPENDICES........................................................................................................30
12.1.
Appendix 1: Abbreviations and Trademarks................................................30
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................32
12.3.
Appendix 3: Study Governance Considerations..........................................33
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................37
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................42
12.6.
Appendix 6: Liver Safety Required Actions and Follow-up 
Assessments ..............................................................................................44
12.7.
Appendix 7: Country-specific requirements.................................................46
12.8.
Appendix 8: Protocol Amendment History...................................................47


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1.
SYNOPSIS
Protocol Title: A single centre, open-label, parallel-group, single oral dose study to 
evaluate the pharmacokinetics, safety and tolerability of Pyrimethamine in healthy 
Japanese and Caucasian male subjects
Short Title: Phase I study of Pyrimethamine in healthy Japanese and Caucasian Subjects
Rationale: Pyrimethamine in combination with a sulphonamide is effective in the 
treatment of toxoplasmosis. However, in Japan, Pyrimethamine has not been approved by 
the Japanese regulatory body (Pharmaceutical and Medical Devices Agency [PMDA]/
Ministry of Health, Labour and Welfare [MHLW]), and the use of Pyrimethamine needs 
to rely on obtaining it via personal import or provided by a grant-in-aid from the Japanese 
government. The development of Pyrimethamine was requested by the Japanese Ministry 
of Health, Labor and Welfare (MHLW) because a high medical need exists for the 
treatment of toxoplasmosis with Pyrimethamine in Japan.
The pharmacokinetics (PK) of Pyrimethamine has been investigated following 
administration of Sulfadoxine/Pyrimethamine tablet (Fansidar®) in healthy Japanese 
subjects [Otomo H, et al. 1985]. However, as this study did not provide sufficient 
information for approval of Pyrimethamine in Japan, the PMDA has requested
confirmation of the PK of Pyrimethamine in another PK study in Japanese and Caucasian 
healthy subjects. The primary adverse reaction of Pyrimethamine is abnormalities of the 
blood and lymphatic system, such as anaemia, leucopenia and thrombocytopenia. 
Therefore, for all subjects receiving Pyrimethamine, coadministration of calcium folinate 
is recommended to reduce the risk of bone marrow depression.
Thus, the primary objective of this study is to investigate the PK following a single oral 
dose of Pyrimethamine 50 mg in a fasted condition in healthy Japanese and Caucasian 
male subjects.
Objectives and Endpoints:
Objective
Endpoint
Primary
!
To investigate PK following a single oral 
dose of Pyrimethamine 50 mg in fasted 
healthy Japanese male subjects.
!
Cmax, AUC(0-t), AUC(0-inf), AUC(0-24), 
tmax, t1/2, CL/F, Vd/F from the plasma 
concentrations of Pyrimethamine in healthy 
Japanese male subjects, as data permit.
Secondary
!
To investigate PK following a single oral 
dose of Pyrimethamine 50 mg in fasted 
healthy Caucasian male subjects.
!
Cmax, AUC(0-t), AUC(0-inf), AUC(0-24), 
tmax, t1/2, CL/F, Vd/F from the plasma 
concentrations of Pyrimethamine in healthy 
Caucasian male subjects, as data permit.


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!
To assess safety and tolerability following a 
single oral dose of Pyrimethamine in fasted 
healthy Japanese and Caucasian male 
subjects.
!
AE and change from the baseline of clinical 
laboratory values, vital signs and ECG.
Overall Design:
This study will be a single centre, open-label, parallel-group, single oral dose study to 
evaluate the PK, safety and tolerability of Pyrimethamine in healthy Japanese and 
Caucasian male subjects.
Number of Participants:
Sufficient Japanese and Caucasian healthy male subjects will be enrolled such 6 subjects 
of each population complete dosing and critical assessments.
If participants prematurely discontinue the study, additional replacement participants may 
be recruited and assigned to the same treatment at the discretion of the Sponsor in 
consultation with the investigator.
Treatment Groups and Duration:
Subjects will have a screening visit within 30 days prior to the first dose of study 
treatment. Subjects will be housed in the Clinical Research Unit from Day -1 through 
Day 8, and return to the unit on Day 15 (±1) and 22 (±1) for the remaining PK samples 
and safety assessments post dose.
During the treatment period, subjects will receive a single oral dose of Pyrimethamine 
50 mg in the fasted state after an overnight fast (at least 10 hours). Oral calcium folinate 
15 mg will be coadministered with Pyrimethamine on Day 1, and will continue to be 
administered once a day until Day 8.
Blood sampling for PK analysis and safety assessments will be performed prior to dosing 
and over 22 days after dosing. The duration of each subject’s participation will be 
approximately 2 months from screening to the follow-up.


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2.
SCHEDULE OF ACTIVITIES (SOA)
Scr
Day 
-1
Day 1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Day 
8
Day 
15 4
Follow-
up
Day 22 4
Pre
0 h
1 h
2 h
4 h
6 h
12 h
24 h
48 h
72 h
96 h
120 
h
144 
h
168 
h
336 
h
504 h
Admission to Unit
X
Informed consent
X
Subject demography/
Medical history
X
Physical examination
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine drug screen
X
X
Alcohol breath test
X
X
CO breath test
X
X
Serological test
X
Haematology, clinical 
chemistry and urinalysis
X
X
X
X
X
X
X
Study treatment dosing
X
Calcium folinate dosing
X 1
X
X
X
X
X
X
X
PK Sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
SAEs 2
===========================================================================================================  
AEs 3
========================================================================================  
Con Med review
===========================================================================================================  
Discharge
X
Outpatient Visit
X
X
X
1.
Calcium folinate will be coadministered with Pyrimethamine on Day 1.
2.
All SAEs will be collected from the signing of the ICF until the follow-up visit at the time points specified.
3.
All AEs will be collected from the start of treatment until the follow-up visit at the time points specified.
4.
Subjects will return to the unit on Day 15 (±1) and 22 (±1) for the remaining PK samples and safety assessments post dose.


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3.
INTRODUCTION
3.1.
Study Rationale
Pyrimethamine in combination with a sulphonamide is effective in the treatment of 
toxoplasmosis. However, in Japan, Pyrimethamine has not been approved by the 
Japanese regulatory body PMDA/MHLW, and the use of Pyrimethamine needs to rely on 
obtaining it via personal import or provided by a grant-in-aid from the Japanese 
government. The development of Pyrimethamine was requested by the Japanese MHLW 
because a high medical need exists for the treatment of toxoplasmosis with 
Pyrimethamine in Japan.
The PK of Pyrimethamine has been investigated following administration of 
Sulfadoxine/Pyrimethamine tablet (Fansidar®) in healthy Japanese subjects [Otomo H, et 
al. 1985]. However, as this study did not provide sufficient information for approval of 
Pyrimethamine in Japan, the PMDA has requested confirmation of the PK of 
Pyrimethamine in another PK study in Japanese and Caucasian healthy subjects. The 
primary adverse reaction of Pyrimethamine is abnormalities of the blood and lymphatic 
system, such as anaemia, leucopenia and thrombocytopenia. Therefore, for all subjects 
receiving Pyrimethamine, coadministration of calcium folinate is recommended to reduce 
the risk of bone marrow depression.
Thus, the primary objective of this study is to investigate the PK following a single oral 
dose of Pyrimethamine 50 mg in a fasted condition in healthy Japanese and Caucasian 
male subjects.
3.2.
Background
Pyrimethamine is an inhibitor of the enzyme dihydrofolate reductase (DHFR). It blocks 
the reduction of dihydrofolic acid to tetrahydrofolic acid which is an essential coenzyme 
in the production of nucleic acids, thereby leading to disruption of protein synthesis and 
nuclear division. The affinity of Pyrimethamine for protozoal DHFR is much greater than 
that for the mammalian enzyme. Sulphonamides act synergistically with Pyrimethamine 
by arresting production of dihydrofolic acid from para-aminobenzoic acid. This results in 
sequential blockade of the folate pathway of Toxoplasma Gondii which, in contrast to 
man, is unable to utilise preformed folate. Pyrimethamine peak plasma levels in humans
generally occur 2 to 4 hours after oral administration of a 100 mg dose of Pyrimethamine 
and the plasma half-life is approximately 90 hours following a single oral dose of the 
combination of Sulfadoxine 1000 mg/Pyrimethamine 50 mg (Fansidar®). In healthy 
Japanese subjects, the peak plasma concentrations of Pyrimethamine occurred at 
3.3 hours and the mean elimination half-life was 106.9 hours [Otomo H, et al. 1985].
Pyrimethamine in combination with a sulphonamide is effective in the treatment of 
toxoplasmosis, including ocular and congenital infections and toxoplasmosis in immune-
deficient individuals. Pyrimethamine for the treatment of toxoplasmosis in combination 
with a sulphonamide was approved in 69 countries including in the US, UK, Germany, 
Canada and Australia., as of Dec 2014. The trade name is DARAPRIMTM.


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Summary information of this medicine is described in the PRODUCT INFORMATION 
DARAPRIM TABLETS [Amended 22Apr2016].
3.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events (AEs) of Pyrimethamine may be found in the 
PRODUCT INFORMATION DARAPRIM TABLETS [Amended 22Apr2016].
3.3.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Investigational Product (IP) Pyrimethamine
Pancytopenia (hematologic 
effects of folate deficiency)
The GSK safety database 
contains 45 case reports of 
pancytopenia. 24 of these are 
related to Pyrimethamine as 
the only causative agent. The 
rest of the cases are 
confounded by concomitant 
use of sulphonamides, since it 
is recommended that 
Pyrimethamine be given 
simultaneously with 
sulphonamides to achieve 
optimum effectiveness. Some 
cases are also confounded by 
antibiotics and antivirals.
The majority of pancytopenia 
cases result from insufficient 
folate supplementation during 
therapy. Substantial folate 
deficiency - apart from 
pancytopenia - may cause 
isolated blood dyscrasias, such 
as: anemia, leucopenia or 
thrombocytopenia and such 
events have also been 
reported.
This association has been 
known for decades and it is 
supported by many literature 
reference articles [Pajor A, 
1990].
Subjects will be supplemented 
with a single daily oral dose of
calcium folinate for 
8 consecutive days (See the 
SoA for details).
Frequent laboratory 
assessments for hematologic 
effects (full blood counts) will 
be carried out during the study 
period, and subjects monitored 
for signs and symptoms of 
depression of haematopoesis 
(e.g., leucopenia, anaemia, 
thrombocytopenia, etc.).


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Dermatitis
GSK safety database contains 
8 case reports of dermatitis, 
consisting of: 4 reports of 
exfoliative dermatitis, 2 cases 
of bullous dermatitis and 
2 cases of allergic dermatitis. 
Six of the 8 reports of severe 
skin reactions were 
confounded by the use of 
either sulphonamides (e.g.,
sulphadiazine) or by other co-
suspect medications, so 
determination of the 
contribution of each drug in 
these events is difficult. The 
remaining 2 cases are 
inconclusive due to insufficient 
information.
Since it is recommended that 
Pyrimethamine be given 
simultaneously with 
sulphonamides and since long-
acting sulphonamides are well-
known for causing various skin 
and subcutaneous tissue 
disorders, the risk of severe 
cutaneous reactions should be 
always considered when 
combined therapy is used 
[Taylor WRJ, et al. 2004].
Subjects will not receive 
sulphonamide in this study as 
a concomitant medicine 
(because the safety concern is 
associated with the 
recommended combined anti-
parasite therapy rather than 
with Pyrimethamine alone and 
is most probably directly 
related to the second 
component of the therapy, i.e.,
to a sulphonamide).
Subjects will be monitored for 
signs and symptoms of 
dermatitis during the study 
period.
3.3.2.
Benefit Assessment
This study is being conducted in healthy subjects with no significant medical history. 
Subjects will not receive benefit from this study. Knowledge from this study may 
contribute to the development of Pyrimethamine in Japan and may benefit patients with 
toxoplasmosis in the future.
3.3.3.
Overall Benefit: Risk Conclusion
Based upon the safety assessments and risk mitigation strategy of this protocol and the 
potential benefits to the Japanese patients with toxoplasmosis, it is concluded that there is 
a positive risk benefit.


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In consideration of the potential benefits and risk reviewed above, GSK concludes the 
Benefit:Risk for a subject’s participation in the GSK study 204678 is favourable and 
supports the study conduct.
4.
OBJECTIVES AND ENDPOINTS
Objective
Endpoint
Primary
!
To investigate PK following a single oral 
dose of Pyrimethamine 50 mg in fasted 
healthy Japanese male subjects.
!
Cmax, AUC(0-t), AUC(0-inf), AUC(0-24), 
tmax, t1/2, CL/F, Vd/F from the plasma 
concentrations of Pyrimethamine in healthy 
Japanese male subjects, as data permit.
Secondary
!
To investigate PK following a single oral 
dose of Pyrimethamine 50 mg in fasted 
healthy Caucasian male subjects.
!
Cmax, AUC(0-t), AUC(0-inf), AUC(0-24), 
tmax, t1/2, CL/F, Vd/F from the plasma 
concentrations of Pyrimethamine in healthy 
Caucasian male subjects, as data permit.
!
To assess safety and tolerability following a 
single oral dose of Pyrimethamine in fasted 
healthy Japanese and Caucasian male 
subjects.
!
AE and change from the baseline of clinical 
laboratory values, vital signs and ECG.
5.
STUDY DESIGN
5.1.
Overall Design
This study will be a single centre, open-label, parallel-group, single oral dose study to 
evaluate the PK, safety and tolerability of Pyrimethamine in healthy Japanese and 
Caucasian male subjects.
5.2.
Number of Participants
Sufficient Japanese and Caucasian healthy male subjects will be enrolled such 6 subjects 
of each population complete dosing and critical assessments.
If participants prematurely discontinue the study, additional replacement participants may 
be recruited and assigned to the same treatment at the discretion of the Sponsor in 
consultation with the investigator.


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5.3.
Participant and Study Completion
A participant is considered to have completed the study if he has completed all phases of 
the study including the last visit.
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.4.
Scientific Rationale for Study Design
The PK of Pyrimethamine has been investigated following administration of 
Sulfadoxine/Pyrimethamine tablet (Fansidar®) in healthy Japanese subjects [Otomo H, et 
al. 1985]. However, this study did not include sufficient information for approval of 
Pyrimethamine in Japan. Confirmation of the PK of Pyrimethamine in a Japanese
population, as well as comparison of the data in Japanese relative to Caucasian subjects
under the same conditions should be beneficial when confirming the relevance of the 
existing global experience with Pyrimethamine for patients in Japan.
Daily therapeutic doses of Pyrimethamine have been shown to depress haematopoesis in 
some 25% to 50% of patients. The likelihood of inducing leucopenia, anaemia or 
thrombocytopenia is reduced by concurrent administration of calcium folinate. In 
addition, PMDA recommends using calcium folinate in this study to be conducted in the 
healthy subjects. Calcium folinate 15 mg will be dosed from Day 1 to Day 8 to prevent 
bone marrow depression.
The elimination half-life was approximately 107 hours after dosing 50 mg 
Pyrimethamine (i.e., two Sulfadoxine/Pyrimethamine (500 mg/25 mg) tablets in healthy
Japanese subjects and the mean elimination half-life is reported to be approximately 
90 hours in non-Japanese subjects. Considering the long half-life of Pyrimethamine, the 
follow-up period for 22 days together with the parallel study design are considered to be 
appropriate for evaluation of the PK characteristics of Pyrimethamine in both Japanese 
and Caucasian subjects, as well as the evaluation of safety in Japanese subjects because 
this is the first clinical study of this Pyrimethamine formulation in Japanese.


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5.5.
Dose Justification
Pyrimethamine has been approved in the US, UK and Australia and the recommended 
doses for adults with toxoplasmosis are as shown in the table below;
Country
Regimen
US
The adult starting dose is 50 to 75 mg of the drug daily, together with 1 to 
4 g daily of a sulfonamide of the sulfapyrimidine type, e.g. sulfadoxine. This 
dosage is ordinarily continued for 1 to 3 weeks, depending on the response 
of the patient and tolerance to therapy. The dosage may then be reduced to 
about one half that previously given for each drug and continued for an 
additional 4 to 5 weeks [DARAPRIM® (pyrimethamine) 25 mg tablets Rx 
Only PRESCRIBING INFORMATION].
UK
A loading dose of DARAPRIM 100 mg should be given for the first 1 to 
2 days, followed by 25 to 50 mg daily. This should be given together with 2 
to 4 g of sulphadiazine daily in divided doses [DARAPRIM® Tablets].
Australia
50 mg for initial dose and 25 mg for subsequent daily dose with 
sulphadiazine or other sulphonamides [DARAPRIM® Tablets].
While a different dose is recommended for malaria, one of the proposed dose regimens
for Japan for the treatment of toxoplasmosis in combination with a sulphonamide is as 
follows; 100 mg on the first day and 25-50 mg for subsequent daily doses. This dosage 
regimen is used clinically in the UK and was referred to in three randomized studies
[Bosch-Driessen LH, et al. 2002; Soheilian M, et al. 2005; Rothova A, et al. 1993].
The previous study in healthy Japanese subjects using two Sulfadoxine/Pyrimethamine
(500 mg/25 mg) tablets has confirmed the safety of administration of 50 mg 
Pyrimethamine in Japanese [Otomo H, et al. 1985; Kusuhara H, et al. 2011]. However, 
there is no report in which the safety has been confirmed after dosing with 100 mg 
Pyrimethamine in healthy Japanese subjects.
The 50 mg Pyrimethamine is within the range of that approved in the US, UK and 
Australia, and taking safety in healthy subjects mentioned above into consideration, 
50 mg is considered the appropriate dose to investigate PK in both populations. This 
study will use the Pyrimethamine tablets (DARAPRIMTM, Arrow Pharmaceuticals) 
approved and marketed in Australia.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.


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6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Between 20 and 64 years of age inclusive, at the time of signing the informed 
consent.
Type of Participant and Disease Characteristics
2.
Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests, and cardiac monitoring.
Weight
3.
Body weight ∀50 kg and body mass index (BMI) within the range 18.5 – 30.0 kg/m2
(inclusive).
Sex and Ancestry
4.
Japanese or Caucasian male.
!
A male participant must agree to use contraception as detailed in Appendix 5 of this 
protocol during the treatment period and until follow-up.
!
Japanese ethnic origin defined as having been born in Japan, having four ethnic 
Japanese grandparents, holding a Japanese passport or identity papers and being able 
to speak Japanese. Subjects should also have lived outside Japan for less than 
10 years at the time of screening.
!
Caucasian subjects as defined as an individual having four grandparents who are all 
descendants of the original peoples of Europe.
Informed Consent
5.
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Alanine aminotransferase (ALT) > 1.5x upper limit of normal (ULN)
2.
and bilirubin > 1.5xULN (isolated bilirubin > 1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin < 35%).
3.
QTcF > 450 msec
NOTES:


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!
The QTc is the QT interval corrected for heart rate according to Fridericia’s 
formula (QTcF), and/or another method, machine-read or manually over-read.
!
The specific formula that will be used to determine eligibility and 
discontinuation for an individual subject should be determined prior to initiation 
of the study. In other words, several different formulae cannot be used to 
calculate the QTc for an individual subject and then the lowest QTc value used 
to include or discontinue the subject from the trial.
!
For purposes of data analysis, QTcF, another QT correction formula, or a 
composite of available values of QTc will be used as specified in the Reporting 
and Analysis Plan (RAP).
4.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert’s syndrome or asymptomatic gallstones).
5.
History of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, 
hematological, or neurological disorders capable of significantly altering the 
absorption, metabolism, or elimination of drugs; constituting a risk when taking the 
study treatment; or interfering with the interpretation of data.
6.
Abnormal blood pressure as determined by the investigator.
7.
Hematological values: outside normal range at screening.
8.
Serum creatinine level: outside normal range at screening visit.
Prior/Concomitant Therapy
9.
Past or intended use of over-the-counter or prescription medication including herbal 
medications within 14 days prior to dosing. 
Prior/Concurrent Clinical Study Experience
10. Participation in the study would result in loss of blood or blood products in excess of 
500 mL within 3 months.
11. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day.
12. Current enrolment or past participation within the last 30 days before signing of 
consent in this clinical study involving an investigational study treatment or any 
other type of medical research.
Diagnostic assessments
13. Presence of Hepatitis B surface antigen (HBsAg) at screening or positive Hepatitis C 
antibody test result at screening.
NOTE:
!
Subjects with positive Hepatitis C antibody due to prior resolved disease can be 
enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained.
14. Positive Hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study treatment.


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NOTE:
!
Test is optional and subjects with negative Hepatitis C antibody test are not 
required to also undergo Hepatitis C RNA testing.
15. Positive pre-study drug/alcohol screen.
16. Positive human immunodeficiency virus (HIV) antibody test.
17. Regular use of known drugs of abuse.
Other Exclusions
18. Regular alcohol consumption within 6 months prior to the study defined as:
For an average weekly intake of > 14 units for males. One unit is equivalent to 10 g 
of alcohol: a can of mid-strength (~375 mL) beer, 1 glass (100 mL) of table wine or 
1 measure (30 mL) of spirits (including rice wine).
19. History or regular use of tobacco- or nicotine-containing products within 6 months 
prior to screening.
20. Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy that, in the opinion of the investigator or medical monitor, contraindicates 
participation in the study.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions
!
Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice
and/or pummelos, citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to
the first dose of study medication until after the last PK sample.
!
Subjects should fast for a minimum of 10 hours prior to any blood draws for safety 
laboratory testing.
!
During the in-house period there are meal restrictions (e.g., timing of meals on Day 1
and limitations on number of meals/snacks per day).
!
During hospitalization, subjects can consume water, however they should refrain 
from any drinking from 1 hour prior to dosing until 4 hours post dose. Also, they 
should refrain from excessive drinking after 4 hours post dose.
6.3.2.
Caffeine, Alcohol, and Tobacco
!
Participants will abstain from ingesting caffeine- or xanthine-containing products 
(e.g., coffee, tea, cola drinks, and chocolate) for 24 hours prior to the start of dosing 
until collection of the final PK sample.
!
Participants will abstain from alcohol for 24 hours prior to the start of dosing until 
collection of the final PK sample.


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!
Participants who use tobacco products will be instructed that use of nicotine-
containing products (including nicotine patches) will not be permitted for 6 months 
prior to the screening until collection of the final PK sample.
6.3.3.
Activity
Participants will abstain from strenuous exercise for 48 hours prior to each blood 
collection for clinical laboratory tests. Participants will remain in a sitting or semi-supine 
position for approximately 4 hours after dosing on Day 1 of treatment period. Participants 
may participate in light recreational activities during studies (e.g., watching television, 
reading).
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse events 
(SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may not be rescreened.
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
Pyrimethamine (DARAPRIMTM, Arrow Pharma Pty Ltd., Australia) will be purchased 
and labelled at Pharmaceutical Packaging Professionals, Australia. 
Calcium folinate (Leucovorin®, Pfizer Japan Inc., Japan) will be purchased by GSK 
Japan, and labelled at Pharmaceutical Packaging Professionals, Australia.


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7.1.
Treatments Administered
Study Treatment Name:
Pyrimethamine
Calcium folinate
Dosage formulation:
Tablet
Tablet
Unit dose strength(s)/Dosage 
level(s):
25 mg/unit dose
5 mg/unit dose
Route of Administration:
Oral
Oral
Dosing instructions:
2 tablets will be taken on 
Day 1 in fasted condition with 
240 mL water
3 tablets will be taken on 
Day 1 together with 
Pyrimethamine, and once a 
day until Day 8 (a total of 
8 days). Each administration 
will be with 240 mL water.
(See Section 7.7)
Packaging and Labeling:
Study Treatment will be 
provided in container. Each 
container will be labelled as 
required per country 
requirement.
Study Treatment will be 
provided in container. Each 
container will be labelled as 
required per country 
requirement.
Manufacturer:
Arrow Pharma Pty Ltd., 
Australia
Pfizer Japan Inc., Japan
7.2.
Dose Modification
This is a single-dose study and dose modification will not be considered.
7.3.
Method of Treatment Assignment
This is an open-label and non-randomized study which consists of two groups (Japanese 
and Caucasian). Subjects in each group will be assigned in accordance with the unique 
number (randomization schedule) generated by the Biomedical Data Sciences 
Department at GSK, prior to the start of the study, using validated internal software.
7.4.
Blinding
This is an open-label study.
7.5.
Preparation/Handling/Storage/Accountability
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.


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2.
Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized site staff.
3.
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study treatment 
are provided in the Study Reference Manual.
!
Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff. Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, Medical Monitor and/or 
GSK study contact.
!
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
7.6.
Treatment Compliance
!
When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff. 
!
When participants are dosed at the site, they will receive study treatment directly 
from the investigator or designee, under medical supervision. The date and time of 
each dose administered in the clinic will be recorded in the source documents. The 
dose of study treatment and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person 
administering the study treatment. Study site personnel will examine each 
participant’s mouth to ensure that the study treatment was ingested.
7.7.
Concomitant Therapy
This study includes, as a part of the study treatment, administration of calcium folinate to 
mitigate a potential risk of pancytopenia that has developed following administration of
Pyrimethamine (Section 3.3.1). 
Calcium folinate 15 mg will be coadministered with Pyrimethamine on Day 1, and will 
continue to be administered once a day at the same time as Day 1 until Day 8 (a total of 
8 days). Details for the administration with calcium folinate are also found in SoA and 
Section 7.1.
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with:


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!
reason for use
!
dates of administration including start and end dates
!
dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
Participants must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study 
treatment until completion of the follow-up visit, unless, in the opinion of the investigator 
and sponsor, the medication will not interfere with the study.
7.8.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because only healthy volunteers are eligible for study participation.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
8.1.1.
Liver Chemistry Stopping Criteria
Study treatment will be discontinued for a participant if liver chemistry stopping criteria 
are met:
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
 Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
 Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*


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Liver Safety Required Actions and Follow-up Assessments Section can be found in 
Appendix 6.
8.1.2.
QTc Stopping Criteria
A subject that meets the bulleted criterion based on the average of triplicate 
electrocardiogram (ECG) readings will be withdrawn from study treatment.
!
QTcF > 500 msec
8.2.
Withdrawal from the Study
!
A participant may withdraw from the study at any time at his own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance or administrative reasons.
!
If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent.
!
If a participant withdraws from the study, he may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study 
records.
!
Refer to the SoA for data to be collected at the time of study discontinuation and
follow-up and for any further evaluations that need to be completed.
8.3.
Lost to Follow-Up
A participant will be considered lost to follow-up if he repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:
!
The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.
!
Before a participant is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 
3 telephone calls and, if necessary, a certified letter to the participant’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the participant’s medical record.
!
Should the participant continue to be unreachable, he will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 


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9.
STUDY ASSESSMENTS AND PROCEDURES
!
Study procedures and their timing are summarized in the SoA. 
!
Protocol waivers or exemptions are not allowed.
!
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.
!
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
!
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
!
Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA.
!
The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 
500 mL.
!
Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
9.1.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study (see Section 8). 
9.1.1.
Time Period and Frequency for Collecting AE and SAE 
Information
!
All SAEs will be collected from the signing of the ICF until the follow-up visit at the 
time points specified in the SoA (Section 2).
!
All AEs will be collected from the start of treatment until the follow-up visit at the 
time points specified in the SoA (Section 2).
!
Medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the Medical History/Current Medical 
Conditions section of the case report form (CRF) not the AE section.


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!
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, 
as indicated in Appendix 4. The investigator will submit any updated SAE data to the 
sponsor within 24 hours of it being available.
!
Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he considers the 
event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the sponsor.
!
The method of recording, evaluating, and assessing causality of AEs and SAEs and 
the procedures for completing and transmitting SAE reports are provided in 
Appendix 4.
9.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
9.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 8.3). Further information on follow-up procedures is given in 
Appendix 4.
9.1.4.
Regulatory Reporting Requirements for SAEs
!
Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and 
the safety of a study treatment under clinical investigation are met. 
!
The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study treatment under clinical 
investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, IEC, and 
investigators.
!
Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and sponsor 
policy and forwarded to investigators as necessary.
!
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAE) from the sponsor will 
review and then file it along with the Investigator’s Brochure (IB) and will notify the 
IEC, if appropriate according to local requirements.


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9.1.5.
Pregnancy
!
Details of all pregnancies in female partners of male participants will be collected 
after the start of study treatment and until the follow-up visit.
!
If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5.
!
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.2.
Treatment of Overdose
For this study, any dose of Pyrimethamine greater than 50 mg within a 24-hour time 
period will be considered an overdose.
GSK does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
Pyrimethamine can no longer be detected systemically (at least 22 days).
3.
Obtain a plasma sample for PK analysis within 22 (±1) days from the date of the last 
dose of study treatment if requested by the Medical Monitor (determined on a case-
by-case basis).
4.
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
9.3.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
9.3.1.
Physical Examinations
!
A physical examination will include, at a minimum, assessments of the Skin,
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. 
!
Height and weight will also be measured and recorded only at screening.
!
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
9.3.2.
Vital Signs
!
Oral temperature, pulse rate, and blood pressure will be assessed.


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!
Blood pressure and pulse measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available.
!
Blood pressure and pulse measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions (e.g., television, cell 
phones).
!
Single vital signs will be measured in a semi-supine position after 5 minutes rest and 
will include temperature, systolic and diastolic blood pressure, and pulse rate. 
9.3.3.
Electrocardiograms
!
Single 12-lead ECG will be obtained as outlined in the SoA (see Section 2) using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, 
QT, and QTc intervals. Refer to Section 8.1 for QTc withdrawal criteria and 
additional QTc readings that may be necessary.
9.3.4.
Clinical Safety Laboratory Assessments
!
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency. 
!
The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. 
!
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or 
baseline or are no longer considered significantly abnormal by the investigator or 
medical monitor. 
!
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.
!
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
!
If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification), then the results must be recorded in the CRF.
9.4.
Pharmacokinetics
!
Whole blood samples of approximately 2 mL will be collected in EDTA blood 
collection tube for measurement of plasma concentrations of Pyrimethamine as 
specified in the SoA. Instructions for the collection and handling of biological 
samples will be provided by the sponsor. The actual date and time (24-hour clock 
time) of each sample will be recorded.


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10.
STATISTICAL CONSIDERATIONS
The objectives of this study are to evaluate safety and tolerability of Pyrimethamine and 
to estimate Pyrimethamine PK parameters in healthy Japanese and Caucasian male 
subjects. No formal statistical hypotheses will be tested. Descriptive statistics will be 
used to assess safety and tolerability objectives by group. An estimation approach will be 
used to address the PK study objectives, where point estimates and corresponding 95% 
confidence intervals (CI) will be constructed, unless otherwise stated.
10.1.
Sample Size Determination
10.1.1.
Sample Size Assumptions
The sample size is based on feasibility where sufficient subjects will be enrolled into the 
study to support the inclusion of 12 evaluable subjects for analysis and 6 subjects are 
assigned to each group (Japanese or Caucasian).
Between-subject estimates of variability of the PK endpoints Cmax and AUC(0-inf) of 
Pyrimethamine are estimated to be 18.1% (coefficient of variance, CV%) and 44.6% 
(CV%), respectively (based on Japanese PK data reported by Otomo H, et al. 1985). 
Based on these variability estimates, and a sample size of 6 (active treatment per group), 
the upper and lower bounds of 95% CI will be approximately 20.7% for Cmax and 56.4% 
for AUC(0-inf) respectively. For instance, the 95% CI of geometric mean will be 331.3-
483.0 if the geometric mean of Cmax (ug/mL) is 400, and the 95% CI of geometric mean 
will be 25.6-62.5 if the geometric mean of AUC(0-inf) (ug∙hr/mL) is 40.
10.1.2.
Sample Size Sensitivity
Based on sample size of 6, if the between-subject CVb% observed in the Cmax is 10% 
(CVb%:19.9%) and 20% (CVb%:21.7%) greater than between-subject CVb% in the 
reference report, the precision estimate for the upper limit value and lower limit value of 
a mean of 95% CI will be 23.0% and 25.3%, respectively.
If the between-subject CVb% observed in the AUC is 10% (CVb%:49.1%) and 20% 
(CVb%:53.5%) greater than between-subject CVb% in the reference report, the precision 
estimate for the upper limit value and lower limit value of a mean of 95% CI will be 
62.8% and 69.3%, respectively.
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Screened
Consisting of all participants screened in the study.
Screening Failure
Participants who sign the ICF in the study but are never 
subsequently administered. All participants who sign the ICF have 


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the screening test in the study.
Safety
All participants who take at least one dose of study treatment. 
Pharmacokinetic
This population is defined as all participants administered at least 
one dose of study treatment and who have PK sample taken and 
analyzed.
10.3.
Statistical Analyses
The study results will be presented in tabular and/or graphical format and summarised 
descriptively. These analyses will be performed in each group. Complete details of the 
planned statistical analyses will be provided in the RAP.
10.3.1.
Safety Analyses
All safety analyses will be performed on the Safety Population. 
Statistical Analysis Methods
AE, clinical laboratory values, vital signs, ECG will be summarized by group.
10.3.2.
Pharmacokinetic Analyses
All PK analyses will be described in the PK Population. The details of the PK analysis 
will be provided in the RAP.
Statistical Analysis Methods
Pyrimethamine concentrations
Plasma concentrations of Pyrimethamine at each assessment point will be listed to 
prepare figures showing individual concentration-time profiles on both linear and semi-
log scales. In addition, the mean and median plasma concentrations at each assessment 
point will be calculated from concentration data of individual subjects to prepare figures 
showing mean and median plasma concentration-time profiles on both linear and semi-
log scales by group.
Pyrimethamine PK parameters
The PK parameters [i.e., Cmax, AUC(0-t), AUC(0-inf), AUC(0-24), tmax, t1/2, CL/F, 
Vd/F] will be calculated by non-compartmental analysis from plasma Pyrimethamine 
concentration-time data using Phoenix WinNonlin (version 6.3 or higher), as data permit. 
Calculations will be based on the actual sampling times recorded during the study. All 
derived parameters will be listed and summarized descriptively by each group.


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Others
An exploratory analysis will be performed using PK parameter plots in order to assess 
the results in the Japanese and Caucasian subjects.
10.3.3.
Interim Analyses
No interim analyses will be planned.


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11.
REFERENCES
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Pharmacokinetics of antimalarial Fansidar® in healthy Japanese subjects. Journal of New 
Remedies & Clinics 1985; 34 (3): 415-423.
Pajor A. Pancytopenia in a patient given pyrimethamine and sulphamethoxidiazine 
during pregnancy. Archives of Gynecology and Obstetrics 1990; 247 (4): 215-217.
Taylor WRJ, White NJ. Antimalarial drug toxicity: a review. Drug Safety 2004; 27 (1): 
25-61.
Bosch-Driessen LH, Verbraak FD, Suttorp-Schulten MSA, van Ruyven RLJ, Klok AM, 
Hoyng CB, Rothova A. A Prospective, Randomized Trial of Pyrimethamine and 
Azithromycin Vs Pyrimethamine and Sulfadiazine for the Treatment of Ocular 
Toxoplasmosis. American Journal of Ophthalmology 2002; 134 (1): 34-40.
Soheilian M, Sadoughi MM, Ghajarnia M, Dehghan MH, Yazdani S, Behboudi H, 
Anisian A, Peyman GA. Prospective Randomized Trial of
Trimethoprim/Sulfamethoxazole versus Pyrimethamine and Sulfadiazine in the
Treatment of Ocular Toxoplasmosis. Ophthalmology 2005; 112 (11): 1876-1882.
Rothova A, Meenken C, Buitenhuis HJ, Brinkman CJ, Baarsma GS, Boen-Tan TN, de 
Jong PTVM, Klaassen-Broekema N, Schweitzer CMC, Timmerman Z, de Vries J,. Zaal
MJW, Kijlstra A. Therapy for Ocular Toxoplasmosis. American Journal of 
Ophthalmology 1993; 115 (4): 517–523.
Kusuhara H, Ito S, Kumagai Y, Jiang M, Shiroshita T, Moriyama Y, Inoue K, Yuasa H,
Sugiyama Y. Effects of a MATE Protein Inhibitor, Pyrimethamine, on the Renal 
Elimination of Metformin at Oral Microdose and at Therapeutic Dose in Healthy Subjects. 
Clinical pharmacology & Therapeutics 2011; 89 (6): 837-844.
PRODUCT INFORMATION DARAPRIM TABLETS [Amended 22Apr2016]
“DARAPRIM® (pyrimethamine) 25 mg tablets Rx Only PRESCRIBING 
INFORMATION” Revised 03/2017 U.S. Food and Drug Administration.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/008578s019lbl.pdf
[accessed 22/06/2017]
“Daraprim Tablets” Revised 27/05/2016 EMC.
http://www.medicines.org.uk/emc/medicine/729/SPC/
[accessed 22/06/2017]


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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AUC(0-24)
Area under the concentration-time curve from time 0 to 24
AUC(0-inf)
Area under the concentration-time curve from time 0 to infinity
AUC(0-t)
Area under the concentration-time curve from time 0 to t
BMI
Body mass index
BUN
Blood urea nitrogen
CFR
Code of Federal Regulations
CI
Confidence intervals
CIOMS
Council for International Organizations of Medical Sciences
CL/F
Apparent clearance following oral dosing
Cmax
Maximum observed concentration
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatine phosphokinase
(e)CRF
(electronic) Case report form
CSR
Clinical Study Report
CV
Coefficient of variation
DHFR
Dihydrofolate reductase
ECG
Electrocardiogram
e.g.
exempli gratia
GCP
Good Clinical Practice
GSK
GlaxoSmithKline
h/hr(s)
Hour(s)
HBsAg
Hepatitis B surface antigen
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HPLC
High performance liquid chromatography
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
i.e.
id est
IEC
Independent Ethics Committees
IgG
Immunoglobulin G
IgM
Immunoglobulin M
INR
International Normalized Ratio
IP
Investigational Product
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system


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kg
Kilogram
LDH
Lactate dehydrogenase
MCH
Mean Corpuscular Hemoglobin
MCV
Mean Corpuscular Volume
mg
Milligram
MHLW
Ministry of Health, Labor and Welfare
mL
Milliliter
MSDS
Material Safety Data Sheet
msec
Millisecond
pH
Pondus Hydrogenii
PK
Pharmacokinetic(s)
PMDA
Pharmaceutical and Medical Devices Agency
QTc
QT interval corrected
QTcF
QT interval corrected for heart rate by Friderician formula
RAP
Reporting and Analysis Plan
RBC
Red Blood Cells
RNA
Ribonucleic acid
SAE
Serious adverse event
SoA
Schedule of Activities
SUSAR
Suspected unexpected serious adverse reactions
t1/2
Terminal half-life
tmax
Time to maximum observed concentration
ug
Microgram
ULN
Upper limit of normal
Vd/F
Apparent volume of distribution following oral dosing
WBC
White blood cells
WOCBP
Women of Childbearing Potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
DARAPRIM
Fansidar
WinNonlin
Leucovorin


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12.2.
Appendix 2: Clinical Laboratory Tests
!
The tests detailed in Table 1 will be performed by the local laboratory.
!
Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol.
!
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
!
The results of each test must be electronic transfer of data, except drug screen, 
breath tests and serology.
Table 1
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
BUN
Potassium
Aspartate 
Aminotransferase
(AST)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)
Total Protein
Glucose fasting
Calcium
Alkaline 
phosphatase
Routine 
Urinalysis
!
Specific gravity
!
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick
!
Microscopic examination (if blood or protein is abnormal)
Other tests
!
Breath test (Alcohol and CO)
Other 
Screening 
Tests
!
Urine drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines)
!
Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis 
C virus antibody)
NOTES :
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 8.1 and Appendix 7 All events of ALT ∀3 × upper limit of normal (ULN) and 
bilirubin ∀2 × ULN (> 35% direct bilirubin) or ALT ∀3 × ULN and international normalized ratio (INR) > 1.5, if INR 
measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis).


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12.3.
Appendix 3: Study Governance Considerations
Regulatory and Ethical Considerations
!
This study will be conducted in accordance with the protocol and with:
!
Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines
!
Applicable ICH Good Clinical Practice (GCP) Guidelines
!
Applicable laws and regulations
!
The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IEC by the 
investigator and reviewed and approved by the IEC before the study is initiated. 
!
Any amendments to the protocol will require IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 
!
The investigator will be responsible for the following:
!
Providing written summaries of the status of the study to the IEC annually 
or more frequently in accordance with the requirements, policies, and 
procedures established by the IEC
!
Notifying the IEC of SAE or other significant safety findings as required 
by IEC procedures
!
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process
!
The investigator or his/her representative will explain the nature of the study to 
the participant or his legally authorized representative and answer all questions 
regarding the study. 
!
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 


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informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IEC or study center. 
!
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.
!
Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 
!
A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 
The ICF may contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research in accordance with SOP-GSKF-410. The 
investigator or authorized designee will explain to each participant the objectives of the 
exploratory research. Participants will be told that they are free to refuse to participate 
and may withdraw their consent at any time and for any reason during the storage period. 
A separate signature will be required to document a participant’s agreement to allow any 
remaining specimens to be used for exploratory research. Participants who decline to 
participate will not provide this separate signature.
Data Protection
!
Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 
!
The participant must be informed that his personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 
!
The participant must be informed that his medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by 
the sponsor, by appropriate IEC members, and by inspectors from regulatory 
authorities.
Publication Policy
!
The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.
!
The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.


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!
Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
Data Quality Assurance
!
All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF. 
!
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 
!
The investigator must permit study-related monitoring, audits, IEC review, and 
regulatory agency inspections and provide direct access to source data 
documents. 
!
The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
!
Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 
!
Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. 
Source Documents
!
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.
!
Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.
!
Definition of what constitutes source data can be found in the list of the source 
documents.


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Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:
!
Failure of the investigator to comply with the protocol, the requirements of the IEC 
or local health authorities, the sponsor’s procedures, or GCP guidelines
!
Inadequate recruitment of participants by the investigator
!
Discontinuation of further study treatment development


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12.4.
Appendix 4: Adverse Events: Definitions and Procedures for
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition
!
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.
!
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 
!
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related 
to progression of underlying disease).
!
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
!
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.
!
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
!
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.
Events NOT Meeting the AE Definition 
!
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.
!
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.
!
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.
!
Situations in which an untoward medical occurrence did not occur (social and/or 


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convenience admission to a hospital).
!
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity
!
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
!
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:
!
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 


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be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Recording AE and SAE
AE and SAE Recording
!
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
related to the event.
!
The investigator will then record all relevant AE/SAE information in the CRF.
!
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK/AE/SAE CRF page.
!
There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.
!
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 
!
Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.
!
Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.
!
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality
!
The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.


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!
A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.
!
The investigator will use clinical judgment to determine the relationship.
!
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.
!
The investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment.
!
For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.
!
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.
!
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.
!
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE
!
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.
!
If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.
!
New or updated information will be recorded in the originally completed CRF.
!
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.


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Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool
!
The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.
!
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper SAE data collection tool (see next section).
!
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
!
The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF.
!
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.
!
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form.
SAE Reporting to GSK via Paper CRF
!
Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor.
!
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
!
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.


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12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Contraception Guidance
Male participants
!
Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined time 
frame in Section 6.1:
!
Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent
!
Agree to use a male condom plus an additional method of contraception with a 
failure rate of < 1% per year as described in Table 2 when having penile-vaginal 
intercourse with a woman of childbearing potential 
!
Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile 
penetration during the protocol-defined time frame
!
Refrain from donating sperm for duration of study and until follow-up visit
Table 2
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of < 1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulationb
!
oral
!
intravaginal 
!
transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb
!
injectable 
Highly Effective Methods That Are User Independent 
!
Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb
!
Intrauterine device (IUD)
!
Intrauterine hormone-releasing system (IUS)
!
bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 


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the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.)
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)
NOTES: 
a. Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for participants in clinical studies.
b. Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of the 
contraceptive method. In this case two highly effective methods of contraception should be utilized during the 
treatment period and for at least, corresponding to time needed to eliminate study treatment plus 30 days for study 
treatments with genotoxic potential  after the last dose of study treatment.
Collection of Pregnancy Information
Male participants with partners who become pregnant
!
Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to participants who receive study treatment.
!
After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy. 
!
Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK.
!
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 


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12.6.
Appendix 6: Liver Safety Required Actions and Follow-up 
Assessments
Phase I liver chemistry stopping criteria and required follow-up assessments
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT ≥3xULN
If ALT ≥3xULN AND bilirubin1,2 ∀2xULN (> 35% direct bilirubin) or INR > 1.5, 
Report as an SAE.
See additional Actions and Follow-Up Assessments listed below
Required Actions and Follow-up Assessments 
Actions
Follow-Up Assessments
!
Report the event to GSK within 24 hrs
!
Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2
!
Perform liver event follow-up assessments 
!
Monitor the subject until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT ≥3xULN AND bilirubin ∀2xULN or INR 
> 1.5
!
Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow-up assessments within
24 hrs
!
Monitor subjects twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline
!
A specialist or hepatology consultation is 
recommended
If ALT ≥3xULN AND bilirubin < 2xULN and 
INR ≤1.5:
!
Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow-up assessments within 24-
72 hrs
!
Viral hepatitis serology3
!
Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend
!
Obtain blood sample for PK analysis, 
obtained within 24 hrs of the dose
!
Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH)
!
Fractionate bilirubin, if total bilirubin
∀2xULN
!
Obtain complete blood count with 
differential to assess eosinophilia
!
Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form
!
Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications
!
Record alcohol use on the liver event 
alcohol intake case report form
If ALT ≥3xULN AND bilirubin ≥2xULN or 
INR > 1.5:
!
Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 


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Liver Chemistry Stopping Criteria 
!
Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins
!
Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in subjects with definite or likely 
acetaminophen use in the preceding week 
[James LP, 2009]
!
Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and/or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT ∀3xULN and bilirubin ∀2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT ∀3xULN and bilirubin ∀2xULN (> 35% direct bilirubin) or ALT ∀3xULN and INR > 1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will 
not apply to subjects receiving anticoagulants.
3.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); Hepatitis E IgM antibody.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Protein Adducts in Adults with 
Acetaminophen Overdose and Acute Liver Failure. Drug Metabolism and Disposition
2009; 37 (8): 1779-1784.


2017N318316_00
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12.7.
Appendix 7: Country-specific requirements
Not applicable.


2017N318316_00
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12.8.
Appendix 8: Protocol Amendment History
Not applicable.

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
204678
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for 204678
A single centre, open-label, parallel-group, single oral dose 
study to evaluate the pharmacokinetic, safety and tolerability 
of Pyrimethamine in healthy Japanese and Caucasian male
subjects
Compound Number 
:
GR99352
Effective Date 
:
15-SEP-2017
Description :

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 204678.

This RAP is intended to describe the Pharmacokinetic (PK) and safety analyses 
required for the study. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
Author’s Name and Functional Area: 
23-AUG-2017
Biostatistics Group 1 , Biomedical Data Sciences Dept.
23-AUG-2017
Clinical Pharmacology & Science Promotion Office.
23-AUG-2017
Statistical Programming & Reporting Group, Biomedical Data 
Sciences Dept.
Approved by (Approvals captured electronically in CARS system): 
15-SEP-2017
Manager, Statistical Programming & Reporting Group, Biomedical 
Data Sciences Dept.
15-SEP-2017
Manager, Biostatistics Group 1 , Biomedical Data Sciences Dept.
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNPOSIS.........................................................4
1.1.
History ..........................................................................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Objective(s) and Endpoint(s)...............................................................6
2.3.
Study Design ................................................................................................7
2.4.
Statistical Hypotheses...................................................................................7
3.
PLANNED ANALYSES ............................................................................................7
3.1.
Interim Analyses ...........................................................................................7
3.2.
Final Analyses ..............................................................................................7
4.
ANALYSIS POPULATIONS .....................................................................................8
4.1.
Protocol Deviations.......................................................................................8
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.......................................................................................................9
6.
STUDY POPULATION ANALYSES .......................................................................10
6.1.
Overview of Planned Analyses ...................................................................10
7.
SAFETY ANALYSES .............................................................................................11
7.1.
Overview of Planned Analyses ...................................................................11
7.2.
Overview of Planned Clinical Laboratory Analyses .....................................11
7.3.
Overview of Planned Other Safety Analyses...............................................12
8.
PHARMACOKINETIC ANALYSES.........................................................................13
8.1.
Overview of Planned Pharmacokinetic Analyses ........................................13
8.2.
Drug Concentration Measures ....................................................................13
8.3.
Pharmacokinetic Parameters......................................................................14
8.3.1.
Derived Pharmacokinetic Parameters..........................................14
8.3.2.
Summary of Pharmacokinetic Parameters...................................16
9.
REFERENCES.......................................................................................................17
10. APPENDICES........................................................................................................18
10.1.
Appendix 1: Protocol Deviation Management .............................................19
10.2.
Appendix 2: Time & Events.........................................................................20
10.2.1.
Protocol Defined Time & Event....................................................20
10.3.
Appendix 3: Treatment States and Phases.................................................22
10.3.1.
Treatment Phases .......................................................................22
10.4.
Appendix 4: Data Display Standards & Handling Conventions....................23
10.4.1.
Study Treatment & Sub-group Display Descriptors......................23
10.4.2.
Baseline Definition & Derivations .................................................23
10.4.3.
Reporting Process & Standards...................................................23
10.5.
Appendix 5: Derived and Transformed Data ...............................................26
10.5.1.
General........................................................................................26
10.5.2.
Study Population..........................................................................26


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10.5.3.
Safety ..........................................................................................27
10.5.4.
Pharmacokinetic ..........................................................................28
10.6.
Appendix 6: Premature Withdrawals & Handling of Missing Data ...............29
10.6.1.
Premature Withdrawals................................................................29
10.6.2.
Handling of Missing Data.............................................................29
10.7.
Appendix 7: Values of Potential Clinical Importance ...................................30
10.7.1.
Laboratory Values........................................................................30
10.7.2.
ECG.............................................................................................31
10.7.3.
Vital Signs....................................................................................31
10.8.
Appendix 8 – Abbreviations & Trade Marks ................................................32
10.8.1.
Abbreviations...............................................................................32
10.8.2.
Trademarks .................................................................................32
10.9.
Appendix 9: List of Data Displays ...............................................................33
10.9.1.
Data Display Numbering..............................................................33
10.9.2.
Mock Example Shell Referencing ................................................33
10.9.3.
Deliverable [Priority].....................................................................33
10.9.4.
Study Population Tables..............................................................34
10.9.5.
Safety Tables...............................................................................35
10.9.6.
Pharmacokinetic Tables...............................................................37
10.9.7.
Pharmacokinetic Figures .............................................................38
10.9.8.
ICH Listings .................................................................................40
10.10. Appendix 10: Example Mock Shells for Data Displays ................................43


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1.
REPORTING & ANALYSIS PLAN SYNPOSIS
Overview
Key Elements of the RAP
Purpose

The purpose of this RAP is to describe the planned analyses and 
output to be included in the Clinical Study Report for Protocol 
204678.
Protocol

This RAP is based on the original protocol Dated:19/JUL/2017 of 
study204678 (GSK Document Number.: 2017N318316_00).
Primary 
Objective 

To investigate PK following a single oral dose of Pyrimethamine 
50 mg in fasted healthy Japanese male subjects.
Primary 
Endpoint

Cmax, AUC(0-t), AUC(0-inf), AUC(0-24), tmax, t1/2, CL/F, 
Vd/F from the plasma concentrations of Pyrimethamine in healthy 
Japanese male subjects, as data permit.
Study Design

This study will be a single centre, open-label, parallel-group, 
single oral dose study to evaluate the pharmacokinetic (PK), 
safety and tolerability of Pyrimethamine in healthy Japanese and 
Caucasian male subjects.

Sufficient Japanese and Caucasian healthy male volunteer 
subjects will be enrolled such that 6 subjects of each population 
complete dosing and critical assessments.
Analysis 
Populations

Screened: Consisting of all participants screened in the study.

Screening Failure: Participants who sign the ICF in the study but 
are never subsequently administered study treatment.

Safety: All participants who take at least one dose of study 
treatment.

Pharmacokinetic: This population is defined as all participants 
administered at least one dose of study treatment and who have 
PK sample taken and analyzed.
Hypothesis

The objectives of this study are to evaluate safety and tolerability 
of Pyrimethamine and to estimate Pyrimethamine 
pharmacokinetic parameters in healthy male Japanese and 
Caucasian subjects. No formal statistical hypotheses will be 
tested. Descriptive statistics will be used to assess safety and 
tolerability objectives. An estimation approach will be used to 
address the pharmacokinetic study objectives, where point 
estimates and corresponding 95% confidence intervals will be 
constructed, unless otherwise stated.


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Overview
Key Elements of the RAP
Pharmacokinetic 
Analyses

Individual Pyrimethamine plasma concentration-time profiles (by 
group, and subject) and median/mean (±SD) profiles by group 
will be plotted and listed. 

Plasma concentration time data for Pyrimethamine will be 
analyzed by non-compartmental methods using Phoenix 
WinNonlin (version 6.3 or higher) and all derived PK parameters 
will be graphically presented, summarised and listed. No formal 
statistical analyses will be conducted.
Safety Analyses

Safety data will be presented in tabular and/or graphical format 
and summarised descriptively.
1.1.
History
Version
Issue Date
Amendments
Reason
00
15-SEP-2017
Original (New document)
-


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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were no changes or deviations to the originally planned statistical analysis 
specified in the protocol (Dated: 19/JUL/2017).
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To investigate PK following single 
dose of Pyrimethamine 50 mg in 
fasted status in healthy Japanese 
male subjects.

Cmax, AUC(0-t), AUC(0-inf), AUC(0-24), tmax, t1/2, 
CL/F, Vd/F of the plasma concentration of Pyrimethamine 
in healthy Japanese male subjects, as data permit.
Secondary Objectives
Secondary Endpoint

To investigate PK following single 
dose of Pyrimethamine 50 mg in 
fasted status in healthy Caucasian 
male subjects.

Cmax, AUC(0-t), AUC(0-inf), AUC(0-24), tmax, t1/2, 
CL/F, Vd/F of the plasma concentration of Pyrimethamine
in healthy Caucasian male subjects, as data permit.

To assess safety and tolerability 
following single dose of 
Pyrimethamine in fasted status in 
healthy Japanese and Caucasian 
male subjects.

AE and change from the baseline of clinical laboratory 
values, vital signs and ECG.


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2.3.
Study Design
Overview of Study Design and Key Features
Design
Features

This study will be a single centre, open-label, parallel-group, single oral dose 
study to evaluate the PK, safety and tolerability of Pyrimethamine in healthy 
male Japanese and Caucasian subjects.
Dosing

Subjects will have a screening visit within 30 days prior to the first dose of 
study treatment, one treatment period, and re-visits 15 (±1) and 22 (±1) days 
after the dose for follow-up assessments including PK sampling. 

Subjects will be housed in the Clinical Research Unit from Day -1 through Day 
8, and return to the unit on Day 15 (±1) and 22 (±1) for the remaining PK 
samples and safety assessments post dose. 

During the treatment period, subjects will receive single dose of Pyrimethamine 
50 mg in the fasted state after overnight fast (at least 10 hours). Calcium 
folinate 15 mg will be coadministered with Pyrimethamine at Day 1, and will 
continue to be administered once a day until Day 8. 

Blood sampling for PK analysis and safety assessments will be performed prior 
to dosing and over 22 days after dosing. The duration of each subject’s 
participation will be approximately 2 months from screening to the follow-up.
Treatment 
Assignment

Sufficient Japanese and Caucasian healthy male subjects will be enrolled 
such that 6 subjects of each population complete dosing and critical 
assessments.
Interim 
Analysis

No interim analyses will be planned.
2.4.
Statistical Hypotheses
The objectives of this study are to evaluate safety and tolerability of Pyrimethamine and 
to estimate Pyrimethamine pharmacokinetic parameters in healthy Japanese and 
Caucasian male subjects. No formal statistical hypotheses will be tested. Descriptive 
statistics will be used to assess safety and tolerability objectives by group (Japanese, 
Caucasian). An estimation approach will be used to address the pharmacokinetic study 
objectives, where point estimates and corresponding 95% confidence intervals will be 
constructed, unless otherwise stated. 
3.
PLANNED ANALYSES
3.1.
Interim Analyses
An interim analysis is not planned.
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:


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8
1.
All subjects have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management.
3.
Even though single arm study, randomisation codes have been distributed according 
to RandAll NG procedures.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened

Consisting of all participants screened in the 
study

Study Population
Screening Failure

Participants who sign the ICF in the study but 
are never subsequently administered study 
treatment. All participants who sign the ICF
have the screening test in the study. 

Study Population
Safety

All participants who take at least one dose of 
study treatment.

Study Population

Safety
Pharmacokinetic

This population is defined as all participants 
administered at least one dose of study 
treatment and who have PK sample taken and 
analysed.

PK
4.1.
Protocol Deviations

Important protocol deviations (including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarised and listed.

Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan.
o
Data will be reviewed prior to freezing the database to ensure all important 
deviations and deviations which may lead to exclusion from the analysis are 
captured and categorised on the protocol deviations dataset. 
o
This dataset will be the basis for the summaries and listings of protocol 
deviations.

A separate listing of all inclusion/exclusion criteria deviations will also be provided. 
This will be based on data as recorded on the inclusion/exclusion page of the eCRF.


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
Table 1 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 1
Overview of Appendices
Section
Component
10.1
Appendix 1: Protocol Deviation Management 
10.2
Appendix 2: Time & Events
10.3
Appendix 3: Treatment States and Phases
10.4
Appendix 4: Data Display Standards & Handling Conventions
10.5
Appendix 5: Derived and Transformed Data
10.6
Appendix 6: Premature Withdrawals & Handling of Missing Data
10.7
Appendix 7: Values of Potential Clinical Importance


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population analyses will be based on the Safety population, unless otherwise 
specified.
Table 2 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 9: List of Data Displays.
Table 2
Overview of Planned Study Population Analyses
Display Type
Data Displays Generated
Table
Figure
Listing
Subject Disposition
Subject Disposition and Reason for Study Withdrawal
Y
Y
Screening Status and Reasons for Screen Failure
Y
Y
Protocol Deviations
Important Protocol Deviations
Y
Y
Subjects with Inclusion/Exclusion Criteria Deviations
Y
Populations Analysed
Study Populations
Y
Subjects Excluded from Any Population
Y
Demographic and Baseline Characteristics
Demographic Characteristics
Y
Y
Demographic Characteristics for Screening Failure
Y
Age Ranges
Y
Race and Racial Combinations
Y
Y
Race and Racal Combination for Failure
Y
Medical Conditions and Concomitant Medications
Medical Conditions
Y
Concomitant Medications
Y
Exposure and Treatment Compliance
Exposure to Study Treatment
Y
NOTES :

Y = Yes display generated.


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7.
SAFETY ANALYSES
The safety analyses will be based on the Safety population, unless otherwise specified.
7.1.
Overview of Planned Analyses
Table 3 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 9: List of Data Displays.
Table 3
Overview of Planned Safety Analyses
Display Type
Absolute
Summary
Individual
T
F
L
Adverse Events (AEs)
All AEs by SOC and PT
Y
Y
All AEs by Maximum Intensity
Y
Drug-Related AEs by SOC and PT
Y
Drug-Related AEs by Maximum Intensity
Y
Subject Numbers for Individual AEs
Y
Relationship Between AE SOCs, PT and Verbatim Text
Y
Serious and Other Significant AEs
Serious AEs
Y
AEs Leading to Withdrawal from Study 
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, SOC = System Organ Class, PT = Preferred 
Term.

Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
7.2.
Overview of Planned Clinical Laboratory Analyses
Table 4 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 9: List of Data Displays.
Table 4
Overview of Planned Clinical Laboratory Analyses
Display Type
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
F
L
T
F
L
Chemistry
Chemistry Data
Y
Y
Y
Y
Chemistry Results Relative to Normal Range
Y
All Chemistry Data for Subjects with any Value of 
Potential Clinical Concern/PCI
Y


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Display Type
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
F
L
T
F
L
Hematology
Hematology Data
Y
Y
Y
Y
Hematology Results Relative to Normal Range
Y
All Hematology Data for Subjects with any Value of 
Potential Clinical Concern/PCI
Y
Urinalysis
Dipstick Data (Glucose, Protein, Blood, Ketones, 
Bilirubin, Urobilinogen)
Y
Y*
Gravity and pH
Y
Y
Hepatobiliary (Liver)
Liver Monitoring/Stopping Event Reporting
Y
Medical Conditions for Subjects with Liver Stopping 
Events
Y
Substance Use for Subjects with Liver Stopping Events
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, PCI = Potential Clinical Importance

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.
Individual = Represents FL related to any displays of individual subject observed raw data.
*: If blood or protein is abnormal, microscopic examination will be included.
7.3.
Overview of Planned Other Safety Analyses
Table 5 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 9: List of Data Displays.
Table 5
Overview of Planned Other Safety Analyses
Display Type
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
F
L
T
F
L
ECG
ECG Findings
Y
Y
ECG Values
Y
Y
Y
Y
All ECG Values for Subjects with any Value of PCI
Y
Vital Signs
Vitals Values
Y
Y
Y
Y
All Vital Signs for Subjects with any Value of PCI
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, PCI = Potential Clinical Importance

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.


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8.
PHARMACOKINETIC ANALYSES
8.1.
Overview of Planned Pharmacokinetic Analyses
The pharmacokinetic (PK) analyses will be based on the Pharmacokinetic population, 
unless otherwise specified.
Table 6 provides an overview of the planned analyses, with full details being presented in
Appendix 9: List of Data Displays.
Table 6
Overview of Planned Pharmacokinetic Analyses
Display Type
Untransformed
Log-Transformed
Summary
Individual
Summary
Individual
F
T
F
L
F
T
F
L
Plasma Drug Concentrations
Y [1] [2]
Y
Y [1]
Y
Derived PK Parameters
Y
Y
Y
Y
NOTES :

T = Table, F = Figures, L = Listings, Y = Yes display generated.

Summary = Represents TFL related to any summaries (descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
1.
Linear and Semi-Log plots will be created on the same display.
2.
Separate Mean (± SD) and Median plots will be generated.
8.2.
Drug Concentration Measures
Plasma concentrations of Pyrimethamine at each nominal time will be listed and 
summarised by group. Standard summary statistics will be calculated (i.e. mean, standard 
deviation, median, minimum and maximum).
Individual plasma concentration-time profiles and median/mean profiles by group will be 
plotted. Each of the figures will contain one plot on the untransformed scale (i.e. a linear 
plot) and one plot on the log transformed scale (i.e. log-linear plot).
All individual plasma concentration-time profiles will be plotted. Each of the figures will 
contain one plot on the untransformed scale (i.e. a linear plot) and one plot on the log 
transformed scale (i.e. log-linear plot).
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 10.4.3
Reporting Process & Standards).


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8.3.
Pharmacokinetic Parameters
8.3.1.
Derived Pharmacokinetic Parameters

Derivation of pharmacokinetic parameters will be performed by, or under the direct 
auspices of, Clinical Pharmacology & Science Promotion Office, GlaxoSmithKline 
K.K.

Refer to Appendix 4: Data Display Standards & Handling Conventions 
(Section 10.4.3 Reporting Process & Standards).

The pharmacokinetic parameters will be calculated by non-compartmental analysis 
using Phoenix WinNonlin (version 6.3 or higher)

All calculations of non-compartmental parameters will be based on actual sampling 
times recorded during the study.
Pharmacokinetic parameters described in Table 7 will be determined from plasma 
Pyrimethamine concentration-time data, as data permits. 


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Table 7
Derived Pharmacokinetic Parameters
Parameter
Parameter Description
AUC(0-24)
Area under the concentration-time curve will be calculated to fixed nominal time 24 hours 
after administration (AUC(0-24)),using the combination of linear and logarithmic trapezoidal 
methods (i.e., Linear Up/Log Down calculation method in Phoenix WinNonlin) .
If a sampling time deviation occurred at nominal time 24 hours after administration (and 24 < 
t), AUC(0-24) will be calculated using the concentration at time 24 hours after administration 
post-dose estimated by the method of interpolation.
If nominal time 24 hours after administration > t (or if the concentration at time 24 hours after 
administration was below the limit of quantification), then the concentration (y) at time 24 
hours after administration is estimated using λz and last observed Ct according to the 
formula:
y=Ct(obser) x e-lambda_z(24-t)
Then the following equation will be used to calculate AUC(0-24) where t is the time of last 
quantifiable plasma concentration.
AUC(0-24) = AUC(0-t) + AUC(t-24)
If lambda_z is not estimable, AUC(0-24) is not calculated (when 24 > t).
AUC(0-t)
Area under the concentration-time curve from time zero time (pre-dose) to the time of last 
quantifiable concentration (AUC(0-t)) will be calculated by a combination of linear and 
logarithmic trapezoidal methods. The linear trapezoidal method will be employed for all 
incremental trapezoids arising from increasing concentrations and the logarithmic 
trapezoidal method will be used for those arising from decreasing concentrations (i.e., Linear 
Up/Log Down calculation method in Phoenix WinNonlinl).
AUC(0-inf)
Area under the concentration-time curve from zero time (pre-dose) extrapolated to infinite 
time (AUC(0-inf)) will be calculated as follows: 
AUC(0-inf) = AUC(0-t) + C(t) / lambda_z
%AUCex
The percentage of AUC (0-∞) obtained by extrapolation (%AUCex) will be calculated as:
%AUCex = [AUC(0-inf) – AUC(0-t)] / AUC(0-inf) x 100
Cmax
Maximum observed concentration will be obtained directly from the concentration-time data.
Tmax
Time to first occurrence of Cmax will be obtained directly from the concentration-time data.
t½
Apparent terminal phase half-life will be calculated as: 
t½ = ln2 / lambda_z
Tlast
The time of the last measurable (positive) concentration.
lambda_z
The first order rate constant associated with the terminal (log-linear) portion of the curve.
lambda_z
lower
The lower limit on time for values to be included in the calculation of lambda_z.
lambda_z
upper
The upper limit on time for values to be included in the calculation of lambda_z.
#pts
The number of time points used in computing lambda_z.
R-square
Square of the correlation coefficient.
CL/F
Apparent clearance following oral dosing will be calculated as:
CL/F = Dose / AUC (0-inf)
Vd/F
Apparent volume of distribution following oral dosing will be calculated as:
Vd/F = Dose / lambda_z * AUC(0-inf)


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NOTES:

Additional parameters may be included as required.

Lambda_z is the terminal phase rate constant.

Ct is the last observed quantifiable concentration.
8.3.2.
Summary of Pharmacokinetic Parameters

For each of these parameters, except for tmax, the following summary statistics will 
be calculated for each treatment:
o
Non-transformed: median, maximum, minimum, arithmetic mean, 95% 
confidence interval for the arithmetic mean and standard deviation
o
Loge-transformed: geometric mean, 95% confidence interval for the geometric 
mean, standard deviation of logarithmically transformed data and between 
geometric coefficient of variation (CVb (%))

For tmax, median, maximum, minimum, arithmetic mean, standard deviation and 
95% Confidence Interval (CI) for the arithmetic mean will be calculated.

An exploratory analysis will be performed using PK parameter plots in order to 
assess the results in Japanese and Caucasian subjects. Plots of AUC(0-t), AUC(0-inf), 
Cmax and T1/2 versus group (Japanese, Caucasian) will be produced.


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9.
REFERENCES
GlaxoSmithKline Document Numbers 2017N318316_00 Study Protocol of 204678. A 
single centre, open-label, parallel, single oral dose study to evaluate the pharmacokinetic, 
safety and tolerability of Pyrimethamine in healthy Japanese and Caucasian subjects  
(Effective date: 19-JUL-17)


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10.
APPENDICES
Section
Appendix
RAP Section 4 : Analysis Populations
Section 10.1
Appendix 1: Protocol Deviation Management 
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions
Section 10.2
Appendix 2: Time and Events
Section 10.3
Appendix 3: Treatment States & Phases
Section 10.4
Appendix 4: Data Display Standards & Handling Conventions

Study Treatment & Sub-group Display Descriptors

Baseline Definitions & Derivations

Reporting Process & Standards
Section 10.5
Appendix 5: Derived and Transformed Data

General 

Study Population 

Safety

Pharmacokinetic
Section 10.6
Appendix 6: Premature Withdrawals & Handling of Missing Data

General

Study Population & Safety
Section 10.7
Appendix 7: Values of Potential Clinical Importance

Laboratory Values

ECG

Vital Signs
Other RAP Appendices
Section 10.8
Appendix 8: Abbreviations & Trade Marks
Section 10.9
Appendix 9: List of Data Displays
Section 10.10
Appendix 10: Example Mock Shells for Data Displays


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10.1.
Appendix 1: Protocol Deviation Management
Details will be referred latest Protocol Deviation Management Plan and data handling 
will be decided prior to final data base release.


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10.2.
Appendix 2: Time & Events
10.2.1.
Protocol Defined Time & Event
Scr
Day 
-1
Day 1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Day 
8
Day 
15 4
Follow-
up
Day 22 4
Pre
0 h
1 h
2 h
4 h
6 h
12 h
24 h
48 h
72 h
96 h
120 
h
144 
h
168 
h
336 
h
504 h
Admission to Unit
X
Informed consent
X
Subject 
demography/Medical 
history
X
Physical examination
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine drug screen
X
X
Alcohol breath test
X
X
CO breath test
X
X
Serological test
X
Haematology, clinical 
chemistry and urinalysis
X
X
X
X
X
X
X
Study treatment dosing
X
Calcium folinate dosing
X 1
X
X
X
X
X
X
X
PK Sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
SAEs 2
===========================================================================================================
AEs 3
========================================================================================  
Con Med review
===========================================================================================================
Discharge
X
Outpatient Visit
X
X
X


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1.
Calcium folinate will be coadministered with Pyrimethamine on Day 1.
2.
All SAEs will be collected from the signing of the ICF until the follow-up visit at the time points specified.
3.
All AEs will be collected from the start of treatment until the follow-up visit at the time points specified.
4.
Subjects will return to the unit on Day 15 (±1) and 22 (±1) for the remaining PK samples and safety assessments post dose.


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10.3.
Appendix 3: Treatment States and Phases
10.3.1.
Treatment Phases
Assessments and events will be classified according to the time of occurrence relative to 
the assessment date.
10.3.1.1.
Treatment States for AE Data
Treatment State
Definition
Pre-Treatment
AE Start Date < Study Treatment Start Date and Time
On treatment 
Dosing Start Date and Time in each group ≤ AE Start Date and Time
Onset Time Since 
First Dose
(Minute)
If Dosing Start Date and Time ˃ AE Onset Date and Time = AE Onset Date and Time –
Dosing Start Date and Time
If dosing Start Date and Time ≤ AE Onset Date and Time = AE Onset Date and Time -
Dosing Start Date and Time +1
Missing otherwise
Onset Time Since 
Last Dose 
(Minute)
AE Start Date and Time – Most Recent Treatment Start Date and Time + 1
Duration (Minute) 
AE Resolution Date and Time – AE Onset Date and Time + 1
Drug-related
If relationship is marked ‘YES’ on eCRF


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10.4.
Appendix 4: Data Display Standards & Handling 
Conventions
10.4.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Schedule
Description
Description
Order [1]
1
D
Caucasian
2
2
D
Japanese
1
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.
10.4.2.
Baseline Definition & Derivations
10.4.2.1.
Baseline Definitions
Parameter
Study Assessments Considered 
As Baseline
Baseline Used in 
Data Display
Screening
Day -1
Day 1   
(Pre-Dose)
Safety
12 Lead ECG & Vital Signs
X
X
Day 1
(Pre Dose)
Haematology 
X
X
Day -1
Clinical Chemistry
X
X
Day -1
10.4.2.2.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
NOTES :

Unless otherwise specified, the baseline definitions specified in Section 10.4.2.1 Baseline Definitions will be used 
for derivations for endpoints / parameters and indicated on summaries and listings.

Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing.
10.4.3.
Reporting Process & Standards
Reporting Area
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
N/A


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Reporting Area
HARP Area
N/A
QC Spreadsheet
N/A
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.1.3 & 
AdaM IG Version 1.0).
Generation of RTF Files

N/A 
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated:
o
4.03 to 4.23: General Principles
o
5.01 to 5.08: Principles Related to Data Listings
o
6.01 to 6.11: Principles Related to Summary Tables
o
7.01 to 7.13: Principles Related to Graphics 
Formats

All data will be reported according to the actual treatment the subject received unless 
otherwise stated.

GSK IDSL Statistical Principles (4.24) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected.

Numeric data will be reported at the precision collected on the eCRF.
o
The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of DP’s.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses :

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated..

For PK parameters derivation, actual times are used.

The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 

Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will 
be included in listings but omitted from figures, summaries and statistical analyses.
Unscheduled Visits

Unscheduled visits will not be included in summary tables.

Unscheduled visits will not be included in figures.


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Reporting Standards

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Reporting of Pharmacokinetic Concentration Data
Descriptive 
Summary Statistics
Refer to IDSL Statistical Principle 6.06.1
Assign zero to NQ values (Refer to GUI_51487 for further details)
Reporting of Pharmacokinetic Parameters
Descriptive 
Summary Statistics
(Log Transformed)
N, n, geometric mean, 95% CI of geometric mean, standard deviation (SD)
of logged data and between geometric coefficient of variation (CVb (%)) will 
be reported.
CVb (%) = √(exp(SD2) - 1) * 100
(SD = SD of log transformed data)
Parameters Not 
Being Log 
Transformed
Tmax
Parameters Not 
Being Summarised
The following PK parameters will not be summarised but listed: %AUCex, 
Tlast, lambda_z, lambda_z_lower, lambda_z_upper, #pts, R2
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.


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10.5.
Appendix 5: Derived and Transformed Data
10.5.1.
General
Multiple Measurements at One Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics 
but if listed, all data will be presented.

If there are two values within a time window the value closest to the target day for that window 
will be used. If values are the same distance from the target then the mean will be taken.

Subjects having both High and Low values for Normal Ranges at any post-baseline visits for 
safety parameters will be counted in both the High and Low categories of “Any visit post-
baseline” row of related summary tables. This will also be applicable to relevant Potential 
Clinical Importance summary tables.
Study Day

Calculated as the number of days from study day of start of dosing date :
o
Ref Date = Missing           → Study Day = Missing 
o
Ref Date < Dosing Start Date → Study Day = Ref Date – Dosing Start Date
o
Ref Data ≥ Dosing Start Date → Study Day = Ref Date – (Dosing Start Date) + 1
10.5.2.
Study Population
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as:
o
Any subject with a missing day will have this imputed as day ‘15’.
o
Any subject with a missing date and month will have this imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.

Reference date for calculation of age at screening will be from visit 1 (Screening visit) date, 
however this will be from screen failure date for a screen failure subject.

Analysis age group will be categorized (Years):
   <=18, 19-64, 65-74, >=75

Age will be categorized for EudraCT:
   Adults (18-64 years)
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)2


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10.5.3.
Safety
ECG Parameters
RR Interval

IF RR interval (msec) is not provided directly, then RR can be derived as :
[1]  If QTcB is machine read & QTcF is not provided, then :
[2]  If QTcF is machine read and QTcB is not provided, then: 

If ECGs are manually read, the RR value preceding the measurement QT interval should be a 
collected value THEN do not derive.
Corrected QT Intervals

When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and 
Fredericia’s (QTcF) formulas will be calculated, in msec, depending on the availability of other 
measurements.

IF RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as : 
Laboratory Parameters

If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the 
comment field) is present, the number of significant digits in the observed values will be used to 
determine how much to add or subtract in order to impute the corresponding numeric value. 
o Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01
o Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1
o Example 3: 0 Significant Digits = ‘< x’ becomes x – 1
Laboratory Assessments
Haematology
Platelet Count, RBC Count, Haemoglobin, Hematocrit, RBC Indices (MCV, 
MCH, MCH, %Reticulocytes), WBC count with Differential (Neutrophils, 
Lymphocytes, Monocytes, Eosinophils, Basophils)
Clinical Chemistry
BUN, Creatinine, Glucose (fasting), Potassium, Sodium, Calcium, Aspartate 
Aminotransferase (AST), Alanine Aminotransferase (ALT), Alkaline 
phosphatise, Total and direct bilirubin, Total Protein
Routine Urinalysis
Specific gravity, pH (assessed by dipstick)

glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick


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Laboratory Assessments

Microscopic examination (if blood or protein is abnormal)
ECG (12-lead ECG)
ECG findings, ECG values (Heart rate, PR interval, QRS duration, QT interval, and QTcF intervals)
Vital Signs
Pulse rate, Blood pressure (Systolic, Diastolic), respiratory rate, Temperature
10.5.4.
Pharmacokinetic
PK Parameters

If one or more non-quantifiable (NQ) values occur in a profile before the first measurable
concentration, they will be assigned a value of zero concentration. For linear plots, zero
concentration value(s) before the first measurable concentration will be included in the plot. For 
log-linear plots, zero concentration value(s) before the first measurable concentration will be 
assigned a missing value.

If a single NQ value occurs between measurable concentrations in a profile, the NQ should 
generally be set to missing in the derivation of pharmacokinetic parameters, statistical analysis, 
and the individual subject plots.

If two or more NQ values occur in succession between measurable concentrations, the profile 
will be deemed to have terminated at the last measurable concentration prior to these NQs. For 
the purpose of individual subject plots, these NQs will be set to 0, and the subsequent 
measurable concentrations will be retained. For the derivation of pharmacokinetic parameters, 
these NQs and any subsequent measurable concentrations will be set to missing.

NQs which occur after the last measurable concentration will be omitted (set to missing) in the 
derivation of pharmacokinetic parameters and from the individual subject plots.

Individual’s PK parameters reported as 'NC' (Not Calculable) or 'ND' (Not Determined) will be 
included in listings but omitted (set to missing) from figures, summaries and statistical analyses.


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10.6.
Appendix 6: Premature Withdrawals & Handling of Missing 
Data
10.6.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion was defined as a participant has completed all phases 
of the study including the last visit or the last scheduled procedure (Follow-up)
as described in the protocol.

Withdrawn subjects maybe replaced in the study.

All available data from subjects who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, 
unless otherwise specified.
10.6.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument:
o These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table.
o Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
10.6.2.1.
Handling of Partial Dates
Element
Reporting Detail
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.


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10.7.
Appendix 7: Values of Potential Clinical Importance
10.7.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 1
Male
0.54
Female
0.54
∆from BL
↓0.075
Hemoglobin 
g/L
Male
180
Female
180
∆from BL
↓25
Lymphocytes 
x109/ L
0.8
Neutrophil Count 
x109/ L
1.5
Platelet Count 
x109/ L
100
550
While Blood Cell Count (WBC)
x109/ L
3
20
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Calcium
mmol/L
2
2.75
Creatinine
μmol/L
∆from BL
↑ 44.2
Glucose
mmol/L
3
9
Potassium
mmol/L
3
5.5
Sodium
mmol/L
130
150
Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
2x ULN
AST/SGOT 
U/L
High
2x ULN
AlkPhos 
U/L
High
2x ULN
T Bilirubin 
µmol/L
High
1.5xULN
T. Bilirubin + ALT
µmol/L
High
1.5xULN T. Bilirubin
+
U/L
2x ULN ALT


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10.7.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 450 [1]
Absolute PR Interval
msec
< 110 [1]
> 220 [1]
Absolute QRS Interval
msec
< 75 [1]
> 110 [1]
Change from Baseline
Increase from Baseline QTc
msec
> 60 [1]
NOTES:
1.
Represent standard ECG values of PCI for HV studies
10.7.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 85
> 160
Diastolic Blood Pressure
mmHg
< 45
> 100
Heart Rate
bpm
< 40
> 110


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10.8.
Appendix 8 – Abbreviations & Trade Marks
10.8.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
A&R
Analysis and Reporting 
AUC
Area under the concentration-time curve
AUC(0-inf)
Area under the concentration-time curve from time 0 to infinity
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
Cmax
Maximum observed concentration
CSR
Clinical Study Report
CVb 
Coefficient of Variation (Between) 
eCRF
Electronic Case Record Form
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IDSL
Integrated Data Standards Library
GUI
Guidance
PCI
Potential Clinical Importance 
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
SAC
Statistical Analysis Complete
SDTM
Study Data Tabulation Model
TFL
Tables, Figures & Listings 
GSK
GlaxoSmithKline
10.8.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
SAS
WinNonlin


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10.9.
Appendix 9: List of Data Displays
10.9.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.7
N/A
Safety
2.1 to 2.17
N/A
Pharmacokinetic
3.1 to 3.3
4.1 to 4.13
Section
Listings
ICH Listings
1 to 36
Other Listings
N/A
10.9.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required an example 
mock-up displays provided in Appendix 10: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / TST ID / Example Shell’ or ‘Programming Notes’ column as 
‘[Non-Standard] + Reference.’
10.9.3.
Deliverable [Priority]
Delivery [Priority] [1]
Description
SAC [X]
Final Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort.


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10.9.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
Safety 
ES1
Summary of Subject Disposition
Completed or withdrawn and the 
reason for withdrawal.
SAC [1]
1.2.
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure
The number (%) of Randomized or 
screening failure subjects as the 
screening status, and the reason for 
screening failure.
SAC [1]
Protocol Deviation
1.3.
Safety 
DV1
Summary of Important Protocol Deviations
Data is from DV dataset.
SAC [1]
Population Analysed
1.4.
Safety 
SP1
Summary of Study Populations
SAC [1]
Demographic and Baseline Characteristics
1.5.
Safety 
DM1
Summary of Demographic Characteristics
SAC [1]
1.6.
Screened
DM11
Summary of Age Ranges
Adults (18-64 years)
1.7.
Safety 
DM5
Summary of Race and Racial Combinations
SAC [1]


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10.9.5.
Safety Tables
Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
2.1.
Safety
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term
SAC [1]
2.2.
Safety
AE5A
Summary of All Adverse Events by Maximum Intensity 
SAC [1]
2.3.
Safety
AE1
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term
SAC [1]
2.4.
Safety
AE5A
Summary of All Drug-Related Adverse Events by Maximum 
Intensity 
SAC [1]
Laboratory: Chemistry 
2.5.
Safety
LB1
Summary of Chemistry 
SAC [1]
2.6.
Safety
LB1
Summary of Chemistry Changes from Baseline
SAC [1]
2.7.
Safety
LB4
Summary of Chemistry Data Shifts from Baseline with Respect 
to the Normal Range
SAC [1]
Laboratory: Hematology
2.8.
Safety
LB1
Summary of Hematology
SAC [1]
2.9.
Safety
LB1
Summary of Hematology Changes from Baseline
SAC [1]
2.10.
Safety
LB4
Summary of Hematology Data Shifts from Baseline with Respect 
to the Normal Range
SAC [1]


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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory: Urinalysis
2.11.
Safety
UR3b
Summary of Urinalysis (Glucose, Protein, Blood, Ketones, 
Bilirubin, Urobilinogen nitrite, leukocyte esterase) Data
SAC [1]
2.12.
Safety
LB1
Summary of Urinalysis (Specific Gravity and pH)
SAC [1]
ECG
2.13.
Safety
EG1
Summary of ECG Findings
SAC [1]
2.14.
Safety
EG2
Summary of ECG Value 
SAC [1]
2.15.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit
SAC [1]
Vital Signs
2.16.
Safety
VS1
Summary of Vital Signs
SAC [1]
2.17.
Safety
VS1
Summary of Change from Baseline in Vital Signs
SAC [1]


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10.9.6.
Pharmacokinetic Tables
Pharmacokinetic : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.1.
PK
PK01: PKCT1
Summary of Pyrimethamine Plasma Concentration 
SAC [1]
3.2.
PK
PK03: PKPT1
Summary of Pyrimethamine Pharmacokinetic Parameters (non-
transformed) 
SAC [1]
3.3.
PK
PK05: PKPT3
Summary of Pyrimethamine Pharmacokinetic Parameters (loge-
transformed) 
SAC [1]


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10.9.7.
Pharmacokinetic Figures
Pharmacokinetic: Figures
IDSL / 
TST 
ID / 
Exam
ple 
Shell
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.1.
PK 
PK16a: 
PKCF1p
Individual Pyrimethamine Plasma Concentration-Time Plots by 
Subject (from Pre-Dose to Day 22) 
by Subject (Linear and Semi-Log)
Time: from Pre-dose to Day 22
SAC [1]
4.2.
PK 
PK24: pkcf6
Individual Pyrimethamine Plasma Concentration-Time Plots by 
group (from Pre Dose to Day 22)
By group (Linear and Semi-Log)
Time: from Pre-dose to Day 22
SAC [1]
4.3.
PK 
PK19: PKCF4
Mean (+SD) Pyrimethamine Concentration-Time Plots (from Pre 
Dose to Day 22)
Time: from Pre-dose to Day 22
SAC [1]
4.4.
PK 
PK18: PKCF3
Median Pyrimethamine Plasma Concentration-Time Plots (from 
Pre Dose to Day 22)
Time: from Pre-dose to Day 22
SAC [1]
4.5.
PK 
PK16a: 
PKCF1p
Individual Pyrimethamine Plasma Concentration-Time Plots by 
Subject (from Pre Dose to 72 hr)
by Subject (Linear and Semi-Log)
Time: from Pre-dose to 72 hr
SAC [1]
4.6.
PK 
PK24: pkcf6
Individual Pyrimethamine Plasma Concentration-Time Plots by 
group (from Pre Dose to 72 hr)
By rgroup (Linear and Semi-Log)
Time: from Pre-dose to 72 hr
SAC [1]
4.7.
PK 
PK19: PKCF4
Mean (+SD) Pyrimethamine Concentration-Time Plots (from Pre 
Dose to 72 hr)
Time: from Pre-dose to 72 hr
SAC [1]
4.8.
PK 
PK18: PKCF3
Median Pyrimethamine Plasma Concentration-Time Plots (from 
Pre Dose to 72 hr)
Time: from Pre-dose to 72 hr
SAC [1]
4.9.
PK 
PK28
Plot of Pyrimethamine Treatment and PK Parameters 
AUC(0-t), AUC(0-inf), Cmax, t1/2
Plot and Mean with 95%CI
X axis: Japanese, Caucasian
Y axis: PK parameters
SAC [1]


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Pharmacokinetic: Figures
IDSL / 
TST 
ID / 
Exam
ple 
Shell
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.10.
PK 
Study Specifics
(PK_F1)
Individual Pyrimethamine Plasma Concentration-Time Plots 
(from Pre-Dose to Day 22)
Japanese & Caucasian
(Linear and Semi-Log)
Time: from Pre-dose to Day 22
SAC [1]
4.11.
PK 
Study Specifics
(PK_F1)
Individual Pyrimethamine Plasma Concentration-Time Plots 
(from Pre-Dose to 72 hr)
Japanese & Caucasian 
(Linear and Semi-Log)
Time: from Pre-dose to 72 hr
SAC [1]
4.12.
PK
Study Specifics
(PK_F2)
Mean (+SD) Pyrimethamine Concentration-Time Plots (from Pre 
Dose to Day 22)
Japanese & Caucasian 
Time: from Pre-dose to Day 22
SAC [1]
4.13.
PK
Study Specifics
(PK_F2)
Mean (+SD) Pyrimethamine Concentration-Time Plots 
(from Pre Dose to 72 hr)
Japanese & Caucasian 
Time: from Pre-dose to 72 hr
SAC [1]


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10.9.8.
ICH Listings
Note: ‘Inv.’ in the standard displays will be replaced to ‘Centre’.
ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
Screening 
Failure
ES7
Listing of Reasons for Screen Failure
SAC [1]
2.
Safety 
ES2
Listing of Reasons for Study Withdrawal
SAC [1]
Protocol Deviations
3.
Safety 
DV2
Listing of Important Protocol Deviations 
SAC [1]
4.
Screened
IE4
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
SAC [1]
Populations Analysed
5.
Safety 
Study Specifics  
(SP_T1)
Listing of Subjects Excluded from PK Population
SAC [1]
Demographic and Baseline Characteristics
6.
Safety 
DM2
Listing of Demographic Characteristics
“Age at Screening” is added.
SAC [1]
7.
Screening 
Failure
DM2
Listing of Demographic Characteristics for Screening Failure 
Subjects
SAC [1]
8.
Safety 
DM9
Listing of Race
SAC [1]
9.
Screening 
Failure
DM9
Listing of Race for Screening Failure Subjects
SAC [1]
Medical Conditions and Concomitant Medications
10.
Screened
MH3
Listing of Medical Conditions
SAC [1]


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ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
11.
Safety
CM5
Listing of Concomitant Medications
SAC [1]
12.
Safety
CM6
Relationship between ATC Level 1, Ingredient and Verbatim Text
SAC [1]
Exposure and Treatment Compliance
13.
Safety 
EX3
Listing of Exposure Data
SAC [1]
Adverse Events
14.
Safety 
CP_AE8
Listing of All Adverse Events
SAC [1]
15.
Safety 
AE7
Listing of Subject Numbers for Individual Adverse Events
SAC [1]
16.
Screened
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
SAC [1]
Serious and Other Significant Adverse Events
17.
Safety
CP_AE8
Listing of Serious Adverse Events
SAC [1]
18.
Screening 
Failure
CP_AE8
Listing of Serious Adverse Events for Screening Failure Subject
SAC [1]
19.
Safety 
CP_AE8
Listing of Adverse Events Leading to Withdrawal from Study 
SAC [1]
Laboratory (Chemistry Data)
20.
Safety 
CP_LB5
Listing of All Chemistry Data
Change from baseline is included.
SAC [1]
21.
Safety 
CP_LB5
Listing of All Chemistry Data for Subjects with Any Value of 
Potential Clinical Importance
SAC [1]
Laboratory (Hematology Data)
22.
Safety 
CP_LB5
Listing of All Hematology Data
Change from baseline is included.
SAC [1]
23.
Safety 
CP_LB5
Listing of All Hematology Data for Subjects with Any Value of 
Potential Clinical Importance
SAC [1]


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ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory (Urinalysis Data)
24.
Safety 
UR2a
Listing of All Urinalysis Dipstick and Microscopy Data
Time will be displayed after ‘Date’.
SAC [1]
25.
Safety 
CP_LB5
Listing of Urinalysis Data (Gravity and pH) 
SAC [1]
Hepatobiliary (Liver)
26.
Safety 
LIVER5
Listing of Liver Monitoring/Stopping Event Reporting 
SAC [1]
27.
Safety 
MH2
Listing of Medical Conditions for Subjects with Liver Stopping
Events
SAC [1]
28.
Safety 
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events 
SAC [1]
ECG
29.
Safety 
EG3
Listing of All ECG Values
SAC [1]
30.
Safety 
EG3
Listing of Change from Baseline in ECG Values
SAC [1]
31.
Safety 
EG5
Listing of ECG Findings
SAC [1]
32.
Safety 
CP_EG3
Listing of All ECG Data for Subjects with Any Value of Potential 
Clinical Importance
SAC [1]
Vital Signs
33.
Safety 
VS4
Listing of All Vital Signs
Change from baseline is included.
SAC [1]
34.
Safety 
CP_VS4
Listing of All Vital Signs Data for Subjects with Any Value of 
Potential Clinical Importance
SAC [1]
PK
35.
PK 
PK07: PKCL1p
Listing of Pyrimethamine Plasma Concentration
SAC [1]
36.
PK 
PK13: PKPL1p
Listing of Pyrimethamine Pharmacokinetic Parameters
SAC [1]


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10.10.
Appendix 10: Example Mock Shells for Data Displays
Example: PK_F1
Protocol: 12345                                                                                              Page 1 of 1
Population: PK
Table X
Individual Plasma Concentration-Time Plots
NOTE: LLQ = XX unit
USER ID:directory/program.sas  27JUN2014 12:00


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Example: PK_F2
Protocol: 12345                                                                                              Page 1 of 1
Population: PK
Table X
Mean + SD Concentration-Time Plots (Linear and Semi-log)
NOTE: LLQ = XX unit
USER ID:directory/program.sas  27JUN2014 12:00