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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03258762




Registration number
NCT03258762
Ethics application status
Date submitted
21/08/2017
Date registered
23/08/2017

Titles & IDs
Public title
Phase I Study of Pyrimethamine in Healthy Japanese and Caucasian Subjects
Scientific 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
Secondary ID [1] 0 0
204678
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Toxoplasmosis 0 0
Condition category
Condition code
Infection 0 0 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Pyrimethamine
Treatment: Drugs - Calcium folinate

Experimental: Healthy Japanese male subjects - 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.

Experimental: Healthy Caucasian male subjects - 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.


Treatment: Drugs: Pyrimethamine
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.

Treatment: Drugs: Calcium folinate
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.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Maximum Observed Concentration (Cmax) of Pyrimethamine in Healthy Japanese Male Participants
Timepoint [1] 0 0
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Primary outcome [2] 0 0
Area Under the Concentration-time Curve From Time 0 to t (AUC[0-t]) of Pyrimethamine in Healthy Japanese Male Participants
Timepoint [2] 0 0
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Primary outcome [3] 0 0
Area Under the Concentration-time Curve From Time 0 to Infinity (AUC[0-inf]) of Pyrimethamine in Healthy Japanese Male Participants
Timepoint [3] 0 0
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Primary outcome [4] 0 0
Area Under the Concentration-time Curve From Time 0 to 24 (AUC[0-24]) of Pyrimethamine in Healthy Japanese Male Participants
Timepoint [4] 0 0
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Primary outcome [5] 0 0
Terminal Half-life (t1/2) of Pyrimethamine in Healthy Japanese Male Participants
Timepoint [5] 0 0
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Primary outcome [6] 0 0
Time to Maximum Observed Concentration (Tmax) of Pyrimethamine in Healthy Japanese Male Participants
Timepoint [6] 0 0
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Primary outcome [7] 0 0
Apparent Clearance Following Oral Dosing (CL/F) of Pyrimethamine in Healthy Japanese Male Participants
Timepoint [7] 0 0
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Primary outcome [8] 0 0
Apparent Volume of Distribution Following Oral Dosing (Vd/F) of Pyrimethamine in Healthy Japanese Male Participants
Timepoint [8] 0 0
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Secondary outcome [1] 0 0
Cmax of Pyrimethamine in Healthy Caucasian Male Participants
Timepoint [1] 0 0
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Secondary outcome [2] 0 0
AUC (0-t) of Pyrimethamine in Healthy Caucasian Male Participants
Timepoint [2] 0 0
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Secondary outcome [3] 0 0
AUC (0-inf) of Pyrimethamine in Healthy Caucasian Male Participants
Timepoint [3] 0 0
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Secondary outcome [4] 0 0
AUC (0-24) of Pyrimethamine in Healthy Caucasian Male Participants
Timepoint [4] 0 0
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Secondary outcome [5] 0 0
Tmax of Pyrimethamine in Healthy Caucasian Male Participants
Timepoint [5] 0 0
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Secondary outcome [6] 0 0
T1/2 of Pyrimethamine in Healthy Caucasian Male Participants
Timepoint [6] 0 0
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Secondary outcome [7] 0 0
CL/F of Pyrimethamine in Healthy Caucasian Male Participants
Timepoint [7] 0 0
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Secondary outcome [8] 0 0
Vd/F of Pyrimethamine in Healthy Caucasian Male Participants
Timepoint [8] 0 0
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Secondary outcome [9] 0 0
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
Timepoint [9] 0 0
Up to Day 23
Secondary outcome [10] 0 0
Change From Baseline of Clinical Chemistry Parameters: Glucose, Sodium, Calcium, Potassium, and Urea.
Timepoint [10] 0 0
Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Secondary outcome [11] 0 0
Change From Baseline of Clinical Chemistry Parameters: Alkaline Phosphatase, Alanine Aminotransferase (ALT), and Aspartate Aminotransferase (AST)
Timepoint [11] 0 0
Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Secondary outcome [12] 0 0
Change From Baseline of Clinical Chemistry Parameters: Direct Bilirubin, Bilirubin, Creatinine.
Timepoint [12] 0 0
Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Secondary outcome [13] 0 0
Change From Baseline of Clinical Chemistry Parameters: Protein
Timepoint [13] 0 0
Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Secondary outcome [14] 0 0
Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelet and Leukocytes
Timepoint [14] 0 0
Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Secondary outcome [15] 0 0
Change From Baseline in Hematology Parameter: Reticulocytes
Timepoint [15] 0 0
Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Secondary outcome [16] 0 0
Change From Baseline in Hematology Parameter: Hematocrit
Timepoint [16] 0 0
Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Secondary outcome [17] 0 0
Change From Baseline in Hematology Parameter: Hemoglobin
Timepoint [17] 0 0
Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Secondary outcome [18] 0 0
Change From Baseline in Hematology Parameter: Mean Corpuscular Hemoglobin
Timepoint [18] 0 0
Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Secondary outcome [19] 0 0
Change From Baseline in Hematology Parameter: Mean Corpuscular Volume
Timepoint [19] 0 0
Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Secondary outcome [20] 0 0
Change From Baseline in Hematology Parameter: Erythrocytes
Timepoint [20] 0 0
Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Secondary outcome [21] 0 0
Number of Participants With Abnormal Urinalysis Parameter
Timepoint [21] 0 0
Day -1, 24, 96, 168, 336 and follow up (504 hours)
Secondary outcome [22] 0 0
Specific Gravity at Indicated Time Points
Timepoint [22] 0 0
Day -1, 24, 96, 168, 336 hours and follow up (504 hours)
Secondary outcome [23] 0 0
Urine Potential of Hydrogen (pH) at Indicated Time Points
Timepoint [23] 0 0
Day -1, 24, 96, 168, 336 hours and follow up (504 hours)
Secondary outcome [24] 0 0
Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)
Timepoint [24] 0 0
Baseline (Pre-dose on Day 1), 4, 12, 24, 48, 72, 96, 120, 144, 168, 336 and 504 hours
Secondary outcome [25] 0 0
Change From Baseline in Pulse Rate
Timepoint [25] 0 0
Baseline (Pre-dose on Day 1), 4, 12, 24, 48, 72, 96, 120, 144, 168, 336 and 504 hours
Secondary outcome [26] 0 0
Change From Baseline in Temperature
Timepoint [26] 0 0
Baseline (Pre-dose on Day 1), 4, 12, 24, 48, 72, 96, 120, 144, 168, 336 and 504 hours
Secondary outcome [27] 0 0
Change From Baseline of Electrocardiogram (ECG) Parameters: PR Interval, QRS Duration, QT Interval, and QT Interval Corrected for Heart Rate by Fredericia's Formula (QTcF) Interval
Timepoint [27] 0 0
Baseline (Pre-dose on Day 1), 4, 12, 24, 48, and 504 hours
Secondary outcome [28] 0 0
Change From Baseline of ECG Parameter: ECG Mean Heart Rate
Timepoint [28] 0 0
Baseline (Pre-dose on Day 1), 4, 12, 24, 48, and 504 hours

Eligibility
Key inclusion criteria
* Subjects should be between 20 and 64 years of age inclusive, at the time of signing the informed consent.
* Subjects who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring.
* Body weight >= 50 kilograms (kg) and body mass index (BMI) within the range 18.5 to 30.0 kilogram per square meters (kg/m^2) (inclusive).
* Japanese or Caucasian male.
* A male subject must agree to use contraception 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 subject will be defined as an individual having four grandparents who are all descendants of the original people of Europe.
* Capable of giving signed informed consent which includes compliance with the requirements and restrictions of the study.
Minimum age
20 Years
Maximum age
64 Years
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
* Alanine aminotransferase (ALT) > 1.5 times upper limit of normal (ULN).
* Bilirubin > 1.5 times ULN (isolated bilirubin > 1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35 percent).
* QT interval corrected for heart rate according to Fridericia's formula (QTcF) > 450 milliseconds (msec).
* Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
* 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.
* Abnormal blood pressure as determined by the investigator.
* Hematological values: outside normal range at screening.
* Serum creatinine level: outside normal range at screening visit.
* Past or intended use of over-the-counter or prescription medication including herbal medications within 14 days prior to dosing.
* Participation in the study would result in loss of blood or blood products in excess of 500 milliliters (mL) within 3 months.
* Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
* Current enrollment 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.
* Presence of Hepatitis B surface antigen (HBsAg) at screening or positive Hepatitis C antibody test result at screening. 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.
* Positive Hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose of study treatment. Test is optional and subjects with negative Hepatitis C antibody test are not required to also undergo Hepatitis C RNA testing.
* Positive pre-study drug/alcohol screen.
* Positive human immunodeficiency virus (HIV) antibody test.
* Regular use of known drugs of abuse.
* 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 grams (g) of alcohol: a can of mid-strength (equivalent to 375 mL) beer, 1 glass (100 mL) of table wine or 1 measure (30 mL) of spirits (including rice wine).
* History or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
* 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
25/09/2017
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
19/11/2017
Sample size
Target
Accrual to date
Final
14
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
GSK Investigational Site - Melbourne
Recruitment postcode(s) [1] 0 0
3004 - Melbourne

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
GlaxoSmithKline
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
GSK Clinical Trials
Address 0 0
GlaxoSmithKline
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
IPD for this study will be made available via the Clinical Study Data Request site.

Supporting document/s available: Study protocol, Statistical analysis plan (SAP), Informed consent form (ICF), Clinical study report (CSR)
When will data be available (start and end dates)?
IPD is available via the Clinical Study Data Request site (click on the link provided below)
Available to whom?
Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
Available for what types of analyses?
How or where can data be obtained?
IPD available at link: https://clinicalstudydatarequest.com/Posting.aspx?ID=20305


What supporting documents are/will be available?




Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT03258762