ToxoplasmosisPhase 1NCT03258762
Phase I Study of Pyrimethamine in Healthy Japanese and Caucasian Subjects
A Phase 1 study testing Pyrimethamine and Calcium folinate in people with Toxoplasmosis, run by GlaxoSmithKline at 1 site in Australia.
Trial 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]). Read more about this study
- Who is it for?
- Ages 20 to 64 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Toxoplasmosis
- What is being tested?
- Pyrimethamine and Calcium folinate
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 14 participants
- Where
- 1 siteAustralia
- Study dates
- 25 Sep 2017to 19 Nov 2017
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 20 to 64 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official 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
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.
- Conditions
- Toxoplasmosis
- Being tested
- Pyrimethamine, Calcium folinate
- Keywords
- Japanese, Caucasian, pharmacokinetics, pyrimethamine, toxoplasmosis
- Medical subject headings
- Toxoplasmosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PyrimethamineDrug
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.
Calcium folinateDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Healthy Japanese male subjects | Experimental | 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. Receives: Drug: Pyrimethamine; Drug: Calcium folinate |
| Healthy Caucasian male subjects | Experimental | 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. Receives: Drug: Pyrimethamine; Drug: Calcium folinate |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum Observed Concentration (Cmax) of Pyrimethamine in Healthy Japanese Male Participants
Blood samples were collected at indicated time points. The Pharmacokinetic (PK) parameters were calculated by non-compartmental analysis. PK Population is defined as all participants who administered at least one dose of study treatment and who have PK sample taken and analyzed.
Measured: 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
Area Under the Concentration-time Curve From Time 0 to t (AUC[0-t]) of Pyrimethamine in Healthy Japanese Male Participants
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
Measured: 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
Area Under the Concentration-time Curve From Time 0 to Infinity (AUC[0-inf]) of Pyrimethamine in Healthy Japanese Male Participants
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
Measured: 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
Area Under the Concentration-time Curve From Time 0 to 24 (AUC[0-24]) of Pyrimethamine in Healthy Japanese Male Participants
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
Measured: 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
Terminal Half-life (t1/2) of Pyrimethamine in Healthy Japanese Male Participants
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
Measured: 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
Time to Maximum Observed Concentration (Tmax) of Pyrimethamine in Healthy Japanese Male Participants
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
Measured: 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
Apparent Clearance Following Oral Dosing (CL/F) of Pyrimethamine in Healthy Japanese Male Participants
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
Measured: 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
Apparent Volume of Distribution Following Oral Dosing (Vd/F) of Pyrimethamine in Healthy Japanese Male Participants
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
Measured: 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 outcomes (28)
Cmax of Pyrimethamine in Healthy Caucasian Male Participants
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
Measured: 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
AUC (0-t) of Pyrimethamine in Healthy Caucasian Male Participants
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
Measured: 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
AUC (0-inf) of Pyrimethamine in Healthy Caucasian Male Participants
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
Measured: 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
AUC (0-24) of Pyrimethamine in Healthy Caucasian Male Participants
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
Measured: 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
Tmax of Pyrimethamine in Healthy Caucasian Male Participants
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
Measured: 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
T1/2 of Pyrimethamine in Healthy Caucasian Male Participants
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
Measured: 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
CL/F of Pyrimethamine in Healthy Caucasian Male Participants
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
Measured: 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
Vd/F of Pyrimethamine in Healthy Caucasian Male Participants
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
Measured: 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
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or events associated with liver injury and impaired liver function were categorized as SAE. All participants who take at least one dose of study treatment were included in Safety Population.
Measured: Up to Day 23
Change From Baseline of Clinical Chemistry Parameters: Glucose, Sodium, Calcium, Potassium, and Urea.
Blood samples were collected for the analysis of clinical chemistry parameters including glucose, sodium, calcium, potassium, and urea at indicated time points. Day -1 value was defined as Baseline for clinical chemistry parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.
Measured: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Change From Baseline of Clinical Chemistry Parameters: Alkaline Phosphatase, Alanine Aminotransferase (ALT), and Aspartate Aminotransferase (AST)
Blood samples were collected for the analysis of clinical chemistry parameters including alkaline phosphatase, ALT and AST at indicated time points. Day -1 value was defined as Baseline for clinical chemistry parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.
Measured: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Change From Baseline of Clinical Chemistry Parameters: Direct Bilirubin, Bilirubin, Creatinine.
Blood samples were collected for the analysis of clinical chemistry parameters including direct bilirubin, bilirubin and creatinine at indicated time points. Day -1 value was defined as Baseline for clinical chemistry parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.
Measured: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Change From Baseline of Clinical Chemistry Parameters: Protein
Blood samples were collected for the analysis of clinical chemistry parameter including protein at indicated time points. Day -1 value was defined as Baseline for clinical chemistry parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.
Measured: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelet and Leukocytes
Blood samples were collected for the analysis of hematology parameters including basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelet and leukocytes at indicated time points. Day -1 value was defined as Baseline for hematology parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value. Data was not available as all basophil values were below the detection limit. Hence, the change from baseline in basophil values were not calculated.
Measured: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Change From Baseline in Hematology Parameter: Reticulocytes
Blood samples were collected for the analysis of hematology parameter including reticulocytes at indicated time points. Day -1 value was defined as Baseline for hematology parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.
Measured: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Change From Baseline in Hematology Parameter: Hematocrit
Blood samples were collected for the analysis of hematology parameter including hematocrit at indicated time points. Day -1 value was defined as Baseline for hematology parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.
Measured: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Change From Baseline in Hematology Parameter: Hemoglobin
Blood samples were collected for the analysis of hematology parameter including hemoglobin at indicated time points. Day -1 value was defined as Baseline for hematology parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.
Measured: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Change From Baseline in Hematology Parameter: Mean Corpuscular Hemoglobin
Blood samples were collected for the analysis of hematology parameter including mean corpuscular hemoglobin at indicated time points. Day -1 value was defined as Baseline for hematology parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.
Measured: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Change From Baseline in Hematology Parameter: Mean Corpuscular Volume
Blood samples were collected for the analysis of hematology parameter including mean corpuscular volume at indicated time points. Day -1 value was defined as Baseline for hematology parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.
Measured: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Change From Baseline in Hematology Parameter: Erythrocytes
Blood samples were collected for the analysis of hematology parameter including erythrocytes at indicated time points. Day -1 value was defined as Baseline for hematology parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.
Measured: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Number of Participants With Abnormal Urinalysis Parameter
The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters of can be read as Trace, + and ++ indicating proportional concentrations in the urine sample. Only participants with abnormal findings for urinalysis at any visit has been presented.
Measured: Day -1, 24, 96, 168, 336 and follow up (504 hours)
Specific Gravity at Indicated Time Points
Urine samples were collected for analysis of specific gravity of urine. Urinary specific gravity is a measure of the concentration of solutes in the urine. It measures the ratio of urine density compared with water density and provides information on the kidney's ability to concentrate urine.
Measured: Day -1, 24, 96, 168, 336 hours and follow up (504 hours)
Urine Potential of Hydrogen (pH) at Indicated Time Points
Urine samples were collected for analysis of urine pH. pH is calculated on a scale of 0 to 14, values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0).
Measured: Day -1, 24, 96, 168, 336 hours and follow up (504 hours)
Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)
Blood pressure of participants were measured at indicated time points in semi-supine position after 5 minutes rest. Day 1 (Pre-dose) value was defined as Baseline for vital sign parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.
Measured: Baseline (Pre-dose on Day 1), 4, 12, 24, 48, 72, 96, 120, 144, 168, 336 and 504 hours
Change From Baseline in Pulse Rate
Pulse rate of participants were measured at indicated time points in semi-supine position after 5 minutes rest. Day 1 (Pre-dose) value was defined as Baseline for vital sign parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.
Measured: Baseline (Pre-dose on Day 1), 4, 12, 24, 48, 72, 96, 120, 144, 168, 336 and 504 hours
Change From Baseline in Temperature
Temperature of participants were measured at indicated time points in semi-supine position after 5 minutes rest. Day 1 (Pre-dose) value was defined as Baseline for vital sign parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.
Measured: Baseline (Pre-dose on Day 1), 4, 12, 24, 48, 72, 96, 120, 144, 168, 336 and 504 hours
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
A single 12-lead ECG was obtained at indicated time points using an ECG machine that automatically measures PR, QRS, QT, and QTcF intervals. Day 1 (Pre-dose) value was defined as Baseline for ECG parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.
Measured: Baseline (Pre-dose on Day 1), 4, 12, 24, 48, and 504 hours
Change From Baseline of ECG Parameter: ECG Mean Heart Rate
A single 12-lead ECG was obtained at indicated time points using an ECG machine that automatically calculates mean ECG heart rate. Day 1 (Pre-dose) value was defined as Baseline for ECG parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.
Measured: Baseline (Pre-dose on Day 1), 4, 12, 24, 48, and 504 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Aug 2017
- Study start25 Sep 2017
- Primary completion19 Nov 2017
- Study completion19 Nov 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for ToxoplasmosisStudies of the same condition, open and under way.
- More trials run by GlaxoSmithKlineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 14 participants (actual)
Sponsor and investigators
- Lead sponsor
- GlaxoSmithKline
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- GSK Clinical Trials, Study director, GlaxoSmithKline
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03258762
- Sponsor's protocol ID
- 204678
- Status last verified
- Mar 2020
- First submitted
- 21 Aug 2017
- Last updated
- 27 Mar 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: IPD for this study will be made available via the Clinical Study Data Request site.
Publications
Iida T, Nand RA, Ino H, Ogura H, Itoh H, Igarashi H, Numachi Y, Gross AS. Evaluation of the Pharmacokinetics, Safety, and Tolerability of a Single Oral Dose of Pyrimethamine in Healthy Male Subjects of Japanese and European Ancestry. Clin Pharmacol Drug Dev. 2020 Aug;9(6):768-773. doi: 10.1002/cpdd.771. Epub 2020 Jan 16.
PubMed 31950646
Study at a glance
From the registry record, last updated by the sponsor on 27 Mar 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official 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
- ClinicalTrials.gov ID
- NCT03258762
- Acronym / sponsor ID
- 204678
- Conditions
- Toxoplasmosis
- Keywords
- Japanese, Caucasian, pharmacokinetics, pyrimethamine, toxoplasmosis
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 14 participants (actual)
- Lead sponsor
- GlaxoSmithKlineIndustry (pharma, biotech, devices)
- Study start
- 25 Sep 2017 (actual)
- Primary completion
- 19 Nov 2017 (actual)
- Study completion
- 19 Nov 2017 (actual)
- First posted
- 23 Aug 2017 (actual)
- Results
- Posted 27 Mar 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Healthy Japanese male subjects | Experimental | Drug: Pyrimethamine, Drug: Calcium folinateHealthy 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. |
| Healthy Caucasian male subjects | Experimental | Drug: Pyrimethamine, Drug: Calcium folinateHealthy 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. |
Who may qualify
- Ages
- 20 to 64 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (8 listed)
- 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.
Key exclusion criteria (20 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PyrimethaminePyrimethamine 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. | Drug | Healthy Caucasian male subjects, Healthy Japanese male subjects |
| Calcium folinateCalcium 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. | Drug | Healthy Caucasian male subjects, Healthy Japanese male subjects |
Primary outcome
Maximum Observed Concentration (Cmax) of Pyrimethamine in Healthy Japanese Male Participants
Time frame: 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
Blood samples were collected at indicated time points. The Pharmacokinetic (PK) parameters were calculated by non-compartmental analysis. PK Population is defined as all participants who administered at least one dose of study treatment and who have PK sample taken and analyzed.
Area Under the Concentration-time Curve From Time 0 to t (AUC[0-t]) of Pyrimethamine in Healthy Japanese Male Participants
Time frame: 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
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
Area Under the Concentration-time Curve From Time 0 to Infinity (AUC[0-inf]) of Pyrimethamine in Healthy Japanese Male Participants
Time frame: 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
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
Area Under the Concentration-time Curve From Time 0 to 24 (AUC[0-24]) of Pyrimethamine in Healthy Japanese Male Participants
Time frame: 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
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
Terminal Half-life (t1/2) of Pyrimethamine in Healthy Japanese Male Participants
Time frame: 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
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
Time to Maximum Observed Concentration (Tmax) of Pyrimethamine in Healthy Japanese Male Participants
Time frame: 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
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
Apparent Clearance Following Oral Dosing (CL/F) of Pyrimethamine in Healthy Japanese Male Participants
Time frame: 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
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
Apparent Volume of Distribution Following Oral Dosing (Vd/F) of Pyrimethamine in Healthy Japanese Male Participants
Time frame: 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
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
28 secondary outcomes
Cmax of Pyrimethamine in Healthy Caucasian Male Participants
Time frame: 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
AUC (0-t) of Pyrimethamine in Healthy Caucasian Male Participants
Time frame: 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
AUC (0-inf) of Pyrimethamine in Healthy Caucasian Male Participants
Time frame: 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
AUC (0-24) of Pyrimethamine in Healthy Caucasian Male Participants
Time frame: 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
Tmax of Pyrimethamine in Healthy Caucasian Male Participants
Time frame: 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
T1/2 of Pyrimethamine in Healthy Caucasian Male Participants
Time frame: 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
CL/F of Pyrimethamine in Healthy Caucasian Male Participants
Time frame: 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
Vd/F of Pyrimethamine in Healthy Caucasian Male Participants
Time frame: 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
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
Time frame: Up to Day 23
Change From Baseline of Clinical Chemistry Parameters: Glucose, Sodium, Calcium, Potassium, and Urea.
Time frame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Change From Baseline of Clinical Chemistry Parameters: Alkaline Phosphatase, Alanine Aminotransferase (ALT), and Aspartate Aminotransferase (AST)
Time frame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Change From Baseline of Clinical Chemistry Parameters: Direct Bilirubin, Bilirubin, Creatinine.
Time frame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Change From Baseline of Clinical Chemistry Parameters: Protein
Time frame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelet and Leukocytes
Time frame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Change From Baseline in Hematology Parameter: Reticulocytes
Time frame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Change From Baseline in Hematology Parameter: Hematocrit
Time frame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Change From Baseline in Hematology Parameter: Hemoglobin
Time frame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Change From Baseline in Hematology Parameter: Mean Corpuscular Hemoglobin
Time frame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Change From Baseline in Hematology Parameter: Mean Corpuscular Volume
Time frame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Change From Baseline in Hematology Parameter: Erythrocytes
Time frame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Number of Participants With Abnormal Urinalysis Parameter
Time frame: Day -1, 24, 96, 168, 336 and follow up (504 hours)
Specific Gravity at Indicated Time Points
Time frame: Day -1, 24, 96, 168, 336 hours and follow up (504 hours)
Urine Potential of Hydrogen (pH) at Indicated Time Points
Time frame: Day -1, 24, 96, 168, 336 hours and follow up (504 hours)
Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)
Time frame: Baseline (Pre-dose on Day 1), 4, 12, 24, 48, 72, 96, 120, 144, 168, 336 and 504 hours
Change From Baseline in Pulse Rate
Time frame: Baseline (Pre-dose on Day 1), 4, 12, 24, 48, 72, 96, 120, 144, 168, 336 and 504 hours
Change From Baseline in Temperature
Time frame: Baseline (Pre-dose on Day 1), 4, 12, 24, 48, 72, 96, 120, 144, 168, 336 and 504 hours
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
Time frame: Baseline (Pre-dose on Day 1), 4, 12, 24, 48, and 504 hours
Change From Baseline of ECG Parameter: ECG Mean Heart Rate
Time frame: Baseline (Pre-dose on Day 1), 4, 12, 24, 48, and 504 hours
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Mar 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 31950646Iida T, Nand RA, Ino H, Ogura H, Itoh H, Igarashi H, Numachi Y, Gross AS. Evaluation of the Pharmacokinetics, Safety, and Tolerability of a Single Oral Dose of Pyrimethamine in Healthy Male Subjects of Japanese and European Ancestry. Clin Pharmacol Drug Dev. 2020 Aug;9(6):768-773. doi: 10.1002/cpdd.771. Epub 2020 Jan 16.
- Individual participant dataSharing planned: Yes. IPD for this study will be made available via the Clinical Study Data Request site.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
GSK Clinical Trials study director
GlaxoSmithKline
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Pyrimethamine and Calcium folinate in people with Toxoplasmosis, run by GlaxoSmithKline at 1 site in Australia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 27 Mar 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 27 Mar 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximum Observed Concentration (Cmax) of Pyrimethamine in Healthy Japanese Male Participants (time frame: 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). The study lists 8 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03258762, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Mar 2020.