Clinical trial NCT03739541: Benznidazole Absorption, Metabolism and Excretion Study
Official title: A Phase I, Open-label, Study of the Absorption, Metabolism and Excretion, of [14C]-Benznidazole (BNZ) Following a Single Oral Dose in Healthy Male Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Male Subjects
Lead sponsor: Insud Pharma
Sponsor class: INDUSTRY
Collaborators: name: Insud Pharma
First posted: 2018-11-14
Enrollment: 6
Sex: MALE
Minimum age (years): 35
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief summary: This Phase I ADME study will be conducted to evaluate the pharmacokinetics of benznidazole.

Detailed description: This will be a single-site, open-label, non-randomized, single oral dose absorption, metabolism and excretion study in healthy male subjects. Potential subjects will be screened to assess their eligibility to enter the study within 28 days prior to dosing on Day 1. Subjects will be admitted into the Clinical Research Unit (CRU) on Day -1. Subjects will be confined to the CRU until at least Day 11 (240 hours postdose), and will be discharged from the CRU on Day 11 if all the following discharge criteria are met: \>90% mass balance recovery; OR plasma/blood radioactivity levels below the limit of quantitation for 2 consecutive collections; and \<1% of the total radioactive dose recovered in combined excreta (urine and faeces) in 2 consecutive 24-hour periods. If these criteria are not met by Day 11, subjects will remain in the CRU until all discharge criteria are met up to a maximum of Day 15 to continue 24-hour blood, urine and faeces collections for the analysis of total radioactivity, unless otherwise agreed upon by the Sponsor and Investigator. If the discharge criteria are not met by Day 15, subjects may be asked to collect 24-hour excreta samples on up to 2 further occasions on a nonresidential basis to allow extrapolation of urinary and faecal excretion. If needed, the 2 additional 24-hour nonresidential collections will occur on Day 21 (±1 day) and Day 28 (±1 day). If on the second occasion the subject has still not met the desired criterion, then the subject will be discharged from the study, per Investigator and Sponsor decision. Pharmacokinetic samples and radioanalytical samples will be obtained through at least 240 hours postdose, and possibly up to 4 weeks postdose (radioanalytical samples only), in case of not meeting discharge criteria. Samples for metabolite profiling/identification will be obtained through 240 hours postdose.

Eligibility criteria: Inclusion Criteria:

1. Males of any race, between 35 and 65 years of age, inclusive, at screening.
2. Body mass index between 18.0 and 32.0 kg/m2, inclusive, at screening.
3. In good health, determined by no clinically significant findings from medical history, physical examination, 12-lead ECG, vital signs measurements, and clinical laboratory evaluations (congenital nonhemolytic hyperbilirubinemia \[eg, Gilbert's syndrome\] is acceptable) at screening or check-in as assessed by the Investigator (or designee).
4. Will agree to use contraception as detailed in Section 7.6.
5. History of a minimum of 1 bowel movement per day.
6. Able to comprehend and willing to sign an Inform Consent Form and to abide by the study restrictions.

Exclusion Criteria:

1. Significant history or clinical manifestation of any metabolic, allergic, dermatological, hepatic, renal, haematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder, as determined by the Investigator (or designee).
2. History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the Investigator (or designee).
3. History of dermatological conditions within the 6 months prior to dosing, such as rash, pruritus, and dermatitis, as determined by the Investigator (or designee).
4. History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs (uncomplicated appendectomy and hernia repair will be allowed). Cholecystectomy is acceptable.
5. History of alcoholism or drug/chemical abuse within 2 years prior to check-in.
6. Alcohol consumption of \>28 units per week for males. One unit of alcohol equals

   ½ pint (285 mL) of beer or lager, 1 glass (125 mL) of wine, or 1/6 gill (25 mL) of spirits.
7. Positive alcohol breath test or positive urine cotinine test result, or positive urine drug screen (confirmed by repeat) at screening or check-in.
8. Positive hepatitis panel and/or positive human immunodeficiency virus test (Appendix 3).
9. Participation in a clinical study involving administration of an investigational drug (new chemical entity) in the past 3 months prior to check-in.
10. Use or intend to use any medications/products known to alter drug absorption, metabolism, or elimination processes, including St. John's wort, within 30 days prior to check-in, unless deemed acceptable per Investigator (or designee) and Sponsor decision.
11. Use or intend to use any prescription medications/products within 14 days prior to check-in, unless deemed acceptable by the Investigator (or designee).
12. Use or intend to use slow-release medications/products considered to still be active within 14 days prior to check-in, unless deemed acceptable by the Investigator (or designee).
13. Use or intend to use any nonprescription medications/products including vitamins, minerals, and phytotherapeutic/herbal/plant-derived preparations within 7 days prior to check-in, unless deemed acceptable per Investigator (or designee) and Sponsor decision.
14. Use of tobacco- or nicotine-containing products within 3 months prior to check-in.
15. Receipt of blood products within 2 months prior to check-in.
16. Donation of blood from 3 months prior to screening, plasma from 2 weeks prior to screening, or platelets from 6 weeks prior to screening.
17. Poor peripheral venous access.
18. Have previously completed or withdrawn from this study or any other study investigating BNZ, and have previously received the investigational product.
19. Subjects with exposure to significant diagnostic or therapeutic radiation (eg, serial X-ray, computed tomography scan, barium meal) or current employment in a job requiring radiation exposure monitoring within 12 months prior to check-in.
20. Subjects who have participated in any clinical trial involving a radiolabelled investigational product within 12 months prior to check-in.
21. Subjects who, in the opinion of the Investigator (or designee), should not participate in this study.

Primary outcomes:
measure: Cmax of BNZ in plasma
timeFrame: Days 1-29
measure: Mass balance of [14C]-BNZ
timeFrame: Days 1-29
measure: Chemical structure of [14C]-BNZ metabolites
timeFrame: Days 1-29
measure: tmax of BNZ in plasma
timeFrame: Days 1-29
measure: AUC0-t of BNZ in plasma
timeFrame: Days 1-29
measure: AUC0-∞ of BNZ in plasma
timeFrame: Days 1-29
measure: % AUC extrap of BNZ in plasma
timeFrame: Days 1-29
measure: t1/2 of BNZ in plasma
timeFrame: Days 1-29
measure: CL/Fof BNZ in plasma
timeFrame: Days 1-29
measure: Vz/F of BNZ in plasma
timeFrame: Days 1-29
measure: Cmax of [14C]-BNZ in plasma
timeFrame: Days 1-29
measure: tmax of [14C]-BNZ in plasma
timeFrame: Days 1-29
measure: AUC0-t of [14C]-BNZ in plasma
timeFrame: Days 1-29
measure: AUC0-∞ of [14C]-BNZ in plasma
timeFrame: Days 1-29
measure: % AUC extrap of [14C]-BNZ in plasma
timeFrame: Days 1-29
measure: t1/2 of [14C]-BNZ in plasma
timeFrame: Days 1-29
measure: Cmax of [14C]-BNZ in whole blood
timeFrame: Days 1-29
measure: tmax of [14C]-BNZ in whole blood
timeFrame: Days 1-29
measure: AUC0-t of [14C]-BNZ in whole blood
timeFrame: Days 1-29
measure: AUC0-∞ of [14C]-BNZ in whole blood
timeFrame: Days 1-29
measure: % AUCextrap of [14C]-BNZ in whole blood
timeFrame: Days 1-29
measure: t1/2 of [14C]-BNZ in whole blood
timeFrame: Days 1-29
measure: Total radioactivity AUC ratio
timeFrame: Days 1-29
Secondary outcomes:
measure: The incidence and severity of Adverse Events (AEs)
timeFrame: Days 1-29
measure: The incidence of laboratory abnormalities (haematology)
timeFrame: Days 1-29
measure: The incidence of laboratory abnormalities (clinical chemistry)
timeFrame: Days 1-29
measure: The incidence of laboratory abnormalities (urinalysis)
timeFrame: Days 1-29
measure: Measurement of QT interval (QTcB)
timeFrame: Days 1-29
measure: Measurement of QT interval (QTcF)
timeFrame: Days 1-29
measure: Measurement of PR intervals
timeFrame: Days 1-29
measure: Measurement of QT intervals
timeFrame: Days 1-29
measure: Measurement of QRS duration
timeFrame: Days 1-29
measure: Measurement of RR
timeFrame: Days 1-29
measure: Measurement of heart rate
timeFrame: Days 1-29
measure: Measurement of blood pressure
timeFrame: Days 1-29
measure: Measurement of Physical Examination
timeFrame: Days 1-29
measure: Measurement of supine pulse rate
timeFrame: Days 1-29
measure: Measurement body temperature
timeFrame: Days 1-29
measure: Measurement of Weight
timeFrame: Days 1-29
measure: Measurement of Height
timeFrame: Days 1-29
Other outcomes:
Locations:
city: Leeds
country: United Kingdom
facility: Covance
Study officials:
affiliation: Covance
name: Sunu Valasseri, MBBS, MSc
role: PRINCIPAL_INVESTIGATOR
References: