Clinical trial NCT04270981: ADME Study of Acoziborole in Healthy Subjects
Official title: An Open Label, Single-dose, Single Period Study to Assess the Mass Balance Recovery, Metabolite Profile and Metabolite Identification of 14C-Acoziborole
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Trypanosomiases, African
Lead sponsor: Drugs for Neglected Diseases
Sponsor class: OTHER
First posted: 2020-02-17
Enrollment: 6
Sex: MALE
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: single centre, open-label, single group, non-randomised, single oral dose study in healthy male subjects
Primary purpose: TREATMENT

Brief summary: This is a single centre, open-label, single group, non-randomised, single oral dose study in healthy male subjects designed to assess the mass balance recovery, PK, metabolite profile and metabolite identification, and exploratory pharmacodynamics of acoziborole. It is planned to enrol 6 subjects.

All subjects will receive an oral dose of 960 mg \[14C\] acoziborole on a single occasion as 4 capsules containing a small amount of radioactivity (not more than \[NMT\] 1000 nCi \[37 KBq\] 14C).

Detailed description: The present study aims to further understand and quantify the absorption, distribution, metabolism and elimination (ADME) of acoziborole in humans through the assessment of the mass balance recovery after a single oral dose of \[14C\]-acoziborole. The routes and rates of elimination of \[14C\]-acoziborole will be determined and plasma, urine and faecal samples will be used for metabolic profiling and structural identification.

Subjects will be screened for inclusion in the study up to 28 days before dosing. Subjects will be admitted in the evening on the day before dosing (Day 1).

Subjects will be dosed on the morning of Day 1 following an overnight fast of a minimum of 9 h, and will remain resident in the clinic until up to 240 h after dosing (up to Day 11). Subjects will return to the clinical unit for 5 additional 48 h collection periods, admitting to the clinical unit the evening before the collection period. The additional collection periods will be on Days 14 to 17, 28 to 31, 58 to 61, 88 to 91 and 118 to 121. A follow up call will take place 5 to 10 days post-final discharge to ensure the ongoing wellbeing of subjects.

Eligibility criteria: Inclusion Criteria:

* Healthy Caucasian males.
* Age 18 to 55 years of age at the time of signing informed consent.
* Body mass index (BMI) of 18.0 to 30.0 kg/m2 as measured at screening.
* Must be willing and able to communicate and participate in the whole study.
* Must have regular bowel movements (i.e., average stool production of ≥1 and ≤3 stools per day).
* Normal blood pressure (BP): Systolic BP between 90 and 140 (160 if \>45 years old) mmHg (inclusive), diastolic BP 45 to 90 mmHg (inclusive), measured after 10 min rest in supine position at screening and pre-dose.
* A resting heart rate (HR) between 45 and 100 bpm (inclusive), measured after 10 min rest in supine position at screening and pre-dose.
* ECG recording without clinically significant abnormality, including QTcF measure of ≤450 msec at screening and pre-dose.
* Must provide written informed consent.
* Must agree to adhere to the contraception requirements
* Subjects must be able to swallow multiple capsules.

Exclusion Criteria:

* Subjects who have received any IMP in a clinical research study within the 90 days prior to Day 1.
* Subjects who are study site employees, or immediate family members of a study site or sponsor employee.
* History of any drug or alcohol abuse in the past 2 years
* Regular alcohol consumption \>21 units per week and (1 unit = ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 units = 125 mL glass of wine, depending on type) as confirmed by a positive alcohol breath test at screening or any on admission to the clinical unit.
* Current smokers and those who have smoked within the last 6 months. As confirmed by a breath carbon monoxide reading of greater than 10 ppm at screening or admission
* Subjects with pregnant or lactating partners.
* Radiation exposure, including that from the present study, excluding background radiation but including diagnostic x-rays and other medical exposures, exceeding 5 mSv in the last 12 months or 10 mSv in the last 5 year. No occupationally exposed worker shall participate in the study.
* Subjects who have been enrolled in an ADME study in the last 12 months.
* Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator or delegate at screening.
* Clinically significant abnormal clinical chemistry, haematology, urinalysis (especially alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase) or clinically significant abnormal physical examination findings as judged by the investigator .
* Abnormal thyroid function test results
* Abnormal renal function (estimate glomerular filtration rate \[eGFR\] \<80 mL/min).
* Confirmed positive drugs of abuse test result .
* Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results.
* History of any clinically significant acute or chronic cardiovascular, renal, hepatic, neurological (especially seizures), immunological, psychiatric, myopathies, bleeding tendency, respiratory and particularly GI disease, especially peptic ulceration and chronic gastritis, GI bleeding, ulcerative colitis, Crohn's Disease or Irritable Bowel Syndrome, as judged by the investigator.
* Any relevant GI complaints within 7 days of dosing.
* Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients.
* Presence or history of clinically significant allergy requiring treatment (including asthma, urticaria, clinically significant allergic rash or other severe allergic diathesis), as judged by the investigator. Hay fever is allowed unless it is active.
* Donation or loss of greater than 400 mL of blood within the previous 3 months or more than 100 mL within 30 days before signing ICF to this trial.
* Subjects who are taking any prescribed drug in the 14 days before screening or require regular use of any prescription medication during the study
* Subjects who have taken, any over-the-counter medications, including vitamins, analgesics or antacids, herbal remedies or St. John's wort in the 7 days before IMP administration . Exceptions may apply on a case by case basis, if considered not to interfere with the objectives of the study, as determined by the PI.
* Use of enzyme-altering drugs (e.g. barbiturates, phenothiazines, cimetidine) within 30 days or 5 half-lives, whichever is longer, of study Day 1.
* Surgery within 12 weeks prior to screening, with the exception of appendectomy or at the discretion of the Investigator for minor surgery.
* Any surgery (e.g. gastric bypass) or medical condition that may affect absorption of orally administered drugs.
* Failure to satisfy the investigator of fitness to participate for any other reason.

Primary outcomes:
measure: total radioactivity in urines and feces
timeFrame: 121 days
Secondary outcomes:
measure: Plasma and urine concentrations of acoziborole and of its main metabolite, SCYX 3109
timeFrame: 121 days
measure: Total radioactivity in whole blood (optional), plasma, urine and faeces
timeFrame: 121 days
measure: Quantitative metabolite profiling and identification of metabolites in pooled samples of plasma, urine and faeces
timeFrame: 121 days
measure: safety and tolerability of 14C acoziborole after single dose as measured by number of subjects with adverse events
timeFrame: 126 days
measure: safety and tolerability of 14C acoziborole after single dose as measured by adverse events severity
timeFrame: 126 days
measure: safety and tolerability of 14C acoziborole after single dose as measured by number of subjects with vital signs findings
timeFrame: 121 days
measure: safety and tolerability of 14C acoziborole after single dose as measured by number of subjects with 12 -lead ECG findings
timeFrame: 121 days
measure: safety and tolerability of 14C acoziborole after single dose as measured by number of subjects with clinical laboratory tests findings (hematology)
timeFrame: 121 days
measure: safety and tolerability of 14C acoziborole after single dose as measured by number of subjects with clinical laboratory tests findings (biochemistry)
timeFrame: 121 days
measure: safety and tolerability of 14C acoziborole after single dose as measured by number of subjects with physical examination findings
timeFrame: 121 days
measure: Amount of radioactivity in plasma, faeces and urine over time
timeFrame: 121 days
Other outcomes:
Locations:
city: Nottingham
country: United Kingdom
facility: Quotient Sciences
Study officials:
affiliation: Quotient Clinical
name: Sharan Sidhu, MBChB
role: PRINCIPAL_INVESTIGATOR
References: