Absolute BA and OZ439 PK Effect of Different OZ439 Dose Volumes and Cobicistat Co-administration Study

NCT04069221 | Completed Phase 1 Results

• 1 other identifier: MMV_OZ439_16_01
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

Brief Summary

This study is an open-label, two-part study to determine the absolute bioavailability (BA) of OZ439 using simultaneous intravenous \[14C\]-OZ439 microdose/800mg oral dosing and to investigate the pharmacokinetics (PK) of OZ439 granules administered as single doses suspended in different volumes and when co-administered with a single dose of Cobicistat, a strong CYP3A4 inhibitor, to healthy subjects in fasted state.

Conditions

Malaria

Outcome Measures

Primary Outcomes (5)

• OZ439 Fpo

  OZ439 Absolute oral bioavailability

  OZ439: Pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96, 168 hours post-dose. [14C]-OZ439: 10, 15, 20, 30 and 45 minutes after start of iv infusion then 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96, 168 hours

• OZ439 Cmax

  OZ439 maximum concentration observed

  Pre-dose, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96, 168, 216, 264, 312 hours post-dose

• OZ439 C168h

  OZ439 concentration observed at 168h

  168 hours post-dose

• OZ439 AUC0-168h

  Area under the OZ439 plasma concentration time curve from time zero to 168h

  Pre-dose, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96, 168 hours post-dose

• OZ439 AUC0-inf

  Area under the OZ439 plasma concentration time curve from time zero to infinity

  Pre-dose, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96, 168, 216, 264, 312 hours post-dose

Study Arms (4)

Part 1, single arm

EXPERIMENTAL

This was an open-label study in 8 healthy subjects to determine the absolute bioavailability of OZ439 following a single oral dose of OZ439 and co-administration of a single iv infusion of a \[14C\]-OZ439 radiolabeled microdose at the anticipated Tmax of the oral dose. Subjects received the following treatment: Treatment A: A single oral dose of 800 mg OZ439 simple granules administered as a 100-mL dispersion followed by a 15-minute 10-mL iv infusion of 100 μg \[14C\]-OZ439 (47 kBq \[1.27 μCi\]) beginning 3 hours after the oral dose administration.

Drug: Single oral dose of 800 mg OZ439; Drug: iv infusion of [14C]-OZ439

Part 2, Treatment B: single oral dose of 800 mg OZ439

EXPERIMENTAL

This was an open-label, randomized, single-dose, 3-way cross-over study in 18 healthy subjects. Each subject participated in 3 treatment periods and each subject received a single dose of each of the following 3 treatments in a randomized order with a 14-day wash-out period between each treatment: Treatment B: A single oral dose of 800 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment C: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment D: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion and co-administered with a 150 mg cobicistat tablet (CYP3A4 inhibitor)

Drug: Single oral dose of 800 mg OZ439

Part 2, Treatment C: single oral dose of 400 mg OZ439

EXPERIMENTAL

This was an open-label, randomized, single-dose, 3-way cross-over study in 18 healthy subjects. Each subject participated in 3 treatment periods and each subject received a single dose of each of the following 3 treatments in a randomized order with a 14-day wash-out period between each treatment: Treatment B: A single oral dose of 800 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment C: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment D: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion and co-administered with a 150 mg cobicistat tablet (CYP3A4 inhibitor)

Drug: Single oral dose of 400 mg OZ439

Part 2, Treatment D:single oral dose 400 mg OZ439+cobicistat

EXPERIMENTAL

This was an open-label, randomized, single-dose, 3-way cross-over study in 18 healthy subjects. Each subject participated in 3 treatment periods and each subject received a single dose of each of the following 3 treatments in a randomized order with a 14-day wash-out period between each treatment: Treatment B: A single oral dose of 800 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment C: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment D: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion and co-administered with a 150 mg cobicistat tablet (CYP3A4 inhibitor)

Drug: Single oral dose of 400 mg OZ439; Drug: Single oral dose of cobicistat

Interventions

Single oral dose of 800 mg OZ439 DRUG

Single oral dose of 800 mg OZ439

Part 1, single arm; Part 2, Treatment B: single oral dose of 800 mg OZ439

Single oral dose of 400 mg OZ439 DRUG

Single oral dose of 400 mg OZ439

Part 2, Treatment C: single oral dose of 400 mg OZ439; Part 2, Treatment D:single oral dose 400 mg OZ439+cobicistat

Single oral dose of cobicistat DRUG

Single oral dose of 150 mg cobicistat

Part 2, Treatment D:single oral dose 400 mg OZ439+cobicistat

iv infusion of [14C]-OZ439 DRUG

15-minute 10-mL iv infusion of 100 μg \[14C\]-OZ439

Part 1, single arm

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Body mass index (BMI) : 18.0-30.0 kg/m2, inclusive, at screening
• Weight : \>50 kg, at screening
• Status : healthy subjects
• Female subjects must be of non-childbearing potential (either surgically sterilized or physiologically incapable of becoming pregnant, or post-menopausal \[defined as spontaneous amenorrhoea for at least 1 year or spontaneous amenorrhoea for at least 6 months confirmed by a follicle stimulating hormone (FSH) result indicating a post-menopausal status\]) and have a negative pregnancy test at screening and at (each) admission to the clinical research center. As all female subjects must be of non-childbearing potential, they are not required to use any contraception during this study.
• Male subjects must use adequate contraception and not donate sperm from (first) admission to the clinical research center until 90 days after the follow-up visit. Adequate contraception for the male subject (and his female partner) is defined as surgical sterilization (vasectomy), using hormonal contraceptives (implantable, patch, oral, injectable) or an intrauterine device or system combined with at least 1 of the following forms of contraception (barrier method): a diaphragm or cervical cap, or a condom. Also, total abstinence, in accordance with the lifestyle of the subject is acceptable.
• Must have QTcF ≤450 ms and QTcB ≤450 ms (male subjects); QTcF ≤470 ms and QTcB ≤470 ms (female subjects), and PR-interval ≤200 ms for screening, and Day -1 and pre-dose ECG measurements of the (first) treatment period
• Ability and willingness to abstain from alcohol and methylxanthine-containing beverages or food (coffee, tea, cola, chocolate, energy drinks) from 48 hours prior to (each) admission to the clinical research center
• Willing and able to communicate and participate in the whole study
• Willing and able to sign the ICF

You may not qualify if:

• Male subjects who have currently pregnant partners or who have partners planning to be pregnant in the 90 days after discharge
• Evidence or history of clinically significant oncological, pulmonary, chronic respiratory, hepatic, cardiovascular, hematological, metabolic, neurological, immunological, nephrological, endocrine or psychiatric disease, or current infection
• Clinically relevant (as decided by the Principal Investigator \[PI\]) abnormalities in the 12-lead ECG, including asymptomatic bundle branch block
• Family history of sudden death or of congenital prolongation of the QTc-interval or known congenital prolongation of the QTc-interval or any clinical condition known to prolong the QTc-interval
• History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia, heart rate ≤39 beats per minute (bpm)
• Electrolyte disturbances, particularly hypokalemia, hypocalcemia or hypomagnesemia
• Any condition that could possibly affect drug absorption, e.g. gastrectomy or diarrhea
• History of post-antibiotic colitis
• History of any drug or alcohol abuse in the past 2 years prior to screening
• Subjects who regularly smoke more than 5 cigarettes a day
• Receipt of an investigational drug or participation in another clinical research study within 90 days prior to the first dose of study drug
• Subjects who are PRA employees, or immediate family members of PRA or Sponsor employees
• Subjects who have previously been enrolled in this study
• Use of moderate/strong inhibitors or inducers of CYP cytochromes or transporters within 30 days or 5 half-lives (whichever is longer) prior to the first dose of study drug
• Consumption of grapefruit, grapefruit juice or grapefruit-related citrus fruits (e.g. Seville oranges, pomelos) within 14 days prior to the first dose of study drug

Sponsors & Collaborators

• Medicines for Malaria Venture: lead

Study Sites (1)

PRA Health Sciences (PRA) - Early Development Services (EDS)

Groningen, 9728, Netherlands

Location

MeSH Terms

Conditions

Malaria

Interventions

artefenomel

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Results Point of Contact

• Title: Dr Myriam El Gaaloul, PharmD
• Organization: Medicines for Malaria Venture

elgaaloulm@mmv.org

+41 22 555 0377

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Part1: Open label, one treatment Part 2: Open-label, randomized, single-dose, 3-way cross-over study

Study Record Dates

• First Submitted: August 22, 2019
• First Posted: August 28, 2019
• Study Start: February 28, 2017
• Primary Completion: May 30, 2017
• Study Completion: May 30, 2017
• Last Updated: November 26, 2019
• Results First Posted: November 26, 2019

Record last verified: 2019-11

Locations

NL (1)