Safety, Tolerability and Antimalarial Activity of Single Doses of OZ439 and PQP

NCT03542149 | Completed Phase 1 Results DMC

• 1 other identifier: QP17C19
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

A single-centre Phase 1b study to assess the safety, tolerability, pharmacokinetic profile, and antimalarial activity of single doses of coadministered artefenomel (OZ439) and piperaquine phosphate (PQP) against early Plasmodium falciparum blood stage infection in healthy adult volunteers.

Conditions

Malaria

Outcome Measures

Primary Outcomes (3)

• Characterize the PK/PD Relationship Between OZ439 and PQP Plasma Concentrations (Cmax)

  Maximum observed drug concentration in observed individual concentration-time profile.

  PK data up to Day 28 post-dose

• Characterize the PK/PD Relationship Between OZ439 and PQP and Blood Stage Asexual Parasitaemia Measured by Parasite Reduction Ratio at 48 Hours (PRR48)

  Ratio between parasitemia at the onset of drug treatment and 48 hours later. The PRR is defined as the ratio of the number of parasites at time of treatment divided by the number after a given amount of time has elapsed post-treatment. This time period is normally 48 hours as this is the time taken for P. falciparum parasites to pass through their asexual erythrocytic life cycle.

  From IP administration to 48 hours

• Characterize the PK/PD Relationship Between OZ439 and PQP and Blood Stage Asexual Parasitaemia Measured by Parasite Clearance Half-life

  PCt1/2 = Parasite Clearance Half-life;

  from IP administration to 108 hours

Study Arms (7)

Cohort 1: Treatment Group A: 200mg of OZ439 and 480 mg PQP

EXPERIMENTAL

200mg of OZ439 and 480 mg PQP. (OZ439 + α-tocopherol polyethylene glycol 1000 succinate (TPGS) granules for oral suspension) and PQP.

Drug: 480 mg Piperaquine phosphate; Drug: 200 mg OZ 439

Cohort 1:Treatment Group B: 200mg of OZ439 and 640 mg PQP

EXPERIMENTAL

200mg of OZ439 and 640 mg PQP. (OZ439 + α-tocopherol polyethylene glycol 1000 succinate (TPGS) granules for oral suspension) and PQP.

Drug: 640 mg Piperaquine phosphate; Drug: 200 mg OZ 439

Cohort 1:Treatment Group C: 400mg of OZ439 and 480 mg PQP

EXPERIMENTAL

400mg of OZ439 and 480 mg PQP. (OZ439 + α-tocopherol polyethylene glycol 1000 succinate (TPGS) granules for oral suspension) and PQP.

Drug: 480 mg Piperaquine phosphate; Drug: 400 mg OZ 439

Cohort 1Treatment Group D and Cohort 3 Treatment group A : 400mg of OZ439 and 640 mg PQP

EXPERIMENTAL

400mg of OZ439 and 640 mg PQP. (OZ439 + α-tocopherol polyethylene glycol 1000 succinate (TPGS) granules for oral suspension) and PQP.

Drug: 640 mg Piperaquine phosphate; Drug: 400 mg OZ 439

Cohort 2: Treatment Group A: 800mg of OZ439 and 960 mg PQP

EXPERIMENTAL

800mg of OZ439 and 960 mg PQP.

Drug: 800 mg OZ 439; Drug: 960 mg PQP

Cohort 2: Treatment Group B: 200mg of OZ439 and 320 mg PQP

EXPERIMENTAL

200mg of OZ439 and 320 mg PQP.

Drug: 400 mg OZ 439; Drug: 320 mg PQP

Cohort 3: Treatment Group B: 800mg of OZ439 and 640 mg PQP

EXPERIMENTAL

800mg of OZ439 and 640 mg PQP

Drug: 640 mg Piperaquine phosphate; Drug: 800 mg OZ 439

Interventions

480 mg Piperaquine phosphate DRUG

480 mg Piperaquine is a bis 4-aminoquinoline and was used mainly in China from the 1960's to the 1980's as an antimalarial monotherapy.

Also known as: PQP

Cohort 1: Treatment Group A: 200mg of OZ439 and 480 mg PQP; Cohort 1:Treatment Group C: 400mg of OZ439 and 480 mg PQP

640 mg Piperaquine phosphate DRUG

640 mg Piperaquine is a bis 4-aminoquinoline and was used mainly in China from the 1960's to the 1980's as an antimalarial monotherapy.

Also known as: PQP

Cohort 1:Treatment Group B: 200mg of OZ439 and 640 mg PQP; Cohort 1Treatment Group D and Cohort 3 Treatment group A : 400mg of OZ439 and 640 mg PQP; Cohort 3: Treatment Group B: 800mg of OZ439 and 640 mg PQP

200 mg OZ 439 DRUG

200 mg OZ439 + α-tocopherol polyethylene glycol 1000 succinate (TPGS) granules for oral suspension

Also known as: Artefenomel

Cohort 1: Treatment Group A: 200mg of OZ439 and 480 mg PQP; Cohort 1:Treatment Group B: 200mg of OZ439 and 640 mg PQP

400 mg OZ 439 DRUG

400 mg OZ439 + α-tocopherol polyethylene glycol 1000 succinate (TPGS) granules for oral suspension

Also known as: Artefenomel

Cohort 1:Treatment Group C: 400mg of OZ439 and 480 mg PQP; Cohort 1Treatment Group D and Cohort 3 Treatment group A : 400mg of OZ439 and 640 mg PQP; Cohort 2: Treatment Group B: 200mg of OZ439 and 320 mg PQP

800 mg OZ 439 DRUG

800 mg OZ439 + α-tocopherol polyethylene glycol 1000 succinate (TPGS) granules for oral suspension

Also known as: Artefenomel

Cohort 2: Treatment Group A: 800mg of OZ439 and 960 mg PQP; Cohort 3: Treatment Group B: 800mg of OZ439 and 640 mg PQP

960 mg PQP DRUG

960 mg Piperaquine is a bis 4-aminoquinoline and was used mainly in China from the 1960's to the 1980's as an antimalarial monotherapy.

Also known as: Piperaquine Phosphate

Cohort 2: Treatment Group A: 800mg of OZ439 and 960 mg PQP

320 mg PQP DRUG

320 mg Piperaquine is a bis 4-aminoquinoline and was used mainly in China from the 1960's to the 1980's as an antimalarial monotherapy.

Also known as: Piperaquine Phosphate

Cohort 2: Treatment Group B: 200mg of OZ439 and 320 mg PQP

Eligibility Criteria

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

You may qualify if:

• Adult (male and female) subjects between 18 and 55 years of age inclusive, who do not live alone (from inoculation day until at least the end of the Riamet® treatment) and will be contactable and available for the duration of the trial and contactable up to 2 weeks following the End of Study visit (approximately 8.5 weeks).
• Body weight minimum 50 kg, body mass index between 18 and 32 kg/m2, inclusive.
• Certified as healthy by a comprehensive clinical assessment (detailed medical history, complete physical examination and special investigations).
• Vital signs after 5 minutes resting in supine position:
• mmHg ≤ systolic blood pressure (SBP) ≤ 140 mmHg,
• mmHg ≤ diastolic blood pressure (DBP) ≤ 90 mmHg,
• bpm ≤ heart rate (HR) ≤ 100 bpm.
• Must have QTcF ≤450 ms, QTcB ≤450 ms for male subjects, QTcF ≤470 ms, QTcB ≤470 ms for female subjects and PR interval ≤210 ms at screening and at pre-inoculation on inoculation day.
• Heterosexual women of childbearing potential should be surgically sterile or using an insertable, injectable, transdermal or combination oral contraceptive approved by the TGA combined with a barrier contraceptive for the duration of the study, and have negative results on a urine pregnancy test done before inoculation. Abstinent, heterosexual female subjects must agree to start a double method if they start a sexual relationship during the study. Adequate contraception does not apply to subjects of childbearing potential with same sex partners (abstinence from penile-vaginal intercourse), when this is their preferred and usual lifestyle. Female subjects with same sex partners must not be planning in vitro fertilisation within the required contraception period.
• Women of non-childbearing potential who will not require contraception during the study are defined as: post-menopausal (spontaneous amenorrhoea for ≥ 12 months, or spontaneous amenorrhoea for 6-12 months and follicle-stimulating hormone (FSH) ≥ 40 IU/mL; either should be together with the absence of oral contraceptive use for \> 12 months).
• Male subjects participating must agree to use a double-barrier method of contraception including condom plus diaphragm or condom plus intrauterine device or condom plus stable oral/transdermal/injectable hormonal contraceptive by the female partner from the time of informed consent through to 90 days after the last dose of OZ439 and PQP. Abstinent male subjects must agree to start a double-barrier method if they begin sexual relationships during the study and up to 90 days after the last dose of study drug.
• Male subjects with female partners that are surgically sterile, or male subjects who have undergone sterilisation and have had testing to confirm the success of the sterilisation may also be included.
• Having given written informed consent prior to undertaking any study-related procedure.
• Must be willing and able to communicate and participate in the whole study. -

You may not qualify if:

• Haematology, clinical chemistry, coagulation or urinalysis results at screening or on admission prior to Inoculation or IMP administration that are outside of Sponsor-approved clinically acceptable laboratory ranges documented in the laboratory manual or are considered clinically relevant.
• Any history of malaria or participation in a previous malaria challenge study.
• Must not have travelled to or lived (\>2 weeks) in a malaria-endemic region during the past 12 months or planned travel to a malaria-endemic region during the course of the study (for endemic regions see https://map.ox.ac.uk/country-profiles/#!/). Bali is not considered a malaria-endemic region.
• Participation in any investigational product study within the 12 weeks preceding IMP administration.
• Has evidence of increased cardiovascular disease risk (defined as \>10%, 5-year risk for those greater than 35 years of age, as determined by the Australian Absolute Cardiovascular Disease Risk Calculator (http://www.cvdcheck.org.au/)). Risk factors include sex, age,systolic blood pressure (mm/Hg), smoking status, total and HDL cholesterol (mmol/L), and reported diabetes status.
• Symptomatic postural hypotension at screening on two consecutive readings, irrespective of the decrease in blood pressure, or asymptomatic postural hypotension defined as a decrease in systolic blood pressure ≥20 mmHg within 2-3 minutes when changing from supine to standing position.
• History of splenectomy.
• History or presence of diagnosed (by an allergist/immunologist) or treated (by a physician) food or known drug allergies (including but not limited to allergy to any of the antimalarial rescue medications to be used in the study), or history of anaphylaxis or other severe allergic reactions. Note. Subjects with seasonal allergies/hay fever, house dust mite or allergy to animals that are untreated and asymptomatic at the time of dosing can be enrolled in the study
• History of malignancy of any organ system (other than localised basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within 5 years of screening, regardless of whether there is evidence of local recurrence or metastases.
• Subjects with history of schizophrenia, bi-polar disease, or other severe (disabling) chronic psychiatric diagnosis including depression or receiving psychiatric drugs or who has been hospitalised within the past 5 years prior to enrolment for psychiatric illness, history of suicide attempt, or confinement for danger to self or others.
• History of serious psychiatric condition that may affect participation in the study or preclude compliance with the protocol, including but not limited to past or present psychoses, disorders requiring lithium, a history of attempted or planned suicide, more than one previous episode of major depression, any previous single episode of major depression lasting for or requiring treatment for more than 6 months, or any episode of major depression during the 5 years preceding screening.The Beck Depression Inventory (Appendix 4) will be used as an objective tool for the assessment of depression at screening. In addition to the conditions listed above, subjects with a score of 20 or more on the Beck Depression Inventory and/or a response of 1, 2 or 3 for item 9 of this inventory (related to suicidal ideation) will not be eligible for participation. These subjects will be referred to a general practitioner or medical specialist as appropriate. Subjects with a Beck score of 17 to 19 may be enrolled at the discretion of the Investigator if they do not have a history of the psychiatric conditions mentioned in this criterion and their mental state is not considered to pose additional risk to the health of the subject or to the execution of the study and interpretation of the data gathered.
• History of recurrent headache (e.g. tension-type, cluster or migraine) with a frequency of ≥2 episodes per month on average and/or severe enough to require medical therapy.
• Presence of acute infectious disease or fever (e.g. sublingual temperature ≥38.5°C) within the 5 days prior to inoculation with malaria parasites.
• Evidence of acute illness within the 4 weeks prior to screening that the Investigator deems may compromise subject safety.
• Significant inter-current disease of any type, in particular liver, renal, cardiac, pulmonary, neurologic, rheumatologic, or autoimmune disease by history, physical examination, and/or laboratory studies including urinalysis.

Sponsors & Collaborators

• Medicines for Malaria Venture: lead
• QIMR Berghofer Medical Research Institute: collaborator
• Clinical Network Services (CNS) Pty Ltd: collaborator
• Q-Pharm Pty Limited: collaborator

Study Sites (1)

Q-Pharm

Herston, Queensland, 4006, Australia

Location

Related Publications (1)

• Abd-Rahman AN, Kaschek D, Kummel A, Webster R, Potter AJ, Odedra A, Woolley SD, Llewellyn S, Webb L, Marquart L, Chalon S, Gaaloul ME, McCarthy JS, Mohrle JJ, Barber BE. Characterizing the pharmacological interaction of the antimalarial combination artefenomel-piperaquine in healthy volunteers with induced blood-stage Plasmodium falciparum to predict efficacy in patients with malaria. BMC Med. 2024 Nov 28;22(1):563. doi: 10.1186/s12916-024-03787-0.

  PMID: 39609822 DERIVED

MeSH Terms

Conditions

Malaria

Interventions

piperaquine; artefenomel

Condition Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Dr. Helen Demarest
• Organization: Medicines for Malaria Venture (MMV)

demaresth@mmv.org

: +41 22 555 03 24

Study Officials

• Rebecca Webster, Dr

  QIMR Berghofer Medical Research Institute

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

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

Model Details: Based on safety and tolerability data up to Day 35 post-dose, and pharmacokinetic/pharmacodynamic (PK/PD) analysis outcomes (based on PD data up to Day 35 and PK data up to Day 28 post-dose) of the drugs given in combination, the dose(s) for the subsequent cohort will be determined. A similar analysis will be done at the end of cohort 2 combining cohorts 1 and 2 data to decide the dose(s) to be tested in cohort 3.

Study Record Dates

• First Submitted: May 11, 2018
• First Posted: May 31, 2018
• Study Start: April 23, 2018
• Primary Completion: April 19, 2019
• Study Completion: April 19, 2019
• Last Updated: May 10, 2024
• Results First Posted: May 10, 2024

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1)