A Study to Characterise the Antimalarial and Transmission Blocking Activity of a Single Dose of DSM265 or OZ439 in Healthy Subjects With Induced Blood Stage Plasmodium Falciparum or Plasmodium Vivax Infection

NCT02573857 | Terminated Phase 1 Results

• 1 other identifier: QP15C11
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

Part A

• Cohort 1 DSM265 will be administered as a single dose (400 mg). For cohort 1 only, an additional single dose (400 mg) of DSM265 may be given if gametocytemia develops. Treatment with DSM265 will be given after an overnight fasting period of ≥ 8 hours. If dosing is to occur in the evening, subjects will be required to fast for ≥4 hours prior to receiving treatment. Subjects will be required to fast for a further four hours anytime after dosing with DSM265. Part B
• Cohort 2 OZ439 will be administered as a single 200 mg dose. If recrudescence is observed, a single 400 mg dose of OZ439 will be given. Treatment with OZ439 will be administered after an overnight fasting period of ≥ 6 hours. If dosing is to occur in the evening, subjects will be required to fast for ≥4 hours prior to receiving treatment. Participants will drink 200 mL of milk prior to drug administration, and then swallow the appropriate volume of OZ439 suspension. Subjects will be required to fast for a further six hours anytime after dosing with OZ439.
• Cohort 3 DSM265 will be administered as a single dose (400 mg) as described for cohort 1. No additional dose will be administered.

Conditions

Malaria

Keywords

Induced blood stage malaria; Transmission; Gametocytemia

Outcome Measures

Primary Outcomes (3)

• Efficacy (PRR) of DSM265 or OZ439

  Efficacy of a single 400 mg dose of DSM265 or a 200mg dose of OZ439. The primary efficacy variable is parasite reduction ratio (PRR) of asexual parasites based on qPCR analysis of blood level parasitemia pre-dose and following administration of study drug. The parasite reduction ratio (PRR) provides an estimate of the efficacy of an antimalarial treatment and is the ratio of the parasite density between admission and 48 h post antimalarial treatment.

  From baseline to 48 hours post antimalarial treatment

• Efficacy of OZ439 on P. Vivax

  From baseline to 48 hours post antimalarial treatment

• Safety of DSM265 or OZ439 - Number of Adverse Events

  Assessement of Adverse Events (AE) (unexpected toxicities, adverse events encountered during or after investigational drug administration)

  From challenge inoculum (day 0) up to day 28 (+/-3 days)

Secondary Outcomes (4)

• Gametocytemia Clearance With DSM265

  From Drug administration up to day 28 (+/-3 days) following inoculum

• P. Vivax Transmission

  From challenge inoculum (day 0) and up to day 28 (+/-3 days)

• Parasite Density (Parasite/ml) Assessed by qPCR

  From From drug administration until Standard of Care administration, or up to day 28 (+/-3 days)

• Drug Concentration (PK) (ng/ml)

  From From drug administration until Standard of Care administration, or up to day 28 (+/-3 days)

Study Arms (3)

DSM265 P. falciparum

EXPERIMENTAL

Cohort 1: the efficacy of a single administration of 400 mg DSM265 for the clearance of asexual blood stages of P. falciparum will be determined. Activity of a second single dose of 400 mg DSM265 against gametocytes will be assessed in this cohort only if sexual stages are identified by PCR following the initial drug treatment.

Drug: DSM265

OZ439 P. vivax

EXPERIMENTAL

Cohort 2: subjects will be infected with P. vivax by IBSM, then treated with a single 200 mg dose OZ439. If recrudescence occurs following initial drug treatment with 200 mg OZ439, then affected participants who reach the treatment threshold will receive a single 400 mg dose of OZ439.

Drug: OZ439

DSM265 P. vivax

EXPERIMENTAL

Cohort 3: subjects will be infected with P. vivax by IBSM, then treated with a single 400 mg dose of DSM265

Drug: DSM265

Interventions

DSM265 DRUG

Oral suspension from bulk powder

DSM265 P. falciparum; DSM265 P. vivax

OZ439 DRUG

Oral suspension from powder in a bottle

Also known as: Artefenomel

OZ439 P. vivax

Eligibility Criteria

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

You may qualify if:

• Health status:
• Certified as healthy by a comprehensive clinical assessment (detailed medical history and complete physical examination).
• Normal 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.
• Normal standard 12-lead electrocardiogram (ECG) after 5 minutes resting in supine position, QTcF≤450 ms (males and females) with absence of second or third degree atrioventricular block or abnormal T wave morphology.
• Laboratory parameters within the normal range, unless the Investigator considers an abnormality to be clinically irrelevant for healthy participants enrolled in this clinical investigation. More specifically for serum creatinine, hepatic transaminase enzymes (aspartate aminotransferase, alanine aminotransferase), and total bilirubin (unless the Participant has documented Gilbert syndrome) should not exceed the upper laboratory norm and haemoglobin must be equal or higher than the lower limit of the normal range
• As there is the risk of adverse effects of the investigational drugs (DSM265 and OZ439), and standard curative treatment (Riamet and primaquine - cohort 1 only) in pregnancy, it is important that any participants involved in this study do not get pregnant or get their female partners pregnant (refer to Section 6.7).
• For cohort 1 and 3 (treatment with DSM265):
• Female participants of childbearing potential (WOCBP) may be enrolled in the DSM265 cohorts but must have adequate contraception in place for the duration of the study and up to 60 days (9 weeks) after the last dose of DSM265, with adequate contraception defined as:
• Stable hormonal contraception (with an approved oral, transdermal or depot regimen) for at least 3 months prior to screening i.e. oral contraceptives, either combined or progestogen alone, hormonal implantable contraception, vaginal ring, contraceptive patches
• Intrauterine (IUD) device or system in place for at least 3 months prior to screening
• Male partner sterilization prior to the female participant's entry into the study, and this male is the sole partner for that participant Abstinent female participants must agree to start a double method if they start a sexual relationship during the study and for up to 60 days (9 weeks) following the last dose of DSM265.
• Male participants to be dosed with DSM265 in cohort 1 or 3 must agree to use a double method of contraception including condom plus diaphragm or condom plus stable oral/transdermal/injectable hormonal contraceptive by female partner from at least 14 days prior to the time of the dose of the study drug through 120 days (17 weeks) after the last dose of DSM265.

You may not qualify if:

• Medical history and clinical status:
• Any history of malaria or participation to a previous malaria challenge study
• Must not have travelled to or lived in a malaria-endemic country during the past 12 months or planned travel to a malaria-endemic country during the course of the study.
• Has evidence of increased cardiovascular disease risk (defined as \>10%, 5 year risk) 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.
• History of splenectomy.
• Presence or history of drug hypersensitivity, or allergic disease diagnosed and treated by a physician or history of a severe allergic reaction, anaphylaxis or convulsions following any vaccination or infusion.
• Presence of current or suspected serious chronic diseases such as cardiac or autoimmune disease (HIV or other immunodeficiencies), insulin-dependent and non-insulin dependent diabetes, progressive neurological disease, severe malnutrition, acute or progressive hepatic disease, acute or progressive renal disease, psoriasis, rheumatoid arthritis, asthma, epilepsy or obsessive compulsive disorder
• History of malignancy of any organ system (other than localized 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
• Participants with history of schizophrenia, bi-polar disease, or other severe (disabling) chronic psychiatric diagnosis including depression or receiving psychiatric drugs or who has been hospitalized within the past 5 years prior to enrollment for psychiatric illness, history of suicide attempt or confinement for danger to self or others.
• Frequent headaches and/or migraine, recurrent nausea, and/or vomiting (more than twice a month)
• Presence of acute infectious disease or fever (e.g., sub-lingual temperature ≥ 38.5°C) within the five days prior to inoculation with malaria parasites.
• Evidence of acute illness within the four weeks before trial 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.
• Participant has a clinically significant disease or any condition or disease that might affect drug absorption, distribution or excretion, e.g. gastrectomy, diarrhoea.
• Participation in any investigational product study within the 12 weeks preceding the study.

Sponsors & Collaborators

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

Study Sites (1)

Q-Pharm Clinics

Herston, Queensland, 4006, Australia

Location

Related Publications (3)

• Dini S, Zaloumis SG, Price DJ, Gobeau N, Kummel A, Cherkaoui M, Moehrle JJ, McCarthy JS, Simpson JA. Seeking an optimal dosing regimen for OZ439/DSM265 combination therapy for treating uncomplicated falciparum malaria. J Antimicrob Chemother. 2021 Aug 12;76(9):2325-2334. doi: 10.1093/jac/dkab181.

  PMID: 34179977 DERIVED

• Collins KA, Abd-Rahman AN, Marquart L, Ballard E, Gobeau N, Griffin P, Chalon S, Mohrle JJ, McCarthy JS. Antimalarial Activity of Artefenomel Against Asexual Parasites and Transmissible Gametocytes During Experimental Blood-Stage Plasmodium vivax Infection. J Infect Dis. 2022 Mar 15;225(6):1062-1069. doi: 10.1093/infdis/jiaa287.

  PMID: 32479608 DERIVED

• Collins KA, Ruckle T, Elliott S, Marquart L, Ballard E, Chalon S, Griffin P, Mohrle JJ, McCarthy JS. DSM265 at 400 Milligrams Clears Asexual Stage Parasites but Not Mature Gametocytes from the Blood of Healthy Subjects Experimentally Infected with Plasmodium falciparum. Antimicrob Agents Chemother. 2019 Mar 27;63(4):e01837-18. doi: 10.1128/AAC.01837-18. Print 2019 Apr.

  PMID: 30858218 DERIVED

MeSH Terms

Conditions

Malaria

Interventions

DSM265; artefenomel

Condition Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Dr Joerg Moehrle
• Organization: Medicines for Malaria Venture

moehrlej@mmv.org

+41 22 555 0330

Study Officials

• James McCarthy, Prof

  Q-Pharm Pty Limited

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: October 6, 2015
• First Posted: October 12, 2015
• Study Start: October 1, 2015
• Primary Completion: May 1, 2016
• Study Completion: May 1, 2016
• Last Updated: June 5, 2020
• Results First Posted: June 5, 2020

Record last verified: 2020-05

Locations

AU (1)