A Phase Ib Induced Malaria Infection Study With the Combination of OZ439 and DSM265

NCT02389348 | Completed Phase 1

• 1 other identifier: QP14C12
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

Brief Summary

This is a single-centre, open-label, dose finding study using induced blood stage malaria (IBSM) infection to characterize the pharmacodynamic interaction between OZ439 and DSM265, administered around 120 minutes apart for treatment of early Plasmodium falciparum blood stage infection. The study will be conducted in up to three cohorts (n=8 per cohort) using different doses of OZ439 and DSM265. The doses of OZ439 and DSM265 that will be investigated in the first cohort will be 200 mg of OZ439 and 100mg of DSM265, both administered as single doses around 120 minutes apart. Subsequent doses in subsequent cohort(s) will be determined following a review of observed OZ439 and DSM265 safety, and pharmacokinetic and pharmacodynamic interaction outcomes, particularly the antimalarial activity of the drugs given in combination as defined by parasite clearance kinetics. The doses used in Cohort 2 and 3 may be adjusted but will not exceed the maximum acceptable doses predefined for this study (which are 400 mg for DSM265 and 500mg for OZ439) as determined in previous safety and pilot efficacy studies. The dose will be determined by the funding sponsor and the principal investigator (PI) following Safety Review team (SRT) and scientific evaluation. If no safe alternative dose can be determined the option exists to curtail the study to less than three cohorts. Each participant in the cohort will be inoculated on Day 0 with \~1,800 viable parasites of Plasmodium falciparum-infected human erythrocytes (BSPC) administered intravenously. On an outpatient basis, participants will be monitored daily via phone call and then daily (AM) from day 4 (until PCR positive for presence of malaria parasites). Once PCR positive they will be monitored twice-daily morning (AM) and evening (PM) until treatment, for adverse events and the unexpected early onset of symptoms, signs or parasitological evidence of malaria. On the day designated for commencement of treatment, as determined by qPCR results, participants will be admitted to the study unit and monitored. The threshold for commencement of treatment will be when PCR quantification of all participants is = 1,000 parasites/mL. If the PCR quantification of any participant is = 5,000 parasites/mL and is accompanied by a clinical symptom score \>5, or if clinical or parasitological evidence of malaria occurs in any participant before all participants have reached the treatment threshold (PCR quantification of = 1,000), then treatment of that participant will begin within a 24 h period. Following treatment with OZ439 and DSM265, participants will be followed up as inpatients for at least 48 hours to ensure tolerance of the treatment and clinical response, then if clinically well on an outpatient basis for safety and clearance of malaria parasites via PCR. Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) will occur on study day 16 ±3 days post OZ439 and DSM265 treatment unless required earlier. Early standard anti-malarial drug intervention can occur if either poor responses or fast responses are seen following OZ439 and DSM265 treatment. This is to ensure participant safety and to avoid participant inconvenience if useful data cannot be obtained. A poor response is defined as a decrease in parasitaemia of less than 20% from baseline by 3 days post OZ439 and DSM265 treatment. A fast response occurs when, within the seven day period following the treatment, two consecutive PCR assessments in 48 hours are negative. However, pre-emptive treatment with Riamet® can commence whenever deemed necessary by the investigator. Participants will be monitored, either in clinic, or by telephone for three days to ensure adherence to Riamet® therapy. Participants will be treated with a single dose (45 mg) of primaquine as described in section 4.3 in this protocol at the end of their Riamet® treatment if gametocytes are identified, to ensure complete clearance of any gametocytes present. Adverse events will be monitored via telephone monitoring, within the clinical research unit, and on outpatient review after malaria challenge inoculation and antimalarial study drugs administration. Blood samples for safety evaluation, malaria monitoring, and red blood cell antibodies will be drawn at screening and/ or baseline and at nominated times after malaria challenge.

Conditions

Malaria

Keywords

Induced blood stage malaria

Outcome Measures

Primary Outcomes (1)

• PK/PD relationship on clearance of P falciparum parasites from the blood

  The Parasite Reduction Ratio (PRR) is estimated using the slope of the optimal fit of the log-linear relationship of the parasitemia decay.

  From treatment administration to clearance of parasites or administration of Standard of Care therapy, whichever comes first, and up to 42 days following inoculum

Secondary Outcomes (2)

• Incidence, relation to study drug and severity of AE

  From challenge inoculum and up to 42 days following inoculum

• Cmax, Tmax, AUC of DSM265 and OZ439

  From Drug administration up to 42 days following inoculum

Study Arms (1)

combination OZ439 and DSM265

EXPERIMENTAL

Subjects will receive 1800 P falciparum infected red blood cells. Development of parasitemia will be monitored by quantitative PCR. When the parasitemia reached the threshold of 1000 p/ml subjects will receive a single oral dose of OZ439 and DSM265. Subsequent doses in subsequent cohort(s) will be determined following a review of observed OZ439 and DSM265 safety, and pharmacokinetic and pharmacodynamic interaction outcomes as well as the activity of the drugs as defined by parasite clearance kinetics.

Drug: DSM265; Drug: OZ439

Interventions

DSM265 DRUG

Single oral doses of DSM265

combination OZ439 and DSM265

OZ439 DRUG

Single oral doses of OZ439

combination OZ439 and DSM265

Eligibility Criteria

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

You may qualify if:

• Demography
• Adults (male and non-pregnant and non-lactating females) participants between 18 and 55 years of age, inclusive who do not live alone (from Day 0 until at least the end of the antimalarial drug treatment) and be contactable and available for the duration of the trial (maximum of 4 months).
• Female participants of childbearing potential must have adequate contraception in place (see section 6.7) for the duration of the study and extended duration, and have negative results on a serum or urine pregnancy test done before administration of study product. Males prepared to use adequate contraception for the duration of study and extended duration (See section 6.7)
• Body weight, minimum 50.0 kg, body mass index between 18.0 and 32.0 kg/m2, inclusive.
• 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.
• Oral body temperature between 35.0 - 37.5◦C
• Normal standard 12-lead electrocardiogram (ECG) after 5 minutes resting in supine position, QTcF=450 ms 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 normal and haemoglobin must be equal or higher than the lower limit of the normal range, Regulations
• Having given written informed consent prior to undertaking any study-related procedure.

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 (\>2 weeks) 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 method of Gaziano et al. (1). Risk factors include sex, age, systolic blood pressure (mm/Hg), smoking status, body mass index (BMI, kg/m2) 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. Lactose Intolerant.
• Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the subject in case of participation in the study. The Investigator should make this determination in consideration of the subject's medical history and/or clinical or laboratory evidence of any of the following:
• Inflammatory bowel disease, ulcers, gastrointestinal or rectal bleeding in the last 6 months;
• Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection;
• Pancreatic injury or pancreatitis in the last 6 months;
• 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 QP14C12\_OZ439-DSM265 MMV Challenge Protocol\_v1.1\_26Nov 2014 Page 9 of 71 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 urin analysis.

Sponsors & Collaborators

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

Study Sites (1)

Q-Pharm Clinics

Herston, Queensland, 4006, Australia

Location

Related Publications (2)

• 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

• McCarthy JS, Ruckle T, Elliott SL, Ballard E, Collins KA, Marquart L, Griffin P, Chalon S, Mohrle JJ. A Single-Dose Combination Study with the Experimental Antimalarials Artefenomel and DSM265 To Determine Safety and Antimalarial Activity against Blood-Stage Plasmodium falciparum in Healthy Volunteers. Antimicrob Agents Chemother. 2019 Dec 20;64(1):e01371-19. doi: 10.1128/AAC.01371-19. Print 2019 Dec 20.

  PMID: 31685476 DERIVED

MeSH Terms

Conditions

Malaria

Interventions

DSM265

Condition Hierarchy (Ancestors)

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

Study Officials

• James McCarthy, Prof

  Q-Pharm Pty Limited

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: February 20, 2015
• First Posted: March 17, 2015
• Study Start: February 1, 2015
• Primary Completion: June 1, 2015
• Study Completion: June 1, 2015
• Last Updated: October 7, 2015

Record last verified: 2015-10

Locations

AU (1)