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MMV390048 Against Early Plasmodium Falciparum Blood Stage Infection in Healthy Participants

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ClinicalTrials.gov Identifier: NCT02281344
Recruitment Status : Terminated (Inconsistent and unpredictable exposures were observed. Drug needed to be reformulated.)
First Posted : November 2, 2014
Results First Posted : June 9, 2020
Last Update Posted : June 9, 2020
Sponsor:
Collaborator:
Q-Pharm Pty Limited
Information provided by (Responsible Party):
Medicines for Malaria Venture

Tracking Information
First Submitted Date  ICMJE October 30, 2014
First Posted Date  ICMJE November 2, 2014
Results First Submitted Date  ICMJE April 30, 2020
Results First Posted Date  ICMJE June 9, 2020
Last Update Posted Date June 9, 2020
Actual Study Start Date  ICMJE October 2014
Actual Primary Completion Date December 19, 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 27, 2020)
MMV390048 Area Under the Plasma Concentration Versus Time Curve (AUClast) up to Day 21 Post-dose [ Time Frame: At pre-dose, and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24 (D1), 30, 36, 48 (D2), 72 (D3), and 144 hours (D6) and Days 8, 10, 14, 18 and D21. ]
Pharmacokinetic-pharmacodynamic relationship of MMV390048 on clearance of Plasmodium falciparum parasites from the blood in healthy participants following infection with blood stage parasites. The area under the plasma concentration time curve from time zero to the last measured time point.
Original Primary Outcome Measures  ICMJE
 (submitted: October 30, 2014)
Parasite reduction rate (PRR) following MMV390048 treatment [ Time Frame: up to Day 21 Post-dose ]
The clearance of malaria parasitemia by Polymerase Chain Reaction (PCR) measurement
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 27, 2020)
  • Parasite Reduction Rate (PRR) Following MMV390048 Treatment [ Time Frame: From dosing up to Day 21 Post-dose ]
    The clearance of malaria parasitemia by Polymerase Chain Reaction (PCR) measurement.
  • MMV390048 Maximum Plasma Concentration (Cmax) [ Time Frame: At pre-dose, and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24 (D1), 30, 36, 48 (D2), 72 (D3), and 144 hours (D6) and Days 8, 10, 14, 18 and D21. ]
    Maximum Plasma Concentration (Cmax) of MMV390048
  • MMV390048 Time to Maximum Plasma Concentration (Tmax) [ Time Frame: From dosing up to Day 21 Post-dose ]
    Time to Maximum Plasma Concentration (Tmax) of MMV390048
Original Secondary Outcome Measures  ICMJE
 (submitted: October 30, 2014)
  • MMV390048 Area Under the Plasma Concentration Versus Time Curve (AUC 0-t) up to Day 21 Post-dose [ Time Frame: Up to Day 21 post-dose ]
    pharmacokinetic-pharmacodynamic relationship of MMV390048 on clearance of Plasmodium falciparum parasites from the blood in healthy participants following infection with blood stage parasites
  • MMV390048 Maximum Plasma Concentration (Cmax) [ Time Frame: Up to Day 21 Post-dose ]
    Maximum Plasma Concentration (Cmax) of MMV390048
  • MMV390048 Time to Maximum Plasma Concentration (Tmax) [ Time Frame: up to Day 21 Post-dose ]
    Time to Maximum Plasma Concentration (Tmax) of MMV390048
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE MMV390048 Against Early Plasmodium Falciparum Blood Stage Infection in Healthy Participants
Official Title  ICMJE A Proof-of-concept Study to Assess the Effect of MMV390048 Against Early Plasmodium Falciparum Blood Stage Infection in Healthy Participants.
Brief Summary A single-centre, open-label, study using induced blood stage malaria infection to characterize the activity of MMV390048 against early Plasmodium falciparum blood stage infection.
Detailed Description

Study using induced blood stage malaria infection to characterize the activity of MMV390048 against early Plasmodium falciparum blood stage infection. There will be two or more cohorts of 8 subjects. In the first cohort a single dose of 20 mg of MMV390048 will be investigated. Depending on the data obtained, the dose in Cohort 2 may be adjusted but will not exceed the maximum tolerated dose (or highest achieved dose based on a predefined exposure cap) as determined in an ongoing single ascending dose study. Each participant will be inoculated on Day 0 with ~1,800 viable parasites of Plasmodium falciparum-infected human erythrocytes intravenously. On an outpatient basis, participants will be monitored daily until positive for presence of malaria parasites. Once positive they will be monitored twice-daily 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, participants will be admitted to the study unit and monitored. The threshold for commencement of treatment will be when quantification of all participants is ≥ 1,000 parasites/mL. If the 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 (quantification of ≥ 1,000), then treatment of that participant will begin within a 24 h period.

Following treatment with MMV390048, participants will be followed up as inpatients for at least 72 hours to ensure tolerance of the treatment and clinical response, then on an outpatient basis if clinically well for monitoring of safety and clearance of malaria parasites. Compulsory treatment with Riamet® (artemether-lumefantrine) will start on day 16 (±3 days) post study treatment unless required earlier. Early intervention can occur if either poor responses or fast responses are seen following MMV390048 treatment. This is to ensure participant safety and to avoid participant inconvenience if useful data cannot be obtained. Pre-emptive treatment with Riamet® can commence whenever necessary. Participants will be treated with a single dose (45 mg) of primaquine (Primacin™) at the end of their Riamet® treatment if gametocytes are identified, to ensure complete clearance of any gametocytes present.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE Malaria, Falciparum
Intervention  ICMJE Drug: MMV390048 20mg
Supplied as a powder to be prepared as a suspension for oral use
Study Arms  ICMJE Experimental: Cohort 1
Cohort 1 will receive a single dose of 20mg MMV390048.
Intervention: Drug: MMV390048 20mg
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: May 19, 2016)
6
Original Estimated Enrollment  ICMJE
 (submitted: October 30, 2014)
24
Actual Study Completion Date  ICMJE December 19, 2014
Actual Primary Completion Date December 19, 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Participants who do not live alone from Day 0 until at least the end of the antimalarial drug treatment, and are contactable and available for the duration of the trial (≤4 months)
  • Body weight ≥50kg, body mass index between 18.0 and 32.0 kg/m2, inclusive
  • Healthy by clinical assessment
  • Normal vital signs
  • Normal 12-lead electrocardiogram
  • Lab tests in normal range
  • Agrees 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 female partner for ≥14 days prior to the first dose of study drug until 90 days after the last dose
  • Written informed consent before any study procedure

Exclusion Criteria:

  • History of malaria or participation in a previous malaria challenge study
  • Must not have travelled to or lived >2 weeks in a malaria-endemic area in past 12 months nor plan to travel to one during study
  • Evidence of increased cardiovascular disease risk
  • History of splenectomy
  • Presence / history of drug hypersensitivity, or allergic disease diagnosed and treated or history of a severe allergic reaction, anaphylaxis or convulsions following any vaccination or infusion
  • Presence of current / suspected serious chronic diseases such as cardiac or autoimmune disease, diabetes, progressive neurological disease, severe malnutrition, acute or progressive hepatic or renal disease, psoriasis, rheumatoid arthritis, asthma, epilepsy or obsessive compulsive disorder, skin carcinoma excluding non-spreadable skin cancers such as basal cell and squamous cell carcinoma, schizophrenia, bi-polar disease, or other severe (disabling) chronic psychiatric diagnosis
  • History of photosensitivity
  • History of schizophrenia, bi-polar disease, or other severe (disabling) chronic psychiatric diagnosis, including depression or receiving psychiatric drugs or hospitalized in past 5 yrs for psychiatric illness, history of suicide attempt or confinement for danger to self/others
  • Frequent headache and/or migraine, recurrent nausea, and/or vomiting (≥2 / month)
  • Acute infectious disease/fever in 5 days pre-inoculation with malaria parasites
  • Acute illness in 4 weeks pre-screening which may compromise subject safety
  • Any significant intercurrent disease, in particular liver, renal, cardiac, pulmonary, neurologic, rheumatologic, or autoimmune disease by history, physical exam or lab test
  • Clinically significant disease or any condition that might affect drug absorption distribution or excretion
  • Participation in any investigational study in last 12 weeks
  • Any blood sampling/donation in last 8 weeks
  • Unwilling to defer blood donation for 6 months
  • Any blood donation, in 1 month before inclusion.
  • Medical requirement for intravenous immunoglobulin or blood transfusion
  • Ever had a blood transfusion
  • Symptomatic postural hypotension, irrespective of the decrease in blood pressure, or asymptomatic postural hypotension
  • History or presence of alcohol abuse (≥40g per day) or drug habituation, or any prior intravenous use of an illicit substance
  • Smoking ≥5 cigarettes or equivalent /day and unable to stop smoking during confinement period
  • Poppy seeds in 24h pre-screening
  • Excessive consumption of xanthine bases, including red bull, chocolate
  • Any medication (including St John's Wort) in 14 days pre-study or within 5 times the medication half-life if longer
  • Vaccination in the last 28 days
  • Any corticosteroids, anti-inflammatory, immunomodulators or anticoagulants. Any currently or previous immunosuppressive therapy, including systemic steroids including adrenocorticotrophic hormone or inhaled steroids in dosages associated with hypothalamic-pituitary-adrenal axis suppression or chronic use of inhaled high potency corticosteroids
  • Recent or current systemic therapy with an antibiotic / potential antimalarial
  • Likely to be noncompliant, or unable to cooperate
  • Not contactable in case of emergency throughout and for 2 weeks after end of study
  • Staff directly involved in study conduct
  • Without good peripheral venous access
  • Positive for: hepatitis B surface antigen, anti-hepatitis B core antibodies, anti-hepatitis C virus antibodies, or anti-human immunodeficiency virus 1/2 antibodies
  • glucose-6-phosphate dehydrogenase deficiency
  • Positive urine drug screen or alcohol urine or breath test
  • Cardiac/QT risk: Known pre-existing prolongation of the QTcB/QTcF interval considered clinically significant. Family history of sudden death or of congenital prolongation of the corrected QT interval interval or known congenital prolongation of the corrected QT interval or any clinical condition known to prolong the corrected QT interval interval. History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia. Electrolyte disturbances, particularly hypokalaemia, hypocalcaemia or hypomagnesaemia. Clinically relevant 12-lead electrocardiogram abnormality at screening or which will interfere with the analysis, or history of clinically significant abnormalities
  • Known hypersensitivity to MMV390048 or any of its excipients or 4-aminoquinolines, artemether or other artemisinin derivatives, lumefantrine, or other arylaminoalcohols
  • Unwillingness to abstain from citrus (grapefruit, Seville orange, etc.) or juice, as well as quinine containing foods/beverages for the study period
  • Lactose intolerance
  • Unwilling to restrict exposure to direct sunlight during the study. Must use sunglasses and sunblock for the study period
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02281344
Other Study ID Numbers  ICMJE QP14C11
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Medicines for Malaria Venture
Study Sponsor  ICMJE Medicines for Malaria Venture
Collaborators  ICMJE Q-Pharm Pty Limited
Investigators  ICMJE
Principal Investigator: James McCarthy, Dr. Q-Pharm Pty Limited
PRS Account Medicines for Malaria Venture
Verification Date May 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP