Clinical trial NCT02281344: MMV390048 Against Early Plasmodium Falciparum Blood Stage Infection in Healthy Participants
Official title: A Proof-of-concept Study to Assess the Effect of MMV390048 Against Early Plasmodium Falciparum Blood Stage Infection in Healthy Participants.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Malaria, Falciparum
Keywords: induced blood stage malaria infection
Lead sponsor: Medicines for Malaria Venture
Sponsor class: OTHER
Collaborators: name: Q-Pharm Pty Limited
First posted: 2014-11-02
Enrollment: 6
Sex: MALE
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: 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

Primary outcomes:
measure: MMV390048 Area Under the Plasma Concentration Versus Time Curve (AUClast) up to Day 21 Post-dose
timeFrame: 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.
Secondary outcomes:
measure: Parasite Reduction Rate (PRR) Following MMV390048 Treatment
timeFrame: From dosing up to Day 21 Post-dose
measure: MMV390048 Maximum Plasma Concentration (Cmax)
timeFrame: 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.
measure: MMV390048 Time to Maximum Plasma Concentration (Tmax)
timeFrame: From dosing up to Day 21 Post-dose
Other outcomes:
Locations:
city: Brisbane
country: Australia
facility: Q-Pharm Clinics, Royal Brisbane and Women's Hospital
state: Queensland
Study officials:
affiliation: Q-Pharm Pty Limited
name: James McCarthy, Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sinxadi P, Donini C, Johnstone H, Langdon G, Wiesner L, Allen E, Duparc S, Chalon S, McCarthy JS, Lorch U, Chibale K, Mohrle J, Barnes KI. Safety, Tolerability, Pharmacokinetics, and Antimalarial Activity of the Novel Plasmodium Phosphatidylinositol 4-Kinase Inhibitor MMV390048 in Healthy Volunteers. Antimicrob Agents Chemother. 2020 Mar 24;64(4):e01896-19. doi: 10.1128/AAC.01896-19. Print 2020 Mar 24.
citation: Burel JG, Apte SH, McCarthy JS, Doolan DL. Plasmodium vivax but Not Plasmodium falciparum Blood-Stage Infection in Humans Is Associated with the Expansion of a CD8+ T Cell Population with Cytotoxic Potential. PLoS Negl Trop Dis. 2016 Dec 8;10(12):e0005031. doi: 10.1371/journal.pntd.0005031. eCollection 2016 Dec.