Effect of ACT-451840 Against Early Plasmodium Falciparum Blood Stage Infection in Healthy Subjects
Condition: Healthy Subjects
MeSH terms: Infections; Malaria
Intervention: ACT-451840:; Plasmodium falciparum-infected human erythrocytes:; Artemether 20 mg and lumefantrine 120mg combination tablet:; Primaquine:
Intervention description: ACT-451840 500 mg was provided in 100 mL amber glass bottles formulated as a powder for oral suspension. The ACT-451840 suspension was prepared extemporaneously by addition of 25 mL of water and administered orally under fed condition.; Each participant was inoculated on Day 0 with approximately 1,800 viable Plasmodium falciparum-infected human erythrocytes administered intravenously.; Rescue treatment to ensure clearance of Plasmodium falciparum comprising six doses of four tablets (total course of 24 tablets) given over a period of 60 hours. Each dose of tablets administered orally was immediately followed by food or drinks rich in fat (e.g., milk).; Rescue treatment to ensure clearance of Plasmodium falciparum, to be taken as a single oral 45 mg dose with food only if gametocytes were identified after administration of Riamet® rescue medication.
Intervention MeSH terms: Lumefantrine; Artemether; Primaquine
Phase: Phase 1
Study type: Interventional
Primary purpose: Other
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 8.0
Sex: Male
Minimum age: 18 Years
Maximum age: 50 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Malaria; ACT-451840

Summary:

      This was a single-center study using induced blood stage malaria infection to characterize
      the activity of ACT-451840 against early Plasmodium falciparum blood stage infection
    

Eligibility criteria:

        Inclusion Criteria:

          -  Body weight, minimum 50 kg, body mass index 18-32 kg/m^2.

          -  Certified healthy by detailed medical history and physical examination.

          -  Normal vital signs.

          -  Normal standard 12-lead electrocardiograph (ECG).

          -  Laboratory parameters within normal range, unless the investigator considered an
             abnormality to be clinically irrelevant.

          -  Use a double barrier method of contraception (male condom plus diaphragm or plus
             intrauterine device or plus hormonal contraceptive by female partner) for at least 14
             days prior to the first dose of study drug until 90 days after the last dose.

          -  Written informed consent prior to undertaking any study procedure.

        Exclusion Criteria:

          -  Any history of malaria.

          -  Traveled to or lived (>2 weeks) in a malaria-endemic country in the past 12 months or
             planned travel to a malaria-endemic country during the course of the study.

          -  Evidence of increased cardiovascular disease risk.

          -  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 disease.

          -  Receiving psychiatric drugs or 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.

          -  Known inherited genetic anomaly.

          -  Presence of acute infectious disease or fever within the 5 days prior to study product
             administration.

          -  Evidence of acute illness within 4 weeks prior to screening.

          -  Significant intercurrent disease.

          -  Clinically significant disease or condition that might affect drug absorption,
             distribution or excretion.

          -  Any investigational product study within the 12 weeks preceding the study.

          -  Participation in a research study involving blood sampling greater than 450 mL/ unit
             of blood, or blood donation to a blood bank during the 8 weeks preceding the reference
             drug dose in the study.

          -  Subject unwilling to defer blood donations for 6 months.

          -  Blood donation within 1 month before inclusion.

          -  Medical requirement for intravenous immunoglobulin or blood transfusions.

          -  Previous blood transfusion.

          -  Symptomatic postural hypotension.

          -  History or presence of alcohol consumption of more than 40 g per day or drug
             habituation, or any prior intravenous usage of an illicit substance.

          -  Smoking more than 5 cigarettes or equivalent per day, unable to stop smoking during
             the study.

          -  Ingestion of poppy seeds within 24 hours of the screening blood test.

          -  Excessive consumption of beverages containing xanthine bases.

          -  Any medication within 14 days before inclusion or within 5 times the elimination
             half-life of the medication, vaccination within the last 28 days.

          -  Corticosteroids, anti-inflammatory drugs, immunomodulators or anticoagulants.

          -  Recent or current therapy with an antibiotic or drug with potential antimalarial
             activity.

          -  Subject who, in the judgment of the investigator, was likely to be non-compliant, or
             unable to cooperate because of a language problem or poor mental development; was in
             the exclusion period of a previous study; lived alone; who could not be contacted in
             case of emergency; who was directly involved in conducting the study; who had no good
             peripheral venous access.

          -  Positive result on any of the following tests: hepatitis B surface antigen,
             anti-hepatitis B core antibodies, anti-hepatitis C virus antibodies, anti-human
             immunodeficiency virus 1 and 2 antibodies.

          -  Amphetamine, methamphetamines, barbiturates, benzodiazepines, cocaine, methadone,
             opiates, phencyclidine, tetrahydrocannabinols, tricyclic antidepressants detected in
             the urine drug screen unless there was an explanation acceptable to the medical
             investigator.

          -  Positive alcohol test.

          -  Pre-existing prolongation of the interval from beginning of the Q wave until end of
             the T wave corrected according to Bazett's formula (QTcB interval ) and considered
             clinically significant.

          -  Family history of sudden death, congenital prolongation of QTc interval, known
             congenital prolongation of QTc interval, or any clinical condition known to prolong
             the QTc interval. History of symptomatic cardiac arrhythmias or clinically relevant
             bradycardia. Electrolyte disturbances.

          -  ECG abnormalities at screening which in the opinion of the investigator is clinically
             relevant or will interfere with the ECG analysis.

          -  History of clinically significant ECG abnormalities.

          -  Known hypersensitivity to ACT-451840 or any of its excipients or artemether or other
             artemisinin derivatives, lumefantrine or other aryl aminoalcohols.

          -  Unwillingness to abstain from consumption of citrus fruits or their juices, as well as
             all fruit juices from admission to the end of the confinement period.

          -  Any history or presence of lactose intolerance.

          -  Ingestion of any drug since the recruitment interview (other than the doses
             administered in this study) which, in the opinion of the investigator, could
             compromise the study.

          -  Ingestion of any drug in the week prior to dosing or during the blood sampling period
             which, in the opinion of the investigator, could compromise the study.

          -  Failure to conform to the requirements of the protocol.

          -  Detection of any drug listed in the protocol in the urine drug screen unless there was
             an explanation acceptable to the investigator.

          -  Vital signs outside the reference range and clinically significant.