MMV390048 POC in Patients With P. Vivax and P. Falciparum Malaria
Condition: Malaria
MeSH terms: Malaria; Malaria, Falciparum
Intervention: MMV390048
Intervention description: Tablets of 20mg each
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 8.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: No

Summary:

      The present proof-of-concept Phase IIa study aims to confirm, in patients, the observed
      activity of MMV390048 against P. falciparum in pre-clinical models and the human Induced
      Blood-Stage Malaria (IBSM) challenge model, and to determine the activity against P. vivax
      malaria in patients, both over 14 and 28 days. Additional aims are to characterise the safety
      of MMV390048 in patients. Patient safety will be monitored for up to 35 days post-dose
      including pharmacokinetic assessments. The study will investigate descending single doses of
      MMV390048 in response to results obtained in the first cohort/dose in each malaria sub-type.
      The results of this trial will identify active, well-tolerated doses for investigation in
      combination with a partner drug within a Phase IIb clinical trial.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Body weight between 40 kg and 90 kg inclusive

          -  Presence of P. vivax or P. falciparum monoinfection confirmed by:

          -  Fever, as defined by axillary temperature ≥37.5°C or oral/rectal/tympanic temperature
             ≥38°C, or history of fever in the previous 48 hours for P. vivax and 24 hours for P.
             falciparum and,

          -  Microscopically confirmed parasite infection: 1,000 to 40,000 asexual parasite
             count/µL blood

          -  Written informed consent provided by the patient in accordance with local practice. If
             the patient is unable to write, witnessed consent is permitted according to local
             ethical considerations.

          -  Ability to swallow oral medication

          -  The patient is able to understand and comply with protocol requirements, instructions
             and protocol-stated restrictions and is likely to complete the study as planned

          -  Willing to be hospitalized for at least 72 hours or until malarial parasites are not
             detected by microscopy on 2 consecutive occasions whichever comes later and return to
             clinic for all follow-up visits

          -  Women must be of non-childbearing potential (WNCBP) as per one of the following
             definitions:

          -  postmenopausal defined as having age-appropriate, natural (spontaneous) amenorrhea for
             at least 12 months prior to screening in the absence of an alternative medical cause
             for the amenorrhea, or

          -  premenopausal with irreversible surgical sterilization by hysterectomy and/or
             bilateral oophorectomy or salpingectomy at least 6 months prior to screening (as
             determined by subject medical history)

          -  Sexually active men must agree to comply with strict appropriate contraception rules
             (barrier contraception, e.g. condom) or complete abstinence when this is in line with
             the preferred and usual lifestyle of the patient. The contraception coverage in this
             situation should ensure full elimination of MMV390048, i.e. until 120 days after
             MMV390048 administration to the enrolled male patient (covering a full sperm cycle of
             90 days starting after 5 x t½ of the drug). Abstinent patients must agree to use the
             above-mentioned contraceptive methods if they start sexual relationships during the
             study, and to continue these methods until 120 days after study medication.

        Exclusion Criteria:

          -  Patients with signs and symptoms of severe / complicated malaria according to the
             World Health Organisation Criteria 2012

          -  Mixed Plasmodium infection

          -  Vomiting more than three times in the 24 hours prior to inclusion in the study or
             inability to tolerate oral treatment, or diarrhea equivalent to three or more watery
             stools per day

          -  Women who are nursing (lactating)

          -  Presence of other serious or chronic clinical condition requiring hospitalisation

          -  Severe malnutrition (defined as a body mass index [BMI] of less than 16 kg/m2 as per
             local guidelines)

          -  Presence of concurrent febrile illness (e.g. typhoid fever)

          -  Known history or evidence of clinically significant:

          -  cardiovascular disease (including arrhythmia, QTcF interval >450 msec, personal or
             family history of long QT syndrome, PR interval >200msec; any relevant
             intra-ventricular heart block [QRS >120msec]),

          -  respiratory conditions (including active tuberculosis),

          -  history of jaundice or other hepatic dysfunction,

          -  renal insufficiency,

          -  gastrointestinal disorder, or any condition that may affect absorption of the study
             medication (e.g. vomiting or diarrhea),

          -  immunological disorders (including known pre-existing HIV infection),

          -  endocrine disorders (including any type of diabetes mellitus whether controlled or
             not, diabetes insipidus, uncontrolled hypo- or hyperthyroidism, endocrine reproductive
             disorders not requiring concurrent medication, disorders of adrenal function),

          -  infectious conditions (other than minor skin or soft tissue infections or confirmed
             minor lower urinary tract infection),

          -  malignancy,

          -  psychiatric or neurological disorders (including a history of convulsions, major head
             trauma, focal neurological signs, psychosis, bipolar or major depressive disorder), or

          -  any other disorder or condition that in the opinion of the investigator may render the
             patient unfit for participation in the trial, may limit his/her ability to provide
             informed consent, may interfere with protocol adherence or place the patient at
             increased risk through participation in the study

          -  Known to have any of the following markers of active hepatitis:

          -  Hepatitis A IgM (HAV-IgM),

          -  Hepatitis B surface antigen (HBsAg), or

          -  Hepatitis C antibody (HCV Ab) and HCV RNA

          -  Have received any antimalarial treatment (alone or in combination) during the
             following periods before screening (list of prohibited medication is provided in
             Appendix 2):

          -  Piperaquine, mefloquine, naphthoquine or sulphadoxine-pyrimethamine within 6 weeks
             prior to screening

          -  Amodiaquine, chloroquine, pyronaridine or tafenoquine within 4 weeks prior to
             screening

          -  Any artemisinin derivative (artesunate, artemether, arteether or dihydroartemisinin),
             quinine, halofantrine, lumefantrine and any other anti-malarial treatment or
             antibiotic with antimalarial activity (including cotrimoxazole, tetracyclines,
             quinolones and fluoroquinolones and azithromycin) within 14 days prior to screening

          -  Any herbal products or traditional medicines during the 7 days prior to screening

          -  Receipt of an investigational drug within 8 weeks or 5 half-lives (whichever is
             longer) prior to screening

          -  Current participation in any other clinical trial

          -  A history of regular abuse of alcohol, or use of drugs of abuse during the past 6
             months, or any clinical signs of substance abuse

          -  Neutrophil count <1,000/µL

          -  Elevated liver function tests as follows:

          -  AST/ALT >2 x the upper limit of normal (ULN), regardless of the level of total
             bilirubin

          -  AST/ALT >1.5 and ≤2 x ULN and total bilirubin >ULN

          -  AST/ALT >ULN and ≤1.5 x ULN

          -  and total bilirubin >1.5 and ≤2 x ULN,

          -  and conjugated bilirubin ≥35% of the total bilirubin

          -  Total bilirubin >2 x ULN, regardless of the level of AST/ALT

          -  Hb level <8g/dL

          -  Serum creatinine levels >2 x ULN

          -  Platelet level <50,000/mm3.