Malaria
Conditions
Keywords
safety, tolerability, malaria
Brief summary
This is a first-in-human study of MMV390048. The study will evaluate the safety, tolerability and pharmacokinetic properties of escalating single and multiple doses of MMV390048 when administered to healthy male volunteers and female volunteers of non-childbearing potential. In addition, the effect of food on the pharmacokinetics and tolerability of MMV390048 will be investigated.
Detailed description
The study is a single centre, double-blind, randomised, placebo-controlled, ascending dose study in healthy male and female volunteers (of non-childbearing potential) aged 18 to 55 years. The study will be divided into two parts. The first part will comprise up to seven fasted cohorts (8 to 10 volunteers in each) that will receive a single, ascending dose (SAD) of MMV390048 to assess its safety, tolerability and pharmacokinetic profile. The starting dose administered to the first cohort will be 5 mg. An additional cohort (cohort 8, re-using volunteers from one of the previous cohorts) will receive a single dose of MMV390048 in a fed state to evaluate the effect of food on the pharmacokinetics and tolerability of the compound. The data obtained from each cohort during the SAD part of the study will undergo a formal review by the Safety Review Team (SRT). Should the safety profile of the compound be deemed acceptable, and the pharmacokinetic parameters indicate that acceptable levels of the drug to elicit a pharmacodynamic response can be achieved in human plasma, the study will then proceed to the second part. During the second part of the study volunteers will receive multiple, ascending doses (MAD) of MMV390048 to assess the pharmacokinetics, safety and tolerability following multiple oral doses. Up to three cohorts of eight volunteers each will be enrolled into this part of the study. Each volunteer will receive three consecutive daily doses of MMV390048.
Interventions
DRUGMMV390048 5mg
Supplied as powder in bottle formulation for reconstitution pre-dose
DRUGMMV390048 20mg
Supplied as powder in bottle formulation for reconstitution pre-dose.
DRUGMMV390048 40mg
Supplied as powder in bottle formulation for reconstitution pre-dose
DRUGMMV390048 80mg
Supplied as powder in bottle formulation for reconstitution pre-dose
DRUGMMV390048 120mg
Supplied as powder in bottle formulation for reconstitution pre-dose
DRUGPlacebo to match MMV390048
Supplied as powder in bottle formulation for reconstitution pre-dose
Sponsors
University of Cape Town
Medicines for Malaria Venture
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* written informed consent * Male and female (of non-childbearing potential); age 18 to 55 years, in good health as determined by past medical history, physical examination, vital signs, electrocardiogram, and laboratory tests at screening * Hematology, clinical chemistry and urinalysis results at screening that are within the local laboratory reference range or, if outside the range, not clinically significant. AST, ALT, lactate dehydrogenase, total bilirubin, haptoglobin and hemoglobin must be within the normal reference ranges * Body weight at least 50kg and body mass index within 18 to 32kg/m2 * Good peripheral venous access * Able to communicate well with the investigator, to understand and comply with the requirements of the study * Agree to stay in contact with the study site for the duration of the study, provide updated contact information as necessary, and have no current plans to move away from the study area for the duration of the study
Exclusion criteria
* Any acute illness upon admission to the unit on Day -1 or prior to dosing on Day 1 * Use of any other investigational drug within 30 days or five half-lives (whichever is longer) prior to the first dose of MMV390048 * history of hypersensitivity to any drugs * history of anaphylaxis or severe allergic reaction * Resting vital signs at either screening or baseline outside the defined ranges * Orthostatic changes in blood pressure and heart rate measurements greater than: 20 mmHg drop in systolic blood pressure; 10 mmHg drop in diastolic blood pressure; 20 beats per minute increase in heart rate * history of clinically significant ECG abnormalities, or any of the defined ECG abnormalities at either screening or baseline * History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past five years, regardless of whether there is evidence of local recurrence or metastases * Pregnant or nursing (lactating) women * Women of child-bearing potential * males physiologically capable of conceiving offspring UNLESS the volunteer agrees to use condoms and ensure that his partner(s) is either not of child-bearing potential or uses a highly effective method of contraception for the entire duration of the study and for twelve weeks following the last study drug administration * Smokers (use of tobacco products in the previous three months) * Use of any prescription drugs, herbal supplements, over--the--counter medication or dietary supplements (vitamins included) within four weeks prior to initial dosing * Intake of grapefruit, grapefruit juice or other products containing grapefruit within 28 days of the first drug administration of the study drug * Excessive intake of caffeine drinks or energy drinks within 48 hours before admission defined as more than three 250 ml cups of coffee a day * Donation or loss of 400 ml or more of blood within eight weeks prior to screening or initial dosing * Plasma donation (\>100 ml) within 60 days prior to first dosing * Hemoglobin levels below 12.5 g/dl (males) or 11.5 g/dl (females) at screening * Haptoglobin levels outside the reference range * Positive direct anti-globulin test * Liver enzymes other than ALT, AST and lactate dehydrogenase elevated ≥1.5 x ULN within two weeks prior to initial dosing * history of autonomic dysfunction within 3 years and/or recurrent history * History of immunodeficiency diseases, including a confirmed positive HIV test result * Positive Hepatitis B surface antigen or Hepatitis C antibody test result * History of recurrent infection * history of endocrine disease, in particular adrenal disorders such as Cushing's syndrome or Addison's disease, or diabetes mellitus * history of Gilbert's Syndrome * history of photosensitivity * history of any food allergy * Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardise the safety of the volunteer or the objectives of the study * History or presence of impaired renal function as indicated by clinically significantly abnormal creatinine or urea values, or abnormal urinary constituents * History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such abuse as indicated by the tests and laboratory assays at screening and/or baseline * Any clinically significant mental disorder that could limit the validity of informed consent or the volunteer's ability to comply with protocol requirements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | up to D29 or longer according to half life | Subject will be in-house up to D3, and then have a follow up visit at the site on D5, 7, 10, 14, 19, 26, 29 or longer according to half life |
| Area Under the Plasma Concentration Versus Time Curve (AUC) of MMV390048 | 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, 216, 312, 432, 600, 672 hours post-dose | Pk blood collection - additional PK point may be planned final visit depending on emerging PK data, unnecessary PK points could be eliminated for the latter cohorts Investigate the effect of food on the pharmacokinetic and tolerability of the investigational drug in cohort 4 and 8 |
| Half-life of MMV390048 | 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, 216, 312, 432, 600, 672 hours post-dose | Pk blood collection Investigate the effect of food on the pharmacokinetic and tolerability of the investigational drug in cohort 4 and 8 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Determine ex Vivo Efficacy (IC50) | up to 144 hr post dose | Blood collection to determine efficacy of investigational drug against parasites using an ex vivo malaria assay - this was done only for cohort 3 The experimentally obtained bioassay IC50 values were determined and compared to IC50 obtained with reference serum sample spiked with a known amount of MMV390048 titrated into the P. falciparum assay. |
Countries
South Africa
Participant flow
Recruitment details
For the purposes of this study, subjects that were re-used in SAD6 were treated as separate subjects, i.e. the entire trial population comprised 48 subjects, eight subjects in 6 cohorts.
Participants by arm
| Arm | Count |
|---|---|
| Cohort SAD1 Fasted 5mg of MMV390048: Single administration, supplied as powder in bottle formulation for reconstitution pre-dose | 6 |
| Cohort SAD2 Fasted 20mg of MMV390048: Single administration, supplied as powder in bottle formulation for reconstitution pre-dose | 6 |
| Cohort SAD3 Fasted 40mg of MMV390048: Single administration, supplied as powder in bottle formulation for reconstitution pre-dose | 6 |
| Cohort SAD4 Fasted 80mg of MMV390048: Single administration, supplied as powder in bottle formulation for reconstitution pre-dose | 6 |
| Cohort SAD5 Fasted 120mg of MMV390048: Single administration, supplied as powder in bottle formulation for reconstitution pre-dose | 6 |
| Cohort SAD6 Fed Cohort SAD6, reusing volunteers from previous cohorts, will receive a single dose in a fed state to evaluate the effect of food on the pharmacokinetics and tolerability
40mg of MMV390048: Single administration, supplied as powder in bottle formulation for reconstitution pre-dose | 6 |
| Placebo Placebo to match MMV390048: Single administration, supplied as powder in bottle formulation for reconstitution pre-dose
Two volunteers within each cohort (SAD1 to SAD6) were scheduled to receive placebo in a double blind manner. | 12 |
| Total | 48 |
Baseline characteristics
| Characteristic | Cohort SAD1 Fasted | Total | Placebo | Cohort SAD6 Fed | Cohort SAD5 Fasted | Cohort SAD4 Fasted | Cohort SAD3 Fasted | Cohort SAD2 Fasted |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 29.3 years | 31.7 years | 32.7 years | 34 years | 23.7 years | 30 years | 37 years | 34 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 35 Participants | 9 Participants | 4 Participants | 6 Participants | 4 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 12 Participants | 2 Participants | 2 Participants | 0 Participants | 2 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 0 Participants | 8 Participants | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 6 Participants | 40 Participants | 11 Participants | 4 Participants | 6 Participants | 5 Participants | 4 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 6 | 5 / 6 | 5 / 6 | 6 / 6 | 6 / 6 | 6 / 6 | 11 / 12 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 1 / 6 | 0 / 6 | 0 / 12 |
Outcome results
Primary
Area Under the Plasma Concentration Versus Time Curve (AUC) of MMV390048
Pk blood collection - additional PK point may be planned final visit depending on emerging PK data, unnecessary PK points could be eliminated for the latter cohorts Investigate the effect of food on the pharmacokinetic and tolerability of the investigational drug in cohort 4 and 8
Time frame: 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, 216, 312, 432, 600, 672 hours post-dose
Population: One subject (SAD5 120 mg) was excluded from the PK analysis population due to concomitant use of prohibited medications known to produce drug-drug interactions with pharmacokinetic consequences.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort SAD1 Fasted | Area Under the Plasma Concentration Versus Time Curve (AUC) of MMV390048 | 2136.9 h*ng/mL |
| Cohort SAD2 Fasted | Area Under the Plasma Concentration Versus Time Curve (AUC) of MMV390048 | 32727.2 h*ng/mL |
| Cohort SAD3 Fasted | Area Under the Plasma Concentration Versus Time Curve (AUC) of MMV390048 | 21050.7 h*ng/mL |
| Cohort SAD4 Fasted | Area Under the Plasma Concentration Versus Time Curve (AUC) of MMV390048 | 58668.2 h*ng/mL |
| Cohort SAD5 Fasted | Area Under the Plasma Concentration Versus Time Curve (AUC) of MMV390048 | 156036.2 h*ng/mL |
| Cohort SAD6 Fed | Area Under the Plasma Concentration Versus Time Curve (AUC) of MMV390048 | 29004.6 h*ng/mL |
Primary
Half-life of MMV390048
Pk blood collection Investigate the effect of food on the pharmacokinetic and tolerability of the investigational drug in cohort 4 and 8
Time frame: 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, 216, 312, 432, 600, 672 hours post-dose
Population: One subject (SAD5 120 mg) was excluded from the PK analysis population due to concomitant use of prohibited medications known to produce drug-drug interactions with pharmacokinetic consequences.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort SAD1 Fasted | Half-life of MMV390048 | 163.1 hours |
| Cohort SAD2 Fasted | Half-life of MMV390048 | 326.1 hours |
| Cohort SAD3 Fasted | Half-life of MMV390048 | 192.6 hours |
| Cohort SAD4 Fasted | Half-life of MMV390048 | 200.3 hours |
| Cohort SAD5 Fasted | Half-life of MMV390048 | 252.3 hours |
| Cohort SAD6 Fed | Half-life of MMV390048 | 210.8 hours |
Primary
Number of Participants With Adverse Events
Subject will be in-house up to D3, and then have a follow up visit at the site on D5, 7, 10, 14, 19, 26, 29 or longer according to half life
Time frame: up to D29 or longer according to half life
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort SAD1 Fasted | Number of Participants With Adverse Events | 4 Participants |
| Cohort SAD2 Fasted | Number of Participants With Adverse Events | 5 Participants |
| Cohort SAD3 Fasted | Number of Participants With Adverse Events | 5 Participants |
| Cohort SAD4 Fasted | Number of Participants With Adverse Events | 6 Participants |
| Cohort SAD5 Fasted | Number of Participants With Adverse Events | 6 Participants |
| Cohort SAD6 Fed | Number of Participants With Adverse Events | 6 Participants |
| Placebo | Number of Participants With Adverse Events | 11 Participants |
Secondary
Determine ex Vivo Efficacy (IC50)
Blood collection to determine efficacy of investigational drug against parasites using an ex vivo malaria assay - this was done only for cohort 3 The experimentally obtained bioassay IC50 values were determined and compared to IC50 obtained with reference serum sample spiked with a known amount of MMV390048 titrated into the P. falciparum assay.
Time frame: up to 144 hr post dose
Population: Samples received from the remaining participants were not processed due to the fact that they were either placebo samples, or failed to reach the pre-determined in vitro IC50 of MMV390048.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort SAD3 Fasted | Determine ex Vivo Efficacy (IC50) | 9.475 ng/ml |