A Single Site, Randomized, Double-blind, Placebo-controlled Phase Ib Study, to Evaluate the Chemoprotective Activity of a Single Dose of MMV390048 in a Controlled P. Falciparum Sporozoite Infection Model in Non-immune Healthy Volunteers
A Single Site, Randomized, Double-blind, Placebo-controlled Phase Ib Study, to Evaluate the Chemoprotective Activity of a Single Dose of MMV390048 in a Controlled P. Falciparum Sporozoite Infection Model in Non-immune Healthy Volunteers
This study follows a First-In-Human dose-escalation study of MMV390048 (5 to 120 mg MMV390048 powder-in-bottle formulation), a formulation bioavailability study to establish suitable tablet formulation, and a two-part dose-escalation (40 to 120 mg of MMV390048) / induced blood stage malaria (ISBM) challenge study with the new tablet formulation. After identification of the predicted efficacious MMV390048 plasma concentrations in the IBSM model, the current study will evaluate the chemoprotective efficacy of MMV390048 in a standardised and validated controlled human malaria infection (CHMI) model using direct venous inoculation (DVI) of aseptic, purified, cryopreserved, vialed P. falciparum sporozoites (PfSPZ Challenge).
Three sequential cohorts of healthy men and women of non-childbearing potential (WONCBP) will be administered the investigational medicinal product (IMP, i.e. MMV390048) under different conditions. This may identify preventative regimens, to be further investigated in a Phase II program. In the first two cohorts, protective administration of the IMP will occur 1 and 7 days before DVI of PfSPZ challenge. The timing of IMP administration and dosage in the last cohort will be determined on the basis of emerging data from the preceding cohorts, but will not exceed 28 days prior to the challenge nor 120 mg MMV390048.
Subjects are enrolled into one of three cohorts of 12 subjects each. Cohorts are recruited sequentially, to facilitate on-going review of data.
Investigational medicinal product (IMP) administration takes place between 28 and 1 days before the P. falciparum sporozoites (PfSPZ) challenge. Subjects are randomised to receive either MMV390048 120 mg or placebo in a 3:1 ratio.
After IMP administration, each subject is inoculated with 3200 PfSPZ. The dose of IMP to be administered and the interval between IMP administration and the PfSPZ challenge are as follows:
Parasitaemia and malaria symptoms and signs are monitored daily from Day 6 and as long as subjects exhibit parasitaemia (defined as either a positive thick blood smear microscopy or three positive quantitative polymerase chain reactions at least 12 hours apart with one measurement greater 100 parasites per mL), or until Day 28 if no parasitemia is not detected. All subjects receive antimalarial rescue therapy upon positive parasitaemia or at the end of the treatment period if parasites are not detected during follow-up. A final safety follow-up visit takes place on Day 60.
After treating cohorts 1 and 2 (up to, and including Day 28 assessments), a safety review team (SRT) meeting takes place, to consider enrolment of the subsequent cohort. At the first meeting, the SRT reviews safety and parasitaemia data to Day 28 and determines whether progression to treatment of cohort 2 is indicated. If no safety concerns are identified by the SRT and the geometric mean time to parasitaemia is less than 12 days for Cohort 1, progression to Cohort 2 takes place. Should Cohort 2 be enrolled, safety and parasitaemia data to Day 28 and PK data to at least Day 14 from this cohort are reviewed by the SRT prior to enrolling Cohort 3.
Recruitment of cohort 3 will be put on hold if:
Dosing of a subsequent cohort at the same or lower dose with the same or increased interval between dosing and inoculation, will not be performed if:
• The cohort-specific geometric mean time to parasitaemia is less than 12 days.
If progression of the study to recruiting cohort 3 is approved the by SRT, the optimal dose of MMV390048, as well as the time point of its administration will be estimated based on PK modelling, using data from all trials and assuming that asexual liver and blood stage have similar MMV390048 sensitivities.
Inclusion Criteria:
Completion of written informed consent for study participation by the volunteer
Able and willing to answer all questions on the informed consent quiz correctly, demonstrating an understanding of the study information and of the procedures associated with the study
Men or WONCBP aged ≥ 18 and ≤ 45 at screening
Good health based on the absence of significant medical history and clinically significant findings on physical examination and special investigations at screening and prior to IMP administration
Body mass index >18 and < 30 [kg/m2]
Negative alcohol breath test and urine drug screening test at screening (amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, opiates) and upon admission prior to IMP administration
Sexually active male volunteers with female partners must agree to use a highly effective, medically acceptable form of contraception from the day of IMP administration until 120 days thereafter (covering a full sperm cycle of 90 days starting after 5 x t½ of the drug). Abstinent male volunteers or male volunteers with same-sex partners must agree to use the above-mentioned contraceptive methods if they commence heterosexual relations during the study, and to continue these methods until 120 days after IMP administration. Acceptable methods of contraception include the following:
Women must be of non-childbearing potential as per one of the following definitions:
Consent to permit the investigators to discuss the volunteer's medical history with their General Practitioner and to sign a request to release medical information concerning contraindications for participation in the study
Able and willing (in the investigator's opinion) to comply with all study requirements for the duration of the study
Agreement to undergo all study procedures, to attend all study visits and stay overnight for observations as required, up to and including the last follow-up visit
Willingness to undergo a CHMI by DVI with PfSPZ Challenge
Reachable (24/7) by mobile phone or electronic mail during the whole study period
Agreement to refrain from blood donation during the course of the study and after the end of their involvement in the study according to the local and national blood banking eligibility criteria (currently 4 years in Germany)
Willingness to take a curative regimen of artemether-lumefantrine (Riamet®) or another registered antimalarial if necessary
Exclusion Criteria:
Any history of malaria
Volunteer has travelled to or lived in a malaria-endemic area for more than 4 weeks during the 12 months prior to IMP administration, or spent any time in an endemic area during the 4 weeks prior to IMP administration
Plans to travel to malaria endemic region during the study period up to last follow-up visit
Plans to travel outside of Germany during the challenge period
Volunteer is unable to be closely followed for social, geographic or psychological reasons
Previous participation in any malaria vaccine or CHMI study
Previous participation in a trial with MMV390048
Participation in any other clinical study within 30 days or five half-lives of the investigational compound in that study (whichever is longer) prior to IMP administration in this study, or plans to participate in other investigational vaccine/drug research during the study period
Participation in any research study involving blood sampling during the 8 weeks prior to IMP administration. (Volunteers from whom blood was last drawn at least 4 weeks prior to IMP administration, and from whom less than 450 ml of blood was taken during the 8 weeks leading up to the last study-related blood draw, may be considered on a case by case basis by the Investigator.)
Blood product donation to any blood bank during the 8 weeks (whole blood) or 4 weeks (plasma and platelets) prior to IMP administration
Blood loss of more than 100 ml during the 4 weeks prior to IMP administration
Male volunteers with a female partner(s) who is (are) pregnant or lactating at the time of the administration of the IMP
Women of childbearing potential, or nursing (lactating) women
Positive HIV, HBV (seropositive for hepatitis B surface antigen) or HCV tests
Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV infection, asplenia (e.g. post-splenectomy), recurrent, severe infections, or the use of chronic (more than 14 days) immunosuppressant or immune-modifying drugs within the 6 months prior to IMP administration. (The use of oral antihistamines, topical steroids or inhaled steroids at doses less than the equivalent of 800 ug budesonide or 750 ug fluticasone daily are not classified as immunosuppressant or immune-modifying for the purpose of this criterion.)
History of serious psychiatric condition that may affect participation in the study or preclude compliance with the protocol, including but not limited to past or present psychoses, disorders requiring lithium, a history of attempted or planned suicide, more than one previous episode of major depression, any previous single episode of major depression lasting for or requiring treatment for more than 6 months, or any episode of major depression during the 5 years preceding screening. The Beck Depression Inventory will be used as an objective tool for the assessment of depression at screening. In addition to the conditions listed above, subjects with a score of 20 or more on the Beck Depression Inventory and/or a response of 1, 2 or 3 for item 9 of this inventory (related to suicidal ideation) will not be eligible for participation. Subjects with a Beck score of 17 to 19 may be enrolled at the discretion of the Investigator if they do not have a history of the psychiatric conditions mentioned in this criterion and their mental state is not considered to pose additional risk to the health of the volunteer or to the execution of the study and interpretation of the data gathered
History of convulsions or of severe head trauma
History of frequent headaches (either severe in nature or requiring continuous daily treatment or treatment more than three times per week on average) and/or migraines
A history of clinically significant systemic disorders including haematological, renal, endocrine, gastrointestinal, hepatic, cardiovascular, pulmonary, dermatological, neurological, immunological or other conditions which could interfere with the interpretation of the study results or compromise the health of the volunteers
History of cancer (except localised basal cell carcinoma of the skin)
History of diabetes mellitus
History of asthma
Falling in moderate or higher risk category for a fatal or non-fatal cardiovascular event within 5 years (> 10%) determined by non-invasive criteria for cardiac risk
History of arrhythmias or documented prolonged QTcB- or QTcF-interval (> 450 msec), any previous episode of syncope thought to be of cardiac origin, or a family history of long QT syndrome or unexplained sudden death
Positive family history of cardiac disease in first and second degree relatives < 50 years
Recent (within the last three years) and/or recurrent history of autonomic dysfunction (e.g. recurrent episodes of fainting, palpitations, etc.)
Any surgical or medical condition possibly affecting drug absorption (e.g. cholecystectomy, gastrectomy, bowel disease), distribution, metabolism or excretion
History or presence of diagnosed food or known drug allergies (including but not limited to allergy to any of the antimalarial rescue medications to be used in the study), or history of anaphylaxis or other severe allergic reactions. (Subjects with seasonal allergies that are untreated and asymptomatic at the time of dosing will not be excluded.)
History of psoriasis or porphyria
Sickle cell anaemia or other red blood cell disorders
G6PD deficiency
Symptoms, physical signs and laboratory values suggestive of systemic disorders including haematological, renal, endocrine, gastrointestinal, hepatic, cardiovascular, pulmonary, dermatological, neurological, immunological or other conditions which could interfere with the interpretation of the study results or compromise the health of the volunteers
Resting vital signs (measured after 5 minutes in the supine position) at screening, admission to the CCT, or baseline prior to IMP administration as follows:
Symptomatic postural hypotension at screening, irrespective of the decrease in blood pressure, or asymptomatic postural hypotension defined as a decrease in systolic blood pressure ≥20 mmHg 2 minutes after changing from a supine to standing position
Clinically significant abnormalities in electrocardiogram at screening, admission to the CCT, or baseline prior to IMP administration as follows:
Haematology, clinical chemistry, coagulation or urinalysis results at screening or on admission to the CCT prior to IMP administration that are outside of Sponsor-approved clinically acceptable laboratory ranges documented prior to study start or are considered clinically relevant
Contraindications to the use of chloroquine phosphate, atovaquone-proguanil, artemether or lumefantrine
Use of any prescription drugs, herbal supplements (e.g. St John's Wort), or over-the-counter medication within 7 days or five half-lives (whichever is longer) prior to IMP administration, or an anticipated requirement for the use of these during the course of the study. (If necessary, the incidental use of NSAIDs, vitamins and topical treatments may be acceptable after approval by the study Sponsor and will be documented in the case report form [CRF]. The use of nutritional supplements during this time that are not believed to have the potential to affect subject safety nor the overall results of the study, may be permitted on a case-by-case basis following approval by the Sponsor in consultation with the Investigator.)
Use of systemic antibiotics with known antimalarial activity within 30 days of IMP administration (e.g. trimethoprim-sulfamethoxazole, doxycycline, tetracycline, clindamycin, erythromycin, fluoroquinolones, or azithromycin) or an anticipated requirement for the use of these during the study period
Use of medications known to interact with chloroquine, atovaquone-proguanil (Malarone®) or artemether-lumefatrine (Riamet®) such as cimetidine, metoclopramide or antacids, or an anticipated requirement for the use of these at any point during the study period
Ingestion of any poppy seeds within 24 hours prior to the screening or pre-dose urine drug screen
Intake of grapefruit or grapefruit juice within 5 days of IMP administration, or unwillingness to abstain from the consumption of these products from 5 days prior to IMP administration until collection of the final PK blood sample
Use of immunoglobulins or blood products within 3 months prior to IMP administration
Suspected or known history of, or current alcohol abuse, or heavy intake defined as greater than 28 g (men) or 18 g (women) per day or a carbohydrate deficient transferrin level ≥ 2.5%
Current drug habituation, or suspected or known intravenous drug abuse in the 5 years preceding enrolment
Current smoking of more than 10 cigarettes or equivalent per day and/or unwilling to abstain from smoking during the admission period
Plan for major surgery between enrolment and completion of study follow-up
Personnel (e.g. investigator, sub-investigator, research assistant, pharmacist, study coordinator or anyone mentioned in the delegation log) directly involved in the conduct of the study
The subject has been committed to an institution by virtue of an order issued by either the judicial or administrative authorities