Study in Blood Stage Malaria Infection After DVI of Cryopreserved P. Falciparum (NF54 Strain) Sporozoites

• Status: Completed
• Trial end date: 2020-12-17
• Target enrollment: 0
• Participant gender: All

Summary

This is a single-centre, open-label, Phase Ib study designed to assess if intravenous injection of approximately 3200 P. falciparum (NF54 strain) sporozoites can be safely administered to achieve blood-stage parasitaemia with a kinetics/PCR profile that will allow for the future characterisation of antimalarial blood-stage activity of new chemical entities in a relatively small number of participants during early drug development.

Healthy, malaria-naïve adults, aged 18-55 years, will be enrolled in a maximum of 2 cohorts. Enrolment into the cohorts will proceed sequentially, with two target levels of parasitaemia, i.e., 5000 parasites/mL blood in Cohort 1 and 10000 parasites/mL blood in Cohort 2.

(Based on observed levels of parasitaemia in Cohort 1, the target threshold for treatment in Cohort 2 was maintained at 5,000 p/mL (vs 10,000 p/mL in the protocol)).

The 3-day antimalarial therapy regimen will be further administered and monitored until parasite clearance. Safety and tolerability will be monitored during the whole study duration.

• Phase: Phase 1
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Medicines for Malaria Venture
• Collaborators: FGK Representative Service B.V., The Netherlands; Institute of Tropical Medicine, Belgium; Iqvia Pty Ltd; PrimeVigilance Ltd., UK; Sanaria Inc.; SGS Life Sciences; SGS Life Sciences, a division of SGS Belgium NV; Swiss BioQuant A.G., Switzerland
• Treatments: Artemether; Artemether, Lumefantrine Drug Combination; Lumefantrine

Criteria

Inclusion Criteria:

1. Informed Consent Form signed voluntarily before any study-related procedure is performed, indicating that the participant understands the purpose of and procedures required for the study and is willing to participate in the study, including administration of registered antimalarial therapy;

2. Male or female, between 18 and 55 years old (extremes included) at screening;

3. Body weight of at least 50 kg and a body mass index (BMI) of 19.0 to 30.0 kg/m2 (extremes included);

4. Good general health without clinically relevant medical illness, physical exam findings including vital signs, and laboratory abnormalities (e.g., without liver transaminases >1x ULN and according to the clinically acceptable ranges for study inclusion laboratory tests in Attachment 4) as determined by the Investigator;

5. Willing to adhere to the prohibitions and restrictions specified in this protocol (see Section 4.3), including willingness to stay confined to the inpatient unit for the required duration and willingness to avoid travelling outside of Benelux during the study period;

6. Female participants should fulfil one of the following criteria:

1. At least 1 year postmenopausal (amenorrhea >12 months and follicle-stimulating hormone [FSH] >30 mIU/mL) prior to screening;

2. Surgically sterile (bilateral oophorectomy, hysterectomy or bilateral salpingectomy);

3. Will use contraceptives as outlined in inclusion criterion 7;

7. Female participants of childbearing potential (excluding females with female partners) must agree to the use of a highly effective method of birth control from the screening visit until 40 days after the EOS visit at Day 28 (covering a full menstrual cycle of 30 days starting after 5 half-lives of last dose of Riamet®); Note: Highly effective birth control methods include: combined (oestrogen- and progestogen-containing) oral/intravaginal/transdermal hormonal contraception associated with inhibition of ovulation, progestogen-only oral/injectable/implantable hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner or sexual abstinence from heterosexual intercourse.

8. Female participant has a negative pregnancy test at screening and upon admission in the clinical unit; Note: Pregnancy testing will consist of serum β-human chorionic gonadotropin (β-HCG) tests at screening and at the EOS visit and a urine β-HCG tests on Day -1, in all women.

9. Different ways of being reachable 24/7 (e.g., by mobile phone, regular phone or electronic mail) during the whole study period.

Exclusion Criteria:

• 1. Nursing (lactating) women; 2. Participation in any other clinical drug or vaccine study within 30 days (or 5 half-lives for drugs) preceding the day of PfSPZ-DVI Challenge (whichever is longer), or plans to participate in other investigational drug or vaccine research during the study period; 3. Participants who took standard vaccinations within 3 months before the start of the study or are planning to take standard vaccinations during the study period up to 8 weeks after PfSPZ-DVI Challenge;

4. Blood product donation to any blood bank during the 8 weeks (whole blood) or 4 weeks (plasma and platelets) prior to admission in the clinical unit on Day -1; 5. Mean ECG outside normal range and deemed clinically relevant by the Investigator. Examples of clinically significant ECG abnormalities for this study include:

• PR-interval >220 ms;

• QRS-complex >120 ms;

• Absolute QT greater than >500 ms;

• QT interval corrected according to Bazett's formula (QTcB) or QTcF >450 ms for male participants, >470 ms for female participants;

• Pathologic Q wave;

• Significant ST-T wave changes;

• Left or right ventricular hypertrophy;

• Non-sinus rhythm except isolated premature atrial contractions and ventricular extrasystole <2 per 10 s ECG lead;

• Incomplete left bundle branch block, or complete or intermittent right or left bundle branch block;

• Second or third degree A-V heart block. 6. Seropositive human immunodeficiency virus (HIV), hepatitis A immunoglobulinM (IgM) antibody, hepatitis B virus (HBV) (hepatitis B surface antigen [HBsAg]), hepatitis C virus (HCV) (antibody), hepatitis D antibody, hepatitis E IgM antibody, cytomegalovirus (CMV) IgM antibody or Epstein Barr Virus (EBV) IgM antibody; 7. Previous or current diagnosis of hepatitis including but not limited to viral hepatitis, auto-immune hepatitis, non-alcoholic steatohepatitis (NASH), alpha-1-antitrypsin deficiency, alcoholic liver disease, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), hemochromatosis, Wilson disease or suspected hepatocellular carcinoma (HCC).

8. History or presence of diagnosed food or known drug allergies (including but not limited to allergy to any of the antimalarial medications to be used in the study, see Section 5.1), or history of anaphylaxis or other severe allergic reactions; Note: Participants with seasonal allergies/hay fever, house dust mite or allergy to animals that are untreated and asymptomatic at the time of dosing can be enrolled in the study.

9. History of convulsion or severe head trauma, excluding fever convulsion under 5 years of age; Note: A medical history of a single febrile convulsion during childhood is not an exclusion criterion.

10. 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; Note: The Beck Depression Inventory (Attachment 2) will be used as an objective tool for the assessment of depression at screening. In addition to the conditions listed above, participants 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. Participants 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.

11. A medical, occupational or family problem as a result of alcohol or illicit drug abuse during the past 12 months or current alcohol or illicit drug abuse or addiction (positive alcohol breath test or positive drug screen for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine or opiates at screening or upon check-in at the clinical unit); Note: Excessive use of alcohol is defined as an intake of >21 units per week for males and >14 units per week for females where one alcohol unit is defined as 10 mL or 8 g of pure alcohol. A single unit is equal to one 25-mL (single) measure of whisky (alcohol by volume [ABV] 40%), or a third of a pint of beer (190 mL; ABV 5-6%) or half a standard (175 mL) glass of wine (ABV 12%).

12. Participants are non-smokers or ex-smokers for more than 90 days prior to screening, or smoke no more than 5 cigarettes per day. If users of nicotine products (i.e., spray, patch, e-cigarette, etc.), they should use the equivalent of no more than 5 cigarettes per day. Participants must agree to abstain from smoking while in the unit; 13. Use of any prescription drugs, herbal supplements (e.g., St John's Wort) or over-the-counter medication within 7 days or 5 half-lives (whichever is longer) prior to the PfSPZ-DVI Challenge, or an anticipated requirement for the use of these during the course of the study (see Section 6.2); Note: If necessary, the incidental use of non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol (2 g/day, 10 g/week) may be acceptable at the Investigator's discretion and will be documented in the eSource system. The use of nutritional supplements during this time that are not believed to have the potential to affect participant safety nor the overall results of the study, may be permitted on a case-by-case basis by the Investigator.

14. Any surgical or medical condition possibly affecting drug absorption (e.g., cholecystectomy, gastrectomy, bowel disease), distribution, metabolism or excretion;

15. 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; 16. Any condition that in the opinion of the Investigator would jeopardise the safety or rights of a person participating in the study or would render the person unable to comply with the protocol; 17. Personal history of malaria; 18. Volunteer has travelled to or lived in a malaria-endemic area within 6 months prior to planned study enrolment; 19. Plans to travel to malaria-endemic region during the study period up to last follow-up visit; 20. Previous participation in any malaria vaccine or Controlled Human Malaria Infection (CHMI) study/VIS; 21. Falling in moderate or higher risk category for a fatal or non-fatal cardiovascular event within 5 years (> 5%) determined by a validated risk estimation system, e.g., SCORE [21]; 22. Use of systemic antibiotics with known antimalarial activity within 5 half-lives of PfSPZ-DVI Challenge (e.g., trimethoprim-sulfamethoxazole, doxycycline, tetracycline, clindamycin, erythromycin, fluoroquinolones or azithromycin) or an anticipated requirement for the use of these during the study period (see Section 6.2); 23. Receipt of blood or blood-derived products (including immunoglobulin) within 3 months prior to screening. Receipt of packed RBCs given for an emergent indication in an otherwise healthy person, and not required as ongoing treatment is not exclusionary (for example packed RBCs emergently given during an elective surgery).

Note: In case of an out-of-range clinical laboratory test (according to the clinically acceptable ranges for study inclusion laboratory tests in Attachment 4), vital sign or ECG value that will determine a participant's eligibility, or in case of a positive drug screen, a retest or expert evaluation can be requested. Results of any retest must be available prior to inoculation. The result of the retest will be considered for participant eligibility at the Investigator's discretion. Participants can be rescreened at the discretion of the Investigator.