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

Primary Purpose

Malaria,Falciparum, Parasitemia, Protozoan Infections

Status
Completed
Phase
Phase 1
Locations
Belgium
Study Type
Interventional
Intervention
Artemether-Lumefantrine 20 Mg-120 Mg Oral Tablet
PfSPZ-DVI Challenge
Sponsored by
Medicines for Malaria Venture
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Malaria,Falciparum focused on measuring Malaria, PfSPZ Challenge

Eligibility Criteria

18 Years - 55 Years (Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

  • SGS Belgium NV Clinical Pharmacology Unit

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

PfSPZ-DVI challenge and artemether lumefantrine

Arm Description

16 healthy, malaria-naïve males and females, aged 18-55 years, were enrolled in 2 cohorts (8 participants/cohort; a participant may be enrolled in one cohort only). There were two target levels of parasitaemia previously achieved in healthy participants in malaria VIS at other study sites, 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). qPCR was performed, malaria clinical score assessed twice daily and participants were administered registered antimalarial therapy, i.e., Riamet®, when the following criteria were met: Cohort 1: ≥5000 parasites/mL blood or earlier if a participant has a malaria clinical score >6 or at Investigator's discretion. Cohort 2: ≥10000 parasites/mL blood or earlier if a participant has a malaria clinical score >6 or at Investigator's discretion.

Outcomes

Primary Outcome Measures

Incidence and Severity of Observed or Self-reported Adverse Events (AEs) Considered PfSPZ-DVI Challenge Inoculum-related.
Based on their start date(time), AEs will be allocated to the phase during which they started (Screening, Challenge, Rescue). Each AE will therefore be reported in only one phase.
Change in Malaria Clinical Score From PfSPZ-DVI Challenge Until Parasite Clearance.
Malaria Clinical Score 14 signs/symptoms frequently associated with malaria will be graded using a 4-point scale (absent: 0; mild: 1; moderate: 2; severe: 3): headache, myalgia (muscle ache), arthralgia (joint ache), fatigue/lethargy, malaise (general discomfort/uneasiness), chills/shivering/rigors, sweating/hot spells, anorexia, nausea, vomiting, abdominal discomfort, fever, tachycardia and hypotension. Malaria clinical score is calculated as the sum of all (14) malaria sign and symptoms scores (maximum score is 42).
Time to First PCR Positivity.
For the purpose of this study, 'PCR positivity' is used for the 'protocol-defined PCR positivity'
Parasitaemia at First PCR Positivity
POSITIVE PARASITAEMIA IS DEFINED AS qPCR OUTCOME >=250 PARASITES per mL BLOOD.
Time to Parasitaemia of ≥5000 Parasites Per mL Blood (Cohorts 1 and 2)
Parasitaemia at the Time Parasitaemia ≥5000 Parasites Per mL Blood (Cohorts 1 and 2)
Time to First Dose of Treatment With Artemether-lumefantrine (Riamet®) (Cohorts 1 and 2)
Parasitaemia at First Dose of Treatment With Riamet® (Cohorts 1 and 2)
Incidence of Positive PCR and Parasitaemia of ≥5000 Parasites Per mL Blood.

Secondary Outcome Measures

Full Information

First Posted
March 9, 2020
Last Updated
September 3, 2021
Sponsor
Medicines for Malaria Venture
Collaborators
SGS Life Sciences, a division of SGS Belgium NV, Institute of Tropical Medicine, Belgium, Swiss BioQuant A.G., Switzerland, PrimeVigilance Ltd., UK, Sanaria Inc., Iqvia Pty Ltd, FGK Representative Service B.V., The Netherlands
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1. Study Identification

Unique Protocol Identification Number
NCT04310085
Brief Title
Study in Blood Stage Malaria Infection After DVI of Cryopreserved P. Falciparum (NF54 Strain) Sporozoites
Official Title
A Single Centre, Open Label, Pilot Phase Ib Study to Investigate Blood Stage Malaria Infection After Direct Venous Inoculation of Cryopreserved P. Falciparum (NF54 Strain) Sporozoites (PfSPZ-DVI) in Malaria naïve Healthy Adult Volunteers
Study Type
Interventional

2. Study Status

Record Verification Date
September 2021
Overall Recruitment Status
Completed
Study Start Date
February 19, 2020 (Actual)
Primary Completion Date
December 17, 2020 (Actual)
Study Completion Date
December 17, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Medicines for Malaria Venture
Collaborators
SGS Life Sciences, a division of SGS Belgium NV, Institute of Tropical Medicine, Belgium, Swiss BioQuant A.G., Switzerland, PrimeVigilance Ltd., UK, Sanaria Inc., Iqvia Pty Ltd, FGK Representative Service B.V., The Netherlands

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
No

5. Study Description

Brief 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.
Detailed Description
Up to 16 healthy, malaria-naïve males and females, aged 18-55 years, will be enrolled in a maximum of 2 cohorts (up to 8 participants per cohort; a participant may be enrolled in one cohort only). Enrolment into the cohorts will proceed sequentially, with two target levels of parasitaemia previously achieved in healthy participants enrolled in malaria Volunteer Infection Studies (VIS) at other study sites, 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)). Each participant will be admitted to the clinical unit in the morning of Day -1 and inoculated with approximately 3200 P. falciparum sporozoites (NF54 strain) by DVI on Day 1. Participants will be discharged 2 h post inoculation on Day 1 and will be monitored daily via phone call from Day 2 until Day 6 to solicit any AEs. Participants will come to the clinical unit daily from Day 7 until Day 9 and together with the malaria clinical score (see Attachment 1), the presence of parasites will be assessed once daily by a specific qPCR targeting the varATS (the acidic terminal segment in Plasmodium falciparum var genes) multigenic family; this to accurately describe parasite growth even in case PCR positivity, i.e., a qPCR outcome ≥250 parasites per mL blood, is confirmed this early (very low probability and with low densities). Participants will be confined to the clinical unit from Day 10 in the morning. qPCR will be performed and malaria clinical score assessed twice daily and participants will be administered registered antimalarial therapy, i.e., Riamet®, when the following criteria are met: Cohort 1: ≥5000 parasites/mL blood or earlier if a participant has a malaria clinical score >6 or at Investigator's discretion. Cohort 2: ≥10000 parasites/mL blood or earlier if a participant has a malaria clinical score >6 or at Investigator's discretion. The registered 3-day antimalarial therapy regimen will be further administered and monitored. qPCR assessments of parasitaemia will be carried out at multiple time points (2, 6, 8, 12, 16, 24, 36, 48 and 72 h) following initiation of Riamet® and malaria clinical score will be assessed twice daily during confinement in the clinical unit. Safety and tolerability will be monitored during the whole study duration, specific assessments will be done at periodic pre-specified time points from Day 10 and for at least 72 h after initiating antimalarial therapy, i.e., during confinement in the clinical unit (see below). Of note, all participants must consent to receiving antimalarial therapy, i.e., the registered 3-day Riamet® regimen approved for treatment of uncomplicated malaria. Even in the case of withdrawal from the study, all participants administered the PfSPZ-DVI Challenge are to receive antimalarial therapy as soon as possible, and to have all appropriate visits and assessments as required. If an intolerance or contraindication to Riamet® develops, Malarone® will be administered. Upon parasite clearance (defined as a qPCR value of 0 parasites per mL blood after initiating antimalarial therapy) and at least 72 h after initiating antimalarial therapy (estimated to occur on or before Day 19 and on or before Day 22 for Cohort 1 and Cohort 2, respectively), and if clinically well, participants will be discharged from the clinical unit and will be followed up for safety assessments, clinical evaluation and malaria qPCR in the clinical unit at the EOS visit on Day 28. All participants who received antimalarial therapy will be asked non-leading questions to determine the occurrence of any AEs throughout the study and at the EOS visit. All participants inoculated with PfSPZ-DVI Challenge will commence antimalarial therapy no later than Day 24 for both cohorts, regardless if they reach pre-defined cohort-specific PCR parasitaemia/malaria clinical score thresholds (i.e., 5000 parasites/mL blood for Cohort 1 and 10000 parasites/mL blood for Cohort 2 and/or a malaria clinical score ≥6 for Cohorts 1 and 2). Participants who start antimalarial therapy on Day 24 will only be discharged from confinement at the end of the EOS visit on Day 28. Antimalarial therapy may be initiated whenever deemed necessary by the Investigators, e.g., if there is a concern regarding the safety of a study participant. Therapy may be amended according to the treating physician if the participant does not respond to treatment or the condition worsens.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malaria,Falciparum, Parasitemia, Protozoan Infections, Parasitic Disease
Keywords
Malaria, PfSPZ Challenge

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Model Description
All subjects will receive the PfSPZ Challenge product. In cohort 1 parasitaemia will be allowed to develop until a threshold of 5000 parasites/mL blood or a malaria clinical score ≥6 is reached. In cohort 2 the threshold is 10 000/mL or a malaria clinical score of ≥6.
Masking
None (Open Label)
Allocation
N/A
Enrollment
16 (Actual)

8. Arms, Groups, and Interventions

Arm Title
PfSPZ-DVI challenge and artemether lumefantrine
Arm Type
Experimental
Arm Description
16 healthy, malaria-naïve males and females, aged 18-55 years, were enrolled in 2 cohorts (8 participants/cohort; a participant may be enrolled in one cohort only). There were two target levels of parasitaemia previously achieved in healthy participants in malaria VIS at other study sites, 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). qPCR was performed, malaria clinical score assessed twice daily and participants were administered registered antimalarial therapy, i.e., Riamet®, when the following criteria were met: Cohort 1: ≥5000 parasites/mL blood or earlier if a participant has a malaria clinical score >6 or at Investigator's discretion. Cohort 2: ≥10000 parasites/mL blood or earlier if a participant has a malaria clinical score >6 or at Investigator's discretion.
Intervention Type
Drug
Intervention Name(s)
Artemether-Lumefantrine 20 Mg-120 Mg Oral Tablet
Other Intervention Name(s)
Riamet
Intervention Description
artemether-lumefantrine 6 x of 4 tablets at approximately 0, 8, 24, 36, 48 and 60 h
Intervention Type
Biological
Intervention Name(s)
PfSPZ-DVI Challenge
Intervention Description
3200 P. falciparum Sporozoites by direct venous inoculation (DVI)
Primary Outcome Measure Information:
Title
Incidence and Severity of Observed or Self-reported Adverse Events (AEs) Considered PfSPZ-DVI Challenge Inoculum-related.
Description
Based on their start date(time), AEs will be allocated to the phase during which they started (Screening, Challenge, Rescue). Each AE will therefore be reported in only one phase.
Time Frame
Screening until end of study, day 28.
Title
Change in Malaria Clinical Score From PfSPZ-DVI Challenge Until Parasite Clearance.
Description
Malaria Clinical Score 14 signs/symptoms frequently associated with malaria will be graded using a 4-point scale (absent: 0; mild: 1; moderate: 2; severe: 3): headache, myalgia (muscle ache), arthralgia (joint ache), fatigue/lethargy, malaise (general discomfort/uneasiness), chills/shivering/rigors, sweating/hot spells, anorexia, nausea, vomiting, abdominal discomfort, fever, tachycardia and hypotension. Malaria clinical score is calculated as the sum of all (14) malaria sign and symptoms scores (maximum score is 42).
Time Frame
Day 1 until end of study, day 28.
Title
Time to First PCR Positivity.
Description
For the purpose of this study, 'PCR positivity' is used for the 'protocol-defined PCR positivity'
Time Frame
Day 1 to day 21
Title
Parasitaemia at First PCR Positivity
Description
POSITIVE PARASITAEMIA IS DEFINED AS qPCR OUTCOME >=250 PARASITES per mL BLOOD.
Time Frame
Day 1 to day 21
Title
Time to Parasitaemia of ≥5000 Parasites Per mL Blood (Cohorts 1 and 2)
Time Frame
Day 1 to day 21
Title
Parasitaemia at the Time Parasitaemia ≥5000 Parasites Per mL Blood (Cohorts 1 and 2)
Time Frame
Day 1 to day 21
Title
Time to First Dose of Treatment With Artemether-lumefantrine (Riamet®) (Cohorts 1 and 2)
Time Frame
Day 1 to day 21
Title
Parasitaemia at First Dose of Treatment With Riamet® (Cohorts 1 and 2)
Time Frame
Day 1 to day 21
Title
Incidence of Positive PCR and Parasitaemia of ≥5000 Parasites Per mL Blood.
Time Frame
Day 1 with PfSPZ-DVI Challenge and Day 28 (per cohort).

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: 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; Male or female, between 18 and 55 years old (extremes included) at screening; Body weight of at least 50 kg and a body mass index (BMI) of 19.0 to 30.0 kg/m2 (extremes included); 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; 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; Female participants should fulfil one of the following criteria: At least 1 year postmenopausal (amenorrhea >12 months and follicle-stimulating hormone [FSH] >30 mIU/mL) prior to screening; Surgically sterile (bilateral oophorectomy, hysterectomy or bilateral salpingectomy); Will use contraceptives as outlined in inclusion criterion 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. 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. 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Farouk Chughlay, MD
Organizational Affiliation
Medicines for Malaria Venture
Official's Role
Study Director
Facility Information:
Facility Name
SGS Belgium NV Clinical Pharmacology Unit
City
Antwerpen
ZIP/Postal Code
2060
Country
Belgium

12. IPD Sharing Statement

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

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