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

NCT04310085 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: PfSPZ-DVI Blood Stage_19_012019-004317-14
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

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.

Conditions

Malaria,Falciparum; Parasitemia; Protozoan Infections; Parasitic Disease

Keywords

Malaria; PfSPZ Challenge

Outcome Measures

Primary Outcomes (9)

• 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.

  Screening until end of study, day 28.

• 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).

  Day 1 until end of study, day 28.

• Time to First PCR Positivity.

  For the purpose of this study, 'PCR positivity' is used for the 'protocol-defined PCR positivity'

  Day 1 to day 21

• Parasitaemia at First PCR Positivity

  POSITIVE PARASITAEMIA IS DEFINED AS qPCR OUTCOME \>=250 PARASITES per mL BLOOD.

  Day 1 to day 21

• Time to Parasitaemia of ≥5000 Parasites Per mL Blood (Cohorts 1 and 2)

  Day 1 to day 21

• Parasitaemia at the Time Parasitaemia ≥5000 Parasites Per mL Blood (Cohorts 1 and 2)

  Day 1 to day 21

• Time to First Dose of Treatment With Artemether-lumefantrine (Riamet®) (Cohorts 1 and 2)

  Day 1 to day 21

• Parasitaemia at First Dose of Treatment With Riamet® (Cohorts 1 and 2)

  Day 1 to day 21

• Incidence of Positive PCR and Parasitaemia of ≥5000 Parasites Per mL Blood.

  Day 1 with PfSPZ-DVI Challenge and Day 28 (per cohort).

Study Arms (1)

PfSPZ-DVI challenge and artemether lumefantrine

EXPERIMENTAL

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: 1. Cohort 1: ≥5000 parasites/mL blood or earlier if a participant has a malaria clinical score \>6 or at Investigator's discretion. 2. Cohort 2: ≥10000 parasites/mL blood or earlier if a participant has a malaria clinical score \>6 or at Investigator's discretion.

Drug: Artemether-Lumefantrine 20 Mg-120 Mg Oral Tablet; Biological: PfSPZ-DVI Challenge

Interventions

Artemether-Lumefantrine 20 Mg-120 Mg Oral Tablet DRUG

artemether-lumefantrine 6 x of 4 tablets at approximately 0, 8, 24, 36, 48 and 60 h

Also known as: Riamet

PfSPZ-DVI challenge and artemether lumefantrine

PfSPZ-DVI Challenge BIOLOGICAL

3200 P. falciparum Sporozoites by direct venous inoculation (DVI)

PfSPZ-DVI challenge and artemether lumefantrine

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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);
• 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);
• 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.

You may not qualify if:

• \. 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).
• \. 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.
• \. 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.
• \. 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%).
• \. 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.

Sponsors & Collaborators

• Medicines for Malaria Venture: lead
• SGS Life Sciences, a division of SGS Belgium NV: collaborator
• Institute of Tropical Medicine, Belgium: collaborator
• Swiss BioQuant: collaborator
• PrimeVigilance Ltd., UK: collaborator
• Sanaria Inc.: collaborator
• Iqvia Pty Ltd: collaborator
• FGK Representative Service B.V., The Netherlands: collaborator

Study Sites (1)

SGS Belgium NV Clinical Pharmacology Unit

Antwerp, 2060, Belgium

Location

MeSH Terms

Conditions

Malaria, Falciparum; Parasitemia; Protozoan Infections; Parasitic Diseases; Malaria

Interventions

Artemether, Lumefantrine Drug Combination

Condition Hierarchy (Ancestors)

Infections; Mosquito-Borne Diseases; Vector Borne Diseases; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Artemether; Artemisinins; Reactive Oxygen Species; Free Radicals; Inorganic Chemicals; Organic Chemicals; Lumefantrine; Fluorenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sesquiterpenes; Terpenes; Polycyclic Compounds; Drug Combinations; Pharmaceutical Preparations

Limitations and Caveats

This exploratory study focused on the methodology of malaria inoculation in healthy participants. No formal sample size calculation was performed. No formal statistical analysis was performed for the primary endpoint "Changes from baseline in haematology, clinical chemistry and urinalysis parameters, vital signs and electrocardiogram (ECG) parameters". A qualitative interpretation is available if requested.

Results Point of Contact

• Title: Dr Stephan Chalon
• Organization: Medicines for Malaria Venture

chalons@mmv.org

+41 22 555 0379

Study Officials

• Farouk Chughlay, MD

  Medicines for Malaria Venture

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: March 9, 2020
• First Posted: March 17, 2020
• Study Start: February 19, 2020
• Primary Completion: December 17, 2020
• Study Completion: December 17, 2020
• Last Updated: September 5, 2021
• Results First Posted: September 5, 2021

Record last verified: 2021-09

Locations

BE (1)