Clinical trial NCT04083508: Vivax Malaria Human Infection Studies in Thailand
Official title: A Clinical Study to Assess the Feasibility of a Controlled Human Plasmodium Vivax Malaria Infection Model Through Sporozoite Infection in Thai Adults
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Plasmodium Vivax Infection
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: Mahidol University
First posted: 2019-09-10
Enrollment: 6
Sex: ALL
Minimum age (years): 20
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Mosquito-bite controlled human challenge infection
Primary purpose: OTHER

Brief summary: This study is a human challenge study to assess the feasibility and safety of controlled human malaria infection (via P. vivax sporozites) in healthy volunteers, and to develop a bank of P. vivax-infected blood for use in future controlled human P. vivax malaria infection studies. Additional objectives are to obtain data on host immune response to P. vivax infection and pre-treatment gametocytaemia.

This study is funded by the UK Wellcome Trust. The grant reference number are Oxford/MORU: 212336/Z/18/Z and 212336/Z/18/A, and Mahidol University: 212336/A/18/Z and 212336/A/18/A.

Detailed description: Six healthy, malaria-naïve Thai adults, aged between 20 and 55 years will be recruited at the Clinical Therapeutics Unit (CTU) in the Hospital for Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok. The overall period of participation will be 15 months: a 3-month screening process prior to the Day 0 challenge, followed by 1 year after challenge. All inclusion and exclusion criteria will be checked to ensure eligibility criteria have been met prior to Day 0.

Volunteers will be admitted as inpatients to the CTU on Day -1 ( a day prior to the challenge day). Challenge (bites from 5 infected mosquitoes) will be administered at the Insectarium unit, Department of Entomology, Faculty of Tropical Medicine, Mahidol University. The infected mosquitoes will be prepared by the Malaria Vivax Research unit (MVRU, Faculty of Tropical Medicine, Mahidol University). Following successful feeding by the infectious mosquitoes, volunteers will be monitored daily as inpatients for parasitemia and clinical presentation of malaria infection (Days 1-5).

Beginning on Day 6, volunteers will be assessed twice a day and, at a timepoint that will depend upon the level of parasitaemia and/or degree of the volunteer's symptoms, up to 250 mL of blood will be drawn and then antimalarial treatment will be prescribed. The standard malaria radical cure according to Thai national guideline will be chloroquine, followed by a 2-week course of direct observed oral primaquine (PQ). Upon confirmation of clinical recovery, completion of chloroquine treatment and laboratory absence of infection, volunteers will be discharged and followed daily as outpatients through completion of oral primoquine therapy.

After completion of antimalarial therapy, all volunteers will continue to be followed for 1 year after Day 0:

* Outpatient CTU visits on Days 28, 90, 180, and 365 post-challenge. Procedures to be performed during these visits will include review of symptom diary cards, medical history, physical examination and assessment of adverse events. Blood samples will also be obtained to detect malaria antigens and assess immune response.
* Volunteers will be contacted by study staff every 2 weeks between visits until Day 365, to inquire for malaria symptoms or other adverse events.

Eligibility criteria: Inclusion Criteria:

* Healthy adult aged 20 to 55 years with weight more than 50 kg.
* Blood group O.
* Red blood cells positive for the Duffy antigen/chemokine receptor (DARC).
* Normal CYP2D6 genotype.
* Normal blood levels of Glucose-6-phosphate dehydrogenase (G6PDH) by the WHO definition.
* COVID-19 vaccination at least two doses of COVID-19 vaccine(s) approved by WHO.
* Agree to practice continuous effective contraception for the duration of study period until 3 months post-challenge.
* Agreement to refrain from blood donation during the course of the study and for 1 year after the end of their involvement in the study.
* Willing to take a curative antimalarial regimen following challenge.
* Willing to be admitted in the Hospital for Tropical Diseases for blood donation and clinical monitoring, until antimalarial treatment is completed and their symptoms are settling.
* Willing to reside in Bangkok for the duration of the study, until all antimalarial treatment has been completed.
* Reachable (24/7) by mobile phone during the period between challenge CHMI and completion of all antimalarial treatment.
* Able to read and write in Thai and able to answer ALL questions on the informed consent questionnaire correctly.
* Provided written informed consent to participate in the trial.
* Educational level: has at least an undergraduate degree.
* Cardiovascular risk assessment is low (less than 10% in the next 10 years according to the cardiovascular risk assessment from Thai NCD Division, DDC, MoPH (2016)

Exclusion Criteria:

* History of clinical malaria.
* Positive malaria PCR OR malaria film OR malaria serology (recent exposure)
* History of severe allergy to mosquito bite
* Presence of any medical condition (either physical or psychological) which in the judgment of the investigator would place the participant at undue risk or interfere with the results of the study (e.g. serious underlying cardiac, renal, hepatic or neurological disease; severe malnutrition; congenital defects or febrile condition)
* Presence of chronic disease or chronically use of medication.
* Plan to travel outside of Bangkok within the period of challenge until 3 months after.
* Use of systemic antibiotics with known antimalarial activity in the 30 days before challenge (e.g. trimethoprim-sulfamethoxazole, doxycycline, tetracycline, clindamycin, erythromycin, fluoroquinolones and azithromycin).
* Use of immunoglobulins or blood products (e.g. blood transfusion) at any time in the 1 year preceding enrolment.
* Venipuncture unlikely to allow blood donation according to the protocol as determined by the investigator.
* Receipt of an investigational product or any vaccine in the 30 days preceding enrolment (D0), or planned receipt during the study period.
* Prior receipt of an investigational vaccine likely to impact on interpretation of the trial data or the P. vivax parasite as assessed by the Investigator.
* Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV infection, asplenia, history of splenectomy, recurrent, severe infections, and chronic infection.
* Immunosuppressant medication within the past 6 months preceding enrolment (D0) (inhaled and topical steroids are allowed).
* History of allergic disease or reactions likely to be exacerbated by malaria infection.
* Female participant who is pregnant, lactating or planning pregnancy during the course of the study.
* Contraindications to the use of antimalarial treatment (e.g. chloroquine or primaquine or atovaquone / proguanil, DHA piperaquine). \*\*
* Use of medications known to have a potentially clinically significant interaction with antimalarial drug that will be used in this study (chloroquine or primaquine or atovaquone / proguanil, DHA/ piperaquine).
* Use of medications known to cause prolongation of the QT interval as state in the section of prohibited drugs that may have effect on prolongation of the QT interval.
* Known existing positive family history in both 1st AND 2nd degree relatives \< 50 years old for cardiac disease.
* Family history of congenital QT prolongation or sudden death.
* Any clinical condition known to prolong the QT interval.
* History of cardiac arrhythmia, including clinically relevant bradycardia.
* Screening ECG demonstrates a QTc interval ≥ 450 ms
* Suspected or known or history of alcohol abuse
* Suspected or known or history of drug abuse.
* Concurrently participating in another clinical study, at any time during the study period.
* Haemoglobin \< 13 g/dL in male, \< 12g/dL in female (Thai Red Cross).
* Finding on safety laboratory values as defined below:
* AST \> 40 U/L for male, and \> 32 U/L for female (upper normal range), or
* ALT \> 41 U/L for male, and \> 33 U/L for female (upper normal range), or
* Total Bilirubin \> 1.2 mg/dL, (upper normal range), or
* Creatinine (Cr) \> 1.17 mg/dL for male, and \> 0.95 mg/dL for female (upper normal range), or
* Abnormalities corrected calcium and magnesium blood levels, or
* Fasting blood sugar (FBS) \> 100 mg/dL
* Thalassaemia disease or haemoglobinopathies.
* Positive for a blood borne or vector borne infectious disease (HIVI-II, HBV, HCV, Dengue, Zika, Chikungunya, Filariasis, JE, and malaria antigen, Anti HTLVI and Anti-HTLVII antibody, Syphilis test (TPHA)
* Positive for COVID-19 testing as diagnosed by RT-PCR \*\* Link of the lists of medications with QTc prolongation: https://crediblemeds.org/pdftemp/pdf/CombinedList.pdf

Primary outcomes:
measure: Successful infection of controlled P. vivax sporozoite human challenge
timeFrame: up to 21 days after challenge
measure: (Serious) Adverse Event(s) occurrences of controlled P. vivax sporozoite human challenge
timeFrame: up to 90 days after challenge
measure: Collection and freezing down of up to 250 mL P. vivax-infected blood from each of the 6 volunteers.
timeFrame: up to 21 days after challenge
Secondary outcomes:
measure: Cellular Immune response to primary P. vivax infection.
timeFrame: up to 1 year after challenge
measure: Humoral Immune response to primary P. vivax infection.
timeFrame: up to 1 year after challenge
measure: Gametocytaemia following primary P. vivax infection delivered by the mosquito bite
timeFrame: up to 1 year after challenge
Other outcomes:
Locations:
city: Bangkok
country: Thailand
facility: Faculty of Tropical Medicine
Study officials:
affiliation: University of Oxford
name: Nicholas Day, MD
role: PRINCIPAL_INVESTIGATOR
References: