Immunization With Plasmodium Falciparum Sporozoites Under Chloroquine or Chloroquine/Azithromycin Prophylaxis

Study Overview
=================
Brief Summary
-----------------
This study will assess the superior protective immunity of the combination of chloroquine and azithromycin prophylaxis under Chemoprophylaxis Sporozoites (CPS) immunization versus a standard chloroquine prophylactic regimen.

Detailed Description
-----------------
This study assesses the superiority of protective immunity of the combination of chloroquine and azithromycin prophylaxis under Chemoprophylaxis Sporozoites (CPS) immunization versus a standard chloroquine prophylactic regimen.

Official Title
-----------------
Immunization With Plasmodium Falciparum Sporozoites Under Chloroquine or Chloroquine/Azithromycin Prophylaxis

Conditions
-----------------
Malaria, Falciparum

Intervention / Treatment
-----------------
* Drug: Azithromycin capsules
* Drug: Placebo
* Biological: Immunization with falciparum


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 and ≤ 35 years healthy volunteers (males or females) Good health based on history and clinical examination Negative pregnancy serum test For females who are sexually active: use of adequate contraception (incl. condom use) Signing of the informed consent form, thereby demonstrating understanding of the meaning and procedures of the study Agreement to inform the general practitioner and to sign a request to release medical information concerning contra-indications for participation in the study Willingness to undergo a Pf controlled infection through mosquito bites Agreement to stay in a hotel room close to the trial centre during a part of the study (Day 7 till day 15 after challenge) Reachable (24/7) by mobile phone during the whole study period Available to attend all study visits Agreement to refrain from blood donation or for other purposes, during the whole study period Willingness to undergo HIV, hepatitis B and hepatitis C tests Negative urine toxicology screening test at screening visit and the day before challenge Willingness to take a prophylactic regime of chloroquine or chloroquine/azithromycin combination and a curative regimen of Malarone® after challenge. Exclusion Criteria: History of malaria Plans to travel to malaria endemic areas during the study period Plans to travel outside of the Netherlands during the challenge period History of stay in malaria endemic areas for more than 6 months Previous participation in any malaria vaccine study and/or positive serology for Pf Symptoms, physical signs and laboratory values suggestive of systemic disorders including renal, hepatic, cardiovascular, pulmonary, skin, immunodeficiency, psychiatric, and other conditions which could interfere with the interpretation of the study results or compromise the health of the volunteer History of diabetes mellitus or cancer (except basal cell carcinoma of the skin) History of arrhythmias or prolonged QT-interval Positive family history in 1st and 2nd degree relatives for cardiac events < 50 years old An estimated, ten year risk of fatal cardiovascular disease of ≥5%, as estimated by the Systematic Coronary Risk Evaluation (SCORE) system Clinically significant abnormalities in electrocardiogram (ECG) at screening Body Mass Index (BMI) below 18 or above 30 kg/m2 Any clinically significant deviation from the normal range in biochemistry or haematology blood tests or in urine analysis Positive HIV, HBV or HCV tests Participation in any other clinical study within 30 days prior to the onset of the study Enrolment in any other clinical study during the study period Pregnancy or lactation for women Volunteers unable to give written informed consent Volunteers unable to be closely followed for social, geographic or psychological reasons History of (soft) drugs or alcohol abuse interfering with normal social function A history of treatment for psychiatric disease A history of epileptic insults in the volunteer Contra-indications for use of Malarone®, chloroquine or azithromycin. This includes hypersensitivity or treatment taken by the volunteer that interferes with mentioned study drugs. The use of chronic immunosuppressive drugs, antibiotics, or other immune modifying drugs within three months of study onset (topical corticosteroids and oral anti-histaminic are allowed) and during the study period Any confirmed or suspected immunosuppressive or immunodeficient condition, including (functional) asplenia Co-workers or trainees of the departments of Medical Microbiology, Parasitology, or Internal Medicine of the Leiden University Medical Centre A history of sickle cell anaemia, sickle cell trait, thalassemia, thalassemia trait or G6PD deficiency

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: CQ and falciparum immunization<br>This arm will receive chloroquine prophylaxis, a placebo during immunizations and three times 5 infected mosquito-bites (immunizations). Standard Chloroquine prophylactic regime: a loading dose of 300 mg on day 1 and day 3 and then 300 mg once a week, starting on day 7, for a total duration of 13 weeks. Placebo capsules daily on three consecutive days starting on each of three immunization days. Challenge: Exposure to the bites of 5 Plasmodium falciparum infected mosquitoes. When thick smear positive, of at day 21 after challenge, a standard 3 day treatment of Malarone will be given. | Drug: Placebo<br>* Placebo capsules will be administered at each immunization<br>Biological: Immunization with falciparum<br>* three inoculations with 5 infected mosquito bites<br>|
| Experimental: CQ/AZM and falciparum immunization<br>This arm will receive chloroquine and azithromycin prophylaxis and three times 5 infected mosquito-bites (immunizations). Standard Chloroquine prophylactic regime: a loading dose of 300 mg on day 1 and day 3 and then 300 mg once a week, starting on day 7, for a total duration of 13 weeks. Azithromycin capsules 1000mg daily on three consecutive days starting on each of three immunization days. Challenge: Exposure to the bites of 5 Plasmodium falciparum infected mosquitoes. When thick smear positive, of at day 21 after challenge, a standard 3 day treatment of Malarone will be given. | Drug: Azithromycin capsules<br>* Azithromycin capsules will be administered at each immunization<br>* Other names: Zithromax;Biological: Immunization with falciparum<br>* three inoculations with 5 infected mosquito bites<br>|
| Placebo Comparator: CQ and AZM control<br>This arm will receive chloroquine and azithromycin prophylaxis and three times 5 uninfected mosquito-bites during immunization. Standard Chloroquine prophylactic regime: a loading dose of 300 mg on day 1 and day 3 and then 300 mg once a week, starting on day 7, for a total duration of 13 weeks. Azithromycin capsules 1000mg daily on three consecutive days starting on each of three immunization days. Challenge: Exposure to the bites of 5 Plasmodium falciparum infected mosquitoes. When thick smear positive, of at day 21 after challenge, a standard 3 day treatment of Malarone will be given. | Drug: Azithromycin capsules<br>* Azithromycin capsules will be administered at each immunization<br>* Other names: Zithromax;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Volunteers falciparum positive by thick smear | Percentage of P. falciparum thick smear negative volunteers on day 21 (protection against challenge infection) | One year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of pre-patent period by thick smear | Duration of pre-patent period after challenge infection as measured by microscopy (thick smear) | One year | 
| Kinetics of parasitemia by PCR | Development of parasitemia as measured by PCR | One year | 
| Adverse events | Frequency of adverse events in study groups | One year | 
| Immune responses | Immune responses between study groups | One year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Malaria, P falciparum, Chloroquine, Azithromycin, Immunization