Immunization With Plasmodium Falciparum Sporozoites Under Chloroquine or Chloroquine/Azithromycin Prophylaxis (MMV)

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.

Study Overview

• Status: Withdrawn
• Conditions: Malaria, Falciparum
• Intervention / Treatment: Drug: Placebo; Biological: Immunization with falciparum; Drug: Azithromycin capsules

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.

• Study Type: Interventional
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Leiden, Netherlands, 2333ZA
    • Leiden University Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥ 18 and ≤ 35 years healthy volunteers (males or females)
2. Good health based on history and clinical examination
3. Negative pregnancy serum test
4. For females who are sexually active: use of adequate contraception (incl. condom use)
5. Signing of the informed consent form, thereby demonstrating understanding of the meaning and procedures of the study
6. Agreement to inform the general practitioner and to sign a request to release medical information concerning contra-indications for participation in the study
7. Willingness to undergo a Pf controlled infection through mosquito bites
8. 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)
9. Reachable (24/7) by mobile phone during the whole study period
10. Available to attend all study visits
11. Agreement to refrain from blood donation or for other purposes, during the whole study period
12. Willingness to undergo HIV, hepatitis B and hepatitis C tests
13. Negative urine toxicology screening test at screening visit and the day before challenge
14. Willingness to take a prophylactic regime of chloroquine or chloroquine/azithromycin combination and a curative regimen of Malarone® after challenge.

Exclusion Criteria:

1. History of malaria
2. Plans to travel to malaria endemic areas during the study period
3. Plans to travel outside of the Netherlands during the challenge period
4. History of stay in malaria endemic areas for more than 6 months
5. Previous participation in any malaria vaccine study and/or positive serology for Pf
6. 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
7. History of diabetes mellitus or cancer (except basal cell carcinoma of the skin)
8. History of arrhythmias or prolonged QT-interval
9. Positive family history in 1st and 2nd degree relatives for cardiac events < 50 years old
10. An estimated, ten year risk of fatal cardiovascular disease of ≥5%, as estimated by the Systematic Coronary Risk Evaluation (SCORE) system
11. Clinically significant abnormalities in electrocardiogram (ECG) at screening
12. Body Mass Index (BMI) below 18 or above 30 kg/m2
13. Any clinically significant deviation from the normal range in biochemistry or haematology blood tests or in urine analysis
14. Positive HIV, HBV or HCV tests
15. Participation in any other clinical study within 30 days prior to the onset of the study
16. Enrolment in any other clinical study during the study period
17. Pregnancy or lactation for women
18. Volunteers unable to give written informed consent
19. Volunteers unable to be closely followed for social, geographic or psychological reasons
20. History of (soft) drugs or alcohol abuse interfering with normal social function
21. A history of treatment for psychiatric disease
22. A history of epileptic insults in the volunteer
23. Contra-indications for use of Malarone®, chloroquine or azithromycin. This includes hypersensitivity or treatment taken by the volunteer that interferes with mentioned study drugs.
24. 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
25. Any confirmed or suspected immunosuppressive or immunodeficient condition, including (functional) asplenia
26. Co-workers or trainees of the departments of Medical Microbiology, Parasitology, or Internal Medicine of the Leiden University Medical Centre
27. A history of sickle cell anaemia, sickle cell trait, thalassemia, thalassemia trait or G6PD deficiency

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: CQ and falciparum immunization; 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; Placebo capsules will be administered at each immunization; Biological: Immunization with falciparum; three inoculations with 5 infected mosquito bites
Experimental: CQ/AZM and falciparum immunization; 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.	Biological: Immunization with falciparum; three inoculations with 5 infected mosquito bites; Drug: Azithromycin capsules; Azithromycin capsules will be administered at each immunization; Other Names: Zithromax
Placebo Comparator: CQ and AZM control; 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; Azithromycin capsules will be administered at each immunization; 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

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: Leiden University Medical Center; Medicines for Malaria Venture
• Investigators: Study Director: RW Sauerwein, MD PhD, Radboud University Medical Center; Principal Investigator: LG Visser, MD PhD, Leiden University Medical Centre

Publications and helpful links

General Publications

• Roestenberg M, McCall M, Hopman J, Wiersma J, Luty AJ, van Gemert GJ, van de Vegte-Bolmer M, van Schaijk B, Teelen K, Arens T, Spaarman L, de Mast Q, Roeffen W, Snounou G, Renia L, van der Ven A, Hermsen CC, Sauerwein R. Protection against a malaria challenge by sporozoite inoculation. N Engl J Med. 2009 Jul 30;361(5):468-77. doi: 10.1056/NEJMoa0805832.

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Anticipated): December 1, 2013
• Study Completion (Anticipated): April 1, 2014

Study Registration Dates

• First Submitted: January 31, 2013
• First Submitted That Met QC Criteria: January 31, 2013
• First Posted (Estimate): February 4, 2013

Study Record Updates

• Last Update Posted (Estimate): November 13, 2014
• Last Update Submitted That Met QC Criteria: November 12, 2014
• Last Verified: November 1, 2014

More Information

Terms related to this study

• Keywords: Malaria; Azithromycin; Chloroquine; Immunization; P falciparum
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Malaria, Falciparum; Anti-Infective Agents; Anti-Bacterial Agents; Azithromycin
• Other Study ID Numbers: MMV; NL42517.000.12 (Other Identifier: CCMO)