This is an open label, Phase 2 study with controlled human malaria infection (CHMI). Twenty three subjects will be enrolled into 2 groups (15 subjects in the Chloroquine-Azithromycin \[CQ/AZ\] Intervention Group, and 8 subjects in the Chloroquine \[CQ\] Group). The CQ/AZ Group will receive experimental intervention of 300 mg of CQ and 2 g of azithromycin (AZ). The CQ Group will receive 300 mg of CQ only. All subjects will participate in the CHMI and will be required to stay at a hotel for evaluation for a maximum of 14 nights starting 7 days after the challenge. A standard dose of atovaquone-proguanil (Malarone®) will be administered to all symptomatic parasitemic subjects under directly observed treatment.
This study is a Phase 2, open-label study of the combination of a single dose-level of AZ (Zithromax) plus CQ given weekly as a prophylaxis against CQ-resistant P falciparum in healthy adults. After signing informed consent, subjects will undergo screening procedures between Day -77 to Day -18. If enrolled, subjects who are still eligible at Study Day -18 will be randomized to either the CQ/AZ group (Group 1 of 15 subjects: 2 g AZ (Zithromax) plus 300 mg CQ base weekly for 6 weeks), or the CQ control group (Group 2 of 8 subjects: 300 mg chloroquine base weekly for 6 weeks) and start intervention on Study Day -17. The rationale for the CQ control group to receive CQ is to show that the strain utilized (7G8) is indeed chloroquine resistant in humans: we expect all of the subjects in the CQ control group to become symptomatically parasitemic. If 3 or more subjects in the CQ control group do not become symptomatic with malaria, the CHMI will be considered uncontrolled either due to 7G8 not being CQ-resistant, or the parasite not being infective.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Chloroquine-Azithromycin (CQ/AZ); Chloroquine (CQ) 300mg and 2g of azithromycin (AZ) given orally
Chloroquine (CQ); 300 mg of CQ only given orally
All subjects will participate in the Controlled Human Malaria Infection (CHMI) and will be required to stay at a hotel for evaluation for a maximum of 14 nights starting 7 days after the challenge. A standard dose of atovaquone-proguanil (Malarone®) will be administered to all symptomatic parasitemic subjects under directly observed treatment.
Clinical Research Unit, Uniformed Services University of Health Sciences
Bethesda, Maryland, United States
WRAIR
Silver Spring, Maryland, United States
Efficacy: Proportion of subjects free from symptomatic parasitemic subjects
CQ/AZ Group will be compared to endpoint in CQ Group by Fisher's Exact Test. Symptomatic is defined as any one of the following solicited adverse events that first occurred concurrent with parasitemia: fever (temperature \> 100.4 °F), chills, headache, arthralgia, myalgia, nausea, vomiting, or abdominal pain. Subjects will only undergo malaria treatment after both criteria are met.
Time frame: Days 1 thru 56
Safety: Solicited and unsolicited Adverse Events in each group
Groups will be analyzed by descriptive statistics and safety monitoring will be conducted throughout the study
Time frame: Days 1 thru 56
Electrocardiogram baseline vs peak concentration for AZ
QTcF will be analyzed for CQ/AZ Group subjects at presumed field-effective time point (Day 11 post challenge) 6 hours after dosing, which will coincide with time to peak concentration for AZ. This will be compared to baseline reading
Time frame: Day 11 post challenge, 6 hours after dosing
Pharmacokinetics: Cmax - comparison for CQ/AZ-Group subjects
Cmax will be compared for CQ/AZ-Group subjects who become symptomatic and parasitemic to CQ/AZ-Group subjects who do not become parasitemic.
Time frame: Days 11 thru 15
Pharmacokinetics: Tmax - comparison for CQ/AZ-Group
Tmax will be compared for CQ/AZ-Group subjects who become symptomatic and parasitemic to CQ/AZ-Group subjects who do not become parasitemic.
Time frame: Days 11 thru 15
Pharmacokentics: T½ - comparison for CQ/AZ Group
T½ will be compared for CQ/AZ-Group subjects who become symptomatic and parasitemic to CQ/AZ-Group
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Time frame: Days 11 thru 15
Pharmacokentics: AUC - comparison for CQ/AZ Group
Area under the curve (AUC) will be compared for CQ/AZ-Group subjects who become symptomatic and parasitemic to CQ/AZ-Group subjects who do not become parasitemic.
Time frame: Days 11 thru 15