Chloroquine (CQ) and Azithromycin (AZ) Combination for Malaria Prophylaxis

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.

Inclusion Criteria:

- Healthy adults (male or non-pregnant, non-lactating female) 18 to 50 years of age
(inclusive) at the time of screening.

- If the subject is female:

1. Non-childbearing potential (ie., either surgically sterilized (bilateral tubal
ligation, tubes tied, hysterectomy, removal of the uterus, bilateral
oophorectomy, removal of both ovaries) at least 6 months before dosing) or one
year post menopausal), abstinent or using adequate contraceptive precautions (eg,
intrauterine contraceptive device; oral contraceptives; diaphragm, cervical cap,
or condom in combination with contraceptive jelly, cream or foam; Norplant® or
Depo-Provera®) from 3 months prior to this study through 56 days after challenge

2. A negative pregnancy test at the time of enrollment

- Free of significant health problems as established by medical history, laboratory, and
clinical examination before entering the study

- Subjects must have low cardiac risk factors according to the NHANES I criteria,
medical history and family history, blood pressure measurements, and a normal or
normal variant ECG including QTcF no greater than 450 msec for males and 470 msec for
females.

- Available to participate in all planned study visits and reachable by phone for
duration of study (approximately 4 months).

- Willing to comply with all protocol procedures and time commitments

- No plans to participate in another clinical research study for the duration of this
study.

- Written informed consent must be obtained from the subject before screening procedures
are performed

- If a subject is active duty military, he or she must obtain approval from his or her
supervisor per Walter Reed Army Institute of Research (WRAIR) Policy 11-45

- Subjects must score at least 80% correct on a multiple-choice quiz that assesses their
understanding of this study

1. If they do not score 80% on the initial quiz, the protocol information will be
reviewed with them, and they will have the opportunity to retest

2. If a subject fails to correctly answer 80% of the questions after 2 attempts, he
or she will be excluded from the study

Exclusion Criteria:

- Subjects with a history or presence of gastrointestinal, hepatic or renal disease, or
other condition known to interfere with the absorption, distribution, metabolism or
excretion of drugs.

- Subjects with a history of retinopathy, sickle cell disease or trait, psoriasis, or
porphyria.

- Subjects who take certain prescribed or over the counter (OTC) concomitant medication
including: ampicillin, antacids (including kaolin), cimetidine, digoxin, ergot
alkaloids, statins (HMG-CoA reductase inhibitors), cyclosporine, warfarin,
fluconazole, nelfinavir, or rifabutin, within 2 weeks of dosing start, and during the
duration of the study.

- Are known or suspected of drinking too much alcohol (for men, more than 28 standard
alcohol drinks and for women more than 21 standard alcohol drinks per week (standard
drink is defined as a 12 oz beer, 5 oz glass of wine, or 1.5 oz of distilled spirit)

- Positive urine drug screen for amphetamine, methamphetamine, cocaine, and opioids at
screening.

- Subjects who have donated more than 1500 mL (males) or 1000 mL (females) blood in the
previous 12 months, including the maximum volume of blood (328 mL) to be taken in this
study.

- Subjects who are currently enrolled in another study involving an investigational
product, or if recently involved in another clinical trial which has ended, have not
received any investigational products within the past 3 months or 5 half-lives
(whichever is longer) from the time of screening.

- Any history of malaria infection in the past 3 years.

- History of travel to malaria endemic areas in the 3 months prior to day of challenge,
or plans to travel to malaria endemic areas during the duration of the study (56 days
post challenge).

- Any history of receiving a malaria vaccine

- History of receipt of malaria prophylaxis during the 2 months prior to day of
challenge

- History of use of any antibiotics with significant antimalarial activity (examples
include tetracycline, doxycycline, clindamycin, azithromycin, and sulfa drugs) during
the course of the study period

- Pregnant (positive β-human chorionic gonadotropin test, β-HCG) or lactating female at
screening or plans to become pregnant or breastfeed from the time of enrollment until
three months after challenge

- Allergy to antimalarial drugs or use of medications known to interact with CQ

- Significant (e.g., systemic) hypersensitivity reactions to mosquito bites (local
hypersensitivity reactions at the site of mosquito bites are not an exclusion
criterion)

- History of splenectomy

- Any confirmed or suspected immunodeficiency, including HIV infection, or taking
immunosuppressive medications

- Acute or chronic, ally significant, pulmonary, cardiovascular, endocrine, hepatic, or
renal functional abnormality, as determined by history, physical examination, or
laboratory evaluation

- Chronic or active neurologic disease including seizure disorder and chronic migraine
headaches

- Any abnormal baseline laboratory screening tests listed below

1. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) above twice
the upper limit of normal for the reference lab

2. Creatinine above normal range

3. Hemoglobin out of normal range

4. Platelet count out of normal range

5. Total white blood cell (WBC) count out of normal range Note: If screening lab
values are out of the normal range but are expected to be temporary (e.g. due to
dehydration), they may be re-assessed one time at the discretion of the
investigator.

- Seropositive for Human immunodeficiency virus (HIV) or Hepatitis C virus (HCV) or
hepatitis B surface antigen (HBsAg) positive

- An abnormal baseline screening ECG suggestive of cardiac disease as determined by a
clinical investigator. QTcF of >450 msec for males and >470 msec for females.

- Any other significant finding that in the opinion of the PI would increase the risk of
having an adverse outcome from participating in this study