Intermittent preventive treatment of falciparum malaria in pregnant women (IPTp).

Background and Rationale

Malaria is a serious protozoal infection caused by any of the five species of Plasmodia and

transmitted by anopheline mosquitoes; it continues to be one of the largest global health

problems.1 2 As per the World Health Organization (WHO) World Malaria Report 2009,3

about half of the world's population is at risk of infection in 108 endemic countries and

territories. In 2008, there were an estimated 243 million cases and 863,000 malaria-related

deaths.3 Malaria in pregnancy (MIP) is one of the most common causes of preventable

mortality and morbidity in pregnant women and infants in sub-Saharan Africa. An estimated

30 million pregnancies are at risk of malaria infection in sub-Saharan Africa each year;4

about 200,000 infants and 10,000 women die of malaria in pregnancy each year.5

Important progress has been made in the control of malaria in pregnancy in Africa with the

introduction of intermittent preventive treatment in pregnancy (IPTp). The WHO

recommends the administration of IPTp with sulfadoxine-pyrimethamine (SP) during

antenatal visits in high malaria transmission areas of sub-Saharan Africa.6 However, SP

resistance has become widespread especially in East and Southern Africa, greatly limiting the

protective effect of IPTp with SP. The development of safe, efficacious and affordable

replacement of SP for IPTp is an urgent priority.

The combination of azithromycin (AZ) and chloroquine (CQ) could potentially replace

SP for IPTp. AZ and CQ are synergistic in vitro and in vivo against CQ resistant strains of

P. falciparum. Co-administration of AZ and CQ has demonstrated efficacy, safety and

tolerability in two multi-country Phase 3 clinical studies (A0661134 and A0661155) in the

treatment of symptomatic uncomplicated malaria in non-pregnant adults in sub-Saharan

Africa. AZ and CQ have been on the market for several years and have extensive safety

records in adults, children and pregnant women. Both AZ and CQ have been widely used in

all trimesters of pregnancy and are considered safe in pregnant women as individual agents.

In high-income countries, AZ is commonly used to treat and prevent sexually transmitted

infections (STIs) including Neisseria gonorrhoeae and Chlamydia trachomatis infections. In

sub-Saharan Africa, two randomized controlled clinical trials.21, 22 found that a single dose of

1000 mg AZ was comparable to benzathine penicillin G in curing syphilis. The incidence of

adverse fetal outcomes has been shown to be reduced by about 30% when these three STIs

were treated in pregnancy.23 In addition, AZ has also demonstrated protective effect against

Trichomonas vaginalis when used as chemoprophylaxis24 and reduced the risk of preterm

delivery attributable to T. vaginalis, even in the second trimester when first-line treatment,

metronidazole, should be avoided.25

090177e1811d3ccb\Approved\Approved On: 19-Feb-2010 20:59

Azithromycin/Chloroquine Combination

A0661201

Final Protocol, 14 February 2010

PFIZER CONFIDENTIAL

Page 3

A fixed dose combination tablet formulation of AZ and CQ (AZCQ, 250 mg AZ/155 mg

CQ base) has been developed specifically for the IPTp indication and will be evaluated in

IPTp studies. In a clinical pharmacology study A0661186, AZCQ administration resulted in

the systemic exposures to AZ, CQ and des-ethyl CQ (an active metabolite of CQ) at levels

comparable to those achieved following administration of commercial standalone tablets of

AZ (Zithromax) and CQ (Aralen) evaluated in adult treatment studies.

A Phase 3 randomized controlled clinical study to demonstrate the superiority of AZCQ IPTp

regimen over SP IPTp regimen is planned in East and Southern sub-Saharan Africa where SP

resistance is emerging as an issue and where SP is the current standard of care for IPTp. This

will be the pivotal study for regulatory submissions to European Medicines Agency (EMA)

and to the national regulatory agencies in Sub-Saharan African countries.

AZCQ is expected to exert IPTp effect through multiple mechanisms including peripheral

parasitological clearance in pregnant women, prevention of re-infections,

prevention/treatment of placental malaria and prevention/treatment of STIs. The relative

contributions of these mechanisms towards IPTp effect are not yet known. The study

A0661201 is an open label, non-comparative parasitological clearance study of a single

3-day treatment course of AZCQ in about 166 pregnant women in second and third trimesters

of pregnancy with asymptomatic parasitemia. This study will help to characterize the

magnitude of parasitological clearance required for the IPTp effect observed in A0661158

study, and will serve as a supportive study in IPTp regulatory dossier. A0661201 study will

also evaluate pharmacokinetic (PK) exposures, of both AZ and CQ in pregnant women

following administration of a single 3-day treatment course of AZCQ. Subjects will be

followed up to Day 42 after the first dose, and followed through delivery or to pregnancy

termination for safety assessments of Exposure in Utero (EIU).