Quinine vs. Artemether/Lumefantrine in Uncomplicated Malaria During Pregnancy

A) for the treatment of uncomplicated malaria during second and third trimester pregnancy to oral Quinine hydrochloride. The PCR-corrected adequate clinical and parasitological response (ACPR) on day 42 is considered as the primary efficacy criterion. Newborns will be followed for growth and development indicators.

Study Title:

Efficacy and Safety of Quinine vs Artemether/Lumefantrine in uncomplicated malaria during pregnancy, Mbarara, Uganda (2006/2007).

Regulatory Status:

Investigational - Phase IV

Investigational Product and route:

* Quinine hydrochloride, oral route.
* Coartem® (Novartis Pharma AG, Basel, Switzerland), oral route.

Lead Investigator and Study Centre Primary objective - To establish that, in pregnant women with uncomplicated Plasmodium falciparum malaria, the PCR-adjusted efficacy of Artemether/Lumefantrine is not inferior to oral Quinine.

Secondary objectives

* To define the pharmacokinetics of the combination artemether-lumefantrine (AL) in the treatment of uncomplicated P. falciparum infections in the last two trimesters of pregnancy.
* To collect baseline data on maternal, obstetric and infant outcomes.
* To estimate the incidence of malaria infection, both microscopic and sub-microscopic (by PCR) during pregnancy.
* women attending Mbarara National Referral Hospital (MNRH) ante-natal clinic (ANC).
* Women with a positive blood smear during follow-up will be invited to participate in a non-inferiority, open, randomised, non- inferiority trial comparing the efficacy and tolerance of Coartem® (Artemether-Lumefantrine) for the treatment of uncomplicated malaria during second and third trimester pregnancy to oral Quinine hydrochloride. PCR-corrected adequate clinical and parasitological response (ACPR) on day 42 is considered as the primary efficacy criterion.
* Women with uncomplicated malaria from the efficacy study, will be followed to obtain an efficacy endpoint at 42 days OR at delivery, whichever timepoint is the last.
* Newborns will be followed monthly up to the age of 1 year.

Inclusion Criteria (Efficacy Study):

* Pregnant woman
* Malaria infection, detected by microscopy, with P. falciparum (mixed or mono-infection)
* Age of gestation: 13 weeks and beyond
* Efficacy study signed informed consent form

Exclusion Criteria (Efficacy Study):

* P. falciparum parasitaemia above 250,000 parasites/μl
* Severe anaemia
* Signs or symptoms of severe/complicated malaria requiring parenteral treatment (WHO 2000)
* Known allergy to artemisinin derivatives, lumefantrine or quinine;
* Previous participation in the efficacy study
* Inability to attend the efficacy study follow-up schedule.

Study drugs and Administration

* Group 1 (Active Control): Quinine hydrochloride (10 mg/Kg/8h for 7 days) administered orally.
* Group 2 (Test): Coartem®, fixed Artemether-Lumefantrine (20/120 mg) GMP manufactured by Novartis Pharma AG (Basel, Switzerland), 4 tablets twice a day for 3 days with 200 ml of milk tea at each dose .

Endpoints

- Primary efficacy endpoint: PCR-corrected adequate clinical and parasitological response (ACPR) on Day 42.

* Secondary efficacy endpoints:
* PCR-corrected(ACPR)at delivery
* Pharmacokinetic parameters
* Symptom clearance Time
* Proportion of patients who have fever cleared at Day 1, 2 and 3
* Safety endpoints:
* Incidence of any adverse events
* Pregnancy outcome
* Infant development during the first year of life

Eligibility Criteria:
Inclusion Criteria:

Cohort Study:

* Weeks of pregnancy between 13 and 22 weeks
* Resident in Mbarara Municipality (radius of 15km from MNRH)
* Cohort study signed informed consent form

Efficacy Study:

* Pregnant woman
* Malaria infection, detected by microscopy, with P. falciparum (mixed or mono-infection)
* Age of gestation: 13 weeks and beyond
* Efficacy study signed informed consent form

Exclusion Criteria:

Efficacy Study:

* P. falciparum parasitaemia above 250,000 parasites/μl
* Severe anaemia
* Signs or symptoms of severe/complicated malaria requiring parenteral treatment (WHO 2000)
* Known allergy to artemisinin derivatives, lumefantrine or quinine;
* Previous participation in the efficacy study
* Inability to attend the efficacy study follow-up schedule.