Clinical trial NCT00495508: Quinine vs. Artemether/Lumefantrine in Uncomplicated Malaria During Pregnancy
Official title: A Randomised, Open-label Non-inferiority Trial of Artemether-lumefantrine Versus Quinine for the Treatment of Uncomplicated Falciparum Malaria During Pregnancy, Mbarara, Uganda (2006-2007)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Malaria
Keywords: Quinine
Artemether
Lumefantrine
malaria
Uganda
Artemisinin- based combination therapy
pregnancy
Malaria In Pregnancy
Lead sponsor: Epicentre
Sponsor class: OTHER
Collaborators: name: Medecins Sans Frontieres, Netherlands
name: University of Cape Town
name: Shoklo Malaria Research Unit
First posted: 2007-07-03
Enrollment: 300
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Primary outcomes:
measure: PCR-corrected adequate clinical and parasitological response (ACPR) on Day 42 or at delivery.
timeFrame: 3 years
Secondary outcomes:
measure: Pharmacokinetic parameters
timeFrame: 3.5 years
measure: Incidence of adverse events
timeFrame: 3 years
measure: Pregnancy outcome
timeFrame: 3.5 years
measure: Infant development during the first year of life
timeFrame: 3 years
measure: Histopathological findings in the placenta
timeFrame: 4 years
Other outcomes:
Locations:
city: Mbarara
country: Uganda
facility: Epicentre
state: Mbarara District
Study officials:
affiliation: Epicentre
name: Patrice Piola, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: Epicentre
name: Philippe J Guerin, MD, MPH, PhD
role: STUDY_CHAIR
affiliation: Epicentre
name: Elizabeth Ashley, MB BS
role: STUDY_CHAIR
affiliation: Shoklo Malaria Research Unit (SMRU)
name: Rose McGready, MD, PhD
role: STUDY_CHAIR
affiliation: SMRU
name: François Nosten, MD, PhD
role: STUDY_CHAIR
References:
citation: De Beaudrap P, Turyakira E, Nabasumba C, Tumwebaze B, Piola P, Boum Ii Y, McGready R. Timing of malaria in pregnancy and impact on infant growth and morbidity: a cohort study in Uganda. Malar J. 2016 Feb 16;15:92. doi: 10.1186/s12936-016-1135-7.
citation: De Beaudrap P, Turyakira E, White LJ, Nabasumba C, Tumwebaze B, Muehlenbachs A, Guerin PJ, Boum Y, McGready R, Piola P. Impact of malaria during pregnancy on pregnancy outcomes in a Ugandan prospective cohort with intensive malaria screening and prompt treatment. Malar J. 2013 Apr 24;12:139. doi: 10.1186/1475-2875-12-139.
citation: Muehlenbachs A, Nabasumba C, McGready R, Turyakira E, Tumwebaze B, Dhorda M, Nyehangane D, Nalusaji A, Nosten F, Guerin PJ, Piola P. Artemether-lumefantrine to treat malaria in pregnancy is associated with reduced placental haemozoin deposition compared to quinine in a randomized controlled trial. Malar J. 2012 May 3;11:150. doi: 10.1186/1475-2875-11-150.
citation: Piola P, Nabasumba C, Turyakira E, Dhorda M, Lindegardh N, Nyehangane D, Snounou G, Ashley EA, McGready R, Nosten F, Guerin PJ. Efficacy and safety of artemether-lumefantrine compared with quinine in pregnant women with uncomplicated Plasmodium falciparum malaria: an open-label, randomised, non-inferiority trial. Lancet Infect Dis. 2010 Nov;10(11):762-9. doi: 10.1016/S1473-3099(10)70202-4.