Clinical trial NCT01838902: Primaquine's Gametocytocidal Efficacy in Malaria Asymptomatic Carriers
Official title: Primaquine's Gametocytocidal Efficacy in Malaria Asymptomatic Carriers Treated With Dihydroartemisinin-piperaquine in The Gambia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Malaria
Keywords: Malaria
Falciparum
Direct membrane feeding
QT-NASBA
Asexual parasite
Asymptomatic carrier
Gametocytocidal, Gametocyte
Transmission blocking
Sexual stage
Primaquine
Dihydroartemisinin
Piperaquine
Gambia
Africa
Lead sponsor: London School of Hygiene and Tropical Medicine
Sponsor class: OTHER
First posted: 2013-04-24
Enrollment: 467
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: In this study, the investigators are interested to know if lower doses of Primaquine together with dihydroartemisinin-piperaquine can produce a similar effect of clearing both sexual and asexual parasites in asymptomatic carriers compared to the recommended dose of primaquine but with a decreased risk of haemolysis.

Children (\> 1 year) and adults with normal Glucose-6-phosphate dehydrogenase enzyme levels but with asexual Plasmodium falciparum parasites on the day of screening will be invited to take part in this study.

Detailed description: To date, primaquine (PQ), an 8-aminoquinoline, is the only currently registered product able to clear P. falciparum mature gametocytes. However, its use has been and is still limited by its haematological toxicity (haemolytic anaemia), particularly but not exclusively in individuals with glucose-6-phosphate dehydrogenase deficiency (G6PDd), in whom haemolysis can occur after a single PQ dose. Such an effect is dose-dependent. Considering that the current recommended dose was established several decades ago on a small number of experimentally challenged volunteers, it may be possible to obtain the same effect with a lower dose and hence decrease the risk of haemolysis. The proposed study is a four-arm, open label, randomized, controlled trial. G6PD-normal asymptomatic P. falciparum infected individuals identified through population screening will be randomized to receive either a complete course of dihydroartemisinin-piperaquine (DHA-PPQ) alone (control arm) or a complete course of DHA-PPQ plus a single dose of PQ at 3 differing dose strengths (intervention arms), i.e. 0.75mg/kg, 0.4mg base/kg and 0.2mg base/kg.

The study is planned to enroll 1,200 individuals with an asymptomatic malaria infection during the rainy /transmission season (June - December) from villages around the MRC's field stations at Walikunda and Basse in The Gambia. Asymptomatic parasite carriers identified by qualitative (RDT) and quantitative (parasites counts \>20/µl by slide microscopy) methods during population screening exercises at the villages will be invited for a written informed consent and further screening to confirm eligibility, including tests for qualitative G6PD enzyme function (fluorescence spot test) and haemoglobin. If eligible, they will be assigned to one of four study arms using a block randomization scheme in a 1:1:1:1 ratio ensuring a balance in enrollment between the four groups. Enrolled participants will receive ACT treatment on days 0, 1 and 2. On day 2, participants allocated to the PQ arms will receive a dose of primaquine based on determined body weight.

Each participant involvement consists of a maximum of 11 visits over a 42 day period after initiation of treatment. The primary end point is the prevalence of P. falciparum gametocyte carriers at day 7, as determined by QT-NASBA.

Eligibility criteria: Inclusion Criteria:

Age ≥1 year

* Weight \>10 Kg
* P. falciparum mono-infection, density of at least 20 parasites/μL
* Axillary temperature \< 37.5ºC
* Resident in the study area and willingness to reside for the duration of the study
* Written informed consent (plus an assent in children \>12years of age)

Exclusion Criteria:

* G6PD Deficiency Haemoglobin \<8g/dl

  * Known allergy to any of the study medications
  * Known Pregnancy or breastfeeding
  * Clear/documented history of anti-malarial treatment 2 weeks before contact with study team
  * History of blood transfusion in the previous 3 months
  * Any chronic or acute conditions that might interfere with the study as judged by the research clinician
  * History of sickle cell anaemia

Primary outcomes:
measure: Prevalence of P. falciparum gametocyte carriers (QT-NASBA)
timeFrame: Day 7
Secondary outcomes:
measure: Prevalence of P.Falciparum gametocytes carriers
timeFrame: Days 3, 10, 14, 28 and 42
measure: Proportion of individuals infectious to mosquitoes (DMFA)
timeFrame: Day 7
measure: Haemoglobin change
timeFrame: Day 0 and days 3, 7, 10, 14, 21, 28, 35 and 42
measure: Prevalence of infection (asexual stages)
timeFrame: Day 3
measure: Proportion of participants with recurrent infection (PCR adjusted and unadjusted)
timeFrame: Day 7 to Day 42
measure: Occurrence of adverse events (AEs) and serious adverse events (SAEs)
timeFrame: Day 3 to Day 42
Other outcomes:
Locations:
city: Fajara
country: Gambia
facility: Medical Research Council Unit (MRC), The Gambia
Study officials:
affiliation: MRC Unit, Fajara The Gambia
name: Umberto D'Alessandro, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Okebe J, Bousema T, Affara M, Di Tanna GL, Dabira E, Gaye A, Sanya-Isijola F, Badji H, Correa S, Nwakanma D, Van Geertruyden JP, Drakeley C, D'Alessandro U. The Gametocytocidal Efficacy of Different Single Doses of Primaquine with Dihydroartemisinin-piperaquine in Asymptomatic Parasite Carriers in The Gambia: A Randomized Controlled Trial. EBioMedicine. 2016 Nov;13:348-355. doi: 10.1016/j.ebiom.2016.10.032. Epub 2016 Oct 23.
citation: Okebe J, Bousema T, Affara M, DiTanna G, Eziefula AC, Jawara M, Nwakanma D, Amambua-Ngwa A, Van Geertruyden JP, Drakeley C, D'Alessandro U. The gametocytocidal efficacy of primaquine in malaria asymptomatic carriers treated with dihydroartemisinin-piperaquine in The Gambia (PRINOGAM): study protocol for a randomised controlled trial. Trials. 2015 Mar 1;16:70. doi: 10.1186/s13063-015-0597-1.