Dihydroartemisinin-piperaquine With Low Dose Primaquine to Reduce Malaria Transmission

Malaria Clinical Trial

— DAPPI  

Official title:

A Double Blind Randomized Controlled Trial of Dihydroartemisinin-piperaquine Alone and in Combination With Single Dose Primaquine to Reduce Post-treatment Malaria Transmission.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02259426
• Other study ID #: DAPPI-1
• Status: Completed
• Phase: Phase 3
• First received: September 29, 2014
• Last updated: January 13, 2016
• Start date: October 2014
• Est. completion date: December 2015

Study information

• Verified date: January 2016
• Source: London School of Hygiene and Tropical Medicine
• Contact: n/a
• Is FDA regulated: No
• Health authority: Kenya: Ethical Review Committee
• Study type: Interventional

Clinical Trial Summary

Primaquine (PQ) is currently the only available drug that can clear the mature transmission stages of P. falciparum parasites. PQ was previously shown to clear gametocytes that persist after artemisinin-combination therapy. A major caveat to the use of primaquine in mass adminsitrations for the reduction of malaria transmission is that metabolism of the drug in individuals with glucose-6 phosphate dehydrogenase (G6PD) deficiency can lead to transient haemolysis. The haemolytic side effect of PQ is dose-related. Haemolysis is more commonly observed after prolonged PQ treatment but has also been observed in African populations following a single dose of PQ. This haemolysis was self-limiting, largely restricted to G6PD deficient individuals and did not lead to clinical symptoms. Nevertheless, any drug-induced haemolysis is reason for concern and the World Health Organization has therefore reduced the recommended dose of single low dose primaquine from 0.75mg/kg to 0.25mg/kg. This dosage is deemed safe without prior G6PD or Hb screening. However, there is limited direct evidence on the extent to which this dosage of PQ prevents malaria transmission to mosquitoes.

In the current study, the investigators will assess the efficacy of DP in combination with low-dose PQ to prevent onward malaria transmission. The investigators will perform the investigators study in individuals aged 5-15 years who are carry microscopically detectable densities of P. falciparum gametocytes. This age group is chosen because asexual parasite carriage and gametocyte carriage are common in this age group. All enrolled individuals will receive a full three-day course of DP, and will be randomized to receive a dose of primaquine or placebo with their third dose. Efficacy will be determined based on gametocyte carriage during follow-up, measured by molecular methods. For all individuals, the effect of treatment on infectivity to mosquitoes will be assessed by membrane feeding assays at two time points.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 120
• Est. completion date: December 2015
• Est. primary completion date: September 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 5 Years to 15 Years

Eligibility

Inclusion Criteria:

• Microscopically detectable P. falciparum gametocyte carriage

Exclusion Criteria:

• Age < 5 years or > 15 years

• Non-falciparum malaria co-infection

• Malaria parasite density = 200,000 parasites/µL

• Clinical symptoms indicating severe malaria

• Axillary temperature = 39°C

• Body Mass Index (BMI) below 16 or above 32 kg/m2

• Haemoglobin concentration below 9.5 g/dL

• Anti-malarials taken in last 2 days

• For women: Pregnancy (assessed by clinical examination and urine pregnancy test) or lactation

• Known hypersensitivity to DP or PQ

• History and/or symptoms indicating chronic illness

• Current use of tuberculosis or anti-retroviral medication

• Unable to give written informed consent

• Unwillingness to participate in two membrane feeding assays

• Travel history to Angola, Cameroon, Chad, Central African Republic, Congo, DR Congo,
• Equatorial Guinea, Ethiopia, Gabon, Nigeria and Sudan

• Family history of congenital prolongation of the QTc interval or sudden death or with any other clinical condition known to prolong the QTc interval such as history of symptomatic cardiac arrhythmias, with clinically relevant bradycardia or with severe cardiac disease

• Taking drugs that are known to influence cardiac function and to prolong QTc interval, such as class IA and III: neuroleptics, antidepressant agents, certain antibiotics including some agents of the following classes - macrolides, fluoroquinolones, imidazole, and triazole antifungal agents, certain non-sedating antihistaminics (terfenadine, astemizole) and cisapride

• Known disturbances of electrolyte balance, e.g. hypokalaemia or hypomagnesaemia

• Taking drugs which may be metabolized by cytochrome enzyme CYP2D6 (e.g., flecainide, metoprolol, imipramine, amitriptyline, clomipramine)

• Blood transfusion within last 90 days

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Asymptomatic Malaria
• Malaria
• Plasmodium Falciparum

Intervention

Drug:
• Dihydroartemisinin-piperaquine combination (Artekin)

• Primaquine
Single-dose 0.25mg/kg

Locations

Country	Name	City	State
Kenya	ICIPE	Mbita	Nyanza

Sponsors (3)

Lead Sponsor	Collaborator
London School of Hygiene and Tropical Medicine	International centre for Insect Physiology and Ecology (ICIPE), Radboud University

Country where clinical trial is conducted

Kenya, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Gametocyte prevalence on day 7 after initiation of treatment	Gametocyte prevalence on day 7 after initiation of treatment is measured by molecular methods.	day 7 of follow-up	No
Secondary	Transmission to Anopheles gambiae mosquitoes	Mosquito membrane feeding assays will be used to determine the proportion of infected mosquitoes and the oocyst burden in infected mosquitoes.	Day 3 and 7 during follow-up	No
Secondary	Haematological recovery	Haemoglobin concentration will be determined at enrolment and on days 2, 3, 7 and 14 during follow-up. Haemoglobin concentration will be presented as grams per decilitre and as concentration relative to enrollment value.	14 days during follow-up	Yes
Secondary	Gametocyte sex-ratio	The ratio of male:female gametocytes will be determined at enrolment and on days 2, 3, 7 and 14 during follow-up by qRT-PCR.	14 days of follow-up	No
Secondary	Gametocyte carriage during follow-up	Gametocyte prevalence at enrolment and on days 2, 3, 7 (primary outcome measure), and 14 during follow-up. The duration of gametocyte carriage in days will be estimated.	14 days during follow-up	No