Efficacy and Safety of a Naphthoquine-Azithromycin Coformulation for Malaria Prophylaxis in Southeast Asia: A Phase 3, Double-blind, Randomized, Placebo-controlled Trial

Clin Infect Dis. 2021 Oct 5;73(7):e2470-e2476. doi: 10.1093/cid/ciaa1018.

Abstract

Background: A prophylactic antimalarial drug that is both effective for protection and improves compliance is in high demand.

Methods: We conducted a randomized, placebo-controlled, double-blinded phase 3 trial to evaluate the 1:1 fixed-dose combination of naphthoquine-azithromycin (NQAZ) for safety and protection against Plasmodium infections in villages along the China-Myanmar border. A total of 631 residents, 5-65 years of age, were randomized into the drug group (n = 319) and the placebo group (n = 312) to receive NZAQ and placebo, respectively, as a single-dose monthly treatment. Follow-ups were conducted weekly to monitor for adverse events and malaria infections.

Results: Of the 531 subjects completing the trial, there were 46 and 3 blood smear-positive Plasmodium infections in the placebo and treatment groups, respectively. For the intent-to-treat analysis, the single-dose monthly NQAZ treatment had 93.62% protective efficacy (95% confidence interval [CI]: 91.72%-95.52%). For the per-protocol analysis, NQAZ treatment provided a 93.04% protective efficacy (95% CI: 90.98%-95.1%). Three smear-positive cases in the NQAZ group were all due to acute falciparum malaria. In comparison, NQAZ treatment provided 100% protection against the relapsing malaria Plasmodium vivax and Plasmodium ovale. The treatment group had 5.6% of participants experiencing transient elevation of liver aminotransferases compared with 2.2% in the placebo group (P > .05).

Conclusions: Monthly prophylaxis with NQAZ tablets was well tolerated and highly effective for preventing Plasmodium infections. It may prove useful for eliminating P. vivax in areas with a high prevalence of glucose-6-phosphate dehydrogenase deficiency in the population.

Clinical trials registration: ChiCTR1800020140.

Keywords: malaria; naphthoquine-azithromycin; prophylaxis; protective efficacy; safety.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Naphthylamine / analogs & derivatives
  • Adolescent
  • Adult
  • Aged
  • Aminoquinolines
  • Antimalarials* / adverse effects
  • Asia, Southeastern
  • Azithromycin / adverse effects
  • Child
  • Child, Preschool
  • Double-Blind Method
  • Humans
  • Malaria* / drug therapy
  • Malaria* / prevention & control
  • Malaria, Falciparum* / drug therapy
  • Malaria, Falciparum* / epidemiology
  • Malaria, Falciparum* / prevention & control
  • Malaria, Vivax* / drug therapy
  • Malaria, Vivax* / epidemiology
  • Malaria, Vivax* / prevention & control
  • Middle Aged
  • Young Adult

Substances

  • Aminoquinolines
  • Antimalarials
  • naphthoquine
  • Azithromycin
  • 1-Naphthylamine