A Trial of Seasonal Malaria Chemoprevention Plus Azithromycin in African Children (SMCAZ)

The primary objective of this study is to determine whether addition of azithromycin (AZ) to Seasonal Malaria Chemoprevention (SMC) using sulphadoxine/pyrimethamine (SP) +amodiaquine (AQ) will provide an additional reduction in deaths and severe illness in young African children. The secondary objectives include an assessment of the safety and cost-effectiveness of the addition of AZ to SMC with SP+AQ.

This a double blind, randomised, placebo controlled trial. The unit of randomisation will be the household. Children aged 3 - 59 months will be randomised to receive four cycles of either SP+AQ+AZ or SP+AQ+ placebo at monthly intervals during the peak malaria transmission season.

Study Sites: Hounde district in Burkina Faso and in Bougouni district, Mali. Children of 3-59 months of age at the start of each period of drug administration will be eligible for inclusion in the trial provided that parental consent is obtained. Children with a severe, chronic illness or known allergy to one of the study drugs will be excluded.

Primary endpoint: Incidence of the combination of death or hospital admission for at least 24 hours, not due to trauma or elective surgery during the intervention period

Secondary endpoints:

1. incidence of the primary endpoint during the whole study period
2. attendance at a study health centre with a nonmalaria febrile illness
3. attendance at a study health centre with malaria,
4. the prevalence of moderate anaemia at the end of each malaria transmission season,
5. nutritional status at the end of each malaria transmission season,
6. prevalence of nasopharyngeal carriage with pneumococci and macrolide resistant pneumococci before and at the end of each malaria transmissions season,
7. prevalence of resistance markers to SP at the end of the study,

Sample size: 19,200 children (9600 in each country) will be enrolled.

Study Overview

• Status: Completed
• Conditions: Malaria; Respiratory Infections
• Intervention / Treatment: Drug: Sulphadoxine-pyrimethamine + amodiaquine + placebo azithromycin; Drug: Sulphadoxine-Pyrimethamine+ Amodiaquine+ Azithromycin

• Study Type: Interventional
• Enrollment (Actual): 22090
• Phase: Phase 3

Contacts and Locations

Study Locations

• Burkina Faso
  • Hounde, Burkina Faso
    • Hounde district Hospital
• Mali
  • Bougouni, Mali
    • Bougouni Koulikoro District hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months to 4 years (Child)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Children of either sex aged 3-59 months of age at the start of each period of drug administration
• parental consent is obtained.

Exclusion Criteria:

• a severe, chronic illness,
• a known allergy to one of the study drugs.
• HIV+ children on cotrimoxazole prophylaxis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Seasonal malaria chemoprevention; Sulphadoxine-Pyrimethamine Amodiaquine Placebo Azithromycin	Drug: Sulphadoxine-pyrimethamine + amodiaquine + placebo azithromycin; Sulphadoxine-pyrimethamine + amodiaquine + placebo azithromycin 4 rounds during malaria transmission season
Experimental: seasonal malaria chemoprevention plus AZ; Sulphadoxine-Pyrimethamine+ Amodiaquine + Azithromycin 4 rounds during malaria transmission season	Drug: Sulphadoxine-Pyrimethamine+ Amodiaquine+ Azithromycin; Sulphadoxine-Pyrimethamine+ Amodiaquine+ Azithromycin 4 rounds during malaria transmission season

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
severe morbidity and mortality	Incidence of the combination of death or hospital admission for at least 24 hours, not due to trauma or elective surgery during the intervention period.	from the time of enrolment upto the end of malaria transmission in year 3 ( the person time at risk will be restricted to three malaria transmission seasons)

Secondary Outcome Measures

Outcome Measure	Time Frame
macrolide resistant pneumococci carriage	before administration of first dose of SMC and at the end of malaria transmission season in year 1, 2 and 3,

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
out patient attendance for non malaria febrile illness	(b) attendance at a study health centre with a febrile illness that is not due to malaria (including acute respiratory infections and diarrhoea),	from enrolment until the end of malaria transmission season in year 3
OPD attendance for malaria	(c) attendance at a study health centre with RDT or microscopically proven malaria,	from enrollment until the end of malaria transmission season in year 3
moderate anaemia	(d) the prevalence of moderate anaemia (Hb <8 g/dL) at the end of each malaria transmission season,	at the end of each malaria transmission season in year 1, 2, and 3
nutritional status	(e) nutritional status at the end of each malaria transmission season,	at the end of malaria transmission season in year 1, 2 and 3
nasopharyngeal carriage	(f) the prevalence of nasopharyngeal carriage with pneumococci before and at the end of each malaria transmissions season,	before the administration of first dose of SMC and at the end of malaria transmission season in year 1, 2, and 3
SP resistance markers	(h) the prevalence of resistance markers to SP in children with Plasmodium falciparum malaria at the end of the study,	at the end of the malaria transmission season in year 3
adverse events	solicited adverse events 7 days after administration of SMC+AZ after each round in the year one of the study	7 days after administration of SMC in rounds 1, 2, 3 and 4 in year one

Collaborators and Investigators

• Sponsor: London School of Hygiene and Tropical Medicine
• Collaborators: Malaria Research and Training Center, Bamako, Mali; Institut de Recherche en Sciences de la Sante, Burkina Faso

Publications and helpful links

General Publications

• Hema-Ouangraoua S, Tranchot-Diallo J, Zongo I, Kabore NF, Nikiema F, Yerbanga RS, Tinto H, Chandramohan D, Ouedraogo GA, Greenwood B, Ouedraogo JB. Impact of mass administration of azithromycin as a preventive treatment on the prevalence and resistance of nasopharyngeal carriage of Staphylococcus aureus. PLoS One. 2021 Oct 13;16(10):e0257190. doi: 10.1371/journal.pone.0257190. eCollection 2021.
• Cairns ME, Sagara I, Zongo I, Kuepfer I, Thera I, Nikiema F, Diarra M, Yerbanga SR, Barry A, Tapily A, Coumare S, Milligan P, Tinto H, Ouedraogo JB, Chandramohan D, Greenwood B, Djimde A, Dicko A. Evaluation of seasonal malaria chemoprevention in two areas of intense seasonal malaria transmission: Secondary analysis of a household-randomised, placebo-controlled trial in Hounde District, Burkina Faso and Bougouni District, Mali. PLoS Med. 2020 Aug 21;17(8):e1003214. doi: 10.1371/journal.pmed.1003214. eCollection 2020 Aug.
• Chandramohan D, Dicko A, Zongo I, Sagara I, Cairns M, Kuepfer I, Diarra M, Barry A, Tapily A, Nikiema F, Yerbanga S, Coumare S, Thera I, Traore A, Milligan P, Tinto H, Doumbo O, Ouedraogo JB, Greenwood B. Effect of Adding Azithromycin to Seasonal Malaria Chemoprevention. N Engl J Med. 2019 Jun 6;380(23):2197-2206. doi: 10.1056/NEJMoa1811400. Epub 2019 Jan 30.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2014
• Primary Completion (Actual): December 31, 2017
• Study Completion (Actual): December 31, 2017

Study Registration Dates

• First Submitted: July 17, 2014
• First Submitted That Met QC Criteria: August 6, 2014
• First Posted (Estimate): August 7, 2014

Study Record Updates

• Last Update Posted (Actual): March 7, 2018
• Last Update Submitted That Met QC Criteria: March 6, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Respiratory Tract Diseases; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Respiratory Tract Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Folic Acid Antagonists; Anti-Infective Agents, Urinary; Renal Agents; Pyrimethamine; Azithromycin; Sulfadoxine; Fanasil, pyrimethamine drug combination; Amodiaquine
• Other Study ID Numbers: MR/K007319/1