Evaluation of an Intensive 3-round MDA Strategy Towards Yaws Eradication

Defining the Best Distribution Strategy of Azithromycin for Yaws Eradication (The Yaws 3 Trial)

The current principle of yaws eradication (the Morges strategy) is based on single round mass drug administration (MDA) of azithromycin (AZI) called total community treatment (TCT) followed by targeted treatment of active cases every 6 months to detect and treat cases and contacts called total targeted treatment (TTT). Studies done in Papua New Guinea (PNG) show that 1 round of MDA will probably not suffice to stop transmission of infection. It may be preferable to conduct 3 rounds of MDA prior to the switch to TTT because of high coverage requirements to achieve elimination, particularly of latent cases. The investigators plan to determine whether 3 rounds of MDA are more effective for reaching yaws elimination. This research is needed to guide national programmatic implementation and needs to be done as soon as possible to scale up the program in the country.

The aim of this proposal is to ascertain the number of rounds of MDA with AZI to be included in an improved strategy towards yaws eradication. The study will be implemented in 38 wards of New Ireland Province (NIP). The investigators will compare two different distribution strategies of MDA: (A) strategy with 3 biannual rounds of MDA and (B) a single mass treatment round of MDA followed by targeted treatment of cases and contacts. The investigators will also monitor the risk of appearance of antimicrobial resistance in Treponema pertenue.

Study Overview

• Status: Completed
• Conditions: Yaws
• Intervention / Treatment: Drug: R1-Total community treatment with azithromycin; Drug: R2-Total community treatment with azithromycin; Drug: R3-Total community treatment with azithromycin; Drug: R2-Total targeted treatment with azithromycin; Drug: R3-Total targeted treatment with azithromycin

Detailed Description

In 2013 WHO piloted the yaws eradication MDA strategy in several countries, including PNG. A study carried out on Lihir Island has shown that 1-round MDA with single-dose oral AZI reduced the prevalence of yaws by 90% at 12-months. However, this did not suffice to stop transmission of infection. At baseline, the estimated prevalence of PCR-confirmed active infection was 1.8% and greatly reduced to 0.4% at 6-months, and 0.1% at 24 months; but prevalence increased again to 0.4% at 42 months after MDA. The relapse of untreated latent infections appeared to hinder elimination efforts in this community. Almost half of subjects with newly identified active yaws cases during follow up targeted treatment programs reported having not been present for MDA. T. p. pertenue may become resistant to macrolide antibiotics, as has occurred with T. p. pallidum (the causative agent of syphilis) in some developed countries, which necessitates close monitoring for the emergence of resistance. The investigators recently reported the first documented genotypic macrolide resistance in T. p. pertenue infections in PNG. A total of five clinical specimens, out of 208 samples tested during the post-MDA period of 3·5 years, demonstrated a T. p. pertenue strain carrying the A2059G point mutation. There was only local spread of the resistant clone among relatives and friends and further spread was immediately stopped through the use of alternative (benzathine penicillin) antibiotic to treat the newly identified cases and contacts.

The eligible population will be people targeted for MDA treatment living in the three LLG study areas at time of implementation. The 38 wards will be randomly assigned (1:1) to receive 1 vs 3 rounds of MDA using AZI. All villages within a ward will receive the same intervention in an effort to minimize contamination between villages. The intervention arm will receive 3 rounds (0, 6, 12 months) of MDA with AZI, each round known as total community treatment (TCT); control arm will receive 1 round (0 months) of MDA with AZI followed by total targeted treatment (TTT) (6 and 12 months). During each MDA round all study participants will receive 30 mg/Kg (maximum 2 g) of AZI orally under direct observation.

The primary outcome will be prevalence of PCR-confirmed active yaws measured in the entire population at 18 months. The investigators will estimate the evolution of latent yaws prevalence measured as the proportion of children 1-15 years who are dually positive on the DPP test at two time-points (0, 18 months).

• Study Type: Interventional
• Enrollment (Actual): 56000
• Phase: Phase 4

Contacts and Locations

Study Locations

• Papua New Guinea
  • New Ireland
    • Kavieng, New Ireland, Papua New Guinea, 08912
      • Namatanai Rural Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• all people resident or not in wards in the study region present at time of implementation or in subsequent surveys

Exclusion Criteria:

• Children younger than 6 months
• Known allergy to macrolide antibiotics
• Refusal at village or individual levels

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention; Repeated total community treatment, TCT with study drug: Azithromycin tablets, 30mg/Kg (maximum 2g), a single dose every 6 months, for 12 months (3 doses). Study interventions are: R1-Total community treatment with azithromycin, R2-Total community treatment with azithromycin, R3-Total community treatment with azithromycin.	Drug: R1-Total community treatment with azithromycin; At month 0, all study participants (regardless of their yaws status) will receive 30 mg/Kg (maximum 2 g) of azithromycin orally under direct observation. Benzathine benzylpenicillin will be reserved as a backup for patients who cannot be treated with AZI, and who are not allergic to penicillin.; Other Names: R1-TCT; Drug: R2-Total community treatment with azithromycin; At month 6, all study participants (regardless of their yaws status) will receive 30 mg/Kg (maximum 2 g) of azithromycin orally under direct observation. Benzathine benzylpenicillin will be reserved as a backup for patients who cannot be treated with AZI, and who are not allergic to penicillin.; Other Names: R2-TCT; Drug: R3-Total community treatment with azithromycin; At month 12, all study participants (regardless of their yaws status) will receive 30 mg/Kg (maximum 2 g) of azithromycin orally under direct observation. Benzathine benzylpenicillin will be reserved as a backup for patients who cannot be treated with AZI, and who are not allergic to penicillin.; Other Names: R3-TCT
Active Comparator: Control; Single total community treatment, TCT, with study drug: Azithromycin tablets, 30mg/Kg (maximum 2g), a single, at month 0 (1 dose); followed by two total targeted treatment, TTT, with study drug: Azithromycin tablets, 30mg/Kg (maximum 2g), a single, at months 6 and 12. Study interventions are: R1-Total community treatment with azithromycin, R2-Total targeted treatment with azithromycin, R3-Total targeted treatment with azithromycin.	Drug: R1-Total community treatment with azithromycin; At month 0, all study participants (regardless of their yaws status) will receive 30 mg/Kg (maximum 2 g) of azithromycin orally under direct observation. Benzathine benzylpenicillin will be reserved as a backup for patients who cannot be treated with AZI, and who are not allergic to penicillin.; Other Names: R1-TCT; Drug: R2-Total targeted treatment with azithromycin; At 6 months, study participants will be screened for active yaws. Participants with yaws and their contacts will receive 30 mg/Kg (maximum 2 g) of azithromycin orally under direct observation. Benzathine benzylpenicillin will be reserved as a backup for patients who cannot be treated with AZI, and who are not allergic to penicillin.; Other Names: R2-TTT; Drug: R3-Total targeted treatment with azithromycin; At 12 months, study participants will be screened for active yaws. Participants with yaws and their contacts will receive 30 mg/Kg (maximum 2 g) of azithromycin orally under direct observation. Benzathine benzylpenicillin will be reserved as a backup for patients who cannot be treated with AZI, and who are not allergic to penicillin.; Other Names: R3-TTT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevalence of active and of latent yaws at 18 months	Prevalence of active yaws confirmed by PCR at 18 months and prevalence of latent yaws determined by reaginic and non-reaginic positive DPP tests at 18 months	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Appearance of macrolide resistant yaws strains across the study population	T. p. pertenue molecular analyses	18 months

Collaborators and Investigators

• Sponsor: Lihir Medical Centre
• Collaborators: World Health Organization; Harvard School of Public Health (HSPH); Barcelona Institute for Global Health; National Department of Health of Papua New Guinea; University of Masarykova

Publications and helpful links

General Publications

• Mitja O, Godornes C, Houinei W, Kapa A, Paru R, Abel H, Gonzalez-Beiras C, Bieb SV, Wangi J, Barry AE, Sanz S, Bassat Q, Lukehart SA. Re-emergence of yaws after single mass azithromycin treatment followed by targeted treatment: a longitudinal study. Lancet. 2018 Apr 21;391(10130):1599-1607. doi: 10.1016/S0140-6736(18)30204-6. Epub 2018 Feb 7.
• Mitja O, Houinei W, Moses P, Kapa A, Paru R, Hays R, Lukehart S, Godornes C, Bieb SV, Grice T, Siba P, Mabey D, Sanz S, Alonso PL, Asiedu K, Bassat Q. Mass treatment with single-dose azithromycin for yaws. N Engl J Med. 2015 Feb 19;372(8):703-10. doi: 10.1056/NEJMoa1408586.
• John LN, Beiras CG, Houinei W, Medappa M, Sabok M, Kolmau R, Jonathan E, Maika E, Wangi JK, Pospisilova P, Smajs D, Ouchi D, Galvan-Femenia I, Beale MA, Giacani L, Clotet B, Mooring EQ, Marks M, Vall-Mayans M, Mitja O. Trial of Three Rounds of Mass Azithromycin Administration for Yaws Eradication. N Engl J Med. 2022 Jan 6;386(1):47-56. doi: 10.1056/NEJMoa2109449.

Study record dates

Study Major Dates

• Study Start (Actual): April 16, 2018
• Primary Completion (Actual): April 1, 2020
• Study Completion (Actual): April 1, 2020

Study Registration Dates

• First Submitted: March 29, 2018
• First Submitted That Met QC Criteria: April 4, 2018
• First Posted (Actual): April 6, 2018

Study Record Updates

• Last Update Posted (Actual): June 23, 2021
• Last Update Submitted That Met QC Criteria: June 18, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: Eradication; Azithromycin; Mass drug administration; Papua New Guinea; Endemic treponematoses
• Additional Relevant MeSH Terms: Skin Diseases; Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Skin Diseases, Infectious; Skin Diseases, Bacterial; Spirochaetales Infections; Treponemal Infections; Yaws; Anti-Infective Agents; Anti-Bacterial Agents; Azithromycin
• Other Study ID Numbers: Yaws3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: Possible statistical and modelling exercises

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No