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

Primary Purpose

Yaws

Status
Completed
Phase
Phase 4
Locations
Papua New Guinea
Study Type
Interventional
Intervention
R1-Total community treatment with azithromycin
R2-Total community treatment with azithromycin
R3-Total community treatment with azithromycin
R2-Total targeted treatment with azithromycin
R3-Total targeted treatment with azithromycin
Sponsored by
Lihir Medical Centre
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Yaws focused on measuring Azithromycin, Endemic treponematoses, Mass drug administration, Eradication, Papua New Guinea

Eligibility Criteria

6 Months - undefined (Child, Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

  • Namatanai Rural Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Intervention

Control

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Appearance of macrolide resistant yaws strains across the study population
T. p. pertenue molecular analyses

Full Information

First Posted
March 29, 2018
Last Updated
June 18, 2021
Sponsor
Lihir Medical Centre
Collaborators
Barcelona Institute for Global Health, National Department of Health of Papua New Guinea, World Health Organization, University of Masarykova, Harvard School of Public Health (HSPH)
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1. Study Identification

Unique Protocol Identification Number
NCT03490123
Brief Title
Evaluation of an Intensive 3-round MDA Strategy Towards Yaws Eradication
Official Title
Defining the Best Distribution Strategy of Azithromycin for Yaws Eradication (The Yaws 3 Trial)
Study Type
Interventional

2. Study Status

Record Verification Date
June 2021
Overall Recruitment Status
Completed
Study Start Date
April 16, 2018 (Actual)
Primary Completion Date
April 1, 2020 (Actual)
Study Completion Date
April 1, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Lihir Medical Centre
Collaborators
Barcelona Institute for Global Health, National Department of Health of Papua New Guinea, World Health Organization, University of Masarykova, Harvard School of Public Health (HSPH)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Yaws
Keywords
Azithromycin, Endemic treponematoses, Mass drug administration, Eradication, Papua New Guinea

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
Community intervention study
Masking
Outcomes Assessor
Masking Description
Data collection teams separate from the teams responsible for MDA and screening.
Allocation
Randomized
Enrollment
56000 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Intervention
Arm Type
Experimental
Arm Description
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.
Arm Title
Control
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
R1-Total community treatment with azithromycin
Other Intervention Name(s)
R1-TCT
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
R2-Total community treatment with azithromycin
Other Intervention Name(s)
R2-TCT
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
R3-Total community treatment with azithromycin
Other Intervention Name(s)
R3-TCT
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
R2-Total targeted treatment with azithromycin
Other Intervention Name(s)
R2-TTT
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
R3-Total targeted treatment with azithromycin
Other Intervention Name(s)
R3-TTT
Intervention Description
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.
Primary Outcome Measure Information:
Title
Prevalence of active and of latent yaws at 18 months
Description
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
Time Frame
18 months
Secondary Outcome Measure Information:
Title
Appearance of macrolide resistant yaws strains across the study population
Description
T. p. pertenue molecular analyses
Time Frame
18 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Months
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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
Facility Information:
Facility Name
Namatanai Rural Hospital
City
Kavieng
State/Province
New Ireland
ZIP/Postal Code
08912
Country
Papua New Guinea

12. IPD Sharing Statement

Plan to Share IPD
Undecided
IPD Sharing Plan Description
Possible statistical and modelling exercises
Citations:
PubMed Identifier
29428183
Citation
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.
Results Reference
background
PubMed Identifier
25693010
Citation
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.
Results Reference
background
PubMed Identifier
34986286
Citation
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.
Results Reference
derived

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

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