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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03490123
Recruitment Status : Active, not recruiting
First Posted : April 6, 2018
Last Update Posted : August 13, 2019
Sponsor:
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
Information provided by (Responsible Party):
Oriol Mitja, Lihir Medical Centre

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 43 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.


Condition or disease Intervention/treatment Phase
Yaws 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 Phase 4

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. A new enumeration of all eligible population will be carried out before implementation, collecting also GPS coordinates of the village. A unique identification (ID) number will be given to each person. The 43 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. As a primary outcome, examination of suspected yaws lesions during TCT and TTT is important for determining the prevalence of active yaws for research purposes, but also for ascertaining who needs a follow up visit 4 weeks later to ensure that treatment was effective and, in TTT rounds, to trigger the process of treating contacts or community. The investigators will estimate the evolution of latent yaws prevalence measured as the proportion of children who are dually positive on the DPP test at two time-points (0, 24 months).Treatment of latent yaws is a crucial component of the WHO yaws eradication strategy to prevent relapse and the resulting transmission. Single-dose AZI has been shown effective in participants with latent yaws in PNG on the basis of the decline in serological titres. In this line, as the second primary outcome, the investigators plan to carry out 2 cross sectional surveys of asymptomatic children 1-9 years at baseline and for the outcome at 24 months to be able to more precisely estimate the impact of the two strategies of MDA.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 56000 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Community intervention study
Masking: Single (Outcomes Assessor)
Masking Description: Data collection teams separate from the teams responsible for MDA and screening.
Primary Purpose: Treatment
Official Title: Defining the Best Distribution Strategy of Azithromycin for Yaws Eradication (The Yaws 3 Trial)
Actual Study Start Date : April 1, 2018
Estimated Primary Completion Date : April 2020
Estimated Study Completion Date : April 2020

Resource links provided by the National Library of Medicine


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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: R3-TTT




Primary Outcome Measures :
  1. Prevalence of active and of latent yaws at 24 months [ Time Frame: 24 months ]
    Prevalence of active yaws confirmed by PCR at 24 months and prevalence of latent yaws determined by reaginic and non-reaginic positive DPP tests at 24 months


Secondary Outcome Measures :
  1. Appearance of macrolide resistant yaws strains across the study population [ Time Frame: 24 months ]
    T. p. pertenue molecular analyses



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   6 Months and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03490123


Locations
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Papua New Guinea
Namatanai Rural Hospital
Kavieng, New Ireland, Papua New Guinea, 08912
Sponsors and Collaborators
Lihir Medical Centre
Barcelona Institute for Global Health
National Department of Health of Papua New Guinea
World Health Organization
University of Masarykova
Harvard School of Public Health

Publications:
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Responsible Party: Oriol Mitja, MD, PhD, Lihir Medical Centre
ClinicalTrials.gov Identifier: NCT03490123    
Other Study ID Numbers: Yaws3
First Posted: April 6, 2018    Key Record Dates
Last Update Posted: August 13, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Possible statistical and modelling exercises

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Oriol Mitja, Lihir Medical Centre:
Azithromycin
Endemic treponematoses
Mass drug administration
Eradication
Papua New Guinea
Additional relevant MeSH terms:
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Yaws
Treponemal Infections
Gram-Negative Bacterial Infections
Bacterial Infections
Skin Diseases, Bacterial
Spirochaetales Infections
Skin Diseases, Infectious
Infection
Skin Diseases