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

NCT ID: NCT03490123

Last Updated: 2021-06-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 56000 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-04-16
• Study Completion Date: 2020-04-01

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).

Conditions

Yaws

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

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.

Group Type: EXPERIMENTAL

R1-Total community treatment with azithromycin

Intervention Type: DRUG

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.

R2-Total community treatment with azithromycin

Intervention Type: DRUG

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.

R3-Total community treatment with azithromycin

Intervention Type: DRUG

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.

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.

Group Type: ACTIVE_COMPARATOR

R1-Total community treatment with azithromycin

Intervention Type: DRUG

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.

R2-Total targeted treatment with azithromycin

Intervention Type: DRUG

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.

R3-Total targeted treatment with azithromycin

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

R1-TCT; R2-TCT; R3-TCT; R2-TTT; R3-TTT

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

• Minimum Eligible Age: 6 Months
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Barcelona Institute for Global Health

OTHER

Sponsor Role: collaborator

National Department of Health of Papua New Guinea

UNKNOWN

Sponsor Role: collaborator

World Health Organization

OTHER

Sponsor Role: collaborator

University of Masarykova

UNKNOWN

Sponsor Role: collaborator

Harvard School of Public Health (HSPH)

OTHER

Sponsor Role: collaborator

Lihir Medical Centre

OTHER

Sponsor Role: lead

Responsible Party

Oriol Mitja

MD, PhD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Namatanai Rural Hospital

Kavieng, New Ireland Province, Papua New Guinea

Countries

Papua New Guinea

References

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.

Reference Type: BACKGROUND

PMID: 29428183 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25693010 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34986286 (View on PubMed)

Other Identifiers

Yaws3

Identifier Type: -

Identifier Source: org_study_id