Trial design Trachoma is targeted for global elimination. Infection rates with Chlamydia trachomatis are higher in new arrivals to a community and in travelers who leave for extended periods, suggesting they are sources of re-infection. This community-randomized, clinical trial was designed to determine if a surveillance program that targeted newcomers and travelers, identified weekly, would result in more communities achieving levels of infection of 1%. Methods 52 communities were randomly allocated 1:1 to the control (annual MDA alone if warranted) or intervention arm (annual MDA if warranted, plus a surveillance program to identify and treat newcomers and travelers). In each community, surveys were completed every six months on a random sample of 100 children ages 1±9 years for trachoma and infection. The primary outcome was the proportion of communities in the intervention arm, compared to the control arm, which had a prevalence of infection at 1% by 24 months. Registered: clinicaltrials. gov(NCT01767506). Results Intervention communities experienced an average of 110 surveillance events per month. At 24 months, 7 (27%) of 26 intervention communities achieved a prevalence of infection 1% compared to 4 (15%) of the 26 control communities (odds ratio = 2-6, 95%CI = 0-56±11-9). At 24 months, the average infection prevalence in the intervention communities was 4-8, compared to 6-9 in the control communities (p = -06). Conclusion Despite surveillance programs for community newcomers and travelers, the proportion of intervention communities with a level of infection 1% was lower than expected and not significantly different from control communities.
The trial was conducted in the Kongwa district, Tanzania, where every community in the previous three years had undergone annual Mass Drug Administration (MDA). Details on the methods were described in detail previously[17] The final survey for a previous cluster randomized trial provided a complete census that only needed updating as well as a survey that provided an estimate of the trachoma and infection prevalence for each study community.[15] The previous trial on coverage rates found no impact on infection with very high coverage versus high coverage, and thus the communities could be combined and re-randomized for this trial.[15] The overall rates for the study communities at the end of that trial were 9% and 3% respectively. In 2012, we re-randomized the communities for the current trial as described below, and enrolled them from February to July 2013 All residents in a study community were eligible for MDA unless the community had infection ≤1% or TF< 5%. For the study surveys every 6 months, all children ages 1–9 years in study communities were eligible for participation and, based on the most recent census in each community, a simple random sample of 100 children was chosen, plus an additional random sample of 20 children for replacement to allow for loss to follow up. The trial is registered with ClincalTrials.Gov: ({"type":"clinical-trial","attrs":{"text":"NCT01767506","term_id":"NCT01767506"}}NCT01767506). The ASANTE Trial was a cluster-randomized trial, with the community as the cluster. All communities had agreed to be in the trial before any fieldwork was started. The communities were stratified by whether or not infection was 1% or less at the survey prior to the start of the trial. A constrained randomization approach as suggested by Moulton[18] was used to reduce the likelihood of an imbalance of infection across treatment arms. Fifty-two communities were allocated 1:1, 26 to each arm, using the allocations that meet the balance criteria, and employing a SAS Macro (SAS, Carey NC). The senior biostatistician (BM) conducted the randomization and was the only person to have access to the assignment until all communities were assigned. Once all were assigned, the biostatistician provided a master list prior to any fieldwork to the Project Director, who implemented the randomization as assigned. Because of the nature of the intervention, masking of the communities was not feasible after randomization. The laboratory, however, was masked and received specimens with no indication of assignment. The survey team members were independent of the other teams, and masked to the assignment; however, during field data collection, the survey team could have been unmasked. This trial had a fixed sample size of 52 communities. Power calculations were based on the primary outcome, proportion of communities with prevalence of C. trachomatis of ≤1% at 24 months post baseline survey. A two-sided Fisher’s exact test and a significance level of α = 0·05 were used to estimate the power. We made the following assumptions, based on previous data on the decline in infection and our study on the increased risk of in migration[11]: We observed an average starting prevalence of infection of 3% and expected to observe a decrease in the infection rate by half after one year. We expected that 8 of the 26 communities (p0 = 0·308) in the control arm would have a prevalence of infection of ≤1% by 24 months, accounting for re-emergence observed in other studies. We had 80% power to detect differences if the number of communities at or below 1% in the intervention arm was at least 19 of 26, or 2·4 times or more (i.e. p1≥0·731 or p1/p0≥2·38) than the communities in the control arm after two years. This difference, if we found it, was felt to be of sufficient significance to warrant consideration of a surveillance program. A complete census was performed prior to the baseline survey with updates annually. The census was used to collect information on each household and to provide information for the selection of households with eligible children for the survey within the community. Additionally, the census was used as the database for mass treatment. A household was defined as a unique doorway belonging to a resident; a resident in the household was defined as a person who had slept in the household for at least three months (or if age less than 3 months, was born into the household) or who intended to reside with the family for the next six months. For each household, the census team member obtained a list of the names, ages, and gender of all persons resident in the household. The ages of the children were determined from vaccination or Maternal and Child health clinic cards if possible. Other demographic information collected included education, completed by the head of the household, distance to the closest source of water, observations on clean face status of children aged 5 and under, and presence of latrines. At census updates, the same census information was collected for each household. If the household or person was new to the community since the last census, these individuals were asked how long they lived in their present location. Surveys for trachoma, and infection based on a laboratory test of an ocular swab, were done at baseline and every 6 months to 24 months. The procedures were always the same. Based on the census (or updated census), a random sample of 120 children ages 1 to 9 years were selected from each community. A trained trachoma grader, using a flashlight and 2·5 loupes, assessed each eyelid for the presence or absence of trachoma inflammation-follicular (TF) and trachoma inflammation-intense (TI) using the World Health Organization simplified grading scheme.[19] An ocular photograph, taken of the right eye of every 5th child plus all children with trachoma, ensured at least 50 photographs for purposes of monitoring drift in grading over time. A handheld Nikon D-series camera (D-40) with a 105mm f/2·8D AF Macro Nikkor Autofocus Lens (fully extended, in manual setting) was used. Following a strict protocol to avoid field contamination, a swab was taken of the left eye of every child, stored dry in a refrigerator for up to 30 days, shipped to Johns Hopkins University International Chlamydia laboratory, where it was stored at -80° until processed. In addition, a negative field control ("blue air swab") was taken on a randomly chosen 5% sample to monitor contamination. For each negative field control, the examiner will pass a sterile Dacron swab within 1 inch of the individual’s conjunctiva, and these were labeled and processed identically to true conjunctival swabs. The laboratory personnel were masked to intervention and control arms, and to field control and regular swabs. The swabs were processed using a published pooling strategy[20,21] (4–5 per pool) within 90 days of arrival, using the APTIMA Combo 2 (AC2) commercial test for C. trachomatis (Hologic/Gen-Probe Inc., San Diego CA). The results were recorded as positive or negative for C. trachomatis, equivocal, or invalid. Equivocal or invalid pools were repeated. For pools that yielded a negative result, all specimens in that pool were recorded as negative for C. trachomatis. For each pool that yielded a positive result, the original samples were retested in order to determine which sample (s) had a positive result. Equivocal pools were retested as well as the individual samples contained in that pool, to determine a final positive or negative result. MDA in all communities was carried out by a network of Community Drug Distributors (CDDs) who were trained community residents. The treatment team had a list of all community residents, based on the latest census update, which was used to note who received drug and to calculate treatment coverage. The coverage target was 80% of children treated. A community found to have decreased infection to ≤1% or TF <5%, on the basis of a survey prior to baseline or at 6 or 18 months, was eligible to have cessation of MDA at the next scheduled round. According to our Data and Safety Monitoring Committee recommendations, if a community which had MDA stopped experienced a re-emergence of infection to 6% on either the 6 or 18-month survey, MDA was to be re-started at the next annual cycle. In the intervention arm, even though infection may have decreased to 1% or TF <5%, the surveillance and treatment program was still active and treatment within the surveillance program for eligible families continued per protocol. All communities were provided two days of mass treatment in their neighborhoods. More treatment days were scheduled depending on the tally of coverage at the end of the two days. The dosage of azithromycin was 20mg/kg, up to 1 gm in a single dose of either liquid or tablets. In Tanzania, pregnant women can be treated with azithromycin, but children under 6 months are given topical tetracycline. After each community completed mass treatment, treatment verification occurred in a random sample of five households among the households assigned to each CDD. A staff treatment supervisor visited each of the five homes after mass treatment, and asked the head of the household to verify the treatment status of each member of the household. The staff member was unaware of the treatment status at the time of the visit, and this was reconciled in the office. In the 26 communities randomized to the intervention arm, in addition to MDA (if warranted) a community-based Surveillance and Treatment Program (STP) was instituted. The STP program was designed to be simple and locally appropriate, but the monitoring of the program was intense to be certain it was implemented as planned for the trial. Local Community Monitors (CMs) were hired, trained, and given defined areas in their communities to survey each week, going house to house. They identified newcomer families, and resident families that have traveled outside the community for at least eight weeks, and offer azithromycin treatment to these families. Treatment was provided regardless of MDA status of the community. We defined “newcomer” as any guardian with at least one child under age 10 years that migrated to the community and planned to live either with an existing family or in a new home for at least one month. Newcomers received treatment if they came from a community that had not received MDA in the last year. We defined “traveler” as any family with children under age 10 years that returned to the community, having left for eight weeks or more. If travelers left for another community that had not received MDA in the last year, they received treatment upon their return. The CMs used the latest census to verify that each household within their defined areas was present at the last verification during the previous week, and whether any new family must be added. The CMs in a community were monitored for a week each month by supervisors who had to verify all surveillance events, as defined above, spot check a sample of households with no event, and visit all households where a newcomer or traveler “event” was recorded. Payment to the CM for case finding was contingent on correct identification and treatment. Of note, the district did not have any formal trachoma control activities related to facial hygiene or environmental improvements ongoing during the trial, apart from radio spots from the National program. The Community Health Workers collected data on adverse events after each newcomer and traveler family was identified and treated. There were no serious adverse events, and all were reviewed by a physician monitor. All census data were double entered into a custom-built Access database, where range and consistency checks were instituted. Survey data and Community Monitor supervisor validated data were entered into Samsung tablets (Samsung Electronics, Seoul, Korea) that also included range and some consistency checks. Tablet data were uploaded to a custom built Access databases as well, to allow data checking before exporting. All data were encrypted and sent to the Data Coordinating Center at Johns Hopkins where further data cleaning, using SAS (Carey, NC) for checking across forms, was undertaken. All analyses were conducted on intent-to-treat basis. Population characteristics were measured at the child and household level. These were summarized at cluster (community)-level and then summarized by treatment assignment. The median of cluster means for each arm were presented, along with the median (IQR) of cluster medians for each characteristic. The Wilcoxon rank sum test was used to compare the two groups. C. trachomatis infection/follicular trachoma prevalence are presented by randomization arm, and the proportion of communities at or below the threshold for infection/ follicular trachoma were estimated. Differences between arms in the proportion at or below the threshold at 24 months were tested using a two-sided Fisher’s exact test as specified in sample size determination. Multivariable models were constructed at the community level. For the primary analysis, logistic regression was used to model the probability of a community being at or below threshold for infection/follicular trachoma at the 24-month survey adjusting for baseline infection/follicular trachoma. Linear mixed models with random intercept and slope were used to estimate the yearly change in infection/trachoma by randomization arm. All procedures and protocols, including verbal consent as described below, were approved by the Johns Hopkins University Institutional Review Board and the Tanzania National Institute for Medical Research. The research was conducted according to the principles expressed in the Declaration of Helsinki. Community leaders were approached about participation in their communities in the trial after randomization, and all who were approached agreed to allow us to approach community members. Written informed consent was obtained from all guardians of children in the surveys, and verbal assent obtained from children of school age. Verbal informed consent was obtained from all newcomers and travelers to an intervention community who received a single dose of azithromycin outside of the community MDA, documented by the community health workers on the medication distribution sheet. Written consent was not obtained, as azithromycin is normally provided as part of community MDA and, community leadership did not want procedures different than those used by programs. Further details on consent procedures were presented previously[17].
DIMA AI Care
