Study design and participants
We conducted a multicenter, three-arm parallel group, randomized control trial undertaken at 4 immunization centers in Karachi, Pakistan. The study was conducted in Landhi Town which constitutes one of the largest peri-urban towns in the south of Karachi city, in Pakistan’s Sindh province with an estimated population of around one million and an annual birth cohort of 41,000 children in 2017-18. Administratively, Landhi Town is subdivided into 12 Union Councils (UCs), 5 of which are primarily Pashtun dominated while the rest are represented by Urdu speaking, Punjabi and Sindhi ethnicities with income levels ranging from lower middle income to low-income communities. The town also contains a large industrial zone with a substantial proportion of the workforce employed as factory workers and migration being a distinctive feature within the overall population.
Health care provision in Landhi Town falls under a network of both public and private health care providers. Specifically, immunizations are provided by government-run Expanded Programme on Immunization (EPI) centers consisting of a network of 29 vaccinators who administer vaccines. Out of a total 17 EPI centers in the Town, we selected 4 contiguously located high volume centers, whose catchment areas included 7 out of 12 union councils in Landhi Town. As per the Pakistan Demographic and Health Survey (2017-18) [4] , 82% of all 12-23 month old children in Sindh province had received the (BCG; Bacille Calmette Guérin) vaccination. The coverage for Pentavalent-3 and Measles-1 vaccine was 59% and 61% respectively.
The inclusion criteria for the study included children presenting to any of the four selected immunization centers for BCG or Pentavalent-1 vaccination, accompanied by a primary caregiver, healthy, and had been residents of the catchment area for more than six months. Exclusion criteria included children older than 3 months of age or their caregivers planning to visit a non-study immunization center for the follow-up immunizations. Written informed consent was obtained from the parents or caregivers of all children.
The study was approved by the Committee on the Use of Human Subjects at Harvard University, USA and the Institutional Review Board of Interactive Research and Development, Pakistan. The trial was registered with ClinicalTrials.gov, number NCT03310762.
EPI vaccination Schedule
Pakistan’s routine immunization schedule in 2018 included BCG (Bacille Calmette-Guérin) vaccine at birth, three doses of pentavalent (DPT, HepB, Hib) vaccine, three doses of pneumococcal vaccine (PCV) and three doses of oral polio vaccine at 6, 10 and/or 14 weeks of age, and two doses of measles vaccine at 9 and 15 months of age.
Procedures
Among the caregiver-child pairs visiting the centers, eligible children identified through the screening process were approached by our trained field staff for obtaining written consent (from their caregivers). Those who consented to participate were enrolled in the study, randomized and information was collected about the child’s current and past vaccination as well as demographic characteristics and socio-economic status. Depending upon the child’s allocated group, the child was provided the intervention (detailed below). After that, data was collected on the child’s vaccination status each time the child visited the immunization center, and if the child was in the treatment group, the relevant intervention procedures were followed (detailed below). As per the recommended EPI schedule, each child was due to visit the center 3-4 times (depending on enrollment vaccine) up till the final vaccine visit for the study at Measles 1 vaccine. At the Measles 1 vaccine visit, a completion form was administered to collect data on experiences of using the bracelets as well as self-reported compliance of wearing the bracelet.
For children who did not visit the center for the recommended number of visits by 12 months of age, we conducted phone calls to document the child’s immunization status. The primary caregiver who had brought the child for immunization was asked to refer to the child’s immunization card to determine the vaccines given and their dates. In case the immunization card was lost, the caregiver could not read the immunization card or the caregiver’s phone number was not available, a household visit was done to document the child’s immunization history. During the household visit, the immunization status was determined through the official EPI card and if this was not available, a verbal recall for the immunization history was taken. A schematic representation of the study procedures is included in the supplementary figure 1.
Intervention
Our two intervention groups comprised of two different types of immunization reminder bracelets. Intervention Group A was provided with a bracelet developed by Alma Sana Inc., a 501(c)3 non-profit organization founded in Indianapolis, Indiana, US. Following a short formative phase, the bracelet was adapted to the Pakistani context through feedback from mothers and vaccinators and involved changes in the color, choice of symbols and denotation of the child’s age on the bracelet, as well as adapting it to suit Pakistan’s EPI schedule. The final adapted bracelet had the recommended age of the child denoted in weeks/months for receiving the vaccine followed by symbols representing each of the vaccines due at that age.
Each time the child came for vaccination with the bracelet, our study staff perforated a hole in the particular symbol denoting the vaccine that the child had received on that visit and explained to the caregivers the number of vaccines the child still had to receive to complete the routine immunization schedule. Caregivers could, therefore, look at the bracelet and know which vaccines the child had already received and the recommended age of the future visits. The bracelets were manufactured in 2 different sizes to ensure they fit the child’s wrist as he/she grew older.
Intervention Group B was provided with a simple silicon bracelet “Star Bracelet” that consisted of six symbols (5 crescents and one star) denoting the 6 visits that the child is supposed to make to the immunization clinic to complete the routine immunization schedule. The bracelet was designed with the rationale to motivate parents to make all 6 visits to the immunization center in order to reach the ‘star’ symbol on the bracelet. Similar to Intervention Group A, each time the child visited the center with the bracelet, the study staff punched a hole to denote the child’s visit to the immunization center and explained to the caregiver to complete all 6 immunization visits to reach the star symbol on the bracelet. The bracelets were manufactured in 2 different sizes and colours (pink for girls and blue for boys).
“As explained above, although the rationale behind the two different types of bracelets and their mode of use was the same, the bracelets differed in aspect of their designs. The adapted Alma Sana bracelet presented the entire vaccination schedule, along with the different antigens and their stipulated times of administration. The Star bracelet on the other hand had a simpler design, only denoting the 6 immunization visits (without specifications of the antigens and the timings of the visits). A simpler design provided information in an easily comprehensible way, specifically for mothers with low literacy levels who cannot read and understand the complicated EPI schedules. Through using these two different types bracelets, we can evaluate if there is any difference in vaccination outcomes as a result of conveying varying degrees of information, in different formats to caregivers regarding their child’s immunization schedule.”
The control group participants received the standard of care which included receiving the routine EPI vaccinations as per Pakistan’s EPI Immunization schedule and the vaccinator recording the child’s immunization data in the EPI immunization card provided to the caregivers. The difference between the intervention and standard care was only the provision of bracelets and no extra counselling/information was provided to the caregivers.
Sample size
We expected a 60% coverage rate of Pentavalent-3/ vaccine and a 50% coverage rate of Measles-1 vaccine in the control group, and hypothesized an increase in coverage by an absolute number of 10% in the Pentavalent-3 vaccine coverage (from 60% to 70%) or Measles-1 vaccine coverage (from 50% to 60%). With 80% power (and a 2-sided type 1 error of 5%), we estimated a sample of 1,062 participants (354 in each group) to detect a difference of 10% between intervention and control group proportion for pentavalent-3 vaccine coverage rate, and a sample size of 1,155 participants (385 in each group) to detect a difference of 10% between intervention and control group proportion for Measles-1 vaccine coverage rate. On the basis of these numbers, a sample size of 1,155 participants was needed to achieve at least 80% power to realize both objectives. Accounting for a potential dropout rate of 20% during the follow-up period, our final sample size was 1,446 infants (482 in each study group).
Randomization
Participants were randomly assigned (1:1:1) to either the Intervention Group A (Alma Sana Bracelet). Intervention Group B (Star Bracelet) or control group. The randomization sequence was generated in Stata version 13 using random block sizes of 3, 6, 9 and 12. After confirming the eligibility criteria, the next available randomization number in the immunization center (in chronological order) was assigned. The allocation sequence was concealed from the study staff responsible for screening and enrolling participants in sequentially numbered, opaque, sealed envelopes and was only revealed post-randomization. The statistical analysis plan was developed prior to start of the study.
Measures
Our study outcome of interest included the coverage and timeliness of Pentavalent-3 and Measles-1 vaccines at 12 months of age in the intervention versus control groups. We also investigated the self-reported compliance of caregivers on the child actually wearing the bracelet along with some general feedback on the bracelet itself.
Analysis
All study data were collected on paper based forms and transferred to a secure electronic database on a daily basis. The data were analyzed using STATA version 15 (StataCorp. 2017. Stata Statistical Software: Release 15. College Station, TX: StataCorp LLC).
For baseline characteristics, we used frequencies (%) for categorical data, means, and standard deviation (SD) for continuous data. The baseline characteristics were compared by using the Student’s t-test for continuous variables and the Pearson’s chi-square test for categorical variables. We analyzed data using the intention-to-treat population between groups. The unadjusted and adjusted Risk Ratios (RR) and 95% confidence interval (CI) for Pentavalent-3 and Measles-1 coverage at 12 months of age were estimated through bivariate and multivariate analysis. Two-sided P values were reported, and the values of ≤.05 were considered statistically significant. The variable selection was performed using a stepwise forward model (p<0·10) for each of our two outcomes (Pentavalent-3 and Measles-1) separately. Time-to-Pentavalent-3 and Measles 1 immunization curves were calculated using the Kaplan–Meier method. The intervention and control groups were compared for effect on timely completion of Pentavalent-3 and Measles-1 immunization using the log-rank test.
We also assessed the Pentavalent-3 and Measles-1 coverage at 12 months of age among the 3 allocation groups and performed chi-squared tests to determine the effect of the treatment on coverage. Additionally, caregiver feedback in the two intervention groups regarding their overall satisfaction with the bracelets and visibility of bracelet was assessed through data collected in the completion form. Caregiver satisfaction was measured through feedback on the utility of the bracelets, its ease of use and whether caregivers would recommend it to others. Visibility of the bracelet was assessed by enquiring the self-reported compliance of children wearing the bracelet and where it was kept when the child was not wearing it.