Comparison of methods to assess adherence to small-quantity lipid-based nutrient supplements (SQ-LNS) and dispersible tablets among young Burkinabé children participating in a community-based intervention trial

Adherence to supplementation provided during an intervention trial can affect interpretation of study outcomes. We compared different approaches for estimating adherence to small-quantity lipid-based nutrient supplements (SQ-LNS) and dispersible tablets in a randomised clinical trial in Burkina Faso. A total of 2435 children (9-18 months) were randomly assigned to receive daily 20g SQ-LNS with varying contents of zinc and a dispersible tablet containing 0 or 5mg zinc. Adherence to SQ-LNS and tablets was assessed for all children through weekly caregiver interviews, and disappearance rate was calculated based on empty and unused packages returned during home visits. Additional adherence data were collected in different randomly selected subgroups of children: 12-h home observations were completed for children 11 and 16 months of age (n=192) to assess consumption of SQ-LNS and dispersible tablets, and plasma zinc concentration was measured at baseline and 18 months (n=310). Apparent adherence to SQ-LNS and dispersible tablets differed according to the assessment method used. Average daily caregiver-reported adherence to both SQ-LNS and dispersible tablets was 97±6%. Disappearance rates showed similarly high average weekly adherence (98±4%). In contrast, only 63% and 54% of children at 11 and 16 months, respectively, received SQ-LNS during the 12-h home observation periods, and fewer (32% and 27%) received a tablet. The lack of change in plasma zinc concentration after 9 months of supplementation suggests low adherence to the zinc tablet. Better methods are needed to assess adherence in community-based supplementation trials. The iLiNS‐ZINC study was a community‐based, partially double‐masked, placebo‐controlled, randomised clinical trial conducted in the Dandé health district in southwestern Burkina Faso. Ethical approval was provided by the Institutional Review Boards of the Centre Muraz in Bobo‐Dioulasso (Burkina Faso) and the University of California, Davis (USA). The study was registered with the U.S. National Institutes of Health (http://www.ClinicalTrials.gov; {“type”:”clinical-trial”,”attrs”:{“text”:”NCT00944281″,”term_id”:”NCT00944281″}}NCT00944281). Nine‐month‐old children were identified during periodic censuses conducted in 34 participating communities; 25 communities were stratified to intervention cohort (IC) and 9 to non‐IC (NIC). Further details of the study design are reported elsewhere (Hess et al. 2013). For the present analyses, only children in the IC are considered. Eligible children in these communities were randomly assigned to receive one of the following interventions from 9 to 18 months of age: (1) SQ‐LNS without zinc and a placebo tablet (LNS‐Zn0); (2) SQ‐LNS with 5 mg zinc and a placebo tablet (LNS‐Zn5); (3) SQ‐LNS with 10 mg zinc and a placebo tablet (LNS‐Zn10); or (4) SQ‐LNS without zinc and a 5 mg zinc tablet (LNS‐TabZn5). A second randomisation was completed at the concession level to select subgroups for the different adherence assessment methods [12‐h home observations at 11 and 16 months; knowledge, attitudes and practices (KAP) interview at 15 months; and baseline and final plasma zinc concentration (PZC)]. The first child from each concession was eligible to participate in just one of the adherence sub‐studies (Fig. 1). Scheme of timing of different adherence assessment methods. Caregivers were instructed to give a total of 20 g of SQ‐LNS/day in two separate doses. At the beginning of the study, SQ‐LNS was distributed in 140 g cups for weekly use; this was later changed to 20 g sachets for daily administration. For the cups, caregivers were given a teaspoon and instructed to give one spoonful of SQ‐LNS at each of two separate times during the day, mixed in a small portion of the child’s meal (such as porridge) to ensure that the child consumed the full dose of SQ‐LNS. Similarly, for the sachets, caregivers were instructed to squeeze half of the sachet into a small portion of the child’s meal. For the placebo/zinc dispersible tablets, caregivers were instructed to disperse the tablet in one teaspoon of drinking water or breast milk, and to give the child the entire dose once a day, at least 30 min after a meal. The purpose of the latter instruction was to reduce potential inhibition of zinc absorption if the tablet was given with food (Brown et al. 2007). Both SQ‐LNS and tablets were colour coded by study group and provided by Nutriset SAS (Malaunay, France). In addition to the dietary supplementation instructions, brief feeding messages were provided to promote continued breastfeeding and diverse, nutritious child diets. Instructions on how to give the SQ‐LNS and dispersible tablets were repeated monthly, while general feeding instructions were repeated irregularly. Daily reported adherence and disappearance rates were assessed in the whole IC. The sample size estimates were based on the number of children needed in each group to detect (with a significance of P < 0.05 and power >0.80) an effect size of >0.22 for diarrhoea incidence, malaria incidence and physical growth, assuming an attrition rate of 15%. The sample size estimate for change in PZC was based on an effect size of 0.6 and an attrition rate of 20%. For both 12‐h home observations and the 15‐month KAP interview, sample sizes of 10% and 20%, respectively, were chosen for convenience. Timing and frequency of data collection in both of the latter subsamples were chosen based on considerations of participant burden, cost constraints, and time needed for the data collection and quality control supervision. Field workers visited the children weekly for morbidity surveillance using standardised data collection tools and delivery of SQ‐LNS and tablets. In case of reported illnesses, treatment was provided free of charge for confirmed cases of malaria, non‐malaria fever and diarrhoea. At the same time, information on consumption of SQ‐LNS and dispersible tablets was collected by interviewing the mother or another adult caregiver (N = 2418) for the period since the previous home visit. Caregivers were asked to recall the child’s daily SQ‐LNS consumption (morning and afternoon, yes or no) and tablet consumption (yes or no). SQ‐LNS daily adherence was calculated by summing all consumption episodes each day. Any special case (e.g. SQ‐LNS/tablet served but not consumed or vomited) was recorded separately as a comment. To facilitate recall, a pictorial chart was distributed weekly, on which the caregivers were encouraged to record the consumption of SQ‐LNS/tablet and any morbidity symptoms each day, using simple tallying marks, which was used as memory aid during the interview. During the same weekly visit, field workers collected both empty and unused SQ‐LNS and tablet packages. The field workers recorded the number of unused packages as a proportion of the total distributed during the previous visit. This was done by estimating the percentage remaining in the cup or by counting the number of unused sachets for SQ‐LNS, and by counting the number of unused tablets. Daily disappearance rate was calculated as the difference between the distributed SQ‐LNS or tablets and the unused packages divided by the number of observation days. In a randomly selected subsample (N = 192), field workers spent 12 h in the family home on two occasions when the child was approximately 11 and 16 months of age to observe the child. Three data collectors were trained to collect the 12‐h home observation data unobtrusively. Caregivers were told that the main purpose of the observation was to record the child’s activity level. Data collectors emphasised upon arrival that the caregivers should not change their behaviour towards the child and should follow their usual routine. While present in the home, the data collectors also recorded the consumption of SQ‐LNS and dispersible tablets, breastfeeding, and feeding of other solid or liquid food. Field workers were trained not to show any particular interest in child feeding and/or SQ‐LNS and tablet consumption (e.g. not to move closer to examine the SQ‐LNS pot/sachet, the tablet or the child’s plate). During each home visit, the child was observed by two data collectors alternating the observations from 6 am to 6 pm and recording the relevant activities every 5 min using a standardised tool on a personal digital assistant (PDA, Hewlett‐Packard Development Company, L.P., Palo Alto, CA, USA). Child observations were carried out when the children’s general health status was reported as normal, and were rescheduled in case of illness. Information recorded about SQ‐LNS and dispersible tablet adherence included whether the supplement was served, the time of administration, the estimated amount consumed by the child, the way the products were offered (with food or alone) and any sharing with other family members. The consumed amounts of SQ‐LNS and tablets were calculated as the sum of all portions administered and consumed. At 15 months, a separate data collection team interviewed the child’s caregiver to assess the caregiver’s knowledge, attitude and practices related to complementary feeding (N = 349). KAP interviews were conducted by study personnel who were not involved in the distribution of SQ‐LNS or tablets, so less reporting bias might be expected during these interviews. In particular, caregivers were interviewed on: (1) SQ‐LNS consumption during the previous week; (2) SQ‐LNS consumption on the previous day; (3) acceptance of SQ‐LNS by the child and any reasons for non‐acceptance; (4) sharing of SQ‐LNS with other household members; and (5) method of serving the SQ‐LNS during the previous week (with any liquid or solid food). No information was collected on tablet consumption during these interviews on child feeding practices. Venous blood samples were collected from children in a randomly selected subgroup (N = 310) at enrollment (age 9 months) and after 9 months of intervention (age 18 months) using specimen collection and processing methods recommended by the International Zinc Nutrition Consultative Group (Brown et al. 2004). Children had to be reported free from fever and diarrhoea symptoms during the 2 days preceding the blood draw. At both time points, blood was drawn 1–2 h after the last breastfeeding episode. Blood was collected in trace element‐free, lithium heparin vacutainer tubes (Sarstedt AG & Co, Nümbrecht, Germany). Blood samples were stored on ice and transported to the field laboratory, where plasma was separated by centrifuging at 2800 rpm for 10 min and stored at −20°C until analyses. PZC was measured with inductively coupled plasma optical emission spectrophotometry (Vista; Varian Inc, Walnut Creek, CA, USA) at the Children’s Hospital of Oakland Research Institute (Killilea & Ames 2008; Wessells et al. 2012). Acute phase proteins (C‐reactive protein and α‐1‐acid glycoprotein) were analysed by enzyme‐linked immunosorbent assay (DBS‐Tech, Willstaett, Germany) (Erhardt et al. 2004) to adjust PZC for the effect of subclinical inflammation (Thurnham et al. 2010). Baseline data on maternal age, education level and marital status, number of children in the household, and data on household food insecurity access scale (Coates et al. 2007) were collected via interview for all study households within 2 weeks of enrollment. Children with less than 1 week of data collected (n = 17) were not included in the analysis. All the data were checked for consistency during cleaning and analysis. Inconsistent data were excluded based on pre‐defined criteria. Outcomes for the different adherence assessment methods (reported daily adherence and disappearance rate, 12‐h home observation, 15‐month KAP interview and adjusted PZC) were compared by study group using analysis of covariance for continuous outcome variables and logistic regression for categorical outcome variables. Additionally, outcomes for the 12‐h home observation were analysed using mixed model analysis to account for repeated measurements from the same subject. Group was used as the main effect, and age, initial PZC and sex as covariates for PZC analysis. All the analyses accounted for the random effect of the community, and for the family compound (i.e. concession) in case of daily reported adherence and disappearance rate. Group means were compared post hoc using least‐square means with the Tukey–Kramer test. Associations between reported daily adherence and disappearance rate, reported daily adherence and 12‐h home observation, and between reported daily adherence and 15‐month KAP interview of the same child and during the same observation day were calculated by non‐parametric Spearman correlation. Prevalence of reported non‐adherence and its association with illness days (fever, diarrhoea, malaria, vomiting, anorexia or hospitalisation) were analysed using mixed model adjusted for the random effect of the village and the concession. All statistical analyses were carried out using SAS software for Windows (9.3, SAS Institute, Cary, NC, USA).