Participants, interventions and outcomes
Study setting {9}
The study site for participant enrollment is the Gugulethu Midwife Obstetric Unit (MOU), based at the Gugulethu Community Health Centre near Cape Town, South Africa. The MOU serves Gugulethu as well as the surrounding informal settlements, and is often attended by women who come from the Eastern Cape to have their babies in Cape Town, resulting in travel to and from the Eastern Cape during pregnancy and postpartum [42]. The local antenatal HIV prevalence is high (~30%), and the mother-to-child HIV transmission rate is estimated at 2-4% [43]. The MOU team has helped to deliver HIV care and treatment services in this setting since 2003 and has a history of successful ART service delivery and research in partnership with the provincial government. Members of the study team have conducted studies at the MOU since 2006 [44].
Eligibility criteria {10}
Eligible subjects are adult (≥18 years) women living with HIV who are in the third trimester of pregnancy (≥28 weeks gestation) and are willing to be randomized. Subjects must be able to speak and understand isiXhosa and/or English. Basic smartphone-level literacy must be demonstrated by asking the participant to read aloud the following sentence in either English or isiXhosa: “I can look up a new clinic on the phone.” Lastly, eligible participants must currently own a smartphone that meets the technical requirements of the app and be willing to opt-in to installation of the app on her personal phone and to agree to mobility tracking. The specific technical requirements of the app include a) a touchscreen, b) capable of accessing the internet, c) operating system Android, version 5.0 or later, d) cellular service is provided by one of the four major networks in South Africa (Cell-C, MTN, Telkom or Vodacom), e) capable of using GPS to show current location, and f) requires charging the battery less than twice a day, on average. In our preliminary work, nearly 90% of smartphones of women approached for study participation used the Android system [45].
Late pregnancy was selected in order to allow for a nine-month total follow-up time within the time constraints of a three-year project. In South Africa, most women present for their first antenatal visit around 20 weeks gestation or later [13,46,47], and attendance for antenatal visits is generally high [13,17], so we do not believe there will be substantial bias introduced by enrolling women later in pregnancy. isiXhosa is the predominant language in the region of the study site, and English also is widely spoken, so we do not anticipate excluding potential participants due to language. Basic smartphone-level literacy will be required of participants in order to assess the impact of messages. However, we anticipate that most women who own a smartphone already have a basic smartphone-level literacy ability. We acknowledge that women who own a smartphone may be different than those who do not, in terms of employment, education, or other factors.
Who will take informed consent? {26a}
Written informed consent is obtained by a study team member fluent in isiXhosa and English who has completed Human Subjects Protections and Good Clinical Practice certification. All women who meet the eligibility criteria and are interested in participating in the study will undergo written informed consent, which will be available in English and isiXhosa. The consent form will confirm the eligible woman’s understanding of the study procedures and her informed willingness to participate. The key messages of the informed consent process will include: 1) a description of the study goals and procedures, 2) voluntary participation in the study, 3) confidentiality and privacy with use of the app and study data, 4) the right to withdraw at any time, and 5) the standard of care received at the MOU or any other healthcare facility will not differ according to participation in the study.
Once the consent form has been explained to the participant, any questions she may have will be answered. If the participant agrees to provide consent for participation, she will indicate this with her signature on the consent form. If she does not wish to participate or does not provide her consent for all the activities, she will not sign the consent form and will not be enrolled. A second copy of the form will be provided for her to sign and keep, if requested. The study staff member who administered the form will provide his or her name, signature and date as a witness to the signing. Signed informed consent forms will be stored in binders within a locked office and only accessible by study staff.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
The informed consent form specifically requests permission for installation of the app, location tracking, data collection, medical record review (participant and infant), one blood draw, and re-contacting by study staff.
Interventions
Explanation for the choice of comparators {6b}
In order to assess CareConekta’s ability to track participant location, the CareConekta app will be installed for all study participants – regardless of study arm. This also will allow all participants to passively search for new clinics using the facility finder. To assess the potential of using real-time location data in order to improve engagement in HIV care, participants in the intervention arm will receive enhanced follow-up when they travel.
Intervention description {11a}
Participants in the control arm (n=100) will receive standard CareConekta, which will track their mobility and allow the participant to look up new ART facilities upon request. Participants in the intervention arm (n=100) also will receive standard CareConekta with the following additions:
- Push notifications prompting the participant to open the app to view nearby ART facilities when they have traveled >50 km from the study site for >7 days
- Phone call(s) and/or WhatsApp message(s) from study staff when they have traveled >50 km from the study site for >7 days. The study staff calls and messages will ask about medication supply and will provide assistance with nearby facilities, if requested.
Criteria for discontinuing or modifying allocated interventions {11b}
The additional communication included in the intervention arm will be discontinued at participant request.
Strategies to improve adherence to interventions {11c}
The intervention will be delivered only if the participant has met the travel threshold described above. No additional participant behavior is required in order to receive the intervention. To ensure staff fidelity of the intervention, push notifications are standardized, and a brief script has been developed (in English and isiXhosa) for items to be addressed in the phone calls and/or WhatsApp messages to participants. If app “heartbeats” are not received, participants will be contacted to troubleshoot technical problems, regardless of study am.
Relevant concomitant care permitted or prohibited during the trial {11d}
Subjects are ineligible for study participation if they are currently involved in another research study which may impact the study outcomes. Routine clinical care will continue as usual for all participants.
Provisions for post-trial care {30}
During and after the trial, participants will continue to receive routine care at the clinic of their choice.
Outcomes {12}
This study will collect data in the following three methods:
- GPS location (mobility) data collected through the CareConekta app
- Participant responses to questionnaires at the enrollment and follow-up visits, and during a brief postpartum interim phone call.
- Post-study review of participant electronic and paper medical records
Primary outcome: Mobility within the study period
We will use data from all 200 participants to describe mobility within a complete observational cohort. In order to assess mobility comprehensively, we will use multiple data sources: time- and date-stamp data as well as geographic location data from CareConekta, participant self-report during questionnaires, and electronic medical records during the file review.
Secondary outcome 1: Impact of mobility on engagement in HIV care in the absence of the intervention
Limiting the analysis to only the 100 participants in the control arm, we will explore the impact of mobility on engagement in HIV care in the absence of intervention by using GPS location data and engagement in HIV care data retrieved through medical record review. To assess engagement in HIV care, we will report retention in care, which will be assessed at the six-month postpartum point and defined as no documented HIV-specific contact with any healthcare facility (including medication pick-ups) for >3 months. We also will report viral suppression six months after delivery based on the viral load test closest to the six-month period, using thresholds of ≤50 and ≤1000 copies/ml. Additionally, we will report vertical HIV transmission and completion of the routine 10-week infant PCR test.
Secondary outcome 2: Acceptability and feasibility of CareConekta
Acceptability and feasibility data will be collected among all 200 participants. Those in the intervention arm will receive additional questions related to the enhanced app features. The outcomes selected for analysis correspond with the Technology Acceptance Model for Resource-Limited Settings (TAM-RLS) framework, which was designed to draw attention to end-user acceptability as a predictor of mHealth technology adoption in low-resource settings [48].
Secondary outcome 3: Initial efficacy of the intervention
The overall efficacy analysis will include participants in both arms (n=200). Engagement in HIV care will be defined as in secondary outcome measure 1 above. Study arm assignment is the primary exposure of interest.
Participant timeline {13}
Sample size {14}
We will enroll 200 participants in total. For this pilot trial formal sample size estimation was not conducted. The sample size was reached based on the feasible enrolment from the study site within the study timeline. Approximately 4,000 women seek antenatal care at the MOU annually; ~30% of these are HIV-positive, about 1,200 per year, or 100 per month. Our formative work at the study site showed that over half of these women own smartphones. If we conservatively estimate that 30% of all pregnant, HIV-positive women seeking antenatal care each month will be eligible and interested, this equals 30 participants enrolled per month. We anticipate that it will take approximately seven months to reach our enrolment target of 200 participants.
Recruitment {15}
Each week during the study recruitment period, study staff will review the list of upcoming appointments at the study site to assess who may be eligible for study participation. Pregnant women attending routine antenatal care services at the Gugulethu Community Health Centre will be approached by trained study recruiters and given brief information about the pilot study. If they are interested, they will be screened to ensure they meet the eligibility criteria using an eligibility checklist. If eligible, they also will be shown a demonstration of CareConekta and its functionality prior to the informed consent process.
Assignment of interventions: allocation
Sequence generation {16a}
The randomization sequence will be generated in R with a 1:1 allocation ratio within randomly permuted blocks to ensure balanced allocation to the intervention and control arms.
Concealment mechanism {16b}
Randomization assignment will be concealed in sequentially-numbered, opaque sealed envelopes until opened after enrollment with the participant.
Implementation {16c}
The sequence will be generated by a statistician independent of the study team. The randomization assignment envelopes will be created by an individual at the University of Cape Town independent of the study team following the generated sequence. After enrolling a participant, the site staff will select the next consecutive sealed envelope to reveal study arm assignment.
Assignment of interventions: Blinding
Who will be blinded {17a}
Due to the open-label nature of this study, no blinding will be used.
Procedure for unblinding if needed {17b}
Due to the open-label nature of this study, no blinding will be used.
Data collection and management
Plans for assessment and collection of outcomes {18a}
Mobility data will be collected throughout the study using the GPS tracking feature of the CareConekta app.
For recording participant characteristics, several study measures have been used previously by the study investigators in similar populations at the study site and in other areas of South Africa. In addition, we are using the following widely-used, validated measurement scales:
- ART adherence: 3-item self-report measure (Wilson, et al.)[49]
- Alcohol use: Alcohol Use Disorders Identification Test-Concise (AUDIT-C)[50]
- Drugs: Question 1 from Drug Use Disorders Identification Test (DUDIT)[51]
- Depression: Patient Health Questionnaire-4 (PHQ-4)[52]
- Intimate partner violence: World Health Organization Violence Against Women (WHO VAW) measurement[53]
- Life events[54]
- Patient-Healthcare provider relationship[55]
- Perceived availability of support[56]
- Social impact scale[57]
Study forms are available by request to the investigators.
Plans to promote participant retention and complete follow-up {18b}
In order to maximize the potential of re-contacting each participant and accessing medical records, we will collect identifying information on a separate paper-based linkage form, including contact information, name, study number, clinic record number, phone number, national identification number, address, date of birth, and we will also update this form with infant information, when available. As is standard practice for research studies at the study site, the participant may also provide details for an alternative contact person in the event that we are unable to reach the participant after multiple attempts. No details about the participant will be shared with the alternative contact; study staff simply will ask that the participant return to the clinic when she can. For the interim phone call and follow-up visit, a minimum of three contact attempts by phone and/or home visit will be made for each participant. If participant mobility data ceases to transmit at least once per day, the study team will follow up with the participant to find out if there are problems with her phone.
Data management {19}
All hard copies of study documents, including signed consent forms, linkage forms, and logs will be stored in locked cabinets in the study office with only the study team having access to the data. For increased protection, the linkage form and signed consent forms will be stored separately from other study documents.
Enrollment and follow-up questionnaires are designed in REDCap and will be administered electronically using the REDCap mobile app. REDCap (Research Electronic Data Capture) is a secure, web-based application designed to support data capture for research studies, providing 1) an intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to common statistical packages; and 4) procedures for importing data from external sources [58]. Range checks for numerical values and prompts about skipped questions are built into the REDCap database. The data will be collected with the study interviewer/fieldworker – who is fluent in isiXhosa and English – during a face-to-face interaction with the participant. The study coordinator will review all participant data to ensure completion. The PI also will monitor the study safety data on an ongoing basis. The encrypted REDCap data servers will be housed at Vanderbilt University Medical Center. Participant questionnaire data and medical record data will be exported from REDCap, and mobility data from CareConekta will be imported from .csv files to SAS for data analysis.
The transmission and storage of sensitive participant information will follow best practices regarding smartphone app confidentiality. All information collected by CareConekta, including location, device ID and timestamp, will be encrypted and transmitted to secure study servers using the secure https protocol. Time-stamped GPS coordinates will be stored in a longitudinal history. Electronic mobility data will be stored on a back-end storage system at the South African Medical Research Council (MRC) that meets Health Normative Standards Framework guidelines, which call for restricted access, and the separation of patient demographics and health data. The user reference (unique ID or demographic information of the patient) is separated from the user’s cell number and phone ID, as well as separated from the location information for security and purposes.
Confidentiality {27}
Certainly the concept of tracing an individual’s personal location is one that must address substantial protections of human subjects. First, our formative research with potential users in focus group discussions specifically addressed issues of privacy regarding a mobility-tracing app and notifications. For both issues, we found high acceptability [59].
While we feel that our formative research clearly indicates initial acceptability of mobility tracing and notifications, we have designed this work with a strong commitment to offering the highest level of protection of our participants’ privacy and confidentiality. First, the location data of interest is at the macro-level, showing movement between towns, cities or regions, not at the micro-level, showing specific whereabouts. Thus, to protect participants’ privacy, the transmitted location information will be made “fuzzy” by transmitting a random location within 1 km of each participant’s exact location. Any participant’s exact location within that radius will be unknown. All information collected by the app, including location, device ID and timestamp, will be transmitted to secure study servers using the secure https protocol. The participant’s numerical study ID number will be used during installation; and no identifiable participant information will be recorded in the app.
There is always the possibility of a breach of confidentiality of study materials when conducting research. While this is acknowledged, there is very low likelihood because of the precautions that will be taken to protect confidentiality. Study staff will be trained on the expectations that they are not to disclose any information collected in the study to anyone outside the study team. All identifying information associated with the study participants will be maintained in locked storage cabinets and password-protected computers that themselves are kept in locked rooms or cabinets. All participants will be encouraged to contact the clinic staff, principal investigators, or other staff to report any undesirable conduct associated with the study. These reports will be brought to the attention of the PI.
Another risk to participants is that an HIV-positive status may be discerned through disclosure of participation in the study. However, we will do everything possible to minimize the risk of disclosure. No communication, whether on the phone or by text message, will identify the participant as HIV-positive. Importantly, among participants in the intervention arm who receive notifications of new facilities and phone calls and/or WhatsApp messages, the study staff will not use HIV-specific language. To avoid the possibility of inadvertent disclosure, ART facilities will only be referred to generically as “clinics” and any reference to ART will be to “tablets,” a common term for any medication that we demonstrated was acceptable in an earlier mHealth study in South Africa [46].
Risk to subjects will be minimized by: 1) training research staff in the ethical conduct of research; 2) strict protection of confidentiality by detailed standard operating procedures and on-site monitoring; 3) careful handling of sensitive data, procedures and processes in place to ensure data is securely stored and transferred; and 4) referral of participants to appropriate social and health services when necessary. The study site is well connected with the social worker and psychology services at the site as well as local non-governmental organizations providing counselling and support. While the potential risks to subjects are low, any social harm will be reported to the PI and a serious event will be reported to the Vanderbilt University and University of Cape Town IRBs within 48 hours of becoming aware of the event. Should any respondent experience discomfort or distress from participation in the study, we will provide the participant with the appropriate referral needed for follow-up and care.
Risk to subjects from participation in the study is minimal. All possible precautions will be taken to ensure complete confidentiality and protection of study participants. Given the minimal risk, the overall benefit of the study outweighs the risks.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
We will not collect blood or other biological specimens during this study. In routine care in this setting, viral load tests are to be repeated every three months in pregnancy and every six months during breastfeeding, so we expect that most women will have a routine viral load completed before six months postpartum. To avoid additional blood draws for the participant, at the follow-up visit, the study staff will check electronic health records to determine the most recent viral load test. If the participant has had no viral load test within three months prior to the six-month study follow-up visit, she will be referred for a blood draw for routine viral load testing at the clinic. Study staff will not conduct the blood draw and blood will not be stored.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
Primary outcome: Mobility within the study period
To assess the primary outcome of interest, we will report the number of participants who travel during the study period (defined as >50 km for >7 days), over the denominator of all participants. Among those who travel, we will report the median and interquartile range number of trips during the study period and will determine timing and frequency of travel as it relates to delivery date, which will be obtained from participant questionnaire and/or medical records. Median and interquartile range duration of travel will be reported in days, and we will also assess temporicity (frequency of trips * duration of trips). Reasons for travel will be obtained from the enrollment and follow-up questionnaire and will be grouped by theme, such as family, work, housing, and education.
For a more detailed assessment of mobility, we will use ArcMap to geographically place all locations in which participants were recorded during the study period. We will plot origin and destination locations on a map of South Africa, and neighboring countries (if necessary). We will connect origin and destination locations using ArcMap’s XY-to-line tool, and will use a spherical calculator to estimate the distance between origin and destination. The geographic data will be used in conjunction with the novel metrics of mobility developed by Dr. Camlin, which are reflective of the complex forms of mobility in sub-Saharan Africa. For example, we will apply geopolitical boundaries to location codes so that measures of internal migration and localized mobility within and across those boundaries can be estimated, such as inter- and intra-provincial mobility. We also will map mobility flow according to origin and destination pairs, classified by geopolitical categories. We will thereby demonstrate how geographic data can be used to characterize the mobility of populations – providing a vital alternative to survey measures – in order to measure the impacts of that mobility on care cascade outcomes, with broad applicability to the measurement of its impact on other health outcomes. We also will conduct a secondary analysis to validate whether self-reported anticipated travel matches data collected from the CareConekta app.
Secondary outcome 1: Impact of mobility on engagement in HIV care in the absence of the intervention
We will limit the analysis to the control arm only to explore the impact of mobility on engagement in HIV care in the absence of intervention. We will report baseline participant characteristics as collected on the enrollment questionnaire. We will report proportions and 95% confidence intervals for categorical variables and medians and interquartile ranges for continuous variables
To assess engagement in HIV care, we will report retention in care, which will be assessed at the six-month postpartum point and defined as no documented HIV-specific contact with any healthcare facility (including medication pick-ups) for >3 months. We also will report viral suppression six months after delivery, using thresholds of ≤50 and ≤1000 copies/ml. Additionally, we will report vertical HIV transmission and completion of the routine 10-week infant PCR test.
We will fit a series of models of mobility metrics on outcomes. For one, we will use a dichotomous exposure of mobility (any travel >50 km: yes/no), we will use Cox proportional hazard regression models to estimate the association of mobility on these outcomes, and will produce adjusted hazard ratios and 95% confidence intervals for retention in care and achieving viral suppression. We also will identify other predictors of engagement in HIV care. We will produce crude Kaplan-Meier curves to time to loss to follow-up and time to viral suppression by mobility group. Additionally, we will perform sensitivity analyses to explore how the estimated effect size changes when using varying cut-off points to define mobility.
Secondary outcome 2: Acceptability and feasibility of CareConekta
We will report proportions and 95% confidence intervals for categorical variables and medians and interquartile ranges for continuous variables. Open-ended questions will be reviewed for key themes. Themes will be abstracted and quantified.
Secondary outcome 3: Initial efficacy of the intervention
We will use Cox proportional hazard regression models to estimate the association of study arm assignment on these outcomes, and will produce adjusted hazard ratios and 95% confidence intervals for retention in care and achieving viral suppression by study arm. We also will identify other predictors of engagement in HIV care. We will produce crude Kaplan-Meier curves to time to loss to follow-up and time to viral suppression by study arm. In a secondary analysis, we will perform an as-treated analysis using self-reported data regarding actually reading the notifications and/or WhatsApp messages or staff phone calls to analyze the effect of receiving the intervention.
Interim analyses {21b}
No interim analyses are anticipated, and no stopping guidelines have been established, due to the low risk of participant harm during this study.
Methods for additional analyses (e.g. subgroup analyses) {20b}
Anticipated analyses are as described above.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
The primary study analysis will be an intention-to-treat analysis based on actual random allocations. Secondary per-protocol analyses will be presented if there has been protocol non-adherence.
The nature of missing data will be assessed and, where appropriate, sensitivity analyses will be conducted using multiple imputation.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
This study is registered on ClinicalTrials.gov (NCT03836625), so the protocol is publicly available. De-identified participant-level data and statistical code will be available by request of the study investigators.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
Due to the relatively small nature of the study team, additional coordinating centers and committees will not be convened.
Composition of the data monitoring committee, its role and reporting structure {21a}
As this is a pilot study, a data safety and monitoring committee is not required and will not be convened.
Adverse event reporting and harms {22}
We anticipate that the potential for adverse events (AEs) and serious adverse events (SAEs) related to study participation to be low. However, we will document, investigate, and follow-up with all potential study-related AEs, in accordance with IRB guidelines and sponsor policies. All reports will be made in writing to the study sponsor program officer.
Additionally, there is always the potential for social harms for participants of clinical trials, particularly when the clinical trial is limited to individuals with HIV. Any social harm will be reported to the PI and considered an adverse event and/or serious adverse event and reported according to the schedule above. Should any respondent experience discomfort or distress from participation in the study, we will provide the participant with the appropriate referral needed for follow-up and care.
Frequency and plans for auditing trial conduct {23}
Study data and procedures will be regularly reviewed by the study team. No formal study audits are planned.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
In the unlikely event that we must revise our consent form to reflect changes to the study protocol, study staff will recontact participants to bring them back to the clinic to be reconsented. Home visits will be used, if necessary. The public study record available on ClinicalTrials.gov also will be updated at the time of IRB approval of the new documents.
Dissemination plans {31a}
We anticipate numerous manuscripts resulting from this study. Manuscripts will be written by members of the study team, and we will also welcome predoctoral and postdoctoral trainees affiliated with our institutions to lead secondary manuscripts to facilitate capacity building. Study results will also be shared at national and international HIV meetings and with the municipal, provincial, and national departments of health in South Africa.