Hiv, Tuberculosis
Conditions
Brief summary
The purpose of this study is to characterize the role of human mobility in fueling TB epidemics and estimate the potential impact of innovative case finding interventions tailored to mobile populations
Detailed description
The investigators propose a randomized trial of two novel TB case-finding interventions among household members of patients diagnosed with active TB: holiday-based screening in a rural South African province (Limpopo) and off-peak (weekend/evening) screening in an urban settlement into which many residents of Limpopo migrate for work. The investigators will enroll index cases of TB plus their household contacts in each setting and randomize them to novel versus standard contact investigation. In Specific Aim 1, investigators will use whole genome sequencing of all cases, overlaying transmission trees with data on human movement, to evaluate associations between mobility and TB transmission in this population. In Specific Aim 2, investigators will employ a multidisciplinary approach to compare novel versus standard contact investigation in each setting along the following dimensions: (a) effectiveness (number of secondary TB cases diagnosed and starting treatment); (b) implementation (reach, fidelity, and maintenance of contact investigation outside of business hours); (c) cost-effectiveness (cost per disability-adjusted life year) and budget impact; and (d) projected population-level impact on TB incidence. Successful completion of these aims will have long-term impact by characterizing the role of mobility in fueling TB epidemics and testing two tailored approaches to improve TB control in highly mobile populations - an underserved group that is increasingly recognized as playing a major role in global TB transmission.
Interventions
BEHAVIORALHousehold contact tracing
Household contact tracing to test and diagnose Tuberculosis of household contacts of Tuberculosis patients.
Sponsors
Perinatal HIV Research Unit of the University of the Witswatersrand
Setshaba Research Centre
The National Institute for Communicable Diseases
Johns Hopkins Bloomberg School of Public Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
SINGLE (Investigator)
Masking description
The principal investigators are blinded as to the assignment of treatment to participants
Eligibility
Sex/Gender
ALL
Age
No minimum to 99 Years
Healthy volunteers
Yes
Inclusion criteria
TB index cases: Inclusion criteria: * Age 0-99 years (Including those recently deceased) * Diagnosed with pulmonary TB at a study hospital or clinic (microbiological and/or chest x-ray diagnosis)
Exclusion criteria
* Unwilling/unable to provide informed consent (including next of kin, for those recently deceased) * Plan not to pursue TB treatment within the study district * Unwilling/unable to comply with study procedures Contacts: Inclusion criteria: * Age 0-99 years * Currently resides with or visiting eligible TB index case
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effectiveness: Mean Number of Secondary TB Cases Identified and Started on Treatment Per Index Case in Each Arm | Up to 35 months | The mean number of secondary TB cases identified and started on treatment per index case for each arm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| TB Strain Relatedness Using Maximum Likelihood Transmission Trees. | Duration of study (30 months) | TB natural history, epidemiological, and whole genome sequencing (WGS)-derived phylogenetic data will be integrated into a statistical modeling framework to draw probabilistic conclusions about the likelihood of transmission between persons. Transmitters will be defined as individuals from whom at least one secondary case most likely originated. |
| Relative Acceptability of Each Novel Strategy Compared to Standard Contact Investigation | Duration of study (30 months) | Relative acceptability of each novel strategy, compared against routine contact investigation. Acceptability of the intervention will be measured among index cases and contacts using a short questionnaire given to a randomly selected participant at a randomly selected 15% of the households visited. The interview will cover acceptability of the visit timing, notification, visit activities (TB screening, HIV testing) and study team interaction among others. |
| Feasibility of Each Strategy: Proportion of Potentially Eligible Index Cases for Whom a Household Visit Was Conducted | Duration of study (30 months( | Feasibility of each strategy as the proportion of potentially eligible index cases for whom a household visit was conducted. All reasons why visits were unable to be conducted will be recorded (e.g. could not find household, no one ever home, visit not conducted during expected off-peak period). |
| The TB Prevalence Ratio, Comparing Highly Mobile to Less Mobile Index Patients | Duration of study (30 months) | The TB prevalence ratio, comparing highly mobile to less mobile individuals, measuring mobility on two scales (neighborhood/intra-urban and regional/intra-national). For the analysis: amount of time spent in transit, truncating long excursions at 50km (one hour). |
| Sustainability of Each Novel Strategy Relative to Standard Contact Tracing | Duration of study (30 months) | Sustainability of each novel strategy by reporting the primary outcome and fidelity measures according to six-month time period over the course of the study. |
| Incremental Cost-effectiveness Ratio for Each Novel Strategy Relative to Standard Contact Tracing | Duration of study (30 months) | Defined as (cost of contact tracing strategy 2 - cost of strategy 1)/(effectiveness of strategy 2 - effectiveness of strategy 1), where effectiveness is modeled as the number of disability-adjusted life years (DALYs) averted by the intervention. The primary cost-effectiveness measures will be the incremental cost per DALY averted using novel strategies (holiday and off-hours contact tracing) compared to routine contact tracing in each setting separately. |
| Relative Fidelity of Each Novel Strategy Compared to Standard Contact Investigation | Duration of study (30 months) | Relative fidelity of each novel strategy using a process checklist for each index case and household, including whether the household visit was offered and accepted, whether the visit was attempted, whether the visit was successful (i.e., enrolled at least one contact), whether symptom screening and sputum collection were completed and whether newly identified TB cases were notified and referred for treatment. |
Countries
South Africa
Participant flow
Recruitment details
Consecutive eligible index participants with TB were recruited from among 12 public hospitals in Limpopo and 33 primary health care clinics and 2 public hospitals in Soshanguve.
Pre-assignment details
The actual enrollment in the study contains the 4417 index TB cases, and within the index participants' households, 6162 contact persons, for a total of 10579 enrolled individuals. Only the 4417 index TB cases were randomized to arms.
Participants by arm
| Arm | Count |
|---|---|
| Standard Tracing- Limpopo This arm was located in the Limpopo site. Households of tuberculosis index patients receive standard household contact tracing during regular weekday business hours.
Household contact tracing: Household contact tracing to test and diagnose Tuberculosis of household contacts of Tuberculosis patients. | 4,368 |
| Holiday Tracing Households of tuberculosis index patients in rural South Africa receive household contact tracing during holidays (Christmas and Easter).
Household contact tracing: Household contact tracing to test and diagnose Tuberculosis of household contacts of Tuberculosis patients. | 1,952 |
| Evening / Weekend Tracing Households of tuberculosis index patients in urban South Africa receive household contact tracing during evenings and weekends.
Household contact tracing: Household contact tracing to test and diagnose Tuberculosis of household contacts of Tuberculosis patients. | 1,320 |
| Standard Tracing- Soshanguve This arm was located in the Soshanguve site. Households of tuberculosis index patients receive standard household contact tracing during regular weekday business hours.
Household contact tracing: Household contact tracing to test and diagnose Tuberculosis of household contacts of Tuberculosis patients. | 2,939 |
| Total | 10,579 |
Baseline characteristics
| Characteristic | Standard Tracing- Limpopo | Total | Standard Tracing- Soshanguve | Evening / Weekend Tracing | Holiday Tracing |
|---|---|---|---|---|---|
| Age, Continuous Contact person participants | 18 years | 27 years | 34 years | 33 years | 18 years |
| Age, Continuous Index TB participants | 41 years | 41 years | 41 years | 42 years | 42 years |
| Race (NIH/OMB) Contact person participants American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Contact person participants Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Contact person participants Black or African American | 3020 Participants | 6144 Participants | 1325 Participants | 514 Participants | 1285 Participants |
| Race (NIH/OMB) Contact person participants More than one race | 13 Participants | 18 Participants | 2 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Contact person participants Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Contact person participants Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Contact person participants White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Index TB Participants American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Index TB Participants Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Index TB Participants Black or African American | 1325 Participants | 4393 Participants | 1601 Participants | 801 Participants | 666 Participants |
| Race (NIH/OMB) Index TB Participants More than one race | 10 Participants | 24 Participants | 11 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) Index TB Participants Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Index TB Participants Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Index TB Participants White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment South Africa Contact person participants | 3033 Participants | 6162 Participants | 1327 Participants | 516 Participants | 1286 Participants |
| Region of Enrollment South Africa Index TB Participants | 1335 Participants | 4417 Participants | 1612 Participants | 804 Participants | 666 Participants |
| Sex: Female, Male Contact person participants Female | 1884 Participants | 3864 Participants | 849 Participants | 346 Participants | 785 Participants |
| Sex: Female, Male Contact person participants Male | 1149 Participants | 2298 Participants | 478 Participants | 170 Participants | 501 Participants |
| Sex: Female, Male Index TB participants Female | 584 Participants | 1766 Participants | 566 Participants | 330 Participants | 286 Participants |
| Sex: Female, Male Index TB participants Male | 751 Participants | 2651 Participants | 1046 Participants | 474 Participants | 380 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Effectiveness: Mean Number of Secondary TB Cases Identified and Started on Treatment Per Index Case in Each Arm
The mean number of secondary TB cases identified and started on treatment per index case for each arm.
Time frame: Up to 35 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Standard Tracing- Limpopo | Effectiveness: Mean Number of Secondary TB Cases Identified and Started on Treatment Per Index Case in Each Arm | 1.7 mean secondary TB cases |
| Holiday Tracing | Effectiveness: Mean Number of Secondary TB Cases Identified and Started on Treatment Per Index Case in Each Arm | 1.2 mean secondary TB cases |
| Evening / Weekend Tracing | Effectiveness: Mean Number of Secondary TB Cases Identified and Started on Treatment Per Index Case in Each Arm | 2.3 mean secondary TB cases |
| Standard Tracing- Soshanguve | Effectiveness: Mean Number of Secondary TB Cases Identified and Started on Treatment Per Index Case in Each Arm | 2.4 mean secondary TB cases |
Secondary
Feasibility of Each Strategy: Proportion of Potentially Eligible Index Cases for Whom a Household Visit Was Conducted
Feasibility of each strategy as the proportion of potentially eligible index cases for whom a household visit was conducted. All reasons why visits were unable to be conducted will be recorded (e.g. could not find household, no one ever home, visit not conducted during expected off-peak period).
Time frame: Duration of study (30 months(
Secondary
Incremental Cost-effectiveness Ratio for Each Novel Strategy Relative to Standard Contact Tracing
Defined as (cost of contact tracing strategy 2 - cost of strategy 1)/(effectiveness of strategy 2 - effectiveness of strategy 1), where effectiveness is modeled as the number of disability-adjusted life years (DALYs) averted by the intervention. The primary cost-effectiveness measures will be the incremental cost per DALY averted using novel strategies (holiday and off-hours contact tracing) compared to routine contact tracing in each setting separately.
Time frame: Duration of study (30 months)
Secondary
Relative Acceptability of Each Novel Strategy Compared to Standard Contact Investigation
Relative acceptability of each novel strategy, compared against routine contact investigation. Acceptability of the intervention will be measured among index cases and contacts using a short questionnaire given to a randomly selected participant at a randomly selected 15% of the households visited. The interview will cover acceptability of the visit timing, notification, visit activities (TB screening, HIV testing) and study team interaction among others.
Time frame: Duration of study (30 months)
Secondary
Relative Fidelity of Each Novel Strategy Compared to Standard Contact Investigation
Relative fidelity of each novel strategy using a process checklist for each index case and household, including whether the household visit was offered and accepted, whether the visit was attempted, whether the visit was successful (i.e., enrolled at least one contact), whether symptom screening and sputum collection were completed and whether newly identified TB cases were notified and referred for treatment.
Time frame: Duration of study (30 months)
Secondary
Sustainability of Each Novel Strategy Relative to Standard Contact Tracing
Sustainability of each novel strategy by reporting the primary outcome and fidelity measures according to six-month time period over the course of the study.
Time frame: Duration of study (30 months)
Secondary
TB Strain Relatedness Using Maximum Likelihood Transmission Trees.
TB natural history, epidemiological, and whole genome sequencing (WGS)-derived phylogenetic data will be integrated into a statistical modeling framework to draw probabilistic conclusions about the likelihood of transmission between persons. Transmitters will be defined as individuals from whom at least one secondary case most likely originated.
Time frame: Duration of study (30 months)
Secondary
The TB Prevalence Ratio, Comparing Highly Mobile to Less Mobile Index Patients
The TB prevalence ratio, comparing highly mobile to less mobile individuals, measuring mobility on two scales (neighborhood/intra-urban and regional/intra-national). For the analysis: amount of time spent in transit, truncating long excursions at 50km (one hour).
Time frame: Duration of study (30 months)