Comparative Effectiveness/Implementation of TB Case Finding in Rural South Africa (Kharitode TB)

The purpose of this study is to compare three strategies for finding TB cases in a rural Sub-Saharan African setting: 1) Screening all attendees of primary care clinics for TB; 2) Conducting household contact investigations of newly diagnosed TB cases; 3) Providing incentives to newly diagnosed TB cases and their contacts to promote contact screening for TB. For each intervention, investigators will measure comparative effectiveness in terms of cases identified as well as the cost-effectiveness and feasibility of implementation.

Study Overview

• Status: Completed
• Conditions: Tuberculosis
• Intervention / Treatment: Other: Active TB case finding

• Study Type: Interventional
• Enrollment (Actual): 4852
• Phase: Not Applicable

Contacts and Locations

Study Locations

• South Africa
  • Limpopo
    • Louis Trichardt, Limpopo, South Africa
      • Vhembe health subdistrict
    • Mokopane, Limpopo, South Africa
      • Waterberg health subdistrict

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 99 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Facility-based screening arm

• Age 0-99 years
• Informed consent provided (or assent plus parent/guardian consent)
• Attending any of the study 28 study clinics in the facility-based screening arm

Contact tracing arm- Index Case

• Age 0-99 years
• Informed consent provided (or assent plus parent/guardian consent)
• Newly diagnosed (last 2 months) with TB at any of the 28 study clinics in the contact tracing arm

Contact tracing arm- Household Contact

• Age 0-99 years
• Informed consent provided (or assent plus parent/guardian consent)
• Living in the same household as an enrolled Index case (see above)

Contact tracing arm- Non-household Close Contact

• Age 0-99 years
• Informed consent provided (or assent plus parent/guardian consent)
• Referred to the study as a close contact of an enrolled Index case (see above)

Exclusion Criteria (all arms):

• Unable to provide informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Facility-based screening; This strategy will be implemented at all clinics (n=28) within this arm for 18 months. Study staff will encourage providers at each of the clinics to screen all consenting patients attending the clinic, regardless of the original reason for clinic presentation. Upon presenting for care (e.g., while waiting for their healthcare provider), patients will be informed about the study and screened for cough of any duration, fever, weight loss, or night sweats. Participants who are symptomatic and provide a sputum specimen (according to the clinic standard of care) will be given a study flyer informing them that they may be contacted by study staff, and a brief summary of the study. Per standard of care, all sputum samples will be sent to the local National Health Laboratory Service laboratory for Xpert testing.	Other: Active TB case finding; Active TB case finding (ACF) refers to any number of strategies used to identify individuals with active TB disease, outside of passive case finding. In passive case finding, individuals with symptoms present at health centers for diagnosis. In active case finding, the health system makes an effort to identify TB cases before they present passively.
Experimental: Contact screening; This arm is comprised of two sub-arms: In the household contact screening sub-arm, a mobile field team visits the household of each consenting newly diagnosed pulmonary TB index case. Each visit consists of a household census, consent of all eligible household members for TB screening, administration of a brief questionnaire, sputum collection for testing with Xpert Mycobacterium tuberculosis (MTB)/rifampin (RIF) and the offer of HIV testing. In the incentive-based contact screening sub-arm, all consenting newly diagnosed active TB cases are provided with 10 coupons for free TB screening to give to close contacts. When a contact presents at clinic with a coupon, they and the index case each receive a small amount of money. If the contact is diagnosed with active TB and starts treatment, the index case receives an additional larger amount of money. Each contact receives a brief questionnaire, TB symptom screen, optional HIV testing, and sputum sample collection for Xpert MTB/RIF.	Other: Active TB case finding; Active TB case finding (ACF) refers to any number of strategies used to identify individuals with active TB disease, outside of passive case finding. In passive case finding, individuals with symptoms present at health centers for diagnosis. In active case finding, the health system makes an effort to identify TB cases before they present passively.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment Initiation Ratio in Facility Versus Contact Investigation Clinics	The primary analysis was based on the facility- level rate ratio, and we first calculated an unadjusted ratio of the treatment initiation rates between the two arms and the corresponding 95% confidence interval (CI). We then adjusted for any residual confounding by district stratification and the historical annual number of people started on TB following a two-stage approach. The first step of this approach fits a Poisson regression to the facility-level counts and the district and historical volume covariates irrespective of study arm. The residuals ratios, calculated as the ratio of the observed over the expected counts, are then used in the second stage to estimate the between-arm rate ratio and the corresponding 95% CI.	18 months
Comparative Treatment Initiation Ratio in the Incentive-based Versus Household-based Contact Investigation Arms	The primary outcome of the study was the comparative number of people with incident TB diagnosed and started on treatment at study clinics in the two contact tracing arms, excluding the six-month washout period.	36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparative Costs and Cost-effectiveness of Active TB Case Finding Strategies	The primary outcome for this analysis will be the incremental cost-effectiveness ratio, defined as (cost of ACF strategy 2 - cost of ACF strategy 1 [or no ACF])/(effectiveness of ACF strategy 2 - effectiveness of ACF strategy 1 [or no ACF]), where effectiveness is modeled as the number of disability-adjusted life years (DALYs) averted by the intervention.	3.5 years
Comparative Number of Secondary TB Cases Identified in Incentive-based Versus Household-based Contact Tracing	The pre-specified secondary study outcome was the number of Xpert-based TB diagnoses made among enrolled contacts ("secondary cases") by arm.	36 months

Collaborators and Investigators

• Sponsor: Johns Hopkins Bloomberg School of Public Health
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); Perinatal HIV Research Unit of the University of the Witswatersrand
• Investigators: Principal Investigator: David Dowdy, MD, PhD, Johns Hopkins Bloomberg School of Public Health

Publications and helpful links

General Publications

• Baik Y, Hanrahan CF, Mmolawa L, Nonyane BAS, Albaugh NW, Lebina L, Siwelana T, Martinson N, Dowdy DW. Conditional Cash Transfers to Incentivize Tuberculosis Screening: Description of a Novel Strategy for Contact Investigation in Rural South Africa. Clin Infect Dis. 2022 Mar 23;74(6):957-964. doi: 10.1093/cid/ciab601.
• Hanrahan CF, Nonyane BAS, Mmolawa L, West NS, Siwelana T, Lebina L, Martinson N, Dowdy DW. Contact tracing versus facility-based screening for active TB case finding in rural South Africa: A pragmatic cluster-randomized trial (Kharitode TB). PLoS Med. 2019 Apr 30;16(4):e1002796. doi: 10.1371/journal.pmed.1002796. eCollection 2019 Apr.
• Kerrigan D, West N, Tudor C, Hanrahan CF, Lebina L, Msandiwa R, Mmolawa L, Martinson N, Dowdy D. Improving active case finding for tuberculosis in South Africa: informing innovative implementation approaches in the context of the Kharitode trial through formative research. Health Res Policy Syst. 2017 May 30;15(1):42. doi: 10.1186/s12961-017-0206-8.

Study record dates

Study Major Dates

• Study Start (Actual): July 18, 2016
• Primary Completion (Actual): January 17, 2018
• Study Completion (Actual): January 30, 2020

Study Registration Dates

• First Submitted: June 1, 2016
• First Submitted That Met QC Criteria: June 16, 2016
• First Posted (Estimated): June 21, 2016

Study Record Updates

• Last Update Posted (Actual): June 22, 2023
• Last Update Submitted That Met QC Criteria: May 25, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis
• Other Study ID Numbers: 15-0005; R01AI116787-02 (U.S. NIH Grant/Contract)