CTRI Number	CTRI/2020/05/025059 [Registered on: 06/05/2020] Trial Registered Prospectively
Last Modified On:	06/02/2021
Post Graduate Thesis	No
Type of Trial	Interventional
Type of Study	Diagnostic Preventive Screening
Study Design	Randomized, Parallel Group Trial
Public Title of Study Modification(s)	Tuberculosis (TB) Aftermath: a trial to find recurrent TB among people who have had TB previously
Scientific Title of Study Modification(s)	Tuberculosis (TB) Aftermath
Secondary IDs if Any Modification(s)	Secondary ID  Registry  NCT04333485  ClinicalTrials.gov
Details of Principal Investigator or overall Trial Coordinator (multi-center study)	Name  Dr Madhusudan Barthwal  Address  Department of Respiratory Medicine Dr. D.Y. Patil Medical College Hospital and Research Centre Pimpri Pune Pune MAHARASHTRA 411018 India  Phone  9209643151   Fax     Email  msbarthwal2019@gmail.com
Details Contact Person Scientific Query Modification(s)	Name  Dr Vidya Mave  Address  BJ medical College 1st Floor, Pathology Museum Jai Prakash Narayan Road Pune Maharashtra India Pune MAHARASHTRA 411001 India  Phone  912026052419   Fax     Email  vidyamave@gmail.com
Details Contact Person Public Query	Name  Dr Madhusudan Barthwal  Address  Department of Respiratory Medicine Dr. D.Y. Patil Medical College Hospital and Research Centre Pimpri Pune Pune MAHARASHTRA 411018 India  Phone  9209643151   Fax     Email  msbarthwal2019@gmail.com
Source of Monetary or Material Support	National Institutes of Health (NIH)
Primary Sponsor	Name  National Institutes Of Health NIH USA  Address  National Institutes of Health (NIH) 9000 Rockville Pike Bethesda Maryland 20892  Type of Sponsor  Government funding agency
Details of Secondary Sponsor	Name  Address  NIL  NIL
Countries of Recruitment	India
Sites of Study Modification(s)	No of Sites = 1   Contact Person  Name of Site  Site Address  Phone/Fax/Email  Dr Madhusudan Barthwal  Dr. D.Y.Patil Medical College, Hospital and Research Centre Pune (DYPMCHRC)  Department of Respiratory Medicine,Dr. D.Y.Patil Medical College, Sant Tukaram Nagar Pimpri Pune-411018 Pune   9209643151 msbarthwal2019@gmail.com
Details of Ethics Committee Modification(s)	No of Ethics Committees= 1   Name of Committee  Approval Status  Ethics Committee of Dr. D.Y. Patil Vidyapeeth, Pune  Approved
Regulatory Clearance Status from DCGI	Status  Not Applicable
Health Condition / Problems Studied	Health Type  Condition  Healthy Human Volunteers  Household contacts of TB cases  Patients  Tuberculosis of lung
Intervention / Comparator Agent	Type  Name  Details  Comparator Agent  Household Active case Finding (HHACF)  Existing health workers at the RNTCP TB Units will visit all patient homes at 6 and 12 months post-treatment completion. They will administer standardised WHO-recommended TB symptom screen questionnaire (amended to include cough of any duration) to treated TB cases and their HH contacts. All those with any TB symptom will have a spot sputum taken at the home.   Intervention  Telephonic Active case finding (TACF)  Standardised WHO-recommended TB symptom screen questionnaire will be administered to TB patients by existing health workers at the RNTCP via telephone calls at 6 and 12 months post-treatment completion. The TB patient (index case) will also be asked about any TB symptoms among household (HH) contacts. All HHs with suspected TB among the index TB case or a HH contact will be visited by RNTCP health workers to collect spot sputum specimens at their home.
Inclusion Criteria Modification(s)	Age From  18.00 Year(s) Age To  80.00 Year(s) Gender  Both  Details  1. Those who are registered at one of the study TB Units (TUs) in Pune district as treatment completed or cured (regardless of type of TB or duration of treatment). 2. Confirmed treatment completion or cure status by the referring medical officer of the study TU. 3. Date of treatment completion within 60 days of date of enrolment. 4. Ability and willingness of participant or legal guardian/representative to provide informed consent to participate in Arm 1 House Hold Active Case Finding (HHACF) or Arm 2 Active case finding through telephone(TACF) (NOTE: Illiterate participants or participants with cognitive disabilities may be enrolled based on local regulatory policies, with the appropriate provisions for informed consent.) 5. All household contacts of TB cases who are able and willing to provide informed consent to participate are eligible. HH contacts who are <18 years old are eligible for enrolment if a legal guardian/representative provides informed consent.
ExclusionCriteria	Details  1. Completed anti-TB treatment at a private sector clinic or TU outside of the study (final visit not registered at one of the study TB units) 2. Actively on anti-TB treatment
Method of Generating Random Sequence	Computer generated randomization
Method of Concealment	On-site computer system
Blinding/Masking	Open Label
Primary Outcome	Outcome  TimePoints  The primary outcome of the study will be number of TB cases diagnosed per enrolled index TB patient, by study arm, within 12 months following index TB patient’s treatment completion date. TB disease will be diagnosed as microbiologically confirmed (positive acid fast bacilli smear or positive Xpert® MTB/RIF assays or positive culture) or clinically diagnosed (initiated on TB treatment with no microbiological confirmation).   The enrolment of TB cases will be within 60 days from the treatment completion and follow up with them and their household will be at 6th month, 12th month and 18th month from the enrolment date.
Secondary Outcome	Outcome  TimePoints  The secondary outcome will be proportion of eligible Household (HH) contacts 6 years of age, by study arm, initiated on TB Preventative Therapy (TPT) after ruling out active TB disease.   Follow up at 6th, 12th and 18th month
Target Sample Size	Total Sample Size="3228" Sample Size from India="3228"
Phase of Trial	N/A
Date of First Enrollment (India) Modification(s)	03/08/2020
Date of First Enrollment (Global)	No Date Specified
Estimated Duration of Trial	Years="5" Months="0" Days="0"
Recruitment Status of Trial (Global) Modification(s)	Not Applicable
Recruitment Status of Trial (India)	Open to Recruitment
Publication Details Modification(s)	NIL
Brief Summary	India is home to 1/3rd of the world’s estimated three million annual undetected TB cases. The primary objective of our Tuberculosis (TB) Aftermath study is to develop, implement and measure feasible case finding strategies among recently treated TB patients in India, a population known to be at high risk for recurrent disease. In a recent analysis of the TB treatment cascade in Indian public-sector hospitals, of the 1.2 million patients who successfully complete treatment each year, approximately 10% experience TB recurrence within 1 year, giving them a TB incidence rate 50 times higher than the overall population. Thus, active case finding (ACF) approaches targeting recently treated TB cases may be an effective component of a combination strategy to reduce India’s TB burden and help detect many of the “missing millions.” The Indian National TB Control Program (RNTCP)’s new strategic plan for TB elimination strongly recommends developing and implementing a scalable surveillance system for recurrent TB. Our formative discussions with the RNTCP leadership revealed that a key knowledge gap is insufficient evidence on the yield and cost-effectiveness of ACF strategies among treated TB patients. These discussions also emphasized the RNTCP’s strong interest in household (HH) follow-up screening for these patients. The World Health Organization’s Systematic Screening for Active TB guidelines suggest that screening for recurrent TB in treated TB patients is a “conditional recommendation”; conditional only because there is a lack of evidence. TB Aftermath will compare effectiveness, cost-effectiveness and feasibility of two ACF strategies that are presently being considered by the RNTCP for detecting recurrent TB and provide evidence needed to implement and scale the preferred intervention. While treated TB patients and their HH contacts represent a high risk population for recurrent and incident TB, with over 1 million TB cases diagnosed annually in India, it may not be feasible to intensively follow all patients after TB treatment. Thus, lower-cost approaches such as telephone-based outreach could increase the reach of ACF, and targeted implementation may be needed to prioritize resources. Thus, we will determine if visiting every HH of treated TB patients or visiting just those identified as symptomatic through an initial telephonic screening call will identify a similar yield of recurrent TB. Our prior work in India has shown higher risk of recurrent disease among TB patients who smoke, consume alcohol, and those with untreated diabetes or respiratory impairment. The proposed study will address this gap, through the following specific aims: Aim 1: To conduct a non-inferiority randomized trial to measure the comparative effectiveness of two potentially implementable ACF interventions within the RNTCP, conducted by existing RNTCP “home visitors”: (i) Household ACF (HHACF) by symptom screen and sputum collection among treated TB patients and their HH contacts and (ii) ACF by periodic telephonic interviews (TACF) followed by HH screen for HHs reporting any symptomatic members among treated TB patients and their HH contacts. We will implement both interventions at 6 and 12 months following treatment completion by the index TB patient, and all HHs will have a final HH ACF visit 18 months post-treatment completion (“mop up”) for comparison between arms. For both strategies, we will calculate and compare the number of TB cases (recurrent and new HH cases) detected per index patient in each study Arm. Aim 2: To characterize implementation processes of the ACF interventions using the RE-AIM framework to inform their future scale-up and sustainability. We will use the RE-AIM framework to:                     (1) understand barriers and facilitators to implementation of the two interventions; (2) identify sub-populations that are best reached by the interventions and sub-populations who may benefit the most from the interventions; and (3) contribute knowledge to improve health services that span from the clinic to the community and home. We will enhance the RE-AIM approach, by exploring the acceptability of the strategies in depth across three key stakeholder groups (TB patients, HH members, and health care personnel) to optimize implementation. Aim 3: To model the impact and cost effectiveness of the ACF interventions evaluated in the trial, and of potential alternative strategies for the targeting and timing of those interventions: To better inform RNTCP decisions using locally-collected data, we will use data from the trial (on TB incidence and detection, targetable risk heterogeneity, and intervention costs) to model and compare potential strategies for ACF in terms of expected diagnostic yield, cost effectiveness, and impact on TB control in India. A Markov model of the burden of new and recurrent TB at the HH level over time after index case diagnosis will be used to model the lifetime impact of ACF interventions on HH TB morbidity, mortality, and time with infectious TB. We will estimate cost-effectiveness by calculating the incremental cost per Disability Adjusted Life Years (DALY) averted. Estimates of the contributions of recurrent TB and HH transmission to population-wide TB incidence will be used within a population-level transmission model to predict impact on India’s TB epidemic. TB Aftermath will answer key questions in a population that is often ignored by the TB community once treatment is complete, despite being at considerable risk for recurrent TB disease. We will provide evidence for an effective and scalable strategy targeting HHs of treated TB cases, a high priority of the RNTCP. Our high TB burden setting, strong multidisciplinary team, communication with the RNTCP and state TB program, and proven research infrastructure ensures successful implementation of TB Aftermath.