Open access Protocol

The RATIONS (Reducing Activation of

Tuberculosis by Improvement of

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Nutritional Status) study: a cluster
randomised trial of nutritional support
(food rations) to reduce TB incidence in

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household contacts of patients with
microbiologically confirmed pulmonary
tuberculosis in communities with a high
prevalence of undernutrition,
To cite: Bhargava A,
Bhargava M, Velayutham B,
Jharkhand, India
et al. The RATIONS (Reducing
Activation of Tuberculosis by
Improvement of Nutritional Anurag Bhargava ‍ ‍,1,2 Madhavi Bhargava ‍ ‍,2,3 Banurekha Velayutham,4
Status) study: a cluster Kannan Thiruvengadam,4 Basilea Watson,4 Bharati Kulkarni ‍ ‍,5
randomised trial of nutritional
support (food rations) to reduce Manjula Singh ‍ ‍,6 Rakesh Dayal,7 Rajeev Ranjan Pathak,8 Anindya Mitra,9
TB incidence in household Kiran Rade,10 KS Sachdeva11
contacts of patients with
microbiologically confirmed
pulmonary tuberculosis in
communities with a high
ABSTRACT
prevalence of undernutrition, Strengths and limitations of the study
Jharkhand, India. BMJ Open Introduction India has the largest burden of cases and
2021;11:e047210. doi:10.1136/ deaths related to tuberculosis (TB). Undernutrition is the
►► The Reducing Activation of Tuberculosis by
bmjopen-2020-047210 leading risk factor accounting for TB incidence, while Improvement of Nutritional Status study is the first
severe undernutrition is a common risk factor for mortality trial addressing undernutrition to reduce tuberculo-
►► Prepublication history and
additional supplemental material in patients with TB in India. The impact of nutritional sis (TB) incidence in communities with high preva-
for this paper are available supplementation on TB incidence is unknown, while few lence of poverty, undernutrition and low prevalence
online. To view these files, underpowered studies have assessed its impact on TB of HIV infection.
please visit the journal online mortality. We designed an open-­label, field-­based cluster ►► It is the largest trial to evaluate the impact of nu-
(http://​dx.​doi.​org/​10.​1136/​ randomised trial to assess the impact of nutritional tritional support on TB mortality in a programme-­
bmjopen-​2020-​047210). supplementation (with food rations) on TB incidence in based cohort of patients with pulmonary TB and a
a group at higher risk of TB infection and disease, viz high prevalence of undernutrition.
MB and BV contributed equally.
household contacts (HHC) of patients with microbiologically ►► The follow-­up period of 2 years will ensure detection
Received 23 November 2020 confirmed pulmonary TB (PTB) in Jharkhand, a state with a of most cases of incident TB in household contacts
Revised 23 April 2021 high prevalence of undernutrition. and recurrence of TB in index cases.
Accepted 05 May 2021 Methods and analysis We shall enrol 2800 adult ►► The quantum of food rations per participant is stan-
patients with PTB of the national TB programme, across dardised, and in the absence of individual needs
28 treatment units in 4 districts, and their approximately assessment, the extent to which the intervention
© Author(s) (or their 11 200 eligible contacts. The sample size has 80% meets individual needs is unknown.
employer(s)) 2021. Re-­use power to detect the primary outcome of 50% reduction ►► Food sharing in the families in the control arm and
permitted under CC BY-­NC. No in incidence of active TB in HHC over 2 years of follow-­ extra food consumption from other sources cannot
commercial re-­use. See rights up. Patients and HHC in both the arms will undergo be ruled out.
and permissions. Published by nutritional assessment and counselling. Patients will
BMJ.
receive monthly food rations (supplying 1200 kcal and 52
For numbered affiliations see g proteins/day) and multivitamins along with antitubercular
end of article. effects on nutritional status, non-­TB infections. Secondary
treatment. The HHC in the intervention arm will receive
Correspondence to food rations (supplying 750 kcal and 23 g proteins/day) outcomes in patients are effects on TB mortality,
Dr Anurag Bhargava; and multivitamins while HHC in control arm will be on adherence, adverse effects, nutritional and performance
​anuragb17@​gmail.​com usual diet. The secondary outcomes in HHC will include status. Substudies will examine micronutrient status and

Bhargava A, et al. BMJ Open 2021;11:e047210. doi:10.1136/bmjopen-2020-047210 1

 Open access

effects on dietary intake, body composition, muscle strength and immune and deficiencies of micronutrients. Undernutrition in
function. children is commonly defined by the well-­accepted WHO
Ethics and dissemination The institutional ethics committee of ICMR-­ indicators of low birth weight in newborns, underweight

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NIRT, Chennai, approved the study (289/NIRT-­IEC/2018). The results will (low weight for age), stunting (low height for age) and
be disseminated in publications and presentations. wasting (low weight for height) in preschool children
Trial registration number Clinical Trial Registry of India:
and by age and gender-­specific cut-­offs for body mass
CTRI/2019/08/020490.
index (BMI) in those aged 6–18 years. In adults, under-
nutrition is based on a low BMI, which reflects low body
INTRODUCTION energy stores or chronic energy deficiency. The BMI cut-­
Tuberculosis (TB) is a global public health problem off for underweight proposed by WHO of <18.5 kg/m2

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leading to significant morbidity and mortality, espe- for populations10 has also been accepted as a criterion
cially in low and middle income countries. An estimated for clinical diagnosis of malnutrition/undernutrition in
10 million people developed TB and 1.2 million (HIV-­ a recent consensus statement.11 In addition, there have
negative) people succumbed to it in 2019.1 India was been proposals for diagnosis of undernutrition based on
the major contributor to the global TB burden with an altered body composition, and for higher BMI cut-­offs in
estimated 2.6 million new cases (27% of global) and 0. patients undergoing significant involuntary weight loss,
4 million (35% of global) TB deaths in HIV-­ negative which require further validation.11 12
people in 2019.1 Undernutrition is the leading cause of impaired immu-
The United Nations Sustainable Development Goals-3 nity globally,13 with a consistent inverse exponential rela-
(SDG-3) has a target for ending the TB epidemic by tionship between nutritional status measured by BMI
2030 and aims to reduce TB incidence and TB deaths and TB incidence.14 According to the global TB report
by 80% and 90% of the 2015 levels, respectively.2 As per 2020, undernutrition is a leading risk factor accounting
the National Strategic Plan (2017–2025), the Revised for 2.2 million cases (19%), more than HIV and diabetes
National Tuberculosis Control Programme (renamed as (accounting for 0.76 and 0.35 million cases, respectively).1
National Tuberculosis Elimination Programme, NTEP) Undernutrition is also a consistent risk factor for TB
in India has set an ambitious target of achieving the mortality, regardless of HIV infection, and drug suscep-
2030 SDG milestone by 2025, 5 years ahead of the global tibility.15 Its prevalence was as high as 23% in women
target.3 and 19% in men (BMI: <18.5 kg/m2) in the most recent
The end TB strategy will require a mix of biomedical, National Family Health Survey (NFHS-4) in India.16 It is
public health and social interventions to achieve these higher in the poor, rural residents and those belonging
goals.2 The strategy requires acceleration of the current to the scheduled castes and tribes, who also suffer a high
decline of 1.5% to 10%–17% per year.4 The present burden of TB disease.16 17 The WHO has estimated that
biomedical approach to TB prevention based on vacci- 0.6 million cases of TB in India are attributable to under-
nation and TB preventive treatment (TPT) has its limita- nutrition,1 while other studies indicate that this estimate
tions. The efficacy of BCG vaccine is limited to prevention may be higher.18 A majority of Indian patients with active
of severe forms of childhood TB.5 The TPT with isoni- TB have severe levels of undernutrition (macronutrient
azid in countries like India currently covers only select and micronutrient), which are associated with twofold–
groups of contacts like children under 6 years of age and fourfold higher risk of mortality.19
people living with HIV.6 WHO recently made a condi- A single unit increase in BMI could reduce TB inci-
tional recommendation of offering TPT to all household dence by 14%,14 and a modelling study has shown that
contacts (HHC).7 However, there are considerable logis- TB incidence and mortality could decline by 40%–71%
tical and technical challenges in countries with a high with nutritional interventions.20 There is no randomised
burden of latent TB infection (LTBI).8 controlled trial on the effect of nutritional supplemen-
tation on TB incidence. The studies on the impact of
Rationale for the trial nutritional supplementation on TB mortality have been
The end TB strategy recognises the need for new tools, limited, small and underpowered.21
interventions and strategies to address the problem of TB The Reducing Activation of Tuberculosis by Improve-
incidence and adverse outcomes.2 Globally, an estimated ment of Nutritional Status (RATIONS) study is a cluster
1.7 billion people or 23% of the population have LTBI, randomised trial to assess the impact of nutritional supple-
which remains latent in 90% in the presence of innate mentation on TB incidence among HHC of patients
and cell-­mediated immunity.9 Risk factors like HIV, under- with microbiologically confirmed pulmonary TB (PTB),
nutrition, uncontrolled diabetes, smoking and alcohol living in a community with a high prevalence of under-
impair immunity, lead to active TB, and act as drivers of nutrition. They are a group at higher risk of TB infec-
the TB epidemic. Undernutrition results from deficient tion and disease,22 with a prevalence of 10-­fold–60-­fold
intake or assimilation of energy and nutrients, often in higher than in the general population.23 TB incidence
association with disease-­associated inflammation, and is was 4.8% in the HHC and 21.4% in child contacts in a
a part of the broader spectrum of malnutrition, which previous study from Peru.24 Food insecurity and under-
includes both undernutrition, overweight and obesity nutrition are strong and modifiable risk factors of TB in

2 Bhargava A, et al. BMJ Open 2021;11:e047210. doi:10.1136/bmjopen-2020-047210

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Table 1 Objectives of the RATIONS trial and the outcome variables

Objective Outcome variables Index case HHC

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Primary Objective
Effect of household nutritional supplementation in Difference in number of incident cases of active   ✓
reducing TB incidence among HHC of patients with TB (all forms) in the two arms detected by active
microbiologically confirmed PTB case finding over a follow-­up period of 2 years
after diagnosis of index case
Secondary objectives
Effect of nutritional supplementation on Anthropometric indicators such as weight and ✓ ✓

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anthropometric indicators over 6 months BMI
Non-­TB infectious morbidity and mortality in HHC in Malaria, diarrhoea, lower respiratory tract   ✓
both the arms infection, hospitalisation with fever of any cause
or death with fever of any cause <15 days in
duration
Adherence to anti-­TB therapy Proportion completing the therapy successfully ✓  
Mortality during treatment Proportion of index cases who died during ✓  
treatment
Adverse effects Severe adverse effects with TB drugs ✓  
Recurrence of TB within 2 years after cure Relapse rate of microbiologically confirmed TB ✓  
Performance status Change in ECOG scale at 1 month, 2 months and ✓  
6 months compared with baseline
Dietary substudy
Evaluate the difference in dietary intake of calories Calorie and protein intake at baseline, and end of ✓ ✓
and proteins treatment in intervention and control arms
Micronutrient substudy
Assess vitamins A and D (25-­hydroxyvitamin D) Level of vitamins A and D at baseline ✓ ✓
levels
Body composition substudy
Evaluation of body composition Estimate fat-­free mass, fat mass and other ✓ ✓
bioimpedance analysis parameters at baseline,
and 6 months after treatment
Substudy on grip strength
Evaluate muscle strength using hand grip Grip strength at baseline and 6 months ✓  
dynamometer
Substudy of immune function
Evaluate cellular immunity in patients and HHC Lymphocyte subsets (CD4, CD8, natural killer ✓ ✓
cells and B lymphocytes), fourth generation IGRA
at baseline and end of treatment

BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; HHC, household contacts; IGRA, Interferon Gamma Release Assay; PTB,
pulmonary tuberculosis; RATIONS, Reducing Activation of Tuberculosis by Improvement of Nutritional Status.

the HHC.25 26 The trial is being conducted in Jharkhand Primary objective

(meaning ‘Land of Forests’) a state in eastern India which The primary objective is to evaluate the effect of house-
has a high prevalence of undernutrition in children and hold nutritional supplementation in reducing TB inci-
adults. According to the National Family Health Survey-4 dence among HHC of patients with microbiologically
(2015–6), the state has the highest levels of underweight confirmed PTB.
(47.8%), wasting (29.0%), and the second highest level
of stunting(45.3%) in children under 6 years of age in Secondary objectives in HHC
India.16 27 Similarly, more than two of out of every five The secondary objective is to evaluate the effect of nutri-
(41%) of adult rural women in Jharkhand had a BMI of tional supplementation on anthropometric indicators,
<18.5 kg/m2, and had the highest prevalence of anaemia and non-­TB infectious morbidity and mortality.
in adult women in India,(65.9%), which is largely related
to nutritional deficiencies of iron and folic acid.16 27 Secondary outcomes in index cases
To evaluate the effect of nutritional supplementation on
Objectives adherence to treatment, mortality, frequency of adverse
The objectives and the outcome variables have been tabu- effects due to treatment, performance status of patients
lated in table 1. as measured by the Eastern Cooperative Oncology Group

Bhargava A, et al. BMJ Open 2021;11:e047210. doi:10.1136/bmjopen-2020-047210 3

Open access

(ECOG),28 and relapse of microbiologically confirmed Consortium of the Indian Council of Medical Research
TB on follow-­up. (ICMR) and implemented by the Yenepoya (deemed to
be University), in association with the National Institute

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Substudies: six substudies have been planned in a subset of index for Research in Tuberculosis (ICMR-­NIRT) and National
cases and HHC Institute of Nutrition. The enrolment began on the 16
a. Dietary intakes: to evaluate the difference in dietary August 2019.
intake of calories, proteins at baseline, and at the end Study setting: under the NTEP, each district has one
of treatment in a subsample of the patients in both the district TB centre and there are subdistrict administra-
arms. tive units called TUs. The population is predominantly
b. Micronutrients: vitamin A (serum retinol) and rural (75%) and indigenous communities classified as

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25-­hydroxyvitamin D levels in a subsample of index pa- ‘scheduled tribes’ who comprise 28% of the population
tient and HHC at baseline. (national-8%) and are historically disadvantaged groups
c. Body composition: to evaluate the difference in body with regard to social, economic and health indicators.
composition between patients in the two arms at base- According to NFHS-4, the prevalence of undernutri-
line and 6 months by a multifrequency bioelectric im- tion in Jharkhand was 23.8% and 31.6% in adult men
pedance analyzer (Bodystat Quadscan 4000). and women, respectively, significantly higher than the
d. Muscle function (grip strength) in a subsample of in- national average.16 A total of 44 000 TB cases were noti-
dex cases at baseline, and end of treatment using a dig- fied in the year 2017 when this trial was proposed.29
ital handheld dynamometer.
e. Immune function: to evaluate select aspects of immu- Eligibility criteria
nity in index patient and their HHC before and after The inclusion and exclusion criteria are mentioned in
treatment using the lymphocyte subsets (CD4, CD8, table 2.
natural killer cells and B lymphocytes) and kinetics Inclusion criteria: adult patients (≥18 years) with
of interferon γ responses (by CD4 and CD8 cells) in microbiologically confirmed PTB (irrespective of drug
a fourth generation Interferon Gamma Release Assay sensitivity) will constitute the index cases and will be
(QuantiFERON-­TB Gold Plus: QFT-­Plus). eligible to enrol in the study. The HHC will be persons
f. Qualitative study in a subset of stakeholders: a quali- who have lived in the same house (and eating from the
tative study will also be conducted in a subset of the same kitchen), for one or more nights or for frequent
stakeholders (patients, contacts and field staff) at the or extended periods during the day with the index case
end of the intervention period to assess the percep- during the preceding 3 months.
tions and experiences of nutrition intervention. Exclusion criteria: an index case with no eligible HHC
and any HHC currently on treatment for TB will be
METHODS AND ANALYSIS excluded.
Study design and oversight
This is a cluster randomised open-­ label parallel-­
arm, Study interventions
superiority trial of nutritional supplementation in house- Nature and quantity
holds with microbiologically confirmed patients with PTB The study intervention includes macronutrients and
in the state of Jharkhand, Eastern India. The study will micronutrient supplementation along with nutritional
randomise 28 TB units (TUs) in four districts (Ranchi, East-­ counselling as per national guidelines.30 The index
Singhbhum, West-­Singhbhum and Seraikela-­Kharsawan) patients (in both arms) and the HHC (in the intervention
into control and intervention arms, each with 1400 adult arm) will receive a food basket and a recommended daily
PTB patients. It is supported by the India TB Research allowance of vitamins and micronutrients every month, as

Table 2 Eligibility criteria for RATIONS trial participants

Index cases HHC
Inclusion criteria
 Patients ≥18 years of age with Persons living in the same house, eating from same kitchen as index case for
microbiologically confirmed PTB ≥one night or for frequent or extended periods during the day during the 3 months
before diagnosis in index case
Exclusion criteria
 Non eligible HHC Current smear or GeneXpert or LPA or culture confirmed TB
 Time interval between initiation of Clinically diagnosed PTB or extra-­PTB and currently on treatment
treatment and enrolment is >14 days
HHC, household contacts; LPA, line probe assay; PTB, pulmonary tuberculosis; RATIONS, Reducing Activation of Tuberculosis by
Improvement of Nutritional Status.

4 Bhargava A, et al. BMJ Open 2021;11:e047210. doi:10.1136/bmjopen-2020-047210

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Table 3 Nutritional supplementation in the RATIONS trial

Intervention arm Control arm

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Index case*, quantity Nutritional counselling Nutritional counselling
per person per month 5 kg of rice 5 kg of rice
3 kg roasted Bengal gram powder (locally 3 kg roasted Bengal gram powder (locally called as sattu)
called as sattu) 1.5 kg of milk powder
1.5 kg of milk powder 500 mL vegetable oil
500 mL vegetable oil One RDA of micronutrient
One RDA of micronutrient

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Household contact†, Nutritional counselling Nutritional counselling
quantity per person 5 kg rice Usual food assistance available to eligible households
per month 1.5 kg pulses (split pigeon peas) through public distribution system
One RDA of micronutrient per adult/
adolescent HHC
Half of this amount for children less than
10 years
*Approximately 1200 kcal of energy and 52 g proteins/day.
†Approximately 750 kcal of energy and 23 g of proteins/day.
HHC, household contacts; RATIONS, Reducing Activation of Tuberculosis by Improvement of Nutritional Status; RDA, recommended dietary
allowance.

described in table 3. This will be either delivered by the by the NTEP staff to take chemoprophylaxis with isoni-
study staff or may be picked up from a depot as per the azid after an evaluation will continue to do so.
participant preference.
Risk assessment and referral
Frequency and duration The patients will be evaluated for nutritional status,
The food basket will be provided for 6 months for new oxygen saturation, blood pressure and presence of
patients and 12 months for patients with multidrug resis- complications at baseline and at follow-­up. Patients with
tant TB (MDR-­TB) (and their HHC in intervention arm). severe undernutrition with oedema, extremely severe
Extension of the intervention period to 12 months, for undernutrition (BMI: <14 kg/m2), breathlessness or low
a patient with non-­MDR-­TB will be considered if there oxygen saturation (SpO2: <94) will be referred for inpa-
is evidence of undernutrition (BMI: <18.5 kg/m2) in the tient care as per national guidelines.30
index case even at the end of 6 months. Extension of
rations to an HHC will be considered if an adult contact
Randomisation and intervention allocation
has a BMI of <16 kg/m2; children (<10 years) have weight-­
This is an open label trial; the participants and field staff
for-­age z-­score <−2SD and adolescents (10–18 years) have
are not blinded after assignment. All the TUs from the
BMI-­for-­age z-­scores <−2SD.
selected districts were line-­listed (list of TUs is available
Nutritional counselling and assessing adherence in online supplemental file 1) and randomised equally to
The patients and the HHC will be counselled about the both the arms by computer-­generated random numbers
importance of a balanced diet for the nutritional recovery using restricted randomisation by the statistician at ICMR-­
of the patient and the protection of the health status NIRT, Chennai. The cluster allocation was kept confiden-
of the family. The families will be instructed about the tial until the end of training of the field staff and the TUs
optimal utilisation of the food rations in locally accept- were ready for implementation.
able food recipes.The field staff will undertake follow-­up
visits to monitor weight gain (a proxy indicator for adher- Enrolment of index cases and HHC
ence) and check the empty packets of the milk powder as Figure 1 describes the study flow. Consecutive patients
an indicator of consumption by the patient. diagnosed with microbiologically confirmed PTB in
selected TUs will be enrolled after due consent process,
Co-interventions permitted during the trial during a 6–12-­month period. Information about the study
The patients as well as the HHC will continue to access will be given to the HHC during a home visit by the trial
public distribution system, supplementary feeding staff and enrolled after elicitation of voluntary written
programmes (Integrated Child Development Services informed consent. The need for adherence to treatment
Scheme, mid-­ day meals) as usual and additional INR and food rations, cooperation with study procedures, the
500/month as direct benefit transfer availed by patients stability of residence and the willingness to permit home
with TB in India. The eligible children under 6 years of visits will be discussed with the index cases and HHC
age and those with HIV infection who have been advised during enrolment.

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Open access

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Figure 1 Study flow for the Reducing Activation of Tuberculosis by Improvement of Nutritional Status trial. TU, tuberculosis
unit.

Baseline evaluation of index cases and HHC is unable to stand. Presence of oedema, blood pressure
The study procedures at baseline and follow-­ up are using a digital instrument (OMRON) and oxygen satu-
denoted in table 4. Demographic characteristics, including ration using pulse oximeter will be noted. Assessment
gender, occupation, caste, marital status, education, socio- of performance status will be done using ECOG Scale as
economic assessment with an asset score and education, described in table 5.28
will be noted. The presence of self-­reported risk factors
such as diabetes, alcohol consumption and tobacco use, Clinical examination in contacts
and family/history of TB will also be recorded. This will consist of anthropometric measurements like
weight, height, MUAC (if unable to stand and in children
Clinical examination of index cases under 5 years of age), the presence of oedema and BCG
Weight will be measured with a digital weighing scale scar.
(SECA 803) with accuracy of 100 g, and height using a
portable stadiometer (SECA 213) with accuracy of 0.1 cm Laboratory evaluation of index cases
using standard procedures. Mean of two measurements of The results of the sputum smear microscopy, cartridge-­
weight will be taken for calculation of BMI. Undernutri- based nucleic acid amplification test (CB-­NAAT), Gene
tion is defined as a BMI of <18.5 kg/m2 according to the Xpert MTB/RIF test, blood glucose and HIV tests (if
underweight definition approved by the WHO.10 Patients available) will be retrieved from the NTEP records.
will further be categorised into mild underweight in case Haemoglobin will be measured during the home visit
the BMI is 17.0–18.49 kg/m2, moderate underweight if using HemoCue Hb 201+ using standard procedures and
the BMI is 16.0–16.99 kg/m2 and severely underweight if precautions. Chest X-­ray (CXR) of patients at baseline
the BMI is <16 kg/m2 as suggested by WHO.31 An addi- will be done wherever feasible.
tional category of extremely severe underweight is used
to classify those with a BMI of ≤14 kg/m2.32 Mid-­upper Laboratory evaluation of HHC
arm circumference (MUAC) will be measured to the Symptom screening for TB will be done in all HHC and
nearest of 0.1 cm on the non-­dominant arm, if the patient CXR will be done wherever feasible as per the NTEP

6 Bhargava A, et al. BMJ Open 2021;11:e047210. doi:10.1136/bmjopen-2020-047210

 Table 4 Schedule of enrolment, assessments at baseline and follow-­up in the RATIONS trial
Investigations Baseline M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 M11 M12 M15 M18 M21 M24
In index cases                                  
1 Informed consent X                                
2 Demography, X                                
socio-­economic
status,
comorbidities,
household
characteristics
and access to
PDS
3 Clinical evaluation X X X X X X X X X X X X X X X X X
4 Anthropometry X X X X X X X X X X X X X X X X X
(height, weight
and MUAC)
and SpO2 pedal
oedema
5 *Laboratory X                                

Bhargava A, et al. BMJ Open 2021;11:e047210. doi:10.1136/bmjopen-2020-047210

evaluation RBS,
HIV and Hb
6 Compliance X X X X X X X X X X X X X        
to nutritional
supplement in
new cases (12
months in MDR-­
TB)
7 Performance X X X       X X X X X X X        
status (modified
ECOG Scale)
8 *CB-­NAAT X             (in case of symptoms of recurrent disease)
9 *CXR X           X                    
In subsample of                                  
index cases
1 Dietary recall X           X                    
of calories and
protein intake
2 Body composition X           X                    
(by BIA)
Continued
Open access

7
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8
Table 4 Continued
Investigations Baseline M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 M11 M12 M15 M18 M21 M24
3 Micronutrient X                                
estimation
(vitamins A and D)
Open access

4 Hand grip strength X           X                    

5 Immunological X           X                    
tests (fourth-­
generation IGRA,
lymphocyte
subsets)
In household                                  
contacts
1 Informed consent X                                
2 Baseline X                                
demography,
socioeconomic
status, comorbid
conditions,
household
characteristics
and access to
PDS
3 Symptom screen X X X X X X X     X     X X X X X
4. Clinical evaluation X In case of symptoms of active TB
if symptomatic
5 Anthropometry X X X X X X X     X     X X X X X
(height, weight
and MUAC)
6 Compliance X X X X X X X                    
to nutritional
supplement
(intervention arm)
(12 months in
MDR-­TB)
7. Review of non-­ X X X X X X X X X X X X X X X X X
TB infectious
illnesses†
8 Sputum smear,  In case of symptoms of active TB
CB-­NAAT
Continued

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 Table 4 Continued
Investigations Baseline M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 M11 M12 M15 M18 M21 M24
9 CXR‡ X  In case of symptoms of active TB
In subsample                                  
of household
contacts
1. Dietary recall of X           X                    
calories, protein
intake
2 Body composition X           X                    
(by BIA)

Bhargava A, et al. BMJ Open 2021;11:e047210. doi:10.1136/bmjopen-2020-047210

3 Micronutrient X                                
estimation
(vitamins A and D)
4 Immunological X           X                    
tests (fourth-­
generation IGRA
and lymphocyte
subsets)

*Through public health system.

†Respiratory infections, diarrhoea, hospitalisation with fever of any cause and death due to fever <15 days duration.
‡For children under 5 years of age, symptomatic contacts.
BIA, Bioimpedance analysis; CB-­NAAT, cartridge-­based nucleic acid amplification test; CXR, chest X-­ray; ECOG, Eastern Cooperative Oncology Group; Hb, haemoglobin; HIV, HIV
immunodeficiency virus; IGRA, Interferon Gamma Release Assay; MDR-­TB, multidrug resistant tuberculosis; MUAC, mid upper arm circumference; MUAC, mid-­upper arm circumference; PDS,
public distribution system; RATIONS, Reducing Activation of Tuberculosis by Improvement of Nutritional Status; RBS, random blood sugar; SpO2, oxygen saturation; TB, tuberculosis.
Open access

9
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Open access

Table 5 Eastern Cooperative Oncology Group (ECOG) Scale for functional assessment24
ECOG categories Additional description Score

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Able to carry out normal activity without restriction No physical restriction 0
Unable to do physically strenuous activity, but ambulatory Able to walk around the neighbourhood, but unable to 1
and able to carry out light work do any income-­generating work
Ambulatory and capable of all self-­care, but unable to carry Able to walk around the house and backyard 2
out any work; up and about <50% of waking hours
Capable of only limited self-­care; confined to bed or chair Able to go to the bathroom 3
>50% of waking hours

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Completely disabled; cannot carry out any self-­care and Unable to go to the bathroom 4
totally confined to bed or chair

guidelines.6 In case of symptoms of presumptive TB or The definition of microbiologically confirmed case and
an abnormal CXR, the HHC will be referred for sputum clinically diagnosed cases is as per table 6.
examination. Children with symptoms/abnormal CXR
will be referred for further evaluation by sputum smear Qualitative study about the nutritional intervention
and CB-­ NAAT (if cough is productive) and induced We will use a phenomenological approach to generate
sputum/gastric aspirate, if unable to produce sputum at qualitative data through the in-­ depth interview of TB
a referral hospital. patients and their HHC. The participants will be purpo-
sively selected till conceptual saturation and triangula-
Follow-up of index cases and HHC tion is reached, and will be interviewed using topic guides
The enrolled index cases and their HHC will be prepared in line with the study objectives. Interviews will
followed-­up for 2 years after the diagnosis of the index be tape-­ recorded, transcribed verbatim and translated
case. Jharkhand is a state with potential seasonal labour to English. Open Code software will be used to facilitate
migration from rural areas. All attempts (including tele- analysis. This substudy will be conducted at the end of the
phonic contact) will be made to retain follow-­up in case intervention period.
of temporary migration with an in-­person visit on their
return. Participants will be termed as lost to follow-­up Discontinuation of study intervention and withdrawal of study
if in-­person or telephonic contact is not made for ≥2 participants
months in the intervention period or for ≥6 months in Study participants will be asked about consumption of
the follow-­up period. All participants lost to follow-­up will rations and micronutrients at every visit. Rarely, they may
be approached for an end of study evaluation to ascer- choose to discontinue consumption of the study interven-
tain information on the primary and relevant secondary tion during the intervention period, due to an unrelated
outcomes. illness or perceived adverse effects. The reasons for their
The schedule of follow-­up and assessments is described discontinuation of study intervention will be recorded, but
in table 4. Evaluation will be done for current symp- these participants will remain in the study and undergo
toms, any adverse effect related to treatment, adherence protocol-­specified follow-­up procedures. However, if the
to treatment and rations. All HHC will be evaluated for participant also explicitly withdraws consent for follow-­up
symptoms of active TB on each visit, consumption of and collection of additional information in addition to
rations (in intervention arm) and review of non-­TB infec- discontinuation of consumption of study intervention,
tious morbidity and mortality based on symptoms, hospi- the withdrawal of consent will be recorded, and only the
talisation or death. data collected prior to withdrawal of consent will be used
Patients will undergo repeat sputum examination on in the study. Study participants will be free to withdraw
follow-­up as per NTEP guidelines. Contacts that develop at any time during the trial. The reasons for the with-
any symptoms of active TB (pulmonary or extrapulmo- drawal will be documented, which may include refusal of
nary) will undergo appropriate investigations. follow-­up, lost to follow-­up, participant request, death or
The cases of active TB in HHC will be classified as if the study sponsors decide to stop or cancel the study.
co-­prevalent or incident according to the time of diag- Unless the participants withdraw consent for further
nosis of the index case. A co-­prevalent case is HHC diag- follow-­up, attempts will be made to ascertain outcomes as
nosed with active TB (microbiologically confirmed active mentioned earlier.
TB or as clinically diagnosed TB) at the baseline, or
within 2 months of the baseline screening and evaluation Study outcomes
of the HHC. An incident case is a new case of TB in an The primary outcome in HHC is the difference in
HHC (microbiologically confirmed active TB or as clini- number of incident cases of active TB (all forms) in the
cally diagnosed) that was diagnosed more than 2 months two arms by active case finding over a follow-­up period
following the initial negative screening and evaluation. of 2 years. The secondary outcomes are improvement

10 Bhargava A, et al. BMJ Open 2021;11:e047210. doi:10.1136/bmjopen-2020-047210

 Open access

Table 6 Case definitions for outcomes used in RATIONS trial6

Outcome Case definition

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Active TB Any patient with microbiologically confirmed TB or clinically diagnosed TB
Microbiologically confirmed TB in adults A patient who has a positive sputum smear for Mycobacterium tuberculosis and/or
or children ►► Sputum/gastric aspirate is positive on CB-­NAAT
►► And/or positive on culture
Clinically diagnosed PTB A patient who has symptoms suggestive of TB, is smear negative and/or negative
on CB-­NAAT, and/or who has CXR is suggestive of TB, and where there is no
alternative clinical diagnosis

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Clinically diagnosed extra-­PTB A patient who is either negative on microbiological testing and/or CB-­NAAT,
or where an appropriate specimen is not available, and the findings (clinical/
biochemical/cytological/histopathological/radiological or direct visualisation
procedures) are suggestive of TB, and where alternative diagnosis has been ruled
out
Clinically diagnosed PTB in children A patient who has symptoms suggestive of active PTB (fever, cough, weight loss
or the absence of weight gain), and/or a CXR is suggestive of TB, and there is
absence of alternative diagnosis, who is negative on CB-­NAAT on gastric aspirate
or induced sputum, or when bacteriological confirmation has not been possible
CB-­NAAT, Cartridge-­based nucleic acid amplification test; CXR, chest X-­ray; PTB, pulmonary tuberculosis ; RATIONS, Reducing Activation of
Tuberculosis by Improvement of Nutritional Status.

in the nutritional indicators over 6 months, frequency correlation coefficient of 0.2 for the outcome in HHC
of malaria, diarrhoea, lower respiratory tract infection, and 0.01 between members of the same cluster,22 and
hospitalisation with fever of any cause or death with fever thus a design effect of 6.75. Thus, a sample size of 28 clus-
of any cause less than 15 days in duration in both the trial ters with 2800 patients and approximately 11 200 contacts
arms. equally distributed in both the arms would have 80%
The secondary outcomes in the index cases are power to detect 50% reduction of TB incidence in inter-
successful treatment completion, TB-­ related deaths, vention arm with a type-1 error of 5%.
improvement in performance status, adverse effects and The substudy sample sizes were estimated based on
recurrence of TB during 2-­year follow-­up. The ascertain- the assumptions related to the objective of the substudy.
ment of primary outcomes of incident TB in contacts is by The sample size of 250 cases (125/arm) and 250 contacts
NTEP staff (not part of the trial team). (125/arm) was based on the prevalence of multiple
vitamin deficiencies in patients with PTB,36 and the prev-
Participant timeline alence of vitamin D deficiency in apparently healthy indi-
The trial has a preparatory phase of 3 months for site viduals in India.37
selection, staff recruitment and training, and preparation A sample size of 352 contacts (176/arm) was assumed
of manual of procedures. The intervention phase will be to be needed to detect a 10% difference in mean CD4
6 months for drug-­susceptible cases and 12 months in the counts in the contacts of the two arms after 6 months of
MDR-­TB. The follow-­up phase will continue for 2 years intervention, with 90% power. This proportion is about
from the initiation of treatment. 3% of the HHC and we will enrol a similar 3% of the
Sample size estimation index cases (50/arm) to assess determine the immune
The estimated incidence rate of PTB in the general popu- function at baseline and after intervention in them.
lation in India is 217/100 000 population (0.208 %).4 The The sample size for the dietary intake substudy assumes
incidence rate ratio of TB in HHC is 15.9 (IQR: 2.6–21.4) an SD of 525 kcal, over a wide range of caloric intakes.38
compared with the general population, translating into Assuming a mean difference in caloric intake between
4% incidence in the HHC.22 Assuming a higher burden both the arms as 400 kcal and 20% loss to follow-­up, we
of TB and undernutrition in India, and recent emerging will enrol 45 contacts and 45 patients in each arm.
evidence of significantly higher risk of TB disease
following infection in close contacts,33 we considered Data collection and management
TB incidence in HHC to be 5% over the study period. The data will be collected by field investigators working
We assume 50% reduction in TB incidence at household in close collaboration with the NTEP staff. Study data
level with intervention.34 will be collected and managed using Research Electronic
Our sample size considers design effect at three levels; Data Capture, an electronic data capture tools39 hosted at
the TU level, the families of index cases and finally their ICMR-­NIRT. The data capture will be done real time using
HHC.35 We assumed approximately 100 index cases a handheld device, will be subjected to range and logic
(80–120) and their families in a cluster per annum, a checks and will be monitored by the project technical

Bhargava A, et al. BMJ Open 2021;11:e047210. doi:10.1136/bmjopen-2020-047210 11

Open access

team. A periodic quality check will be performed for accu- The changes in dietary intake of calories and proteins,
racy and completeness by the data management team at body composition parameters and lymphocyte will be
ICMR-­NIRT, which will minimise missing data. Appro- assessed among index and contacts. Interactions between

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priate imputation methods will be used for missing values treatment and change in nutritional and body composi-
in the analysis if required. The final dataset will be acces- tion indicators will be tested using likelihood ratio tests.
sible to the investigators based in Yenepoya (deemed to The effect of subgroups will be analysed based on age,
be University) and ICMR-­NIRT and will be deposited in gender, caste, residence, BMI, asset score and possession
electronic format with the trial sponsor, ICMR, at the end of below poverty line card, alcohol use and family history
of the study. of TB. A p<0.05 (two-­tailed) will be considered statistically
All essential trial documents and consent forms will be significant. All data will be analysed using STATA V.16.1

Protected by copyright, including for uses related to text and data mining, AI training, and similar technologies.
stored under lock and key at the recruitment site under (StataCorp, Texas, USA).
the supervision of investigators. Electronic data will be Interim analysis will be performed on attaining 50% of
password protected and the records will be retained for a outcomes in the control arm (approximately 230 cases)
period of 5 years after completion of the study. with p<0.0054 as statistically significant. The final analysis
We will constitute a data safety management board will be done at the end of attainment of planned sample
(DSMB) comprising of subject experts in clinical trials, size and completion of follow-­up, considering p<0.0492
TB and nutrition along with independent biostatistician as statistically significant.
and ethicist.
Apart from the regular monitoring by the project team, Harm
there is periodic reporting to the ICMR, to the institu- The intervention involves locally consumed food items,
tional ethics committee (IEC) of ICMR-­NIRT, the trial which are part of the daily diet and hence no specific
advisory committee and the DSMB. adverse events are expected. Patients who have lactose
intolerance will be offered alternatives. The possibility
Data analysis feeding syndrome’ in severely undernourished
of ‘re-­
The primary outcome is TB incidence among contacts, patients will be prevented by training the field staff to
expressed as events per 100 000 person-­ months of offer a graded increase in food intake in such patients.
follow-­ up. Follow-­up is defined as time from date of
randomisation until the earliest endpoint, that is, docu-
Ethics, participant information and consent
mented TB disease or censoring (death, loss to follow-­up
Ethics clearance has been obtained from IEC of ICMR-­
or end of the study).
NIRT, Chennai (NIRT-­IEC number: 2018020), to which all
Cox proportional hazards model, accounting for
the amendments of the protocol will be communicated.
varying follow-­up times and clustering effect, will be used
Patients and their HHC who are enrolled in the study will
to compare the rate of progression of TB infection to
receive a detailed ‘Participant Information Sheet’ in local
disease among contacts between the arms and to assess
language before administering the informed consent. A
its association with risk factors. Unadjusted and adjusted
separate consent form will be used for the adult partic-
HRs along with their 95% CIs will be reported. The crude
ipants enrolled in the substudy on micronutrient status
effect of the intervention will be calculated using Kaplan-­
and immune function. No blood specimen will be stored
Meier survival plots and compared using the log rank test.
for any future use. A unique numerical code will be
The primary analysis will be intention to treat. Per-­
allocated to each participant for purpose of their iden-
protocol analysis will also be done. The models will be
tification and for maintaining confidentiality. Personal
adjusted for relevant risk factors (age, smoking, diabetes
identifiers will be deleted in the final research database
and duration of exposure) during the sensitivity analysis.
for analysis. All forms with personal identifiers will be
The secondary outcomes of change in weight and
under lock and key with the trial team.
z-­scores in patients and HHC, and the performance status
in patients, will be compared using unpaired and paired
t-­tests and Bonferroni correction for multiple compari- Responsibility for ancillary care during the trial
sons. Linear mixed regression models adjusted for age, Any index case or HHC found to have an acute illness
gender, TU, caste, asset score, family size and baseline other than TB during the follow-­up visits will be facili-
weight will be done. tated by the field staff to reach the nearest government
The secondary outcomes of frequency of non-­ TB health set-­up.
morbidities and deaths due to infections in the HHC,
and the frequency of deaths, adverse effects, defaults Patient and public involvement statement
and relapse in the index cases in the two arms, will be Patients were not directly involved in the development of
compared using the χ2 test and Cox proportional hazards the research question. The components of food basket
regression for time to first event. were discussed with community health workers during
The patients enrolled in the substudies will be compared the preparatory phase of the trial. The training of the
in their baseline characteristics as these have been drawn field staff involved interaction with TB survivors and two
by non-­random sampling of patients from the main trial. of the field staff in the trial are TB survivors.

12 Bhargava A, et al. BMJ Open 2021;11:e047210. doi:10.1136/bmjopen-2020-047210

 Open access

Dissemination plan Open access This is an open access article distributed in accordance with the
The impact of nutritional support on TB incidence and Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-­commercially,
outcomes in this trial will be of relevance to NTEP, India. and license their derivative works on different terms, provided the original work is

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The results will be disseminated through publications, properly cited, appropriate credit is given, any changes made indicated, and the use
conference presentations and briefs for the programme is non-­commercial. See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/.
managers, Jharkhand’s department of health, policy-­ ORCID iDs
makers and other stakeholders. We intend to share the Anurag Bhargava http://​orcid.​org/​0000-​0001-​7187-​8759
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and community leaders. Bharati Kulkarni http://​orcid.​org/​0000-​0003-​0636-​318X
Manjula Singh http://​orcid.​org/​0000-​0001-​8656-​3768

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Trial status
The trial was started on 16 August 2019 after trial regis-
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Provenance and peer review Not commissioned; externally peer reviewed. patients with pulmonary tuberculosis in rural central India and its
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not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been reducing under-­nutrition on the tuberculosis epidemic in the central
peer-­reviewed. Any opinions or recommendations discussed are solely those eastern states of India: a dynamic modeling study. PLoS One
of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and 2015;10:e0128187.
21 Grobler L, Nagpal S, Sudarsanam TD. Nutritional supplements for
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