Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04331262 |
| Other study ID # |
68722 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
July 26, 2021 |
| Est. completion date |
July 31, 2023 |
Study information
| Verified date |
August 2023 |
| Source |
Corporacion para Investigaciones Biologicas |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Introduction: childhood tuberculosis continues to be a major public health problem, despite
the fact that the visibility of the epidemic in this population group has increased, studies
are still lacking that can resolve the gaps that persist.
Objective: To design, implement and evaluate an integrated care strategy for children under
five years old household contacts of patients with smear positive pulmonary tuberculosis in
Medellín and the Metropolitan Area.
Methodology: quasi-experimental study, in which around 300 children household contacts of
patients with smear positive pulmonary tuberculosis from Medellín and the Metropolitan Area
will be evaluated, who will be recruited in a period of one year. A subgroup of these
children, estimated at 85, who require treatment for latent tuberculosis, will be offered to
receive treatment for latent tuberculosis under a integrated care strategy that includes some
modifications to the currently standardized scheme in Colombia, with rifampicin treatment
daily oral route for four months, follow-up under the project scheme with the availability of
a nurse, general practitioner, specialists, care by professionals from other disciplines such
as social work, psychology, and nutritionist, and the provision of incentives (transport and
food assistance). This strategy will be compared with isoniazid treatment according to the
standardized scheme in the country, which was received by a cohort of children between 2015
and 2018. The study has the CIB Research Ethics Committee approval.
Expected results: this project is expected to contribute with greater local evidence of
integrated care strategies that allow greater compliance with treatment for latent
tuberculosis in children, so that there is a real impact in the control of childhood
tuberculosis and in the reduction of tuberculosis reservoirs in order to achieve the goals
proposed by the World Health Organization's End TB Strategy.
Description:
Objective:
To design, implement and evaluate an integrated care strategy for children under five years
old household contacts of patients with smear positive pulmonary tuberculosis in Medellín and
the Metropolitan Area.
Methodology:
Study design
Quasi-experimental study with a one-year follow-up, which will include a cohort of children
household contacts of patients with smear positive pulmonary TB from Medellín and the Valle
de Aburrá Metropolitan Area, to carry out the contact tracing and treatment for latent TB in
those who is indicated, and who will receive the intervention of the integrated care
strategy. Compliance with the treatment achieved with this strategy will be compared with
compliance achieved with the treatment with isoniazid in the 2015-2018 cohort.
The integrated care strategy for contact children of patients with smear positive pulmonary
TB will have the following components:
- Diagnostic tests (TST, IGRAS, standardized chest x-ray, gastric aspirate, induced
sputum, smear microscopy, culture in solid and liquid media, Xpert Ultra MTB/RIF).
- Staff: Nursing assistant, General practitioner, Specialist (pediatrician, ID specialist,
radiologist), Other disciplines (nutritionist, psychology, social worker).
- Supply of scheme treatment with daily rifampicin for four months.
- Provision of social assistance and/or incentives (transport, food assistance).
- Patient-centered care based on primary health care (active monitoring, permanent
education and contact, among others).
Operational hypothesis
The proportion of treatment compliance for latent TB in contact children of patients with
smear positive pulmonary TB in Medellín and the Metropolitan Area who receive the integrated
care strategy is greater than the proportion of treatment compliance for children who
received isoniazid in the 2015-2018 cohort.
Study population
Sample: the sample will be children under five years old household contacts of patients with
smear positive confirmed pulmonary TB from Medellín and the Metropolitan Area notified to the
surveillance system during 2020, in whom treatment for latent TB is indicated.
Sample
Sampling type: it will correspond to an Incidental Sampling, since the children of the study
will be recruited as new cases (incidents) of smear positive confirmed pulmonary TB
identified in Medellín and the Metropolitan Area.
Sample size: all children household contacts of smear positive pulmonary TB patients from
Medellín and the Metropolitan Area will be follow-up initially for a period of one year,
according to previous studies it is estimated that around 250 to 300 children will be
assessed with a proportion of estimated infection of 73.5%.
The complete intervention of the integrated care strategy (with medication, incentives and
active follow-up) will be provided to a subgroup of children who require treatment for latent
tuberculosis, and who will also be selected incidentally, according to their willingness to
participate. To calculate the sample size of this subgroup, compliance with the treatment
with isoniazid in the 2015-2018 cohort of 59% was considered, hoping that the proposed
strategy achieves at least 80% of compliance (expected goal), with a confidence level of 95%
and a power of 80%, it is estimated that a group of at least 75 children will be required in
the proposed comprehensive care strategy (sample size calculated with Epidat version 4.2), an
additional 10% will be estimated due to loss to follow-up, so the total number of children to
enter the integrated care strategy will be 85.
Description of interventions
The intervention will be the integrated care strategy, in which the effects of interventions
established in the regulations of the TB program at the national level will be observed, such
as the diagnosis and administration of treatment for latent TB in children household contacts
of patients with pulmonary TB, with two main modifications, the supply of daily oral
rifampicin for four months self-administered scheme (instead of daily oral isoniazid for nine
months self-administered scheme), and provision of incentives such as transport and food
assistance (monthly food supplies). In addition to this, immune response tests will be
performed measuring interferon gamma production levels (QuantiFERON®-TB Gold Plus - QFT Plus
test) and tuberculin skin test (TST).
Procedures
- Standardization of the personnel that will participate in the study will be carried out
both in data collection and in clinical assessment and information processing.
- Children recruitment: children will be recruited through contact with the tuberculosis
control program of the Health Authorities of Medellín, and other municipalities in the
Metropolitan Area that agreed to participate, which will immediately supply their
information on children under five years old household contacts of pulmonary TB patients
recruited by the program through epidemiological visits to the homes of patients with
pulmonary tuberculosis recently diagnosed and reported to the program. The staff of the
health authorities will request authorization from those responsible for the children to
share the information with the study staff. Additionally, the staff of the health
authorities will support in socializing the project to promote the participation of
children.
- By telephone contact, it will start the informed consent process to participate in the
study to the parents or guardians of children under five years old identified as
household contacts of smear positive confirmed TB patients from the municipalities of
Medellín and the Metropolitan Area, that meet the inclusion criteria and that do not
have exclusion criteria.
- According to what was previously found, the first two information collection formats
will be filled in by telephone with the variables corresponding to the index case
(person with TB of whom the child under five years old is contact) and some variables
corresponding to the child.
- During the same phone call, an appointment will be assigned, during which the doctor
will carry out the basic clinical assessment with a complete physical examination, tests
for latent TB will be performed. Trained health personnel will apply tuberculin and take
the reading at 72 hours, previously taking a blood sample (5 ml sample of blood taken
through a puncture in the vein) for evaluation of interferon gamma production in
response to CFP-10, ESAT-6 and PHA antigens (QuantiFERON®-TB Gold Plus-QFT Plus test),
as well as biomarker determination. This last test will also be performed on a urine
sample. A radiological chest study will be performed to rule out active disease with a
standardized reading. The first children with criteria for treatment for latent TB will
be invited to participate in the integrated care strategy, in which they will receive
care from the project by Nursing Assistant, General Practitioner, Specialists
(pediatrician, ID specialist, child radiologist), Other disciplines (nutritionist,
psychology, social worker), Treatment provision scheme with daily rifampicin for four
months, Supply of social assistance and / or incentives (transport, food assistance),
Patient-centered care based on primary health care (active monitoring, education and
permanent contact, among others).
- Children with clinical and / or radiological criteria for active TB during the year of
follow-up and uptake will receive studies to confirm the diagnosis of active TB, taking
samples of induced sputum (two samples) and aspirating gastric juice (two samples) with
smear, Xpert MTB/RIF Ultra test, and culture in solid and liquid media to the collected
samples. Stool and urine samples will also be taken.
- Children who receive treatment for latent TB under the integrated care strategy will
have a monthly clinical assessment during the period they receive the medication, to
detect side effects, observe compliance with the treatment, identify the development of
active disease (in those who present respiratory symptoms will be performed the same
tests as in children with suspected initial active TB). Liver function tests will be
performed after two months of treatment to detect liver adverse effects. Biomarkers will
also be measured in a blood sample, as well as in urine. At the end of the treatment, a
blood biomarker study will be performed again.
Research site
Children will be assessed at CIB medical office for clinical and epidemiological conditions
and to rule out the diagnosis of tuberculosis and confirm the diagnosis of latent TB; in
those who enter the integrated care strategy, treatment compliance and side effects will be
assessed, with a clinical assessment at the time of intake, monthly while receiving
medication (rifampin four months) and 12 months after the initial assessment; immune response
(TST and IGRA) at baseline will also be evaluated; as defined in the procedures.
Chest radiography (including standardized reading) and sampling of induced sputum and gastric
juice aspirate will be performed at the Pablo Tobón Uribe Hospital, the samples will be
processed at the Corporation for Biological Research (CIB). Liver function tests will be
taken at CIB, and processed in Laboratorio Echavarría.
Data analysis To describe the characteristics of children's exposure to TB, a univariate
analysis will be carried out, which will include the variables corresponding to the index
case, the child's exposure, and other epidemiological variables. Frequencies distribution and
proportions estimation will be carried out for the qualitative variables such as sex,
socioeconomic stratum, system of affiliation to the social security system in health, history
of BCG vaccination, bacteriological study and other variables.
The characteristics of the children in the 2015-2018 and 2020-2022 cohort will be compared
using the Z test for the difference in proportions for the qualitative variables and using
the Mann-Whitney U test for the quantitative variables according to the normality of those
variables estimated with the Shapiro Wilk test. The characteristics of the index cases and
the characteristics of the children household contacts will be analyzed separately.
To examine the cellular immune response to M. tuberculosis, a univariate analysis will be
carried out. The proportion of response to the TST will be calculated according to categories
in <5 mm, between 5 and 10 mm and ≥10 mm, and the prevalence of positive response with cutoff
point ≥5 mm. Proportion of interferon gamma production (QuantiFERON®-TB Gold Plus - QFT Plus)
will be calculated according to the categories of positive and negative results.
The total agreement between the two immunological tests will be analyzed, as well as the
different possibilities of discordance. The kappa index will also be calculated. The
prevalence ratio of TST ≥5 mm and / or positive QFT will be calculated, and a bivariate
analysis will be made with the characteristics of exposure to TB in children, adjusting for
the index case cluster using Poisson regression. Subsequently, the multivariate analysis will
be performed adjusting for the variables that met the Hosmer-Lemeshow criterion in the
bivariate analysis (p-value <0.25).
A description of the characteristics of the treatment for latent TB will be made, a
univariate analysis of the characteristics of the treatment for latent TB will be made, by
estimating proportions, the qualitative variables related to the characteristics of the
administration of the treatment, side effects (appearance of symptoms such as
gastrointestinal or allergic) and treatment compliance (temporary or permanent suspension,
cause of treatment suspension).
The difference in treatment compliance proportions between the 2015-2018 and 2020-2022
cohorts will be calculated, with 95% confidence.
