Paradoxical Reactions in Non Immuno-compromized Patients With Extrapulmonary Tuberculosis (PARATB)

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2012 by Assistance Publique - Hôpitaux de Paris
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier:
NCT01252992
First received: November 27, 2010
Last updated: June 14, 2012
Last verified: June 2012
  Purpose

Tuberculous paradoxical reactions (PR) are immune reactions occurring during the course of antituberculous treatment and leading to a worsening of tuberculous symptoms after an initial improvement. This phenomenon has very extensively studied in HIV infected patients where it corresponds to the so called IRIS (immune reconstitution syndrome). However, it laso occurs in non immuno-compromized patients, especially those with extra-pulmonary localization of tuberculosis. The aim of the study is to look for risk factors of paradoxical reaction in non immuno-compromized patients with extra-pulmonary tuberculosis. We will consider clinical, radiological and biological variables, including specific immune and genetic markers. Our secondary goals are to estimate the incidence of PR, describe their natural history; characterize the type of immune response they correspond to, and look for better diagnostic tools.The immunological characterization and the finding of predictive factors of PR, especially the genetic ones will allow a better understanding of biological mechanisms that lead to their occurrence during extra-pulmonary tuberculosis treatment. The establishment of predictive criteria could permit a better surveillance of at risk patients for a rapid treatment, or even a prevention of PR. The establishment of new diagnostic criteria at the time of PR could avoid numerous invasive diagnostic procedures, surgery and/or useless prolongation of antibiotic treatment.


Condition Intervention
Extrapulmonary Tuberculosis
Genetic: Genetic analysis
Radiation: Body scan (CERVICO THORACO ABDOMINAL) + Cranian IRM
Other: Immunologic analysis
Other: QuantiferonTB Gold test

Study Type: Observational
Study Design: Time Perspective: Prospective
Official Title: Paradoxical Reactions During Anti-mycobacterial Treatment of Extrapulmonary Tuberculosis in Non Immuno-compromized Patients : Clinical, Radiological et Immunological

Resource links provided by NLM:


Further study details as provided by Assistance Publique - Hôpitaux de Paris:

Primary Outcome Measures:
  • Risk factors of paradoxical reaction [ Time Frame: at 6 months ] [ Designated as safety issue: No ]
    Risk factors of paradoxical reaction : clinical, radiological immune and genetic factors


Secondary Outcome Measures:
  • Incidence and natural history of paradoxical reactions [ Time Frame: during the first 6 months ] [ Designated as safety issue: No ]
  • Immune description of paradoxical reactions [ Time Frame: during the first 6 months ] [ Designated as safety issue: No ]
  • Preliminary study of Diagnosis factors of paradoxical reaction [ Time Frame: during the first 6 months ] [ Designated as safety issue: No ]

Biospecimen Retention:   Samples With DNA

Blood samples (immunologic test), DNA, RNA, Biopsy


Estimated Enrollment: 500
Study Start Date: March 2011
Estimated Study Completion Date: March 2016
Estimated Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
1:paradoxical reaction negative (RP-)
control group with tuberculosis but without paradoxical reaction
Genetic: Genetic analysis
  1. identification of candidates genes by a differential analysis of the whole transcriptome of the peripheral leucocytes of 20 PR+ patients and 20 RP- controls, at D0, D15, M2,;
  2. Genetic association analysis: comparison of allelic distributions of SNPs (diallelic markers) within the candidate genes, between PR+ and PR- patients, in the whole cohort.

One supplementary ACD tube of 5 ml à D0, D15, M2, PR+, for RNA extraction.

Radiation: Body scan (CERVICO THORACO ABDOMINAL) + Cranian IRM
at day 0, Month 2, paradoxical reaction, end of treatment, read by an independent radiologist
Other: Immunologic analysis
For patients included until 20 PR+ : blood puncture of 4 ACD tubes of 10 ml, 1 EDTA tube of 7,5 ml et 1 heparinate lithium tube of 7,5ml at D0, D15, M2, and M6 and at the time of an potential RP+
1:paradoxical reaction negative (RP+)
group with tuberculosis and paradoxical reaction
Genetic: Genetic analysis
  1. identification of candidates genes by a differential analysis of the whole transcriptome of the peripheral leucocytes of 20 PR+ patients and 20 RP- controls, at D0, D15, M2,;
  2. Genetic association analysis: comparison of allelic distributions of SNPs (diallelic markers) within the candidate genes, between PR+ and PR- patients, in the whole cohort.

One supplementary ACD tube of 5 ml à D0, D15, M2, PR+, for RNA extraction.

Radiation: Body scan (CERVICO THORACO ABDOMINAL) + Cranian IRM
at day 0, Month 2, paradoxical reaction, end of treatment, read by an independent radiologist
Other: Immunologic analysis
For patients included until 20 PR+ : blood puncture of 4 ACD tubes of 10 ml, 1 EDTA tube of 7,5 ml et 1 heparinate lithium tube of 7,5ml at D0, D15, M2, and M6 and at the time of an potential RP+
Other: QuantiferonTB Gold test
at M0, M2, M6 and in case of PR+.

Detailed Description:

Primary objective :

Search for predictive factors of tuberculous paradoxical reaction (PR), with assessment of clinical, radiological and biological factors.

Secondary objectives :

  • Descriptive study of PR : incidence, clinical and radiological presentation, clinical course ; characterization of mycobacteria strains- Search for genetic predictive factors of PR
  • Characterization of the specific immune antigene response during PR et analysis of different cell subsets implicated in peripheral blood and locally- Characterization of the anti-bacterial immune response before and after antituberculous treatment
  • Preliminary search for new diagnosis criteria including clinical, biological (immune and genetic) and radiological factors.Methodology : Multicentric cohort study for a total of 5 years (4 years of enrolment and one year of follow-up, with biological collection for scientific purpose

Inclusion Status of patients (determined by a validation comity at M6)

  • PR+ : PR with clinical symptoms
  • rPR : pure radiological PR
  • PR- : absence of RP after 6 months of treatment Development of the study

Primary outcome :

- Association between PR+ occurrence and clinical, biological and radiological factors harvested at the diagnosis of tuberculosis..

Secondary outcomes :

  • Association between PR+ and rPR
  • occurrence and the above quoted factors.- Descriptive study : clinical, biological, and radiological presentation of PR+ and rPR, characterization of isolated BK strains in PR+ patients
  • Immunological study in 20 PR+ patients and 20 RP- : 20 patients per group will allow a 80% power to detect, by means of bilateral Mann-Whitney test with alpha=5%, any difference in the count of specific cells corresponding to at least one standard deviation of the primary immunological outcome
  • controls: variation between tuberculosis diagnostic and either PR time or M2 (in absence of PR), of the specific cells, macrophages, dendritic cells, gamma-delta lymphocytes, NK et CD4 cells counts
  • Preliminary search for diagnostic criteria that can be used at the time of PR occurrence: variation between D0 and the PR of clinical, biological, radiological immunological et genomic of PR+ patients.
  • Evolution specific and non specific immune response of mycobacterial antigen at tuberculosis diagnosis during tuberculosis treatment and after. Sample size calculation
  • prognostic study : Patients will be recruited and followed until the achievement of a 100 PR+ sample. Expecting the PR+ incidence in extra-pulmonary tuberculosis to be 25%, we will have to analyze 400 patients. The sample size of 100 PR+ patients and 300 controls will allow detection of the effect of a factor displaying a prevalence of 0.2 in the control population, conferring a relative risk of PR >2, with a 80% power and an alpha risk of 0.0025 (i.e. a global alpha= 0.05, after BONFERRONI correction for 20 tests). In the genetic association study, the additive effect of a causal allele of frequency 0.2 with an Odds ratio >2, will be detected with a 80% power and an alpha risk of 0.001. Foreseeing that 20% of included patients won't be analysable (diagnosis non confirmed, lost to follow-up etc…), we shall eventually include 500 patients at D0.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

Extra-pulmonary tuberculosis

Criteria

Inclusion Criteria:

  • Extrapulmonary tuberculosis, with associated pulmonary localization or not
  • Treatment started less than 5 days ago
  • Negative HIV serology
  • Social insurance
  • Age >= 18- Foreseeable follow-up of at last one year
  • Signed Free Inform Consent

Exclusion Criteria:

  • HIV infection
  • immuno-suppressive treatment (including corticosteroids > 10 mg /d prednisone equivalent
  • central neurological system tuberculosis and tuberculous pericarditis - pure pulmonary tuberculosis
  • multiresistant tuberculosis
  • pregnancy or breast feeding
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01252992

Contacts
Contact: Brigitte RANQUE, MD 33 1 56 09 27 72 bigitte.ranque@egp.aphp.fr
Contact: Anne BOURGARIT, MD

Locations
France
Georges Pompidou Hospital Recruiting
Paris, France, 75015
Contact: Brigitte RANQUE, MD         
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
Principal Investigator: Anne BOURGARIT, MD Assistance Publique - Hôpitaux de Paris
  More Information

No publications provided

Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT01252992     History of Changes
Other Study ID Numbers: P081253, 2010-A00375-34
Study First Received: November 27, 2010
Last Updated: June 14, 2012
Health Authority: France: Ministry of Health

Keywords provided by Assistance Publique - Hôpitaux de Paris:
Extrapulmonary
Tuberculosis
Paradoxical reaction
Risk factors
Incidence
CT scan
Natural history
Immune system phenomena
Immune markers
Gene Expression Profiling

Additional relevant MeSH terms:
Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections

ClinicalTrials.gov processed this record on October 16, 2014