SpinalTBX: Gene Expression Profiles in Spinal Tuberculosis.

Sponsor

University of Cape Town (Other)

Overall Status

Recruiting

CT.gov ID

NCT05610098

Collaborator

University of Zurich (Other)

100

Enrollment

Location

37.2

Anticipated Duration (Months)

2.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Tuberculosis (TB) is one of the top ten causes of death worldwide with approximately 10 million cases globally and 1.2 million deaths. Sub-Saharan Africa carries the highest burden of TB. South Africa has one of the highest HIV and TB rates worldwide with an HIV prevalence rate in adults of 19% and a TB case notification rate of 615/100,000 in 2019. Over many years, focus has been paid to pulmonary TB and extrapulmonary TB (EPTB) has received only little attention even though it accounts for almost a quatre of all TB cases. The diagnosis of EPTB remains challenging simply because sample collection requires invasive procedures in the absence of a blood-based diagnostic test. Spinal TB (spondylitis or spondylodiscitis caused by Mycobacterium tuberculosis) - often known as Pott's disease - accounts for up to 10% of EPTB and affects young children, people with HIV-coinfection and elderly, and often leads to lifelong debilitating disease due to devastating deformation of the spine and compression of neural structures. Little is known with regards to the extent of disease and isolated TB spine as well as a disseminated form of TB spine have been described. The latter presents with a spinal manifestation plus disseminations to other organs such as the lungs, pleura, lymph nodes, the GIT or urinary tract or even the brain.

In the Spinal TB X cohort, the investigators aim to describe the clinical phenotype of spinal TB using whole body PET/CT and identify a specific gene expression profile for the different stages of dissemination and compare findings to previously described signatures for latent and active pulmonary TB. A blood-based test for spinal TB would lead to earlier diagnosis and treatment in all settings globally and improve treatment outcome of this devastating disease.

Condition or Disease	Intervention/Treatment	Phase
Tuberculosis, Spinal Tuberculosis, Osteoarticular Tuberculosis Mycobacterium Infections Infections Bone Diseases, Infectious Musculoskeletal Diseases Spinal Disease Spondylitis Spondylitis; Tuberculosis (Manifestation) Spondylodiscitis Positron-Emission Tomography Diagnostic Imaging Diagnostic Techniques and Procedures

Detailed Description

The investigators hypothesize that spinal TB may present as two clinical phenotypes: isolated spinal TB with no additional lesion on whole body PET/CT and disseminated spinal TB with a spinal lesion plus an additional extraspinal lesion on whole body PET/CT.
The investigators hypothesize that a specific gene expression profile may distinguish between the two clinical entities above and allows for treatment monitoring during antimicrobial therapy ("personalized medicine")
The investigators hypothesize that whole body PET/CT is superior to MRI in diagnosing spinal and extraspinal TB.

Primary objective

To describe the clinical phenotype of spinal TB using whole body PET/CT and to identify mRNA gene expression profiles of isolated spinal TB versus disseminated spinal TB stratified by HIV status.

Secondary objectives

To identify the distributive patterns of suspected spinal TB using two imaging modalities: MRI and PET/CT.
To analyse the genomes of Mtb. extracted from different sites of the body (if available) and to identify differences in their genome regarding SNPs and drug sensibility.
To analyse imaging findings using PET/CT at treatment initiation, 6 months, and 12 months to better understand treatment outcome using PET/CT.
To compare imaging findings on PET/CT and MRI at baseline to evaluate the role of PET/CT in spinal TB diagnostics (virtual biopsy).

Design

This is a prospective cohort study to develop new diagnostics for isolated spinal TB versus disseminated spinal TB and treatment monitoring. Furthermore, this study investigates genetic variability in spinal TB and its distributional pattern. After MRI-confirmation of spinal TB according to local algorithms, patients will be included in the study. At baseline, clinical examination as well as blood collection will be performed. Every patient with no confirmed HIV will undergo HIV-testing. Sputum will be collected and screening for diabetes and pregnancy will be completed. Whole-body PET/CTs will be performed at 0 months, 6 months, and 12 months. Spinal biopsies will be gathered if surgery is being performed. Samples of the sites of disease will be acquired if applicable and TB culture as well as GeneXpert will be performed.

Recruitment

Patients with newly diagnosed spinal TB at the Department of Orthopaedics, Groote Schuur Hospital, Cape Town, South Africa.

Study Design

Study Type:

Observational

Anticipated Enrollment :

100 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

Comparing Gene Expression Profiles of Adults With Isolated Spinal TB to Disseminated Spinal TB Identified by 18FDG-PET/CT at Time of Diagnosis, 6-and 12-months Follow-up

Actual Study Start Date :

Oct 25, 2022

Anticipated Primary Completion Date :

Dec 1, 2025

Anticipated Study Completion Date :

Dec 1, 2025

Outcome Measures

Primary Outcome Measures

Clinical phenotype of spinal TB [3 years]
To describe the clinical phenotype of spinal TB using whole body PET/CT a semiquantitative approach will be used. Regions of interest (ROIs) will be identified with increased FDG uptake against background and total lesion glycolysis (TLG) of each ROI will be measured using MIM software
mRNA gene expression profiles of spinal TB [3 years]
mRNA gene expression profiles of isolated spinal TB versus disseminated spinal TB described in outcome 1 will be measured and stratified by HIV status.

Secondary Outcome Measures

MRI vs. PET/CT at the site of disease (spine level) [3 years]
To identify the distributive patterns of suspected spinal TB using two imaging modalities: MRI and PET/CT. MRI is measure T1, T2 and diffusion weighted images. Regions of interest (ROIs) in the spine will be identified with increased FDG uptake against background and total lesion glycolysis (TLG) of each ROI will be measured using MIM software
Whole Genome Sequencing of Mtb. isolates [3 years]
To analyse the genomes of Mtb. extracted from different sites of the body (if available) and to identify differences in their genome regarding SNPs and drug sensibility.
PET/CT changes over 12 months [3 years]
Regions of interest (ROIs) in the spine will be identified with increased FDG uptake against background and total lesion glycolysis (TLG) of each ROI will be measured using MIM software at different timepoints: treatment initiation, 6 months, and 12 months

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria

Participant has completed the written informed consent process prior to undergoing any clinical evaluations and willing to undergo HIV testing
TB spine based on clinical and radiological criteria
Age 18 or older with a body weight of at least 40 kg body weight
Able and willing to return to follow-up
Willing to have samples, including DNA including RNA extraction, stored
Willing to consistently practice a highly reliable method of pregnancy prevention

Exclusion Criteria

Pregnancy or active desire to become pregnant within the next 6 months.
Uncontrolled diabetes (HbA1c ≥ 6.5% / random glucose concentration ≥11.1 mmol/l, fasting plasma glucose ≥ 7.0 mmol/l)
Alcohol and substance abuse which might interfere with medication adherence during the trial
Positive SARS-CoV-2 PCR in the past 4 weeks
Suspicion of malignancy on MRI or known malignancy
Suspicion of inflammatory disease and other rheumatological conditions
Any person for whom the physician feels this study is not appropriate