Clinical trial NCT05376189: Oral Vitamin D and Toll Like Receptor in Spondylitis Tuberculosis
Official title: The Effect of Vitamin D Supplementation on Toll-Like Receptor (TLR) 2, 4, and Clinical Outcomes of Spondylitis Tuberculosis
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Spondylitis
Tuberculosis
Keywords: Vitamin D
Spondylitis Tuberculosis
Clinical Improvement
Toll-Like Receptor
Lead sponsor: Hasanuddin University
Sponsor class: OTHER
First posted: 2022-05-17
Enrollment: 37
Sex: ALL
Minimum age (years): 19
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This study involves three arms intervention consists of one control group with standardized tuberculosis treatment, and two intervention groups with different level of vitamin D supplementation;
Primary purpose: TREATMENT

Brief summary: Background :

The toll-like receptor is an essential receptor that stimulates the innate immunity response. In tuberculosis, toll-like receptors, particularly the TLR-2, and TLR-4 are crucial in recognizing various ligands with a lipoprotein structure in the bacilli. Vitamin D deficiency leads to lower expression of these receptors, Hence the immune response against Mycobacterium tuberculosis will be altered. Various studies addressed the importance of vitamin D supplementation in pulmonary tuberculosis but the effect of vitamin D in extrapulmonary tuberculosis, particularly spondylitis tuberculosis is not sufficiently identified.

Objectives:

To assess the effect of oral vitamin D supplementation on the expression of TLR-2, TLR-4, and clinical outcomes in spondylitis tuberculosis patients.

Methodology:

This study proposes a randomized clinical trial of oral vitamin D supplementation in spondylitis tuberculosis patients. Multiple arms will be established with different doses and control groups. The outcome of interest includes the clinical outcomes, the expression of TLR-2, and TLR 4

Hypothesis :

It is assumed that oral supplementation of Vitamin D will increase the activation of Toll-Like Receptors and improves the clinical condition of Spondylitis Tuberculosis patients

Detailed description: Target population:

Patients with spondylitis tuberculosis without the involvement of lung and other extrapulmonary infection

Design:

Randomized Clinical Trial with 3 arms

Primary Intervention:

Standardized Tuberculosis treatment with oral Vitamin D3 Supplementation daily for 8 weeks

Outcome:

1. Toll-Like Receptors (TLR) 2 and 4 levels from the blood sample, measured using Enzyme-linked Immunoassay (ELISA).
2. Clinical Evaluation with Visual Analogue Scale (VAS) and Oswestry Disability Index (ODI).

The outcomes will be measured three times at 4-week intervals (baseline, week 4, and week 8)

Sample Size and Recruitment Participants will be recruited from hospitals and allocated by simple randomization

Biological Sample and consent

1. Participants are aware that clinical data collection and biological samples will be obtained by researchers. This is mentioned in informed consent prior to study recruitment
2. Blood sample will be obtained in a standardized phlebotomy procedure and will not be retained after the study is finish.

Hypothesis Sample Size Calculation:

The trial will be designed to compare 2 experimental treatments to a shared control arm.

The sample size was estimated based on the mathematical calculation by a study below Grayling, M.J et al

With the assumption of :

1. K=2 experimental treatments will be included in the trial.
2. A significance level of α=0.05 will be used, in combination with no multiple comparison correction.
3. The event rate in the control arm will be assumed to be: λ0=5.
4. The marginal power for each null hypothesis will be controlled to level 1-β=0.8 under each of their respective least favorable configurations.
5. The interesting and uninteresting treatment effects will be δ1=2.5 and δ0=0 respectively.
6. The target allocation to each of the experimental arms will be the same as the control arm.
7. The sample size in each arm will not be required to be an integer.

Hence total sample should be 37 participants

Proposed Statistical Analysis

1. Descriptive Statistics
2. Bivariate Analysis
3. The study will apply intention-to-treat analysis
4. Linear Mixed model to measure the effect of intervention adjusted by fixed and random factors.

Eligibility criteria: Inclusion Criteria:

1. Diagnosed as Spondylitis Tuberculosis (Clinically and Laboratory confirmed)
2. Level of Total Vitamin D \<50 nmol/L at baseline

Exclusion Criteria:

1. Participants with pulmonary tuberculosis or other extrapulmonary tuberculosis
2. Participants with osteoporosis, malignancy, cardiovascular disease, diabetes mellitus, and autoimmune disease
3. Participants with liver and kidney dysfunction
4. Participants who received Vitamin D prior to enrollment

Primary outcomes:
measure: The Oswestry Disability Index
timeFrame: Changes of Score from Baseline to 8 weeks
measure: The Visual Analogue Scale
timeFrame: Changes of Score from Baseline to 8 weeks
measure: Toll-Like Receptor 2 (TLR-2)
timeFrame: Changes of TLR-2 level from Baseline to 8 weeks
measure: Toll-Like Receptor 4 (TLR-2)
timeFrame: Changes of TLR-4 level from Baseline to 8 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Makassar
country: Indonesia
facility: Wahidin Sudirohusodo General Hospital
state: South Sulawesi
Study officials:
affiliation: Hasanuddin University
name: Jainal Arifin, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hasanuddin University
name: Nasrum Massi, MD. Ph.D
role: STUDY_CHAIR
affiliation: Hasanuddin University
name: Firdaus Hamid, MD. Ph.D
role: PRINCIPAL_INVESTIGATOR
affiliation: Hasanuddin University
name: Andi Alfian Zainuddin, MD. Ph.D
role: PRINCIPAL_INVESTIGATOR
References:
citation: Grayling MJ, Wason JM. A web application for the design of multi-arm clinical trials. BMC Cancer. 2020 Jan 31;20(1):80. doi: 10.1186/s12885-020-6525-0.
citation: Tang L, Liu S, Bao YC, Gao RX, Han CF, Sun XC, Zhang WL, Feng SQ. Study on the relationship between vitamin D deficiency and susceptibility to spinal tuberculosis. Int J Surg. 2017 Aug;44:99-103. doi: 10.1016/j.ijsu.2017.05.077. Epub 2017 Jun 16.
citation: Panwar A, Garg RK, Malhotra HS, Jain A, Singh AK, Prakash S, Kumar N, Garg R, Mahdi AA, Verma R, Sharma PK. 25-Hydroxy Vitamin D, Vitamin D Receptor and Toll-like Receptor 2 Polymorphisms in Spinal Tuberculosis: A Case-Control Study. Medicine (Baltimore). 2016 Apr;95(17):e3418. doi: 10.1097/MD.0000000000003418.
citation: Ojaimi S, Skinner NA, Strauss BJ, Sundararajan V, Woolley I, Visvanathan K. Vitamin D deficiency impacts on expression of toll-like receptor-2 and cytokine profile: a pilot study. J Transl Med. 2013 Jul 22;11:176. doi: 10.1186/1479-5876-11-176.
citation: Yu, Fang & Cailiang, Shen. (2019). Effect of vitamin D combined with anti-tuberculosis drugs on serum IL-1β, IFN-γ and TH17 cell-associated cytokines for the management of spinal tuberculosis. Tropical Journal of Pharmaceutical Research. 18. 1141-1147. 10.4314/tjpr.v18i5.32.