Clinical trial NCT06618573: Safety of Administering Isoniazid to SLE Patients to Prevent TB
Official title: Study on the Safety of Administering Isoniazid to Systemic Lupus Erythematosus Patients to Prevent Tuberculosis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Tuberculosis
Systemic Lupus Erythematosus
Keywords: Tuberculosis
Systemic Lupus Erythematosus
Lead sponsor: Universitas Padjadjaran
Sponsor class: OTHER
First posted: 2024-10-01
Enrollment: 60
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: SLE patient at the Hasan Sadikin Rheumatology Outpatient Clinic and registered as Lupus Registry study participants with remission or mild SLE disease activity. Subjects fulfilled inclusion criteria will be randomly divided into two groups: treatment group receiving INH 5 mg/kg/day (maximum 300 mg/day) with pyridoxine 10 mg/day and control group receiving placebo.

Monitor ALT/AST and SLE disease activity after two weeks, continued monthly for the first three months (1st, 2nd, 3rd) then every three months for up to a year (6th, 9th, 12th months). Routine SLE medication is continued and routinely recorded at every visit.
Primary purpose: PREVENTION

Brief summary: Systemic Lupus Erythematosus (SLE) is a prototypical systemic autoimmune disease characterized by heterogeneity, multisystem involvement, and production of multiple autoantibodies. Clinical features can vary, from mild skin and joint involvement to severe and life-threatening conditions.

Patients with lupus are more susceptible to infections, in addition to being immunocompromised, and due to the administration of corticosteroid and cytotoxic drugs. The presence of these infections is a cause of death in lupus disease in addition to the activity of the disease itself, especially in Asia-Pacific countries. One infection that often occurs in lupus is Tuberculosis (TB).

Efforts have been made to prevent TB infection in vulnerable populations, including isoniazid (INH) prophylaxis. In 2010, World Heatlh Organization issued guidelines for HIV patients to receive INH prophylaxis to prevent TB infection. The implementation of Isoniazid Preventive Therapy (IPT) is quite cheap using INH with mild side effects.18 A meta-analysis study of INH prophylaxis in patients with HIV found that the efficacy of this prophylaxis significantly reduced TB incidence by 35% with an RR of 0.65%. In addition, INH was found to be safe, with no significant increase in drug reactions, according to a meta-analysis of prophylaxis studies in HIV patients.

However, there is no guideline for INH prophylaxis for SLE patients, as there is for HIV patients, due to lack of data on this issue.

Studies on the effectiveness of INH prophylaxis on the prevention of TB infection for SLE patients should be conducted, but before that, studies on the safety of INH therapy in SLE patients should be conducted.

Detailed description: Systemic Lupus Erythematosus (SLE) is a prototypical systemic autoimmune disease characterized by heterogeneity, multisystem involvement, and production of multiple autoantibodies. Clinical features can vary, from mild skin and joint involvement to severe and life-threatening conditions. The course of lupus is highly variable in the form of relapses and remissions, with mild and severe forms that can be life-threatening. Treatments for SLE includes steroids and immunosuppressants to control disease activity.

Patients with lupus are more susceptible to infections, in addition to being immunocompromised, and due to the administration of corticosteroid and cytotoxic drugs. The presence of these infections is a cause of death in lupus disease in addition to the activity of the disease itself, especially in Asia-Pacific countries. One infection that often occurs in lupus is Tuberculosis (TB).

Tuberculosis is still a problem especially in the Asian region, and Indonesia ranks 2nd with the most cases after India according to World Health Organization in 2019. TB infection is found in 10-11.4% of SLE patients in Asia. The incidence of TB in SLE is reported to range from 150/100,000 patients per year in Turkey to 2,450/100,000 patients per year in India. The annual risk of TB in SLE patients is higher than the normal population. Registry data at Hasan Sadikin Hospital Bandung showed that 11.4% or 93 out of 813 SLE patients were infected with TB after being diagnosed with SLE.

Risk factors for increased TB infection in SLE patients, in addition to SLE disease activity itself (SLEDAI score \>12), renal involvement, lymphopenia, and cumulative dose of steroids used by the patient, are also due to long duration of illness and previous history of TB.

Tuberculosis is also one of the infections that cause death in SLE patients. Mortality from TB in Asian countries ranged from 5-31%. A study in the Philippines found that 14.8% of SLE patients with TB died, those who died had disseminated TB or miliary TB.

Efforts have been made to prevent TB infection in vulnerable populations, including isoniazid (INH) prophylaxis. In 2010, World Health Organization issued guidelines for HIV patients to receive INH prophylaxis to prevent TB infection. The implementation of Isoniazid Preventive Therapy (IPT) is quite cheap using INH with mild side effects. A meta-analysis study of INH prophylaxis in patients with HIV found that the efficacy of this prophylaxis significantly reduced TB incidence by 35% with an RR of 0.65%. In addition, INH was found to be safe, with no significant increase in drug reactions, according to a meta-analysis of prophylaxis studies in HIV patients.

The role of isoniazid prophylaxis for TB prevention in patients with SLE is controversial. To date, there is no consensus on prophylaxis against TB in SLE patients.

Research on this prophylaxis has been presented in an Indian study by Gaitonde et al. They found an 82% reduction in TB incidence in SLE patients with prophylactic INH at 5 mg/kg/day, with a maximum dose of 300 mg/day plus 10 mg pyridoxine (Vitamin B6) for 1 year, and no significant liver toxicity due to this drug. However, a retrospective study conducted in Hong Kong found no significant difference in TB reactivation between those who received INH compared to those who did not receive INH, while patients who received INH were reported to have more relapses of their lupus. Similarly, a retrospective study in Korea found no significant difference in patients with lupus nephritis.

The high incidence of TB in SLE patients, especially in endemic areas such as Indonesia, makes TB prevention an important endeavour. However, there is no guideline for INH prophylaxis for SLE patients, as there is for HIV patients, due to lack of data on this issue.

Studies on the effectiveness of INH prophylaxis on the prevention of TB for SLE patients should be conducted, but before that, studies on the safety of INH therapy in SLE patients should be conducted.

This study was a cohort study, with the following research design:

* LES patients attending the rheumatology clinic of RSHS and enrolled as Lupus Registry study participants, with remission or mild SLE disease activity
* Screening for TB and impaired liver function (Informed Consent, history review, physical examination, laboratory examination, Chest X-Ray) -\> Exclude if have condition: Impaired liver function, including hepatitis B/C positivity, history of allergy to INH, pregnancy, malignancy
* SLE patients who fulfil the inclusion criteria divided into two groups: Received INH 300 mg/day and Pyridoxine 10 mg/day for nine months or placebo.
* Routine SLE medication continued and routinely recorded at each visit.
* Monitor SGOT/SGPT and SLE disease activity after two weeks, continuing monthly in the first three months (months 1/2 1, 2, 3) then every three months until one year (months 6, 9, 12).

Inclusion Criteria:

* SLE patients with conditions of:
* No signs and symptoms of active TB,
* Not under TB treatment,
* No History of TB, malignancy, HIV, liver function test abnormality
* Not in pregnancy/lactation,
* No other active infections
* Remission or low to moderate disease activity state,
* Consented to join the study completely.

Exclusion Criteria:

* SLE patients with conditions of:
* History of allergy to Isoniazid,
* Chronic liver disease, including chronic hepatitis B or C virus,
* Malignancy,
* Pregnancy.

The patients included were patients who had been diagnosed with SLE and were registered in Lupus Registry.

The study was explained and informed consent was obtained. After the patient agreed and signed Informed Consent, screening was conducted to ensure that there was no active TB, impaired liver function (SGOT/SGPT), positive Hepatitis B (HBsAg) and/or Hepatitis C (total Anti HCV), history of Isoniazid (INH) allergy, history of malignancy, and pregnancy. If any of these conditions exist, the subject will be excluded.

Eligible subjects were randomly grouped into two groups: those receiving INH 5 mg/kg/day (maximum 300 mg/day) \& Pyridoxine (Vitamin B6) 10 mg/day, or placebo. Other routine SLE medications were continued.

Sample calculations were carried out based on INH prophylaxis studies conducted in HIV patients, obtaining a risk of drug reaction events of RR 1.2, so that with a confidence level of 95% and 80% power and an effect size of 0.5, the sample size for each group was 27 people, plus 10% to 30 people. So that the total number of patients involved is 60 people divided into 2 groups.

This study was to assess the safety of INH drug administration to lupus patients assessed by the increase in SGPT and SGOT that occurred and their lupus disease activity (using the SLEDAI score) measured at month 1/2 (second week), 1, 2, 3, 6, 9 and 12. The statistical test used was a T-test comparing two groups.

The study was conducted at Dr. Hasan Sadikin Hospital, Bandung. The study was conducted from August 2022 to December 2024.

Eligibility criteria: Inclusion Criteria:

SLE patients with conditions of :

* No signs and symptoms of active TB
* Not under TB treatment
* No History of TB, malignancy, HIV, liver function test abnormality
* Not in pregnancy/lactation
* No other active infections
* Remission or low to moderate disease activity state
* Consented to join the study completely

Exclusion Criteria:

SLE patients with conditions of :

* History of allergy to Isoniazid
* Chronic liver disease, including chronic hepatitis B or C virus
* Malignancy
* Pregnancy

Primary outcomes:
measure: Drug Induce Hepatitis
timeFrame: week 2, months 1, 2, 3, 6, 9, 12
measure: SLE disease activity
timeFrame: month 1, 2, 3, 6, 9, 12
Secondary outcomes:
Other outcomes:
Locations:
city: Bandung
country: Indonesia
facility: Rumah Sakit Dr Hasan Sadikin, Universitas Padjadjaran
state: West Java
Study officials:
affiliation: Universitas Padjadjaran
name: Laniyati Hamijoyo, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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