Safety of Administering Isoniazid to SLE Patients to Prevent TB
NCT ID: NCT06618573
Last Updated: 2024-10-01
Study Results
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Basic Information
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RECRUITING
PHASE2/PHASE3
60 participants
INTERVENTIONAL
2022-08-15
2025-12-01
Brief Summary
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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.
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
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.
PREVENTION
TRIPLE
Study Groups
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Treatment Group
SLE patient at the Hasan Sadikin Rheumatology Outpatient Clinic and registered as Lupus Registry with remission or mild SLE disease activity. The diagnosis of SLE is based on ACR 1997 criteria or SLE SLICC 2012 criteria. Screening will include history review, physical examinations, chest X-Ray, laboratory test such as CBC, ALT/AST, HbsAg, total anti-HCV, complement (C3), dsDNA, creatinine serum, urinalysis (proteinuria, ACR, RBC, WBC, casts), IGRA, to assess if any subject has no active TB and no chronic liver disease.
Treatment group receiving Isoniazid 5 mg/kg/day (maximum 300 mg/day) with pyridoxine 10 mg/day.
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.
Isoniazid/Pyridoxine
Treatment group received isoniazid 300mg and pyridoxine 10mg/day
Control Group
SLE patient at the Hasan Sadikin Rheumatology Outpatient Clinic and registered as Lupus Registry with remission or mild SLE disease activity. The diagnosis of SLE is based on ACR 1997 criteria or SLE SLICC 2012 criteria. Screening will include history review, physical examinations, chest X-ray, laboratory test such as CBC, ALT/AST, HbsAg, total anti-HCV, complement (C3), dsDNA, creatinine serum, urinalysis (proteinuria, ACR, RBC, WBC, casts) IGRA, to assess if any subject has no active TB and no chronic liver disease.
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.
Saccharum Lactis
Control group received placebo
Interventions
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Isoniazid/Pyridoxine
Treatment group received isoniazid 300mg and pyridoxine 10mg/day
Saccharum Lactis
Control group received placebo
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* History of allergy to Isoniazid
* Chronic liver disease, including chronic hepatitis B or C virus
* Malignancy
* Pregnancy
18 Years
55 Years
FEMALE
No
Sponsors
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Universitas Padjadjaran
OTHER
Responsible Party
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Principal Investigators
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Laniyati Hamijoyo, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Universitas Padjadjaran
Locations
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Rumah Sakit Dr Hasan Sadikin, Universitas Padjadjaran
Bandung, West Java, Indonesia
Countries
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Central Contacts
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Facility Contacts
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References
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Hamijoyo L, Candrianita S, Rahmadi AR, Dewi S, Darmawan G, Suryajaya BS, Rainy NR, Hidayat II, Moenardi VN, Wachjudi RG. The clinical characteristics of systemic lupus erythematosus patients in Indonesia: a cohort registry from an Indonesia-based tertiary referral hospital. Lupus. 2019 Nov;28(13):1604-1609. doi: 10.1177/0961203319878499. Epub 2019 Sep 29.
Koesoemadinata RC, McAllister SM, Soetedjo NNM, Febni Ratnaningsih D, Ruslami R, Kerry S, Verrall AJ, Apriani L, van Crevel R, Alisjahbana B, Hill PC. Latent TB infection and pulmonary TB disease among patients with diabetes mellitus in Bandung, Indonesia. Trans R Soc Trop Med Hyg. 2017 Feb 1;111(2):81-89. doi: 10.1093/trstmh/trx015.
Petri M, Orbai AM, Alarcon GS, Gordon C, Merrill JT, Fortin PR, Bruce IN, Isenberg D, Wallace DJ, Nived O, Sturfelt G, Ramsey-Goldman R, Bae SC, Hanly JG, Sanchez-Guerrero J, Clarke A, Aranow C, Manzi S, Urowitz M, Gladman D, Kalunian K, Costner M, Werth VP, Zoma A, Bernatsky S, Ruiz-Irastorza G, Khamashta MA, Jacobsen S, Buyon JP, Maddison P, Dooley MA, van Vollenhoven RF, Ginzler E, Stoll T, Peschken C, Jorizzo JL, Callen JP, Lim SS, Fessler BJ, Inanc M, Kamen DL, Rahman A, Steinsson K, Franks AG Jr, Sigler L, Hameed S, Fang H, Pham N, Brey R, Weisman MH, McGwin G Jr, Magder LS. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012 Aug;64(8):2677-86. doi: 10.1002/art.34473.
Yu YC, Mao YM, Chen CW, Chen JJ, Chen J, Cong WM, Ding Y, Duan ZP, Fu QC, Guo XY, Hu P, Hu XQ, Jia JD, Lai RT, Li DL, Liu YX, Lu LG, Ma SW, Ma X, Nan YM, Ren H, Shen T, Wang H, Wang JY, Wang TL, Wang XJ, Wei L, Xie Q, Xie W, Yang CQ, Yang DL, Yu YY, Zeng MD, Zhang L, Zhao XY, Zhuang H; Drug-induced Liver Injury (DILI) Study Group; Chinese Society of Hepatology (CSH); Chinese Medical Association (CMA). CSH guidelines for the diagnosis and treatment of drug-induced liver injury. Hepatol Int. 2017 May;11(3):221-241. doi: 10.1007/s12072-017-9793-2. Epub 2017 Apr 12.
Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997 Sep;40(9):1725. doi: 10.1002/art.1780400928. No abstract available.
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Pattanaik SS, Muhammed H, Chatterjee R, Naveen R, Lawrence A, Agarwal V, Misra DP, Gupta L, Misra R, Aggarwal A. In-hospital mortality and its predictors in a cohort of SLE from Northern India. Lupus. 2020 Dec;29(14):1971-1977. doi: 10.1177/0961203320961474. Epub 2020 Sep 30.
Lao M, Chen D, Wu X, Chen H, Qiu Q, Yang X, Zhan Z. Active tuberculosis in patients with systemic lupus erythematosus from Southern China: a retrospective study. Clin Rheumatol. 2019 Feb;38(2):535-543. doi: 10.1007/s10067-018-4303-z. Epub 2018 Sep 23.
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Jakes RW, Bae SC, Louthrenoo W, Mok CC, Navarra SV, Kwon N. Systematic review of the epidemiology of systemic lupus erythematosus in the Asia-Pacific region: prevalence, incidence, clinical features, and mortality. Arthritis Care Res (Hoboken). 2012 Feb;64(2):159-68. doi: 10.1002/acr.20683.
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Provided Documents
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Document Type: Study Protocol and Informed Consent Form
Related Links
Access external resources that provide additional context or updates about the study.
Yazdany J, Dall\'Era M. Definition and classification of lupus and lupus-related disorders. In: Wallace DJ, Hahn BH, editors. DUBOIS\' lupus erythematosus and related syndromes. 8th edition. Philadelphia: Elsevier Saunders; 2013. pp. 1-7.
Global tuberculosis report 2020: executive summary. © World Health Organisation 2020.
Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV- Infected Adults and Adolescents
Moon JY, Kwon HM, Ahn EY, Park JK, Song YW, Lee EB. Efficacy of Isoniazid Chemoprophylaxis in Lupus Nephritis Patients \[abstract\]. Arthritis Rheumatol. 2015; 67 (suppl 10).(abstract).
National Cancer Institute. Common terminology criteria for adverse events (CTCAE).
Ministry of Health of the Republic of Indonesia. National Guidelines for Medical Services: Tuberculosis Management. Jakarta (2020).
Other Identifiers
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IPD-202402.01
Identifier Type: -
Identifier Source: org_study_id
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