Clinical trial NCT03785106: Tuberculosis Preventive Therapy Among Latent Tuberculosis Infection in HIV-infected Individuals
Official title: Implementation for Tuberculosis Preventive Therapy Among Latent Tuberculosis Infection in HIV-infected Individuals Using Novel Regimen of Isoniazid/Rifapentine Daily (4 Weeks) Compared to Isoniazid/Rifapentine Weekly (12 Weeks)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: HIV-infected Participants With Latent TB Infection in High TB Burden Country
Keywords: people living with HIV (PLHIV)
Lead sponsor: The HIV Netherlands Australia Thailand Research Collaboration
Sponsor class: OTHER
Collaborators: name: King Chulalongkorn Memorial Hospital
name: Police General Hospital
name: Pranangklao Hospital
name: Taksin Hospital
name: Bhumibol Adulyadej Hospital
name: Klang Hospital
name: Chiang Rai Prachanukroh Hospital
name: Sanpatong Hospital
name: Queen Sawang Vadhana Memorial Hospital
name: Buddhachinnaraj Hospital
name: Maharat Nakhon Ratchasima Hospital
name: HatYai Hospital
name: Srinagarind Hospital, Khon Kaen University
name: Sisaket Hospital
name: The Public Health Centre 28 Krung thon buri
First posted: 2018-12-24
Enrollment: 2500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This study is a multicenter, randomized, open-label, phase III clinical trial comparing a 4-week daily INH/RPT regimen (1HP) to a 12-weekly INH/RPT (3HP) for the treatment of LTBI in HIV-infected participants without evidence of active TB.
Primary purpose: PREVENTION

Brief summary: The investigators want to know if ultra-short, effective treatment for latent tuberculosis (TB) infection (LTBI) could dramatically reduce the global incidence of active TB or not. The investigators hypothesize that short-course (4-week) daily isoniazid/rifapentine (INH/RPT) (1HP) is not inferior to standard -course (12 weeks) INH/RPT weekly regimen (3HP) for the prevention of TB in human immunodeficiency virus (HIV)-infected individuals.

Detailed description: This study is a multicenter, randomized, open-label, phase III clinical trial comparing a 4-week daily INH/RPT regimen (1HP) to a 12-weekly INH/RPT (3HP) for the treatment of LTBI in HIV-infected participants without evidence of active TB. The primary objective will be efficacy of active TB prevention. The study will also assess safety and tolerability of the regimens, adherence to the treatments, and patterns of antibiotic resistance among Mycobacterium tuberculosis (MTB) isolates in participants who fail on these prophylactic regimens.

Under this study, there is one substudy entitled, "Pharmacokinetic study of rifapentine, dolutegravir, and tenofovir alafenamide in HIV-infected individual with latent tubersulosis infection". There will be a subgroup of patients who will participate in this pharmacokinetic study of rifapentine and dolutegravir (DTG) / tenofovir alafenamide (TAF). Randomization is based on cluster of differentiation 4 (CD4) categories : \< 200, 200-350, \> 500 cells/mm3 and VL \<50 or \>50 copies/ml.

Eligibility criteria: Inclusion Criteria:

1. Documented HIV-1 infection by standard HIV test or plasma HIV-1 RNA viral load and received ART within 12 months. Participants received ART more than 12 months would be allowed if CD4 cell counts is less than 350 cells/mm3
2. 18 years and older
3. Evidence of latent TB infection, either by TST ≥5 mm or positive interferon gamma release assay (IGRA) or history of close contact with active pulmonary TB\* within 3 months prior entry visit or residing in a high TB burden area\*\* NOTE \* close contact is referred to person living/sharing in the same room with active pulmonary TB participants for \> 4 hours/day

   \*\* high TB burden areas are defined as areas with an estimated or reported TB prevalence of 100 to 300/100,000, according to the WHO. Thailand is included in high TB burden areas.
4. Laboratory values obtained within 30 days prior to entry

   * Absolute neutrophil count (ANC) \>750 cells/mm3
   * Hemoglobin \>7.4 g/dL
   * Platelet count \>50,000/mm3
   * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) \<3x upper limit of normal (ULN)
   * Total bilirubin \<2.5 X ULN
5. Chest radiograph or chest computed tomography (CT) scan without evidence of active tuberculosis, unless one has been performed within 90 days prior to entry.
6. Female participants who are participating in sexual activity that could lead to pregnancy must agree to use one reliable non-hormonal form of contraceptive (i.e., condoms, IUD, diaphragm) during RPT treatment and contraception should be remain to 6 weeks post RPT NOTE Female participants who are not of reproductive potential or whose male partner(s) have undergone successful vasectomy with documented azoospermia or have documented azoospermia are eligible without requiring the use of contraceptives. Participant-reported history is acceptable documentation of menopause, hysterectomy, or bilateral oophorectomy or bilateral tubal ligation.
7. All participants must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization) while receiving RPT and for 6 weeks after stopping this drug.
8. Body weight \> 40 kg
9. Ability and willingness of participant to provide informed consent

Exclusion Criteria:

1. Treatment for active or latent TB (pulmonary or extrapulmonary) within 2 years prior to study entry or presence of any confirmed or probable active TB at screening.
2. History of Isoniazid (INH) or Rifampicin (RIF)/Rifabutin (RFB) resistant TB at any time prior to study entry or known exposure to INH or RIF/RFB resistant TB (e.g., household member of a person with MDR or XDR TB) at any time prior to study entry.
3. Treatment for \>14 consecutive days with a rifamycin or \>30 consecutive days with INH at any time during the 2 years prior to enrollment.
4. Current or planned use of protease inhibitor-based ART.
5. Currently on a salvage ART regimen, defined as a regimen started due to confirmed HIV virologic failure on a prior ART regimen or due to known HIV drug resistance.
6. History of liver cirrhosis at any time prior to study entry.
7. Evidence of acute hepatitis, such as abdominal pain, jaundice, dark urine, and/or light stools within 90 days prior to entry.
8. Diagnosis of porphyria at any time prior to study entry.
9. Peripheral neuropathy ≥Grade 2 according to the Division of AIDS (DAIDS) Toxicity Table, within 90 days prior to study entry.
10. Known allergy/sensitivity or any hypersensitivity to components of study drug(s) or their formulation.
11. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
12. Acute or serious illness requiring systemic treatment and/or hospitalization within 30 days prior to entry.
13. Pregnancy or breastfeeding

Primary outcomes:
measure: efficacy in preventing active TB (proportion of participants that do not have active TB by the end of the study)
timeFrame: 3 years
measure: safety of the regimens (proportion of participants that do not have any side effects throughout the study period)
timeFrame: 3 years
measure: tolerability to the regimens (proportion of participants that can complete the treatment course)
timeFrame: 3 years
measure: prevalence of drug resistance of MTB
timeFrame: 3 years
Secondary outcomes:
measure: severity of the condition
timeFrame: 3 years
measure: presence of symptoms
timeFrame: 3 years
measure: level of CBC
timeFrame: 3 years
measure: level of ALT
timeFrame: 3 years
measure: level of AST
timeFrame: 3 years
measure: level of total bilirubin
timeFrame: 3 years
measure: level of ALK
timeFrame: 3 years
measure: level of creatinine
timeFrame: 3 years
measure: death
timeFrame: 3 years
measure: when TB culture becomes positive
timeFrame: 3 years
measure: when TB is confirmed by clinical examination
timeFrame: 3 years
measure: adherence to LTBI treatment
timeFrame: 3 years
measure: consistency of taking LTBI treatment
timeFrame: 3 years
measure: treatment discontinuation
timeFrame: 3 years
measure: discontinuation of study due to adverse drug reactions
timeFrame: 3 years
measure: CD4 count
timeFrame: 3 years
measure: CD4 count to confirmed or probable TB
timeFrame: 3 years
measure: time it takes for TB to be confirmed by IGRA
timeFrame: 3 years
measure: TST result at baseline
timeFrame: day 0
Other outcomes:
Locations:
city: Bangkok
country: Thailand
facility: Klang Hospital
city: Bangkok
country: Thailand
facility: Bhumibol Adulyadej Hospital
city: Bangkok
country: Thailand
facility: HIV-NAT, Thai Red Cross AIDS Research Centre
city: Bangkok
country: Thailand
facility: King Chulalongkorn Memorial Hospital
city: Bangkok
country: Thailand
facility: Police General Hospital
city: Bangkok
country: Thailand
facility: Taksin Hospital
city: Bangkok
country: Thailand
facility: the Public Health Centre 28 Krung thon buri
city: Chiang Mai
country: Thailand
facility: Sanpatong Hospital
city: Chiang Rai
country: Thailand
facility: Chiangrai Prachanukroh Hospital
city: Chon Buri
country: Thailand
facility: Queen Savang Vadhana Memorial Hospital
city: Khon Kaen
country: Thailand
facility: Srinagarind Hospital
city: Nakhon Ratchasima
country: Thailand
facility: Maharat Nakhon Ratchasima Hospital
city: Nonthaburi
country: Thailand
facility: Pranangklao Hospital
city: Phitsanulok
country: Thailand
facility: Buddhachinnaraj Hospital
city: Sisaket
country: Thailand
facility: Sisaket Hospital
city: Songkhla
country: Thailand
facility: Hatyai Hospital
Study officials:
affiliation: HIV-NAT, Thai Red Cross - AIDS Research Centre
name: Anchalee Avihingsanon, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: