Clinical trial NCT02178592: Open-label Study of Dolutegravir (DTG) or Efavirenz (EFV) for Human Immunodeficiency Virus (HIV) - Tuberculosis (TB) Co-infection
Official title: ING117175: a Phase IIIb, Randomized, Open-label Study of the Safety and Efficacy of Dolutegravir or Efavirenz Each Administered With Two NRTIs in HIV-1-infected Antiretroviral Therapy-naïve Adults Starting Treatment for Rifampicin-sensitive Tuberculosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Infection, Human Immunodeficiency Virus
HIV Infections
Keywords: integrase inhibitor
Mycobacterium tuberculosis
rifampicin-sensitive
dolutegravir
antiretroviral therapy-naïve
HIV-1 infection
efavirenz
co-infection
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
Collaborators: name: GlaxoSmithKline
First posted: 2014-07-01
Enrollment: 113
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: HIV/Tuberculosis (TB) co-infection have profound effects on the host's immune system. TB is the most common cause of death in patients with HIV worldwide. Rifamycins (such as rifampicin \[RIF\]) are an important component of TB therapy because of their unique activity. The problem is that most protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) used to treat HIV have significant drug-drug interactions with RIF that can lead to reduced concentrations of these agents with risk of treatment failure or resistance. The non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (EFV) does not present the same significant drug interactions with RIF. EFV-based HIV treatment was tested in patients concomitantly treated with RIF-containing TB therapy, demonstrating that their co-administration can be used safely and effectively. However, the side effect profile of EFV overlaps with the RIF-containing TB regimens and makes the management of treatment toxicities very complex. Integrase inhibitors (INI), such as dolutegravir (DTG), may offer an important alternative to EFV-based therapy in TB coinfected patients. A Phase I drug-drug interaction study was conducted in healthy, HIV-seronegative subjects, and showed that DTG at 50 mg twice daily given together with RIF was well-tolerated and resulted in DTG concentrations similar to those of DTG 50 mg given once daily alone, which is the recommended dose for INI-naive patients. Therefore, ART regimens using DTG 50 mg twice daily may represent a new treatment option for TB-infected patients who require concurrent treatment for HIV infection. This is a Phase III b, randomized, open-label study describing the efficacy and safety of DTG and EFV-containing ART regimens in HIV/TB co-infected patients. This study is designed to assess the antiviral activity of DTG or efavirenz (EFV) ART-containing regimens through 48 weeks. A total of approximately 115 +/-5% subjects will be randomly assigned in a 3:2 ratio to DTG (approximately 69 subjects) and EFV (approximately 46 subjects), respectively. This study will include a Screening Period, a Randomized Phase (Day 1 to 48 weeks plus a 4-week extension), and a DTG Open-label extension (OLE). During the DTG OLE, subjects will be supplied with DTG until it is locally approved and commercially available, the subject no longer derives clinical benefit, or the subject meets a protocol-defined reason for discontinuation, which ever comes first.


Eligibility criteria: Inclusion Criteria:

* Subject or the subject's legal representative is willing and able to understand and provide signed and dated written informed consent prior to Screening
* Adult subject (at least 18 years of age) with plasma HIV-1 RNA\>=1000 copies/ milliliter (mL) at Screening
* CD4+ cell count is \>= 50 cells/ cubic millimetre (mm\^3) at Screening
* HIV-1-infected, ART-naïve; (\<=10 days of prior therapy with any antiretroviral drug following a diagnosis of HIV-1 infection)
* A female subject may be eligible to enter and participate in the study if she: is of non-childbearing potential defined as either postmenopausal (12 months of spontaneous amenorrhea and \>=45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy, or bilateral oophorectomy or, is of childbearing potential, with a negative pregnancy test at both Screening and Day 1, and agrees to use one of the following methods of contraception to avoid pregnancy
* Complete abstinence from intercourse from 2 weeks prior to administration of IP, throughout the study, and for at least 2 weeks after discontinuation of all study medications
* Double-barrier method (male condom/spermicide, male condom/diaphragm, diaphragm/spermicide)
* Approved hormonal contraception plus a barrier method while receiving Rifampicin (RIF)-containing TB treatment for subjects randomly assigned to the DTG arm or approved hormonal contraception plus a barrier method for subjects randomly assigned to the EFV arm (regardless of RIF-containing TB treatment)
* Any intrauterine device with published data showing that the expected failure rate is \<1% per year
* Male partner sterilization prior to the female subject's entry into the study and this male is the sole partner for that subject
* Any other method with published data showing that the expected failure rate is \<1% per year
* Any contraception method must be used consistently, in accordance with the approved product label and for at least 2 weeks after discontinuation of study drug. A childbearing potential female subject who starts the study using complete abstinence as her contraceptive method and decides to become sexually active must use the double barrier method either as a bridge to an approved hormonal contraception (if possible) or as a method of choice to be maintained from that moment onwards
* All subjects participating in the study should be counseled on safer sexual practices including the use of effective barrier methods
* New diagnosis of pulmonary, pleural, or Lymph node (LN) TB based on identification of Mycobacterium tuberculosis using culture methods or validated nucleic acid amplification test on sputum or on samples collected by needle aspirate of pleural fluid or an affected LN
* RIF sensitivity of Mycobacterium tuberculosis either by culture or validated nucleic acid amplification test
* RIF-containing first-line TB treatment or an alternate RIF-containing TB treatment started up to a maximum of 8 weeks before randomization and no later than the screening date
* Karnofsky score \>=70% before randomization

Exclusion Criteria:

* Any previous TB treatment (not including treatment for latent disease)
* Evidence of RIF resistance of Mycobacterium tuberculosis either by culture or validated nucleic acid amplification test
* Expected requirement for TB treatment \>9 months
* Concomitant disorders or conditions for which isoniazid, RIF, pyrazinamide, or ethambutol are contraindicated
* Central nervous system, miliary, or pericardial TB
* Women who are pregnant or breastfeeding
* Any evidence of an active Acquired immunodeficiency syndrome (AIDS)-defining disease (Centers for Disease Control and Prevention, Category C). Exceptions include TB, cutaneous Kaposi's sarcoma not requiring systemic therapy, and historic CD4+ cell counts of \<200 cells/mm\^3
* Subjects with moderate to severe hepatic impairment (Class B or C) as determined by Child-Pugh classification unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), cirrhosis, or known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
* Subjects positive for hepatitis B surface antigen (HBsAg) at screening
* Anticipated need for hepatitis C virus (HCV) therapy during the Randomized Phase of the study
* History or presence of allergy or intolerance to the study drugs or their components or drugs of their class
* Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, resected, non-invasive cutaneous squamous cell carcinoma, or cervical intraepithelial neoplasia; other localized malignancies require agreement between the investigator and the study medical monitor for inclusion of the subject
* Subjects who, in the investigator's judgment, pose a significant suicidality risk. Recent history of suicidal behavior and/or suicidal ideation may be considered as evidence of serious suicide risk
* Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening
* Treatment with any of the following agents within 28 days of Screening: radiation therapy, cytotoxic chemotherapeutic agents, any immunomodulators that alter immune response
* Treatment with any agent, other than licensed ART as allowed above with documented activity against HIV-1 in vitro/vivo within 28 days of first dose of IP
* Exposure to an experimental drug or experimental vaccine within either 28 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent, whichever is longer, prior to the first dose of IP
* Any evidence of primary viral resistance to Nucleoside reverse transcriptase inhibitor (NRTIs), Non-nucleoside reverse transcriptase inhibitor (NNRTIs), or Protease inhibitor (PIs) based on the presence of any major resistance-associated mutation (according to the International AIDS Society Update of the Drug Resistant Mutations in HIV-1 ) in the Screening result or, if known, any historical resistance test result. Note: Retests of Screening genotypes are not allowed
* Any verified Grade 4 laboratory abnormality
* Any acute laboratory abnormality at Screening, which, in the opinion of the investigator, would preclude the subject's participation in the study of an investigational compound
* Alanine aminotransferase \>=2 × upper limit of normal
* Hemoglobin \<=7.4 grams per deciliter;
* Platelet count \<50000/mm\^3

Primary outcomes:
measure: Percentage of Participants With Plasma Human Immunodeficiency Virus-1 Ribonucleic Acid (HIV-1 RNA) < 50 Copies/Milliliter at Week 48 in DTG Arm Using the Modified United States (US) Food and Drug Administration (FDA) Snapshot Algorithm
timeFrame: Week 48
Secondary outcomes:
measure: Percentage of Participants With Plasma HIV-1 RNA <50 Copies/Milliliter at Week 48 in EFV Arm Using the Modified Snapshot Algorithm
timeFrame: Week 48
measure: Percentage of Participants With Plasma HIV-1 RNA <50 Copies/Milliliter at Week 24 in Both EFV and DTG Arms Using the Modified Snapshot Algorithm
timeFrame: Week 24
measure: Percentage of Participants Without Confirmed Virologic Withdrawal and Without Discontinuation Due to Treatment-related Reasons at Week 24 and Week 48
timeFrame: Week 24 and Week 48
measure: Change From Baseline in Cluster of Differentiation 4 (CD4+) Counts at Week 24 and Week 48
timeFrame: Baseline (Day 1), Week 24 and Week 48
measure: Number of Participants With Serious Adverse Event (SAE) and Common (>=5%) Non-serious AE (Non-SAE) - Randomized Phase
timeFrame: Up to Week 52
measure: Number of Participants With SAE and Common (>=5%) Non-SAE - OLE Phase
timeFrame: Week 52 to Week 252
measure: Number of Participants With Maximum Post-Baseline-emergent Chemistry Toxicities - Randomized Phase
timeFrame: Up to Week 52
measure: Number of Participants With Maximum Post-Baseline-emergent Chemistry Toxicities- Randomized Phase + OLE Phase
timeFrame: Up to Week 252
measure: Number of Participants With Maximum Post-Baseline-emergent Hematology Toxicities- Randomized Phase
timeFrame: Up to Week 52
measure: Number of Participants With Maximum Post-Baseline-emergent Hematology Toxicities - Randomized Phase + OLE Phase
timeFrame: Up to Week 252
measure: Percent Change From Baseline in the Fasting Lipid Profile at Week 24 and Week 48
timeFrame: Baseline (Day 1), Week 24 and Week 48
measure: Change From Baseline in the Fasting Lipid Profile for Total Cholesterol/HDL Ratio at Week 24 and Week 48
timeFrame: Baseline (Day 1), Week 24 and Week 48
measure: Percentage of Participants Who Permanently Discontinued Study Treatment Due to AEs - Randomized Phase
timeFrame: Up to Week 52
measure: Percentage of Participants Who Permanently Discontinued Study Treatment Due to AEs - OLE Phase
timeFrame: Week 52 to Week 252
measure: Number of Participants With Tuberculosis (TB) Associated (Assoc.) Immune Reconstitution Inflammatory Syndrome (IRIS)
timeFrame: Up to Week 12
measure: Number of Participants With Treatment-emergent Genotypic Resistance
timeFrame: Up to Week 52
measure: Number of Participants With Treatment-emergent Phenotypic Resistance
timeFrame: Up to Week 52
Other outcomes:
Locations:
city: Ciudad de Buenos Aires
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Rosario
country: Argentina
facility: GSK Investigational Site
state: Santa Fe
city: Manaus
country: Brazil
facility: GSK Investigational Site
state: Amazonas
city: Salvador
country: Brazil
facility: GSK Investigational Site
state: Bahía
city: Rio de Janeiro
country: Brazil
facility: GSK Investigational Site
city: São Paulo
country: Brazil
facility: GSK Investigational Site
city: Guadalajara
country: Mexico
facility: GSK Investigational Site
state: Jalisco
city: Guadalajara
country: Mexico
facility: GSK Investigational Site
state: Jalisco
city: Guadalajara
country: Mexico
facility: GSK Investigational Site
state: Jalisco
city: Cuernavaca
country: Mexico
facility: GSK Investigational Site
state: Morelos
city: DF
country: Mexico
facility: GSK Investigational Site
city: San Miguel
country: Peru
facility: GSK Investigational Site
state: Lima
city: Iquitos
country: Peru
facility: GSK Investigational Site
state: Loreto
city: Lima
country: Peru
facility: GSK Investigational Site
city: Lima
country: Peru
facility: GSK Investigational Site
city: Orel
country: Russian Federation
facility: GSK Investigational Site
city: Saint Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Soweto
country: South Africa
facility: GSK Investigational Site
state: Gauteng
city: Durban
country: South Africa
facility: GSK Investigational Site
state: KwaZulu- Natal
city: Bloemfontein
country: South Africa
facility: GSK Investigational Site
city: Cape Town
country: South Africa
facility: GSK Investigational Site
city: Cape Town
country: South Africa
facility: GSK Investigational Site
city: Klerksdorp
country: South Africa
facility: GSK Investigational Site
city: Observatory, Cape Town
country: South Africa
facility: GSK Investigational Site
city: Westdene
country: South Africa
facility: GSK Investigational Site
city: Bangkok
country: Thailand
facility: GSK Investigational Site
city: Bangkok
country: Thailand
facility: GSK Investigational Site
city: Khon Kaen
country: Thailand
facility: GSK Investigational Site
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Dooley KE, Kaplan R, Mwelase N, Grinsztejn B, Ticona E, Lacerda M, Sued O, Belonosova E, Ait-Khaled M, Angelis K, Brown D, Singh R, Talarico CL, Tenorio AR, Keegan MR, Aboud M; International Study of Patients with HIV on Rifampicin ING study group. Dolutegravir-based Antiretroviral Therapy for Patients Coinfected With Tuberculosis and Human Immunodeficiency Virus: A Multicenter, Noncomparative, Open-label, Randomized Trial. Clin Infect Dis. 2020 Feb 3;70(4):549-556. doi: 10.1093/cid/ciz256.