Open-label Study of Dolutegravir (DTG) or Efavirenz (EFV) for Human Immunodeficiency Virus (HIV) - Tuberculosis (TB) Co-infection

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified August 2014 by ViiV Healthcare
Sponsor:
Collaborators:
PPD
GlaxoSmithKline
Information provided by (Responsible Party):
ViiV Healthcare
ClinicalTrials.gov Identifier:
NCT02178592
First received: June 26, 2014
Last updated: August 14, 2014
Last verified: August 2014
  Purpose

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 125 subjects will be randomly assigned in a 3:2 ratio to DTG (approximately 75 subjects) and EFV (approximately 50 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.


Condition Intervention Phase
Infection, Human Immunodeficiency Virus
Drug: DTG 50 mg
Drug: EFV 600 mg
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by ViiV Healthcare:

Primary Outcome Measures:
  • Proportion of participants with HIV type 1 (HIV-1) RNA< 50 copies/milliliter (c/mL) [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    The proportion of responders will be assessed at the study Week 48 for subjects randomized to receive DTG who received at least one dose of this medication. Response will be assessed according to the Snapshot algorithm. In this approach subjects with HIV-1 RNA >= 50 c/mL are considered non responders. Subjects without HIV-1 RNA data at Week 48 [due to missing data or discontinuation of investigational product (IP) prior to visit window] are also considered as non responders, as well as subjects with ART substitutions not permitted per protocol


Secondary Outcome Measures:
  • Proportion of subjects with plasma HIV-1 RNA <50 c/mL [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
    The proportion of responders according to the Snapshot algorithm (as described for the primary outcome) will be assessed in both study arms

  • Proportion of subjects with plasma HIV-1 RNA< 50 c/mL [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    The proportion of responders according to the Snapshot algorithm (as described for the primary outcome) will be assessed in subjects randomized to receive EFV

  • Changes from baseline in CD4+ counts at Week 24 and Week 48. [ Time Frame: Baseline to Week 24 and 48 ] [ Designated as safety issue: No ]
    Blood samples will be collected for assessment of lymphocyte subsets by flow cytometry (total lymphocyte counts, percentage, and absolute CD4+ cell count counts)

  • Proportion of subjects without virologic or tolerability failure by Weeks 24 and 48 [ Time Frame: Week 24 and Week 48 ] [ Designated as safety issue: No ]
    Failure will be defined as treatment-related discontinuation which may include meeting confirmed virologic withdrawal criteria, treatment-related adverse event (AE), safety stopping criteria, or lack of efficacy

  • Incidence and severity of all AEs, serious adverse events (SAEs)[including TB-associated Immune reconstitution inflammatory syndrome(IRIS)], and laboratory abnormalities [ Time Frame: Up to Week 52 ] [ Designated as safety issue: No ]
    Frequency, type and grade of AEs and SAEs, frequency and grade of laboratory abnormalities and incidence of TB IRIS

  • Proportion of subjects with viral resistance [ Time Frame: At Week 24 and Week 48 ] [ Designated as safety issue: No ]
    Proportion of subjects with treatment-emergent genotypic and phenotypic resistance to DTG, EFV and other on-study NRTIs in patients with confirmed virologic withdrawal criterion


Estimated Enrollment: 125
Study Start Date: November 2014
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dolutegravir
Twice-daily DTG 50 mg plus dual NRTI during RIF-containing TB treatment (isoniazid, RIF, pyrazinamide and ethambutol standard doses by the NTP under program conditions or acceptable alternative RIF-containing regimens) and for 2 weeks following discontinuation of TB treatment, then once-daily DTG 50 mg with the same NRTI through Week 52
Drug: DTG 50 mg
DTG is available as 50 mg film-coated tablet. DTG may be administered with or without food
Active Comparator: Efavirenz
Once-daily EFV 600 mg plus dual NRTI through Week 52 along with TB treatment including isoniazid, RIF, pyrazinamide and ethambutol standard doses by the NTP under program conditions.
Drug: EFV 600 mg
EFV is supplied as film-coated capsule-shaped oral tablet containing 600 mg of EFV and must be administered without food

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02178592

Contacts
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com

Sponsors and Collaborators
ViiV Healthcare
PPD
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials ViiV Healthcare
  More Information

No publications provided

Responsible Party: ViiV Healthcare
ClinicalTrials.gov Identifier: NCT02178592     History of Changes
Other Study ID Numbers: 117175
Study First Received: June 26, 2014
Last Updated: August 14, 2014
Health Authority: Peru: Instituto Nacional de Salud
Mexico: Federal Commission for Protection Against Health Risks
South Africa: Medicines Control Council
Russia: Ministry of Health, Department for State Regulation of the Circulation of Medicines
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Thailand: International Affairs and Investigational New Drug Section, Drug Control Division, FDA
Brazil: Agência Nacional de Vigilância Sanitária (ANVISA)

Keywords provided by ViiV Healthcare:
integrase inhibitor
Mycobacterium tuberculosis
rifampicin-sensitive
dolutegravir
antiretroviral therapy-naïve
HIV-1 infection
efavirenz
co-infection

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
Immunologic Deficiency Syndromes
Tuberculosis
Coinfection
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Immune System Diseases
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Infection
Parasitic Diseases
Rifampin
Efavirenz
Dolutegravir
Integrase Inhibitors
Antibiotics, Antitubercular
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antitubercular Agents
Enzyme Inhibitors

ClinicalTrials.gov processed this record on August 27, 2014