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

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Infection, Human Immunodeficiency Virus	Drug: DTG 50 mg; Drug: EFV 600 mg	Phase 3

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	113 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (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
Actual Study Start Date :	January 23, 2015
Actual Primary Completion Date :	November 2, 2017
Estimated Study Completion Date :	December 31, 2019

Arms and Interventions

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Arm	Intervention/treatment
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

Outcome Measures

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Primary Outcome Measures :

1. Percentage of participants with plasma human immuno deficiency virus-1 ribeonucleic acid (HIV-1 RNA) < 50 copies/milliliter at Week 48 using the modified US Food and Drug Administration (FDA) Snapshot algorithm [ Time Frame: Week 48 ]
   The percentage of participants who were responders was assessed at the study Week 48 for participants randomized to receive DTG who received at least one dose of study medication. Response was assessed using a modified FDA Snapshot algorithm in which participants were not penalised for any single protocol allowed background therapy substitution even if occurs after the first trial visit.. In this approach participants with HIV-1 RNA >= 50 copies/milliliter are considered as non responders. Participants 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 participants with anti-retroviral (ART) substitutions were not permitted. Study drug (i.e. DTG or EFV) was not allowed to be substituted.

Secondary Outcome Measures :

1. Percentage of participants with plasma HIV-1 RNA <50 copies/milliliter at Week 48 using the modified Snapshot algorithm in the EFV arm [ Time Frame: Week 48 ]
   The percentage of responders was assessed at the study Week 48 for participants randomized to receive EFV who received at least one dose of study medication. Response was assessed using Modified Snapshot algorithm. In this approach participants with HIV-1 RNA >= 50 copies/milliliter were considered non responders. Participants without HIV-1 RNA data at Week 48 [due to missing data or discontinuation of IP prior to visit window] were also considered as non responders, as well as participants with ART substitutions were not permitted. Substitution of a background NRTI agent was permissible one time if it was due to reasons of drug toxicity.
2. 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 [ Time Frame: Week 24 ]
   The percentage of participants who were responders was assessed at study Week 24 for participants randomized to receive DTG who received at least one dose of this study medication. Response was assessed according to the Modified Snapshot algorithm. In this approach participants with HIV-1 RNA >= 50 copies/milliliter were considered non responders. Participants without HIV-1 RNA data at Week 24 [due to missing data or discontinuation of IP prior to visit window] were also considered as non responders, as well as participants with ART substitutions were not permitted. Substitution of a background NRTI agent was permissible one time if it was due to reasons of drug toxicity.
3. Percentage of participants without confirmed virologic withdrawal and without discontinuation due to treatment-related reasons at Week 24 and Week 48 [ Time Frame: Week 24 and Week 48 ]
   Percentage of participants not meeting confirmed virologic withdrawal criteria nor discontinued due to treatment related reasons at the time of analysis at Week 24 (through Day 210) and Week 48 (through Day 350) is presented by treatment group. The time to meeting confirmed virologic withdrawal criteria or discontinuation due to treatment related reasons (i.e., discontinuation due to drug-related adverse event [AE], or due to protocol defined safety stopping criteria, or due to lack of efficacy) were calculated. Participants who met confirmed virologic withdrawal criteria or discontinuation due to treatment related reasons were considered as Failure. Participants who had not met confirmed virologic withdrawal criteria (per protocol) and were ongoing in the study, or who had discontinued for reasons other than those related to treatment, were censored. This would be the Treatment-Related Discontinuation = Failure (TRDF) data.
4. Change from Baseline in cluster of differentiation 4 (CD4+) counts at Week 24 and Week 48 [ Time Frame: Baseline and Weeks 24 and 48 ]
   Blood samples were collected for assessment of lymphocyte subsets (CD4+ lymphocyte count) by flow cytometry at Baseline and Weeks 24, 48. Baseline was defined as the last pre-treatment value observed (typically from Day 1 visit). Change from Baseline was calculated subtracting the value at the specified time pint from the Baseline value.
5. Number of participants with maximum post-Baseline-emergent chemistry toxicities [ Time Frame: Up to 52 weeks ]
   Blood samples for assessment of clinical chemistry parameters were collected from Day 1 up to 52 weeks. Clinical chemistry assessments included alanine aminotransferase (ALT), albumin, alkaline phosphatase, aspartate aminotransferase (AST), bilirubin, carbon dioxide, chloride, cholesterol, creatine kinase, creatinine, direct bilirubin, glomerular filtration rate (GFR), glucose, high density lipoprotein (HDL) cholesterol direct, low density lipoprotein (LDL) cholesterol calculation and direct, lactate dehydrogenase, lipase, phosphate, potassium, sodium, total cholesterol, triglycerides, and urea. Maximum post-Baseline emergent chemistry toxicities were graded using Division of Acquired Immune Deficiency Syndrome [DAIDS] toxicity grading for HIV-infected participants as Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) and Grade 4 (potentially life-threating).
6. Number of participants with maximum post-Baseline-emergent hematology toxicities [ Time Frame: Up to 52 weeks ]
   Blood samples for assessment of clinical chemistry parameters were collected from Day 1 up to 52 weeks. Hematology assessments included basophils, eosinophils, mean corpuscle volume (MCV), erythrocytes, hematocrit, hemoglobin, leukocytes, lymphocytes, monocytes, neutrophils and platelets. Maximum post-Baseline emergent hematology toxicities were graded using DAIDS toxicity grading for HIV-infected participants as Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) and Grade 4 (potentially life-threating).
7. Percent change from Baseline in the fasting lipid profile at Weeks 24 and 48 [ Time Frame: Baseline, Week 24 and Week 48 ]
   Samples for lipid measurements were obtained in a fasted state at Baseline, Week 24 and Week 48. The parameters assessed during the lipid profile were total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides. Baseline was defined as the last pre-treatment value observed (typically from Day 1 visit). Change from baseline for a parameter was calculated as the observed value - the Baseline value.
8. Change from Baseline in the fasting lipid profile for total cholesterol/HDL ratio at Weeks 24 and 48 [ Time Frame: Baseline and Week 24 and Week 48 ]
   Samples for lipid measurements were obtained in a fasted state at Baseline, Week 24 and Week 48. The parameter assessed during the lipid profile was total cholesterol/HDL ratio. Baseline was defined as the last pre-treatment value observed (typically from Day 1 visit). Change from baseline for a parameter was calculated as the observed value minus the Baseline value.
9. Number of participants with tuberculosis (TB) associated (assoc.) immune reconstitution inflammatory syndrome (IRIS) [ Time Frame: Up to Week 12 ]
   Participants were monitored for signs and symptoms of TB-assoc. IRIS. Participants with IRIS symptoms in any adverse events (grade [G] 1 to 4) or HIV assoc. conditions were classified by the Endpoint Adjudication Committee in the following categories as met criteria for TB-assoc. IRIS, possibly met criteria for TB-assoc. IRIS and suspected TB-assoc. IRIS but not possible to adjudicate. Number of participants who were sent to the adjudication committee and were analyzed have been presented.
10. Number of participants with treatment-emergent genotypic resistance [ Time Frame: Up to 52 weeks ]
    Whole venous blood samples were obtained from each participants at Screening for resistance testing at the central laboratory (or a laboratory contracted by the central laboratory) and on study plasma for storage samples until Week 52 for potential viral genotypic and phenotypic analyses. Genotypic and phenotypic testing was conducted for participants meeting confirmed virologic withdrawal criteria, i.e., confirmed HIV-1 RNA >=400 copies/milliliter from Week 24 onwards. Genotypic and phenotypic analyses was carried out by Monogram Biosciences using, but not limited to, their Standard Phenosense and GenoSure testing methods for protease (PRO), reverse transcriptase (RT), and integrase assays. Genotypic mutations have been presented for the RT region on codons G190G, K101K, K103K, K65K, V106V and Y181Y. Viral Genotypic population comprised of all participants in the ITT-E population with available on-treatment genotypic data at the time confirmed virologic withdrawal was met.
11. Number of participants with treatment-emergent phenotypic resistance [ Time Frame: Up to 52 weeks ]
    Phenotypic susceptibility to all licensed antiretroviral drugs, including DTG and EFV were determined using PhenoSense HIV assays from Monogram Inc. Clinical cutoffs or biological cutoffs by PhenoSense were used to define the phenotypic susceptibility of background treatment and were interpreted as fold change > clinical lower cut-off or biologic cut-off= resistance, fold change >=clinical lower cut-off or biologic cut-off =sensitive (for bilogical cutoff) and fold change > clinical higher cut-off=resistance, fold change <=clinical higher cut-off and > clinical lower cut-off=partially sensitive, fold change <=clinical lower cut-off=sensitive. Viral Phenotypic population will consist of all participants in the ITT-E population with available on-treatment phenotypic resistance data at the time confirmed virologic withdrawal criteria was met. Only participants available at the specified time points were analyzed (represented by n=x in the category titles).

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
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

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  Show 37 Study Locations

Sponsors and Collaborators

ViiV Healthcare

GlaxoSmithKline

Investigators

Study Director:	GSK Clinical Trials	ViiV Healthcare

  Study Documents (Full-Text)

Documents provided by ViiV Healthcare:

Study Protocol  [PDF] March 21, 2016

Statistical Analysis Plan  [PDF] June 16, 2017

More Information

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Responsible Party:	ViiV Healthcare
ClinicalTrials.gov Identifier:	NCT02178592 History of Changes
Other Study ID Numbers:	117175
First Posted:	July 1, 2014
Last Update Posted:	October 4, 2018
Last Verified:	October 2018

Studies a U.S. FDA-regulated Drug Product:		No
Studies a U.S. FDA-regulated Device Product:		No

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:

Infection; Communicable Diseases; Immunologic Deficiency Syndromes; Tuberculosis; Acquired Immunodeficiency Syndrome; HIV Infections; Coinfection; Immune System Diseases; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections	Virus Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Slow Virus Diseases; Parasitic Diseases; Efavirenz; Dolutegravir; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents; Cytochrome P-450 CYP2C9 Inhibitors