Phase 3
N=113
Open-label Study of Dolutegravir (DTG) or Efavirenz (EFV) for Human Immunodeficiency Virus (HIV) - Tuberculosis (TB) Co-infection
Infection, Human Immunodeficiency Virus · HIV Infections
Bottom Line
View on ClinicalTrials.gov: NCT02178592 ↗Enrolled (actual)
113
Serious AEs
9.5%
Results posted
Feb 2019
Primary outcome: Primary: 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 — 75 Percentage of participants
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 3
- Interventions
- DTG 50 mg (Drug); EFV 600 mg (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- ViiV Healthcare
- Primary completion
- Nov 2017
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY 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 |
75 | — |
| SECONDARY Percentage of Participants With Plasma HIV-1 RNA <50 Copies/Milliliter at Week 48 in EFV Arm Using the Modified Snapshot Algorithm |
82 | — |
| SECONDARY 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 |
81; 89 | — |
| SECONDARY Percentage of Participants Without Confirmed Virologic Withdrawal and Without Discontinuation Due to Treatment-related Reasons at Week 24 and Week 48 |
98.4; 95.2; 96.6; 92.7 | — |
| SECONDARY Change From Baseline in Cluster of Differentiation 4 (CD4+) Counts at Week 24 and Week 48 |
153.2; 127.1; 199.0; 194.5 | — |
| SECONDARY Number of Participants With Serious Adverse Event (SAE) and Common (>=5%) Non-serious AE (Non-SAE) - Randomized Phase |
38; 33; 5; 5 | — |
| SECONDARY Number of Participants With SAE and Common (>=5%) Non-SAE - OLE Phase |
36; 16; 5; 2 | — |
| SECONDARY Number of Participants With Maximum Post-Baseline-emergent Chemistry Toxicities - Randomized Phase |
10; 9; 1; 1; 1; 1 | — |
| SECONDARY Number of Participants With Maximum Post-Baseline-emergent Chemistry Toxicities- Randomized Phase + OLE Phase |
12; 10; 3; 2; 1; 1 | — |
| SECONDARY Number of Participants With Maximum Post-Baseline-emergent Hematology Toxicities- Randomized Phase |
2; 1; 0; 0; 0; 0 | — |
| SECONDARY Number of Participants With Maximum Post-Baseline-emergent Hematology Toxicities - Randomized Phase + OLE Phase |
2; 1; 1; 0; 0; 0 | — |
| SECONDARY Percent Change From Baseline in the Fasting Lipid Profile at Week 24 and Week 48 |
6.314; 16.443; -0.375; 17.371; 39.002; 39.174 | — |
| SECONDARY Change From Baseline in the Fasting Lipid Profile for Total Cholesterol/HDL Ratio at Week 24 and Week 48 |
-16.292; 36.562; -11.949; -11.051 | — |
| SECONDARY Percentage of Participants Who Permanently Discontinued Study Treatment Due to AEs - Randomized Phase |
0; 5 | — |
| SECONDARY Percentage of Participants Who Permanently Discontinued Study Treatment Due to AEs - OLE Phase |
4; 0 | — |
| SECONDARY Number of Participants With Tuberculosis (TB) Associated (Assoc.) Immune Reconstitution Inflammatory Syndrome (IRIS) |
1; 0; 2; 3; 1; 0 | — |
| SECONDARY Number of Participants With Treatment-emergent Genotypic Resistance |
2; 0; 0; 1; 2; 0 | — |
| SECONDARY Number of Participants With Treatment-emergent Phenotypic Resistance |
1; 1; 0; 0; 0; 0 | — |
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; ( =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 =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 =2 × upper limit of normal
- Hemoglobin <=7.4 grams per deciliter;
- Platelet count <50000/mm^3
Data sourced from ClinicalTrials.gov (NCT02178592). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.