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NCT02178592

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

Completed Phase 3 Results posted Last updated 12 January 2021
What this trial tests

Phase 3 trial testing DTG 50 mg in Infection, Human Immunodeficiency Virus in 113 participants. Completed in 6 March 2020.

Timeline
23 January 2015
Primary endpoint
2 November 2017
6 March 2020

Quick facts

Lead sponsorViiV Healthcare
PhasePhase 3
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingnone
Primary purposetreatment
Enrollment113
Start date23 January 2015
Primary completion2 November 2017
Estimated completion6 March 2020
Sites28 locations across South Africa, Russia, Peru, Mexico, Argentina, Thailand, Brazil

Drugs / interventions tested

Conditions studied

Sponsor

ViiV Healthcare — full company profile →

Who can join

18 and older, any sex, with Infection, Human Immunodeficiency Virus or HIV Infections. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

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 Primary · Week 48

Plasma samples were collected for quantitative analysis of HIV-1 RNA. The percentage of participants with plasma HIV-1 RNA \<50 copies/milliliter was assessed at Week 48 using the snapshot algorithm in the DTG arm. Response was assessed using a modified FDA Snapshot algorithm in which participants were not penalized 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

GroupValue95% CI
DTG 50 mg7565 – 86
Percentage of Participants With Plasma HIV-1 RNA <50 Copies/Milliliter at Week 48 in EFV Arm Using the Modified Snapshot Algorithm Secondary · Week 48

Plasma samples were collected for quantitative analysis of HIV-1 RNA. The percentage of participants with plasma HIV-1 RNA \<50 copies/milliliter were assessed at Week 48 using the snapshot algorithm in the EFV arm. Response was assessed using a modified FDA Snapshot algorithm in which participants were not penalized 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

GroupValue95% CI
EFV 600 mg8270 – 93
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 Secondary · Week 24

Plasma samples were collected for quantitative analysis of HIV-1 RNA. The percentage of participants with plasma HIV-1 RNA \<50 copies/milliliter were assessed at Week 24 using the snapshot algorithm in the DTG and EFV arm. 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

GroupValue95% CI
DTG 50 mg8172 – 90
EFV 600 mg8979 – 98
Percentage of Participants Without Confirmed Virologic Withdrawal and Without Discontinuation Due to Treatment-related Reasons at Week 24 and Week 48 Secondary · 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) has been 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 discontinu

Week 24
GroupValue95% CI
DTG 50 mg98.489.1 – 99.8
EFV 600 mg95.282.1 – 98.8
Week 48
GroupValue95% CI
DTG 50 mg96.687.0 – 99.1
EFV 600 mg92.779.1 – 97.6
Change From Baseline in Cluster of Differentiation 4 (CD4+) Counts at Week 24 and Week 48 Secondary · Baseline (Day 1), Week 24 and Week 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 point from the Baseline value.

Week 24, n=61,41
GroupValue95% CI
DTG 50 mg153.2± 125.09
EFV 600 mg127.1± 158.14
Week 48, n=49, 33
GroupValue95% CI
DTG 50 mg199.0± 146.22
EFV 600 mg194.5± 137.81
Number of Participants With Serious Adverse Event (SAE) and Common (>=5%) Non-serious AE (Non-SAE) - Randomized Phase Secondary · Up to Week 52

An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is any untoward medical occurrence that, at any dose that results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, all events of possible drug-induced liver injury with hyperbilirubinemia or any other situation according to medical or scienti

Common Non-SAE
GroupValue95% CI
DTG 50 mg38
EFV 600 mg33
SAE
GroupValue95% CI
DTG 50 mg5
EFV 600 mg5
Number of Participants With SAE and Common (>=5%) Non-SAE - OLE Phase Secondary · Week 52 to Week 252

An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is any untoward medical occurrence that, at any dose that results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, all events of possible drug-induced liver injury with hyperbilirubinemia or any other situation according to medical or scienti

Common Non-SAE
GroupValue95% CI
DTG 50 mg36
EFV 600 mg16
SAE
GroupValue95% CI
DTG 50 mg5
EFV 600 mg2
Number of Participants With Maximum Post-Baseline-emergent Chemistry Toxicities - Randomized Phase Secondary · Up to Week 52

Blood samples for assessment of clinical chemistry parameters were collected at indicated time points. Clinical chemistry assessments included alanine aminotransferase (ALT), albumin, alkaline phosphatase, aspartate aminotransferase (AST), bilirubin, carbon dioxide, cholesterol, creatine kinase, creatinine, glucose, low density lipoprotein (LDL) cholesterol calculation, lipase, phosphate, potassium, and sodium. Data for number of participants who experienced maximum post-Baseline emergent chemistry toxicities were summarized. Maximum post-Baseline emergent chemistry toxicities were graded usin

ALT, Grade 1
GroupValue95% CI
DTG 50 mg10
EFV 600 mg9
ALT, Grade 2
GroupValue95% CI
DTG 50 mg1
EFV 600 mg1
ALT, Grade 3
GroupValue95% CI
DTG 50 mg1
EFV 600 mg1
ALT, Grade 4
GroupValue95% CI
DTG 50 mg0
EFV 600 mg0
Albumin, Grade 1
GroupValue95% CI
DTG 50 mg2
EFV 600 mg2
Albumin, Grade 2
GroupValue95% CI
DTG 50 mg8
EFV 600 mg1
Albumin, Grade 3
GroupValue95% CI
DTG 50 mg0
EFV 600 mg0
Albumin, Grade 4
GroupValue95% CI
DTG 50 mg0
EFV 600 mg0
Number of Participants With Maximum Post-Baseline-emergent Chemistry Toxicities- Randomized Phase + OLE Phase Secondary · Up to Week 252

Blood samples for assessment of clinical chemistry parameters were collected at indicated time points. Clinical chemistry assessments included ALT, albumin, alkaline phosphatase, AST, bilirubin, carbon dioxide, cholesterol, creatine kinase, creatinine, glucose, LDL cholesterol calculation, lipase, phosphate, potassium, and sodium. Data for number of participants with maximum post-Baseline emergent chemistry toxicities were summarized. Maximum post-Baseline emergent chemistry toxicities were graded using DAIDS toxicity grading for HIV-infected participants as Grade 1 (mild), Grade 2 (moderate),

ALT, Grade 1
GroupValue95% CI
DTG 50 mg12
EFV 600 mg10
ALT, Grade 2
GroupValue95% CI
DTG 50 mg3
EFV 600 mg2
ALT, Grade 3
GroupValue95% CI
DTG 50 mg1
EFV 600 mg1
ALT, Grade 4
GroupValue95% CI
DTG 50 mg0
EFV 600 mg0
Albumin, Grade 1
GroupValue95% CI
DTG 50 mg2
EFV 600 mg2
Albumin, Grade 2
GroupValue95% CI
DTG 50 mg8
EFV 600 mg1
Albumin, Grade 3
GroupValue95% CI
DTG 50 mg0
EFV 600 mg0
Albumin, Grade 4
GroupValue95% CI
DTG 50 mg0
EFV 600 mg0
Number of Participants With Maximum Post-Baseline-emergent Hematology Toxicities- Randomized Phase Secondary · Up to Week 52

Blood samples for assessment of hematology parameters were collected at indicated time points. Hematology assessments included hemoglobin, leukocytes, neutrophils and platelets. Data for number of participants who experienced maximum post-Baseline emergent hematology toxicities were summarized. 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). Higher grade indicates more severity.

Hemoglobin, Grade 1
GroupValue95% CI
DTG 50 mg2
EFV 600 mg1
Hemoglobin, Grade 2
GroupValue95% CI
DTG 50 mg0
EFV 600 mg0
Hemoglobin, Grade 3
GroupValue95% CI
DTG 50 mg0
EFV 600 mg0
Hemoglobin, Grade 4
GroupValue95% CI
DTG 50 mg0
EFV 600 mg0
Leukocytes, Grade 1
GroupValue95% CI
DTG 50 mg4
EFV 600 mg1
Leukocytes, Grade 2
GroupValue95% CI
DTG 50 mg0
EFV 600 mg0
Leukocytes, Grade 3
GroupValue95% CI
DTG 50 mg0
EFV 600 mg1
Leukocytes, Grade 4
GroupValue95% CI
DTG 50 mg0
EFV 600 mg1
Number of Participants With Maximum Post-Baseline-emergent Hematology Toxicities - Randomized Phase + OLE Phase Secondary · Up to Week 252

Blood samples for assessment of hematology parameters were collected at indicated time points. Hematology assessments included hemoglobin, leukocytes, neutrophils and platelets. Data for number of participants who experienced maximum post-Baseline emergent hematology toxicities were summarized. 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). Higher grade indicates more severity.

Hemoglobin, Grade 1
GroupValue95% CI
DTG 50 mg2
EFV 600 mg1
Hemoglobin, Grade 2
GroupValue95% CI
DTG 50 mg1
EFV 600 mg0
Hemoglobin, Grade 3
GroupValue95% CI
DTG 50 mg0
EFV 600 mg0
Hemoglobin, Grade 4
GroupValue95% CI
DTG 50 mg0
EFV 600 mg0
Leukocytes, Grade 1
GroupValue95% CI
DTG 50 mg5
EFV 600 mg3
Leukocytes, Grade 2
GroupValue95% CI
DTG 50 mg1
EFV 600 mg1
Leukocytes, Grade 3
GroupValue95% CI
DTG 50 mg0
EFV 600 mg1
Leukocytes, Grade 4
GroupValue95% CI
DTG 50 mg0
EFV 600 mg1
Percent Change From Baseline in the Fasting Lipid Profile at Week 24 and Week 48 Secondary · Baseline (Day 1), 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). Percent change from Baseline for a parameter was calculated as the observed value minus the Baseline value divided by Baseline value multiplied by 100. Data for fasting lipid parameters has been summarized.

Cholesterol, Week 24, n=58, 40
GroupValue95% CI
DTG 50 mg6.314± 20.7036
EFV 600 mg16.443± 22.0445
Cholesterol, Week 48, n=47, 34
GroupValue95% CI
DTG 50 mg-0.375± 21.4890
EFV 600 mg17.371± 20.6312
HDL Cholesterol, Week 24, n=58, 40
GroupValue95% CI
DTG 50 mg39.002± 53.5060
EFV 600 mg39.174± 49.1087
HDL Cholesterol, Week 48, n=47, 34
GroupValue95% CI
DTG 50 mg24.987± 48.2471
EFV 600 mg45.423± 52.9949
LDL Cholesterol, Week 24, n=58, 40
GroupValue95% CI
DTG 50 mg4.315± 31.7095
EFV 600 mg13.487± 36.2511
LDL Cholesterol, Week 48, n=47, 34
GroupValue95% CI
DTG 50 mg-2.957± 31.9910
EFV 600 mg9.132± 41.1942
Triglycerides, Week 24, n=58, 40
GroupValue95% CI
DTG 50 mg-22.744± 33.4148
EFV 600 mg16.934± 118.7319
Triglycerides, Week 48, n=47, 34
GroupValue95% CI
DTG 50 mg-18.402± 39.0227
EFV 600 mg13.175± 57.0389

Adverse events — posted to ClinicalTrials.gov

Time frame: Serious adverse events (SAEs) and non-SAEs were collected up to Week 52 for Randomized Phase and from Week 52 to Week 252 for OLE Phase.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

DTG 50 mg- Randomized Phase
Serious: 5/69 (7%)
Deaths: 0/69
EFV 600 mg- Randomized Phase
Serious: 5/44 (11%)
Deaths: 0/44
DTG 50 mg- OLE Phase
Serious: 5/47 (11%)
Deaths: 1/47
EFV 600 mg- OLE Phase
Serious: 2/19 (11%)
Deaths: 0/19

Serious adverse events (22 terms)

ReactionSystemDTG 50 mg- Randomized PhaseEFV 600 mg- Randomized PhaseDTG 50 mg- OLE PhaseEFV 600 mg- OLE Phase
CellulitisInfections and infestations
Immune reconstitution inflammatory syndrome associated tuberculosisInfections and infestations
PneumoniaInfections and infestations
Tuberculosis gastrointestinalInfections and infestations
Patella fractureInjury, poisoning and procedural complications
Skin abrasionInjury, poisoning and procedural complications
Immune reconstitution inflammatory syndromeImmune system disorders
Abortion spontaneousPregnancy, puerperium and perinatal conditions
Suicidal ideationPsychiatric disorders
Acute kidney injuryRenal and urinary disorders
BronchospasmRespiratory, thoracic and mediastinal disorders
Psoas abscessInfections and infestations
Lower limb fractureInjury, poisoning and procedural complications
Foetal deathPregnancy, puerperium and perinatal conditions
Hyperemesis gravidarumPregnancy, puerperium and perinatal conditions
HeadacheNervous system disorders
Hypocalcaemic seizureNervous system disorders
SeizureNervous system disorders
Cholecystitis acuteHepatobiliary disorders
Blood creatine phosphokinase increasedInvestigations
ArthralgiaMusculoskeletal and connective tissue disorders
Ruptured ectopic pregnancyPregnancy, puerperium and perinatal conditions
Other adverse events (60 terms — click to expand)

ReactionSystemDTG 50 mg- Randomized PhaseEFV 600 mg- Randomized PhaseDTG 50 mg- OLE PhaseEFV 600 mg- OLE Phase
Upper respiratory tract infectionInfections and infestations
DiarrhoeaGastrointestinal disorders
Lower respiratory tract infectionInfections and infestations
HeadacheNervous system disorders
ArthralgiaMusculoskeletal and connective tissue disorders
DizzinessNervous system disorders
PharyngitisInfections and infestations
GastroenteritisInfections and infestations
VomitingGastrointestinal disorders
Back painMusculoskeletal and connective tissue disorders
Body tineaInfections and infestations
NauseaGastrointestinal disorders
RashSkin and subcutaneous tissue disorders
GynaecomastiaReproductive system and breast disorders
Urinary tract infectionInfections and infestations
Decreased appetiteMetabolism and nutrition disorders
Blood pressure increasedInvestigations
Herpes zosterInfections and infestations
InsomniaPsychiatric disorders
CoughRespiratory, thoracic and mediastinal disorders
FuruncleInfections and infestations
BronchitisInfections and infestations
InfluenzaInfections and infestations
Viral upper respiratory tract infectionInfections and infestations
PruritusSkin and subcutaneous tissue disorders
Blood creatinine increasedInvestigations
Alanine aminotransferase increasedInvestigations
NasopharyngitisInfections and infestations
Pain in extremityMusculoskeletal and connective tissue disorders
Musculoskeletal painMusculoskeletal and connective tissue disorders
DysuriaRenal and urinary disorders
NeutropeniaBlood and lymphatic system disorders
AcarodermatitisInfections and infestations
Fungal skin infectionInfections and infestations
TonsillitisInfections and infestations
ConjunctivitisInfections and infestations
CystitisInfections and infestations
Pulmonary tuberculosisInfections and infestations
Tinea facieiInfections and infestations
Tuberculosis gastrointestinalInfections and infestations

Most-reported serious reactions: Cellulitis, Immune reconstitution inflammatory syndrome associated tuberculosis, Pneumonia, Tuberculosis gastrointestinal, Patella fracture, Skin abrasion, Immune reconstitution inflammatory syndrome, Abortion spontaneous.

Data from ClinicalTrials.gov NCT02178592 adverse events section.

Sponsor's own description

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.

Publications & conference data

7 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis.
    Nahid P, Dorman SE, Alipanah N, Barry PM, et al · · 2016 · cited 829× · PMID 27516382 · DOI 10.1093/cid/ciw376
  2. Dolutegravir-based Antiretroviral Therapy for Patients Coinfected With Tuberculosis and Human Immunodeficiency Virus: A Multicenter, Noncomparative, Open-label, Randomized Trial.
    Dooley KE, Kaplan R, Mwelase N, Grinsztejn B, et al · · 2020 · cited 88× · PMID 30918967 · DOI 10.1093/cid/ciz256
  3. Oral abstracts of the 22nd International AIDS Conference, 23-27 July 2018, Amsterdam, the Netherlands.
    · 2018 · cited 12× · PMID 30051631 · DOI 10.1002/jia2.25148
  4. HIV & Hepatitis in the Americas 19-21 April 2018, Mexico City, Mexico.
    · 2018 · cited 3× · PMID 29671462 · DOI 10.1002/jia2.25093
  5. Implementation of the Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS™) Across Four Phase IIIb Clinical Trials in HIV-infected Individuals (ARIA, STRIIVING, DAWNING and INSPIRING).
    Brennan C, Whillis H, Man C, Wynne B, et al · · 2018 · cited 2× · PMID 30254794
  6. HIV & Hepatitis in the Americas, 4-6 April 2019, Bogotá, Colombia.
    · 2019 · cited 1× · PMID 30941891 · DOI 10.1002/jia2.25263
  7. Towards an ideal antiretroviral regimen for the global HIV epidemic.
    Grinsztejn B, Coelho LE, Luz PM, Veloso VG. · · 2017 · cited 1× · PMID 28758017 · DOI 10.1016/s2055-6640(20)30328-9

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Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing