GSK Medicine: Study Number: Title: Rationale: Phase: Study Period: Study Design: Centres: Indication: Treatment: Objectives:

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1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. GSK Medicine: dolutegravir/abacavir/lamivudine Study Number: ING Title: A Phase IIIb, randomized, open-label study of the safety and efficacy of dolutegravir/abacavir/lamivudine once daily compared to atazanavir and ritonavir plus tenofovir/emtricitabine once daily in HIV-1 infected antiretroviral therapy naïve women Rationale: Fewer women than men have been enrolled in previous clinical studies of dolutegravir. This study was designed to evaluate the safety and efficacy of dolutegravir/abacavir/lamivudine fixed dose combination ( ) once daily compared to atazanavir and ritonavir plus tenofovir/emtricitabine (ATV+RTV+TDF/FTC ) once daily in human immunodeficiency virus type 1 (HIV-1) infected antiretroviral therapy (ART) naïve women. Phase: IIIb Study Period: 22-AUG ongoing Study Design: Study ING was a 48-week randomized, open-label, active-controlled, multicenter, parallel group, non-inferiority study. The study included a Screening Period, and a Randomized Phase (48 weeks), followed by a Continuation Phase (only for subjects randomized to receive for whom is not locally available). During the Randomized Phase, clinic visits occurred at Day 1, and at Weeks 4, 12, 24, 36 and 48. Centres: A total of 86 investigational centers in 13 countries randomized one or more subjects. There were 3 centers in Argentina, 4 in Canada, 4 in France, 7 in Italy, 2 in Mexico, 3 in Portugal, 1 in Puerto Rico, 6 in Russia, 2 in South Africa, 11 in Spain, 5 in UK, 36 in USA, and 2 in Thailand. Indication: Treatment of HIV-1 infection Treatment: Eligible subjects were randomly assigned 1:1 to receive 50mg/600mg/300mg administered once daily or ATV (300mg) +RTV (100mg) +TDF/FTC (300mg/200mg) administered once daily during the Randomized Phase (48 weeks). Study treatments were administered in an open label fashion. Subject randomization was stratified by Screening plasma HIV-1 RNA ( 100,000 copies/milliliter [c/ml] or >100,000 c/ml), and CD4+ cell count ( 350 cells/mm 3 or >350 cells/mm 3 ). Upon successful completion of the Week 48 visit, subjects in the treatment group (in countries where was not commercially available) were given the opportunity to enter the Continuation Phase during which subjects were supplied with until it was locally available. Objectives: To demonstrate the non-inferior antiviral activity of dolutegravir, abacavir and lamivudine fixed dose combination ( ) once daily compared to atazanavir plus ritonavir and tenofovir disoproxil fumarate/emtricitabine fixed dose combination (ATV+RTV+TDF/FTC ), each administered once daily over 48 weeks in HIV-1 infected ART-naïve women. Primary Outcome (Endpoints)/Efficacy: The proportion of subjects with plasma HIV-1 RNA <50 c/ml at Week 48 using the Snapshot algorithm for the Intent-to-Treat Exposed (ITT-E) Population. Secondary Outcome: Key Secondary Endpoints/Efficacy: Proportion of subjects with plasma HIV-1 RNA <50 and <400 c/ml over time; Absolute values and change from Baseline in plasma HIV-1 RNA over time; Absolute values and changes from Baseline in CD4+ cell counts over time; Incidence of disease progression (HIV-associated conditions, AIDS and death); Incidence of treatment-emergent genotypic and phenotypic resistance in subjects who met confirmed virologic withdrawal criteria. Other Secondary Outcomes: Change from Baseline in health related quality of life using the SF-12 was assessed at Week 48; Treatment satisfaction was compared between treatment groups using the HIV Treatment Satisfaction Questionnaire. Statistical Methods: Assuming an 80% response rate in both treatment groups, the study required a sample size of 237 subjects per treatment group to have 90% power with a -12 % non-inferiority margin and a 1-sided 2.5% level of significance. Efficacy analyses were conducted based on the Intent-to-Treat Exposed (ITT-E) population, which consists of all randomized subjects who received at least one dose of study medication. Subjects were assessed according to their 1

2 randomized treatment, regardless of the treatment they received. Adjusted estimates of the difference in the rate of responders between the two treatment groups were presented along with two-sided confidence intervals (CIs) based on a stratified analysis using Cochran-Mantel-Haenszel (CMH) weights. For the statistical analysis, four strata (subgroups) were formed according to the combinations of levels of the following categorical variables: Baseline plasma HIV-1 RNA ( vs. >100,000 c/ml) and Baseline CD4+ cell count ( vs. >350 cells/mm 3 ). The CMH estimate of the common difference in rates across strata was calculated as the weighted average of the strata-specific estimates of the difference in response rates between the two treatment groups. Safety analyses were conducted based on the Safety population, defined as all subjects who received at least one dose of IP. Subjects were assessed according to the actual treatments received. Health related quality of life was assessed using the SF-12. Change from Baseline at Week 48 for the Total Score, physical component summary (PCS), and the mental component summary (MCS) were summarized for each treatment group. Treatment satisfaction was measured using the HIVTSQ. The Total Score, Lifestyle/ease Sub-score and General Satisfaction/Clinical Sub-score were summarized and compared between the treatment groups at each visit. The incidence of treatment emergent genotypic and phenotypic resistance to NRTIs, protease inhibitors, and integrase inhibitors was summarized by treatment group. Study Population: Key inclusion criteria included HIV-1 infected, ART- naïve women 18 years of age with plasma HIV-1 RNA 500 c/ml at Screening who had a negative HLA-B*5701 allele assessment. The main exclusion criteria were women who were pregnant or breastfeeding, subjects with any degree of hepatic impairment, hepatitis B positive at Screening, subjects needing Hepatitis C therapy, subjects with any evidence of primary viral resistance in the Screening result, subjects with a significant suicidality risk, subjects having an estimated creatinine clearance <50 ml/min via Cockroft-Gault method, or subjects having a corrected QT interval (QTc) (Bazett) 450 msec. Number of Subjects: ATV+RTV+TDF/FTC Planned, N Randomised, N Randomised and Treated (ITT-E), N (%) 248 (100) 247 (100) Completed, n (%) 206 (83) 192 (78) Total Number Subjects Withdrawn, N (%) 42 (17) 55 (22) Withdrawn due to Adverse Events n (%) 10 (4) 18 (7) Withdrawn due to Lack of Efficacy n (%) 5 (2) 4 (2) Withdrawn for other reasons n (%) 27 (11) 33 (13) Demographics (Intent to Treat Exposed [ITT-E]): ATV+RTV+TDF/FTC N (ITT-E) Females, n (%) 248 (100) 247 (100) Median Age, years (range) 37.5 (19-79) 37.0 (20-65) Race, n (%): White 115 (46) 107 (43) Race, n (%): African American/African Heritage 102 (41) 108 (44) Primary Efficacy Results (ITT-E): ATV+RTV+TDF/FTC Proportion of Subjects With Plasma HIV-1 RNA <50 c/ml at Week 48 (Snapshot), n/n (%) 203/248 (82) 176/247 (71) Adjusted Difference in Proportion (95% Confidence Interval) 10.5 (3.1, 17.8) ( - ATV+RTV+TDF/FTC ) Test for superiority: p-value p=

3 Key Secondary Endpoints/Efficacy Results (ITT-E): ATV+RTV+ TDF/FTC Proportion of Subjects With Plasma HIV-1 RNA <50 c/ml at Week 48, 203 (82) 176 (71) (Snapshot) n (%) Proportion of Subjects With Plasma HIV-1 RNA <400 c/ml at Week (83) 187 (76) (Snapshot), n (%) Change from Baseline in Plasma HIV-1 RNA at Week 48 (log10 c/ml), n=207 n=192 Median (IQR) (-3.530, ) (-3.475, ) Change from Baseline in CD4+ Cell Count at Week 48 (cells/mm 3 ), n=208 n=191 Median (IQR) (143.5, 315.5) (113.0, 321.0) Incidence of Disease Progression: HIV-associated Conditions, AIDS and Death: Number of Subjects Progressing to CDC Class C or Death (%) Number of subjects meeting confirmed virologic withdrawal criteria (defined as two consecutive assessments of plasma HIV-1 RNA >400 c/ml on or after Week 24) 7 (3) 7 (3) 6 4 Incidence of treatment-emergent genotypic and phenotypic resistance 0 a 1 (M184M/I/V in subjects who met confirmed virologic withdrawal criteria, n mutation) a Two subjects each receiving had either K219K/Q or E138E/G at confirmed virologic withdrawal with no reduced susceptibility to all antiretroviral drugs tested. Other Secondary Outcomes (ITT-E): Change from Baseline in Health Related Quality of Life Total Score using the SF-12 at Week 48, Mean (SD) HIV Treatment Satisfaction Questionnaire Total Score at Week 48, Mean (SD) n= (5.15) n= (4.38) ATV+RTV+ TDF/FTC n= (5.66) n= (6.00) Safety Results: Adverse events (AEs) and serious adverse events (SAEs) were collected from the start date of investigational product and until the follow up contact. AEs and SAEs reported below are for the Randomized Phase (48 weeks). An on-therapy AE is defined as any Post-baseline AE with onset date before the subject s last follow up visit. AEs were identified post-hoc for two ATV+RTV+TDF/FTC subjects at one site. These AEs are not included in the safety tables below and were not considered to affect the overall safety findings for the study. Most Frequent Adverse Events On-Therapy n (%) ATV+RTV+TDF/FTC n (%) Subjects with any AE(s) 195 (79) 197 (80) Nausea 46 (19) 49 (20) Headache 28 (11) 32 (13) Diarrhea 24 (10) 32 (13) Upper respiratory tract infection 18 (7) 20 (8) Cough 10 (4) 26 (11) Dyspepsia 9 (4) 25 (10) Vomiting 15 (6) 18 (7) Rash 12 (5) 20 (8) Back pain 12 (5) 17 (7) Nasopharyngitis 15 (6) 14 (6) Urinary tract infection 13 (5) 16 (6) 3

4 Serious Adverse Events - On-Therapy n (%) [related] a ATV+RTV+TDF/FTC n (%) [related] a Subjects with any SAEs 12 (5) [0] 20 (8) [3] (includes both fatal and non-fatal events) Pneumonia 1 (<1) 2 (<1) Arthritis infective 0 1 (<1) Bacteraemia 1 (<1) 0 Cellulitis 0 1 (<1) Herpes simplex 0 1 (<1) Infected skin ulcer 1 (<1) 0 Lower respiratory tract infection 1 (<1) 0 Meningitis viral 0 1 (<1) Pneumocystis jirovecii pneumonia 1 (<1) 0 Amnesia 1 (<1) 0 Cerebrovascular accident 1 (<1) 0 Seizure 0 1 (<1) Transient ischemic attack 0 1 (<1) Acute psychosis 0 1 (<1) Intentional self-injury 0 1 (<1) Panic attack 1 (<1) 0 Angioedema 1 (<1) 0 Diabetic foot 1 (<1) 0 Skin ulcer 0 1 (<1) Acute coronary syndrome 1 (<1) 0 Acute myocardial infarction 1 (<1) 0 Abdominal pain 1 (<1) 1 (<1) Nausea 0 1 (<1) Vomiting 0 1 (<1) Cholecystitis chronic 0 1 (<1) [1] Hepatitis acute 0 1 (<1) Ankle fracture 1 (<1) 0 Thermal burn 1 (<1) 0 Endometriosis 0 1 (<1) Rectocele 0 1 (<1) Hypertensive emergency 1 (<1) 0 Peripheral artery stenosis 0 1 (<1) Death 1 (<1) 0 Blood creatinine increased 0 1 (<1) [1] Diabetic ketoacidosis 0 1 (<1) Electrolyte imbalance 1 (<1) 0 Osteonecrosis 0 1 (<1) [1] Scleroderma 0 1 (<1) Abortion spontaneous 0 1 (<1) Acute kidney injury 1 (<1) 0 Chronic kidney disease 1 (<1) 0 Asthma 0 1 (<1) Subjects with fatal SAEs, n (%) 1 (<1) [0] 1 (<1) [0] Death natural causes 1 (<1) 0 Pulmonary tuberculosis b 0 1 (<1) a [related] = number of events considered by the investigator to be related to study medication b SAE started one day prior to starting study medication 4

5 Conclusion: At Week 48, using the Snapshot algorithm, administered once daily demonstrated superiority to once-daily ATV+RTV+TDF/FTC in treatment- naïve HIV-1 infected women with 82% and 71% of subjects respectively, achieving HIV-1 RNA <50 c/ml (adjusted treatment difference and 95% CI; 10.5%, +3.1% to +17.8%; difference in the primary endpoint was statistically significant, [p=0.005]). Differences in the efficacy response rate were due to a lower rate of discontinuations due to AEs (4% vs. 7%) and a lower rate of virologic failure (6% vs. 14%) in the treatment group compared with the ATV+RTV+TDF/FTC treatment group. At Week 48, reductions in HIV-1 RNA and increases in CD4+ cell counts from Baseline were similar in both treatment groups. The incidence of disease progressions in HIV-1 associated conditions, AIDs and death was low and similar between treatment groups (3%). During the Randomized Phase, the frequencies of AEs reported were similar for subjects in both treatment groups: (195 subjects [79%]) vs. ATV+RTV+TDF/FTC (197 subjects [80%]). The most commonly reported AEs were nausea, headache, and diarrhea. Overall, 32 subjects reported SAEs during the Randomized Phase: (12 subjects [5%]) vs. ATV+RTV+TDF/FTC (20 subjects [8%]). All SAEs were reported in no more than one subject per treatment group, except for pneumonia which was reported in 2 subjects in the ATV+RTV+TDF/FTC treatment group. One death was reported in each treatment group during the Randomized Phase ( : natural causes; ATV+RTV+TDF/DTC : pulmonary tuberculosis [started pre-treatment]). In addition, one death was reported during the Continuation Phase ( : acute methadone intoxication). 5