Study No.: Title: Rationale: Phase: Study Period: Study Design: Centres: Indication: Treatment: Objectives: Primary Outcome/Efficacy Variable:

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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. Study No.: CNA19586 Title: Study of Once Daily Abacavir/Lamivudine versus Tenofovir/Emtricitabine, Administered with Efavirenz in Antiretroviral-Naïve, HIV-1 Infected Adult Subjects Rationale: At the time of the study, several three-drug antiretroviral combinations were available for initial use in antiretroviral therapy-naïve, human immunodeficiency (HIV) -infected subjects, all of which potently suppress HIV-1 ribonucleic acid (RNA) to below detectable levels, with accompanying restoration of immune function. The fixed dose combinations (FDCs) of abacavir sulphate 6mg/lamivudine 3mg (ABC/3TC) and tenofovir disoproxyl fumarate 3mg/emtricitabine 2mg (TDF/FTC) have facilitated once daily regimens, combining two nucleoside (-tide) reverse transcriptase inhibitors in one tablet. Since the treatment of HIV is life long, the long-term toxicity profiles of regimens are clinically important. The toxicity profiles of of ABC/3TC and TDF/FTC appear to be different. Abacavir sulphate is associated with a hypersensitivity reaction (which can be largely avoided with HLA-B*571 screening) and recently, a potential association between the use of abacavir and an increased risk of myocardial infarction has been reported in some, but not other, cohort analyses. In preclinical studies with tenofovir, adverse renal and skeletal effects were identified as potential issues, with a small number of serious cases of renal failure and Fanconi syndrome reported and several studies reporting an association of tenofovir with loss of bone mineral density. Efavirenz (EFV) was selected as the third agent since it is recommended by most national and international guidelines and, at the time of the design of the study, was thought to have no relevant impact on renal or bone endpoints. To date, there are limited data available from prospective studies describing toxicities of current antiviral therapies over time, so this study focussed on renal, bone, cardiovascular and other safety endpoints. Phase: IV Study Period: 22Jun27 11Dec29 Study Design: This was a multicentre, randomised, open-label, parallel-group study comparing the safety and efficacy of ABC/3TC FDC and TDF/FTC FDC, both administered with efavirenz, once daily for 96 weeks in antiretroviral-naïve, HLA-B*571 negative, human immunodeficiency virus (HIV) -1 infected adults. The study was made up of a 45-day screening period, a 96-week randomised treatment period for eligible subjects, and a 2 to 4 week follow-up period (conducted after the Week 96 Visit or the Withdrawal Visit, as applicable). Centres: 76 centres across 13 countries in Europe Indication: Human immunodeficiency virus (HIV) Treatment: ABC/3TC FDC was provided as oral tablets, each containing 6 mg ABC (as abacavir sulphate) and 3 mg 3TC. TDF/FTC FDC was provided as oral tablets, each containing 3 mg TDF (equivalent to 245 mg tenofovir disoproxil or 136 mg tenofovir) and 2 mg FTC. EFV was provided or sourced locally as 5 mg, 1 mg or 2 mg capsules, with a 6 mg total daily dose. Treatment arm A: ABC/3TC 1 x 6 mg/3 mg tablet once daily + EFV 1 x 6 mg tablet once daily; Treatment arm B: 1 x 3 mg/2 mg tablet once daily + EFV 1 x 6 mg tablet once daily. Objectives: The primary objective was to demonstrate a superior renal safety profile in subjects receiving ABC/3TC FDC compared with TDF/FTC FDC, both administered with efavirenz Primary Outcome/Efficacy Variable: The primary safety endpoint was the change from baseline in estimated glomerular filtration rate (GFR) calculated by modification of diet in renal disease (MDRD) equation. The primary time point was Week 48. Data from Week 96 are presented in this summary. Secondary Outcome/Efficacy Variable(s): The secondary endpoints included: Change from baseline in estimated GFR, calculated by MDRD and Cockcroft-Gault equations, at Week 24, Week 48, and Week 96 Proportion of subjects with decline from baseline in estimated GFR, calculated by MDRD and Cockcroft-Gault equations, of 1 ml/min/1.73 m 2 (ml/min for Cockcroft-Gault), 2 ml/min/1.73 m 2, 1%, and 2% at Week 24, Week 48, and Week 96 Proportion of subjects with National Kidney Foundation Chronic Kidney Disease Stage 1, 2, 3, 4, or 5 categories 1

2 of renal function at Week 24, Week 48, and Week 96 Change from baseline in lumbar spine and hip BMD, measured by DXA, at Week 24, Week 48 and Week 96 Proportion of subjects with decline from baseline in lumbar spine and hip BMD 2.% and 6.% at Week 24, Week 48 and Week 96 Proportion of subjects met World Health Organization (WHO) criteria for osteopenia (T-score -2.5 to -1.) and osteoporosis (T-score <-2.5) at Week 24, Week 48 and Week 96 Absolute values, change from baseline in absolute values, and proportion of subjects with treatment-emergent Division of AIDS (DAIDS) toxicities and National Cholesterol Education Program (NCEP) thresholds for fasting total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), and triglycerides at Week 24, Week 48, and Week 96 Incidence and severity of adverse events and proportion of subjects who discontinued treatment due to adverse events at Week 24, Week 48, and Week 96 Analysis of viral resistance in protocol-defined failures Proportion of subjects with HIV-1 ribonucleic acid (RNA) <5 copies/ml and <4 copies/ml Absolute values and change from baseline in HIV-1 RNA and cluster difference 4 (CD4 + ) cell count HIV-associated conditions Statistical Methods: The primary analysis was conducted once all subjects had reached Week 48, with a final analysis conducted on the Week 96 data. For the purposes of the sample size calculation, a 1 ml/min/1.73 m 2 difference in change from baseline in estimated GFR (MDRD) was considered clinically relevant in this patient population. Assuming a standard deviation (SD) of 3 ml/min/1.73 m 2 and a two-sided 5% level of significance, it was calculated that a total of 38 subjects (19 per treatment arm) would need to be randomised to provide 9% power to detect a 1 ml/min difference between the treatment arms. The primary analysis was conducted on the ITT-E Population using a repeated measures mixed model adjusted for baseline estimated GFR by MDRD, baseline body mass index (BMI) and race group (the stratification factors). The impact of other relevant baseline characteristics (and interactions) were assessed for inclusion in the model using a stepwise covariate selection method. The difference between treatment arms in total hip and lumbar spine BMD (main secondary endpoints) was assessed using a repeated measures mixed model analysis adjusted for baseline BMD and the randomisation strata - race and baseline BMI. Other baseline factors (and interactions) were explored using a stepwise covariate selection method. Study Population: Eligible subjects were antiretroviral-naïve (no previous therapy with any non-nucleoside reverse transcriptase inhibitor (NNRTI) and <14 days of prior therapy with any other antiretroviral), HLA-B*571 negative adults (>18 years of age) with a plasma HIV-1 ribonucleic acid (RNA) >1, copies/ml at screening. Subjects with an estimated creatinine clearance <5 ml/min (Cockcroft-Gault method) during the screening period were excluded. Similarly, any subject with an active, acquired immune deficiency syndrome (AIDS) defining illness at baseline was excluded (unless the subject was being treated and was clinically improving). All subjects were assessed for transmitted resistance to the antiretrovirals in the study any subject with evidence of resistance at screening or prior documented evidence of genotypic and/or phenotypic resistance was excluded. Number of Subjects: Planned, N Randomised, N Exposed, N Completed, n (%) Total Number Subjects Withdrawn, n (%) 77 (4) 59 (31) Withdrawn due to Adverse Events, n (%) 28 (15) 26 (13) Withdrawn due to Lack of Efficacy (insufficient viral load response, 11 (6) 2 (1) protocol-defined virologic failure), n (%) Withdrawn for other reasons, n (%) 38 (2) 31 (16) 2

3 Demographics N (ITT) Females: Males 33:159 4:153 Mean Age, years (SD) 37.7 (9.27) 37.8 (9.62) White, n (%) African American/African Heritage, n (%) American Indian or Alaska Native, n (%) Asian, n (%) White & African American/African, n (%) Native Hawaiian or other Pacific Islander & White, n (%) GFR (MDRD), n (%) Screen GFR <9 ml/min/1.73 m 2 Screen GFR 9 ml/min/1.73 m 2 BMI Strata, n (%) <25 kg/m 2 25 kg/m 2 Missing Primary Safety Results: 152 (79) 26 (14) 11 (6) 2 (1) 1 (<1) 62 (32) 13 (68) 127 (66) 64 (33) 1 (<1) 15 (78) 3 (16) 7 (4) 5 (3) 1 (<1) 63 (33) 13 (67) 131 (68) 62 (32) Adjusted mean change from baseline in estimated GFR by MDRD at 1.48 (1.22) (.944) Week 96; repeated measures mixed model analysis (SE) Difference between treatments % Confidence Interval (-5.38,.11) p-value.6 Secondary Safety Outcome Variable(s): Secondary endpoint: adjusted mean change from baseline in egfr by Cockcroft-Gault at Week 96; repeated measures mixed model analysis (SE) Difference between treatments % CI (-4.97, 1.61) 4.37 (1.228) 2.68 (1.133) baseline in GFR by MDRD 1 ml/min/1.73 m 2, n/n (%) baseline in GFR by Cockcroft-Gault 1 ml/min, n/n (%) baseline in GFR by MDRD 2 ml/min/1.73 m 2, n/n (%) baseline in GFR by Cockcroft-Gault 2 ml/min, n/n (%) baseline in GFR by MDRD 1%, n/n (%) baseline in GFR by Cockcroft-Gault 1%, n/n (%) baseline in GFR by MDRD 2%, n/n (%) baseline in GFR by Cockcroft-Gault 2%, n/n (%) 15/111 (14) 28/131 (21) 11/111 (1) 19/131 (15) 4/111 (4) 7/131 (5) 4/111 (4) 5/131 (4) 15/111 (14) 27/131 (21) 12/111 (11) 16/131 (12) 3/111 (3) 6/131 (5) 3/111 (3) 4/131 (3) 3

4 Secondary endpoint: proportion of subjects with National Kidney Foundation Chronic Disease Stage 1, 2, 3, 4 or 5 categories of renal function, n/n (%) Missing Normal Stage 1 Stage 2 Stage 3 Stage 4 Stage 5 11/93 (12) 75/93 (81) 3/93 (3) 4/93 (4) /93 /93 /93 18/19 (17) 83/19 (76) 4/19 (4) 4/19 (4) /19 /19 /19 Secondary endpoint: adjusted percentage change from baseline in (.13) (.12) hip BMD; repeated measures mixed model analysis (SE) Difference in percentage change between treatments % CI (-2.2, -.61) Secondary endpoint: adjusted percentage change from baseline in -.87 (.17) -1.7 (.15) lumbar spine BMD; repeated measures mixed model analysis (SE) Difference in percentage change between treatments % CI (-1.87,.2) baseline in lumbar spine and hip BMD, n/n (%) Lumbar spine 2% Lumbar spine 6% Hip 2% Hip 6% Secondary endpoint: proportion of subjects meeting World Health Organization criteria for osteopenia (T-score -2.5 to -1.) and osteoporosis (T-score <-2.5), n/n (%) Spine, osteopenia Spine, osteoporosis Hip, osteopenia Hip, osteoporosis Secondary endpoint: Fasting lipids median value and change from baseline, mg/dl (n) Total cholesterol, absolute value Total cholesterol, change from baseline Low density lipoprotein (LDL), absolute value LDL, change from baseline High density lipoprotein (HDL), absolute value HDL, change from baseline Triglycerides, absolute value Triglycerides, change from baseline 21/59 (36) 3/59 (5) 33/58 (57) 1/58 (2) 21/64 (33) 5/64 (8) 2/65 (31) / (11) 5.66 (97) (97) 27.7 (91) (11) (97) (11) 18.6 (97) 39/79 (49) 8/79 (1) 52/76 (68) 13/76 (17) 34/82 (41) 3/82 (4) 31/8 (39) / (119) (113) (117) 16.5 (11) (119) (113) (119) 6.2 (113) Secondary endpoint: proportion of subjects with baseline cholesterol desirable (according to NCEP guidelines) who shifted to a higher category post baseline, n/n (%) Secondary endpoint: proportion of subjects with baseline LDL optimal (according to NCEP guidelines) who shifted to a higher category post baseline, n/n (%) 95/134 (71) 57/143 (4) 76/94 (81) 64/11 (63) 4

5 Secondary endpoint: proportion of subjects with baseline HDL low (according to NCEP guidelines) who shifted to a higher category post baseline, n/n (%) Secondary endpoint: proportion of subjects with baseline triglyceride normal (according to NCEP guidelines) who shifted to a higher category post baseline, n/n (%) 91/12 (89) 88/111 (79) 6/17 (56) 52/17 (49) Secondary endpoint: proportion of subjects with treatment emergent DAIDS toxicities, n/n Cholesterol, Grade 3 Cholesterol, Grade 4 LDL, Grade 3 LDL Grade 4 Triglycerides, Grade 3 Triglycerides, Grade 4 9/15 /15 13/146 /146 2/15 1/15 1/163 /163 5/162 /162 /163 /163 Secondary endpoint: number of subjects with treatment-emergent resistance to study drug out of the number of subjects classified as protocol-defined failures with resistance sample available at time of failure, n/n Any treatment-emergent mutation Non-nucleoside reverse transcriptase inhibitor Nucleoside reverse transcriptase inhibitor Starting from the first administration of investigational products on Day 1 trough to the Follow-Up Visit, all adverse event and serious adverse event information was collected at each visit. Only serious adverse events relating to study participation and GSK concomitant medications was collected by the investigator during the time period starting from the Screening Visit through to the first administration of investigational products on Day 1. The most frequent adverse events, ie the most frequent adverse events in each treatment group, are detailed below. Most Frequent Adverse Events On-Therapy n (%) n (%) Subjects with any AE(s), n/n (%) 172/192 (9) 175/193 (91) Dizziness 48/192 (25) 48/193 (25) Nasopharyngitis 39/192 (2) 36/193 (19) Diarrhoea 36/192 (19) 27/193 (14) Headache 17/192 (9) 29/193 (15) Abnormal dreams 23/192 (12) 22/193 (11) Insomnia 21/192 (11) 18/193 (9) Rash 18/192 (9) 2/193 (1) Nausea 17/192 (9) 16/193 (8) Cough 17/192 (9) 13/193 (7) Fatigue 14/192 (7) 16/193 (8) Sleep disorder 14/192 (7) 16/193 (8) Depression 14/192 (7) 15/193 (8) Back pain 11/192 (6) 16/193 (8) Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] Subjects with non-fatal SAEs, n (%) 31 (16) 2 (1) n (%) [n considered related] 4/7 2/7 4/7 /3 /3 /3 n (%) [n considered related] Pneumonia 5 (3) [] 1 (<1) [] Drug hypersensitivity 5 (3) [5] 1 (<1) [1] Hypersensitivity 3 (2) [3] 5

6 Gastroenteritis 2 (1) [] Lower respiratory tract infection 1 (<1) [] 1 (<1) [] Pulmonary tuberculosis 1 (<1) [] 1 (<1) [] Immune reconstitution syndrome 2 (1) [1] Abscess limb 1 (<1) [] Endocarditis 1 (<1) [] Erysipelas 1 (<1) [] Eye infection toxoplasmal 1 (<1) [] Herpes zoster 1 (<1) [] Scrotal abscess 1 (<1) [] Staphylococcal sepsis 1 (<1) [] Tuberculosis 1 (<1) [] Viral infection 1 (<1) [] Accidental overdose 1 (<1) [] Ankle fracture 1 (<1) [] Forearm fracture 1 (<1) [] Humerus fracture 1 (<1) [] Meniscus lesion 1 (<1) [] Abdominal hernia 1 (<1) [] Diverticulum 1 (<1) [] Gastritis 1 (<1) [] Rectal haemorrhage 1 (<1) [] Cholecystitis 1 (<1) [] Cholelithiasis 1 (<1) [] Cholestasis 1 (<1) [] Cytolytic hepatitis 1 (<1) [] Hepatitis 1 (<1) [1] Burkitt s lymphoma 1 (<1) [] Lymphoma 1 (<1) [] Thymoma 1 (<1) [] Back pain 1 (<1) [] Osteoarthritis 1 (<1) [] Convulsion 1 (<1) [1] Transient ischaemic attack 1 (<1) [] Acute stress disorder 1 (<1) [] Apathy 1 (<1) [1] Neutropenia 1 (<1) [] Acute myocardial infarction 1 (<1) [] Porphyria non-acute 1 (<1) [] Goitre 1 (<1) [] Pyrexia 1 (<1) [] Cardiac murmur 1 (<1) [] Dehydration 1 (<1) [] Renal failure 1 (<1) [] Epididymitis 1 (<1) [] Asthma 1 (<1) [] Rash maculo-papular 1 (<1) [] Subjects with fatal SAEs, n (%) 1 (<1) n (%) [n considered n (%) [n related] considered Pulmonary oedema Cerebral hypoxia Cocaine overdose related] 1 (<1) [] 1 (<1) [] 1 (<1) [] 6

7 Secondary Efficacy Outcome Variable(s): Secondary endpoint: proportion of subjects with HIV-1 RNA <4 copies/ml, time to loss of virologic response (TLOVR) Analysis, n/n (%) Secondary endpoint: proportion of subjects with HIV-1 RNA <5 copies/ml, TLOVR Analysis, n/n (%) 11/192 (57) 126/193 (65) 98/192 (51) 113/193 (59) Secondary endpoint: Median HIV-1 RNA, log1 copies/ml Absolute value (IQ Range) Change from baseline (IQ Range) Secondary endpoint: Median CD4 + cell count, cells/mm 3 Absolute count (IQ Range) Change from baseline (IQ Range) 1.69 (1.69, 1.69) -3.3 (-3.71, -2.97) 48. (37., 61.) 235. (13., 39.) 1.69 (1.69, 1.69) (-3.77, -3.3) 46. (36., 57.) 22. (15., 315.) Secondary endpoint: total number of subjects with HIV-associated conditions, n (%) 5 (3) 5 (3) Conclusion: Safety Changes in GFR as estimated by MDRD and Cockcroft-Gault formula were similar between treatment arms from baseline through Week 96 and did not change significantly from baseline The proportion of subjects with a decline from baseline in GFR by MDRD 1 ml/min/1.73 m 2 and GFR by Cockcroft and Gault of 1 ml/min at Week 96 was greater in the TDF/FTC treatment arm than the ABC/3TC treatment arm Results of the secondary analysis established the superiority of ABC/3TC over TDF/FTC in a repeated measures mixed model for percent change in hip BMD at Week 96 At Week 96, the TDF/FTC treatment arm had a greater proportion of subjects with 2% and 6% decline from baseline in lumbar spine and hip BMD compared with the ABC/3TC treatment arm Eight subjects in the TDF/FTC treatment arm prematurely discontinued study drug due to a decrease in bone density and one due to osteopenia The incidence of Grade 3 to Grade 4 adverse events was slightly higher in the ABC/3TC treatment arm (24%) than the TDF/FTC treatment arm (21%) The incidence of serious adverse events was slightly higher in the ABC/3TC treatment arm (16%) than the TDF/FTC treatment arm (1%) Overall, the incidence of adverse events that led to premature discontinuation of investigational product was 16%. The most common AE that led to investigational product discontinuation was drug hypersensitivity in the ABC/3TC treatment arm and decreased bone density in the TDF/FTC treatment arm The incidence of most specific treatment-emergent Grade 3 to 4 laboratory abnormalities was low and generally comparable between treatment arms Changes in HDL from baseline to Week 96 were comparable between treatment arms. There were greater median increases in total cholesterol, LDL and triglycerides in the ABC/3TC treatment arm as compared with the TDF/FTC treatment arm from baseline to Week 96, but the TC:HDL ratio improved similarly in both treatment arms There was one death reported in the TDF/FTC; not considered by the investigator to be related to study drug The safety results demonstrated that both ABC/3TC and TDF/FTC containing regimens were generally well- 7

8 Efficacy tolerated in therapy-naïve subjects, with no new safety signals identified in this study Using a TLOVR (ITT-E) analysis, the response rate for the proportion of subjects achieving a plasma HIV-1 RNA <4 copies/ml and <5 copies/ml at Week 96 was 57% and 51% among subjects in the ABC/3TC treatment arm compared with 65% and 59% of subjects in the TDF/FTC treatment arm The rate of virologic failure was lower in the TDF/FTC treatment arm (<4 copies/ml [ABC/3TC: 6%; TDF/FTC:2%]; <5 copies/ml [ABC/3TC: 13%; TDF/FTC: 9%]) Median CD4 + responses were similar between treatment arms at Week 96 Viral Genotyping and Phenotyping There was a 3% protocol-defined virologic failure rate through 96 weeks Only 4/1 subjects (4%) with protocol-defined virologic failure developed treatment-emergent mutations associated with study drug 8