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

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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: atorvastatin/glimepiride (Glim/Atorva) Study Number: ATG Title: STUDY ATG115317, a comparison of atorvastatin and glimepiride fixed dose combination and atorvastatin and glimepiride loose combination in the treatment of patients with Type 2 diabetes mellitus Rationale: Type 2 diabetes mellitus (T2DM) is a chronic illness that requires continuing medical care, ongoing patient self-management, education as well as support to prevent acute complications and reduce risk of long-term complications. Patients are initially provided with lifestyle advice through diet, exercise and weight reduction, however if glucose targets are not achieved by lifestyle interventions alone, treatment with metformin is recommended. Sulphonylurea is added to the treatment regimen in patients who do not gain adequate glycaemic control with first line metformin therapy. T2DM patients are at high risk for several cardiovascular diseases (CVD). Dyslipidemia is one of the major risk factors for CVD and is largely uncontrolled in diabetes mellitus. Although, drug therapy for dyslipidemia must be individualised, most patients with T2DM are candidates for statin therapy to reduce the risk of CVD. Multiple clinical trials have demonstrated significant benefits of statin therapy on CVD outcomes for primary and secondary prevention, irrespective of baseline lipid levels. Based on the results of landmark trials like the Collaborative Atorvastatin Diabetes Study (CARDS), International guidelines recommend statin therapy as the initial pharmacological treatment for lowering low density lipoprotein-cholesterol (LDL-c) levels in T2DM patients. Atorvastatin (Lipitor) is an established statin that is indicated for the prevention of cardiovascular events in adult patients estimated to have a high risk for a first cardiovascular event, as an adjunct to correction of other risk factors. There is widespread use of both glimepiride and atorvastatin, prescribed separately, in the T2DM population. It has been noted that atorvastatin can increase glycated haemoglobin (HbA1c) levels by approximately 0.2% to 0.4%. This is a recognised effect across statins which is acknowledged in the statin product labels. However, the overall benefits of statins strongly outweigh any risks, including in those at risk of developing diabetes or those with pre-existing diabetes. (MHRA Drug Safety Update (MHRA). Safety Information Drug Safety Update. MHRA Drug Safety Update, United Kingdom; 2012) Since glucose control and lipid management have a positive impact on cardio-metabolic risk, a combination of glucose and lipid lowering approach offers an opportunity to improve patient care in T2DM. Fixed-dose combination (FDC) therapies have been shown to improve adherence by reducing costs, pill burden, and the complexity of treatment regimen. A FDC of glimepiride and atorvastatin, once-daily could help reduce the risk of medication nonadherence in patients with T2DM who require additional statin therapy. Phase: III Study Period: 26-Dec-2011 to 20-Sep-2013 Study Design: This was a two-arm, parallel group, comparative, open-label, randomised study with once daily dosing for a 20-week treatment period. The two arms were: glimepiride/atorvastatin FDC (GLIM/ATORVA), and atorvastatin + glimepiride combination taken as separate tablets (). Up titration of glimepiride dose at Weeks 2, 4, 6 and 10 was based on average fasting glucose levels. Up titration of atorvastatin dose at Weeks 6 and 12 was based on LDL cholesterol levels. A total of 424 subjects were planned to be randomised in a 1:1 ratio, i.e., 212 subjects in each treatment arm. Centres: The study was conducted in Mexico ( 6 centres), S Korea ( 10 centres), Philippines ( 6 centres), Russia ( 3 centres), Thailand (3 centres and Malaysia (3 centres) Indication: Control of blood glucose and reduction in serum LDL-c in subjects with Type 2 diabetes mellitus Treatment: Subjects were randomised in a 1:1 ratio to receive either GLIM/ATORVA or glimepiride and atorvastatin given as a loose combination () given concomitantly. Study treatment was to be taken once daily, shortly before or during a substantial breakfast or, if no breakfast was taken, shortly before or during the first main meal. The study treatment period was 20 weeks. Treatment for subjects randomised in the GLIM/ATORVA arm was initiated with GLIM/ATORVA 1/10 mg. Glimepiride was up titrated based on fasting blood glucose while atorvastatin was up titrated based on LDL-c levels. 1

2 GLIM/ATORVA was available in different strengths of 1 mg/10 mg, 2 mg/10 mg, 3 mg/10 mg, 4 mg/10 mg, 1 mg/20 mg, 2 mg/20 mg, 3 mg/20 mg and 4 mg/20 mg. Treatment for subjects randomised to the arm was initiated with 1 mg glimepiride and 10 mg atorvastatin given concomitantly. Glimepride and atorvastatin were up titrated using the same criteria as GLIM/ATORVA arm. Glimepiride single dose tablets were available at strengths 1 mg, 2 mg, 3 mg and 4 mg while atorvastatin single dose tablets were available at strengths 10 mg and 20 mg. Objectives: The co-primary objectives were to demonstrate: Non-inferiority of GLIM/ATORVA compared with the combination of glimepiride + atorvastatin taken concomitantly as separate tablets in reducing HbA1c levels Non-inferiority of GLIM/ATORVA compared with the combination of glimepiride + atorvastatin taken as separate tablets in reducing LDL-c levels Primary Outcome/Efficacy Variable: The co-primary endpoints for the study were: Change from baseline to Week 20 in HbA1c levels Percent change from baseline to Week 20 in LDL-c levels Secondary Outcome/Efficacy Variable(s): Secondary efficacy evaluations were to assess the change in HbA1c from baseline to Week 12 and percent change in LDL-c from baseline to Week 4 and Week 10. Statistical Methods: A sample size of 191 evaluable subjects in each of the GLIM/ATORVA and treatment groups provided 90% power for an HbA1c non-inferiority assessment based on a non-inferiority margin of 0.3%, assuming a standard deviation of 0.9% and a one-sided test with a 2.5% significance level. The sample size of 191 evaluable subjects per group provided 83% power for the LDL non-inferiority assessment based on a margin of 6 percentage points, assuming a standard deviation of 20 percentage points and a one sided test w ith a 2.5% significance level. 212 subjects in each treatment arm were required in order to ensure a minimum of 191 evaluable subjects per arm for the primary analysis, assuming up to 10% of randomised subjects to be non-evaluable. The intent-to-treat (ITT) population consisted of all randomised subjects with at least one post baseline assessment of HbA1c or LDL-c value. The per-protocol (PP) population is the subset of ITT subjects without major protocol deviations. The PP population was the primary population for the evaluation of non-inferiority. An analysis of the ITT population was also performed for sensitivity analysis, and was consistent with the PP anaysis. Only the PP analyses are presented in this summary report.the safety population consisted of all randomised subjects who had taken at least one dose of the study medication. Change from baseline in HbA1c and percentage change from baseline in LDL-c were analysed using a mixed model for repeated measures (MMRM) with restricted maximum likelihood estimation and an unstructured covariance (UN) matrix. If the model did not converge then the results obtained from the Compound Symmetry (CS) matrix was used. Assessment of non-inferiority was based on two-sided 95% confidence interval (CI), if upper limit of CI was less than the non-inferiority margin, the non-inferiority of FDC over was concluded with respect to each endpoint. All safety parameters were summarised by treatment group over time. The clinical interpretation of safety data was based upon review of the summary displays. For primary efficacy analysis using observed case method, missing data was treated as missing in the analysis. Study Population: The study population consisted of T2DM patients with inadequate glycaemic control on metformin monotherapy (stable for at least 3 months), requiring additional anti-diabetic medication as well as statin therapy to reduce cardiometabolic risk. The HbA1c criterion (7.0% and <9.5%) was defined in line with treatment guidelines. The protocol excluded high risk patients with uncontrolled hypertension, significant ongoing cardiovascular disease and significant renal, liver or thyroid disease. The other key inclusion and exclusion criteria were based on the contraindications and safety profiles of the study drugs. 2

3 GLIM/ATORVA Number of Subjects: Randomised, N Completed, n (%) 199 (92.6%) 194 (91.5%) Total Number Subjects Withdrawn, N (%) 16 (7.4%) 18 (8.5%) Withdrawn due to Adverse Events n (%) 2 (0.9%) 2 (0.9%) Withdrawn due to Lack of Efficacy n (%) 0 0 Withdrawn for other reasons n (%) 14 (6.5%) 16 (7.5%) Demographics Females: Males 126:89 135:77 Mean Age, years (SD) 57.3 (8.8) 57.9 (10.7) Race, n (%) Asian-East Asian Heritage Asian-South East Asian Heritage White-White/Caucasian/European Heritage Other: Hispanic-Latin-Mexican Other: Hispanic-Latino 50 (23.3%) 65 (30.2%) 24 (11.2%) 1 (0.5%) 75 (34.9%) 48 (22.6%) 66 (31.1%) 24 (11.3%) 2 (0.9%) 72 (34.0%) Co-Primary Efficacy Results: Change from Baseline in HbA1c % at Week 20 Statistic (n=190) (n=180) (n=370) Least Square Mean HbA1c % CI (L, UCL) (-0.80, -0.57) (-0.80, -0.57) (-0.15, 0.17) Non-inferiority of GLIM/ATORVA to demonstrated: Upper bound of the 2-sided 95% CI of the change from baseline in HbA1c <0.3% Change from Baseline in LDL-c mmol/l at Week 20 Statistic (n=187) (n=183) (n=370) Least Square Mean LDL-c % CI (L, UCL) (-40.72, ) (-41.62, ) (-2.47, 4.21) Non-inferiority of GLIM/ATORVA to demonstrated: Upper bound of the 2-sided 95% CI of the change from baseline in LDL-c <6.0% Secondary Outcome Results: Change from Baseline in HbA1c % at Week 12 (n=193) (n=187) (n=380) Least Square Mean % CI (L, UCL) (-0.86, -0.66) (-0.88, -0.67) -0.13, -0.15) Change from Baseline in LDL-c mmol/l at Week 4 & 10 Week 4 (n=200) (n=193) (n=393) Least Square Mean % CI (L, UCL) (-40.89, ) (-40.08, ) (-3.98, 2.28) Week 10 (n=200) (n=193) (n=393) Least Square Mean % CI (L, UCL) (-41.44, ) (-40.56, ) (-4.20, 2.36) These secondary outcome results support the primary analysis that the GLIM/ATORVA is non-inferior to the 3

4 Most Frequent Adverse Events ( 3% in either GLIM/ATORVA or arms) On-Therapy MedDRA Preferred Term GLIM/ATORVA (N = 215) (N = 212) Total number of Treatment Emergent AEs Number of Subjects Reporting At Least One Treatment Emergent AE At Least One Treatment Emergent LFT AEs 138 (64.2%) 130 (61.3%) Alanine aminotrans ferase increased 52 (24.2%) 38 (17.9%) Aspartate aminotransferase increased 38 (17.7%) 29 (13.7%) Blood bilirubin increased 21 (9.8%) 16 (7.5%) Bilirubin conjugated increased 8 (3.7%) 8 (3.8%) At Least One Other Treatment Emergent AEs Nasophary ngitis 10 (4.7%) 12 (5.7%) Headache 9 (4.2%) 7 (3.3%) My algia 8 (3.7%) 7 (3.3%) Hy pertension 7 (3.3%) 4 (1.9%) Hy pertrigly ceridaemia 7 (3.3%) 0 Upper respiratory tract infection 7 (3.3%) 8 (3.8%) Diarrhoea 6 (2.8%) 7 (3.3%) Phary ngitis 6 (2.8%) 10 (4.7%) AEs are coded using Dictionary MedDRA Version 16.0 On treatment SAEs are included If a subject has more than one AE then the subject is counted only once w ithin respectiv e category 4

5 Summary of Shifts in Liver Function Tests of Potential Clinical Concern Baseline (Laboratory Reference Ranges) Post Baseline GLIM/ATORVA (N = 215) (N = 212) LFTs Classification L N H L N H L AST (SGOT) N (90.2%) 18 (8.4%) (90.1%) 18 (8.5%) H (0.9%) * (0.9%) # L 1 (0.5%) ALT (SGPT) N 2 (0.9%) 183 (85.1%) 28 (13.0%) 2 (0.9%) 178 (84.0%) 29 (13.7%) H (0.5%) 1 (0.5%) # L 3 (1.4%) (1.4%) Total Bilirubin N 2 (0.9%) 199 (92.6%) 4 (1.9%) (94.8%) 3 (1.4%) H 0 3 (1.4%) 3 (1.4%) * 0 3 (1.4%) 1 (0.5%) # Notes; L N H classification at Baseline; L Low normal, H High abnormal N Normal with respect to Local Lab Ref Range LNH Classification Post Baseline: L L: No Change from baseline with respect to Lower Reference Range Limit of Local Laboratory, H High abnormal and N Normal with respect to Potential Clinical Concern Ranges as mentioned in Statistical Analysis Plan The shift table presents the first time Abnormal Potential Clinical Concern Value Post-Baseline. The change from Baseline is considered 'N (Normal)'only if the subjects was retained as 'Normal' for the particular LFTs till the Study Completion/Early Withdrawal. Incidence of Hypoglycaemia; Event of special interest. Category Hy pogly caemic Ev ents GLIM/ATORVA (N = 215) (N = 212) At least one hy pogly caemic ev ent 45 (20.9%) 27 (12.7%) At least one sev ere hypogly caemic ev ent 0 0 At least one serious hy pogly caemic ev ent 0 0 At least one drug-related hy pogly caemic ev ent 12 (5.6%) 9 (4.2%) At least one hy pogly caemic ev ent leading to discontinuation 0 0 Serious Adverse Events - On-Therapy No SAEs were considered related to treatment by the investigators Subjects with non-fatal SAEs, n (%) 5

6 System Organ Class MedDRA Preferred Term GLIM/ATORVA (N = 215) (N = 212) Number of subjects reporting at least one SAE 3 (1.4%) 7 (3.3%) Cardiac disorders Acute my ocardial infarction 0 2 (0.9%) Gastrointestinal disorders Abdominal pain 0 1 (0.5%) Hepatobiliary disorders Bile duct stone 1 (0.5%) 0 Infec tions and infestations Herpes zoster 1 (0.5%) 0 Pneumonia 1 (0.5%) 0 Injury, poisoning and procedural complications Spinal compression fracture 0 1 (0.5%) Neoplasms benign, malignant and unspecified (incl cy sts and poly ps) Pancreatic carcinoma 0 1 (0.5%) Respiratory, thoracic and mediastinal disorders Asthma 0 1 (0.5%) Vascular disorders Hy pertension 0 1 (0.5%) Subjects with fatal SAEs There was a single fatal event of pancreatic cancer reported in the study. One subject in the arm presented with severe general weakness and significant unexplained weight loss within two months of study entry. The study drug was withdrawn and the subject died after 2 weeks of study drug withdrawal. The investigator assessed the event to be unrelated to study drug. Conclusion: GLIM/ATORVA was found to be non-inferior using two sided 95% CI to atorvastatin and glimepiride combination taken concomitantly () in reducing HbA1c and LDL-c levels in T2DM patients who are uncontrolled on metformin therapy. The safety profile of GLIM/ATORVA compared with the was similar with no relevant differences in reporting of clinically significant AEs, or LFTs. Mild hypoglycaemia was reported more frequently in the GLIM/ATORVA arm compared with the arm. 6