Synopsis. None. The trial was started on 13 January 2003 and completed on 02 November Phase 4. Primary Objective:

Transcription

1 Report Body and Synopsis Page: 3 of 53 Synopsis TITLE OF TRIAL A Multinational, Randomised, Controlled, Open-labeled, Parallel Group Evaluation in Terms of Efficacy and Safety of Metformin 1700 mg/day Plus Twice Daily Biphasic Insulin Aspart 30 or Human NPH-insulin in Subjects with Type 2 Diabetes INVESTIGATORS There were a total of 16 principal investigators in Argentina (5) and Brazil (11): Jorge Alvariñas Pedro Lobo Luis de Loredo Martin Rodriguez Gloria Viñes Adriana Costa e Forti, Edgard D Avila Niclewicz, Freddy Goldberg Eliaschewitz, Giuseppe Repetto, Luiz Antonio Raio Granja, Jose Egidio Paulo de Oliveira, Marcos Tambascia, Mauro Cesar Dinato, Rosane Kupfer, Saulo Purisch and Thomas Rodrigues Porto da Cruz. TRIAL SITES The trial was conducted in 16 sites in Argentina (5) and Brazil (11): Hospital Tornu Hospital Austral Hospital Privado de Cordoba Instituto de Clinica Medica y Diabetes Hospital Privado de la Comunidad Centro Integrado de Diabetes e Hipertensao, Centro de Diabetes do Hospital Nossa Senhora das Gracas, Hospital Heliopolis, Hospital Sao Lucas-PUC/RS, Incor/HC/FMUSP, Hospital Universitario Clementino Fraga Filho, Hospital das Clinicas da UNICAMP, Centro Universitario Lusiada, Instituto Estadual de Diabetes e Endocrinologia Luiz Capriglione, Santa Casa de Belo Horizonte and Pavilhao Magalhaes Neto. PUBLICATIONS None. TRIAL PERIOD The trial was started on 13 January 2003 and completed on 02 November 2004 OBJECTIVES Primary Objective: DEVELOPMENT PHASE Phase 4

2 Report Body and Synopsis Page: 4 of 53 To evaluate the glycaemic control of BIAsp 30 insulin twice a day plus metformin 1700 mg/day and human NPH insulin twice a day plus metformin 1700 mg/day in subjects with type 2 diabetes. It will be assessed by means of HbA 1c and by PPBG excursions in both treatment arms during 12 weeks. Secondary Objectives: To evaluate the incidence of hypoglycaemia in BIAsp 30 twice daily plus metformin 1700 mg/day and human NPH insulin twice daily plus metformin 1700 mg/day. To evaluate the safety of BIAsp 30 twice daily plus metformin 1700 mg/day and human NPH insulin twice daily plus metformin 1700 mg/day. METHODOLOGY This was a multicentre, randomised, controlled, open labelled, parallel group trial of twice daily BIAsp 30 or NPH insulin and metformin combination regimen in subjects with type 2 diabetes mellitus. After screening, eligible subjects received either (1:1 ratio) BIAsp 30 or NPH insulin, twice daily in combination with metformin (BIAsp/metformin or NPH/metformin group). This was followed by a 4-week titration period and an 8-week maintenance period (total of 12 weeks treatment). NUMBER OF SUBJECTS PLANNED AND ANALYSED 160 subjects were planned. 192 subjects were screened (29 screen failures). 163 subjects were randomised to treatment. 153 subjects completed the trial as planned. 8 subjects were withdrawn; 3 due to adverse events (1 from BIAsp/metformin group and 2 from NPH/metformin group); 3 subjects withdrew due to non-compliance with protocol (1 from BIAsp/metformin and 2 from NPH/metformin group) and 2 subjects withdrew due to other reasons (BIAsp/metformin group). DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION Subjects diagnosed with type 2 diabetes and currently treated with NPH insulin or insulin-naïve subjects were enrolled. Subjects were 18 years old, had BMI 35.0 kg/m 2 and HbA 1c 7.5% and 11.0%. Other than metformin, subjects treated with other OAD discontinued treatment upon randomisation. TEST PRODUCT, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBER Biphasic insulin aspart Penfill 100 units/ml (Batch No. NP 50839) was administered before meals by subcutaneous injection. The injection area chosen should remain unchanged throughout the trial period but subjects will be asked to change the site of injection within the chosen area. Metformin (Batch No ) was taken orally, at 850 mg dose each time. DURATION OF TREATMENT The trial included a screening of 10 days followed by a 4-week titration period and an 8-week maintenance period. REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBER Novolin N Penfill 100 units/ml (Batch No. NW 51177) was injected subcutaneously with NovoPen 3 with rotation in the region within the chosen injection site. CRITERIA FOR EVALUATION EFFICACY Primary efficacy endpoint HbA 1c level. Secondary efficacy endpoints PPBG values and the 8-point BG profile. CRITERIA FOR EVALUATION SAFETY Incidence of hypoglycaemia, adverse events, vital signs, physical examination and body weight. STATISTICAL METHODS The intent-to-treat (ITT) population included all randomised subjects who were exposed to at least one dose of trial product. The per-protocol (PP) population included all subjects who had completed the trial. The analysis on the primary endpoint was based on the ITT and PP population while all other endpoints were based on ITT population only. Efficacy: The primary endpoint was HbA 1c measured at the end of 12 weeks of treatment. The secondary endpoint was the PPBG excursions at the end of 12 weeks of treatment. The PPBG excursion at each main meal (delta PPBG) was the

3 Report Body and Synopsis Page: 5 of 53 difference in BG before and after meals (post-meal BG minus pre-meal BG). The analysis of the primary and secondary endpoint was based on the analysis of variance (ANOVA) model where: treatment, centre, previous OAD regimen and baseline value were included in the model. Previous OAD regimen is defined as subjects receiving other OAD with or without metformin. Non-inferiority of BIAsp/metformin compared with NPH/metformin was shown if the upper confidence of the treatment difference in HbA 1c was lower than 0.5%, at 5% significance level. The significance level for the analysis on delta PPBG was set at 1% since multiple tests were performed on the same endpoint. Safety: The safety endpoints were the incidence of adverse events, including hypoglycaemia, vital signs, body weight and physical examination. The analysis on hypoglycaemia was performed for episodes occurring during the 8-week maintenance period. The overall incidence of hypoglycaemic episodes was evaluated by estimating the relative risk of hypoglycaemia in the BIAsp/metformin group compared with NPH/metformin group, using a Poisson model with gamma grailty on the intensity parameter to account for over dispersion. The model included: treatment, previous OAD regimen (with or without metformin) and HbA 1c at the end of the trial. The same model was used to analyse major and minor hypoglycaemic episodes. Hypoglycaemic episodes were also analysed by time of occurrence (diurnal and nocturnal). All hypoglycaemic episodes classified as major in severity during the titration period were provided as a listing. Treatment emergent adverse events were summarised by system organ class and preferred term according to treatment group as well as by severity and relation to trial product. Adverse events reported by more than 5% of subjects in a treatment group were presented, categorised by system organ class and preferred term. Adverse events that occurred before treatment or more than 7 days after last day was provided in a listing. Missing observations were not replaced due to the short study period. Observations obtained outside the visit window intervals were not corrected for. The 8-point BG profile was graphically presented showing mean values for each visit by treatment groups and also in summary tables. Body weight was summarised by descriptive statistics showing mean, SD, minimum and maximum by visit. DEMOGRAPHY OF TRIAL POPULATION As shown in the table below, the subjects demography profile appeared similar in both treatment groups. In the BIAsp/metformin and NPH/metformin group, there was a disposition to more females (63% and 61%) and the majority of the subjects in both groups were white (71.6% in BIAsp/metformin and 68.3% in NPH/metformin group). The subjects mean age was approximately 57 years old, with mean BMI of approximately 29 kg/m 2. In both groups, subjects had had diabetes for an average of 11 years and HbA 1c averaged 9.2% at screening. Although randomisation by stratification (previous metformin treatment) was not performed, the profile for metformin-use in both treatment groups was well-balanced. A higher proportion of subjects in BIAsp/metformin and NPH/metformin groups had previously received metformin (56% and 61% respectively). Approximately half of the subjects in either group had pre-trial therapy with NPH insulin. Diabetes-related complication was absent in the majority (between 79% and 93%) of the subjects. Among the subjects who reported complications, the profile was similar; retinopathy was the most commonly reported (21% and 17% in BIAsp/metformin and NPH/metformin groups). BIAsp30 NPH Number of Subjects Exposed 81 (100) 82 (100) Gender N (%) Female 51 (63.0) 50 (61.0) Male 30 (37.0) 32 (39.0) Ethnic Origin N (%) White 58 (71.6) 56 (68.3) Black 9 (11.1) 17 (20.7) Asian 1 ( 1.2) 0 ( 0.0) Other 13 (16.0) 9 (11.0)

4 Report Body and Synopsis Page: 6 of 53 BIAsp30 NPH Age (years) Mean (SD) 56.5 (9.7) 57.9 (9.4) Median Min - Max BMI (kg/m 2 ) Mean (SD) 29.5 (3.6) 28.6 (3.5) Median Min - Max Duration of diabetes (years) N Mean (SD) 11.3 (6.8) 11.5 (6.1) Median Min - Max HbA 1c (%) Mean (SD) 9.23 (1.08) 9.15 (1.08) Median Min - Max Previous OAD treatment No metformin N (%) 36 (44) 32 (39) Metformin N (%) 45 (56) 50 (61) No insulin N (%) 40 (49) 43 (52) Insulin N (%) 41 (51) 39 (48) Diabetes Complications Retinopathy N (%) Yes 17 (21) 14 (17) No 64 (79) 68 (83) Neuropathy Yes 8 (10) 12 (15) No 73 (90) 70 (85) Nephropathy Yes 6 ( 7) 7 ( 9) No 75 (93) 75 (91) Macroangiopathy Yes 12 (15) 12 (15) No 69 (85) 70 (85) EFFICACY RESULTS After 12 weeks of treatment with either BIAsp/metformin or NPH/metformin in type 2 diabetes subjects, the following were observed: Mean HbA 1c was decreased from 9.2% to 7.9% in both groups. Comparable improvement in HbA 1c was observed with both treatment regimens. Mean treatment difference between BIAsp/metformin and NPH/metformin was % (95% CI ; 0.213). Glucose excursion at baseline for the three main meals was comparable. After BIAsp/metformin treatment, only the prandial glucose increment at breakfast was considerably lowered from mg/dl to mg/dl. In the NPH/metformin group, glucose excursions remained largely unchanged compared to baseline for all three main meals. The prandial glucose increment at breakfast was significantly lowered in BIAsp/metformin group compared to NPH/metformin group; mean treatment difference in delta PPBG was mg/dl (95% CI ; -8.89). SAFETY RESULTS After 12 weeks of treatment with either BIAsp/metformin or NPH/metformin in type 2 diabetes subjects, the following were observed: The adverse event profile was comparable between treatment groups; 45.7% reported 75 events and 39.0% reported 70 events in BIAsp/metformin and NPH/metformin group. The majority of events in both treatment groups were assessed as unlikely related to trial product (42.0% reported 71 events and 37.8% reported 62 events). Also, the majority of events were mild in both groups (40.7% reported 64 events and 37.8% reported 58 events). A range of

5 Report Body and Synopsis Page: 7 of 53 different adverse events were reported as possibly or probably related to trial product but diarrhoea was common in both treatment group (two events in BIAsp/metformin and one event in NPH/metformin). Three subjects were withdrawn due to adverse events; one from BIAsp/metformin and two from NPH/metformin. Except for one, all adverse events had a possible/probable relation to trial product. The events leading to withdrawal were: abdominal pain (BIAsp/metformin) in one subject; erythema, rash popular and pruritus in one subject and diarrhoea in another subject. All had recovered from the events. Subjects treated with BIAsp/metformin had lower incidence (77 vs 90 episodes) of hypoglycaemia during the 8-week maintenance period, all of which were minor in severity. There were no reports of major hypoglycaemia during this period. The majority of the hypoglycaemia occurred during the day in both treatment groups. Subjects treated with BIAsp/metformin reported fewer nocturnal hypoglycaemia (8 vs 22 events). The risk of any hypoglycaemia (relative risk [RR] is 0.87 [95% CI 0.46; 1.65]) or any diurnal hypoglycaemia (RR 1.05 [95% CI 0.54; 2.04]) occurring with insulin treatment was similar with either group. However, the risk of nocturnal hypoglycaemia was significantly lower with BIAsp/metformin treatment (RR 0.35 [95% CI 0.13; 0.92]). Two serious adverse events were reported, both from NPH/metformin group. Both events (pneumonia and renal colic) were moderate in severity and assessed as unlikely related to trial product. Subjects have recovered or the condition has stabilised. There were no clinically relevant changes in vital signs and physical examinations. The increase in body weight was comparable in both groups (approximately 1.5 kg). CONCLUSIONS After 12 weeks of treatment with either BIAsp/metformin or NPH/metformin in type 2 diabetes subjects: Comparable improvement in HbA 1c was achieved. The glucose spike at breakfast was significantly dampened in BIAsp/metformin group. The adverse event profile was comparable between treatment groups. The majority of events in both treatment groups were mild in severity and considered unlikely related to trial product. Diarrhoea was common to both treatment groups which has a possible/probable relation to trial product. Three subjects were withdrawn due to adverse events. All, but one event had a possible/probable relation to trial product and subjects had recovered. During the 8-week maintenance period, the incidence of hypoglycaemia was comparable between groups, all of which were minor in severity. There were no reports of major hypoglycaemia during this period. The risk of any hypoglycaemia or any diurnal hypoglycaemia was similar with either group, however, the risk of nocturnal hypoglycaemia was significantly lower with BIAsp/metformin. Two serious adverse events were reported, both from NPH/metformin group. Both events (pneumonia and renal colic) were moderate in severity and considered unlikely related to trial product. Subjects have recovered or the condition has stabilised. Comparable increase in body weight was observed in either group. There were no clinically relevant changes in vital signs and physical examinations. The trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice.