~ I SYNOPSIS. Name of Sponsor/Manufacturer: Name of Active Substance: tinza- Page: pari.n, enoxaparin

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1 This document has been do\\>1lloaded from \.,,._.,,._.,_leo-pharma.c.om subject to the terms of use state on the website. It contains data and results regarding approved and non-approved uses, formulations or treatment regimens, and it is provided for transparency and informational pu!poses only. The content does not reflect the complete results from all studies related to a product. As a document of scientific nature it is not to be seen as a recommendation or advic.e regarding the use of any products and you must always consult the specific prescribing information approved for the product prior to any prescription or use. SYNOPSIS Name of Sponsor/Manufacturer: Location of study report in Regulatory Dossier (For National Authority Use only) Nan1e of Investigational Product/ Volume: pari.n, enoxaparin Title of study/protocol Code Number: innohep 4,500 ru and 40 mg. A pharmacodynamic study at repeated dose - IN FR Publication references : Not applicable Study period details : - first patient enrolled 24-Mar last patient completed 14-Jan-2005 m"""t'v", n ypc)thes ls, Phase of development: Phase III The primary objective was to detect if there was an accumulation effect after rep1ea1:e<1 of tinzaparin (innohep 4,500 nj/0.45 ml) or enoxaparin ( 4,000 nj/0.4 ml) l nrool:tvtact.jic dosage over at least 8 Days, in elderly medical patients (aged over 75), wiili impaired renal fiujlcti onl 1 "lt"''.uu.utc clearance ml/min). An open, prospective, randomised, parallel group, study : tinzaparin vs enoxaparin Nmnber of patients enrolled : 55 patients enrolled tinzaparin group n = 27, enoxaparin group n = 28 Diagnosis and main criteria for patient selection: 1) patients in whom prophylaxis against VTE with LMWH for at least 8 Days was justified 2) age>75 years 3) S.Creatinine clearance ml!min 4) Body weight< 65 Kg mohep, and--. dose 4500 ill/day, method of administration SC route, lot numbers: Reference product, dose 40 mg/day, method of administration SC route, lot numbers: - and. I

2 Dmation of treatment: A minimum of 8 Days± 1 Criteria for evaluation: Efficacy: The primary response criterion was the anti-xa accumulation factor based on Cmax (calculated as the ratio of anti-xa Cmax on Day 8 to anti-xa Cmax on Day 1). Secondary endpoints were : AUC D8 /AUC D1ofthe anti-xa activity, Trough levels H 24 D8/ H24D1, phatmacokinetic curves 0-24H at D1 and D8+/- 1. anti-iia activity. Safety: Bleeding complications, SAEs, Deaths, Thromboembolic events, Heparin Induced Thrombocytopenia. Statistical methodology. SUllllllary statistics (mean, standard deviation, median, minimum and maximum) for the primaty response criterion is presented by treatment group for the full Intention-To-Treat (ITT) Analysis Set. The primary response criterion was the anti-xa accumulation factor based on Cmax (calculated as the ratio of anti-xa Cmax on Day 8 ± 1 to anti-xa Cmax on Day 1). In each treatment group the null hypothesis (no accumulation i.e.: anti-xa accumulation factor based on Cmax = 1) was tested by a one-sample t-test. The mean anti-xa accumulation factor based on Cmax, its 95% confidence interval and a P-value is presented for each treatment group. The two treatment groups were compared in respect of the accumulation factor by a two-sample t-test. The anti-xa accumulation factor based on AUC0-24 calculated as the ratio of anti-xa AUC0-24 on Day 8 ± 1 to anti-xa AUC0-24 on Day 1 and the residual anti-xa activity 24h after injection on Day 1 and on Day 8 were summarised in the same way. Summary - Conclusions Efficacy results: Primruy response criterion In the tinzaparin group, the mean Cmax accumulation factor of anti-xa was 1.05 with a 95% confidence interval range of0.95 to (p=0.3). Thus, no accumulation was detected. In the enoxaparin group, the mean Cmax accumulation factor of anti-xa was 1.22 with a 95% confidence interval range of 1.13 to 1.31 (p<0.001). According to the mles, predefined in the protocol, this accumulation factor > 20% is significant. Moreover, the compru ison between treatment groups of Cmax accumulation factors of anti-xa shows a I

3 statistically significant difference between treatments (p=0.016). The primary analysis is based on anti-xa values obtained with A Till addition, with a standard cw-ve cottesponding to the treatment assigned, in addition, all other analyses (without ATIII, cmde data analysis, worst case analysis) show similar results. The secondary response criteria were the mean anti-xa pharmacokinetic profiles, the area under the curve and residual T24 anti-xa activity. 1) Phannacokinetic profiles In the Enoxaparin group, at each sampling time, the Day 8±1 mean value was always superior to the conesponding Day 1 value. These mean differences range from 0.05 ml/min to 0.13 ml!min. In the tinzaparin group the maximum mean difference of 0.05 ml/min con esponds to the minimum mean difference observed in the enoxaparin group (see figw-e below). 2) Area under the cwve. In the tinzaparin group the mean AUC accumulation factor of anti-xa was 1.12 with a 95% confidence interval range of0.97 to 1.28 (p=o.ll). In the enoxaparin group the mean AUC accumulation factor of anti-xa was 1.26 with a 95% confidence intetval range of 1.12 to 1.40 (p<0.001). 3) Residual T24 anti-xa activity. On Day 1 the mean T24 anti-xa acttvtty was 0.05 ml/min in the tinzaparin group versus 0.06 ml/min in the enoxaparin group. The mean difference was 0.01 with a 95% confidence intetval range of to 0.04 ml/min (p=0.5). On Day 8±1 the mean T24 anti-xa activity was 0.06 ml!min in the tinzaparin group versus 0.11 ml!min in the enoxaparin group. The mean difference was 0.05 with a 95% confidence intetval range of to 0.10 ml/min (p=0.076). The within-treatments comparisons of Day 1 and Day 8+/- 1 T24 values demonstt ated a statistically significant increase of residual T24 activity from Day 1 to Day 8+/- 1 in the enoxaparin group only (p=0.013). I

4 Peak level Cmax anti- Xa D l Cmax anti-xa DS Accumulation factor P-value IU/mL (SD) IU/mL (SD) Cmax DS/Cmax D 1 Tinzaparin 0.43 (0.16) 0.46 (0.19) Enoxaparin 0.55 (0.14) 0.67 (0.23) 1.22 < Between group AUC AUC anti-xa D1 AUC anti-xa DS Accumulation factor P-value IU/mL *min (SD) IU/mL*min (SD) AUC DS/AUC D1 Tinzaparin 252 (103) 273 (111) Enoxaparin 354 (119) 447 (218) 1.26 < Between group 0.1 Trough level A h24 D1 IU/mL (SD) A h24 DS IU/ ml (SD) A h24 DS - Ah24 D l P-value Tinzaparin 0.05 (0.04) 0.06 (0.06) Enoxaparin 0.06 (0.06) 0.11 (0.10) Between group O.OB4 1 1 Within treatment compmison of DB and Dl values by one sample t-test 2 Between treatment comparison of DB and Dl values by two sample!-test 0,7 0,5 0,6 t'\ _, 0,5 Enoxapam 01 - :::> 2 0,4 ---Enoxapam 08 _ 0,3 I 1l i 0,3 0,2... I "\\ 0,2 "' T 0,4 --rr \ + Tnzapam Tnzapam 08! ,1 -- 0, I I I I I Time afte r injection (hours) Time after injection (Hours ) - -., I

5 Safety results: Five bleeding events were reported in the tinzaparin group versus four in the enoxaparin group (p=0.67). Two bleeding events were considered as major in the tinzaparin group versus one in the enoxaparin group (p=0.61). Two deaths occuned in the enoxaparin group - these deaths were due to the natural progression of the cancer and not considered related to the study or study dmg. No symptomatic thromboembolic event (DVT/PE) was recorded in either group during the entire study. No heparin induced thrombocytopenia was recorded. Conclusion: The two LMWHs studied have different pharmacodynamic profiles. The homogeneity of the results on the parameters studied: peak level, trough level & AUC, demonstrate clearly that a statistically significant accumulation effect is detectable for enoxaparin administered at prophylactic dose (4000 IU) in elderly patients with a creatinine clearance ranging from 20 to 50 ml!rnin. No accumulation effect was detected in the same population when treated with tinzaparin (4500 IU). Larger trials, based on clinical endpoints, are necessary to establish the clinical relevance of these observations. Report date: I