: Centyr~ 1.25 mg. ~ Centyl 2.5 mg. ~ Renitec(llllO mg. Norvasc 5 mg

Transcription

1 CE9401 DK 10 November, 1999 SYNOPSIS Studyc:ode: CE9401 OK Study title: Efficacy and safety of Centyl with potassium chloride (bendroflumethiazide) 1.25 mg and 2.5 mg compared to Renitec (enalapril) 10 mg and Norvascl!l (amlodipine) 5 mg in patients with mild to moderate primary hypertension. Main objectives of the study: To compare the antihypertensive effect of Centyl 1.25 mg tablets with potassium chloride, 2.5 mg tablets of Centyl with potassium chloride, Renitec 10 mg tablets and Norvascl!!l 5 mg tablets administered as monotherapy with a once daily dose. Study design: practice. A multi-centre, randomised, open study on patients in general Duration of each study phase: There was a wash-out period of 4 weeks, and a treatment period of 24 weeks with control visits after 4, 8, 16 and 24 weeks. Treatment schedule: : Centyr~ 1.25 mg ~ Centyl 2.5 mg ~ Renitec(llllO mg Norvasc 5 mg weeks This document has been downloaded from \\1\r.. w.teo-pharma.com 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 purposes 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~ 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.

2 10 November, 1999 C 9401 DK Total number of patients included in the study: A total of 300 patients was planned to be included. 312 patients were randornised to the study; 123 patients to treatment with low dose Centyl~ 1.25 mg, 62 patients to Centyl~ 2.5 mg, 62 patients to Renitec~ and 65 patients to Norvasc. Source of patients: The population group was based on male and female patients from general practice above the age of 40 with newly discovered or previously treated hypertension. Patient group studied: The selection of the study population was based on the following main in- and exclusion criteria: Inclusion criteria: Patients above the age of 40 with newly diagnosed or previously treated hypertension (treated with less than two drugs) Patients with a mean diastolic blood pressure at visits 2 and 3 between mmHg Signed informed consent given by the patients prior to entrance in the study Exclusion criteria: Patients with AMI or apoplexy within the past 6 months Patients being treated for heart failure, hypercholesterolaemia (total cholesterol >7 mmoljl) or hypokalaemia (S-potassium <3.0 mmoljl) Patients with arterial stenosis of the kidney, or patients with reduced kidney function ($-creatinine ~150 J..Lmol/1 at inclusion, or >200 J..Lrnol/1 during the active treatment phase Patients with elevated fasting blood glucose values (>7 mmoljl) and/ or hyperuricaemia Patients being treated with drugs that reduce lipid concentration, patients in chronic treatment with non-steroid anti-inflammatory drugs, digoxin, antidiabetics or other medication with effect on blood pressure or biochemical variables.

3 C 9401 DK 10 November, 1999 The primary outcome measure was: Reduction in diastolic blood pressure The secondary outcome measures were: Change in systolic blood pressure and heart rate Adverse events Changes in biochemical variables (potassium, sodium, urate, creatinine, triglyceride, haemoglobin, fasting plasma glucose, cholesterol, U-albumin) Other outcome measures were: Change in self-reported Quality-of-Life (The Psychological General Well-Being Schedule) All changes are from baseline to end of treatment measurements. Treatment costs (drugs, blood samples and visits) in the groups Study procedures: After 4-6 weeks' wash-out period patients compliant to the inclusion and exclusion criteria were randomised to one of the 4 treatments in a proportion of 2:1:1:1 (Centyr~ 1.25 mg with potassium chloride; Centyrs 2.5 mg with potassium chloride; Renitece 10 mg; Norvasc~ 5 mg). Control visits were performed after 4, 8, 16 and 24 weeks' active treatment as described in the study schedule: J

4 10 November, 1999 CE9401DK Study schedule Wash-out Randomisation Control Control Control Control Visit no Week no lnformed consent Eligibility criteria Medical history. Clinical evaluation - Randomisation Quality of Life Blood pressure Biochemical variables ' ' 1) I) Urine analysis Adverse events Drug administration Compliancei collection of used/unused drugs tj S-potassium, S-sodium and S-creatinine (non fasting) Baseline : The four treatment groups were well balanced regarding demographics and baseline disease characteristics. D emokf"llpj h. lc d naa t tb ase I' me CentyJ 1.25 mg CentyJ 2.5 mg Norvascc& Renitecl!> Male 52.0% 53.2% 52.3% 51.6% Mean age (SO) 58.1 (9.3) 57.0 (10.2) 58.2 (10.7) 56.9 (11.1) Mean diastolic blood pressure mmhg (SD) (4.4) (4.3) (4.3) (4.1) Mean systolic blood pressure mmhg (SD) (19.0) (12.9) (16.9) (16.1) Former treatment of hypertension Body mass index (women) kgjm2(sd) Body mass index (men) kgjm2 (50) 54.5% 50.0% 61.5% 61.3% 27.2 (4.1) 28.7 (4.8) 26.2 (3.6) 26.9 (5.4) 27.5 (3.6) 28.4 (3.9) 28.4 (4.8) 28.6 (3.5)

5 CE9401 DK 10 November, 1999 Primary efficacy parameter: The primary efficacy criterion is change in diastolic blood pressure. All four antihypertensive treatments lowered the diastolic blood pressure statistically significant. A statistically significant difference was found between the four treatment groups with respect to the change in diastolic blood pressure (p=0.013). Norvasc lowered the diastolic blood pressure significantly more than Centyl mg. Centyl~ 1.25 mg lowered the diastolic blood pressure 6.8 mmhg (50=8.8), CentyJ 2.5 mg lowered the blood pressure 9.1 mm.hg (50=9.7), Norvasc lowered the blood pressure 10.8 mmhg (50=8.0) and Renited~ lowered blood pressure 6.8 mmhg (50=7.5). Diastolic blood pressure at start tmd end of treatment Diastolic BP (mmhg) CentyJ 1.25 mg Centyl«> 2.5 mg Norvasc«> Renitec<ll Baseline mean (SD) (4.4) (4.0) (4.4) (3.6) End of tteahnent mean (SD) Change in diastolic blood pressure (SO) 98.4 (10.0) 95.1 (10.3) 93.9 (8.7) 97.7 (7.9) -6.8 (8.8) -9.1 (9.7) (8.0) -6.8 (7.5) Secondary efficacy parameters: The secondary response criteria are change in systolic blood pressure, heart rate and bioc~emical parameters. No statistically significant difference was found between the four treatment groups with respect to the change in systolic blood pressure (p=0.069). The mean lowering of systolic blood pressure of Centyl"' 1.25 mg was 12.6 mmhg (50=18.2). Centyl 2.5 mg lowered the systolic blood pressure 13.0 mmhg (50,17.5), and the mean lowering of Norvasc was mmhg (SD l6.0). Renitec 15 lowered the systolic blood pressure 10.2 mmhg (50=14.5). Systolic blood pressure at start and end of treatment Systolic 8P (mmhg) Centyl 1.25 mg CentyJ 2.5 mg Norvasc'~~ Renitec Baseline mean (SD) (18.8) (12.5) (16.7) {16.2) End of treatment mean (SD) Change in systolic blood pressure (SD) (18.6) (16.0) (18.1) (20.8) (18.2) (17.5) (16.0) (14.5)

6 10 November, 1999 CE9401 DK Heart rates over time were stable and there was no significant difference in change of heart rate between the four treatment groups (p = 0.92). Evaluating the change in biochemical variables a significant difference for S. potassium and S..urate was observed between the treatment groups (see table below: "Mean ratio of laboratory parameters measured at end of treatment to the corresponding baseline values"). Centyl~ 1.25 mg and Centyr~ 2.5 mg decreased 5-potassium although both Centyl~ tablets contain 573 mg potassium. Also Norvasc~ decreased the S-potassium level It is weu known that thiazides increase 5-urate and that the values increase with increased doses. These findings are confirmed in this study. Evaluating B-haemoglobin, there was a borderline statistical significance but it was not found to be clinically relevant. Thiazides, especially in high doses, have been characterised for their metabolic side effects on the lipid and glucose metabolism. This study using low doses of thiazides did not show any significant changes in the metabolism of lipids and glucose. For Centyl 2.5 mg the change in total cholesterol is statistically significant (p=0.021), but the change is not clinically relevant because the values are within the reference range or lower. Mean ratio of laboratory parameters measured at ettd of treatment to the corresponding baseline values Centyl~ 1.25 mg CentyJ 2.5 mg Norvasc Renitec ANOVAI 5-Potassium p = Urate p < haemoglobin p = Analysis of variance on log (ratios) with treatment group as factor 2Renitec«> is significantly different from Norvasc, CentyJ 2.5 mg and CentyJ 1.25 mg 3Centyl 2.5 mg is significantly different from CentyJ 1.25 mg, Renitec and Norvasc Norvasc is significantly different from CentyJ 1.25 mg 4Centylt!l 2.5 mg is significantly different from Norvasc and Renitec«> Health-related quality of life was reported and evaluated at baseline and end of treatment There was no statistically significant difference regarding the change in total score from baseline to end of treatment between the groups (p =0.35).

7 CE9401 DK 10 November, 1999 Safety Results: The adverse event profile was favourable in the groups treated with thiazides Centyl 1.25 mg and Centyrl!i 2.5 mg compared to the groups treated with Renitec 10 mg and Norvasc 5 mg. The drug related adverse event rates of Norvasc and Renitec were twice the rate of Centyr~ 1.25 rng and Centyl 2.5 mg. Adverse events, possibly and probably related to study drug Centyl 1.25 mg Centyl 2.5 mg Norvasco& Renitec (n=122) (n=61) (n=64) (n=62) Number of drug related adverse events Number of patients Percentage Conclusion: Norvasc lowered the diastolic blood pressure significantly more than CentyJ mg. All four monotherapies significantly lowered the diastolic blood pressure in patients with mild to moderate hypertension. Only monotherapy with Centyl 2.5 mg and Norvasc 5 mg lowered the mean diastolic blood pressure to 95 mmhg or less: However, for all treatments about 40-60% of the patients would need dose titration or combination therapy to achieve a reduction in blood pressure to 95 mmhg or less. The number of adverse drug reactions of Norvasc and Renitec was twice the number of adverse drug reactions for CentyJ 1.25 mg and Centyl 2.5 mg No clinically relevant changes on the biochemical parameters were observed during the treatment.