Clinical Trial Result Information

Protocol number
ML17560

Title of Study
Randomized, parallel design, multicenter study to compare the effect of Inhibace and atenolol treatment on fibrinolysis and prothrombotic factors in patients with arterial hypertension on diuretic treatment with other concomitant atherosclerosis risk factors

Sponsor
Roche Sp.z.o.o.

Company division
Pharmaceutical

Product name
Inhibace

Generic name
cilazapril

Therapeutic area
Hypertension

Clinical study summary
This was an open-label, parallel group, controlled study of the efficacy, safety, and dose-response of cilazapril (Inhibace) compared with atenolol in the treatment of patients with arterial hypertension on diuretic therapy in the presence of concomitant atherosclerosis risk factors. Patients were randomized to Group A, atenolol 50 mg/day, or Group B, Inhibace 2.5 mg/day, and were treated for 6 weeks.

Study center(s)
15 participating centers.

Phase of development
IV

Objectives
Primary: To compare the effect of Inhibace and atenolol treatment on fibrinolysis and prothrombotic factors in patients with arterial hypertension treated with diuretics and presence of other atherosclerosis risk factors. Secondary: Evaluation of the short-term efficacy, safety, and dose response of Inhibace in the treatment of hypertension in patients >50 years of age with other atherosclerosis risk factors and on diuretic treatment.

Methodology
Open label, parallel trial divided into 2 periods. The screening period lasted 2 weeks, and the treatment period lasted 6 weeks. During the screening period, each patient was treated with 25 mg/day hydrochlorothiazide only and 1 potassium tablet per day. After randomization to 1 of the 2 groups, patients received 2.5 mg/day of Inhibace or 50 mg/day of atenolol (for the first 3 days, half a dose) and continued taking hydrochlorothiazide as previously.

Number of patients (planned/analyzed)
222 randomized.

Diagnosis and main criteria for inclusion
Adult patients with mild or moderate arterial hypertension on hydrochlorothiazide treatment.

Test product, dose and mode of administration or test procedure
Inhibace 2.5 mg/day.

Duration of treatment
6 weeks

Reference therapy, dose and mode of administration or reference procedure
Atenolol 50 mg/day (first 3 days, half dose).

Criteria for evaluation (efficacy, safety)
Primary efficacy parameter: PAI -1 antigen Secondary efficacy parameters: von Willebrand factor, t-PA/PAI complex, TAFI, F1+2, LDL, HDL, TG, total cholesterol

Statistical methods
ITT analysis on all randomized patients. The final results were based on patients for whom laboratory values of given efficacy parameters were available both at visit 2 and visit 4,

To test the hypotheses on equity of mean values of efficacy parameters at the end of the study, the following tests were applied: Student t-test on log transformed values for PAI-1,TAFI, HDL cholesterol and triglycerides, Student t-test for vWF,total cholesterol and LDL cholesterol, and Mann-Whitney non-parametric test for t-PA/PAI complex and F1+2.In cases where an assumption regarding equity of variances in t-tests was not fulfilled, then the Mann-Whitney non-parametric test was applied.

To test the hypotheses on equity of mean values of efficacy parameters at the end of the study, adjusted for baseline values of these parameters, linear regression models were applied with efficacy parameter at the end of the study as dependent variable and the same efficacy parameter at baseline as independent variable, with PAI-1, TAFI, HDL cholesterol and triglycerides ( log-transformed), vWF, total cholesterol and LDL cholesterol (not transformed). T-PA/PAI complex and F1+2 were not adjusted, as they could not be expressed on an interval scale due to the existence of undetectable extremely low and/or extremely high values.

To test the hypotheses on equity of mean values of efficacy parameters at the end of the study, adjusted for baseline values of these parameters and prognostic factors or dose response, linear regression models were applied with efficacy parameter at the end of the study as dependent variable and the same efficacy parameter at baseline and risk factor or dose response as independent variables. Values of the efficacy parameters were transformed as above.

To compare the magnitude of changes in efficacy parameters from the baseline to the end of the treatment (totally and in subgroups), the following test were applied:paired samples t-test on log-transformed values for PAI-1,TAFI, HDL cholesterol and triglycerides, paired samples t-test for vWF, total cholesterol and LDL cholesterol, and Wilcoxon non-parametric test for T-PA/PAI complex and F1+2.

In addition, an analysis of the average values of individual changes in both treatment groups was performed. This analysis was done for PAI-1, vWF, TAFI, total cholesterol, LDL cholesterol, HDL cholesterol and triglicerydes. Nonparametric test (Mann-Whitney) was used. T-PA/PAI complex and F1+2 were not adjusted,as mentioned above.

No interim analysis was performed.

All the patients who were statistically analyzed were included in the safety analysis.

Summary (efficacy, safety, other results)
Final efficacy results were based on those patients for whom efficacy measurements were available at both Visit 2 and Visit 4.

No statistically significant differences in the primary efficacy variable, plasminogen activator inhibitor-1, were found between the two treatment groups.

Statistically significant differences between the treatments were found in high-density lipoprotein (HDL), cholesterol levels in men (higher values in the Inhibace group) and triglycerides in men (lower values in the Inhibace group). However, after adjustment for baseline values, only the effect on triglycerides remained statistically significant. After adjustment for baseline values and prognostic factors, statistically significant differences were found in thrombin-activated fibrinolysis inhibitor (TAFI) in men ( adjusted for dosage modification) with lower values in the Inhibace group, and in triglycerides in men after adjusting for every prognostic variable (lower values in the Inhibace group).

Statistically significant changes of secondary variables before and after the treatment were found for total cholesterol levels in the Inhibace group in men (decrease) and in LDL cholesterol levels in the atenolol group in men (decrease).

A total of 2/49 men taking atenolol and 4/52 men taking Inhibace experienced 2 and 5 adverse events, respectively. A total of 4/58 women taking atenolol and 9/63 women taking Inhibace experienced 7 and 13 adverse events, respectively. The only adverse events considered possibly related to atenolol treatment were mild vertigo, mild diarrhea and life-threatening myocardial infarction, each occurring in one patient. In the Inhibace group, adverse events considered possibly related to treatment were mild erectile dysfunction in one patient, moderate cough in two patients, and two episodes of vertigo in one patient (one mild, one moderate).

A total of 6/107 patients in the atenolol group, and 1/105 patients in the Inhibace group withdrew prematurely from the study. The only withdrawals due to adverse events were one patient with insomnia and one with myocardial infarction in the atenolol group, and one patient with an upper respiratory tract infection in the Inhibace group.

Conclusions
Although both Inhibace and atenolol achieved substantial and similar systolic and diastolic blood pressure reduction in this study, there was no evidence of a beneficial effect of either treatment on fibrinolysis and prothrombotic factors in hypertensive patients treated with hydrochlorothiazide.

Date of report
2/14/2005