Abstract
This paper reviews the critical issues in the control and design of antihypertension (anti-HT) clinical trials. The international guidelines and current clinical and biostatistical practices were reviewed for relevant clinical, design, end-point assessments and regulatory issues. The results are grouped mainly into ethical, protocol and assessment issues. Ethical issues arise as placebo-controlled trials (PCTs) for HT-lowering agents in patients with moderate to severe HT are undertaken. Patients with organ damage due to HT should not be included in long-term PCT. Active-control trials, however, are suitable for all randomized subsets of patients, including men and women, and different ethnic and age groups. Severity subgroups must be studied separately with consideration to specific study design. Mortality and morbidity outcome studies are not required in anti-HT trials except when significant mortality and cardiovascular morbidity are suspected. Generally, changes in both systolic and diastolic blood pressures (BP) at the end of the dosing interval from the baseline are compared between the active and the control arms as the primary endpoint of anti-HT effect. Onset of the anti-HT effect can be studied as the secondary endpoint. For maintenance of efficacy, long-term studies of ≥6 months need to be undertaken. Error-free measurement of BP is a serious issue as spontaneous changes in BP are large and active drug effect on diastolic BP is often small. Placebo-controlled short-term studies (of ~12 weeks) for dose-response and titration are very useful. Safety studies must be very vigilant on hypotension, orthostatic hypotension and effects on heart. In dose-response studies, at least three doses in addition to placebo should be used to well characterize the benefits and side-effects.