This was the main dose-response study. The objectives of the trial were to assess the tolerability of three doses of ranolazine sustained-release compared to placebo and their effects on treadmill exercise performance. It was a double-blind, randomised, placebo-controlled, cross-over study enrolling 191 patients treated with 500, 1,000 and 1,500 mg ranolazine against placebo. Treatment duration was 1 week at each dose level. Improvement of exercise duration was statistically significant compared to placebo for all three doses of ranolazine from 24 s at 500 mg bid. to 46 s at 1,500 mg bid, and showing a clear dose-response pattern. However, the disproportionate increase in adverse events with the 1,500 mg bid dose led to the conclusion that doses above 1,000 mg bid should not be used.

The TERISA study (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina) assessed the efficacy of ranolazine versus placebo on weekly angina frequency and sublingual nitroglycerin use in 949 diabetic patients with coronary artery disease and chronic stable angina despite treatment with up to two anti-anginal agents [24]. Patients were randomized to a parallel 8 week double-blind study of ranolazine (target dose 1 g bid) or placebo. Weekly angina episodes were significantly reduced by ranolazine compared to placebo (3.8 vs. 4.3 episodes, p = 0.008), as was the weekly use of sublingual nitrates (1.7 vs. 2.1, p = 0.003). The study showed that among symptomatic patients with diabetes and despite treatment with up to two anti-anginal agents, ranolazine was effective in reducing the occurrence of angina attacks and the use of sublingual nitrates.

In this study 823 patients were randomised to either ranolazine 750 mg bid. (n = 279), ranolazine 1 g bid or placebo as add-on treatment to atenolol 50 mg od, amlodipine 5 mg od, or diltiazem 180 mg od. All patients had had chronic stable angina for at least 3 months. The pre-qualifying exercise test had to be symptom-limited and show the usual definite signs of myocardial ischaemia during exercise (0.1 mV ST segment depression). Mean age of included patients was 64 years. Mostly Whites and only about 23 % were females. Twenty-three percent were diabetics and 29 % had a diagnosis of congestive heart failure. Over 60 % were hypertensive and 58 % had suffered a previous myocardial infarction. The objective of the study was to determine the effects of ranolazine at doses of 750 mg bid or 1 g bid compared to placebo on symptom-limited exercise duration among patients with chronic stable angina treated with commonly used anti-anginal drugs. The primary efficacy end point was the change from baseline in exercise duration at trough after 12 weeks on study drugs. At baseline there were no differences between the three treatment arms; all showed an exercise duration of approximately 7 min, since one requirement was the ability to perform an exercise test with a duration of 3–9 min (modified Bruce protocol). The mean increases in exercise duration at trough were statistically significantly greater for patients treated with either dose of ranolazine SR than with placebo. A significant improvement in the occurrence of anginal episodes and the use of sublingual nitrates was also observed with ranolazine (Fig. 9.2).

The trial assessed the effect of ranolazine sustained-release in patients with a documented history of coronary artery disease, chronic stable angina for 3 months or longer, and three or more angina episodes a week during the 2-week qualification period despite treatment with amlodipine 10 mg daily. Patients were randomised to receive either ranolazine 500 mg (bd) uptitrated to 1 g after 1 week or placebo on top of Amlodipine 10 mg. Patients were assessed at 2 and 6 weeks after initiation of the full-dose. Out of 565 randomised patients 98 % in each group completed the trial. Patients allocated to ranolazine had a significantly lower incidence of weekly episodes of angina compared with patients receiving placebo. The effect on angina was mirrored by a significant reduction in the average weekly rate of NTG consumption in patients receiving ranolazine.