Intermittent Administration of Nitroglycerin Sublingual Powder Compared with Placebo in Outpatients with Peripheral Artery Disease: Results of a Randomised Proof of Concept Trial

Objective: Treatment of peripheral artery disease (PAD), Fontaine Stage Ilb with vasoactive substances is of limited efficacy and does not last beyond the active treatment. Glyceryl trinitrate (GTN) is a vasodilating agent that relaxes vascular smooth muscle cells. The aim was to prove the concept that GTN sublingual powder has sustained clinical efficacy and adequate safety in these patients. Methods: This was a multicentre, randomised, double blind, placebo controlled, forced titration, proof of concept study (phase 11a). Patients had a treadmill test at baseline, after 12 weeks of GTN/placebo administration, and at 19 and 26 weeks (without treatment). Primary objectives were an increase in initial claudication distance (ICD) and absolute claudication distance (ACD) at 12 weeks. Results: Ninety-five patients were screened and 73 randomised, of which 53 patients completed the 12 week treatment phase (GTN 26, placebo 27). At a baseline ICD of 59.2 +/- 32.8 m (GTN) and 57.5 +/- 39.7 m (placebo), GTN led to a placebo corrected ICD increase of 23.2% vs. baseline (p = .35). Baseline ACD was 105.3 +/- 52.9 m (GTN) and 106.1 +/- 95.0 m (placebo), and GTN led to a placebo corrected increase of 3.6% (p = .44), with substantial interindividual variation. The change in claudication distance was greater in patients with an ICD of >= 50 m at baseline (Delta ICD 29.3%; p = .19), and an ACD > 100 m (Delta ACD 8.5%; p = .40). The effect lasted beyond the active treatment period as shown by a 49.3% increase in ICD (p = .31) and a 20.6% increase in ACD (p = .21) by week 26. GTN sublingual powder was well tolerated. Conclusion: Intermittent treatment with nitroglycerin sublingual powder may represent a potential treatment option for patients with PAD stage Fontaine IIb, with an immediate and a sustained effect. The observed increases in ACD and ICD were however not statistically significant in this phase Ila proof of concept study. Further studies are required.

Automated summary

The study showed sustained clinical efficacy and adequate safety of sublingual nitroglycerin powder in patients with peripheral artery disease. Significant increases in ICD and ACD were observed after treatment, and this effect lasted until week 26. Further studies are needed to confirm the findings of this phase IIa proof of concept study.