Cold pressure test
Each subject performed CPT at screening, day -1, and day 10 of each treatment period, approximately 3.5 hours after the start of a moderate breakfast. CPT was conducted approximately at the same time of the day, to reduce the impact of circadian variations of BP on the study outcomes. BP and haemodynamic variables were collected during the CPT using the Finapres® NOVA monitor (Finapres Medical Systems, Amsterdam). The CPT procedure was conducted using the Advanced Hemodynamics software application (Finapres Medical Systems, Amsterdam) to allow for the characterisation of further haemodynamic parameters. The following parameters were collected: SBP, DBP, HR, mean arterial pressure (MAP), cardiac output (CO), cardiac index (CIn), stroke volume (SV), SV index (SVI), total peripheral resistance (TPR), cardiac contractility (dP/dt) and left ventricular ejection time (LVET).
The test included three phases: i) rest phase (5 minutes), ii) cold stimulus phase (3 minutes), and iii) recovery phase (5 minutes). During the cold stimulus phase of CPT, subjects inserted their left hand up to the wrist in a temperature-controlled (4±0.5 ºC) water bath, for three minutes.
The pharmacodynamics analysis set (PD population) included all subjects who received at least one dose of the IMP and had at least one valid post-dose for the corresponding PD assessment. Those subjects who belong to the PD set and did not deviate from the protocol in a way that might affect the evaluation of the corresponding PD variable were included in the per-protocol pharmacodynamics analysis set (PP-PD population).