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Efficacy and safety of the dual L- and T-type calcium channel blocker, ACT-280778: a proof-of-concept study in patients with mild-to-moderate essential hypertension.

Abstract
ACT-280778 is an oral, non-dihydropyridine, dual L-/T-type calcium channel blocker. This phase 2a, double-blind, randomized, placebo- and active-controlled study investigated the efficacy and safety of 10 mg ACT-280778. Patients with mild-to-moderate essential hypertension received once-daily placebo (n=53), ACT-280778 10 mg (n=52) or amlodipine 10 mg (n=54) for 4 weeks. The primary end point was the change from baseline to week 4 in placebo-adjusted mean trough sitting diastolic blood pressure (SiDBP) with ACT-280778. Tolerability was assessed by recording treatment-emergent adverse events (TEAEs). Baseline clinical characteristics were similar across groups. No significant difference was observed at week 4 in mean trough SiDBP between placebo (-9.9 (95% confidence limit (CL) -12.7, -7.0) mm Hg) and ACT-280778 (-9.5 (-12.4, -6.5) mm Hg; P=0.86); amlodipine reduced mean trough SiDBP by -16.8 (-19.0, -14.5) mm Hg, confirming assay validity. Change in mean PR interval at week 4 (pre-dose) differed between placebo (-1.0 (95% CL -4.4, 2.3) ms) and ACT-280778 (6.5 (3.5, 9.6) ms); amlodipine did not increase PR interval (1.1 (-1.6, 3.9) ms).Treatment-emergent adverse events (TEAE) frequency was 32.1% (placebo), 32.7% (ACT-280778) and 33.3% (amlodipine). The most common TEAEs were headache, peripheral edema, hypertension and second-degree atrioventricular block. ACT-280778 (10 mg) did not lower blood pressure in mild-to-moderate hypertension.
AuthorsJ Dingemanse, P Otasevic, K Shakeri-Nejad, E Klainman, B Putnikovic, H Kracker, M S Mueller, R Zimlichman
JournalJournal of human hypertension (J Hum Hypertens) Vol. 29 Issue 4 Pg. 229-35 (Apr 2015) ISSN: 1476-5527 [Electronic] England
PMID25231512 (Publication Type: Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
Chemical References
  • Antihypertensive Agents
  • Benzimidazoles
  • Bridged Bicyclo Compounds
  • Calcium Channel Blockers
  • Calcium Channels, L-Type
  • Calcium Channels, T-Type
  • isobutyric acid 2-(2-((3-(4,7-dimethoxy-1H-benzoimidazol-2-yl)propyl)methylamino)ethyl)-5-phenylbicyclo(2.2.2)oct-5-en-2-yl ester
  • Amlodipine
Topics
  • Administration, Oral
  • Adult
  • Aged
  • Amlodipine (therapeutic use)
  • Antihypertensive Agents (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
  • Benzimidazoles (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
  • Blood Pressure (drug effects)
  • Bridged Bicyclo Compounds (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
  • Calcium Channel Blockers (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
  • Calcium Channels, L-Type (drug effects, metabolism)
  • Calcium Channels, T-Type (drug effects, metabolism)
  • Double-Blind Method
  • Drug Administration Schedule
  • Female
  • Humans
  • Hypertension (diagnosis, drug therapy, metabolism, physiopathology)
  • Israel
  • Male
  • Middle Aged
  • Serbia
  • Severity of Illness Index
  • Time Factors
  • Treatment Outcome

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