title: 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.
authors.affiliation: Actelion Pharmaceuticals Ltd, Department of Clinical Pharmacology, Allschwil, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Dingemanse
authors.affiliation: Dedinje Cardiovascular Institute, University of Belgrade, Belgrade, Serbia.
authors.forename: P
authors.initials: P
authors.lastname: Otasevic
authors.affiliation: Actelion Pharmaceuticals Ltd, Department of Clinical Pharmacology, Allschwil, Switzerland.
authors.forename: K
authors.initials: K
authors.lastname: Shakeri-Nejad
authors.affiliation: Gefen Cardiac Health Centre, Givatayim and Israeli Academic College, Ramat-Gan, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Klainman
authors.affiliation: Clinical Hospital Center Zemun, University of Belgrade, Belgrade, Serbia.
authors.forename: B
authors.initials: B
authors.lastname: Putnikovic
authors.affiliation: Actelion Pharmaceuticals Ltd, Department of Biostatistics, Allschwil, Switzerland.
authors.forename: H
authors.initials: H
authors.lastname: Kracker
authors.affiliation: Actelion Pharmaceuticals Ltd, Department of Clinical Pharmacology, Allschwil, Switzerland.
authors.forename: M S
authors.initials: MS
authors.lastname: Mueller
authors.affiliation: Wolfson Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Zimlichman
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D017311:Amlodipine / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects*; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000378:metabolism; D020747:Calcium Channels, T-Type / Q000187:drug effects* / Q000378:metabolism; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006973:Hypertension / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007557:Israel; D008297:Male; D008875:Middle Aged; D055771:Serbia; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001643:Bridged Bicyclo Compounds; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; C000592016: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; D017311:Amlodipine