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



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.


Calcium channel blockers (CCBs) are a heterogeneous class of compounds that are effective in the treatment of hypertension and stable angina.1, 2, 3, 4 The majority of traditional CCBs, such as nifedipine and verapamil, are selective for L-type calcium channels, and are often associated with peripheral edema, headache, tachycardia, flushing, negative inotropic effects and reflex tachycardia.5,6 Although these side effects are not considered life threatening, they can contribute to poor patient compliance, particularly in the case of peripheral edema.7

Some newer CCBs inhibit T-type, as well as L-type, calcium channels.8 In randomized trials, the dual L- and T-type CCBs mibefradil and efonidipine have demonstrated similar, or superior, efficacy to L-type CCBs, with lower rates of peripheral edema and negligible reflex tachycardia;8,9, 10, 11, 12 however, the approval and use of efonidipine is largely limited to Asia, and mibefradil was withdrawn from the market due to drug–drug interactions. Thus, blockade of both L- and T-type calcium channels appears to improve CCB efficacy and may offer tolerability benefits.

ACT-280778 (isobutyric acid (1R,2R,4R)-2-(2-{[3-(4,7-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester) is an orally active, non-dihydropyridine, dual L-type and T-type CCB. In preclinical studies, ACT-280778 potently induced vasodilation in coronary arteries to a greater degree than in peripheral arteries, promoted an increase in blood flow and a decrease in systolic blood pressure (SBP), and prevented ischemia-induced vasoconstriction; it was not associated with reduced cardiac contractility or tachyphylaxis (Actelion Pharmaceuticals Ltd, data on file). In healthy male subjects, a single ascending dose (SAD) study demonstrated that oral doses of ACT-280778, up to and including 15 mg, were well tolerated and in a multiple-ascending dose (MAD) study, 5 and 15 mg doses were well tolerated.13 This study was designed as a proof-of-concept study, that is, the first study with the new compound in patients with hypertension. The aim of the study was to assess the efficacy and safety of ACT-280778 in patients with mild-to-moderate essential hypertension. The compound had the potential of a potent antihypertensive drug with better tolerability than existing CCBs.

Materials and Methods

The study protocol was approved by the ethics committee of ‘Institute zu Kardiovaskularne bolesti’ and ‘KBC Zemun’ in Belgrade, Serbia and Helsiniki Committee Mayanei and Wolfson in Tel Aviv, Israel. All subjects gave written informed consent, and the study was conducted in full conformity with the Declaration of Helsinki. The study was conducted at 15 centers in two countries: Israel (9) and Serbia (6) between 6 March 2011 and 8 January 2012.

Study design

Screening (Visit 1) was conducted prior to enrollment (Visit 2) into a single-blind placebo run-in phase (Period 1) of 2–4 weeks (Figure 1). Patients completing Period 1 (and meeting additional blood pressure (BP) criteria; outlined below) were eligible to enter the double-blind treatment phase lasting 4 weeks (Period 2), during which patients visited the clinic once weekly (Visits 3–7) for efficacy, safety and pharmacokinetic assessments, and for medication compliance review. End of study assessments for each patient were performed 1 week (±2 days) after Visit 7 or after premature study drug discontinuation. A telephone follow up for serious adverse events (SAEs) took place 30–35 days after the last dose administration at Visit 7 or after premature study drug discontinuation.

Figure 1

Study design.

Patient enrollment and randomization was controlled by an Interactive Web Response System. The investigator and study staff, patients, monitors, sponsor and contract research organization staff remained blinded to the treatment allocation until study closure (database lock).


Males and females aged 18–75 years, with a history of mild-to-moderate essential hypertension, body mass index (BMI) 18–35 kg m−2, body weight 50 kg, mean of triplicate BP measurements for sitting SBP (SiSBP) of 140–169 mm Hg and sitting diastolic blood pressure (SiDBP) of 95–104 mm Hg (untreated, that is, no antihypertensive therapy in the past 14 days prior to Visit 1) or SiSBP <160 mm Hg and SiDBP <100 mm Hg (treated) were included. Patients were required to have 12-lead bedside electrocardiogram (ECG), clinical chemistry, hematology, coagulation, virus serology and urinalysis test results that did not deviate from the normal range to a clinically relevant extent. At Visit 2, mean trough SiDBP was required to be 95 to <110 mm Hg for patients who were untreated, and at Visit 3 mean trough SiDBP was required to be 95 to <110 mm Hg for all patients. In order to proceed to randomization (Visit 3), patients had to demonstrate >80% compliance during Period 1.

Patients with: mean SBP>180 mm Hg; severe, malignant or secondary hypertension; episodes of hypertensive crisis, hypertensive emergency or angina pectoris within 6 months prior to enrollment; orthostatic drop in SBP>20 mm Hg when moving from the sitting to the standing position; previous history of fainting, collapse, syncope, orthostatic hypotension or vasovagal reactions considered clinically significant were not permitted to enter the study. Patients with: severe coronary artery disease indicated by myocardial infarction, percutaneous coronary intervention or coronary artery bypass graft within 12 months prior to enrollment; mild, moderate or severe hepatic impairment; evidence of severe renal impairment (creatinine clearance <30 ml min−1); or simultaneous treatment with more than two antihypertensive agents within the last 3 months prior to screening could not be enrolled.

Study treatment

In the SAD study, two healthy male subjects who received single oral doses of 40 mg ACT-280778 had abnormal ECG findings.13 Modeling and simulation techniques were applied to estimate the probability of producing exposure levels similar to those observed in the two healthy subjects in the SAD study, and to assess the likelihood of inducing similar abnormalities after multiple-dose administration for 28 days in patients with hypertension. On the basis of these predictions, a dose of 10 mg was selected for this study.

ACT-280778 was administered once-daily in the morning, as two 5 mg oral capsules for 28±2 days. Patients were advised to take the drug on an empty stomach or with a light low-fat breakfast. The active comparator amlodipine (10 mg) and placebo were administered under the same conditions as for ACT-280778. Placebo was formulated with the same excipients, but without ACT-280778.

A 10 mg dose of amlodipine was included here and was the maximum recommended dose according to the product label.14 As this study was not powered to detect a difference in the BP-lowering effects between ACT-280778 and amlodipine, the amlodipine group was independently compared with the placebo group to informally explore the sensitivity of the study.


At Visit 1, demographic, clinical and medical characteristics were recorded. Patients attended clinic visits in a fasted state and without having taken their study medication. All clinical visits (except screening) were required to be performed between 0600 and 1000 hours. Following the first (Visit 3) and the last (Visit 7) intake of study drug, patients remained at the clinical site for 6 h for monitoring and performance of vital signs, ECG assessments and pharmacokinetic blood sampling; at Visits 4–6, patients remained at the clinical site for 3 h.

All centers were equipped with identical standardized and validated automatic oscillometric devices (Omron M10-IT, Omron Healthcare Co., Ltd, Kyoto, Japan). In the context of this proof-of-concept study, accurate and standardized BP assessments at pre-dose steady-state conditions were needed to assess the potential of ACT-280778 to show a statistically significant and clinically relevant BP reduction effect.15 Vital sign measurements were always carried out on the subject’s same arm and at approximately the same time. Orthostatic (sitting and standing) SBP, DBP and heart rate (HR) were measured in triplicate at Visit 1. Sitting BP and HR were measured after a resting period (sitting) of 5 min, whereas standing BP and HR assessments were performed after exactly 1 min in the standing position. At all other time points, only sitting vital signs were measured in triplicate. If, during the study, mean SiSBP or SiDBP was outside the range as defined in the inclusion criteria, the triplicate measurements could be repeated once for confirmation.

Mean trough SiDBP and other efficacy assessments, including the mean change from baseline in trough SiSBP, were recorded at each visit, up to and including Visit 8. Mean trough was defined as the mean of all pre-dose measurements.

For the determination of pharmacokinetic parameters, ~7 ml blood was collected by direct venipuncture, or via an intravenous catheter placed in an antecubital vein. At Visits 4–6, blood samples were obtained pre-dose, and 1, 2 and 3 h post-dose immediately after vital sign and ECG assessments; at Visits 3 and 7, sampling times were pre-dose and 1 , 2, 3, 4 and 6 h post-dose. The concentration of ACT-280778 was determined using a validated liquid chromatography coupled with tandem mass spectrometry method.13 The lower limit of quantification for ACT-280778 in plasma was 10 pg ml−1.

Adverse events (AEs), SAEs, ECGs (12-lead) and laboratory test values were recorded at every visit; 12-lead 24-h Holter ECGs were performed at screening, Visits 3 and 4. At Visits 4–6, standard ECG assessments were performed pre-dose, and 1 h, 2 h and 3 h post-dose during the 6 h observation period; at Visits 3 and 7, sampling times were pre-dose, and 1, 2, 3, 4 and 6 h post-dose.

During Period 1, patients who were non-compliant with placebo were permanently discontinued from the study. At each visit during Period 2, the patient’s diary was reviewed and the number of capsules was counted by the site staff to assess compliance; in the event of drug interruption for more than 1 day per week or during the last 3 days prior to a scheduled clinic visit, the patient was permanently discontinued from the study.

Statistical analysis

A sample size of 36 evaluable patients per-treatment group (using a 1:1 randomization) had 90% nominal power to detect a difference of 7 mm Hg between the means of the primary variable in the ACT-280778 and placebo groups (nQuery Advisor MTTO-1, Statistical Solutions, Boston, MA, USA), assuming the primary end point to be normally distributed in both groups, with a common s.d. of 9 mm Hg. Assuming that 20% of the randomized patients would be excluded from the per-protocol set, randomizing at least 45 patients per-treatment group, and a total of 135, was suggested. To reach this number, at least 171 patients needed to be enrolled in Period 1, assuming a 20% drop-out rate during this period.

The full analysis set included all randomized patients; the safety set included patients who were randomized and received at least one dose of double-blind study drug; and the per-protocol set was a subset of the full analysis set, excluding patients with major protocol deviations that might affect the evaluation of the primary end point.

The primary end point was change from baseline to day 28 (±2 days)/week 4 in mean trough SiDBP. Analysis of covariance was performed on the primary end point variable, change from baseline on SiDBP, with the baseline measurement mean trough SiDBP as a covariable and the treatment arms (ACT-280778 and placebo) as fixed effect.

The main statistical analysis was performed on data from the per-protocol set using the F-test on the difference between the least square means of the investigational drug and placebo. The change from baseline to Day 28 (±2 days) of Period 2 (Visit 7) for the continuous efficacy, variables was displayed using descriptive statistics by treatment and placebo-corrected for the active treatment groups (ACT-280778 and amlodipine), including mean, median, s.d., standard error, quartiles, minimum and maximum, and 95% two-sided confidence limits (CLs) of mean and median.

Safety and tolerability end points were analyzed descriptively. The safety set was used to perform all safety analyses. Treatment-emergent adverse events (TEAE) was defined as any AE temporally associated with the use of a study drug (from study drug initiation until 5 days after study drug discontinuation), whether or not considered related to the study drug.



A total of 196 patients were enrolled into Period 1 (Figure 2); of these, 159 (81.1%) were randomized and received placebo (n=53), ACT-280778 (n=52) or amlodipine (n=54) during Period 2. The most frequently reported reasons for randomization (run-in) failure were patient not meeting the eligibility criteria for entering the double-blind treatment period (12.8%), followed by AEs (3.6%), and withdrawal of consent (3.1%).

Figure 2

Patient disposition.

Demographic data for the 159 patients randomized in this study are presented in Table 1. Notably, baseline BP and the proportion of patients previously treated with at least one antihypertensive medication (77.4–78.8%) were similar across groups. In all three groups, double-blind study treatment was received for a median duration of 29 days, with 74.1–75.5% of patients receiving treatment for at least 4 weeks.

Table 1 Baseline characteristics (full analysis set)

In the placebo, ACT-280778 and amlodipine groups, 15.1, 9.6 and 16.7% of patients, respectively, prematurely discontinued the double-blind study treatment (Figure 2). In each treatment group, the main reason for discontinuation was AEs; the most frequently reported AEs leading to discontinuation of study treatment were second-degree AV block (placebo 5.7%; ACT-280778 1.9%; and amlodipine 1.9%) and peripheral edema (placebo 0%; ACT-280778 0%; and amlodipine 3.7%). No patient met the discontinuation criteria for treatment-emergent ECG abnormalities related to QTcB and QTcF.


The primary efficacy end point of the study was not met: least square mean (95% CL) change in mean trough SiDBP at week 4 in the per-protocol set showed no significant difference (0.4 mm Hg) between the placebo and ACT-280778 groups (−9.9 (−12.7, −7.0) mm Hg vs −9.5 (−12.4, −6.5) mm Hg; P=0.86). Results were similar for the full analysis set; the least square mean change in mean trough SiDBP at week 4 was −8.9 (−11.5, −6.3) mm Hg with placebo vs −9.6 (−12.2, −7.0) mm Hg in the ACT-280778 group (P=0.69).

An exploratory analysis (per-protocol set) showed mean (95% CL) changes in mean trough SiDBP of −9.8 (−12.9, −6.8) mm Hg, −9.5 (−12.2, −6.8) and −16.8 (−19.0, −14.5) mm Hg in the placebo, ACT-280778 and amlodipine groups, respectively; the treatment effect (mean difference from placebo) with ACT-280778 was 0.3 mm Hg (−3.7, 4.4) and with amlodipine was −6.9 mm Hg (−10.7, −3.2). Consistent results were observed with the full analysis set (Figure 3a).

Figure 3

Mean (95% CL) change from baseline over time in (a) mean trough SiDBP and (b) mean trough. SiSBP (full analysis set).

Similar SiSBP results to those for SiDBP were seen across all three treatment groups (mean (95% CL) changes of −8.2 (−11.7, −4.6) mm Hg, −6.4 (−10.5, −2.4) and −20.7 (−24.7, −16.6) mm Hg for the per-protocol set in the placebo, ACT-280778 and amlodipine groups, respectively; Figure 3b, full analysis set).

The primary efficacy end point was not met and the secondary analyses did not achieve statistical significance; therefore, other efficacy end points are not presented herein.

Safety and tolerability

Treatment-emergent adverse events

The frequency of TEAEs was similar among groups (Table 2). Headache was the most frequently reported TEAE and was greater in the placebo and amlodipine groups compared with the ACT-280778 group. Peripheral edema was the next most commonly reported AE, occurring with greater frequency in patients receiving amlodipine compared with those receiving placebo. No instances of peripheral edema were reported in the ACT-280778 group (Table 2). Five AEs of second-degree atrioventricular (AV) block were reported, one each (both type I) with ACT-280778 and amlodipine, and three with placebo (one of which was categorized as type II).

Table 2 Common Treatment-emergent adverse events (TEAEs) reported during the 4-week treatment period (>3% incidence; safety set)

Three subjects experienced a total of six serious TEAEs in the ACT-280778 group (asthma, atrial fibrillation, coronary artery occlusion, myocardial infarction, urinary tract infection, urosepsis); no serious TEAEs were reported by patients in the placebo or amlodipine groups. All serious TEAEs were considered unrelated to ACT-280778 by the investigator and resolved by the end of study. Treatment was continued in two of the three patients; however, ACT-280778 was discontinued in the patient who experienced a myocardial infarction.

12-Lead ECG assessments (standard ECG and 24 h Holter ECG)

There was no observable effect of study treatment on HR in the placebo, ACT-280778 and amlodipine groups at week 4 (pre-dose); mean (95% CL) changes from baseline were 2.2 (0.4, 4.0), −1.6 (−4.0, 0.8) and 2.5 (0.4, 4.5) beats per min, respectively. The maximum effect on HR with ACT-280778 was observed 1 h post-dose, corresponding with Tmax; mean (95% CL) changes at this time point were 0.9 (−1.4, 3.2), −2.6 (−4.7, −0.5) and 0.1 (−2.4, 2.6) in the placebo, ACT-280778 and amlodipine groups, respectively.

Change in mean PR interval from baseline to 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 notably increase the mean PR interval (1.1 (−1.6, 3.9) ms). For ACT-280778, an increase in mean PR interval as compared with baseline was consistently observed for pre-dose and post-dose measurements at weeks 1, 2 and 3, and for post-dose measurements at week 4. This effect appeared to be reversible; at the end of study, the mean change from baseline in PR interval was +1.4 ms (95% CL −1.3, 4.0) in the ACT-280778 group. At week 4, the maximum effect on PR interval with ACT-280778 was observed 4-h post-dose; mean (95% CL) changes were −0.5 (−3.3, 2.4), 9.1 (5.7, 12.5) and 0.1 (−2.7, 2.9) in the placebo, ACT-280778 and amlodipine groups, respectively.

At week 4 (pre-dose), the maximum observed absolute PR interval was 204.0, 218.7 and 207.0 ms and the maximum change in PR interval was 26.0, 30.3 and 26.7 ms in the placebo, ACT-280778 and amlodipine groups, respectively. Prolongation of PR to >200 ms, or increases in PR from baseline of >60 ms, were reported in 15.4% of patients in the ACT-280778 group compared with 9.4% in the placebo group and 5.6% in the amlodipine group. First-degree AV block (PR>200 ms) was observed in 21.2, 11.3 and 3.7% of patients, respectively.

Greater numbers of ECG abnormalities were detected in the ACT-280778 group during 24-h 12-lead Holter monitoring compared with placebo and amlodipine, including supraventricular tachycardia and supraventricular extrasystoles (Table 3). Two patients in the ACT-280778 group were found to have sinus pauses (RR interval>2 s) during 24-h 12-lead Holter monitoring; one patient had sinus pauses on day 1 (13 pauses, with a longest 3.7 s pause) as well as on day 7 (13 pauses >2.0 s long), the patient was asymptomatic and the Holter finding was reported as an AE (ventricular extrasystoles) leading to discontinuation. A second patient in the ACT-280778 group had sinus pauses 7 min prior to the first intake of study drug on day 1.

Table 3 Holter ECG abnormalities (frequency >3%; safety set)


For ACT-280778, mean (s.d.) Cmax,ss (n=45) was 613 (396) pg ml−1 and AUC0-6 (n=41) was 2830 (1667) h pg ml−1. The maximum plasma concentration at steady state (Cmax,ss) and exposure (AUC0-6) observed for 10 mg ACT-280778 on day 28 were within expected ranges based on the SAD and MAD studies.13 The majority of patients in this study reached Cmax within ~1-h post-dose. As the study outcome was negative for the primary end point and secondary analyses, no further pharmacokinetic analyses were performed.


In this phase 2a double-blind, randomized, placebo- and active-controlled, parallel-group proof-of-concept study, the non-dihydropyridine, dual L- and T-type CCB ACT-280778 did not demonstrate significant reductions in SiDBP in patients with mild-to-moderate essential hypertension; the primary end point was not met. Assay sensitivity was confirmed with the active comparator, amlodipine, which significantly reduced SiDBP over the 4-week treatment period, as previously been demonstrated.16

The main pharmacological effect of ACT-280778 observed in non-clinical species was vasodilation, leading to an increase in coronary blood flow and a dose-dependent decrease in arterial BP, which was more marked in hypertensive rats than in normotensive animals (Actelion Pharmaceuticals Ltd, data on file); at lower doses of ACT-280788, BP reduction was not associated with reflex tachycardia and there was no evidence of tachyphylaxis or reduced cardiac contractility. In these studies, the major cardiovascular safety findings (delayed AV conduction, pronounced BP reduction, sinus pauses and HR changes) were consistent with the known profile of CCBs. In hypertensive rats, ACT-280778 affected AV conduction at concentrations above those that decreased BP; in contrast, in normotensive animals ACT-280778 delayed AV conduction and decreased BP at similar doses.

In the SAD and MAD clinical studies, the ECG changes, including effects on the sinus node function and AV conduction, were closely monitored.13 The nature of the observed ECG changes and the fact that they were not associated with major alterations in hemodynamic parameters or clinical symptoms indicated that phase 2a development of ACT-280778 under ECG monitoring conditions was feasible.

In the present study, once-daily 10-mg ACT-280778 treatment appeared to produce a modest pharmacological effect on the heart; evidence that ACT-280778 had pharmacodynamic properties was clear from the prolongation of PR intervals. Pharmacokinetic analysis suggested that the maximum plasma concentration at steady state and the exposure for 10-mg ACT-280778 on Day 28 were within expected ranges as compared with results from the MAD study.13

Despite the use of modeling and simulation techniques to estimate an appropriate ACT-280778 dose, 10 mg may have been too low to produce robust, observable reductions in BP. In addition to clinically active doses, it would be expected that in animal models of, or in patients with, mild-to-moderate hypertension, the effects of antihypertensive agents would be more pronounced than in their normotensive counterparts; however, this was not the case in the present study and therefore the difference in BP-reducing effects may have been less pronounced than hypothesized. Moreover, the Holter ECG findings support the notion that safety outcomes are dose limiting for ACT-280778. The dual L- and T- type CCBs efonidipine and mibefradil reduced BP in patients with hypertension supporting the rationale that these agents are effective in this indication.9, 10, 11, 12,17 As such, it is unclear why ACT-280778 was unable to induce reductions in BP, with the ECG findings limiting the exploration of ACT-280778 at higher doses.

Overall, the type and incidence of TEAEs were similar across groups, and including first-degree AV block, were consistent with those previously described for CCBs;18 however, while AV block may be related to treatment with agents such as diltiazem or verapamil, it does not necessarily indicate that these CCBs are the sole cause.19 Rates of peripheral edema were consistent with the reported ranges for amlodipine,7,20, 21, 22 but no cases occurred in the ACT-280778 group. Serious TEAEs were only observed in the ACT-280778 group; however, the overall number of each of these events was low, all were considered unrelated to study treatment and had resolved by the end of study.

As there were no apparent safety signals reported with 5 or 15 mg doses of ACT-280778,13 it is feasible that patients with hypertension responded differently to ACT-280778 than did healthy subjects. Multiple dosing of ACT-280778 over a longer period of time (4 weeks) may have increased the frequency of ECG abnormalities previously only observed at higher doses due to repeated exposure (although there was no evidence of an increase in effect over time with ACT-280778 in animal studies). In this study, a higher frequency of first-degree AV block or a higher proportion of patients with a mean increase from baseline in PR interval of >200 ms was observed in the ACT-280778 group compared with the placebo and amlodipine groups. None of the AV blocks were symptomatic, and more importantly, higher degree AV blocks were not detected at a greater incidence with ACT-280778 compared with placebo; however, the present study was not designed to detect a statistical difference in these events or in the PR interval between groups. In a study of 625 asymptomatic healthy individuals aged 15–83 years, transient second-degree AV block was observed in 2.2% during 24-h ambulatory ECG monitoring.23 The prevalence of first-degree AV block reported in NHANES III was 3.7%; Type II second-degree AV block is rare in healthy individuals (~0.003%), whereas Type I is observed in 1–2% of healthy young people, especially during sleep.24 Overall, these frequencies are similar to those reported for first- and second-degree AV block in this study involving patients with mild-to-moderate hypertension and are similar to the rate in the placebo group in the present study.

Strengths of the present phase 2a proof-of-concept study design include the large sample size with a sufficient number of patients to meet the required statistical power. The patients enrolled were considered representative of a population with mild-to-moderate hypertension. The randomized, double-blind design is considered as the gold standard when assessing the efficacy and tolerability of investigational compounds, and the inclusion of an active comparator in the present study confirmed assay validity. No major limitations are considered regarding the design or conduct of this study.


The primary objective of demonstrating antihypertensive efficacy of once-daily oral administration of 10 mg ACT-280778 on trough SiDBP compared with placebo after 4 weeks was not met; the reasons for this outcome are unclear, but include insufficient dose or suboptimal binding at calcium channels in vivo. A modest, reversible increase from baseline in PR interval was observed with ACT-280778. Overall, treatment with ACT-280778 was well tolerated. It is unlikely that ACT-280778 has any potential to be further developed as an antihypertensive drug. However, its effects on the PR interval raise the possibility of other indications (ventricular rate control).


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We thank Kim Croskery and Liz Bullock (Watermeadow Medical, Witney, UK) for their writing and editorial assistance, supported by Actelion Pharmaceuticals Ltd.

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Correspondence to J Dingemanse.

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Competing interests

This study was sponsored by Actelion Pharmaceuticals Ltd. Dr Dingemanse, Dr Shakeri-Nejad, Dr Kracker and Dr Mueller were employees and stockholders of Actelion Pharmaceuticals Ltd at the time the study was conducted. Dr Otasevic and Dr Zimlichman received honoraria from Actelion Pharmaceuticals Ltd for assistance with clinical trials, and Dr Klainman and Dr Putnikovic have no conflict of interest relevant to this manuscript.

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Dingemanse, J., Otasevic, P., Shakeri-Nejad, K. et al. 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. J Hum Hypertens 29, 229–235 (2015). https://doi.org/10.1038/jhh.2014.79

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