Nocturnal dosina of a novel delivery system of verapamil for systemic hypertension

June 13, 2017 | Autor: William White | Categoria: Statistical Significance, Delivery System, Ambulatory Blood Pressure, The American
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Nocturnal Dosin of a Novel Delivery System o 9 Verupami/ for Systemic Hypertension William 6. White, Henry R. Black, MD,

Robert J. Anders, PharmD, John M. Macln re, PhD, Domenic A. Sica, MD, and the Verapamil Stu r y Group*

MD,

To evaluate the efficacy and safety of a novel delivery P.M.) and nighttime (8 P.M. to 8 A.M.) BP. The 180,360, system of physiologic ttem release (PPR)-verapamil and 540 mg verapamil doses achieved statistical1 sigadministered nocturna p” ly to patienk with stages I and nificant reductions in trough (6 ta 10 P.M.) diasta ric BP II hypertension usin ambulatory blood pressure (BP) (-3.9 + 1.0, -7.8 f 1.2, and -10.6 f 1.1 mm Hg, remonitoring, we pe Rormed a multicenter (17 centers), spectively). Reductions in peak early morning (6 to 10 double-blind, randomized, placebo-controlled, paralA.M.) diastolic BP were greater (-4.6 f 0.9, -13.3 f 1.2, and -19.0 f 1.2, for 180, 360, and 540 mg, relel-group trial with placebo and 120, 180, 360, and 540 mg of Vera mil in 287 randomized patients. The 5 tively). These data demonstrate that this novel delivery system r as a delay in the release of verapamil 8”elivery system of verapamil administered nocturnalfy for 4 to 6 hours, and then delivers the drug from an produced changes in BP that followed the circadian osmotic pumping system for approximately 12 hours. variability of BP: lower, but significant reductions durPatients were dosed at 10 P.M. The prima end point ing sleep, when ambulatory BP is intrinsically lowest in was change from baseline in trough 7 iastolic BP patients with hypertension, and appropriately larger assessed by ambulatory BP monitoring from 6 to 10 reductions during early morning awakening and dayP.M. after 8 weeks of therapy, whereas secondary mea- time hours when ambulatory BP levels accelerate and plateau to the highest levels over a 24hour period. sures included changes from baseline in peak, ea morning (6 to 10 A.M.) systolic and diastolic BP, trougt (Am J Cardiol 1995;76:375-380) clinic BP, and 24hour average daytime (8 A.M. to 8

hrough ambulatory blood pressure (BP) monitoring T research, it has become clear that a distinct circadian pattcm of BP behaviorlm7exists. In a person with a typical pattern of wakefulness and sleep (i.e, awake during the daytime and asleepduring the nighttime), BP rises substantially on early morning awakening, plateausat the highest values of the day during work or physical activity, and declines about 20% during sleep.6This is not surprising as most neurohormonal systems follow the same pattern and are likely responsible for most of the circadian pattern of BP and heart rate.” In this study, the goal was to assesswhether physiologic pattern release (PPR)--vcrapamil could reduce BP based on the typical diurnal variation of BP. The formulation is an osmotic pump system within a bilayer tablet. An outer shell delays drug releasefor approximately 4 to 5 hours; a semipermeable membrane around the osmotic delivery system allows water from the gastrointestinal tract to fill a hydrocellulose layer and push the verapamil out From the Sect:on of Hypertensron and Vascular Drseases. Unrversity of Connectrcu Heaitn Center, Formington, Ccrnccticut, the Clinical Research ana Biostatis’ics Departments, Searle/lorex Phcrmacwculs, Skokre. Illinois; the Deportment of Pteventve Medcine, Rush Jresby+r:ar-St. LLKC’S M,ed?a Center, Chrcago, Illrnors: and the Sectror of Clinicul Phcrrnacology, Divrsion of Nephrology, Me&a’ College of Vr~grnia, Richmond, Virginia. Monuscrrpt received Feb.2 ary ! 0. 1995: revised manJsc-ipt rcceivea and accepted May 25, i 995 Address for repr,n!s: Willram B. White, MD Sectror: 0’ Hypertcr:sron ana Vascular Crseases, Mail Code 3940, University of Connectrcur Heath Center, 263 Farmington Avenue, ‘crmington, Con recticut 36032. *See

Aapondix

for the ccmT)lete

investigator

I st

of the tablet through a laser-driven orifice. The objective of the PPR-verapamil formulation is to provide optimal verapamil/norverapamil plasma concentrations during the early morning hours when BP generally rises in association with awakening.6.9 METHODS Study design: This was a multicenter, double-blind,

randomized, placebo-controlled, parallel-group design study that compared the efficacy and safety of 4 dosage levels of PPR-verapamil. There were 3 phases to the study: (1) l-week washout period for patients who were currently receiving antihypertensive drug therapy. (2) a 2- to 4-week, single-blind placebo period to establish baseline values, and (3) an 8-week, double-blind treatment period during which placebo or a dosage level of PPR-verapamil (120, 180, 360: or 540 mg once daily) were given. For the 2 higher dosing groups of PPR-verapamil, a fixed dose titration schedule was used: in the 360 mg group, 180 mg was administered during the first 2 weeks of the double-blind period followed by 360 mg/ day for 6 weeks, and in the 540 mg group, 180mg was administered the first 2 weeks, 360 mg during weeks 3 and 4, and 540 mg daily for 4 weeks. The dose was increasedas required by study design, unless patients had unacceptableside clfects (in which casethey were withdrawn from the study). Patient population: Men and women with hypertension were included in the study if their average seated diastolic BP was 295 and 5114 mm Hg on 2 consecutive weeks during the single-blind placebo period, and the 2 diastolic BP values were within 8 mm Hg of each

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TABLE I Baseline Characteristics,

Blood Pressure, and Heart Rate in the Treatment

Parameter Age lyrl Weight (kg) Black (%) Non-Hispanic white (%) Hispanic (%) Other (%) Clinic heart rate (beots/min) Clinic BP (mm Hg) Systolic Diastolic 24-hour heart rate (beats/min) 24-hour BP (mm Hg) Systolic Diastolic Daytime BP (mm Hg) Systolic Diastolic Nighttime BP [mm Hg) Systolic Diastolic

Groups

Placebo (n = 58)

120 mg (n = 59)

180 mg (n = 56)

360 mg (n = 59)

540 mg (n = 55)

52.4 e 1.4 86.5 zt 2.2 26 50 16 2 77 f 1

54.1 f 1.3 82.8 * 2.2 25 49 17 0 77*1

52.0 * 1.4 85 i 2.6 27 54 14 2 77 f 1

53.9 f 1.3 86.9 * 2.6 17 63 15 0 78 i 1

53.3 f 1.1 85.3 zt 1.0 24 53 20 0 77 f 1

156 i 2 101 f 1 80 zt 1

159i2 101 f 1 80 sz 1

155 * 2 loo*1 78 f 1

158i2 102* 1 79 f 1

158*2 101 il 81 zt 1

153*2 95 f 1

154 f 2 95 f 1

147* 1 93 f 1

155*2 95 f 1

152 zt 2 95 f 1

159i2 lOO*l

160*2 101 f 1

154 f 2 99 * 1

16Oi2 101 *l

158i2 lOOi

146i2 89 f 1

147*2 89 zt 1

140 f 2’ 87i 1

149 * 2 90 f 1

145i2 89 iz 1

1

l p = 0.05 versus placebo, but not hosed on TukeyXramer test. Values are expressed QL mean * SE. BP - btocd pressure; Doyiime pressure monitoring period.

BP = 8 A.M.

to 8 P.M.;

Nighttime

BP = overage

of two 8 P.M. to 8 A.M.

periods

derived

from

J&hour

ambulatory

bleed

other. In addition, patients were eligible for double-blind randomization only if the mean daytime (8 A.M. to 8 PM.) diastolic BP was 290 mm Hg. This additional ambulatory BP criterion was usedto assureinclusion of truly hypertensive patients into the trial.iO+ii Patientswith secondaryhypertension,coronary artery disease,congestive heart failure, serious cardiac conduction abnormalities (including atrioventricular block), alcoholism, psychosis, serious chronic medical diseases (e.g., hepatic or renal insufficiency), or malabsorption syndromes were excluded from the study. In addition, patients who worked exclusively at night or worked various shifts were excluded from the study. Measurements of blood pressure and heart KJIIXClinic BP was measuredby mercury column sphygmomanometry in duplicate in the seatedand standing positions at every visit. Heart rate was measured in duplicate in conjunction with each BP measurementfor a minimum of 30 seconds. Ambulatory BP measurementswere obtained with the Spacelabs 90202 monitor (Redmond, Washington).l2 Criteria for an acceptable ambulatory BP recording included a minimum of 80% valid readings obtained within 24 hours after dosing, a minimum of 2 valid readings per hour during the Iirst 20 hours of the 24hour postdosing period, and a minimum of 3 valid readings per hour during at least 3 of the last 4 hours of the 24-hour postdosing period. If these criteria were not met, the patient was asked to repeat the study within 2 days. If a repeat ambulatory BP study failed to meet the quality control criteria, the data were considered nonevaluable. BP and heart rate were recorded every 15 minutes for 36 hours. The baseline ambulatory BP study at the end of the single-blind placebo period and the ambulatory BP study at the end of the &week double-blind treatment period were for 36 hours, with monitoring initiated at 6 to 9 P.M. Thirty-six-hour monitoring was per-

formed becauseof the nocturnal dosing of the study drug and the need to obtain trough measurementsbefore the actual drug dosing at 10 P.M. Statisticalanalysis: Comparability of patients allocated to the treatment groups was determined from the demographic data. Continuous variables were analyzed using an analysis of variance model including terms for treatment, center, and treatment-by-center interaction. In the event that significant (p ~0.05) treatment effectswere observed in the analysis of variance, multiple comparisons were done using Tukey’s multiple comparisons method. Discrete variables were compared using the Co&an-Mantel-Haenszel test controlling for center. If significant (p ~0.05) treatment effects were observed in these analyses, a Student-Newman-Keuls-like method was used to assesspairwise treatment differences. The primary variable for assessingefficacy was the changefrom baseline in diastolic BP before drug administration (pharmacodynamic trough period). These changeswere assessedby mean changesin ambulatory diastolic BP monitored over the 6 to 10 P.M. time intervals (average of nights 1 and 2 of the 36-hour monitoring period) at the final treatment visit. For a given dose, such changeswere deemedsignificant if both of the following were true: the change in the given dose was significantly different from the change in placebo at the p co.05 level (2-sided), and the observedchange was 23.5 mm Hg versus the change in placebo (treatment effect). Secondaryassessmentsof efficacy included changein peak early morning BP using both ambulatory BP from 6 to 10 A.M. and cuff systolic and diastolic BP measured in the clinic between 7 and 10 A.M., as well as a change in 24hour mean, daytime (8 A.M. to 8 P.M.), and nighttime (8 P.M. to 8 A.M.) systolic and diastolic BP from baseline to the end of week 8 acrosstreatment groups. Adverse events were classified by body system and preferred term using a World Health Organization dic-

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OF CARDIOLOGY’

VOL. 76

15,

1995

and 120 mg groups, and the 540 mg group had significantly greater decreasesin systolic BP than the placebo and the 120 and 180 mg groups (Table II). There were also significant reductions in heart rate in the 360 and 540 mg treatment groups. For clinic measurementsat trough, there were similar tindings to the ambulatory BP at 6 to 10 P.M.,except that the 180mg dose achievedmarginally statistically significant differencesfrom placebo, and the 540 mg dose was signiticantly different from the 360 mg dose (Table Il). Early morning blood pressure and heart rate: The changesfrom baseline in early morning ambulatory systolic and diastolic BP (6 to 10 A.M.) are shown in Figure 1 and Table III. There were also highly significant (p
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