Treatment A Placebo to match COREG CR 20 mg OD + Lisinopril 10 mg OD (Days 1-7) Placebo to match COREG CR 40 mg OD + Lisinopril 10 mg OD (Days 8-14)

Transcription

1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No: CFD Title: A study to evaluate the potential incidence of orthostatic hypotension in elderly hypertensive patients following administration of a combination of COREG CR and lisinopril Rationale: Currently, the controlled-release (CR) formulation of carvedilol is being evaluated as a fixed dose combination (FDC) product with lisinopril. Since the tmax of COREG CR (median for both R(+)- and S(-)-carvedilol of approximately 5 hours) is similar to the tmax of lisinopril (approximately 7 hours), it is possible that the coadministration of the two drugs may lead to a greater incidence of orthostatic hypotension. To address this potential in a population at risk, the incidence of orthostatic hypotension with the co-administration of COREG CR and lisinopril was assessed by vital sign measurements in a study with elderly hypertensive patients. The incidence of orthostatic hypotension based on associated symptoms for carvedilol is similar to that reported for lisinopril. With the immediate release (IR) formulation of carvedilol, the incidence of orthostatic hypotension reported as an AE was 1.8% in subjects with hypertension who participated in placebo-controlled studies (placebo: 0%); the incidence of this AE did not appear to be greater in the elderly and did not appear to be related to dose. Similarly, in subjects with hypertension receiving Zestril (branded lisinopril), the incidence of orthostatic effects reported as AEs is 1.2%. This study supports the development of an fixed dose combination (FDC) product of the controlled release (CR) formulation of COREG CR (carvedilol CR) and an ACE inhibitor, lisinopril, for the treatment of patients with hypertension or chronic heart failure as well as individuals who have survived an acute myocardial infarction with left ventricular dysfunction. This study assessed the potential for orthostatic hypotension when COREG CR and lisinopril were co-administered in elderly hypertensive patients. Phase: I Study Period: 25 Sep Jun 2008 Study Design: This was a multi-center, double-blind, randomized, placebo-controlled, 2-session crossover study to evaluate the incidence of orthostatic hypotension in elderly hypertensive subjects following co-administration of COREG CR and lisinopril. The study included a screening visit, a run-in phase with the administration of lisinopril 10 mg once daily (OD), two treatment periods, and a follow-up visit. The screening visit was conducted within 21 days prior to the lisinopril runin period. All subjects, in the opinion of the investigator, must have been able to be safely transitioned from current antihypertensive treatment(s) to lisinopril 10 mg once daily to be eligible for this study. Subjects received lisinopril 10 mg once daily continuously throughout the study to the follow-up visit. During the run-in period, subjects received lisinopril 10 mg once daily on an outpatient basis for 14 days ± 4 days. Subjects were required to attend clinic on day 7 (mid-point of the lisinopril run-in period) and day 1 (end of the lisinopril run-in period) for run-in assessment. Lisinopril run-in assessment was to be conducted at least 30 minutes post dose of lisinopril at the required clinic visits. Orthostatic vital signs were measured at screening, on day 7 (mid-point of the lisinopril run-in period) and at day 1 (end of the lisinopril run-in period). If a subject demonstrated orthostatic hypotension as measured at the screening visit, during or at the end of the run-in period, the subject was withdrawn from the study. Orthostatic hypotension was defined as a decrease in SBP of 20 mmhg and/or a decrease in DBP of 10 mmhg in changing from the supine to the standing position. At the completion of the lisinopril run-in period, subjects must have had a sitting SBP that is > 110 mmhg and < 180 mmhg and a sitting DBP that was 85 mmhg and 109 mmhg to be randomized to treatment. Subjects who completed the run-in period and met eligibility criteria received the following treatments in Session 1 or Session 2 (as randomly assigned): Regimens A Placebo to match COREG CR 20 mg OD + Lisinopril 10 mg OD (Days 1-7) Placebo to match COREG CR 40 mg OD + Lisinopril 10 mg OD (Days 8-14) 1

2 B COREG CR 20 mg OD + Lisinopril 10 mg OD (Days 1-7) COREG CR 40 mg OD + Lisinopril 10 mg OD (Days 8-14) There was a 7- to 10-day washout period between each treatment session. Subjects continued to be administered lisinopril 10 mg OD during the washout period. Centres: 15 in the United States Indication: Hypertension, chronic heart failure, post acute MI : All subjects received lisinopril 10 mg during the run-in period and continuously throughout the study to the follow-up visit. During Study Sessions 1 and 2, subjects received COREG CR 20 mg followed by COREG CR 40 mg or matching placebo according to randomization sequence. On Days 1, 7, 8, and 14 in Sessions 1 and 2, study drug was administered in the unit; study medication on Days 2 through 6 and 9 through 13 of both sessions was administered on an outpatient basis. All doses were to be taken within 30 minutes of the start of breakfast. Drug Strength Lot Number Batch Number COREG CR 20 mg COREG CR 40 mg Placebo to match 20 mg Placebo to match 40 mg Lisinopril 10 mg NA Objectives: To evaluate the incidence of orthostatic hypotension (defined as a decrease in SBP of 20 mmhg and/or a decrease in DBP of 10 mmhg in changing from the supine to the standing position) following coadministration of COREG CR and lisinopril. Statistical Methods: The primary focus of the statistical analysis was to evaluate the effect of COREG CR when combined with lisinopril on the incidence of orthostatic hypotension. Point estimates and the 95% confidence intervals (CI) were constructed to provide a range of plausible values for the difference in incidence rates of orthostatic hypotension between the co-administration of lisinopril and COREG CR and the co-administration of lisinopril and placebo following the method of May and Johnson for correlated binary responses. Point estimates and the exact 95% CI for the rates of orthostatic hypotension were calculated for each treatment regimen, for the treatment differences at Days 1, 7, 8, and 14. Frequency summaries of the incidence of symptomatic orthostatic hypotension (defined changes in blood pressure + related symptoms) were also produced. The change from baseline in orthostatic SBP and orthostatic DBP, were separately analyzed by a mixed effects repeated measures model with subject as a random effect and fixed effect terms for period, regimen, day within period, and regimen by day interaction. Baseline was included as a covariate. Point estimates and associated 95% confidence intervals were determined for the treatment differences for each day, separately, using the residual variance. Baseline was defined as the orthostatic vital signs measurements obtained at the end of the two week run-in period (Day -1). Log transformed plasma renin activity data was analyzed using the same mixed effects repeated measures model as specified above, but without the adjustment for baseline. Point estimates and the associated 95% confidence intervals were determined for the treatment differences on Day 7 and Day 14 using the residual variance. Distributional assumptions underlying the statistical analyses were assessed by visual inspection of the residual plots. Normality was examined by normal probability plots, while homogeneity of variance was assessed by plotting the residuals against the predicted values for the model. Summary statistics for all endpoints were calculated by regimen and day. Plots of the orthostatic SBP and DBP data across study days were generated. In addition, summary statistics for all endpoints were produced by day for the run-in phase. No subgroup analysis was planned; however, exploratory analyses to relate demographic covariates age group (< 75 years versus 75 years) and gender, as well as center, were performed to further investigate the orthostatic 2

3 blood pressure data. Study Population: Major Inclusion Criteria: Subjects were adult men and women at least 65 years of age with a body mass index (BMI) between 24 and 37 kg/m 2. Subjects must have had a documented history of essential hypertension and been controlled on an ACE inhibitor, angiotensin II receptor antagonist, or renin antagonist and no more than one other antihypertensive medication at least 3 months before screening with a sitting SBP less than 180 mmhg and DBP less than 110 mmhg. If the second antihypertensive was a diuretic, then the patient must have been approved by the medical monitor; however, if the subject was receiving treatment with hydrochlorothiazide (HCTZ) at a dose of 12.5 mg/day or less, further approval was not necessary (treatment with HCTZ 12.5 mg/day or less plus a K-sparing agent was considered a single antihypertensive medication). Number of Subjects Total Number of subjects included in Randomized Safety Population: 62 Number of subjects included in PD Population (orthostatic blood pressure): 55 1 Number of subjects included in PD Population (plasma renin activity): 60 2 Number of subjects included in PK Population: 62 3 Number of subjects completed as planned, : 54 (87) Number of subjects withdrawn (any reason), : 8 (13) Reasons for subject withdrawal, Other: 4 (6) 4 Orthostatic hypotension (met withdrawal criteria following assessment): 2 (3) 5 Adverse event: 1 (2) Protocol violation - Met renal insufficiency exclusion criteria: 6 1 (2) Demographics Mean Age (SD), years: 72.0 (5.24) Age range, years: Sex, Female: 26 (42) Male: 36 (58) Ethnicity, Hispanic or Latino: 11 (18) Not Hispanic or Latino: 51 (82) Race, 7 White: 57 (95) African American - African Heritage: 2 (3) American Indian or Alaska Native: 1 (2) Mean Height (SD), cm: (9.07) Mean Weight (SD), kg: 84.9 (12.56) Mean BMI (SD), kg/m 2 : 29.1 (2.94) Child-bearing potential (females only), n Post menopausal: 22 Sterile: 4 1. Subjects with PD data (orthostatic blood pressure measurement) from each treatment regimen. 2. Subjects with PD data (renin activity) from at least 1 visit on either treatment regimen. 3. Subjects with PK plasma drug concentration data. 4. For each category, 1 subject was withdrawn: noncompliance, investigator decision, inability to obtain standing blood pressure measurements, and inability to get consistent blood pressure measurements. 5. The investigator reported the orthostatic hypotension that led to withdrawal for Subject 33 as an AE; however, the subject experienced no associated symptoms. Therefore, the withdrawal is being ascribed to orthostatic hypotension, having met the specified withdrawal criteria. 6. Subject met exclusion criterion #6; creatinine clearance 30 ml/min or less as calculated by Cockroft-Gault. 7. N = 60; race missing for 2 subjects. PK = pharmacokinetic; PD = pharmacodynamic; BMI = body mass index. Pharmacodynamics: Summary of Subjects Who Demonstrated Orthostatic Hypotension At Assessment Days 3

4 Assessment Day Placebo + Lisinopril (A1/A2) N (%) COREG CR +Lisinopril (B1/B2) N (%) 1 5/58 (9%) 3/59 (5%) 7 4/56 (7%) 5/59 (8%) 8 5/56 (15%) 5/58 (9%) 14 8/55 (15%) 4/57 (7%) Overall Incidence 14/58 (24%) 9/59 (15%) Frequency Summary of the Incidence of Symptomatic Orthostatic Hypotension in Subjects Completing Two Sessions Placebo + Lisinopril Coreg CR + Lisinopril (A) (B) Session Day N, (%) with Symptomatic Orthostatic Hypotension N, (%) with Symptomatic Orthostatic Hypotension 1 0/58,(0%) 0/59,(0%) 7 0/56,(0%) 1/59,(2%) 8 0/55,(0%) 0/58,(0%) 14 0/55,(0%) 0/57,(0%) Overall 0/58,(0%) 1/59,(2%) Regimen Key: A= Placebo to match COREG CR 20 mg OD OD (Days 1-7; Placebo to match COREG CR 40 mg OD OD (Days 8-14) B = COREG CR 20 mg OD OD (Days 1-7); COREG CR 40 mg OD + lisinopril 10 mg OD (Days 8-14) Summary of Statistical Analysis of the Comparison of Plasma Renin Activity on Days 7 and 14 of Comparison Day Point Estimate CVw% Test LS mean (B) Reference LS mean (A) 95% Confidence Interval B:A Day (0.40, 1.24) 93.4 Day (0.27, 0.85) CVw% = Estimate of within-subject variability Regimen: A = Placebo match for COREG CR 20 mg OD co-administered with lisinopril 10 mg OD (Days 1-7); Placebo match fo COREG CR 40 mg OD co-administered with lisinopril 10 mg OD (Days 8-14). B = COREG CR 20 mg OD co-administered with lisinopril 10 mg OD (Days 1-7); COREG CR 40 mg OD coadministered with lisinopril 10 mg (Days 8-14) Pharmacokinetics: Plasma levels of both carvedilol and lisinopril were determined at protocol specified timepoints. A PK/PD relationship could not be evaluated. 4

5 Safety results: Any pre-existing conditions or signs and/or symptoms present in a subject prior to the start of the study (ie, before informed consent), as well as any medical occurrences reported after informed consent was obtained but prior to starting active or randomized treatment (ie, Session 1), were to be recorded as Medical/Surgical History. Any signs and symptoms present at the time the first dose was administered during the lisinopril run-in period were to be documented as AEs. Any medical occurrences which presented after administration of study medication and on or before the final follow-up visit were to be reported as AEs. From the time a subject consented to participate in the study until he or she had completed the study (including any follow-up period), all serious adverse events (SAEs) assessed as related to study participation (eg, protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant medication, were to be reported promptly to GSK. Placebo (matching COREG CR 20 mg) (N=58) A Regimen Placebo (matching COREG CR 40 mg) (N=54) COREG CR 20 mg (N=59) B COREG CR 40 m (N=57) Adverse Event (Preferred Term) No. subjects with 1 AE 6 (10) 2 (4) 6 (10) 2 (4) Dizziness 1 (2) 0 2 (3) 0 Headache 1 (2) 0 1 (2) 0 Cough 1 (2) 0 1 (2) 0 n = number of subjects with one or more events. Serious Adverse Events, 0 (0%) No SAEs were reported in this study. GSK has submitted manuscripts of these study results to peer-reviewed scientific journals which were not accepted for publication. Publications: None 5