Pbm-map drug Monograph: Aliskiren




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Villamil et al, 200714
MC, R, DB, PC, PG
213 centers worldwide
n=2776; 2752 (ITT); 2762 (safety)

8 wks


Involvement of sponsor not reported

Inclusion criteria

Men and women > 18 yrs of age, mild to moderate essential HTN (mean sitting DBP > 95 mm Hg and < 110 mm Hg after 2 wks placebo run-in)


Exclusion criteria

Severe HTN (sitting DBP > 110 mm Hg and/or SBP > 180 mm Hg); history secondary HTN; type 1 DM or type 2 DM with HbA1c > 9%; pregnancy or breastfeeding; any medical or surgical condition with potential to affect pharmacokinetics of the drug




Endpoints

Co-Primary: antihypertensive efficacy (change in mean trough sitting DBP at end of study vs. baseline) of 75 mg, 150 mg, 300 mg aliskiren vs. placebo and the antihypertensive efficacy of combination aliskiren with HCTZ vs. monotherapy
Secondary: change in mean trough sitting SBP at end of study vs. baseline of the primary endpoint comparisons; proportion responding to tx (mean sitting DBP < 90 mm Hg and/or > 10 mm Hg decrease in DBP); BP control (mean sitting DBP < 90 mm Hg and SBP < 140 mm Hg); dose response relationship; safety and tolerability of monotherapy and combination therapy; PRA and RC
Wash-out Phase

W/D HTN Rx; 1 wk wash-out



Run-in phase

2-4 wk SB placebo



Treatment phase

Randomized to placebo, aliskiren monotherapy (75 mg, 150 mg, 300 mg), HCTZ (6.25 mg, 12.5 mg, 25 mg) or combination aliskiren and HCTZ (all dose combinations except 300 mg/6.25 mg) once daily



Baseline (mean): age 53.5-55.5yrs; 49.2-60.5% male; Race: 83.2-88.7% Caucasian; Ethnicity: 23.3-31.3% Hispanic/Latin; mean sitting SBP/DBP 152.7-154.6/98.4-100.0 mm Hg

Tx

n

DBP*

P

SBP

Response#

Placebo

192

-6.9




-7.5

45.8%

Aliskiren













75 mg/d

183

-8.7+0.59

<0.05

-9.4

51.9%

150 mg/d

183

-8.9+0.59

<0.05

-12.2

51.9%

300 mg/d

180

-10.3+0.60

<0.0001

-15.7

63.9%

HCTZ
















6.25 mg/d

194

-9.1+0.58

<0.05

-11.0

53.6%

12.5 mg/d

188

-10.1+0.59

<0.0001

-13.9

60.6%

25 mg/d

173

-9.4+0.61

<0.05

-14.3

59.0%

Aliskiren/HCTZ**
















75/6.25 mg/d

187

-10.8

<0.05

-14.3

61.5%

75/12.5 mg/d

189

-11.1




-15.6

63.5%

75/25 mg/d

186

-11.5

<0.05

-17.3

70.4%

150/6.25 mg/d

173

-10.4




-15.3

58.4%

150/12.5 mg/d

184

-11.9

<0.05

-17.6

69.6%

150/25 mg/d

187

-12.7

<0.05

-19.5

71.1%

300/12.5 mg/d

180

-13.9

<0.05

-19.8

80.6%

300/25 mg/d

173

-14.3

<0.05

-21.2

76.9%

* Primary endpoint:s: change from baseline in mean trough sitting DBP (mm Hg) + SEM; P value vs. placebo; ** change from baseline in mean sitting BP (mm Hg) + SEM vs. component monotherapy; P value vs. component monotherapy

# Response: percent of patients with mean sitting DBP < 90 mm Hg and/or > 10 mm Hg decrease in DBP

BP Control: Significant with aliskiren 300 mg vs. placebo (46.7 vs. 28.1%; P=0.0001); all combinations (except aliskiren/HCTZ 75/6.25 mg) significant vs. placebo (P<0.02); trend toward improved BP control with combination therapy (37.4-59.5%) vs. either monotherapy (aliskiren 29.0-46.7%; HCTZ 32.5-37.8%)

Dose Response (DBP): Demonstrated with aliskiren

PRA: Decreased with aliskiren 75 mg (54.2%), 150 mg (65.1%), and 300 mg (57.6%); increased with HCTZ 6.25 mg (3.5%), 12.5 mg (44.7%), and 25 mg (71.9%); placebo (0.7% increase); decreased with combination aliskiren/HCTZ (46.1-63.5%)

RC: Increased with aliskiren (75 mg, 164%; 150 mg, 192%; 300 mg, 348%), also increased with HCTZ 25 mg (108%); increase with HCTZ 6.25 mg (10%) and 12.5 mg (26%) less than placebo (30%)
Study Conclusions

Short-term treatment (8 weeks) with aliskiren 75 mg, 150 mg, and 300 mg once daily significantly reduced mean sitting DBP compared to placebo (only 150 mg and 300 mg significant when adjusted for multiple comparisons) in patients with mild to moderate HTN, with a significant reduction in DBP with all combination therapies compared to either monotherapy (except for aliskiren/HCTZ 150/6.25 mg and 75/12.5 mg)



Completed Trial (ITT Analysis)

Aliskiren: 75 mg, 183/184 (99.5%); 150 mg, 183/185 (98.9%); 300 mg, 180/183 (98.4%)

HCTZ: 6.25 mg, 194/194 (100%); 12.5 mg, 188/188 (100%); 25 mg, 173/176 (98.3%)

Aliskiren/HCTZ: 75/6.25 mg, 187/188 (99.5%); 75/12.5 mg, 189/193 (97.9%); 75/25 mg, 186/186 (100%); 150/6.25 mg, 173/176 (98.3%); 150/12.5 mg, 184/186 (98.9%); 150/25 mg, 187/188 (99.5%); 300/12.5 mg, 180/181 (99.5%); 300/25 mg, 173/173 (100%)

Placebo: 192/195 (98.5%)
Adverse Events

Severe AEs/Serious AEs: 0.5-3.9%/0-2.6%; 1 death (aliskiren/HCTZ 150/25 mg) due to thoracic trauma from MVA


Tx

W/D AE

Total AE

Placebo

3.6%

44.0%

Aliskiren







75 mg

0.5%

37.5%

150 mg

0%

37.3%

300 mg

4.4%

39.2%

HCTZ







6.25 mg

1.0%

38.7%

12.5 mg

0.5%

42.0%

25 mg

2.3%

41.6%

Aliskiren/HCTZ







75/6.25 mg

1.6%

34.6%

75/12.5 mg

3.7%

39.5%

75/25 mg

2.2%

41.4%

150/6.25 mg

4.0%

37.9%

150/12.5 mg

2.2%

39.1%

150/25 mg

3.2%

44.1%

300/12.5 mg

1.7%

45.3%

300/25 mg

2.9%

41.0%

Most common AEs included HA (5.5-7.1% aliskiren vs. 6.2-8.0% HCTZ, 13.5% placebo) and nasopharyngitis (1.7-4.9% aliskiren vs. 3.1-4.8% HCTZ, 5.2% placebo); incidence of hypokalemia with HCTZ decreased with combination aliskiren


AE=adverse event; BP=blood pressure; CV=cardiovascular; d=day; DB=double-blind; DBP=diastolic blood pressure; DM=diabetes mellitus; HA=headache; HCTZ=hydrochlorothiazide; hr=hours; HTN=hypertension; ITT=intention to treat population; MI=myocardial infarction; MVA=motor vehicle accident; n=number of patients; NR=not reported; PAC=plasma aldosterone concentration; PC=placebo-controlled; PG=parallel group; PRA=plasma renin activity; R=randomized; RC=renin concentration; Rx=medication; SB=single-blind; SBP=systolic blood pressure; Tx=treatment; VS=vital signs; W/D=withdrawal; wk=week; yrs=years

December 2007



Updated versions may be found at www.pbm.va.gov or http://vaww.pbm.va.gov
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