Pbm-map drug Monograph: Aliskiren




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

Note: n for distribution of patients in ITT not provided




Tx

Response*

BP control**

Placebo

36.2%

20.3%

Aliskiren





150 mg/d

59.3%

35.9%

300 mg/d

63.3%

41.6%

600 mg/d

69.3%

46.4%

* Response: percent of patients with mean sitting DBP < 90 mm Hg and/or > 10 mm Hg decrease in DBP vs. baseline; P < 0.0001 vs. placebo

** BP control: < 140/90 mm Hg; P < 0.001 vs. placebo


ABPM (n=216): Significant reduction in DBP and SBP with all doses vs. placebo; P < 0.0001

PRA/RC vs. Baseline (n=270): PRA reduced with all doses aliskiren (75-81.1%) vs. increased with placebo (19.5%); RC increased with all doses aliskiren (51.5-228.5%) vs. minimal change (data NR) with placebo

Tx W/D (n=608): DBP remained below baseline (6.8 mm Hg with 150 mg, 6.9 mm Hg with 300 mg, 8.7 mm Hg with 600 mg) vs. 5.3 mm Hg with placebo at 2 wks
Study Conclusions

Short-term treatment (8 weeks) with aliskiren 150 mg, 300 mg, and 600 mg significantly reduced mean sitting DBP compared to placebo in patients with mild to moderate HTN with no demonstration of a rebound effect at 2 wks



Completed Tx Phase of Trial

Aliskiren: 150 mg, 162/172 (94.2%); 300 mg, 159/169 (94.1%); 600 mg, 152/166 (91.6%)

Placebo: 135/165 (81.8%)
Adverse Events

Serious AEs: Aliskiren 150 mg (n=1); 300 mg (n=2); 600 mg (n=1); none thought to be tx-related; no deaths



Tx

W/D AE

Total AE

Placebo (n=165)

3.6%

43.0%

150 mg (n=172)

0.6%

40.1%

300 mg (n=169)

1.8%

46.7%

600 mg (n=166)

1.2%

52.4%

Most common AEs included HA (aliskiren (5.4-7.7% vs. placebo 9.7%) and nasopharyngitis (aliskiren 1.8-3.6% vs. placebo 6.1%); diarrhea occurred in 11.4% on aliskiren 600 mg (P<.0001) vs other tx groups



Kushiro et al, 200610
MC, R, DB, PC
Japan
n=455
13 wks

Involvement of sponsor not reported



Inclusion Criteria

20 to 80 yrs of age, Japanese, essential HTN, mean sitting DBP > 90 mm Hg and < 110 mm Hg during run-in and > 95 mm Hg and < 110 mm Hg at baseline prior to randomization, with < 10 mm Hg difference between measurements


Exclusion Criteria

Severe HTN (sitting DBP > 110 mm Hg and/or SBP > 180 mm Hg); suspected secondary or malignant HTN; type 1 DM or type 2 DM on insulin or HbA1c > 8%; serious cardiac, hepatic, renal or cerebrovascular disease; clinically significant allergies; history of pancreatitis; malignant tumors within 5 yrs; autoimmune diseases; anemia; gout; hyperthyroidism; dehydration; pregnancy; treatment for gastric or duodenal ulcers; receiving investigational drug within 12 wks




Endpoints

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

Secondary: change in mean trough sitting SBP at end of study vs. baseline; proportion responding to Tx (mean sitting DBP < 90 mm Hg and/or > 10 mm Hg decrease in DBP); dose response relationship

Other: AEs (date of onset; ranked mild, moderate, severe; related to study drug); labs (blood chemistries, hematology, urinalysis); weight; ECG; compliance (drug taken > 70% of days per interview)
Run-in Phase

4 wk SB placebo



Treatment Phase

Randomized to placebo or aliskiren 75 mg, 150 mg, or 300 mg once daily between 6:00am and 10:00am > 30 min before meals for 8 wks (drug taken after evaluation on study visits)



Run-out Phase

1 wk W/D


Baseline (mean): age 51.6+9.9-53.3+10.4yrs; 72.5% male; duration HTN 4.6-6.2 yrs; mean sitting SBP/DBP 152.7+11.8-155.6+11.1/99.4 +3.9-99.6+4.4 mm Hg


Tx

n

DBP*

P

SBP

Placebo

115

-3.26+0.75




-2.85+1.17

Aliskiren











75 mg/d

115

-7.22+0.75

0.0002

-8.57+1.17

150 mg/d

112

-7.75+0.76

<0.0001

-8.72+1.18

300 mg/d

113

-10.72+0.75

<0.0001

-14.09+1.18

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


Tx

Response*

OR (95% CI)

P value

Placebo

32/115 (27.8%)







Aliskiren









75 mg/d

55/115 (47.8%)

2.52 (1.42, 4.46)

0.0015

150 mg/d

54/112 (48.2%)

2.60 (1.46, 4.62)

0.0011

300 mg/d

72/113 (63.7%)

5.22 (2.89, 9.42)

0.0001

* Response: percent of patients with mean sitting DBP < 90 mm Hg and/or > 10 mm Hg decrease in DBP; P value vs. placebo
Study Conclusions

Short-term treatment (8 weeks) with aliskiren significantly reduced BP (placebo corrected decrease SBP/DBP (mm Hg) 5.7/4.0, 5.9/4.5, 11.2/7.5 in the 75 mg, 150 mg 300 mg tx groups, respectively) in Japanese patients with HTN, with tolerability similar to placebo



Completed Trial

Aliskiren: 75 mg, 110/115 (95.7%); 150 mg, 109/112 (97.3%); 300 mg, 111/113 (98.2%)

Placebo: 104/115 (90.4%)
Adverse Events

Serious AEs: Aliskiren 75 mg (n=1: AMI); aliskiren 150 mg (n=1: death due to psychiatric drug OD); placebo (n=3: 1 cerebral infarction; 1 pancreatic CA; 1 infective enteritis)


Tx

W/D AE

Total AE

Placebo

3.5%

50.4%

75 mg

1.7%

53.0%

150 mg

1.8%

51.8%

300 mg

1.8%

54.9%

Most common AEs included nasopharyngitis (17.7-20.9% aliskiren vs. 13.9% placebo) and HA (2.6-5.3% aliskiren vs. 3.5% placebo)


Tx

WBC

ALT

K+

Placebo

1.7%

2.6%

0%

75 mg

1.7%

4.3%

1.7%

150 mg

0.9%

3.6%

0%

300 mg

0.9%

1.8%

0%

WBC > 50% baseline; ALT > 150% baseline; K+ > 20% baseline
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