A Phase 2 interventional study of aliskiren and ramipril in Heart Failure, sponsored by Novartis Pharmaceuticals. Completed at 16 sites in 3 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2012-07-26.
Sponsored by Novartis Pharmaceuticals · Phase 2, Interventional, and Treatment
In addition to the blood pressure lowering effects of aliskiren, it may have beneficial effects on blocking the so called RAAS (renin-angiotensin-aldosterone system) at the tissue level. An increase of angiotensin II is associated with progression of heart failure. Although the use of ACE-inhibitors in heart failure shows clinical benefit, an increase in angiotensin II due to an angiotensin II "escape" phenomenon is not desirable. It is not yet known if a direct renin inhibitor can reduce or even prevent the angiotensin II escape phenomenon associated with the use of an ACE-inhibitor. Therefore the study tested the effects of ramipril, aliskiren and the combination of both on levels of angiotensin II in the blood in patients with systolic heart failure
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Exclusion criteria:
Other protocol-defined inclusion/exclusion criteria applied
In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received aliskiren (150 mg once daily) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site and matching placebo of ramipril capsules.
Drug: aliskiren · Drug: ramipril · Drug: Placebo to ramipril
In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received ramipril 10 mg capsule o.d and matching placebo of aliskiren tablet.
Drug: ramipril · Drug: Placebo to aliskiren
In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (period 2), patients received ramipril (10 mg once daily capsule) and aliskiren (150 mg once daily tablet) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site
Drug: aliskiren · Drug: ramipril
Aliskiren 150 mg once daily up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site
2.5 mg , 5.0 mg or 10 mg once daily
matching placebo to aliskiren in double blind phase
Matching placebo to ramipril capsule in double blind phase
Venous Angiotensin II Levels After 12 Weeks of Treatment
Peripheral venous blood was collected after 30 minutes of rest in the sitting position for analysis of biomarkers. Geometric mean ratio to baseline at Week 12 for Venous angiotensin II levels was calculated in patients with decompensated systolic heart failure (SHF) and left ventricular ejection fraction ≤40% at 0 hour pre-dose, 3 hours and 24 hours post-dose.
Time frame: Baseline. 12 Weeks (Day 84, period 2)
Biomarker Plasma Renin Concentration (PRC)After 12 Weeks of Treatment
Peripheral venous blood was collected after 30 minutes of rest in the sitting position for analysis of biomarkers. Geometric Mean Ratio to baseline at 12 weeks for PRC was calculated at 0 hour pre-dose.
Time frame: Baseline, 12 weeks (84 days, period 2)
Biomarker Trapping Plasma Renin Activity (tPRA) After 12 Weeks of Treatment
Peripheral venous blood was collected after 30 minutes of rest in the sitting position for analysis of biomarkers. Geometric Mean Ratio to baseline at Week 12 for tPRA was calculated at 0 hour pre-dose, 3 hour and 24 hour post-dose.
Time frame: Baseline,12 weeks (84 days, Period 2)
Biomarker B-type Natriuretic Peptide (BNP) After 12 Weeks of Treatment
Peripheral venous blood was collected after 30 minutes of rest in the sitting position for analysis of biomarkers. Geometric Mean Ratio to baseline at Week 12 for BNP was calculated at 0 hours pre-dose.
Time frame: Baseline, 12 weeks (Day 84 period 2)
Biomarker Urinary Aldosterone After 12 Weeks of Treatment
24 hour urine collections were performed. Geometric Mean Ratio to baseline at Week 12 for Urinary aldosterone was calculated 24 hours post-dose.
Time frame: Baseline,12 weeks (Day 84 period 2)
Pharmacokinetic of Aliskiren: Time to Reach the Maximum Concentration (Tmax) After Drug Administration
Blood samples (2 mL) for the determination of aliskiren concentration in plasma were collected using an indwelling cannula inserted in a forearm vein. Samples were collected at week 12 (day 84): pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose.
Time frame: 12 weeks
Pharmacokinetic of Aliskiren: The Observed Maximum Plasma Concentration (Cmax) Following Drug Administration
Blood samples (2 mL) for the determination of aliskiren concentration in plasma were collected using an indwelling cannula inserted in a forearm vein. Samples were collected at week 12 (day 84): pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose.
Time frame: 12 weeks
Pharmacokinetic of Aliskiren: The Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau(AUCtau)
Blood samples (2 mL) for the determination of aliskiren concentration in plasma were collected using an indwelling cannula inserted in a forearm vein. Samples were collected at week 12 (day 84): pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose.
Time frame: 12 weeks
Pharmacokinetic of Aliskiren: The Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast)
Blood samples (2 mL) for the determination of aliskiren concentration in plasma were collected using an indwelling cannula inserted in a forearm vein. Samples were collected at week 12 (day 84): pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose.
Time frame: 12 weeks
Pharmacokinetic of Aliskiren: The Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf)
Blood samples (2 mL) for the determination of aliskiren concentration in plasma were collected using an indwelling cannula inserted in a forearm vein. Samples were collected at week 12 (day 84): pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose.
Time frame: 12 weeks
Pharmacokinetic of Aliskiren: The Terminal Elimination Half-life (T½)
Blood samples (2 mL) for the determination of aliskiren concentration in plasma were collected using an indwelling cannula inserted in a forearm vein. Samples were collected at week 12 (day 84): pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose.
Time frame: 12 weeks
| Milestone | Aliskiren | Ramipril | Aliskiren Plus Ramipril |
|---|---|---|---|
| Started | 40 | 42 | 41 |
| Completed | 40 | 38 | 38 |
| Not completed | 0 | 4 | 3 |
| Withdrew: Adverse event | 0 | 2 | 1 |
| Withdrew: Abnormal laboratory values | 0 | 0 | 1 |
| Withdrew: Withdrawal by subject | 0 | 1 | 0 |
| Withdrew: Death | 0 | 1 | 0 |
| Withdrew: Lack of efficacy | 0 | 0 | 1 |
Peripheral venous blood was collected after 30 minutes of rest in the sitting position for analysis of biomarkers. Geometric mean ratio to baseline at Week 12 for Venous angiotensin II levels was calculated in patients with decompensated systolic heart failure (SHF) and left ventricular ejection fraction ≤40% at 0 hour pre-dose, 3 hours and 24 hours post-dose.
| ratio | Aliskiren | Ramipril | Aliskiren Plus Ramipril |
|---|---|---|---|
| 0 Hour pre-dose (n=40, 38, 37) | 0.91 (0.52 to 1.59) | 1.08 (0.64 to 1.81) | 0.66 (0.37 to 1.18) |
| 3 hour post-dose (n=40, 38, 38) | 0.38 (0.23 to 0.62) | 0.44 (0.24 to 0.78) | 0.38 (0.22 to 0.66) |
| 24 hour post-dose (n=40, 38, 38) | 0.79 (0.44 to 1.41) | 0.97 (0.59 to 1.60) | 0.64 (0.34 to 1.24) |
Peripheral venous blood was collected after 30 minutes of rest in the sitting position for analysis of biomarkers. Geometric Mean Ratio to baseline at 12 weeks for PRC was calculated at 0 hour pre-dose.
| ratio | Aliskiren | Ramipril | Aliskiren Plus Ramipril |
|---|---|---|---|
| Biomarker Plasma Renin Concentration (PRC)After 12 Weeks of Treatment | 2.48 (1.67 to 3.66) | 0.96 (0.71 to 1.30) | 4.67 (2.80 to 7.78) |
Peripheral venous blood was collected after 30 minutes of rest in the sitting position for analysis of biomarkers. Geometric Mean Ratio to baseline at Week 12 for tPRA was calculated at 0 hour pre-dose, 3 hour and 24 hour post-dose.
| ratio | Aliskiren | Ramipril | Aliskiren Plus Ramipril |
|---|---|---|---|
| 0 hour pre-dose (n=40,38,37) | 0.14 (0.08 to 0.24) | 1.02 (0.68 to 1.52) | 0.25 (0.15 to 0.41) |
| 3 hour post-dose (n=40,38,38) | 0.07 (0.04 to 0.14) | 1.50 (0.86 to 2.61) | 0.15 (0.09 to 0.24) |
| 24 hour post-dose (n=40,38,38) | 0.12 (0.07 to 0.22) | 0.90 (0.58 to 1.40) | 0.16 (0.11 to 0.25) |
Peripheral venous blood was collected after 30 minutes of rest in the sitting position for analysis of biomarkers. Geometric Mean Ratio to baseline at Week 12 for BNP was calculated at 0 hours pre-dose.
| ratio | Aliskiren | Ramipril | Aliskiren Plus Ramipril |
|---|---|---|---|
| Biomarker B-type Natriuretic Peptide (BNP) After 12 Weeks of Treatment | 0.96 (0.80 to 1.16) | 0.84 (0.69 to 1.03) | 0.78 (0.64 to 0.95) |
24 hour urine collections were performed. Geometric Mean Ratio to baseline at Week 12 for Urinary aldosterone was calculated 24 hours post-dose.
| ratio | Aliskiren | Ramipril | Aliskiren Plus Ramipril |
|---|---|---|---|
| Biomarker Urinary Aldosterone After 12 Weeks of Treatment | 0.83 (0.64 to 1.08) | 0.96 (0.78 to 1.18) | 0.87 (0.63 to 1.21) |
Blood samples (2 mL) for the determination of aliskiren concentration in plasma were collected using an indwelling cannula inserted in a forearm vein. Samples were collected at week 12 (day 84): pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose.
| Hour | Aliskiren |
|---|---|
| Pharmacokinetic of Aliskiren: Time to Reach the Maximum Concentration (Tmax) After Drug Administration | 1.50 ± 1.7896 |
Blood samples (2 mL) for the determination of aliskiren concentration in plasma were collected using an indwelling cannula inserted in a forearm vein. Samples were collected at week 12 (day 84): pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose.
| ng/mL | Aliskiren |
|---|---|
| Pharmacokinetic of Aliskiren: The Observed Maximum Plasma Concentration (Cmax) Following Drug Administration | 257.2 ± 270.23 |
Blood samples (2 mL) for the determination of aliskiren concentration in plasma were collected using an indwelling cannula inserted in a forearm vein. Samples were collected at week 12 (day 84): pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose.
| hr*ng/mL | Aliskiren |
|---|---|
| Pharmacokinetic of Aliskiren: The Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau(AUCtau) | 1707 ± 1321.9 |
Blood samples (2 mL) for the determination of aliskiren concentration in plasma were collected using an indwelling cannula inserted in a forearm vein. Samples were collected at week 12 (day 84): pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose.
| hr*ng/mL | Aliskiren |
|---|---|
| Pharmacokinetic of Aliskiren: The Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) | 3041 ± 1669.1 |
Blood samples (2 mL) for the determination of aliskiren concentration in plasma were collected using an indwelling cannula inserted in a forearm vein. Samples were collected at week 12 (day 84): pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose.
| hr*ng/mL | Aliskiren |
|---|---|
| Pharmacokinetic of Aliskiren: The Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) | 3502 ± 1907.5 |
Blood samples (2 mL) for the determination of aliskiren concentration in plasma were collected using an indwelling cannula inserted in a forearm vein. Samples were collected at week 12 (day 84): pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose.
| hour | Aliskiren |
|---|---|
| Pharmacokinetic of Aliskiren: The Terminal Elimination Half-life (T½) | 31.02 ± 10.624 |
Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Ramipril | — | 7/42 (16.7%) | 6/42 (14.3%) |
| Aliskiren | — | 2/40 (5%) | 3/40 (7.5%) |
| Ramipril + Aliskiren | — | 3/41 (7.3%) | 7/41 (17.1%) |
| Event | Ramipril | Aliskiren | Ramipril + Aliskiren |
|---|---|---|---|
| Cardiac failureCardiac disorders | 4/42 | 2/40 | 0/41 |
| Abdominal painGastrointestinal disorders | 0/42 | 1/40 | 0/41 |
| Adams-Stokes syndromeCardiac disorders | 0/42 | 0/40 | 1/41 |
| BradycardiaCardiac disorders | 0/42 | 0/40 | 1/41 |
| Myocardial infarctionCardiac disorders | 0/42 | 0/40 | 1/41 |
| Acute myocardial infarctionCardiac disorders | 1/42 | 0/40 | 0/41 |
| Cardiac failure chronicCardiac disorders | 1/42 | 0/40 | 0/41 |
| Sudden deathGeneral disorders | 1/42 | 0/40 | 0/41 |
| CholecystitisHepatobiliary disorders | 1/42 | 0/40 | 0/41 |
| Event | Ramipril | Aliskiren | Ramipril + Aliskiren |
|---|---|---|---|
| TachycardiaCardiac disorders | 0/42 | 1/40 | 5/41 |
| Electrocardiogram QT prolongedInvestigations | 4/42 | 2/40 | 1/41 |
| NasopharyngitisInfections and infestations | 2/42 | 0/40 | 3/41 |
| Age Continuous(years) | Aliskiren | Ramipril | Aliskiren Plus Ramipril | Total |
|---|---|---|---|---|
| Mean | 61.3 ± 9.00 | 64.3 ± 9.91 | 62.0 ± 10.47 | 62.6 ± 9.83 |
| Sex: Female, Male(Participants) | Aliskiren | Ramipril | Aliskiren Plus Ramipril | Total |
|---|---|---|---|---|
| Female | 11 | 8 | 7 | 26 |
| Male | 29 | 34 | 34 | 97 |
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Novartis Pharmaceuticals