Efficacy and Safety of Aliskiren/Ramipril/Amlodipine Compared With Ramipril/Amlodipine and Aliskiren/Amlodipine in Patients With Metabolic Syndrome

A Twelve Week, Randomized, Double-blind, Parallel-group, Multicenter Study to Evaluate the Efficacy and Safety of the Combination of Aliskiren/Ramipril/Amlodipine (300/10/5-10 mg) Compared to the Combinations of Ramipril/Amlodipine (10/5-10 mg) and Aliskiren/Amlodipine (300/5-10 mg) in Patients With Essential Hypertension and Metabolic Syndrome Not Adequately Responsive to Amlodipine 5-10 mg

Status

Terminated

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00542269

Acronym

ALTO

Enrollment

178

Registered

2007-10-11

Start date

2008-03-31

Completion date

2009-07-31

Last updated

2011-05-24

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hypertension With Metabolic Syndrome

Keywords

Hypertension, Metabolic Syndrome, Dual combination therapy, Triple combination therapy, Aliskiren, Direct Renin inhibitor

Brief summary

This proof of concept study is designed to evaluate the efficacy and safety of the combination therapy of aliskiren and ramipril as add-on to amlodipine in the treatment of patients with essential hypertension and metabolic syndrome who do not respond adequately to amlodipine monotherapy.

Interventions

DRUGAmlodipine

amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.

DRUGAliskiren

aliskiren 150-300 mg tablets. Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.

DRUGRamipril

ramipril 5-10 mg capsules. Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

Inclusion criteria

* Outpatients 18-75 years of age. * Male or female patients are eligible. * Patients with a diagnosis of hypertension: * Newly diagnosed patients or patients who have not been treated for hypertension within the 4 weeks prior to Visit 1 must have a mean sitting systolic blood pressure (MSSBP) \> 150 mmHg and \< 180 mmHg at Visit 1. * Patients treated with antihypertensive monotherapy must have a MSSBP ≥ 140 mmHg and \<180 mmHg at Visit 1. * Patients taking amlodipine monotherapy MSSBP \> 140 mmHg and \< 180 mmHg at visit 1. * All patients must have a MSSBP ≥ 140 mmHg and \< 180 mmHg at Visit 3, the end of the amlodipine run-in period. * Metabolic syndrome. * Patients who are eligible and able to participate in the study, and who consent to do so after the purpose and nature of the investigation has been clearly explained to them (written inform consent form).

Exclusion criteria

* Severe hypertension (office cuff MSDBP ≥ 115 mmHg and/or MSSBP ≥ 180 mmHg). * History or evidence of a secondary form of hypertension. * History of hypertensive encephalopathy or cerebrovascular accident, transient ischemic cerebral attack (TIA), myocardial infarction, coronary bypass surgery, or any percutaneous coronary intervention (PCI). * Serum sodium \< 135 mmol/L at Visit 1 if confirmed on repeat sample. * Serum potassium \< 3.5 mmol/L or ≥ 5.3 mmol/L at Visit 1, if confirmed on repeat sample. * Type 1 diabetes mellitus. * Type 2 diabetes if oral hypoglycaemic therapy changed (dose change or medication change) in previous 3 months. * Pregnant or nursing (lactating) women. Other protocol-defined inclusion/

Design outcomes

Primary

Measure	Time frame	Description
Change in Mean Sitting Systolic Blood Pressure (msSBP) From Baseline to End of Study - Aliskiren/Ramipril/Amlodipine vs Ramipril/Amlodipine)	Baseline to Week 12	Automated blood pressure determinations were made with the Omron HEM-705CP blood pressure monitor at trough (24 hours ± 3 hours post-dose) and recorded at all study visits following detailed directions specified in the study protocol. Three readings were made and msSBP was calculated as the average of the 3 readings. In the event of aberrant readings, ie, the lowest reading was ≥ 10 mmHg systolic or ≥ 5 mmHg diastolic lower than the highest of the 3 readings, 3 additional readings were obtained. A negative change indicates improvement.
Change in Mean Sitting Systolic Blood Pressure (msSBP) From Baseline to End of Study - Aliskiren/Amlodipine vs Ramipril/Amlodipine	Baseline to Week 12	Automated blood pressure determinations were made with the Omron HEM-705CP blood pressure monitor at trough (24 hours ± 3 hours post-dose) and recorded at all study visits following detailed directions specified in the study protocol. Three readings were made and msSBP was calculated as the average of the 3 readings. In the event of aberrant readings, ie, the lowest reading was ≥ 10 mmHg systolic or ≥ 5 mmHg diastolic lower than the highest of the 3 readings, 3 additional readings were obtained. A negative change indicates improvement.

Secondary

Measure	Time frame	Description
Percentage of Patients Who Achieved Normalized Blood Pressure at End of Study	Week 12	Normalized was defined as a msSBP \< 140 mmHg and/or a msDBP \< 90 mmHg.
Change in HOMA-IR From Baseline to End of Study	Baseline to Week 12	Homeostasis model assessment-insulin resistance (HOMA-IR) was defined as (fasting insulin \[μU/mL\] x fasting glucose \[mmol/L\]) / 22.5.
Change in HOMA-β From Baseline to End of Study	Baseline to Week 12	Homeostasis model assessment-β (HOMA-β) was defined as fasting insulin (μU/mL) x 20 / (fasting glucose (mmol/L) - 3.5).
Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Baseline to End of Study - Aliskiren/Ramipril/Amlodipine vs Ramipril/Amlodipine	Baseline to Week 12	Automated blood pressure determinations were made with the Omron HEM-705CP blood pressure monitor at trough (24 hours ± 3 hours post-dose) and recorded at all study visits following detailed directions specified in the study protocol. Three readings were made and msDBP was calculated as the average of the 3 readings. In the event of aberrant readings, ie, the lowest reading was ≥ 10 mmHg systolic or ≥ 5 mmHg diastolic lower than the highest of the 3 readings, 3 additional readings were obtained. A negative change indicates improvement.
Change in HbA1c (Glycated Hemoglobin) From Baseline to End of Study - Aliskiren/Amlodipine vs Ramipril/Amlodipine)	Baseline to Week 12	—
Percentage of Patients Who Developed Diabetes at End of Study	Week 12	A patient had diabetes if fasting plasma glucose \> 7 mmol/L.
Change in HbA1c (Glycated Hemoglobin) From Baseline to End of Study - Aliskiren/Ramipril/Amlodipine vs Ramipril/Amlodipine	Baseline to Week 12	—
Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Baseline to End of Study - Aliskiren/Amlodipine vs Ramipril/Amlodipine	Baseline to Week 12	Automated blood pressure determinations were made with the Omron HEM-705CP blood pressure monitor at trough (24 hours ± 3 hours post-dose) and recorded at all study visits following detailed directions specified in the study protocol. Three readings were made and msDBP was calculated as the average of the 3 readings. In the event of aberrant readings, ie, the lowest reading was ≥ 10 mmHg systolic or ≥ 5 mmHg diastolic lower than the highest of the 3 readings, 3 additional readings were obtained. A negative change indicates improvement.

Countries

United Kingdom

Participant flow

Participants by arm

Arm	Count
Aliskiren / Ramipril / Amlodipine 6 weeks treatment with aliskiren 150 mg tablets, ramipril 5 mg capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg tablets, ramipril 10 mg capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.	61
Aliskiren /Amlodipine 6 weeks treatment with aliskiren 150 mg tablets, ramipril 5 mg placebo capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg tablets, ramipril 10 mg placebo capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.	60
Ramipril / Amlodipine 6 weeks treatment with aliskiren 150 mg placebo tablets, ramipril 5 mg capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg placebo tablets, ramipril 10 mg capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.	57
Total	178

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Administrative problems	1	1	1
Overall Study	Adverse Event	10	4	5
Overall Study	Protocol Violation	1	1	0
Overall Study	Withdrawal by Subject	1	0	0

Baseline characteristics

Characteristic	Aliskiren / Ramipril / Amlodipine	Aliskiren /Amlodipine	Ramipril / Amlodipine	Total
Age Continuous	61.3 years STANDARD_DEVIATION 8.9	58.3 years STANDARD_DEVIATION 8.95	59.1 years STANDARD_DEVIATION 8.86	59.6 years STANDARD_DEVIATION 8.95
Age, Customized < 65 years	37 participants	47 participants	42 participants	126 participants
Age, Customized ≥ 65 years	24 participants	13 participants	15 participants	52 participants
Sex: Female, Male Female	17 Participants	18 Participants	19 Participants	54 Participants
Sex: Female, Male Male	44 Participants	42 Participants	38 Participants	124 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	27 / 61	24 / 60	26 / 57
serious Total, serious adverse events	3 / 61	1 / 60	3 / 57

Outcome results

Primary

Change in Mean Sitting Systolic Blood Pressure (msSBP) From Baseline to End of Study - Aliskiren/Amlodipine vs Ramipril/Amlodipine

Automated blood pressure determinations were made with the Omron HEM-705CP blood pressure monitor at trough (24 hours ± 3 hours post-dose) and recorded at all study visits following detailed directions specified in the study protocol. Three readings were made and msSBP was calculated as the average of the 3 readings. In the event of aberrant readings, ie, the lowest reading was ≥ 10 mmHg systolic or ≥ 5 mmHg diastolic lower than the highest of the 3 readings, 3 additional readings were obtained. A negative change indicates improvement.