An 8-week Study to Evaluate the Dose Response of AHU377 in Combination With Valsartan 320 mg in Patients With Mild-to-moderate Systolic Hypertension

A Multi-center, Randomized, Double-blind, Placebo and Active Controlled, Parallel Group Study to Evaluate the Dose Response of AHU377 in Combination With Valsartan 320 mg After 8 Week Treatment in Patients With Mild-to-moderate Systolic Hypertension

The purpose of the study is to evaluate dose response of blood pressure lowering for 4 doses of AHU377, given once daily (50 mg, 100 mg, 200 mg and 400 mg) in combination with a fixed dose of valsartan (320 mg).

Study Overview

• Status: Completed
• Conditions: Systolic Hypertension
• Intervention / Treatment: Drug: Valsartan; Drug: AHU377; Drug: LCZ696; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 910
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos aires, Argentina, C1120AAC
    • Novartis Investigative Site
  • Cordoba, Argentina, X5003DCP
    • Novartis Investigative Site
  • Corrientes, Argentina, W3400
    • Novartis Investigative Site
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1440AAD
      • Novartis Investigative Site
    • Lanus, Buenos Aires, Argentina, B8000XAV
      • Novartis Investigative Site
  • Capital Federal
    • Caba, Capital Federal, Argentina, C1179AAB
      • Novartis Investigative Site
  • Santa Fe
    • Rosario, Santa Fe, Argentina, S2000AII
      • Novartis Investigative Site
    • Rosario, Santa Fe, Argentina, S200CXP
      • Novartis Investigative Site
  • Tucuman
    • San Miguel de Tucuman, Tucuman, Argentina, T4000EBR
      • Novartis Investigative Site
• Canada
  • Newfoundland and Labrador
    • Mount Pearl, Newfoundland and Labrador, Canada, A1N 1W7
      • Novartis Investigative Site
  • Quebec
    • Mirabel, Quebec, Canada, J7J 2K8
      • Novartis Investigative Site
    • Ste-Foy, Quebec, Canada, G1V 4G2
      • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, 1045
    • Novartis Investigative Site
  • Budapest, Hungary, 1136
    • Novartis Investigative Site
  • Csongrad, Hungary, 6640
    • Novartis Investigative Site
  • Erd, Hungary, H-2030
    • Novartis Investigative Site
  • Miskolc, Hungary, 3525
    • Novartis Investigative Site
  • Miskolc, Hungary, 3530
    • Novartis Investigative Site
  • Nyiregyháza, Hungary, 4400
    • Novartis Investigative Site
  • Szeged, Hungary, H-6720
    • Novartis Investigative Site
  • Torokbalint, Hungary, 2045
    • Novartis Investigative Site
• India
  • Andhra Pradesh
    • Vishakhapatnam, Andhra Pradesh, India, 530002
      • Novartis Investigative Site
  • Gujarat
    • Ahmedabad, Gujarat, India, 380 051
      • Novartis Investigative Site
  • Maharashtra
    • Nashik, Maharashtra, India, 422005
      • Novartis Investigative Site
    • Nashik, Maharashtra, India, 422 005
      • Novartis Investigative Site
    • Pune, Maharashtra, India, 411005
      • Novartis Investigative Site
  • Punjab
    • Ludhiana, Punjab, India, 141002
      • Novartis Investigative Site
  • Rajasthan
    • Jaipur, Rajasthan, India, 302016
      • Novartis Investigative Site
  • Uttar Pradesh
    • Lucknow, Uttar Pradesh, India, 226003
      • Novartis Investigative Site
    • Lucknow, Uttar Pradesh, India, 226005
      • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 140-743
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 150-713
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 150-950
    • Novartis Investigative Site
  • Gyeonggi-do
    • Bucheon, Gyeonggi-do, Korea, Republic of, 424-717
      • Novartis Investigative Site
    • Goyang, Gyeonggi-do, Korea, Republic of, 411-706
      • Novartis Investigative Site
    • Uijeongbu-Si, Gyeonggi-do, Korea, Republic of, 480-717
      • Novartis Investigative Site
  • Korea
    • Seoul, Korea, Korea, Republic of, 05505
      • Novartis Investigative Site
    • Seoul, Korea, Korea, Republic of, 137-701
      • Novartis Investigative Site
    • Seoul, Korea, Korea, Republic of, 152-703
      • Novartis Investigative Site
  • Kyunggi
    • Koyang, Kyunggi, Korea, Republic of, 410-719
      • Novartis Investigative Site
• Romania
  • Bucharest, Romania, 060011
    • Novartis Investigative Site
  • District 1
    • Bucharest, District 1, Romania, 011422
      • Novartis Investigative Site
    • Bucharest, District 1, Romania, 012064
      • Novartis Investigative Site
    • Bucharest, District 1, Romania
      • Novartis Investigative Site
  • District 2
    • Bucharest, District 2, Romania, 021705
      • Novartis Investigative Site
  • Jud. Bihor
    • Oradea, Jud. Bihor, Romania, 410032
      • Novartis Investigative Site
  • Jud. Dolj
    • Craiova, Jud. Dolj, Romania, 200147
      • Novartis Investigative Site
• Slovakia
  • Bratislava, Slovakia, 831 06
    • Novartis Investigative Site
  • Liptovsky Mikulas, Slovakia, 031 01
    • Novartis Investigative Site
  • Nitra, Slovakia, 949 01
    • Novartis Investigative Site
  • Nitra, Slovakia, 94901
    • Novartis Investigative Site
  • Nove Zamky, Slovakia, 940 01
    • Novartis Investigative Site
  • Partizanske, Slovakia, 958 01
    • Novartis Investigative Site
  • Presov, Slovakia, 080 01
    • Novartis Investigative Site
  • Presov, Slovakia, 081 01
    • Novartis Investigative Site
  • Ruzomberok, Slovakia, 034 26
    • Novartis Investigative Site
  • Sala, Slovakia, 927 03
    • Novartis Investigative Site
  • Sered, Slovakia, 926 00
    • Novartis Investigative Site
  • Zvolen, Slovakia, 960 01
    • Novartis Investigative Site
  • Slovak Republic
    • Nitra, Slovak Republic, Slovakia, 949 01
      • Novartis Investigative Site
    • Presov, Slovak Republic, Slovakia, 08001
      • Novartis Investigative Site
• Spain
  • Barcelona, Spain
    • Novartis Investigative Site
  • Madrid, Spain, 28046
    • Novartis Investigative Site
  • Andalucia
    • Granada, Andalucia, Spain, 18012
      • Novartis Investigative Site
    • Sevilla, Andalucia, Spain, 41009
      • Novartis Investigative Site
  • Cataluña
    • Badalona, Cataluña, Spain, 08914
      • Novartis Investigative Site
    • Centelles, Cataluña, Spain, 08540
      • Novartis Investigative Site
    • Tarragona, Cataluña, Spain, 43350
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Alicante, Comunidad Valenciana, Spain, 03004
      • Novartis Investigative Site
    • Alzira, Comunidad Valenciana, Spain, 46600
      • Novartis Investigative Site
  • Galicia
    • Santiago de Compostela, Galicia, Spain, 15706
      • Novartis Investigative Site
• United States
  • Florida
    • Clearwater, Florida, United States, 33756
      • Novartis Investigative Site
  • Illinois
    • Chicago, Illinois, United States, 60607
      • Novartis Investigative Site
    • Chicago, Illinois, United States, 60610
      • Novartis Investigative Site
  • Louisiana
    • Metairie, Louisiana, United States, 70006
      • Novartis Investigative Site
  • Mississippi
    • Belzoni, Mississippi, United States, 39038
      • Novartis Investigative Site
    • Jackson, Mississippi, United States, 39202
      • Novartis Investigative Site
    • Jackson, Mississippi, United States, 39209
      • Novartis Investigative Site
  • Missouri
    • St. Louis, Missouri, United States, 63141
      • Novartis Investigative Site
    • St. Louis, Missouri, United States, 63031
      • Novartis Investigative Site
  • Nevada
    • Henderson, Nevada, United States, 89014
      • Novartis Investigative Site
    • Las Vegas, Nevada, United States, 89119
      • Novartis Investigative Site
  • New York
    • Buffalo, New York, United States, 14215
      • Novartis Investigative Site
  • North Carolina
    • Charlotte, North Carolina, United States, 28277
      • Novartis Investigative Site
    • Greensboro, North Carolina, United States, 27401
      • Novartis Investigative Site
    • Greensboro, North Carolina, United States, 27408
      • Novartis Investigative Site
    • Shelby, North Carolina, United States, 28152
      • Novartis Investigative Site
  • Pennsylvania
    • Erie, Pennsylvania, United States, 16509
      • Novartis Investigative Site
  • Texas
    • Bryan, Texas, United States, 77802
      • Novartis Investigative Site
    • Houston, Texas, United States, 77030
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Written informed consent must be obtained before any assessment is performed. Patients with mild-to-moderate systolic hypertension, untreated or currently taking antihypertensive therapy.
• Ability to communicate and comply with all study requirements and demonstrate good medication compliance (≥ 80% compliance rate) during the run-in period.

Exclusion Criteria:

• Severe hypertension
• History of angioedema, drug-related or otherwise, as reported by the patient.
• Pregnant or nursing (lactating) women.
• Women of child-bearing potential (WOCBP), UNLESS they are using adequate birth control methods.
• History or evidence of a secondary form of hypertension.
• Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: VAL + AHU 400 mg; Participants were started with AHU377 100 mg + valsartan 160 mg every day (qd) for 1 week, then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for another week, and then were uptitrated to AHU377 400 mg + valsartan 320 mg for the remaining 6 weeks.	Drug: Valsartan; Valsartan was supplied as tablets in blister cards in 160 mg and 320 mg strengths.; Drug: AHU377; AHU377 was supplied in tablets in blister cards in 50 mg and 100 mg strengths.
Experimental: VAL + AHU 200 mg; Participants were started with AHU377 100 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for the remaining 7 weeks.	Drug: Valsartan; Valsartan was supplied as tablets in blister cards in 160 mg and 320 mg strengths.; Drug: AHU377; AHU377 was supplied in tablets in blister cards in 50 mg and 100 mg strengths.
Experimental: VAL + AHU 100 mg; Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 100 mg + valsartan 320 mg for the remaining 7 weeks.	Drug: Valsartan; Valsartan was supplied as tablets in blister cards in 160 mg and 320 mg strengths.; Drug: AHU377; AHU377 was supplied in tablets in blister cards in 50 mg and 100 mg strengths.
Experimental: VAL + AHU 50 mg; Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 50 mg + valartan 320 mg qd for the remaining 7 weeks.	Drug: Valsartan; Valsartan was supplied as tablets in blister cards in 160 mg and 320 mg strengths.; Drug: AHU377; AHU377 was supplied in tablets in blister cards in 50 mg and 100 mg strengths.
Experimental: VAL 320 mg; Participants were started with valsartan 160 mg qd for 1 week and then were uptitrated to valsartan 320 mg qd for the remaining 7 weeks.	Drug: Valsartan; Valsartan was supplied as tablets in blister cards in 160 mg and 320 mg strengths.
Experimental: LCZ 400 mg; Participants were started with LCZ696 200 mg qd for 1 week and then were uptitrated to LCZ696 400 mg qd for the remaining 7 weeks.	Drug: LCZ696; LCZ696 was supplied as tablets in blister cards in 100 mg strengths.
Experimental: Placebo; Participants received matching placebo to LCZ696, AHU377 and valsartan for 8 weeks.	Drug: Placebo; Placebo was supplied as tablets in blister cards.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP)	Sitting BP measurements were performed at trough (23-26 hours post-morning dose). A negative change from baseline indicates improvement.	Baseline, 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Mean Diastolic Blood Pressure (msDBP)	Sitting BP measurements were performed at trough (23-26 hours post-morning dose). A negative change from baseline indicates improvement.	Baseline, 8 weeks
Change From Baseline in Mean 24 Hour Ambulatory SBP (maSBP) and Mean 24 Hour Ambulatory DBP (maDBP)	Twenty four hour ABPM was performed twice duirng the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. A negative change from baseline indicates improvement.	Baseline, 8 weeks
Change From Baseline in Daytime maSBP and maDBP	Twenty four hour ABPM was performed twice during the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. A negative change from baseline indicates improvement.	Baseline, 8 weeks
Change From Baseline in Nighttime maSBP and maDBP	Twenty four hour ABPM was performed twice duirng the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. A negative change from baseline indicates improvement.	Baseline and 8 weeks
Change From Baseline in Mean Sitting Pulse Pressure	Pulse rate measurements were performed. A negative change from baseline indicates improvement.	Baseline, 8 weeks
Change From Baseline in Mean Ambulatory Pulse Pressure	Pulse rate measurements were performed. A negative change from baseline indicates improvement.	Baseline, 8 weeks
Change From Baseline in maSBP and maDBP in Dippers	Twenty four hour ABPM was performed twice during the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. Dippers were defined as participants who showed a decrease of at least 10% in maSBP during the night (10pm-6am) compared with the daytime level. A negative change from baseline indicates improvement.	Baseline, 8 weeks
Change From Baseline in maSBP and maDBP in Non-dippers	Twenty four hour ABPM was performed twice duirng the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. Dippers were defined as participants who showed a decrease of at least 10% in maSBP during the night (10pm-6am) compared with the daytime level. A negative change from baseline indicates improvement.	Baseline, 8 weeks
Change From Baseline in msSBP and msDBP in Participants < 65 Years of Age	Sitting BP measurements were performed at trough (23-26 hours post-morning dose). A negative change from baseline indicates improvement.	Baseline, 8 weeks
Change From Baseline in msSBP and msDBP in Participants >= 65 Years of Age	Sitting BP measurements were performed at trough (23-26 hours post-morning dose). A negative change from baseline indicates improvement.	Baseline, 8 weeks
Change From Baseline in maSBP and maDBP in Participants < 65 Years of Age	Twenty four hour ABPM was performed twice duirng the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. A negative change from baseline indicates improvement.	Baseline, 8 weeks
Change From Baseline in maSBP and maDBP in Participants >= 65 Years of Age	Twenty four hour ABPM was performed twice duirng the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. A negative change from baseline indicates improvement.	Baseline, 8 weeks
Number of Participants Who Achieved Blood Pressure Control and Blood Pressure Response	Sitting BP measurements were performed at trough (23-26 hours post-morning dose). Blood pressure control was defined as msSBP/MSDBP < 140/90 mmHg. Blood pressure response in msSBP was defined as <140 mmHg or a reduction >= 20mmHg from baseline. Blood pressure response in msDBP was defined as < 90 mmHg or a reduction >= 10 mmHg from baseline.	8 weeks
Number of Participants With Adverse Events, Serious Adverse Events and Death	Adverse event monitoring was conducted throughout the study.	8 weeks

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: January 20, 2011
• First Submitted That Met QC Criteria: January 20, 2011
• First Posted (Estimate): January 21, 2011

Study Record Updates

• Last Update Posted (Estimate): January 29, 2016
• Last Update Submitted That Met QC Criteria: December 22, 2015
• Last Verified: December 1, 2015

More Information

Terms related to this study

• Keywords: hypertension; blood pressure; LCZ696; dual-acting; neprilysin; nep inhibitor; vasopeptidase; angiotensin receptor; angiotensin receptor neprilysin inhibitor (ARNi)
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Heart Murmurs; Hypertension; Systolic Murmurs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Valsartan; Sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: CLCZ696A2223; 2010-022326-32