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

Study Overview
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Brief Summary
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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).

Official Title
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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

Conditions
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Systolic Hypertension

Intervention / Treatment
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* Drug: LCZ696
* Drug: Valsartan
* Drug: AHU377
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VAL + AHU 400 mg<br>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<br>* Valsartan was supplied as tablets in blister cards in 160 mg and 320 mg strengths.<br>Drug: AHU377<br>* AHU377 was supplied in tablets in blister cards in 50 mg and 100 mg strengths.<br>|
| Experimental: VAL + AHU 200 mg<br>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<br>* Valsartan was supplied as tablets in blister cards in 160 mg and 320 mg strengths.<br>Drug: AHU377<br>* AHU377 was supplied in tablets in blister cards in 50 mg and 100 mg strengths.<br>|
| Experimental: VAL + AHU 100 mg<br>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<br>* Valsartan was supplied as tablets in blister cards in 160 mg and 320 mg strengths.<br>Drug: AHU377<br>* AHU377 was supplied in tablets in blister cards in 50 mg and 100 mg strengths.<br>|
| Experimental: VAL + AHU 50 mg<br>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<br>* Valsartan was supplied as tablets in blister cards in 160 mg and 320 mg strengths.<br>Drug: AHU377<br>* AHU377 was supplied in tablets in blister cards in 50 mg and 100 mg strengths.<br>|
| Experimental: VAL 320 mg<br>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<br>* Valsartan was supplied as tablets in blister cards in 160 mg and 320 mg strengths.<br>|
| Experimental: LCZ 400 mg<br>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<br>* LCZ696 was supplied as tablets in blister cards in 100 mg strengths.<br>|
| Experimental: Placebo<br>Participants received matching placebo to LCZ696, AHU377 and valsartan for 8 weeks. | Drug: Placebo<br>* Placebo was supplied as tablets in blister cards.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hypertension, blood pressure, LCZ696, dual-acting, neprilysin, nep inhibitor, vasopeptidase, angiotensin receptor, angiotensin receptor neprilysin inhibitor (ARNi)