Safety of Ataciguat in Patients With Moderate Calcific Aortic Valve Stenosis

A Phase Ib Randomized, Placebo-controlled, Double-blinded Study Evaluating the Safety of Ataciguat (HMR1766) in Patients With Moderate Calcific Aortic Valve Stenosis

This study will determine whether Ataciguat (HMR1766) is well-tolerated in patients with mild to moderate calcific aortic valve stenosis. The primary focus of these studies will be on changes in blood pressure and orthostatic tolerance (i.e., ability to stand up without passing out), and determining whether treatment with Ataciguat results in significant reductions in blood pressure in this patient population.

Study Overview

• Status: Completed
• Conditions: Aortic Valve Stenosis
• Intervention / Treatment: Drug: Placebo; Drug: Ataciguat

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age > 50 years
• Male or female sex
• Aortic valve area greater than 1.0 cm2 but less than 2.0 cm2
• Aortic valve calcium levels greater than 300 arbitrary units from chest CT
• Ejection fraction >50%

Exclusion Criteria:

• History of orthostatic intolerance or symptomatic hypotension
• Positive pregnancy test during screening visit
• Nitrate use or α-antagonist medication use within 24 hours
• Systolic blood pressure <110 mm Hg
• Mean systemic arterial pressure <75 mm Hg
• Severe mitral or aortic regurgitation
• Retinal or optic nerve problems
• Recent (≤30 days) acute coronary syndrome
• Oxygen saturation <90% on room air
• Congenital valve disease
• Hepatic dysfunction/elevated liver enzymes
• Prescription of drugs known to alter nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate signaling (sildenafil, nitrates, etc.)
• History of orthostatic intolerance
• Concomitant participation in other trials at Mayo Clinic or elsewhere.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo; Placebo gel capsule, dosage matches number of Ataciguat capsules for each respective dose, capsules taken once daily with breakfast for 14 consecutive days.	Drug: Placebo; Other Names: Placebo gel capsule of identical composition to Active group, but does not have active compound.
ACTIVE_COMPARATOR: Ataciguat; Ataciguat, orally administered gel capsule, 50, 100, or 200 mg, once per day with breakfast for 14 consecutive days	Drug: Ataciguat; Other Names: HMR1766

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients experiencing orthostatic hypotension	The primary objective of the current study is to determine whether Ataciguat (HMR1766) is well-tolerated by patients with moderate calcific aortic valve stenosis. In this particular patient population, incidence of orthostatic intolerance/symptomatic hypotension is a potential concern.	Baseline - 14 days
The change in blood pressure following the transition from sitting to standing	The primary objective of the current study is to determine whether Ataciguat (HMR1766) is well-tolerated by patients with moderate calcific aortic valve stenosis. In this particular patient population, incidence of orthostatic intolerance/symptomatic hypotension is a potential concern. Transitioning from sitting to standing is a functional test that will allow us to examine the effects of Ataciguat on blood pressure regulation in response to a relevant orthostatic stress.	Baseline - 14 days
The change in blood pressure following progressive head-up tilt	The primary objective of the current study is to determine whether Ataciguat (HMR1766) is well-tolerated by patients with moderate calcific aortic valve stenosis. In this particular patient population, incidence of orthostatic intolerance/symptomatic hypotension is a potential concern. Tilt table testing will allow us to examine the effects of Ataciguat on blood pressure regulation in response to a tightly controlled orthostatic stress.	Baseline - 14 days
Subject self-reports of light-headedness/orthostatic intolerance during the standing test and the head-up tilt testing	The primary objective of the current study is to determine whether Ataciguat (HMR1766) is well-tolerated by patients with moderate calcific aortic valve stenosis. In this particular patient population, incidence of orthostatic intolerance/symptomatic hypotension is a potential concern. Evaluating subject perceptions of light-headedness/orthostatic intolerance will help us to understand the relationship between changes in blood pressure and changes in symptoms in this patient population before and after treatment with Ataciguat.	Baseline - 14 days

Collaborators and Investigators

• Sponsor: Jordan D. Miller, Ph.D.
• Collaborators: National Center for Research Resources (NCRR); National Center for Advancing Translational Sciences (NCATS); Sanofi-Synthelabo
• Investigators: Principal Investigator: Jordan Miller, PhD, Mayo Clinic

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (ACTUAL): March 1, 2015
• Study Completion (ACTUAL): March 1, 2015

Study Registration Dates

• First Submitted: January 28, 2014
• First Submitted That Met QC Criteria: January 29, 2014
• First Posted (ESTIMATE): January 30, 2014

Study Record Updates

• Last Update Posted (ESTIMATE): July 7, 2016
• Last Update Submitted That Met QC Criteria: July 5, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Aortic Valve Disease; Heart Valve Diseases; Ventricular Outflow Obstruction; Aortic Valve Stenosis; Constriction, Pathologic; Molecular Mechanisms of Pharmacological Action; Enzyme Activators; 5-chloro-2-(5-chlorothiophene-2-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide
• Other Study ID Numbers: 13-005387; UL1RR024150 (U.S. NIH Grant/Contract)