Sildenafil in US Heart Failure Patients (SilHF-US) (SilHF-US)

This protocol describes a 2-arm randomized controlled pilot study assessing the tolerance, safety and efficacy of sildenafil compared to control. The hypothesis is that sildenafil will be well tolerated and efficacious in patients with chronic heart failure (NYHA class II and III) with evidence of systolic dysfunction (EF ≤40 %) and secondary pulmonary hypertension (SPAP >40mmHg).

Patients that satisfy the inclusion criteria will be randomized to sildenafil (40mg x 3) or placebo therapy for 6 months in a 2:1 blinded fashion. The placebo group will be compared to the active therapy group and analyzed for differences in the main study end-points Patient Global Assessment and 6-Minute Walk Test.

The study will also assess safety, tolerability, symptoms and quality of life.

Study Overview

• Status: Unknown
• Conditions: Heart Failure; Pulmonary Hypertension
• Intervention / Treatment: Drug: Sildenafil; Drug: Placebo oral capsule

Detailed Description

It is estimated that 2-3 % of the adult population suffers from heart failure (HF) and the prevalence is increasing. The European Society of Cardiology (ESC) represents countries with a population > 1,1 billion, and it is estimated that approximately 30 million patients have HF in these 53 countries. Heart failure is particularly prevalent in the elderly population and represents a major burden for both patients and the health services. In United states (US) more than 5 million people, or almost 2% of population have HF (Go at al, 2013) Medicare data indicate that 12% to 27% of patients hospitalized for heart failure are readmitted within 30 days after their discharge, and all-cause mortality reaches 12% in the same period. (Jencks at al, 2009).

Despite optimal non-pharmacological, pharmacological and device therapy, the morbidity among HF patients is high with symptoms such as dyspnoea and fatigue that reduce quality of life. Following diagnosis approximately 50% are dead after 4 years. Forty percent of patients admitted to hospital with HF are either dead or hospitalized within one year.

During the last decade, PDE5-inhibitors have been evaluated as a potential treatment for heart failure (see scientific rationale and reference). However, these investigations have been small and there is still limited data. Trials assessing the acute effects of PDE5-inhibition in patients with symptomatic HF due to systolic dysfunction have been performed primarily with sildenafil. Due to the short half-life of sildenafil the drug is administered 3 times daily when studying its chronic effects.

Previous studies have evaluated the 50 mg dose acutely and 50 mg 3 times daily during short-term chronic studies. Importantly, there is considerable off-label use of sildenafil in symptomatic heart failure patients in most European countries.

Revatio is currently licensed for pulmonary hypertension group 1. The dosing scheme is 20mg x 3. However, we suggest targeting a higher dose to achieve optimal clinical benefit in patients with heart failure and moderate congestion. As mentioned above most of the clinical literature in patients with symptomatic heart failure has been done using the 50mg x 3 regimen. However, it is believed that in the proposed study using 40mg x 3 should be equally efficacious. There is already considerable experience using this dosage scheme in heart failure patients locally.

The hemodynamic profile of PDE-5 inhibitors is favorable with reduction in filling pressures, both systemic and pulmonary, vascular resistance accompanied by improvement in symptoms and sub maximal and peak exercise performance. This pilot study will evaluate the use of the PDE5-inhibitor sildenafil in patients with heart failure, systolic dysfunction and documented secondary pulmonary hypertension.

• Study Type: Interventional
• Enrollment (Anticipated): 25
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • Hartford, Connecticut, United States, 06102
      • Recruiting
      • Hartford Hospital 80 Seymour street
      • Contact: Konstadina Darsaklis, MD; Phone Number: 860-972-1212; Email: konstadina.darsaklis@hhchealth.org
      • Contact: Arben Ademi, CCRP; Phone Number: 860-972-3561; Email: arben.ademi@hhchealth.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Men and women
2. 18 - 80 years of age.
3. Outpatients with chronic HF. NYHA class II-III on optimal treatment in sinus rhythm or atrial fibrillation
4. LVEF ≤ 40% measured during the past 12 months
5. SPAP ≥ 40mmHg using echocardiography
6. 6MWTD < 475 meters
7. NT-pro BNP ≥ 400 pg/ml or BNP ≥100 pg/ml, measured during the past 12 months
8. Receiving optimal therapy, including diuretic, ACE-inhibitor, ARB, beta-blocker and aldosterone antagonist. Doses of all medication should be unchanged during the last 30 days before inclusion.
9. ICDs and CRTs (CRT-P, CRT-D) are permitted. Implantation should have been performed at > 3 months before inclusion to the trial.

Exclusion Criteria: -

1. Acute Coronary Syndrome, including myocardial infarction, or coronary angiography, with or without intervention, within the last 3 months
2. Stroke within the last 3 months
3. Planned coronary angiography or planned device-implantation
4. Moderate to severe obstructive valve disease
5. Documented episodes of sustained ventricular tachycardia
6. Prior (past 30 days before the baseline visit) or ongoing use of oral nitrate therapy.
7. Concomitant disease which interfere with assessment of dyspnea , severe COPD, asthma, restrictive lung disease, severe obesity
8. Anemia (hemoglobin < 10g/dL)
9. Uncontrolled hypertension ( SBP >160 mmHg and / or DBP > 90 mmHg)
10. Symptomatic or orthostatic hypotension or systolic blood pressure < 90 mmHg
11. Clinically important renal dysfunction (GFR < 40m ml/min)
12. Women with child-bearing potential
13. Prior (past 30 days before the baseline visit) or ongoing use of i) alpha-1 antagonist: doxazosin ii) CYP3A4 inhibitors: erytromycin, ritonavir, sakinovir, itrakonazole, ketokonazole iii) CYP3A4-inducers: rifampicin iv) Any calcium channel blockers
14. V) Pulmonary vasodilators at the treatment dose level for Pulmonary hypertensionRetinitis pigmentosa, previous diagnosis of NAION (non-arteritic ischemic opticus-neuropathy), unexplained visual disturbance.
15. Sickle cell anemia, multiple myeloma, leukemia or penile anatomic deformities (angulation, cavernosal fibrosis, Peyronie's disease) that increases the risk of priapism.
16. Hepatic failure.
17. Drug and alcohol abuse which precludes compliance with the protocol.
18. Inability to understand or sign the written informed consent form of the study,

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Sildenafil 40mgx3 daily; Sildenafil 40mgx3 daily for 6 months	Drug: Sildenafil; PDE5 Inhibitor
PLACEBO_COMPARATOR: Placebo tablet x3 daily; Placebo for Sildenafil 40mgx3 daily for 6 months	Drug: Placebo oral capsule; Placebo for Sildenafil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Six minute walk test	Analysis of change from the baseline	Baseline, 8 weeks and 24 weeks
Patient Global Assessment (PGA)	Analysis of change form the baseline	Baseline; 8 weeks and 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
1.Quality of Life (QoL) evaluation by EuroQol5D	Analysis of change from baseline	Baseline, 8 weeks and 24 weeks
Kansas City Cardiomyopathy Questionnaire (KCCQ)	Analysis of change from baseline	Baseline, 8 weeks and 24 weeks
New York Heart Association (NYHA) function class	Analysis of change from baseline	Baseline, 8 weeks and 24 weeks

Collaborators and Investigators

• Sponsor: Hartford Hospital
• Collaborators: Helse Stavanger HF
• Investigators: Principal Investigator: Konstadina Darsaklis, MD, Hartford Hospital

Publications and helpful links

General Publications

• Guazzi M, Dickstein K, Vicenzi M, Arena R. Six-minute walk test and cardiopulmonary exercise testing in patients with chronic heart failure: a comparative analysis on clinical and prognostic insights. Circ Heart Fail. 2009 Nov;2(6):549-55. doi: 10.1161/CIRCHEARTFAILURE.109.881326. Epub 2009 Sep 28.
• Cooper TJ, Guazzi M, Al-Mohammad A, Amir O, Bengal T, Cleland JG, Dickstein K. Sildenafil in Heart failure (SilHF). An investigator-initiated multinational randomized controlled clinical trial: rationale and design. Eur J Heart Fail. 2013 Jan;15(1):119-22. doi: 10.1093/eurjhf/hfs152. Epub 2012 Oct 24.

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 14, 2018
• Primary Completion (ANTICIPATED): December 1, 2018
• Study Completion (ANTICIPATED): December 1, 2018

Study Registration Dates

• First Submitted: March 4, 2018
• First Submitted That Met QC Criteria: March 4, 2018
• First Posted (ACTUAL): March 9, 2018

Study Record Updates

• Last Update Posted (ACTUAL): March 9, 2018
• Last Update Submitted That Met QC Criteria: March 4, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Heart Failure; Hypertension, Pulmonary; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate
• Other Study ID Numbers: HHC-2016-0152

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The SilHF trial is an international, multi-centre effort with five participating European centres.The Steering Committee of the SilHF trial, has elected to pool the individual patient data from the five European centers with a large single center in Hartford Connecticut, USA, PI: Konstadina Darsaklis. The US site will follow an identical protocol to the European sites and enter data on the electronic case report form to the data management centre in Trondheim, Norway. We intend to perform the meta-analysis independent of the results of the separate studies. All sites have obtained the required regulatory approvals.
• IPD Sharing Time Frame: The only US site at Hartford Hospital will complete enrollment by the end of year 2018. Data will be available and study database will be updated within 5 days of any obtained f-u visit.
• IPD Sharing Access Criteria: De-identified coded data will be entered into a secure login study database.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No