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

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ClinicalTrials.gov Identifier: NCT03460470
Recruitment Status : Recruiting
First Posted : March 9, 2018
Last Update Posted : March 9, 2018
Sponsor:
Collaborator:
Helse Stavanger HF
Information provided by (Responsible Party):
Konstadina Darsaklis, Hartford Hospital

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Heart Failure Pulmonary Hypertension Drug: Sildenafil Drug: Placebo oral capsule Phase 3

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  (Clinical Trial)
Estimated Enrollment : 25 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Sildenafil in US Heart Failure Patients (SilHF-US)
Actual Study Start Date : February 14, 2018
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

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




Primary Outcome Measures :
  1. Six minute walk test [ Time Frame: Baseline, 8 weeks and 24 weeks ]
    Analysis of change from the baseline

  2. Patient Global Assessment (PGA) [ Time Frame: Baseline; 8 weeks and 24 weeks ]
    Analysis of change form the baseline


Secondary Outcome Measures :
  1. 1.Quality of Life (QoL) evaluation by EuroQol5D [ Time Frame: Baseline, 8 weeks and 24 weeks ]
    Analysis of change from baseline

  2. Kansas City Cardiomyopathy Questionnaire (KCCQ) [ Time Frame: Baseline, 8 weeks and 24 weeks ]
    Analysis of change from baseline

  3. New York Heart Association (NYHA) function class [ Time Frame: Baseline, 8 weeks and 24 weeks ]
    Analysis of change from baseline



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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,

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03460470


Contacts
Contact: Arben Ademi, CCRP 860972-3561 arben.ademi@hhchealth.org
Contact: Konstadina Darsaklis, MD 860-972-1212 konstadina.Daraklis@hhchealth.org

Locations
United States, Connecticut
Hartford Hospital 80 Seymour street Recruiting
Hartford, Connecticut, United States, 06102
Contact: Konstadina Darsaklis, MD    860-972-1212    konstadina.darsaklis@hhchealth.org   
Contact: Arben Ademi, CCRP    860-972-3561    arben.ademi@hhchealth.org   
Sponsors and Collaborators
Hartford Hospital
Helse Stavanger HF
Investigators
Principal Investigator: Konstadina Darsaklis, MD Hartford Hospital

Publications of Results:
Responsible Party: Konstadina Darsaklis, MD, Hartford Hospital
ClinicalTrials.gov Identifier: NCT03460470     History of Changes
Other Study ID Numbers: HHC-2016-0152
First Posted: March 9, 2018    Key Record Dates
Last Update Posted: March 9, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
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.
Access Criteria: De-identified coded data will be entered into a secure login study database.

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

Additional relevant MeSH terms:
Hypertension, Pulmonary
Heart Failure
Heart Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Sildenafil Citrate
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents