Sildenafil Versus Placebo in Chronic Heart Failure

Brief Title

Sildenafil Versus Placebo in Chronic Heart Failure

Official Title

Sildenafil in Heart Failure (SilHF); An Investigator Initiated Multinational Randomized Controlled Clinical Trial.

Brief Summary

      This protocol describes a 2-arm randomised 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 analysed 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.
    

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. HF is present in
      over 10% of patients admitted to hospital and accounts for ~ 2% of national health expenses.
      Approximately 50% of these costs are related to hospitalisation.

      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 rehospitalised 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 licenced 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 favourable with reduction in filling
      pressures, both systemic and pulmonary, vascular resistance accompanied by improvement in
      symptoms and submaximal 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 Phase

Phase 3

Study Type

Interventional


Primary Outcome

Patient Global Assessment

Secondary Outcome

 Quality of Life (QoL) evaluation by EuroQol5D

Condition

Heart Failure

Intervention

Sildenafil

Study Arms / Comparison Groups

 Sildenafil
Description:  Sildenafil tablets 40 mg x 3 daily

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

75

Start Date

March 2013

Completion Date

December 2019

Primary Completion Date

June 2018

Eligibility 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 < 400 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. Oral nitrate therapy or frequent use of sublingual nitrate

          7. Concomitant disease which interfere with assessment of dyspnoea , 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. Use of

             i) alpha-1 antagonist: doxazosin

             ii) CYP3A4 inhibitors: erytromycin, ritonavir, sakinovir, itraconazole, ketoconazole

             iii) CYP3A4-inducers: rifampicin

             iv) Any calcium channel blockers

         14. Retinitis pigmentosa, previous diagnosis of NAION (non-arteritic ischemic
             optic-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,
      

Gender

All

Ages

18 Years - 85 Years

Accepts Healthy Volunteers

No

Contacts

Kenneth Dickstein, MD, PhD, , 

Location Countries

Israel

Location Countries

Israel

Administrative Informations


NCT ID

NCT01616381

Organization ID

SUS2011DIKE01

Secondary IDs

2011-002829-21

Responsible Party

Sponsor

Study Sponsor

Helse Stavanger HF

Collaborators

 Pfizer

Study Sponsor

Kenneth Dickstein, MD, PhD, Principal Investigator, Helse Stavanger HF


Verification Date

May 2018