Sildenafil Versus Placebo in Chronic Heart Failure (SilHF)

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2013 by Helse Stavanger HF
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
Helse Stavanger HF
ClinicalTrials.gov Identifier:
NCT01616381
First received: June 1, 2012
Last updated: September 13, 2013
Last verified: September 2013
  Purpose

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.


Condition Intervention Phase
Heart Failure
Pulmonary Hypertension
Drug: Sildenafil
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Sildenafil in Heart Failure (SilHF); An Investigator Initiated Multinational Randomized Controlled Clinical Trial.

Resource links provided by NLM:


Further study details as provided by Helse Stavanger HF:

Primary Outcome Measures:
  • Patient Global Assessment [ Time Frame: Baseline, 8 weeks, 24 weeks ] [ Designated as safety issue: No ]
    Analysis of change from baseline.

  • Six minute walk test [ Time Frame: Baseline, 8 weeks, 24 weeks ] [ Designated as safety issue: No ]
    Analysis of change from baseline.


Secondary Outcome Measures:
  • Quality of Life (QoL) evaluation by EuroQol5D [ Time Frame: Baseline, 8 weeks and 24 weeks ] [ Designated as safety issue: No ]
    Analysis of change from baseline.

  • Kansas City Questionaire [ Time Frame: Baseline, 8 weeks and 24 weeks ] [ Designated as safety issue: No ]
    Analysis of change from baseline.

  • New York Heart Association (NYHA) function class [ Time Frame: Baseline, 8 weeks, 16 weeks and 24 weeks ] [ Designated as safety issue: No ]
    Analysis of change from baseline.


Estimated Enrollment: 210
Study Start Date: March 2013
Estimated Study Completion Date: June 2015
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Sildenafil
Sildenafil tablets 40 mg x 3 daily
Drug: Sildenafil
PDE-5 Inhibitor
Other Name: Revatio
Placebo Comparator: Placebo
Placebo tablet x 3 daily
Drug: Placebo
Placebo for sildenafil 40mg x 3 daily
Other Name: Placebo

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.

  Eligibility

Ages Eligible for Study:   18 Years to 85 Years
Genders Eligible for Study:   Both
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 < 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,
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01616381

Contacts
Contact: Trond J Cooper, MD +47 51518000 trond.cooper@gmail.com
Contact: Kenneth Dickstein, MD, PhD +47 51519453 kenneth.dickstein@med.uib.no

Locations
Israel
Lady Davis Carmel Medical CEnter Not yet recruiting
Haifa, Israel, 34362
Contact: Offer Amir, MD       offeram@012.net.il   
Contact: Nabia Salman, MD         
Principal Investigator: Offer Amir, MD         
Sub-Investigator: Nabiha Salman, MD         
Sub-Investigator: Barak Zafrir, MD         
Sub-Investigator: Michael Gavrieli, MD         
Rabin Medical Center Not yet recruiting
Petah Tikva, Israel, 49100
Contact: Tuvia Ben Gal, MD, PhD       bengaltu@gmail.com   
Contact: Israel Matz, MD         
Principal Investigator: Tuvia Ben Gal, MD, PhD         
Sub-Investigator: Israel Matz, MD         
Sub-Investigator: Andrei Valdman, MD         
Italy
San Donato Hospital Not yet recruiting
Milano, Italy, 20097
Contact: Marco Guazzi, MD, PhD       marco.guazzi@unimi.it   
Contact: Serenella Castelvecchio, MD         
Principal Investigator: Marco Guazzi, MD, PhD         
Sub-Investigator: Serenella Castelvecchio, MD         
Sub-Investigator: Lorenzo Menicanti, MD         
Norway
Stavanger University Hospital Recruiting
Stavanger, Rogaland, Norway, 4011
Contact: Trond Cooper, MD    +47 51518000    trond.cooper@gmail.com   
Contact: Kenneth Dickstein, PhD    +47 51519453    kenneth.dickstein@med.uib.no   
Principal Investigator: Trond Cooper, MD         
United Kingdom
Castle Hill Hospital Not yet recruiting
Hull, United Kingdom, HU16 5JQ
Contact: John G. Cleland, MD, PhD       j.g.cleland@hull.ac.uk   
Contact: Mike Lammiman         
Principal Investigator: John G. Cleland, MD, PhD         
Northern General Hospital Not yet recruiting
Sheffield, United Kingdom, S5 7AU
Contact: Abdallah Al-Mohammad, MD       a.al.mohammad.87@googlemail.com   
Contact: Samantha Maher         
Principal Investigator: Abdallah Al-Mohammad, MD         
Sponsors and Collaborators
Helse Stavanger HF
Pfizer
Investigators
Principal Investigator: Kenneth Dickstein, MD, PhD Helse Stavanger HF
  More Information

Publications:
Responsible Party: Helse Stavanger HF
ClinicalTrials.gov Identifier: NCT01616381     History of Changes
Other Study ID Numbers: SUS2011DIKE01
Study First Received: June 1, 2012
Last Updated: September 13, 2013
Health Authority: Norway: Norwegian Medicines Agency
Norway: Regional Ethics Commitee

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

ClinicalTrials.gov processed this record on August 28, 2014