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Sildenafil Versus Placebo in Chronic Heart Failure (SilHF)

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ClinicalTrials.gov Identifier: NCT01616381
Recruitment Status : Active, not recruiting
First Posted : June 11, 2012
Last Update Posted : May 7, 2018
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
Helse Stavanger HF

Tracking Information
First Submitted Date  ICMJE June 1, 2012
First Posted Date  ICMJE June 11, 2012
Last Update Posted Date May 7, 2018
Actual Study Start Date  ICMJE March 2013
Estimated Primary Completion Date June 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 7, 2012)
  • Patient Global Assessment [ Time Frame: Baseline, 8 weeks, 24 weeks ]
    Analysis of change from baseline.
  • Six minute walk test [ Time Frame: Baseline, 8 weeks, 24 weeks ]
    Analysis of change from baseline.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT01616381 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 7, 2012)
  • Quality of Life (QoL) evaluation by EuroQol5D [ Time Frame: Baseline, 8 weeks and 24 weeks ]
    Analysis of change from baseline.
  • Kansas City Questionaire [ Time Frame: Baseline, 8 weeks and 24 weeks ]
    Analysis of change from baseline.
  • New York Heart Association (NYHA) function class [ Time Frame: Baseline, 8 weeks, 16 weeks and 24 weeks ]
    Analysis of change from baseline.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Sildenafil Versus Placebo in Chronic Heart Failure
Official Title  ICMJE 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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Heart Failure
  • Pulmonary Hypertension
Intervention  ICMJE
  • Drug: Sildenafil
    PDE-5 Inhibitor
    Other Name: Revatio
  • Drug: Placebo
    Placebo for sildenafil 40mg x 3 daily
Study Arms  ICMJE
  • Active Comparator: Sildenafil
    Sildenafil tablets 40 mg x 3 daily
    Intervention: Drug: Sildenafil
  • Placebo Comparator: Placebo
    Placebo tablet x 3 daily
    Intervention: Drug: Placebo
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: November 19, 2017)
75
Original Estimated Enrollment  ICMJE
 (submitted: June 7, 2012)
210
Estimated Study Completion Date  ICMJE December 2019
Estimated Primary Completion Date June 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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,
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Israel,   Italy,   Norway,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01616381
Other Study ID Numbers  ICMJE SUS2011DIKE01
2011-002829-21 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Helse Stavanger HF
Study Sponsor  ICMJE Helse Stavanger HF
Collaborators  ICMJE Pfizer
Investigators  ICMJE
Principal Investigator: Kenneth Dickstein, MD, PhD Helse Stavanger HF
PRS Account Helse Stavanger HF
Verification Date May 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP