Efficacy of Sildenafil in the Improvement of Cognition and Quality of Life in Patients With Cirrhosis of Liver. A Proof of Concept Study.

To Study The Proof of Concept in The Improvement of Cognition and Quality of Life in Cirrhotic Patients With Minimal Hepatic Encephalopathy by Means of a Pharmacological Intervention With Sildenafil (A Phosphodiesterase-5 Inhibitor).

The study is being conducted to evaluate the efficacy of Sildenafil (a 5-phosphodiesterase inhibitor) as a means to improve the cognitive impairment encountered in patients of minimal hepatic encephalopathy (MHE) as proposed in different studies.

This study would also assess the role of improvement of cognition as a means of improvement in quality of life.The patients will receive Sildenafil or no treatment for 4 weeks.

This study may prove and provide important therapeutic strategy for cognition impairment in patients with MHE.

Study Overview

• Status: Unknown
• Conditions: Hepatic Encephalopathy.
• Intervention / Treatment: Drug: Sildenafil.

Detailed Description

Primary Aim

1. To study the proof of concept in the improvement of impairment in cognition as assessed by PHES (psychometric hepatic encephalopathy score) in patients of MHE by means of pharmacological intervention by Sildenafil (a phosphodiesterase(PDE)-5 inhibitor) before and after treatment.
2. To study the impact of treatment with Sildenafil administration on the improvement in health-related quality-of-life of patients as assessed by Sickness impact profile (SIP) before and after treatment.

Secondary Aim

1. To study the impact of treatment with Sildenafil on CTP and MELD scores before and after treatment.
2. To study the impact of treatment with Sildenafil on blood ammonia and Interleukin-6 levels before and after treatment.

Study Population: The study population comprises of male adult (age 18-70 years) with cirrhosis of liver. Patients with cirrhosis of liver have been divided into two groups - with MHE and without or no MHE (NMHE) based on the test result of PHES, i.e., abnormal (MHE group) or normal (NMHE group).

Inclusion Criteria:

• Male patients aged 18-70 years diagnosed to have cirrhosis of liver at Liver Clinic of Department of Hepatology, Postgraduate Institute of Medical Education & Research(PGIMER), Chandigarh by means of clinical, biochemical and ultrasonographical/CT or liver biopsy.
• MHE will be defined by PHES ≤-5 and normal Mini-Mental State Examination (MMSE) score of ≥24.

Exclusion Criteria:

• Patients unable to give informed consent.
• H/O alcohol intake during last 12 weeks.
• Significant comorbid illness such as heart disease, respiratory disease, or renal failure.
• Any neurological disease such as Alzheimer disease, Parkinson's disease, stroke, non- hepatic metabolic encephalopathy's.
• Any anatomical deformities or disease of the penis such as Peyronie's disease.
• Patients having psychiatric illness and taking treatment with antidepressant, sedative or neuroleptics.
• Patients who start taking alcohol during the study period will be excluded.
• Patients taking vasodilators such as nitrates.
• Hepatocellular carcinoma.
• Recent history of upper GI bleed in last 6 weeks.
• Active ongoing infection.
• Electrolyte abnormality precipitating MHE.
• Color vision abnormalities.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• India
  • Chandigarh, India, 160012
    • Postgraduate Institute of Medical Education & Research Chandigarh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria: • Male patients aged 18-70 years diagnosed to have cirrhosis of liver at Liver Clinic of Department of Hepatology, PGIMER Chandigarh by means of clinical, biochemical and ultrasonographical/CT or liver biopsy.

• MHE will be defined by PHES ≤-5 and normal MMSE score of ≥24.

Exclusion Criteria:

• Patients unable to give informed consent.
• H/O alcohol intake during last 12 weeks.
• Significant comorbid illness such as heart disease, respiratory disease, or renal failure.
• Any neurological disease such as Alzheimer disease, Parkinson's disease, stroke, non- hepatic metabolic encephalopathy's.
• Any anatomical deformities or disease of the penis such as Peyronie's disease.
• Patients having psychiatric illness and taking treatment with antidepressant, sedative or neuroleptics.
• Patients who start taking alcohol during the study period will be excluded.
• Patients taking vasodilators such as nitrates.
• Hepatocellular carcinoma.
• Recent history of upper GI bleed in last 6 weeks.
• Active ongoing infection.
• Electrolyte abnormality precipitating MHE.
• Color vision abnormalities.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Intervention 'Sildenafil'.; MHE patient receiving Sildenafil. Intervention: Sildenafil Drug Dosage: 25 mg once a day for one week followed by 25 mg twice daily for two weeks then 25 mg thrice daily for one week.	Drug: Sildenafil.; Arm 1 :Sildenafil Drug Dosage: 25 mg once a day for one week followed by 25 mg twice daily for two weeks then 25 mg thrice daily for one week.; Other Names: Suhagra.
NO_INTERVENTION: 'No sildenafil'; Control Arm: MHE patients not receiving SIldenafil Intervention.Followed up for 4 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cognition( PHES)	Improvement of impairment in cognition as assessed by PHES (Psychometric Hepatic Encephalopathy Score) in patients of MHE (Minimal hepatic Encephalopathy) by means of pharmacological intervention by sildenafil (a PDE-5 inhibitor) before and after treatment.	4 weeks
QOL(SIP)	To study the impact of treatment with sildenafil administration on the improvement in health-related quality-of-life of patients as assessed by sickness impact profile (SIP) before and after treatment.	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CTP and MELD score before and after treatment with Sildenafil.	To study the impact of treatment with sildenafil on CTP and MELD scores before and after treatment.	4 weeks
Blood Ammonia and Interleukin-6 levels before and after treatment with Sildenafil.	Blood Ammonia and Interleukin-6 levels before and after treatment.	4 weeks

Collaborators and Investigators

• Sponsor: Postgraduate Institute of Medical Education and Research
• Investigators: Principal Investigator: Radha K Dhiman, MD, DM, FACG, PGIMER Chandigarh

Study record dates

Study Major Dates

• Study Start: July 1, 2012
• Primary Completion (ACTUAL): November 1, 2013
• Study Completion (ANTICIPATED): January 1, 2014

Study Registration Dates

• First Submitted: December 28, 2013
• First Submitted That Met QC Criteria: January 3, 2014
• First Posted (ESTIMATE): January 7, 2014

Study Record Updates

• Last Update Posted (ESTIMATE): January 7, 2014
• Last Update Submitted That Met QC Criteria: January 3, 2014
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Keywords: Minimal Hepatic Encephalopathy (MHE); Psychometric Hepatic Encephalopathy Score (PHES); Sickness Impact Profile (SIP); Model for End-stage Liver Disease (MELD); Child-Turcotte-Pugh score (CTP)
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Failure; Hepatic Insufficiency; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Liver Diseases; Brain Diseases, Metabolic; Hepatic Encephalopathy; Brain Diseases; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate
• Other Study ID Numbers: Hepatology PGIMER 2012