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Lifestyle Intervention Targetting Obesity and Insulin Resistance in Chronic Hepatitis C

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ClinicalTrials.gov Identifier: NCT00755742
Recruitment Status : Completed
First Posted : September 19, 2008
Last Update Posted : September 22, 2011
Sponsor:
Information provided by (Responsible Party):
Venessa Pattullo, University Health Network, Toronto

Tracking Information
First Submitted Date  ICMJE September 17, 2008
First Posted Date  ICMJE September 19, 2008
Last Update Posted Date September 22, 2011
Study Start Date  ICMJE November 2008
Actual Primary Completion Date January 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 28, 2009)
HOMA-IR [ Time Frame: 12 and 24 weeks ]
Original Primary Outcome Measures  ICMJE
 (submitted: September 17, 2008)
HOMA-IR [ Time Frame: 12, 24 and 28 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 5, 2010)
  • TNF-alpha [ Time Frame: 12 and 24 weeks ]
  • leptin [ Time Frame: 12 and 24 weeks ]
  • adiponectin [ Time Frame: 12 and 24 weeks ]
  • fatigue score [ Time Frame: 12 and 24 weeks ]
  • mood score [ Time Frame: 12 and 24 weeks ]
  • cholesterol [ Time Frame: 12 and 24 weeks ]
  • triglycerides [ Time Frame: 12 and 24 weeks ]
  • HDL-cholesterol [ Time Frame: 12 and 24 weeks ]
  • LDL-cholesterol [ Time Frame: 12 and 24 weeks ]
  • RBC fatty acid composition [ Time Frame: 12 and 24 weeks ]
  • BMI [ Time Frame: 12 and 24 weeks ]
  • Waist circumference [ Time Frame: 12 and 24 weeks ]
  • Metabolic Syndrome [ Time Frame: 12 and 24 weeks ]
  • CLDQ (Chronic Liver Disease Questionnaire) [ Time Frame: 12 and 24 weeks ]
  • Liver and Peripheral Insulin Resistance [ Time Frame: 12 and 24 weeks ]
    Scores derived from glucose and insulin levels in the oral glucose tolerance test (OGTT)
Original Secondary Outcome Measures  ICMJE
 (submitted: September 17, 2008)
  • TNF-alpha [ Time Frame: 12, 24, 28 weeks ]
  • leptin [ Time Frame: 12, 24, 28 weeks ]
  • adiponectin [ Time Frame: 12, 24, 28 weeks ]
  • fatigue score [ Time Frame: 12, 24, 28 weeks ]
  • mood score [ Time Frame: 12, 24, 28 weeks ]
  • cholesterol [ Time Frame: 12, 24, 28 weeks ]
  • triglycerides [ Time Frame: 12, 24, 28 weeks ]
  • HDL-cholesterol [ Time Frame: 12, 24, 28 weeks ]
  • LDL-cholesterol [ Time Frame: 12, 24, 28 weeks ]
  • RBC fatty acid composition [ Time Frame: 12, 24, 28 weeks ]
  • BMI [ Time Frame: 12, 24, 28 weeks ]
  • Waist circumference [ Time Frame: 12, 24, 28 weeks ]
  • Metabolic Syndrome [ Time Frame: 12, 24, 28 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Lifestyle Intervention Targetting Obesity and Insulin Resistance in Chronic Hepatitis C
Official Title  ICMJE Evaluation of the Impact of a Combined Program of Diet, Exercise and Behavior Modification on the Insulin Resistance and Adipokine Profile in Obese Patients With Current and Cured Chronic Hepatitis C.
Brief Summary Chronic hepatitis C (CHC) infection affects approximately 1 in 100 Canadians. Untreated, CHC has significant long-term consequences including cirrhosis, liver cancer and liver failure. CHC is intrinsically linked to both obesity and insulin resistance (IR) or "pre-diabetes", their co-existence worsens overall health outcomes. We have demonstrated that obesity (BMI ≥30kg/m2) is over twice as common amongst patients with CHC (28.8%) compared with the general Canadian population. Obesity superimposed on CHC reduces the success of antiviral treatment and promotes liver scarring (hepatic fibrosis), fatty liver (steatosis) and increases the risk of liver cancer. Both CHC and obesity contribute to IR putting these patients at risk of type 2 diabetes. IR, like obesity in CHC, reduces antiviral success rates. We have shown that diabetics are at higher risk of developing liver cancer compared with non-diabetics. It is therefore timely to address lifestyle modification to delay the onset of diabetes. We will examine the impact of a multidisciplinary lifestyle program on the insulin resistance in 52 obese "pre-diabetic" patients with current or past CHC. The 24 week program comprises an individualized nutritional and exercise plan supported by behavior modification counseling. Through gaining a better understanding of links between obesity, insulin resistance and hepatitis C infection we hope to delay the onset of diabetes and reduce the likelihood of all their untoward effects on the liver.
Detailed Description

The hepatitis C virus (HCV) chronically infects an estimated 240,000 in Canada and 170 million worldwide. Untreated, CHC is associated with significant long-term clinical consequences including cirrhosis, liver failure and hepatocellular cancer (HCC), and it is the most common indication for liver transplantation in North America. CHC is associated with metabolic manifestations independent of the degree of hepatic fibrosis which include insulin resistance (IR) and type 2 diabetes (T2DM), which have a significantly higher prevalence in CHC compared with the general population. Patients with CHC and T2DM have an increased risk of HCC in addition to morbidity from systemic complications.

Our previous work demonstrates that the prevalence of obesity (BMI ≥30kg/m2) amongst patients with CHC is 28.8%, over twice the prevalence in the Canadian population, and the presence of obesity is independently associated with viremia (positive HCV-RNA). Obesity promotes hepatic fibrosis progression and is independently associated with IR in non-cirrhotic CHC; the prevalence of IR increases with higher BMI in CHC. Insulin resistance can be reversed if viral clearance is achieved; however loss of IR is less likely to occur in the obese even if they have cleared the virus. Obesity and IR are associated with non-response to antiviral therapy. Whilst IR has been improved with the use of metformin in patients with CHC, this was ineffective in increasing rates of response to antiviral treatment. The aims of our study are:

  1. To evaluate the effect of a three-pronged lifestyle intervention comprising diet, exercise and behavior modification on insulin resistance in obese patients with current and cured chronic hepatitis C.
  2. To formulate specific recommendations for lifestyle changes to improve insulin resistance and lose weight, thereby reducing the risk of diabetes and other metabolic complications, and potentially enhancing response to antiviral therapy in obese patients with CHC.
  3. To examine the impact of this intervention on IR, insulin sensitivity and serum adipokine levels for the purpose of investigating the mechanism of insulin resistance in obesity with and without viremia due to chronic hepatitis C infection.

We will utilize a multidisciplinary approach by collaborating with the disciplines of gastroenterology, nutrition, endocrinology, exercise physiology and psychiatry. This prospective study will include 13 non-cirrhotic and 13 cirrhotic, insulin resistant (HOMA-IR ≥2.1) and obese patients (non-Genotype 3, as the latter have marked fatty liver in absence of obesity); as well as 13 non-cirrhotic and 13 cirrhotic, insulin resistant and obese patients with successfully treated CHC (ie now non-viremic) to act as controls. Assessments for measures of IR and obesity (including oral glucose tolerance test to calculate insulin sensitivity index (ISI), serum adipokines, free fatty acids, anthropometry and body composition by abdominal DEXA) will be made. The HOMA-IR (measuring hepatic IR) will be the primary outcome for the experimental maneuver, which will take place over 24 weeks. It will comprise 3 components:

  1. Diet: participants will be advised on an individually tailored diet of low glycemic foods, low total fat (but rich in omega-3 fatty acid) and high fiber aimed at both weight loss and improvement of insulin resistance.
  2. Exercise: physical activity will be measured with the use of a personal pedometer, and participants given a step target of 10000 steps per day, or an increment of 3000 steps per day from their baseline activity (whichever is greater).
  3. Behavior Modification: the change in diet and physical activity will be facilitated by a 12-week face-to face program followed by a 12-week telephone program based on the principals of motivational interviewing and behavior theory.

The intercurrence of obesity and IR in subjects chronically infected with hepatitis C exacerbates their poor current and future health status. As the pathophysiology of IR in patients with CHC may differ from those who are obese but no longer infected, we will quantify the benefits of the lifestyle intervention in these two patient groups as gauged by fall in HOMA-IR score and improvement in ISI. Our long-term goals are to improve the outcome of antiviral therapy and reduce the burden of CHC, obesity and type 2 diabetes related morbidity. This we hope to achieve through gaining a better understanding of the mechanisms involved in the development of IR in the obese with and without current CHC.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Obesity
  • Insulin Resistance
  • Metabolic Syndrome
  • Hepatitis C
Intervention  ICMJE Other: Lifestyle intervention

The 3-pronged lifestyle intervention is designed to deliver a period of intensive contact (week 0-12) and less-intensive contact (weeks 12-24):

i) Behavior Modification Counseling: The principles of motivational enhancement and cognitive-behavior therapy (MET/CBT) will be utilized at each visit and telephone contact to provide individually tailored counseling. The goal is to enhance internal motivation and facilitate changes in lifestyle that are adaptable to each participant's usual habits.

ii) Physical activity target: increment in activity of at least 3000 steps/day above the baseline, or total activity of 10,000 steps/day (whichever is greater).

iii) Dietary assessment and nutritional plan: A diet plan designed to both lose weight and improve insulin resistance will be provided.

Study Arms  ICMJE
  • Experimental: Group 1 - Viremic / Non-cirrhotic
    13 obese and insulin resistant, non-cirrhotic, non-diabetic (by fasting glucose), non-genotype 3 patients with chronic hepatitis C (HCV RNA positive) will undergo 24 week lifestyle intervention comprising diet, physical activity (monitored by pedometers) in combination with behavior modification counseling. This arm includes patients who are naive to antiviral therapy, relapsed or not responded to antiviral therapy.
    Intervention: Other: Lifestyle intervention
  • Active Comparator: Group 2 - Non-viremic / Non-cirrhotic
    13 obese and insulin resistant, non-cirrhotic, non-diabetic (by fasting glucose), non-genotype 3 patients with cured chronic hepatitis C (HCV RNA negative) will undergo 24 week lifestyle intervention comprising diet, physical activity (monitored by pedometers) in combination with behavior modification counseling. This arm includes patients who have cleared hepatitis C virus with previous antiviral therapy.
    Intervention: Other: Lifestyle intervention
  • Experimental: Group 3 - Viremic / Cirrhotic
    13 obese and insulin resistant, cirrhotic, non-diabetic (by fasting glucose), non-genotype 3 patients with chronic hepatitis C (HCV RNA positive) will undergo 24 week lifestyle intervention comprising diet, physical activity (monitored by pedometers) in combination with behavior modification counseling. This arm includes patients who are naive to antiviral therapy, relapsed or not responded to antiviral therapy.
    Intervention: Other: Lifestyle intervention
  • Active Comparator: Group 4 - Non-viremic / Cirrhotic
    13 obese and insulin resistant, cirrhotic, non-diabetic (by fasting glucose), non-genotype 3 patients with cured chronic hepatitis C (HCV RNA negative) will undergo 24 week lifestyle intervention comprising diet, physical activity (monitored by pedometers) in combination with behavior modification counseling. This arm includes patients who have cleared hepatitis C virus with previous antiviral therapy
    Intervention: Other: Lifestyle intervention
Publications * Not Provided

*   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 Completed
Actual Enrollment  ICMJE
 (submitted: September 21, 2011)
24
Original Estimated Enrollment  ICMJE
 (submitted: September 17, 2008)
50
Actual Study Completion Date  ICMJE August 2011
Actual Primary Completion Date January 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • obese (BMI >/= 30)
  • insulin resistant (HOMA-IR >/= 2.1)

Exclusion Criteria:

  • Genotype 3 patients
  • Women with ongoing pregnancy or who are breast-feeding
  • Patients with any other other underlying liver disease (viral, alcoholic, druginduced, autoimmune, metabolic, genetic).
  • Patients currently on antiviral therapy, or who have ceased therapy within 6 months of recruitment to the study.
  • Patients with other causes for insulin resistance e.g., excess counter-regulatory hormones: glucocorticoids, catecholamines, growth hormone, polycystic ovary syndrome).
  • Patients on steroids or other drug that affects insulin resistance, which are unable to be stopped for 3 days prior to IR testing.
  • Patients with overt diabetes (based on results of fasting plasma glucose) will be excluded from participation as we are focusing on insulin resistance in the absence of diabetes.
  • Conditions which preclude a sudden increase in physical activity:

    • History or other evidence of chronic pulmonary disease associated with functional limitation.
    • History of severe cardiac disease (e.g., NYHA Functional Class III or IV, myocardial infarction within 6 months, ventricular tachyarrhythmias requiring ongoing treatment, unstable angina or other significant cardiovascular diseases).
    • Unable to 10000 steps/day eg physical disability, morbid obesity.
  • Evidence of ongoing substance use (including alcohol consumption >20g/day for men and >10g/day for women) within one year of study recruitment.
  • Poor veins (inadequate venous access)
  • Inability or unwillingness to provide informed consent or abide by study requirements eg severe psychiatric illness, lives remotely, time commitment.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 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 Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00755742
Other Study ID Numbers  ICMJE 08-0545-AE
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Venessa Pattullo, University Health Network, Toronto
Study Sponsor  ICMJE University Health Network, Toronto
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Elizabeth J Heathcote, MD FRCPC University Health Network, Toronto
PRS Account University Health Network, Toronto
Verification Date September 2011

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