A Study to Assess the Effect of Severe Hepatic Impairment on the Pharmacokinetics of Intravenous Conivaptan

A Phase 1, Open-Label Study to Assess the Effect of Severe Hepatic Impairment on the Pharmacokinetics of Intravenous Conivaptan

The purpose of this study is to assess the pharmacokinetics and safety of a 48-hour continuous infusion of conivaptan in subjects with severe liver impairment compared to subjects with normal liver function.

Study Overview

• Status: Completed
• Conditions: Liver Disease
• Intervention / Treatment: Drug: conivaptan hydrochloride

Detailed Description

Subjects will be admitted to the Phase 1 unit Day -2 and will remain confined to the unit until discharge on Study Day 5 after completion of all study procedures.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Anaheim, California, United States, 92801
      • Advanced Clinical Research Institute
  • Colorado
    • Lakewood, Colorado, United States, 80228
      • DaVita Clinical Research
  • Florida
    • Orlando, Florida, United States, 32809
      • Orlando Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Subjects with Normal Hepatic Function:

Female subject must be either:

• post-menopausal prior to Screening, or
• premenarchal prior to Screening, or
• documented surgically sterile or post hysterectomy, or

• if of childbearing potential, must have a negative pregnancy test at Screening and must be using highly effective contraception prior to Screening and throughout the study period and for 28 days after final study drug administration

  • Female subject must not be lactating and must not be breastfeeding at Screening or during the study period, and for 28 days after final study drug administration
  • Female subject must not donate ova starting at Screening or during the study period, and for 28 days after final study drug administration
  • Male subject must:
• be using highly effective contraception consisting of two forms of birth control (one of which must be a barrier method) starting at Screening and continue throughout the study period, and for 28 days after final study drug administration

• not donate sperm starting at Screening and throughout the study period, and for at least 28 days after final study drug administration

  • Subject weighs at least 45 kg and has a body mass index between 18 and 40 kg/m2 inclusive
  • The subject must have clinical laboratory test results within normal range, including liver function tests (LFTs)
  • The subject must have had a normal 12-lead electrocardiogram (ECG)

Hepatic Impaired Subjects:

• Female subject must be either:

  • post-menopausal prior to Screening, or
  • premenarchal prior to Screening, or
  • documented surgically sterile or post hysterectomy, or
  • if of childbearing potential, must have a negative pregnancy test at Screening and must be using highly effective contraception prior to Screening and throughout the study period and for 28 days after final study drug administration
• Female subject must not be lactating and must not be breastfeeding at Screening or during the study period, and for 28 days after final study drug administration
• Female subject must not donate ova starting at Screening or during the study period, and for 28 days after final study drug administration

• Male subject must:

  • be using highly effective contraception consisting of two forms of birth control (one of which must be a barrier method) starting at Screening and continue throughout the study period, and for 28 days after final study drug administration
  • not donate sperm starting at Screening and throughout the study period, and for at least 28 days after final study drug administration
• Subject meets criteria for severe hepatic impairment defined by Child-Pugh method
• Subject weighs at least 45 kg and has a body mass index between 18 and 40 kg/m2 inclusive
• The subject must have clinical laboratory test results within therapeutic range except for hepatic disease
• The subject must have had a normal 12-lead electrocardiogram (ECG)

Exclusion Criteria:

Subjects with Normal Hepatic Function:

• Subject has a history of a clinically significant illness, and associated clinical symptoms, medical condition, or laboratory abnormality within past 3 months that would preclude participation in the study
• Subject has evidence of biliary obstruction or other causes of hepatic impairment
• Subject is known to have hepatitis or is a carrier of hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or is known to be HIV positive or has HIV antibodies
• Subject has an impaired ability to sense thirst
• Subject has serum sodium less than 115mEg/L or greater than 140 mEg/L
• Subject has either a systolic blood pressure (BP) of greater than 140 mmHg or a diastolic BP of less than 56 mmHg
• Subject has taken any prescription or over-the-counter medications except for contraceptives, hormone replacement therapy and occasional acetaminophen, or alternative and complementary medicines within past 14 days
• Subject has a history of carcinoma, except for basal cell or cutaneous squamous cell carcinoma within past 5 years
• Subject drinks greater than 14 units of alcohol per week (Note: one unit = 12 ounces of beer, 4 ounces of wine, or 1 ounce of spirits)
• Subject has a history of substance abuse within past 6 months prior to Screening Visit or the subject tests positive at Screening or clinic admission for alcohol or drugs of abuse
• Subject is currently participating in another clinical trial or has received an investigational medication within past 30 days
• Subject is known to have hypersensitivity to conivaptan or its derivatives
• Subject has had a blood transfusion or donated/lost more than 550ml of blood within past 8 weeks
• Subject is incapable of being compliant with the protocol

Subjects with Hepatic Impairment:

• Subject has a history of a clinically significant illness, and associated clinical symptoms, medical condition, or laboratory abnormality within past 3 months that would preclude participation in the study. Subjects with controlled hypertension may be allowed
• Subject has a condition associated with hepatic disease including; biliary obstruction, or other cause of hepatic impairment not related to parenchymal disorder and/or disease of the liver, fluctuating or rapidly deteriorating hepatic function, biliary liver cirrhosis, history or presence of hepatic encephalopathy greater than Grade 1 within past 3 months or unstable encephalopathy prior to Screening, tense ascites, esophageal/gastric variceal bleeding with past 6 months, server portal hypertension, surgical portal systemic shunt or peritoneal venous shunt, thrombocyte level below 50,000 x 10^9/L and prothrombin time (PT) above 18 seconds
• Subject is hypovolemic or has evidence of orthostatic hypotension
• Subject has an impaired ability to sense thirst
• Subject has serum sodium less than 115mEg/L or greater than 140 mEg/L
• Subject has either a systolic blood pressure (BP) of greater than 140 mmHg or a diastolic BP of less than 56 mmHg
• Subject is known to be HIV positive or has HIV antibodies
• Subject has had a change in dose regimen of medication needed for their underlying medical condition with the past four weeks
• Subject is currently taking a prohibited medication
• Subject drinks greater than 14 units of alcohol per week (Note: one unit equals 12 ounces of beer, 4 ounces of wine, or 1 ounce of spirits)
• Subject has a history of substance abuse within past 6 months prior to Screening Visit or the subject tests positive at Screening or clinic admission for alcohol or drugs of abuse
• Subject is currently participating in another clinical trial or has received an investigational medication with past 30 days
• Subject has had a blood transfusion or donated/lost more than 550ml of blood within past 8 weeks
• Subject is known to have hypersensitivity of conivaptan or its derivatives
• Subject is incapable of being compliant with the protocol

Study Plan

How is the study designed?

Design Details

• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Subjects with normal hepatic function	Drug: conivaptan hydrochloride; Intravenous; Other Names: YM087; Vaprisol
Experimental: Subjects with severe hepatic impairment	Drug: conivaptan hydrochloride; Intravenous; Other Names: YM087; Vaprisol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Assess the effect of severe hepatic impairment on the plasma drug concentration of conivaptan through analysis of blood samples	5 days

Collaborators and Investigators

• Sponsor: Cumberland Pharmaceuticals
• Investigators: Study Director: Art Wheeler, MD, Cumberland Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start: April 1, 2011
• Primary Completion (Actual): February 1, 2014
• Study Completion (Actual): February 1, 2014

Study Registration Dates

• First Submitted: June 8, 2011
• First Submitted That Met QC Criteria: June 8, 2011
• First Posted (Estimate): June 9, 2011

Study Record Updates

• Last Update Posted (Estimate): May 2, 2014
• Last Update Submitted That Met QC Criteria: April 30, 2014
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Liver Disease; Conivaptan; YM087; Protein Binding; Vaprisol
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Antidiuretic Hormone Receptor Antagonists; Conivaptan
• Other Study ID Numbers: 087-CL-099