Hepatic Monitoring for Pazopanib

Postmarketing Hepatic Monitoring for Pazopanib Using Observational Databases

Pazopanib is approved by the FDA and EMA as targeted therapy for the indication of advanced renal cell carcinoma (RCC). Hepatic safety events were observed in the pazopanib pivotal clinical trial and the U.S. pazopanib label information contains a 'black box warning' regarding hepatotoxicity. These clinical observations have prompted GSK to undertake a proactive pharmacovigilance strategy focused on hepatic safety that goes beyond spontaneous reporting of adverse events.

The goals of the study are to assess prescriber compliance with pazopanib label guidelines for liver monitoring among patients with RCC, as well as to quantify and characterize the hepatic safety profile of the product in real-world clinical practice compared to other anti-vascular endothelial growth factor (anti-VEGF) drugs. As part of regulatory commitments, GSK will conduct parallel epidemiologic analyses in different patient populations as represented in multiple databases of electronic medical records. To enhance accrual of data, GSK will conduct this safety surveillance program simultaneously across datasets in order to detect and characterize all cases of liver enzyme elevations in diverse populations of patients receiving pazopanib. Two additional goals of this study are to evaluate the incidence of cases of combinations of liver enzyme elevations indicative of Hy's Law and drug-induced acute liver failure among users of pazopanib compared to users of other anti-VEGF drugs. This research effort will be coordinated by an external coordinating center.

An epidemiologic cohort study design, nested in several databases of electronic medical information, will be employed for the research questions. Following the availability of pazopanib in the relevant medical care system, the study will collect retrospective data at regular intervals over the course of four years among persons exposed to pazopanib and other anti-VEGF agents. Each patient will be characterized based on additional available information in the database (e.g., demographics, concomitant medications). Elevations in liver enzymes will be identified through laboratory data captured in these databases. Potential Hy's Law and acute liver failure cases will be identified through established screening criteria, and screen-positive cases will be reviewed by an adjudication committee of hepatologists for final determination of drug-associated causality.

Study Overview

• Status: Completed
• Conditions: Carcinoma, Renal Cell
• Intervention / Treatment: Drug: Pazopanib use; Drug: Use of sunitinib, bevacizumab, or sorafenib

• Study Type: Observational
• Enrollment (Actual): 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

The study population consists of adult (18+years) new users of pazopanib, sunitinib, bevacizumab, and sorafenib.

Two U.S. healthcare databases and one Dutch-linked medical registry system will contribute de-identified and anonymised data from electronic medical records to the surveillance program.

Description

Inclusion Criteria:

• In the prescriber compliance analysis, all adult (18+ years) new users of pazopanib with an indication of RCC will be eligible for the analysis.
• In the liver enzyme elevation analysis, all adult (18+ years) new users of pazopanib, sunitinib, bevacizumab, and sorafenib in monotherapy for any cancer type who have a baseline liver enzyme value will be eligible for the analysis.
• In the drug-induced liver injury analyses, all adult (18+ years) new users of pazopanib, sunitinib, bevacizumab, and sorafenib with RCC (as defined by ICD-9 codes) will be longitudinally followed up in order to capture occurrences of liver enzyme elevations consistent with Hy's Law and ICD-9 codes indicative of possible ALF to evaluate for drug-induced liver injury.

Exclusion Criteria:

• N/A

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Prescriber compliance group; Adult (18+ years) new users of pazopanib with an indication of RCC evaluated for prescriber compliance	Drug: Pazopanib use; Treatment with pazopanib
Incidence of liver chemistry test (LCT) elevation group; Adult (18+ years) new users of pazopanib, sunitinib, bevacizumab, and sorafenib in monotherapy who have a baseline LCT evaluated for LCT elevations	Drug: Pazopanib use; Treatment with pazopanib; Drug: Use of sunitinib, bevacizumab, or sorafenib; Treatment with any of the three other marketed anti-VEGF drugs: sunitinib, bevacizumab, and sorafenib
Incidence of drug induced liver injury (DILI) cases group; Adult (18+ years) new users of pazopanib, sunitinib, bevacizumab, and sorafenib with RCC (as defined by ICD-9 codes) longitudinally followed up in order to capture occurrences of LCT elevations consistent with Hy's Law to evaluate for drug-induced liver injury	Drug: Pazopanib use; Treatment with pazopanib; Drug: Use of sunitinib, bevacizumab, or sorafenib; Treatment with any of the three other marketed anti-VEGF drugs: sunitinib, bevacizumab, and sorafenib
Incidence of cases of ALF group; Adult (18+ years) new users of pazopanib, sunitinib, bevacizumab, and sorafenib with RCC (as defined by ICD-9 codes) longitudinally followed up in order to capture occurrences of ICD-9 codes indicative of possible ALF to evaluate for drug-induced liver injury	Drug: Pazopanib use; Treatment with pazopanib; Drug: Use of sunitinib, bevacizumab, or sorafenib; Treatment with any of the three other marketed anti-VEGF drugs: sunitinib, bevacizumab, and sorafenib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prescriber compliance with pazopanib label guidelines for liver monitoring	Prescriber compliance with pazopanib label guidelines for liver monitoring	Over four years of treatment with pazopanib
Incidence of liver enzyme elevations including combination liver enzyme elevations suggestive of Hy's Law	Incidence of liver enzyme elevations including combination liver enzyme elevations suggestive of Hy's Law	Over four years of treatment with pazopanib
Incidence of acute liver failure (ALF)	Incidence of ALF	Over four years of treatment with pazopanib

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: October 6, 2011
• First Submitted That Met QC Criteria: October 6, 2011
• First Posted (Estimate): October 10, 2011

Study Record Updates

• Last Update Posted (Estimate): April 21, 2014
• Last Update Submitted That Met QC Criteria: April 17, 2014
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Keywords: epidemiology; pazopanib; hepatic safety; prescriber compliance
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Carcinoma, Renal Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Sorafenib; Sunitinib; Bevacizumab
• Other Study ID Numbers: 114430; WEUKSTV4601 (Other Identifier: GSK)