Journal Club: The Randomized Controlled Trial

1. Journal Club: The Randomized Controlled Trial July 10th, 2008 Rakhi Naik, MD

2. The Article Eltrombopag for Thrombocytopenia in Patients with Cirrhosis Associated with Hepatitis C McHutchinson JG, et al. New England Journal of Medicine November 29th, 2007

3. Study Outline • Hypothesis: Eltrombopag can increase platelet counts in patient with hepatitis C cirrhosis. • Design: Randomized controlled trial • Setting: Multicenter trial in US & Europe • Participants: 74 patients w/Hepatitis C cirrhosis • Data Collection: Measurement of platelet counts before and after eltrombopag administration for 4 weeks; measurement of platelet counts after standard hepatitis C treatment with peg-interferon/ribavirin • Outcome: Platelet counts, safety

4. Background • Chronic liver disease secondary to hepatitis C cirrhosis is often associated with significant thrombocytopenia. • Thrombocytopenia in chronic hepatitis C infection is multifactorial in origin & is thought to be caused by: • splenic sequestration (2/2 portal hypertension/hypersplenism) • decreased thrombopoetin production (2/2 impaired hepatic synthetic function) • bone marrow suppression (2/2 direct toxic effect of the hepatitis virus itself). • Platelet counts below 75,000 are often not eligible for treatment with pegylated interferon & ribavirin because treatment itself leads to cytopenias in almost 100% of cases.

5. Background • Eltrombopag is an oral thrombopoetin receptor agonist that increases megakaryocyte proliferation and differentiation in animal models. • Research questions: • Can eltrombopag increase platelet levels in patients with untreated chronic hepatitis C cirrhosis? • Can continued use of eltrombopag during hepatitis C treatment reduce treatment-related thrombocytopenia? • What dose of eltrombopag is most effective for achieving these goals?

6. Methods • 22 centers in the United States & Europe were involved in recruitment. • Inclusion criteria: • 18 years of age or older • Presence of serum HCV antibody levels • Detectable serum HCV RNA levels • Compensated liver disease (which is not defined explicitly) • Thrombocytopenia with platelet levels between 20,000-70,000. • Evidence of cirrhosis defined as: liver biopsy c/w cirrhosis, radiographic evidence of cirrhosis, or endoscopic evidence of varices • Exclusion criteria: • Pregnancy • History of thrombosis • HIV co-infection • Hepatitis B co-infection

7. Methods Study designed by GlaxoSmithKline & academic principal investigator. Patients randomly assigned to placebo or eltrombopag (30mg, 50mg, 75mg daily) x 4 weeks Daily eltrombopag doses were held if platelet count rose >200,000 and would be resumed when counts dropped to around 100,000 Any patient with plt count >70k or >100k was eligible for treatment with peg-interferon α-2a or peg-interferon α-2b, respectively. The decision to treat was left to the physician & patient. Patients continued with their previous dose of eltrombopag during treatment.

8. Results Uneven number of patients in each arm because this was a mulicenter trial & not all sites contributed to all 4 arms. 5 of total 74 patient listed here were excluded for baseline plt counts >75k but were ultimately eligible for the treatment phase. Approximate bilirubin (converted) 1.5+/- 1mg/dL. INR and creatinine not reported.

9. RESULTS Median platelet values prior to inferon treatment and % responders had significant p values compared to placebo Only 18 patients completed treatment. Only 1 placebo patient completed tx even though 7 were eligible.

10. RESULTS Platelet levels decreased with hep C treatment in all arms. P values for the eltrombopag groups vs. placebo were not statistically significant. Pre-treatment platelet values, especially in the 50mg and 75mg eltrombopag arms, were statistically significant. More patients in the eltrombopag arms completed treatment.

11. Conclusions/Implications • Eltrombopag increases platelet counts in a dose-dependent manner in patients with untreated chronic hepatitis C cirrhosis. • Eltrombopag can be used to boost platelet counts in patients being considered for peg-interferon & ribavirin treatment.

12. Strengths • Clinical relevance: Thrombocytopenia is a very common complication of hepatitis C infection and ineligibility for treatment is a significant public health concern. • Efficacy: Eltrombopag is extremely effective in increasing pre-interferon platelet counts (i.e. the study was able to demonstrate efficacy even though the sample size was low). • Ease of use: Eltrombopag can be taken orally and has an easy daily dosing schedule. • Safety: Eltrombopag has minimal side effects, which do not seem to be dose-dependent, and are not associated with significant morbidity.

13. WEAKNESSES • Small sample size, especially in interferon treatment group (underpowered) • Failed to standardize the protocol for initiation and cessation of interferon treatment phase. • Lack of generalizability • The investigators may have referred only patients with cirrhosis without portal hypertension to the study in order to select for a group who was more likely to benefit from treatment. • Similarly, HCV viral loads were not taken into account. • ? Clinical utility • Could not ultimately answer question of whether pre-treatment with eltrombopag resulted in successful clearance of hepatitis C with treatment (i.e. whether the fact that more patients can receive interferon treatment actually leads to more patients who benefit from treatment).