1. J OURNAL C LUB : T HE R ANDOMIZED C ONTROLLED T RIAL July 10 th, 2008 Rakhi Naik, MD

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

3. S TUDY O UTLINE 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. B ACKGROUND 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. B ACKGROUND 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. M ETHODS 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 o Exclusion criteria: Pregnancy History of thrombosis HIV co-infection Hepatitis B co-infection

7. M ETHODS Patients randomly assigned to placebo or eltrombopag (30mg, 50mg, 75mg daily) x 4 weeks 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. Study designed by GlaxoSmithKline & academic principal investigator. Daily eltrombopag doses were held if platelet count rose >200,000 and would be resumed when counts dropped to around 100,000

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

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

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

11. C ONCLUSIONS / I MPLICATIONS 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. S TRENGTHS 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).