JOURNAL CLUB:
THE RANDOMIZED CONTROLLED TRIAL
July 10th, 2008
Rakhi Naik, MD
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
STUDY OUTLINE
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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 peginterferon/ribavirin
Outcome: Platelet counts, safety
BACKGROUND
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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).
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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.
BACKGROUND
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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?
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METHODS
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22 centers in the United States
& Europe were involved in
recruitment.
Inclusion criteria:
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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
oExclusion criteria:
•Pregnancy
•History of thrombosis
•HIV co-infection
•Hepatitis B co-infection
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 peginterferon α-2a or peginterferon α-2b, respectively.
The decision to treat was
left to the physician &
patient.
Patients continued with
their previous dose of
eltrombopag during
treatment.
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.
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.
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.
CONCLUSIONS/
IMPLICATIONS
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Eltrombopag increases platelet counts in a dosedependent 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.
STRENGTHS
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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 preinterferon 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.
WEAKNESSES
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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.
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? Clinical utility
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Could not ultimately answer question of whether pretreatment 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).