A systematic review of the effectiveness of adalimumab

European Etanercept Investigators Study:
Wajdula and colleagues, 2000 126
This double-blind, multicentre RCT compared four
etanercept treatment regimens (10 mg s.c. once
weekly, 10 mg twice weekly, 25 mg once weekly,
25 mg twice weekly) with placebo. This study was
planned to run for 6 months, but the protocol was
modified to a 3-month double-blind study after
inception for reasons that were unclear. Patients
with at least six swollen joints and 12 tender joints,
and who had failed to respond to at least one
DMARD, were recruited. The primary efficacy endpoints
were change from baseline in the number of
swollen and painful joints at 3 months.
ERA: Bathon and colleagues, 2000; 123 Genovese
and colleagues, 2002 124
This multicentre RCT compared etanercept 10 mg
s.c. twice weekly or 25 mg s.c. twice weekly with
methotrexate. There was a 12-month double-blind
phase and a further 12-month open-label phase.
Results at 2 years were provided by the
manufacturer and are referred to as the end of
study results in this review unless otherwise
specified. Recruited patients had RA for less than
3 years, at least ten swollen joints and 12 tender
joints, and were positive for rheumatoid factor or
had at least three bony erosions on radiographs of
hands, feet and wrists. Patients who had previously
been treated with methotrexate were not eligible.
Patients on other DMARDs at recruitment had a
4-week washout before entry. Fifty-nine per cent of
patients had never received a DMARD.
The primary clinical end-point was ACR-N area
under the curve (AUC) during the first 6 months,
and the primary radiological end-point was the
change in modified Sharp scores over 12 months.
This trial was originally designed to show the
superiority of etanercept over methotrexate in
preventing joint damage. However, this goal was
changed to that of showing equivalence of
etanercept and methotrexate.
TEMPO: Klareskog and colleagues, 2004; 127
van der Heijde and colleagues, 2005 128 2006 110
This multicentre trial consisted of two periods.
Period one was a 52-week double-blind RCT,
followed by a double-blind extension of variable
duration during which patients remained on
randomised treatment. Two-year results were
provided by the manufacturer and are referred to
as the end of study results unless otherwise
specified. TEMPO compared methotrexate alone
(7.5 mg per week escalated to 20 mg per week if
any tender or swollen joints remained), etanercept
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Health Technology Assessment 2006; Vol. 10: No. 42
alone (25 mg s.c. twice weekly), and a combination
of the two. RA patients who had previously
received methotrexate were allowed to enter (at
the discretion of the investigator) provided that
methotrexate had not been used within 6 months
of study entry, had not been discontinued for lack
of efficacy and had not caused toxicity.
Patients with disease durations between 6 months
and 20 years who had failed at least one DMARD
other than methotrexate were recruited. At least
ten swollen joints and 12 tender joints were
required. The primary clinical end-point was the
24-week AUC of the ACR-N. The 52-week change
from baseline in van der Heijde modified total
Sharp score was a conditional primary end-point.
TEMPO appears to be the only trial in established
RA (not early RA) that genuinely compares a
conventional DMARD with a TNF inhibitor.
However, around 42% of patients in each arm of
this trial had previously tried methotrexate. It is
not at all clear why these individuals discontinued
methotrexate in the face of active disease if, as
stated in the entry criteria, the drug was not
ineffective or toxic.
Codreanu and colleagues, 2003 103
The study was only published as an abstract at the
time of review, but a clinical study report was
made available to the authors. This multicentre
trial consisted of two periods. Period one was a 24week
double-blind RCT, which was followed by a
double-blind extension with patients participating
between 60 to 100 weeks. The 24-week results
were provided by the manufacturer and are
referred to as the end of study results. The trial
compared sulfasalazine alone (2–3 g per day),
etanercept alone (25 mg s.c. twice weekly) and the
combination of both in RA patients who were not
adequately controlled while having received
sulfasalazine for at least 4 months. The addition of
other DMARDs was not permitted during the
study. Patients with disease duration less than 20
years, with at least six swollen joints and ten
tender joints were recruited. The primary endpoint
was ACR20 response at 24 weeks.
Lan and colleagues, 2004 130
This single-centre, 12-week RCT compared
etanercept (25 mg s.c. twice weekly) and placebo
in patients who had been receiving stable doses
(12.5–20 mg per week) of methotrexate for at least
4 weeks. Patients with duration of RA longer than
1 year, with at least six swollen joints and six
tender joints despite methotrexate treatment were
recruited. The baseline HAQ score of the patients
in this trial (average 1.1) was better than in other
37