A systematic review and economic model of the effectiveness and ...

TABLE 80 Response a rates (%) estimated in the meta-regression submitted by Eli Lilly
treatment strategies are no treatment, with or
without ATX as first-line therapy. For group 3, the
treatment strategies are DEX, followed by no
treatment, with or without ATX prior to DEX.
Model structure
Patients beginning the model on active treatment
could experience a response to that treatment.
Patients responding to treatment could relapse in
subsequent cycles to become non-responders.
Patients on active treatment could also experience
adverse events, which may resolve in subsequent
cycles, or discontinue with treatment. Patients
could discontinue treatment owing to lack of
response, in reaction to an adverse event or for
other reasons. Discontinuation of treatment is
followed by the next treatment in the prespecified
strategy, until the patient reaches no treatment at
the end of the strategy.
The model was estimated using patient-level
simulation, and 20,000 simulations were executed
for each run of the model. The submission states
that the model was used to determine which of the
five subgroups each simulated patient would fall
into, although further details of this process are
not given. Further details of the execution of the
patient-level simulation are not provided. The
time horizon was 1 year, and so discounting was
not relevant.
Summary of effectiveness data
The response rates were calculated from a metaregression
using patient-level data from five
clinical trials 70,89,142 (two of which are currently
unpublished) comparing ATX with MPH, and in
some cases also to placebo. One of the trials
included ER-MPH (unpublished) and the
remaining four included IR-MPH. Four were
randomised double-blind studies and the fifth was
a randomised open-label study. 70 The model
assumes equivalence of IR-MPH and ER-MPH,
and does not differentiate between study types.
Response was defined as ≥ 25% reduction in
parent-rated ADHD-RS score, and was estimated
using a fixed-effects logistic regression with
treatment, stimulant exposure, age, sex and
Health Technology Assessment 2006; Vol. 10: No. 23
Treatment Stimulant-naïve patients (%) Stimulant-exposed patients (%) Overall (%)
ATX 70.51 62.17 65.08
Methylphenidate 77.27 70.03 73.35
Placebo 41.46 32.75 35.85
a Response is defined as ≥ 25% reduction in parent-rated ADHD-RS.
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duration of treatment as covariates. Duration of
treatment refers to the duration of the acute phase
of each trial. An additional study-level covariate
was included to allow differences in baseline
between studies. The results of the logistic
regression are shown in Table 80.
Data on relapse was obtained from two trials, 56,75
both specifically designed to look at relapse to
ATX and amphetamine sulphate, respectively. The
relapse rates over 9 months were approximately
20% for ATX and 30% for amphetamine sulphate,
compared with placebo rates of 40 and 70%,
respectively. The submission states that owing to
differences in the definition of response and
relapse used in the two trials, and the absence of
data regarding MPH, they deem the evidence
insufficient for differentiating between the
alternative treatments. Hence the probability of
relapse is the same for all active treatments.
The probability of response to treatment in
patients who have failed MPH was taken from a
crossover trial of IR-MPH and DEX 143 where
67.74% of a subgroup of patients who failed to
respond to first-line therapy with MPH
subsequently responded to DEX. The definition of
response in the study was a ≥10-point reduction in
the hyperactivity subscale of the revised CPRS. The
model assumes that the response to ATX in
patients who have failed MPH will be equal to
that with DEX. The submission does not report the
response rate to DEX in patients who have
not failed on MPH. The relative risk of response
for placebo compared with ATX calculated in the
meta-regression was applied to the rate of response
in MPH-failed patients receiving DEX to calculate
the response rate for no treatment. In patients
contraindicated for stimulants, the response rate
for ATX was taken from a clinical trial whose
inclusion criteria included the presence of tics
disorder or Tourette syndrome (unpublished – no
further information provided in submission). The
response rate to ATX is reported to be 66.67% in
this co-diagnosed population. Table 81 shows the
response and relapse rates used for each subgroup
examined in the model.
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