Australian public assessment for Ibuprofen - Therapeutic Goods ...

Analysis populations
AusPAR Caldolor Ibuprofen Phebra Pty Ltd PM-2010-02393-3-1
Final 2 January 2013
Therapeutic Goods Administration
The Safety Analysis Population (SAP) comprised all randomised patients who received at
least one dose of study medication.
The Intention-To-Treat (ITT) population included all patients from the safety population
who had a baseline assessment and at least one post-baseline evaluation of the primary
endpoint.
The Efficacy-Evaluable Population (EEP) at Hour 4 included all patients from the ITT
population who had not received any excluded concomitant medication within the 4 h
prior to first administration. The EEP at Hour 24 included all patients who had received at
least 5 doses of study medication with no excluded concomitant medication(s) within the
24-h treatment period.
Statistical tests
All statistical tests were two-sided, with p-values less than 0.05 for treatment differences
and less than 0.10 for interaction effects considered significant.
The principle analyses were performed in the ITT population and supportive analyses
were performed in the EEP. These efficacy analyses were to be performed without regard
to illness severity stratum (critically ill or not critically ill at the time of randomisation) but
the protocol also provided for optional analyses to be performed separately on each illness
stratum. These were not available in the main study report but were provided in the
Integrated Summary of Efficacy (ISE). Additional analyses requested by the FDA were also
included in the submission.
Missing values were imputed using the last-observation-carried-forward (LOCF) method.
For patients declared as treatment failures and for patients who received corticosteroids
or rescue treatment, temperature measurements subsequent to treatment with any
corticosteroid or rescue treatment were substituted with the mean of the treatment group
temperature for that corresponding time point. Linear interpolation was used to estimate
the time to afebrility when a patient’s temperature was above 101.0°F at one time point
and below 101.0°F at the next time point.
The use of a critical p-value of 0.05 for the between-treatment comparison of the primary
efficacy outcome is acceptable. Although there were 3 Caldolor dose groups (and thus 3
potential comparisons with placebo) multiplicity was avoided by using only one of these
(the 400 mg versus placebo comparison) as the primary outcome. As discussed later,
however, this approach has implications for the sponsor’s proposal that the 200 mg dose
should also be approved.
Participant flow
The report did not state the number of prospective participants who were screened. A
total of 123 patients were randomised and progressed as follows:
• SAP: 120 patients received study medication and were included in the SAP. The 3
patients who did not receive study medication were discontinued prior to dosing due
to poor venous access (n=1) or temperature drop to