Australian public assessment for Ibuprofen - Therapeutic Goods ...

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AusPAR Caldolor Ibuprofen Phebra Pty Ltd PM-2010-02393-3-1 Final 2 January 2013 Therapeutic Goods Administration Consumption of rescue medication (in this case morphine) and area under the painintensity versus time curve are standard efficacy outcomes in pain studies and consistent with the relevant TGA-adopted guideline 16. The VAS is a standard method of assessing pain. The length of time over which the primary outcomes were assessed is consistent with an acute pain indication. Sample size CPI-CL-008A was conducted first, to determine the most appropriate dose of Caldolor for the treatment of post-operative pain. Initially, 225 patients were to be randomised to placebo, 400 mg Caldolor q6h, or 800 mg Caldolor q6 h. After approximately 75% of these (168 patients) had completed the study, an analysis of variance was conducted without breaking the blind and without dividing the information by groups. An independent statistician responsible for running this analysis recommended that the sample size be increased to provide a total EEP of not less than 360. A total of 406 participants were actually randomised, leading to an EEP of 342. Based on the results of CPI-CL-008A, CPI-CL-008B used only the Caldolor 800 mg q6h regimen and was planned to include 145 patients per group in the EEP (290 total) with the expectation of providing 90% power to detect a 20% reduction in morphine use in the Caldolor group compared to placebo, at a significance level of 0.05. Based on the results of CPI-CL-008A, CPI-CL-008C had a planned sample size of 67 per group, which was expected to provide 90% power to detect a 20% reduction in pain-AUC with movement in the Caldolor group compared to placebo, at a significance level of 0.05. Randomisation and blinding methods Randomisation in the pivotal studies was by means of sealed envelopes containing treatment assignments that were prepared centrally and provided to each study site pharmacy. Randomisation to the treatment groups in each study was on a 1:1 basis. Randomisation was stratified by weight (≤75 kg and >75 kg) and age (≤45 years and >45 to 70 years in CPI-CL-008A and B; ≤45 years and >45 to 80 years in 008C). All three studies were double-blind. As in the fever studies, the pharmacists who prepared the study medication were aware of the treatment allocation but were instructed to puncture the additive port of the placebo normal saline bags to maintain the double blind for patients, investigators and nursing staff. Analysis populations In CPI-CL-008A and B, analyses were performed in the following populations: • ITT population: All randomised patients who received at least a partial dose of study medication. • EEP: Patients from the ITT population who received the first 4 doses of study medication within ± 60 minutes of the scheduled time. • Abdominal hysterectomy (AH) population (CPI-CL-008A): Women from the EEP who underwent abdominal hysterectomy. In CPI-CL-008C, analyses were performed in the following populations: • All-treated (AT) population: All randomised patients who received at least one dose of study medication. • ITT population: Patients from the AT population who received at least one postsurgical dose of study medication or at least one dose of morphine for break-through pain. Page 46 of 118
AusPAR Caldolor Ibuprofen Phebra Pty Ltd PM-2010-02393-3-1 Final 2 January 2013 Therapeutic Goods Administration • EEP: Patients from the ITT population who received the first 4 doses of study medication within ± 60 minutes of the scheduled time and who had the 6-h and 24-h VAS pain on movement assessments. In CPI-CL-008C, the first dose of study treatment was given intraoperatively, so the AT population corresponds to the conventional definition of the ITT population or Full Analysis Set. However, the primary efficacy assessment was conducted during the 22-h period after the first scheduled post-operative dose of study medication, so the ITT population includes all of the patients who were eligible to be assessed for the primary efficacy outcome. Statistical methods In CPI-CL-008A and B, the primary efficacy outcome was analysed in the ITT population, the EEP and (for 008A) in the AH population. Secondary efficacy outcomes were analysed in the ITT and EEP populations. Analyses were performed without regard for stratification at the time of randomisation. In CPI-CL-008C, the primary and secondary efficacy outcomes were analysed in the AT population, the ITT population and the EEP. The statistical methods used to analyse each efficacy outcome were summarised in the study report. As previously noted, CPI-CL-008A was conducted first, to determine the optimal dose of Caldolor for the management of post-operative pain. Dose selection for subsequent studies was to be based on a significance level of p ≤0.05 when comparing each Caldolor dose level to placebo and p ≤0.10 when comparing the two Caldolor dose levels, as follows: • If efficacy was demonstrated for the primary outcome when Caldolor was compared to placebo (p ≤0.05) but no statistically significant difference was seen between the 400 mg and 800 mg dose levels (p>0.10), the lower dose of 400 mg was to be selected for subsequent studies. • If significant safety concerns were evident with the 800 mg dose and not observed with the 400 mg dose, the 400 mg dose could be selected for subsequent studies even if the 800 mg dose was shown to be more efficacious than the 400 mg dose (p ≤0.10). The prespecified statistical tests were appropriate. The ITT analyses from CPI-CL-008A and B and the AP and ITT analyses from CPI-CL-008C are the most relevant for assessing the efficacy of Caldolor. Results from the EEP and AH populations exclude patients whose study medication was given outside the specified time window and are likely to overestimate the efficacy of Caldolor in actual clinical practice. Participant flow Table 13 shows the number of patients who were enrolled, randomised, included in the various analysis populations and completed the three pain studies. The number of potential patients who were screened for the three studies was not reported. Page 47 of 118
Page 1 and 2: Australian Public Assessment Report
Page 3 and 4: Contents AusPAR Caldolor Ibuprofen
Page 5 and 6: AusPAR Caldolor Ibuprofen Phebra Pt
Page 11 and 12: Carcinogenicity AusPAR Caldolor Ibu
Page 13 and 14: Nonclinical summary and conclusions
Page 31 and 32: Time to afebrility (temp
Page 39 and 40: Table 12. CPI-CL-006: Patient dispo
Page 41 and 42: Other efficacy studies IND 32803 Au
Page 45: AusPAR Caldolor Ibuprofen Phebra Pt
Page 49 and 50: Baseline data AusPAR Caldolor Ibupr
Page 57 and 58: Dose-response and non-pivotal effic
Page 59 and 60: Combined indications AusPAR Caldolo
Page 79 and 80: continued next page AusPAR Caldolor
Page 85 and 86: IVIb = Caldolor. AusPAR Caldolor Ib
Page 89 and 90: Table 37. IND 32803 (Sepsis syndrom
Page 95 and 96: Pivotal studies AusPAR Caldolor Ibu
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AusPAR Caldolor Ibuprofen Phebra Pt
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Pharmacovigilance plan AusPAR Caldo
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Table 44. Other efficacy outcomes.
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Caldolor is indicated for the reduc
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