EMA Pediatric Web Synopsis Protocol A November 2011 Final PFIZER INC.

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1 PFIZER INC. These results are supplied for informational purposes only. Prescribing decisions should be made based on the approved package insert. For publications based on this study, see associated bibliography. PROPRIETARY DRUG NAME /GENERIC DRUG NAME: Vfend /Voriconazole PROTOCOL NO.: A PROTOCOL TITLE: An Historical Control Study of the Efficacy of Standard Therapy in Acute Aspergillosis to Allow Comparison with the Efficacy of Voriconazole in Protocol Study Centres: A total of 30 centres participated in this study, including 11 in the United States (US) of America, 7 in Germany, 3 in each of the United Kingdom and Belgium, 2 in each of Italy, and Spain, and 1 in each of The Netherlands and Switzerland. Study Initiation Date and Primary Completion or Completion Dates: Data were collected retrospectively for the period 01 January 1993 to 31 December Phase of Development: Phase 3 Study Objectives: To identify and collect temporally related retrospective data on the response to antifungal therapy of immunocompromised subjects with definite or probable acute invasive aspergillosis and to employ these data as an historical control group for those subjects who received primary voriconazole therapy in the acute invasive aspergillosis study, Study , and enable comparison of 90-day survival and response to therapy. METHODS Study Design: This was an historical control survey designed to collect, retrospectively, global response and 90-day survival data on immunocompromised subjects who received standard primary therapy for acute invasive aspergillosis between 1993 and the end of 1995, the approximate recruitment period for uncontrolled voriconazole acute aspergillosis in Study To ensure that all subjects had either definite or probable aspergillosis, the baseline for the study was strictly defined by the inclusion/exclusion criteria in Study Some subjects in Study A had received antifungal therapy on suspicion of infection and therefore prior to the study baseline. Data were collected from sites in Europe and the United States and from the European Organisation for Research and Treatment of Cancer (EORTC) database. The data were collected by the investigator/study coordinator for each subject including the following: relevant demography and medical history; site of aspergillosis; baseline data appropriate for a diagnosis of definite or probable disease as determined by the investigator according to criteria used in Study ; information on neutropenia and graft versus host disease; names, doses and durations of therapy with systemic antifungal medication(s); limited Page 1

2 information on concomitant medications and prior antifungal therapies; clinical signs and symptoms attributable to aspergillosis; reasons for any change/discontinuation of antifungal therapy; final subject outcome at end of therapy in terms of antifungal efficacy as assessed by the investigator and survival up to 90 days from study baseline and attribution of death. Data were collected for subjects who had received antifungal agents including amphotericin B including lipid formulations (Ambisome, Amphocil /Amphotec or Abelcet ), 5- flucytosine, and oral itraconazole. The aim was to match 2 historical control subjects to every 1 Study subject. The following recognised prognostic factors were used: Certainty of diagnosis - probable or definite; underlying disease - haematological malignancy, bone marrow transplant (BMT), or other; site of infection - systemic (non-brain), brain, pulmonary, or other. Where there was an excess of 2:1 historical control to voriconazole subjects within a risk factor combination, historical control subjects were ranked on the remaining 2 matching criteria: age category and sex. Age was considered more prognostic than sex and was therefore more important in the matching of tied subjects. Number of Subjects (Planned and Analysed): Data were to be collected on approximately 300 subjects to provide a well-matched control group for the per protocol primary therapy subjects in Study Three hundred and ninety six (396) subjects were screened and a total of 257 subjects (220 non-eortc subjects and 37 EORTC subjects) were assessed as evaluable for efficacy. Diagnosis and Main Criteria for Inclusion: Male or female subjects aged 14 years or above with a diagnosis of definite or probable acute invasive aspergillosis. Study Treatment: Not Applicable. Efficacy Evaluations: A global assessment of efficacy was elicited by the investigator and classified as 1 of 4 possible responses: complete (complete resolution of symptoms and signs of invasive aspergillosis infection), partial (major improvement short of resolution or normalisation of the same parameters, and not requiring other systemic antifungal treatment), stable (survived, but overall condition unchanged or only minimally improved), and failure (deterioration of the same parameters [including subject death or drug withdrawal with evidence of fungal infection still present]). In addition, the presence or absence of clinical signs and symptoms of aspergillosis, details of all positive Aspergillus cultures, histology or microscopy positive for Aspergillus-like hyphae, and a brief summary of major radiological findings due to aspergillosis were recorded. Data on subject survival up to 90 days from study baseline and attribution of death were collected. Safety Evaluations: No safety evaluations were performed in this study. Statistical Methods: For this retrospective, non-comparative survey no formal hypothesis testing was carried out. A Kaplan-Meier plot of subject survival data was produced. The 90-day survival probability estimated from the survival curve was presented together with the Page 2

3 corresponding 95% confidence intervals. The following 4 populations were analysed for this study report: 1) All subjects: included all A subjects; 2) Evaluable subjects: included all subjects who were not significant protocol deviators. This was the primary population for this study report. Two populations were defined by the matching process (see points 3 and 4 below). In Study , primary therapy subjects were defined as those per protocol subjects (subjects were those who satisfied the study s inclusion and exclusion criteria) who had received less than 10 days previous systemic antifungal treatment. However, for the purpose of matching, a second conservative estimate of 5 days or less previous systemic antifungal treatment was also applied to Study per protocol subjects. All of the evaluable A subjects were available to be matched. Criteria used for matching are discussed in the Study Design section above. 3) Matched evaluable control subjects with Study primary therapy ( 5 day definition) subjects: this analysis population was referred to as the best matched 5 day subjects population in the study report tables. 4) Matched evaluable control subjects with protocol primary therapy (<10 day definition) subjects: this analysis population is referred to as the best matched <10 day subjects population in the study report tables. One hundred and fifty (158 [58%]) evaluable subjects were collected from US study centres and all other subjects were collected from European study centres (including 37 subjects taken from the EORTC database). An exploration of the robustness of the primary results in Study A was carried out to check for a region affect (US versus Europe). RESULTS Subject Disposition and Demography: A summary of subjects deemed to be evaluable for matching against the Study subjects is presented in Table 1. Table 1. Demographic Characteristics for the Evaluable Population Male (N=160) Female (N=97) Total (N=257) Age Range (years) 15 to to to 86 Mean Age (years) Weight Range (kg) 44.8 to to to Mean Weight (kg) Race: White Black Asian Other Other: Unspecified Page 3

4 Comparison with the summary of all screened subjects (249 males and 147 females) shows that a similar proportion of males and females were excluded from the evaluable population. These exclusions did not change the overall demographics of the population. Efficacy Results: Outcome of the Matching Process: The protocol specified 2:1 target match of historical control to voriconazole subjects was achieved for subjects in the evaluable, best matched 5 day and best matched <10 day populations for most of the primary risk factor combinations. Several historical control primary risk factor combinations were not required for matching as there were few (or no) equivalent voriconazole subjects. There was an excess of historical control subjects with pulmonary aspergillosis for all primary risk factor combinations, with the exception of those with a haematological malignancy and a definite diagnosis. For this combination, a 2:1 ratio was achieved for subjects in the best matched 5 day population and the ratio was 1.84:1 for subjects in the evaluable and best matched <10 day populations. Due to the small number of cerebral aspergillosis cases, only the primary risk factor combination of other underlying disease, cerebral aspergillosis and definite diagnosis met the target 2:1 ratio. The main area of imbalance was for those subjects with BMT and cerebral aspergillosis. There were no historical control subjects available to match to the single voriconazole subject in the BMT, systemic (non-brain), probable category in any of the analysis populations. Drug Administration: The most commonly used antifungal therapies in Study A were amphotericin B and itraconazole, received by 213 (82.9%) and 116 (45.1%) evaluable subjects, respectively. Fifty six (56 [21.8%]) subjects received a lipid-associated formulation of amphotericin and 43 (16.7%) subjects received 5-flucytosine as antifungal therapy for this episode of aspergillosis. Dosing regimes could involve use of more than one antifungal therapy taken in sequence or combination. The median duration of therapy was 18 days, and the range of treatment duration was from 1 to 175 days. Global Response and Investigator Assessed Response: Of the evaluable subjects, 75 (29.2%) had a satisfactory global response. This included 40 complete responses and 35 partial responses. Of the 70.8% of unsatisfactory global responses, 39 subjects had a stable response and 143 subjects were failures. Subject Survival at 90 Days: 149 (58.0%) evaluable subjects were dead at 90 days. Of the remainder, 86 (33.5%) subjects were alive and 22 (8.6%) subjects were censored at 90 days. The cumulative probability of survival to 90 days was 0.40 (95% confidence interval [CI]: 0.34, 0.46). Seventy two (72) deaths within 90 days of baseline (48.3%) were assessed as being due to aspergillosis and 45 (30.2%) deaths were with aspergillosis. Twelve (12) deaths were unrelated to aspergillosis and the remaining deaths were assessed as indeterminate (19 subjects [12.8%]) or not recorded (1 subject [0.7%]). Neutropenic Status at End of Study: At the end of the study, the number of subjects without neutropenia had increased from 138 [53.7%] subjects at baseline to 162 [63.0%] Page 4

5 subjects at EOT (EOT was defined as the end of the final antifungal treatment for the current episode of aspergillosis. If the subject continued on long term antifungal therapy, EOT was defined as the point at which the investigator considered the therapy to have become prophylactic or maintenance therapy.). The number of subjects with neutropenia had decreased from 97 (37.7%) subjects at baseline to 32 (12.5%) subjects at EOT. The neutropenic status of the remaining subjects was unknown due to missing information. Of the 97 subjects assessed as neutropenic at baseline, only 22 had confirmed neutropenia at the end of the study. Nine non-neutropenic subjects at baseline became neutropenic by EOT. Graft Versus Host Disease at End of Study: At the end of the study, there were 34 (13.2%) subjects with graft versus host disease (GVHD) compared to 28 (10.9%) subjects at baseline. The number of subjects without GVHD at the end of the study had decreased slightly compared to baseline from 185 (72.0%) subjects to 179 (69.6%) subjects. GVHD emerged during the study in 7 subjects who did not have GVHD at baseline. Post-Hoc Analysis of the Effect of Region: Although region was not considered to be prognostic during the design of the historical control study, in the evaluable population there was strong statistical evidence to suggest that subjects from the US had worse survival than subjects from Europe (p=0.0001). The hazard of death in the US subjects was 2.62 times greater than for the European subjects (associated 95% CI: 1.78 to 3.87). A summary of the effect of region on subject survival at 90 days is presented in Table 2. Table 2. The Effect of Region on Subject Survival at 90 Days Country Survival at 90 Days Probability of Survival 95% Confidence Interval for Survival Europe to 0.67 United States to 0.34 A summary of the effect of region on global response is presented in Table 3. There was also a weak statistical evidence of a difference between regions for global response (p=0.08). The odds of a satisfactory global response in the European group were 1.72 times that observed in the US group (associated 95% CI: 0.93 to 3.17). Both analyses were carried out based on models which were stratified for site of infection at baseline, underlying disease, certainty of diagnosis, age and sex. Table 3. Effect of Region on Global Response Country Global Response Satisfactory Unsatisfactory Total N % N % N Europe United States Total Safety Results: This was a retrospective survey and no subject received voriconazole. No adverse event or serious adverse event data were collected in this study. Page 5

6 CONCLUSIONS: This was a retrospective survey of subjects with acute invasive aspergillosis who received primary standard antifungal therapy treatments available between 1993 and The objective of matching historical control subjects with voriconazole subjects was achieved for the majority of the primary risk factor combinations. The primary risk factors used were certainty of diagnosis, underlying disease, and site of infection. Seventy five (75 [29.2%]) subjects in the evaluable population had a satisfactory global response at the end of the study. The largest category of investigator assessed response was a failed response, accounting for 143 (55.6%) subjects. The cumulative probability of survival to 90 days was 0.40 (95% confidence interval: 0.34, 0.46). Eighty six (86 [33.5%]) subjects were alive 90 days after the start of the study (22 [8.6%] subjects) were censored at 90 days). Page 6