EMA Pediatric Web Synopsis Protocol 150-304 29 November

EMA Pediatric Web SynopsisProtocol 150-304 29 November 2011 Final

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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.: 150-304

PROTOCOL TITLE: An Open, Multicentre, Dose Escalating Study of the Efficacy, Safety and Toleration of UK-109,496 (Voriconazole) in the Treatment of Acute Invasive Aspergillosis

Study Centres: A total of 34 centres participated in the study: 12 in Germany, 6 in each of the United Kingdom and France, 4 in each of Italy and Spain, and 1 each in The Netherlands and Belgium.

Study Initiation Date and Primary Completion or Completion Dates: 18 January 1994 to 23 July 1996

Phase of Development: Phase 2

Study Objectives: To assess the efficacy, safety and toleration of voriconazole in the treatment of acute invasive aspergillosis. Correlation of voriconazole plasma concentration data with efficacy and safety results was to be addressed separately in a pharmacokinetic/pharmacodynamic report.

METHODS

Study Design: This was an open, uncontrolled, multicentre study of voriconazole. Subjects with acute invasive aspergillosis who completed the screening and baseline assessments and fulfilled the inclusion and exclusion criteria were entered into the study. Initially subjects were to be given intravenous (iv) infusions of voriconazole for a maximum of 28 days followed by dosing with oral voriconazole. The duration of treatment was to be a minimum of 4 weeks to a maximum of 24 weeks, depending on the response of the subject. Individual subjects exhibiting incomplete clinical and/or radiological response could have their treatment duration extended beyond 24 weeks if their condition warranted it. Although originally intended as a formal dose escalation study, the results of an interim analysis lead to a protocol amendment that allowed subjects to have their dose increased if their response was sub-optimal, plasma levels of voriconazole were below what was deemed clinically acceptable, and there were no safety concerns.

Efficacy was assessed at Week 1, 2, 3, 4, 8, 12, 16, 20, 24, and at end of therapy (EOT) and at 4 weeks and 12 weeks after EOT to assess efficacy at a suitable interval after voriconazole had been cleared from the body. If the subject was hospitalised, additional assessments were 09

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made at Week 6 and Week 10. Laboratory safety data and adverse events (AEs) were collected at Weeks 1, 2, 3, 4, 8, 12, 16, 20, 24, EOT, and at 4 weeks and 12 weeks after EOT.

EOT was planned to be at Week 24, however some subjects ended therapy before or after this point. If EOT was before Week 24, then visits were not made at subsequent weeks apart from for the follow-up assessments. If the duration of therapy was extended beyond 24 weeks then a Week 24 assessment was made and additional visits were conducted every four weeks until EOT and at follow-up Week 4 and Week 12.

Number of Subjects (Planned and Analysed): A target of 120 subjects was planned to enroll in the study. A total of 141 subjects were screened and 137 subjects were entered inthe study. Of these, 137 subjects were analysed for efficacy (intention to treat [ITT]), 101 subjects were analysed for clinical response (per protocol [PP]), 112 subjects were analysed for clinical response (expert evaluable), 137 subjects were analysed for safety(AEs), and 118 subjects were analysed for safety laboratory tests.

Diagnosis and Main Criteria for Inclusion: Male or female inpatients aged 1475 years either with a diagnosis of definite or probable acute invasive aspergillosis (primary subjects) or with definite acute invasive aspergillosis who had not responded to an adequate course of other anti-fungal therapy or were unable to tolerate previous anti-fungal therapy (eg iv amphotericin B) (salvage subjects).

Study Treatment: Oral voriconazole: 50 mg or 100 mg white hard gelatine capsules;iv voriconazole: 10 mL, 20 mL, 45 mL, or 50 mL ampoules containing 10 mg/mL aqueoussolution. The dosing and duration of voriconazole was as follows: iv dosing on Day 1 every 12 hours at 6 mg/kg body weight and from Day 2 to a maximum of Day 28 at 3 mg/kg body weight. After iv therapy, oral dosing at 200 mg twice a day (bid) (100 mg bid for subjects <40kg). The maximum duration of treatment was intended to be 24 weeks (iv + oral), but subjects could continue treatment if necessary in this study or to treatment on a named patient basis. Interim analysis conducted on the first evaluable cohort of subjects (10 subjects) enrolled into the study revealed a clinical response rate of 70%, resulting in a protocol amendment that allowed dose escalation on an individual basis.

Efficacy Evaluations: Plasma concentrations of voriconazole were to be measured at Weeks 1, 2, 4, 8, 12, 24, EOT and 4 weeks after EOT.1 Investigator assessments: clinical response was assessed at Weeks 1, 2, 3, 4, 8, 12, 16, 20, 24, end of treatment (EOT; the primary efficacy endpoint), follow-up Week 4 and follow-up Week 12 on a four point scale. Additional assessments were made at Weeks 6 and 10 if the subject was hospitalised. The investigator’s other efficacy assessment was mycological response. Survival analysis at 30, 60, and 90 days of treatment was assessed by the sponsor. Efficacy at EOT was also assessed by the presence or absence of neutropenia and by the site of infection at baseline. The Expert assessed efficacy as global response at EOT, and this was split according to underlying disease, site of infection, and certainty of diagnosis. Two additional experts assessed clinical response for a subset of the study population and their assessments were

1 Results are presented in a separate report.

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compared by the sponsor’s clinical team with the first expert. Efficacy was also assessed according to the investigator, sponsor, and Expert’s definition of primary/salvage therapy.

Safety Evaluations: Laboratory safety test data and AEs were collected at Weeks 1, 2, 3, 4, 8, 12, 16, 20, 24, EOT, and at follow-up 4 weeks and 12 weeks after EOT. If the duration of therapy was extended beyond 24 weeks then additional tests were conducted every 4 weeks until EOT and at follow-up Week 4 and Week 12.

Statistical Methods: As this was a non-comparative study no formal hypothesis tests were carried out. Kaplan-Meier plots were produced for the subject survival data. The exact 95% confidence intervals were calculated using the mathematical link between the binomial distribution and the F distribution.

The ITT population includes all subjects who received at least one dose of study treatment.

The PP population includes all subjects who: 1) Had a definite or probable diagnosis of acute aspergillosis (primary subjects) or a definite diagnosis of acute aspergillosis (salvage subjects) as assessed by the Expert; 2) Satisfied the inclusion criterion as described above. After agreement with the clinical team, the 1 subject aged 13 years old at entry into the study (thus violating this inclusion criterion) was included in the PP population; 3) Satisfied the following exclusion criterion: Subjects were excluded if they had aspergilloma or allergic bronchopulmonary aspergillosis without evidence of invasive infection; 4) Did not take concomitant systemic anti-fungal therapy between the baseline and the EOT assessment; 5) According to clinical review had adequate plasma concentrations of voriconazole; 6) Had an EOT Clinical Response assessment made within 2 weeks of the end of voriconazole treatment; 7) Did not take rifamycin for more than 3 days in total (within 14 days prior to the start of treatment) or barbiturates (known to be metabolised predominantly by hepatic cytochrome P450 enzymes or which induce or inhibit the same enzyme system) during treatment; 8) Had not reported severe vomiting, nausea or diarrhoea during the treatment period.

The Expert evaluable population includes all subjects who satisfied the ITT criterion plus the following criteria: 1) Subjects who had a definite or probable diagnosis of acute aspergillosis as assessed by the Expert; 2) Subjects who had not taken any prohibited concomitant anti-fungals from baseline until the EOT assessment, as defined by the sponsor; 3) Subjects who had not taken any other medications which may affect efficacy, as defined by the sponsor.

RESULTS

Subject Disposition and Demography: Of the 137 subjects who entered the study and received study drug, 33 (24.1%) subjects completed the study and 104 (75.9%) subjects discontinued. The majority of discontinuations were due to deaths and AEs, as may be expected in such a seriously ill population.

A summary of the demographic characteristics for the ITT population is presented in Table 1. A similar number of male and female subjects entered the study and their demographic characteristics were comparable.

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Table 1. A Summary of Demographic Characteristics for the Population

ITT PopulationMale

(N=77)Female(N=60)

Total(N=137)

Age range (years) 1874 1375a 1375Mean age (years) 46.5 43.8 45.3Weight range (kg) 4597 3890 3897Mean weight (kg) 69.7 58.8 64.9Race: White 76 58 134

Black 0 1 1Other 1 1 2

ITT=intention-to-treat; N=number of subjects. a One subject violated an inclusion criterion by being 13 years old at entry into the study.

Exposure to Study Drug: The median duration of treatment (ie the actual number of days on which a subject received at least 1 dose of study drug) was 44 days (range = 1 to 246 days).

Efficacy Results

Clinical Response at End of Therapy (Primary Efficacy Endpoint): The clinical response at the EOT is summarised in Table 2. In the ITT population, 74 (54.0%) subjects were assessed as having a satisfactory response (complete or partial response) at EOT. The proportion of subjects with a satisfactory response was 0.540 (95% confidence interval = 0.453 to 0.626). The clinical response at EOT was similar in the ITT and PP populations.

Table 2. Clinical Response at the End of Therapy in the ITT and PP Populations

ITT Population PP PopulationClinical Response

Number (%) Subjects Number (%) Subjects

Complete 49 (35.8) 37 (36.6)Partial 25 (18.2) 17 (16.8)Stable 28 (20.4) 22 (21.8)Failure 33 (24.1) 24 (23.8)a

No Evaluable Data 2 (1.5) 1 (1.0)ITT=intention-to-treat; PP=per protocol.a Three subjects who entered the study did not have any on treatment clinical response due to their sudden deaths. Their end of therapy clinical responses were therefore set to ‘failure’ in the PP analyses.

Clinical Responses at Follow-Up: The clinical responses at follow-up Week 4 and Week 12 are summarised against the clinical responses at EOT for the ITT and PP populations in Table 3. There were 65 subjects in the ITT population who remained in the study long enough to receive the Week 4 follow-up evaluation and 8 of these subjects (12.3%) had relapsed. By the Week 12 follow-up, there were 53 subjects in the ITT population remaining in the study and a small number of these had relapsed (3 of 53; 5.7%). There was a verysimilar clinical response in the PP populations at follow-up Week 4 and Week 12. Although the number of subjects involved was small, a very small number of complete and partial responders relapsed. In the ITT population, 4 stable subjects and 1 failure subject relapsed at Week 4.

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Table 3. Clinical Response at Follow-Up by Clinical Response at EOT

Clinical Response at EOTaClinical Response at Follow-Up Complete Partial Stable FailureITT Population

Relapse Week 4 follow-up

2/39 (5.1%) 1/11 (9.1%) 4/10 (40.0%) 1/5 (20.0%)


2/36 (5.6%) 1/10 (10.0%) 0/4 0/3

PP PopulationRelapse Week 4

follow-up1/30 (3.3%) 1/9 (11.1%) 4/7 (57.1%) 0/3


2/28 (7.1%) 1/8 (12.5%) 0/3 0/3

EOT=end of therapy; ITT=intention-to-treat; PP=per protocol.a Percentages refer to the percentage of subjects with that clinical response at EOT, not to the total population.

Note (1): subjects were not included in the post-hoc analysis if they had either completed treatment or had been discontinued from the study. Thus, at the Week 4 follow-up there were 65 subjects remaining in the study and by Week 12 this number had fallen to 53.

Note (2): a relapse was defined as being a worsening in the symptoms and signs of aspergillosis, so that a subject classified as ‘failure’ at EOT could still be counted as relapsing at follow-up.

Clinical Response by Primary/Salvage Therapy:

From baseline to EOT: In the ITT population there were 93 primary therapy subjects (subjects who had received less than 10 days of previous systemic anti-fungals at a therapeutic dose), 39 salvage therapy subjects and 5 unclassified subjects. The 5 unclassified subjects were not given any classification as primary or salvage therapy subjects by the investigator. However, after clinical review of the data over the whole of the study by the sponsor and Expert they were subsequently classified as being 3 primary subjects and 2 salvage subjects.

At Week 4, 48 primary therapy subjects (51.6% of this population) and 15 salvage therapy subjects (38.5% of this population) had a satisfactory response. The superior response of primary subjects was maintained at Week 12 although at this time point more than 60% of the subjects had no evaluable data. By EOT, 55 primary subjects (59.1%) had had a satisfactory response compared with 16 salvage subjects (41.0%). It must be noted that there were more ‘no evaluable’ salvage subjects at Week 4, Week 12, and EOT. Similar results were seen in the PP population, where there were 76 primary therapy subjects, 21 salvage therapy subjects, and 4 unclassified subjects.

Note (1): EOT did not occur at the same time for all subjects. EOT was planned to occur at Week 24, but for many subjects their EOT occurred before or after this time point.

Note (2): Two subjects withdrew from the study prior to their Week 4 visit but had clinical responses within the Week 4 window; these subjects were therefore included in the Week 4 analysis.

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Note (3): After review of the data by the Expert and sponsor, it was found that some subjects that had been classified by the investigator as ‘primary’ with a probable diagnosis of aspergillosis were in fact ‘salvage’ subjects. These subjects were reallocated to the salvage group for the sponsor and Expert analyses.

From EOT to Follow-up Week 12: The incidence of relapse for primary and salvage subjects (where known) at Week 4 and Week 12 for the ITT and PP populations, is shown in Table 4.

Table 4. Incidence of Relapse for Primary and Salvage Subjects at Week 4 and Week 12 for the ITT and PP Populations

Number (%) of Subjects who RelapsedType of TherapyWeek 4 Follow-up Week 12 Follow-up

ITT PopulationPrimary 6 (11.5) 3 (6.7)Salvage 1 (10.0) 0Not classified 1 (33.3) 0

PP PopulationPrimary 4 (9.8) 3 (8.3)Salvage 1 (20.0) 0Not classified 1 (33.3) 0

ITT=intention- to-treat; PP=per protocol.

There were 3 subjects in the ITT population at Week 4 who could not be classified as being primary or salvage therapy subjects. One subject had improved, 1 subject had no change and 1 subject experienced a relapse. At Week 12, there were 2 unclassified subjects remaining in the study and both were assessed as having no change in their clinical response.

Subgroup Analysis

Clinical Response at EOT by Baseline Neutropenia: ITT population: A higher clinical response at EOT was seen in neutropenic subjects (62.8% had a satisfactory response) than non-neutropenic subjects (48.3% had a satisfactory response). Neutropenic subjects were defined as having an absolute neutrophil count <550 cells/mm3 or a white blood cell (WBC) count <1000 cells/mm3 at baseline.

In the ITT population, 43 subjects were neutropenic at baseline and 89 subjects were non-neutropenic at baseline. Five subjects did not have a neutrophil count or WBC count at baseline and therefore could not be assessed. The fact that 65.0% of the ITT subjects were non-neutropenic is unexpected as approximately 70% of the ITT subjects were assessed with a haematological malignancy or bone marrow transplant (BMT) as their underlying disease/condition.

A complete clinical response was seen for 21 neutropenic subjects (48.8%) and a partial response was seen for 6 subjects (14.0% of this population). Twenty five of the non-neutropenic subjects (28.1% of this population) had a complete response and 18 subjects (20.2%) had a partial response. Two subjects did not have any evaluable data.

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PP Population analysed by primary/salvage therapy: 35 (34.7%) subjects were neutropenic and 62 (61.4%) subjects were non-neutropenic at baseline. Four subjects did not have a neutrophil count or WBC count at baseline and therefore their neutrophil status could not be classified. Thirty one (31) neutropenic subjects (88.6% of the PP population with neutropenia) were also primary therapy subjects, and 42 non-neutropenic subjects (67.7% of the non-neutropenic PP population without neutropenia) were primary subjects.

Twice as many neutropenic subjects had a complete or partial response as had a stable or failure response (Table 5) and the response was better than for the non-neutropenic subjects. For non-neutropenic subjects, slightly more had a stable or failure response than a complete or partial response.

Table 5. Clinical Response at EOT by Baseline Neutropenia for the PP Population

Number (%) of Subjects

Clinical ResponseNeutropenica

(N=35)Non-Neutropenica,b

(N=62)No Neutrophil/WBC Count Informationa

(N=4)PP Population Complete 19 (54.3) 16 (25.8) 2 (50.0)Partial 4 (11.4) 12 (19.4) 1 (25.0)Stable 6 (17.1) 15 (24.2) 1 (25.0)Failure 6 (17.1) 18 (29.0) 0EOT=end of therapy; N=number of subjects in the neutrophil status group; PP=per protocol; WBC=white blood cell.a The percentages refer to the percentage of subjects in this neutrophil status group. b One non-neutropenic subject did not have any evaluable data for a clinical response to be assessed.

Looking at the primary therapy subjects in the PP population, 21 neutropenic subjects (67.8% of this population) had a satisfactory response and 21 non-neutropenic subjects (50.0% of this population) had a satisfactory response. In the salvage population there were only two neutropenic subjects and 18 non-neutropenic subjects so a comparison between the primary and salvage therapy groups was not appropriate. One salvage therapy neutropenic subject (50.0% of this population) and five salvage therapy non-neutropenic subjects (27.7%) had a satisfactory response.

Clinical Response at EOT by Site of Infection at Baseline:The clinical response at EOT by site of aspergillosis infection for the ITT population is presented in Table 6. Sixty five of the 101 subjects with pulmonary aspergillosis (64.4%) had a complete or partial clinical response at EOT. Only a small number of subjects was diagnosed with cerebral aspergillosis or sinus aspergillosis (6 subjects each). A partial clinical response at EOT was recorded for 1 subject with cerebral aspergillosis (16.7%) and for 3 subjects with sinus aspergillosis (50.0%). The other subjects with cerebral or sinus aspergillosis had stable (3 subjects) or failure (4 subjects) responses. Of the 20 subjects with disseminated aspergillosis, 4 had a complete response and 1 had a partial response but the majority (15 of 20) had a stable or failure response.

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Table 6. Clinical Response at EOT by Site of Aspergillosis Infection for the ITT Population

Number (%) Subjects for Each Site of Aspergillosis Infection at Baselinea

Clinical Response Pulmonary(N=101)

Cerebral(N=6)

Sinus(N=6)

Disseminated(N=20)

Complete 45 (44.6) 0 0 4 (20.0)Partial 20 (19.8) 1 (16.7) 3 (50.0) 1 (5.0)Stable 17 (16.8) 3 (50.0) 0 6 (30.0)Failure 18 (17.8) 2 (33.3) 2 (33.3) 9 (45.0)

No evaluable data 1 (1.0) 0 1 (16.7) 0EOT = end of therapy; ITT = intention-to-treat; N=number of subjects in the specified site of infection group.a The percentages refer to the percentage of subjects in the site of infection group.The duration of survival for 5 of the cerebral aspergillosis subjects was 59, 78, 11, 62, and 47 days from the start of the study. The other cerebral aspergillosis subject was still alive 90 days after the start of therapy.

The duration of survival for 5 of the cerebral aspergillosis subjects was 59, 78, 11, 62, and 47 days from the start of the study. The other cerebral aspergillosis subject was still alive 90 days after the start of therapy.

Survival Analysis:The number and percentage of subjects in the ITT population alive 30, 60, and 90 days post first dose are shown in Table 7. Similar results were seen in the PP population.

Table 7. Survival Analysis for the ITT Population

Number of Days from First DoseNumber (%) Subjects (N=137): 30 60 90

Alive 107 (78.1) 84 (61.3) 76 (55.5)Dead 30 (21.9) 53 (38.7) 61 (44.5)

Proportion alive 0.781 0.613 0.555Exact 95% Confidence Interval for Alive

0.7020.847 0.5260.695 0.4670.640

ITT=intention-to-treat; N=number of subjects.

At 30, 60, and 90 days post first dose, there was a much higher proportion of subjects alive in the primary therapy group (62 [81.6%] subjects; 49 [64.5%] subjects; 46 [60.5%] subjects) than in the salvage therapy group (13 [61.9%] subjects; 8 [38.1%] subjects; 6 [28.6%]subjects) at 30, 60 and 90 days post first dose. As the study progressed, the difference between survival in the primary therapy group and the salvage therapy group widened. Using the sponsor’s definitions of primary and salvage therapy, there was a less marked difference in survival between the two groups (see Clinical Response According to the Sponsor’s Definitions of Primary/Salvage Therapy).

Mycological Response:Twenty subjects in the ITT population (14.6%) had no evaluable data and 83 other subjects (60.6%) had an indeterminate mycological response. Of the remaining 34 subjects, 15 (10.9%) were assessed as having a ‘persistent’ mycological presence and 19 (13.9%) had an ‘eradication’ of the mycological presence. Of those subjects who were assessed as having pulmonary aspergillosis, 17 (16.8%) subjects were assessed as ‘eradication’ and 11 (10.9%) subjects as ‘persistence’. The remaining subjects had an indeterminate response or had no

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evaluable data. An analysis of mycological response for the other sites of infection was not possible as few subjects had been assessed by the investigator and the majority of these subjects were classified as ‘indeterminate’ or did not have any evaluable data.

Clinical response according to the sponsor’s definitions of primary/salvage therapy:Clinical response at EOT was comparable between the sponsor’s definition and the investigator’s definition of primary/salvage therapy.

A better satisfactory clinical response was seen for primary therapy subjects than salvage therapy subjects at Week 4, Week 12, and EOT.

The incidence of relapse (where follow-up information was available) was low for both primary therapy (6.1% at Week 12 follow-up) and salvage therapy subjects (11.1% at Week 12 follow-up).

A better clinical response was seen for primary therapy subjects (40 subjects; 55.6% satisfactory response) than for salvage therapy subjects (14 subjects; 48.3% satisfactory response) at EOT. The majority of neutropenic subjects were also primary therapy subjects.

A similar clinical response to that assessed by the investigator was seen when response was analysed by site of infection according to the sponsor’s definition of primary/salvage therapy.

The survival rates for the sponsor-defined primary therapy subjects (58.3% alive at 90 days) were similar to those for the investigator-defined primary therapy subjects. The survival rates for the sponsor-defined salvage subjects (44.8% alive at 90 days) were higher than for the investigator-defined salvage subjects.

Expert’s Assessment of Global response:It was expected that the investigators’ assessment of clinical response would differ from the Expert’s assessment of global response. It was also likely that the investigator and Expert would interpret any available imaging results differently. Generally the Expert and the investigator drew similar conclusions although the Expert tended to give more pessimistic outcomes than the investigator. The investigator and Expert agreed on the clinical response at EOT for 53 of 101 subjects (52.5%). The Expert assessed that subjects had responded better than the investigator had assessed for nine subjects (8.9%) and worse than the investigator had assessed for 39 subjects (38.6%). The overall assessments of a satisfactory or unsatisfactory response were similar between the investigator and the Expert.

Expert’s Assessment of Global Response by Underlying Disease: As neither the investigator nor sponsor analysed efficacy according to underlying disease/condition, a short description of the results is provided. Of the 112 subjects in the Expert evaluable population, 58 (51.8%) had ‘haematological malignancy’ as their underlying disease/condition. The other subjects were classified under acquired immunodeficiency syndrome (AIDS), allogenic or autologous BMT, organ transplant, cancer, or ‘other’. A summary of the results for 93 of the 112 Expert evaluable subjects is presented in Table 8. 09

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Table 8. Global Response by Underlying Disease/Condition

Number (%) Subjects with Underlying Disease/Conditiona

Global ResponseAllogenic BMT Haem. Malignancy Organ Transplant Cancer

Satisfactory 6 (27.3) 30 (51.7) 3 (50.0) 7 (87.5)Unsatisfactory 16 (72.7) 27 (46.6) 3 (50.0) 1 (12.5)BMT=bone marrow transplant; Haem.=haematological. a The percentages refer to the percentage of subjects with specified underlying disease.b One subject in this group was deemed to be ‘unaccessable’.

Both subjects in the AIDS group were assessed as failing therapy and both subjects in the autologous BMT group were assessed as having a partial global response.

Expert’s Assessment of Global Response by Certainty of Diagnosis: The As neither the investigator nor sponsor analysed efficacy according to certainty of diagnosis, a short description of the results is provided. Forty five subjects (40.2%) were assessed as having a definite diagnosis and 67 (59.8%) with a probable diagnosis. A better global response was seen for the probable diagnosis subjects (56.7% had a satisfactory response) than for the definite diagnosis subjects (37.8% had a satisfactory response).

Other Expert Assessments

The Expert also assessed global response according to site of infection during the study and presence of baseline neutropenia subdivided by primary/salvage therapy. The Expert’s assessments of survival rates were similar to the investigator’s and sponsor’s assessments for the primary subjects. However, the Expert assessed that a greater proportion of salvage subjects was alive at 30 days (72.2%) and at 90 days (46.3%) than the investigator.

Comparison of Independent Expert Assessments: Two Experts assessed the efficacy data for a subset of the population discussed in this study report. There was complete agreement between the global response assessments of these Experts and another Expert in 49 (49%) cases and a minor difference (eg complete to partial or stable to failure – resulting in no change in the overall therapeutic outcome of satisfactory or unsatisfactory) in 21 other cases (21%). A number of the differences in assessment appeared to be based upon interpretation of changes in imaging, especially in the assessment of a partial or stable response and particularly for subjects with ‘probable’ disease.

Clinical Outcome for Paediatric Subjects: Paediatric subjects (<18 years of age) were not analysed in this study as a separate subgroup. However, a summary of the 4 paediatric subjects is shown below:

One subject (13 years old) was withdrawn from the study as a protocol violator because she had cholestasis at baseline. At EOT (9 days of treatment) she was assessed as ‘stable’ but had relapsed by follow-up Week 4.

One subject (15 years old) withdrew from the study due to increased alanine transaminase levels. At EOT she had a ‘complete’ response but had relapsed by follow-up Week 4.0901

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One subject (17 years old) received ten days of treatment for pulmonary aspergillosis and then died due to inadequate response to study drug.

One subject (17 years old) had a ‘complete’ response at EOT which was unchanged at follow-up Weeks 4 and 12

Safety Results

A summary of safety during the study is presented in Table 9.

Table 9. Summary of Safety During the Study

Number (%) of Subjects with: N=137Adverse Events (all causality) 128 (93.4)Adverse Events (treatment related) 47 (34.3)Severe Adverse Events (all causality) 98 (71.5)Severe Adverse Events (treatment related) 13 (9.5)Serious Adverse Events (all causality) 94 (68.6)Serious Adverse Events (treatment related) 19 (13.9)Dose reductions or temporary discontinuations due to adverse events (all causality)

17 (12.4)

Dose reductions or temporary discontinuations due to adverse events (treatment related)

4 (2.9)

N=number of subjects evaluable for safety.

All causality treatment-emergent AEs: 128 (93.4%) reported 631 treatment-emergent all causality AEs. The body systems most commonly affected by these AEs were: body as a whole (82 subjects; 59.9%), respiratory (56 subjects; 40.9%), metabolic and nutritional (46 subjects; 33.6%), digestive (44 subjects; 32.1%), and skin and appendages (42 subjects; 30.7%). As many of the subjects who entered the study had pulmonary aspergillosis, it is not surprising that respiratory AEs were commonly reported. All causality AEs affecting the special senses were reported in 25 subjects (18.2%).

A summary of the 10 most commonly occurring all causality AEs is presented in Table 10.

Table 10. Incidence of the 10 Most Commonly Occurring Adverse Events

SeverityAdverse Event

Total number (%) of subjects with the specified event Mild Moderate Severe

Rash 27 (19.7) 15 10 2Fever 24 (17.5) 7 10 7Sepsis 21 (15.3) 4 5 12Increased AP 20 (14.6) 4 10 6Abnormal Vision 16 (11.7) 15 1 Pneumonia 15 (10.9) a 5 10Headache 13 (9.5) 6 6 1Diarrhoea 12 (8.8) 8 4 Bilirubinaemia 11 (8.0) 8 3

Abdominal Painb 10 (7.3) 4 6 AP=alkaline phosphatase.a A dash () indicates no incidence of this adverse event.b Vomiting also occurred in 10 subjects but with less severity than abdominal pain.

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Ninety eight (98 [71.5%]) subjects had severe all causality AEs, 45 subjects discontinued due to all causality AEs, and 17 subjects had their dose of voriconazole reduced or temporarily discontinued due to AEs.

Treatment-related, treatment-emergent AEs: 47 (34.3%) subjects reported 93 treatment-emergent, treatment-related AEs. The body systems most commonly affected by these AEs were metabolic and nutritional (17 subjects; 12.4%), special senses (17 subjects; 12.4%), skin and appendages (11 subjects; 8.0%), body as a whole (9 subjects; 6.6%), and digestive (8 subjects; 5.8%). A summary of the 10 most commonly occurring treatment-related AEs is presented in Table 11.

Table 11. Incidence of the 10 Most Commonly Occurring Treatment-Related Adverse Events

SeverityAdverse Event

Total number (%) of subjects with the specified event Mild Moderate Severe

Abnormal vision 13 (9.5) 13 a Increased AP 9 (6.6) 2 4 3Rash 8 (5.8) 4 3 1Hepatic enzymes increased

4 (2.9) 1 3

SGPT increased 4 (2.9) 1 3 Bilirubinaemia 3 (2.2) 3 Dry mouth 3 (2.2) 2 1 Nausea 3 (2.2) 1 2 Thrombocythemiab 2 (1.5) 2

Hypercholesteremiab 2 (1.5) 1 1

AP=alkaline phosphatase; SGPT=alanine transaminase.a

A dash () indicates no incidence of this severity.b Three other adverse events (headache, increased aspartate transaminase, dry skin) occurred in 2 subjects, but thrombocythemia and hypercholesteremia occurred with the greatest severity.

Discontinuations due to Adverse Events: In total there were 104 of 137 subjects (75.9%) who discontinued from the study. Forty subjects (29.2%) subjects discontinued due to death during therapy or within 7 days of the end of therapy. Seventeen subjects (12.4%) discontinued study treatment due to treatment-emergent AEs. Five of these subjects (3.6% of the total) were assessed by the investigator to have discontinued due to treatment- related AEs, and 12 (8.8% of the total) due to non-treatment-related AEs.

The 5 subjects who discontinued due to treatment-emergent treatment- related AEs are summarised in Table 12.

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Table 12. Discontinuations due to Treatment-Emergent, Treatment-Related Adverse Events

Event Groupa Duration of Therapy (Days) Adverse Event1 5 Pneumonia, hypoglycaemia and hypoxia2 105 Rash3 42 Psoriasis4 2 Rash5 96 Erythema Multiforme

a Reported for an individual subject.

Of the 12 subjects who din individualscontinued due to non-treatment-related AEs, 8 subjects subsequently died (Table 13); 1 subject discontinued due to a ‘post therapy’ serious adverse event (SAE), and 3 subjects discontinued due to non-SAEs.

Table 13. Discontinuations due to Non-Treatment-Related Adverse Events

Event Groupa Duration of Therapy (Days) Adverse Event1 64 Severe fungal infection (Rhinocerebral Mucor) on

Day 28 leading to death on Day 732 46 Cardiac arrest and coma leading to death on

Day 473 51b Leukaemia leading to death on Day 53 (Day 54

according to the adverse event monitoring database)

4 5 Cerebral infarction and cerebrovascular accident (attributed to a surgical procedure) leading to death on Day 13

5 19 Acute lymphoblastic leukaemia/acute myeloblastic leukaemia and sepsis leading to death on Day 21

6 5 Encephalitis leading to death on Day 77 130 Thrombocytopaenia8 22 Bone pain and neoplasm

a Reported for an individual subject. b Fifty two days according to the adverse event monitoring database.

During treatment with voriconazole, 16 subjects temporarily discontinued study drug, of whom 4 subjects temporarily discontinued due to treatment-related AEs and 12 subjects temporarily discontinued study drug because of AEs due to other illnesses, concomitant treatments, the disease under study, or due to receiving amphotericin B prior to the study start. Two subjects had their dose of voriconazole reduced without temporarily discontinuing study drug because of AEs.

Deaths: 62 subjects (45.3%) died during the study or within 30 days EOT(or the last follow-up visit) according to the AE monitoring (AEM) database. Of these:

None of the deaths were assessed by the investigators as being treatment related. The most common reason for death assigned by the investigator was ‘other illness’, which accounted for 40 subjects. ‘Other illness’ most commonly included AIDS/human immunodeficiency virus, pneumonia (including Pneumocystis carinii pneumonia), and leukaemia.

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Twenty subjects died due to the ‘disease under study’. Six subjects discontinued from the study due to an inadequate response to study drug and then subsequently died. The duration of treatment for these subjects was between 3 and 52 days. The other 14 subjects died due to aspergillosis with or without other causality (10 subjects),cerebellum and lung haemorrhage (1 subject), cardiovascular failure (2 subjects) and massive hemoptysis (1 subject).

One subject died due to a cerebral infarction (causality assigned by the investigator as surgical procedure) on Day 13 and 1 subject died due to encephalopathy and haemolysis (causality assigned by the investigator as encephalopathy and haemolysis) on Day 21.

Eighteen subjects died more than 30 days after the end of therapy. Of these, 13 subjects died from ‘other illness’, 4 subjects died because of the ‘disease under study’, and 1 subject died because of study drug related reasons, according to the investigator.

Serious adverse events: 92 (67.2%) subjects had treatment-emergent SAEs occurring during therapy or within 30 days of EOT (or the last follow-up visit). Eighteen subjects discontinued from the study due to SAEs, of which five were treatment-related SAEs:

One subject was reported as discontinuing on Day 5 due to hypoglycaemia and, what was eventually diagnosed as acute respiratory distress syndrome. The subject subsequently died on Day 44 due to an intraperitoneal haemorrhage at the site of a liver biopsy. According to the investigator, the subject died because of study drug related reasons.

One subject had elevated liver function test results on Day 16. Study drug was discontinued on Day 16 and the subject was hospitalised. The hepatic abnormalities were considered resolved on Day 36. In the opinion of the investigator the abnormal test results were due to voriconazole.

One subject developed a severe erythematous rash on her face and neck on Day 94 and discontinued from the study on Day 105. The event was considered to have resolved by Day 177. In the opinion of the investigator the rash was related to study drug.

One subject discontinued from the study on Day 42 due to a skin reaction (psoriasis vulgaris) and eosinophilia. By Day 141 the skin rash had completely resolved and the subject’s eosinophil count had returned to normal by Day 86. In the opinion of the investigator, skin rash (pruritus, burning skin and peeling) was due to study drug.

One subject developed moderate erythema on his face and arms on Day 87 which resolved by Day 147. The subject was withdrawn from the study on Day 102. In the opinion of the investigator, the erythema and erythema multiforme were due to a combination of voriconazole and his concomitant medication carmustine.

Nine subjects discontinued (and subsequently died) because of SAEs that were related to another illness, as assessed by the investigator:

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One subject was diagnosed with rhinocerebral mucormycosis on Day 28 and discontinued from the study on Day 66. The subject subsequently died and causality was assigned by the investigator to rhinocerebral mucormycosis.

One subject had a cardiac arrest and went into a coma on Day 46. The subject discontinued from the study and subsequently died. Causality was assigned by the investigator to haemochromatotic cardiomyopathy.

One subject was diagnosed with progression of acute leukaemia on Day 36 anddiscontinued from the study on Day 52. The subject subsequently died and causality was assigned by the investigator to leukaemia.

One subject had a relapse of acute myeloid leukaemia on Day 113 and discontinued from the study on Day 135. The subject subsequently died and causality was assigned by the investigator to ‘a relapse of acute myeloid leukaemia’.

One subject was diagnosed with progression of acute myeloid leukaemia on Day 6 of the study and discontinued from the study also on this day. The subject subsequently died and causality was assigned by the investigator to progression of acute myeloid leukaemia.

One subjecthad brain oedema due to cerebral aspergillosis on Day 2 and voriconazole was discontinued at the request of the subject’s relatives on Day 60 due to his worsening condition. The subject subsequently died and causality was assigned by the investigator to cardiovascular failure.

One subject was diagnosed with progression of leukaemia and sepsis on Day 19 and discontinued from the study also on this day. The subject subsequently died and causality was assigned by the investigator to acute myeloid and lymphatic leukaemia.

One subject with acute invasive cerebral and pulmonary aspergillosis, discontinued from the study on Day 5. The subject subsequently died and causality was assigned by the investigator to sepsis, cardiovascular failure and acute aspergillosis.

One subject was diagnosed with Guillain-Barre syndrome on Day 2 and discontinued from the study also on this day. The subject subsequently died and causality was assigned by the investigator to cardiac and respiratory arrest and progression of acute myeloid leukaemia.

Four subjects discontinued from the study because of other reasons, not related to study drug:

One subject was diagnosed with an exacerbation of acute invasive aspergillosis on Day 43 and discontinued from the study on Day 48. The subject was hospitalised and causality was assigned by the investigator to progression of AIDS.

One subject underwent surgery for opening of the orbits on Day 2 but experienced a post surgical cerebral infarction and left hemiparesis and discontinued from the study on 0901

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Day 5. The subject was hospitalised and subsequently died. Causality was assigned by the investigator to a cerebral infarction.

One subject had an epileptic attack (type unspecified) and leukoencephalopathy on Day 21 of the study and discontinued from the study also on this day. The subject subsequently died and causality was assigned by the investigator to encephalopathy and haemolysis.

One subject was hospitalised with thoracic/left-base lung pain and expectorated a large volume of non-haematic sputum on Day 25 and discontinued from the study on Day 26. Causality was assigned by the investigator to the ‘disease under study’, ie aspergillosis.

Visual Adverse Events: 2 subjects reported a treatment-emergent SAE involving the eye:

One subject was diagnosed with a retinal detachment of her right eye on Day 28. The subject’s condition improved and no further action was taken. Causality was unknown but was not assigned by the investigator to study drug.

One subject reported an SAE involving the eye (opening of the orbits) but this subject died (due to a cerebral infarction).

Fifteen subjects (10.9%) reported mild or moderate treatment-related visual AEs, and none of these subjects discontinued from the study: seven subjects had enhanced/altered visual perception, three had mildly blurred vision, one had a change in colour vision and one had mild photophobia. Six had visual AEs categorised to ‘other’ of which five, according to the investigator, had ‘visual disturbance’ and one had ‘short term visual deterioration and worsening of visual acuity after dosing’. Of the 15 subjects who had treatment related visual AEs, 9 reported that they resolved without treatment.

Clinical Laboratory Test Results: Ninety four subjects (79.7%) had a normal baseline and developed a clinically significant laboratory abnormality with respect to the primary criteriaof clinical significance and 85 (72.0%) subjects with an abnormal baseline had a clinically significant laboratory abnormality with respect to the secondary criteria. Eleven subjects were discontinued from the study due to treatment-related laboratory test abnormalities. The median changes from baseline to the last observation for laboratory data were mostly small and clinically insignificant.

CONCLUSIONS:

Taking into account the general health of this immunocompromised population, voriconazole was efficacious (especially in the primary treatment of high risk neutropenic subjects) and was generally safe and well tolerated. The availability and convenience of the oral formulation allowed long term treatment (up to 246 days) with voriconazole.

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Documents

EMA Pediatric Web Synopsis Protocol 150-304 29 November