A Study of Palifermin for the Reduction of Oral Mucositis in Subjects With Multiple Myeloma

Number of participants from the primary cataract subset showing an increase from baseline of \>= 0.3 in the Lens Opacities Classification System III (LOCS III score). The LOCS III is a standard system used for grading and comparison of cataract severity and type. The ophthalmologist trained in LOCS III uses a slit lamp for examining the lens of the eye. The classification evaluates four features: posterior subcapsular cataract(P),cortical cataract(C),nuclear opalescence(NO) and nuclear color(NC). NO and NC are graded on a decimal scale of 0.1 to 6.9, based on a set of 6 standardized photographs. C and P are graded on a decimal scale of 0.1 to 5.9, based on a set of 5 standardized photographs each. In the current study, cataract development or progression was defined as an increase from baseline of ≥ 0.3 on any of the three features P, C or NO (NC is of less importance and has not been analysed further in this study).

Time frame: 12 months

Population: Of the 281 subjects who participated in the acute phase of the study a total of 101 subjects study were eligible for participation in the cataract assessment procedures, 22 in the placebo group and 79 in the palifermin group.

For the primary efficacy endpoint maximum severity of Oral Mucositis (OM) was assessed, the number of participants who had the different severity. To assess severity of OM, a 5-grade WHO scale (0, 1, 2, 3, or 4) was used. 0 = no findings or erythema only, 1= soreness present with or without erythema, 2=ulcers present but able to take solid food, 3 =ulcers present and only able to take liquids, 4 =ulcers present/not able to take anything orally.

Time frame: at Day 32

Population: Full analysis set that includes all randomized subjects, and was used to compare treatment effects for all efficacy endpoints. This set of subjects was analyzed according to their randomized treatment assignment.

To study the change in cataract from baseline visit to months 12, regarding the three cataract main types: nuclear, cortical and posterior subcapsular measured on the Lens Opacities Classification System III (LOCS III) Scale. To assess the effect of palifermin on the incidence of cataract development or progression at Month 6 and Month 12 based on an increase of ≥ 0.3 in the Lens Opacities Classification System (LOCS III) score for Posterior Subcapsular cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO). The LOCS III is a standard system used for grading and comparison of cataract severity and type. The ophthalmologist uses a slit lamp for examining the lens of the eye. The classification evaluates: P,C and NO. NO is graded on a decimal scale of 0.1 to 6.9, based on a set of 6 standardized photographs. C and P are graded on a decimal scale of 0.1 to 5.9, based on a set of 5 standardized photographs each.

Time frame: Months 12

Population: All subjects in the acute phase study were also assessed for their eligibility for cataract assessment procedures according to predefined criteria. If a subject was not eligible for cataract assessment procedures, the subject could still have been eligible for inclusion in the study but was exempt from the cataract assessments.

To study the change in cataract from baseline visit to months 6, three cataract main types: nuclear, cortical and posterior subcapsular measured on the Lens Opacities Classification System III (LOCS III) Scale. To assess the effect of palifermin on the incidence of cataract development or progression at Month 6 and Month 12 based on an increase of ≥ 0.3 in theLOCS III score for Posterior Subcapsular cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO). The LOCS III is a standard system used for grading and comparison of cataract severity and type. The ophthalmologist uses a slit lamp for examining the lens of the eye. The classification evaluates: P,C and NO. NO is graded on a decimal scale of 0.1 to 6.9, based on a set of 6 standardized photographs. C and P are graded on a decimal scale of 0.1 to 5.9, based on a set of 5 standardized photographs each.

Time frame: Months 6

Population: All subjects in the acute phase study were also assessed for their eligibility for cataract assessment procedures according to predefined criteria. If a subject was not eligible for cataract assessment procedures, the subject could still have been eligible for inclusion in the study but was exempt from the cataract assessments.

The duration of ulcerative mucositis measured the number of days the participants had different WHO grades 2, 3, and 4: 2=ulcers present but able to take solid food, 3 =ulcers present and only able to take liquids, 4 =ulcers present/not able to take anything orally. Patients that did not have any ulcerative mucositis were given a value of 0 days.

Time frame: at Day 32

Population: Full analysis set that includes all randomized subjects (total 281 subjects), and was used to compare treatment effects for all efficacy endpoints. This set of subjects was analyzed according to their randomized treatment assignment.

To study if the treatment has effected on the visual acuity from baseline to months 12, by using Best Corrected Visual Acuity (BCVA) as measured by a Change of 10 Letters on the ETDRS (Early Termination Diabetic Retinopathy Study) at 4 Meters. To assess the effect of palifermin on the incidence of cataract development or progression at Month 6 and Month 12 based on an increase of ≥ 0.3 in the Lens Opacities Classification System (LOCS III) score for Posterior Subcapsular cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO).

Time frame: Month 12

Population: All subjects in the acute phase study were also assessed for their eligibility for cataract assessment procedures according to predefined criteria. If a subject was not eligible for cataract assessment procedures, the subject could still have been eligible for inclusion in the study but was exempt from the cataract assessments.

To study if the treatment has effected on the visual acuity from baseline to months 6, by using Best Corrected Visual Acuity (BCVA) as measured by a Change of 10 Letters on the ETDRS (Early Termination Diabetic Retinopathy Study) at 4 Meters. To assess the effect of palifermin on the incidence of cataract development or progression at Month 6 and Month 12 based on an increase of ≥ 0.3 in the Lens Opacities Classification System (LOCS III) score for Posterior Subcapsular cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO).

Time frame: Months 6

Population: All subjects in the acute phase study were also assessed for their eligibility for cataract assessment procedures according to predefined criteria. If a subject was not eligible for cataract assessment procedures, the subject could still have been eligible for inclusion in the study but was exempt from the cataract assessments.

Incidence of Adverse Events CTCAE grade 3 or higher reported

Time frame: at Day 32

To assess the effect of palifermin on the incidence of cataract development or progression at Month 6 and Month 12 based on an increase of ≥ 0.3 in the Lens Opacities Classification System (LOCS III) score for Posterior (P), Cortical Cataract (C) and Nuclear Opalescence (NO). For Subcapsular cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO): at month 6 and 12 adjusted difference of rate of cataract, Palifermin - Placebo were used and the confidence interval were calculated on the adjusted difference.

Time frame: at Month 6 and Month 12

Population: 281 subjects participated in the acute phase study of those 101 subjects were eligible for the cataract assessment study, 22 placebo and 79 palifermin. Month 6: 69 completed (17/22 \[77.3%\] in the placebo, 52/79 \[65.8%\] in the palifermin. Month 12: 66 completed (14/22 \[63.6%\] in the placebo, 52/79 \[65.8%\] in the palifermin group.

Number of participants from the primary cataract subset showing an increase from baseline of \>= 0.3 in the Lens Opacities Classification System III (LOCS III score). The LOCS III is a standard system used for grading and comparison of cataract severity and type. The ophthalmologist trained in LOCS III uses a slit lamp for examining the lens of the eye. The classification evaluates four features: posterior subcapsular cataract(P),cortical cataract(C),nuclear opalescence(NO) and nuclear color(NC). NO and NC are graded on a decimal scale of 0.1 to 6.9, based on a set of 6 standardized photographs. C and P are graded on a decimal scale of 0.1 to 5.9, based on a set of 5 standardized photographs each. In the current study, cataract development or progression was defined as an increase from baseline of ≥ 0.3 on any of the three features P, C or NO (NC is of less importance and has not been analysed further in this study).

Time frame: 6 Months

Population: Of the 281 subjects who participated in the acute phase of the study a total of 101 subjects study were eligible for participation in the cataract assessment procedures, 22 in the placebo group and 79 in the palifermin group. Number of patients with non-missing values at Months 6; were 17 in the placebo group and 53 in the palifermin group.

All comparisons for the long-term safety endpoints were based on the combined palifermin group versus placebo (placebo over palifermin). Incidence of new or secondary malignancies by treatment group was provided (incidence of new or secondary malignancies at the follow-up visit - yes, no, no assessment -, and number of subjects with new or secondary malignancies, per type of malignancies). The long-term safety evaluations were summarized for the subgroups defined by the factors used for randomization using descriptive statistics.

Time frame: During long-term follow up phase (maximum of 10 years)

Population: total of 277 subjects were included in the Safety subset of the original study report (220 Palifermin and 57 placebo). Follow-up time for all subjects, defined as the date of randomization to the last known alive date. For subjects who were alive at the last contact the number of subjects for the palifermin group was 162 and for the placebo 47.

The incidence of ulcerative mucositis WHO grades 2, 3, and 4. Measured the number of participants who had WHO grades 2, 3, and 4: 2=ulcers present but able to take solid food, 3=ulcers present and only able to take liquids, 4=ulcers present/not able to take anything orally.

Time frame: at Day 32

Population: Full analysis set that includes all randomized subjects (total 281 subjects), and was used to compare treatment effects for all efficacy endpoints. This set of subjects was analyzed according to their randomized treatment assignment.

Overall survival (OS) is based on death from any cause, not just the condition being treated, thus it picks up death from side effects of the treatment, and effects on survival after relapse.

Time frame: During long-term follow up phase (maximum of 10 years)

Population: A total of 277 subjects were included in the Safety subset of the original study report (220 Palifermin and 57 placebo). Follow-up time for all subjects, defined as the date of randomization to the last known alive date. For subjects who were alive at the last contact the number of subjects for the palifermin group was 162 and for the placebo 47

Progression-free survival (PFS) is the length of time during and after the treatment during which the disease being treated does not get worse. In this study the event for Progression-free survival was death from all causes or disease progression. Time to each event was defined as the time elapsed between the date of the first dose of investigational product, and the date of the given event.

Time frame: During long-term follow up phase (maximum of 10 years)

Population: A total of 277 subjects were included in the Safety subset of the original study report (220 Palifermin and 57 placebo). Follow-up time for all subjects, defined as the date of randomization to the last known alive date. For subjects who were alive at the last contact the number of subjects for the palifermin group was 162 and for the placebo 47.

The mean daily scores were calculated using the subject daily assessment of Patient-reported mouth and throat soreness (MTS) on the 5 point scale with higher values in MTS indicating a worse self assessed MTS. A 5-grade WHO scale (0, 1, 2, 3, or 4). 0=no findings or erythema only, 1=soreness present with or without erythema, 2=ulcers present but able to take solid food, 3=ulcers present and only able to take liquids, 4=ulcers present/not able to take anything orally. The incidence of ulcerative mucositis WHO grades 2, 3, and 4. Measured the number of participants who had WHO grades 2, 3, and 4: 2=ulcers present but able to take solid food, 3=ulcers present and only able to take liquids, 4=ulcers present/not able to take anything orally. The area under the curve were calculated at the time points; Day(D)-2, up to Day 32.

Time frame: at Day 32

For the analysis of time to disease progression, competing risks time-to-event analysis was used, since a subject destined to develop disease progression could die from unrelated causes before the disease progression event takes place. Kaplan-Meier survival estimates, with death due to other causes than progression considered as a competing risk, were provided: event rate at 3 month intervals, with 95% confidence interval, the number of subjects at risk at the beginning of the time period, and the number of events of interest.

Time frame: During long-term follow up phase (maximum of 10 years)

Population: A total of 277 subjects were included in the Safety subset of the original study report (220 Palifermin and 57 placebo). Follow-up time for all subjects, defined as the date of randomization to the last known alive date. For subjects who were alive at the last contact the number of subjects for the palifermin group was 162 and for the placebo 47.