Palifermin for the Reduction of Oral Mucositis in Patients With Locally Advanced Head and Neck Cancer

• Sponsor: Swedish Orphan Biovitrum (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00101582
• Collaborator: Amgen (Industry)
• Enrollment: 188
• Arms: 2
• Duration (Months): 132

Study Details

Study Description

Brief Summary

The purpose of this research study is to test the safety and effectiveness of palifermin to determine if weekly doses can be safely administered to reduce the incidence (occurrence of), duration (length of time) and severity (amount of pain) of oral mucositis (painful sores in the mouth). Mucositis is a common side effect for patients receiving chemotherapy (cancer-killing drug) and radiotherapy (cancer-killing x-rays) for the treatment of head and neck cancer (HNC).

Condition or Disease	Intervention/Treatment	Phase
Mucositis; Solid Tumors; Stomatitis; Head and Neck Cancer; Squamous Cell Carcinoma	Drug: Placebo; Drug: palifermin; Drug: cisplatin chemotherapy; Radiation: Radiotherapy	Phase 3

Detailed Description

This study consisted of 2 phases. The acute oral mucositis (OM) evaluation phase includes the time from randomization to the time of severe OM (WHO Grade 3 or 4) resolution (up to Week 12 or up to Week 15 for participants whose severe OM is not resolved at Week 12). In the acute OM evaluation phase, participants were randomized to receive either a single IV dose of palifermin or placebo at 180 μg/kg, 3 days before the start of radiotherapy, plus 7 once-weekly palifermin or placebo doses at the same dose level during a 7-week radio/chemotherapy course. In the long-term follow up phase, participants are followed until death, withdrawal of consent, or loss to follow-up. The long-term follow up phase is still ongoing.

Study Design

• Study Type: Interventional
• Actual Enrollment: 188 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Weekly Doses of Palifermin (rHuKGF) for the Reduction of Oral Mucositis in Subjects With Advanced Head and Neck Cancer Receiving Radiotherapy With Concurrent Chemotherapy (RT/CT)
• Study Start Date: Aug 1, 2005
• Actual Primary Completion Date: Sep 1, 2007
• Actual Study Completion Date: Aug 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Palifermin Participants received a single intravenous dose of palifermin at 180 μg/kg three days before the start of radiotherapy, and then 7 once weekly palifermin doses at the same dose level during a 7-week radiotherapy/chemotherapy course.	Drug: palifermin; Other Names: Kepivance Recombinant Human Keratinocyte Growth Factor (rHuKGF) ; Drug: cisplatin chemotherapy; Commercially available cisplatin was administered as an intravenous infusion at a dose of 100 mg/m^2 on Days 1, 22, and 43.; Radiation: Radiotherapy; Radiotherapy was delivered in 200 cGy daily fractions, 5 days a week.
Placebo Comparator: Placebo Participants received a single IV dose of placebo three days before the start of radiotherapy, and then 7 once weekly placebo doses during a 7-week radiotherapy/chemotherapy course.	Drug: Placebo; Drug: cisplatin chemotherapy; Commercially available cisplatin was administered as an intravenous infusion at a dose of 100 mg/m^2 on Days 1, 22, and 43.; Radiation: Radiotherapy; Radiotherapy was delivered in 200 cGy daily fractions, 5 days a week.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Severe (Grade 3 or 4) Oral Mucositis [Up to Week 15]

   Participants underwent evaluations of oral mucosal (OM) surfaces (mucositis assessments) 2 times weekly throughout radio/chemotherapy, and 2 times weekly thereafter until severe OM returned to grade ≤ 2 or until Week 15. During each evaluation, the following anatomical areas were assessed: upper lip; lower lip; right cheek; left cheek; right ventral & lateral tongue; left ventral & lateral tongue; floor of the mouth; hard palate; soft palate. A trained evaluator documented the findings using the World Health Organization (WHO) oral toxicity scale according to the following: Grade 0 = None; Grade 1 = Soreness, erythema; Grade 2 = Erythema, ulcers, ability to eat solids; Grade 3 = Ulcers, requires liquid diet; Grade 4 = Alimentation not possible.

Secondary Outcome Measures

1. Duration of Severe (WHO Grade 3 or 4) Oral Mucositis [Up to 15 weeks]

   The duration of severe oral mucositis (OM) was calculated as the number of days from the onset of severe OM (first time a WHO grade 3 or 4 was observed) to the day when severe OM was resolved (first time WHO grade 2 or less was observed after last WHO grade 3 or 4). Durations of 0 days were assigned to those participants who did not experience any WHO grade 3 or 4 during the study.

2. Time to Onset of Severe (WHO Grade 3 or 4) Oral Mucositis [Up to 15 weeks]

   Time to onset of severe (WHO Grade 3 or 4) oral mucositis (OM) was analyzed using the Kaplan-Meier procedure. Participants without an assessed event by the end of the acute OM evaluation phase were censored at the date of last assessment for severe OM.

3. Number of Participants With Xerostomia at Month 4 (Grade 2 or Higher) [Month 4]

   The number of participants with grade 2 or higher xerostomia (dryness of the oral mucosa) at the Month 4 visit, graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v3.0 Dry Mouth/Xerostomia scale.

4. Patient-Reported Mouth and Throat Soreness Score [Assessed twice a week for up to 15 weeks.]

   The average patient-reported mouth and throat soreness (MTS) score as reported on question 3 of the Oral Mucositis Weekly Questionnaire for Head and Neck Cancer [OMWQ-HN]): "How much mouth and throat soreness did you experience in the past 24 hours?" Participants answered on a scale from 0 (no soreness) to 4 (extreme soreness). For each participant, an average patient-reported mouth and throat soreness score was calculated by dividing the sum of the MTS scores at each assessment by the total number of assessments.

5. Total Dose of Opioid Analgesics Used for Mucositis Within 15 Weeks [Up to 15 weeks]

   The total dose of opioid analgesics (mg of intravenous [IV] morphine equivalents) used by all participants. Participants with at least one reported administration of opioid analgesic (parenteral, peroral or transdermal) were considered to have received opioid analgesics. The total dose of opioid analgesics is the sum of all opioid analgesic administrations that have been converted to morphine equivalents.

6. Number of Participants With Unplanned Breaks in Cisplatin Chemotherapy Treatment [During the 7 weeks of chemotherapy treatment]

   Cisplatin was administered on Days 1, 22, and 43. An unplanned break in cisplatin refers to a delay of ≥ 5 days from the scheduled Day 22 or Day 43 cisplatin administration or a discontinuation of cisplatin for any reason.

7. Number of Participants With Unplanned Breaks in Radiotherapy [During the 7 weeks of radiotherapy]

   Participants with a duration of 5 days or more without an administration of radiotherapy or who discontinue radiotherapy prior to completion of planned radiotherapy were considered to have an unplanned break in radiotherapy.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Histologically documented squamous cell carcinoma involving either the oral cavity, oropharynx, nasopharynx, hypopharynx, or larynx

• Newly diagnosed, locally advanced stage head and neck cancer (unresectable/unresected disease); American Joint Committee on Cancer [AJCC] Stage III, IVA or IVB amenable to radiotherapy with concurrent chemotherapy as the definitive treatment modality

• At least 50 Gray of radiation treatment to areas of the oral cavity/oropharynx mucosa that can be visualized

• Concurrent chemotherapy regimen of Cisplatin 100mg/m^2 on days 1, 22, and 43

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) less than or equal to 2

• Adequate hematologic, renal and hepatic function

• Negative pregnancy test by serum or urine

• Signed informed consent

Key Exclusion Criteria:

• Presence or history of any other primary malignancy (other than curatively treated in situ cervical cancer, or basal cell carcinoma of the skin without evidence of disease for greater than 3 years)

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Swedish Orphan Biovitrum
• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Swedish Orphan Biovitrum
• ClinicalTrials.gov Identifier: NCT00101582
• Other Study ID Numbers: 20020402; NCT00963456
• First Posted: Jan 13, 2005
• Last Update Posted: Sep 27, 2016
• Last Verified: Aug 1, 2016

• Keywords provided by Swedish Orphan Biovitrum: SCCHN; Palifermin; Mucositis; Oral Cavity; Oropharynx; Nasopharynx; Hypopharynx; Larynx; Mouth Pain; Mouth Sores; Radiation Therapy; Radiotherapy; Radiochemotherapy; Concurrent Chemotherapy; Xerostomia; Stomatitis; Mucosa; KGF; rHuKGF; Keratinocyte Growth Factor; HNC; Head and Neck Cancer; Oral Mucositis
• Additional relevant MeSH terms: Head and Neck Neoplasms; Mucositis; Stomatitis; Cisplatin

Study Results

Participant Flow

Recruitment Details	This study was conducted from 03 August 2005 (first participant enrolled) to 11 September 2007 (last participant's last visit at 4 months of follow-up) at 46 study centers in the United States, Canada, and Europe At the time of this report, the long-term safety follow-up period is ongoing.

Arm/Group Title	Placebo	Palifermin
Arm/Group Description	Participants received a single intravenous (IV) dose of placebo three days before the start of radiotherapy, and then 7 once weekly placebo doses during a 7-week radiotherapy/chemotherapy course. Chemotherapy consisted of 100 mg/m^2 cisplatin administered by IV infusion on Days 1, 22, and 43.	Participants received a single intravenous dose of palifermin at 180 μg/kg three days before the start of radiotherapy, and then 7 once weekly palifermin doses at the same dose level during a 7-week radiotherapy/chemotherapy course. Chemotherapy consisted of 100 mg/m^2 cisplatin administered by IV infusion on Days 1, 22, and 43.
Period Title: Overall Study
STARTED	94	94
Received Study Drug	91	94
COMPLETED	83	79
NOT COMPLETED	11	15

Baseline Characteristics

Arm/Group Title	Placebo	Palifermin	Total
Arm/Group Description	Participants received a single IV dose of placebo three days before the start of radiotherapy, and then 7 once weekly placebo doses during a 7-week radiotherapy/chemotherapy course.	Participants received a single intravenous dose of palifermin at 180 μg/kg three days before the start of radiotherapy, and then 7 once weekly palifermin doses at the same dose level during a 7-week radiotherapy/chemotherapy course.	Total of all reporting groups
Overall Participants	94	94	188
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.4 (8.3)	55.5 (8.6)	55.5 (8.5)
Sex: Female, Male (Count of Participants)
Female	14 14.9%	15 16%	29 15.4%
Male	80 85.1%	79 84%	159 84.6%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	90 95.7%	83 88.3%	173 92%
Black	2 2.1%	7 7.4%	9 4.8%
Hispanic	2 2.1%	3 3.2%	5 2.7%
American Indian/ Alaska Native	0 0%	1 1.1%	1 0.5%
Weight (kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms]	71.8 (15.7)	74.5 (16.4)	73.2 (16.1)
Disease Stage (participants) [Number]
Stage III	29 30.9%	26 27.7%	55 29.3%
Stage IV A	54 57.4%	60 63.8%	114 60.6%
Stage IV B	11 11.7%	8 8.5%	19 10.1%
Tumor Site (participants) [Number]
Oral Cavity	9 9.6%	5 5.3%	14 7.4%
Oropharynx	51 54.3%	55 58.5%	106 56.4%
Nasopharynx	3 3.2%	4 4.3%	7 3.7%
Larynx	9 9.6%	16 17%	25 13.3%
Hypopharynx	22 23.4%	14 14.9%	36 19.1%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Severe (Grade 3 or 4) Oral Mucositis
Description	Participants underwent evaluations of oral mucosal (OM) surfaces (mucositis assessments) 2 times weekly throughout radio/chemotherapy, and 2 times weekly thereafter until severe OM returned to grade ≤ 2 or until Week 15. During each evaluation, the following anatomical areas were assessed: upper lip; lower lip; right cheek; left cheek; right ventral & lateral tongue; left ventral & lateral tongue; floor of the mouth; hard palate; soft palate. A trained evaluator documented the findings using the World Health Organization (WHO) oral toxicity scale according to the following: Grade 0 = None; Grade 1 = Soreness, erythema; Grade 2 = Erythema, ulcers, ability to eat solids; Grade 3 = Ulcers, requires liquid diet; Grade 4 = Alimentation not possible.
Time Frame	Up to Week 15

Outcome Measure Data

Analysis Population Description

The Full Analysis Set included all randomized participants.

Arm/Group Title	Placebo	Palifermin
Arm/Group Description	Participants received a single IV dose of placebo three days before the start of radiotherapy, and then 7 once weekly placebo doses during a 7-week radiotherapy/chemotherapy course.	Participants received a single intravenous dose of palifermin at 180 μg/kg three days before the start of radiotherapy, and then 7 once weekly palifermin doses at the same dose level during a 7-week radiotherapy/chemotherapy course.
Measure Participants	94	94
Yes	62 66%	51 54.3%
No	29 30.9%	43 45.7%
Unknown	3 3.2%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Palifermin
	Comments	Sample size calculations were based on the number of participants needed to detect, with 90% power and 5% type 1 error rate, at least a 25% difference in the incidence of severe OM between the treatment groups. A 25% absolute reduction in the incidence of severe OM from the placebo group was considered by investigators as clinically meaningful in this clinical setting.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0410
	Comments	Generalized Cochran-Mantel-Haenszel test for general association. Participants having no assessment were assumed as having WHO grade 3 or 4 oral mucositis in hypothesis testing.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by disease stage (III versus IV) and primary anatomical tumor location (oral cavity / oropharynx vs. nasopharynx vs. hypopharynx / larynx).
Method of Estimation	Estimation Parameter	Chi-Square Statistic
	Estimated Value	4.1764
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Duration of Severe (WHO Grade 3 or 4) Oral Mucositis
Description	The duration of severe oral mucositis (OM) was calculated as the number of days from the onset of severe OM (first time a WHO grade 3 or 4 was observed) to the day when severe OM was resolved (first time WHO grade 2 or less was observed after last WHO grade 3 or 4). Durations of 0 days were assigned to those participants who did not experience any WHO grade 3 or 4 during the study.
Time Frame	Up to 15 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Placebo	Palifermin
Arm/Group Description	Participants received a single IV dose of placebo three days before the start of radiotherapy, and then 7 once weekly placebo doses during a 7-week radiotherapy/chemotherapy course.	Participants received a single intravenous dose of palifermin at 180 μg/kg three days before the start of radiotherapy, and then 7 once weekly palifermin doses at the same dose level during a 7-week radiotherapy/chemotherapy course.
Measure Participants	94	94
Median (Inter-Quartile Range) [days]	26.0	5.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Palifermin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0160
	Comments	Generalized Cochran-Mantel-Haenszel test for mean score difference.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by disease stage (III versus IV) and primary anatomical tumor location (oral cavity / oropharynx vs. nasopharynx vs. hypopharynx / larynx).
Method of Estimation	Estimation Parameter	Chi-Square Statistic
	Estimated Value	5.8002
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Palifermin
	Comments	To protect the overall type 1 error, the Hochberg procedure was used to adjust for multiple statistical testing of the secondary efficacy endpoints.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1122
	Comments	Adjusted p-value was based on Hochberg procedure to control for the Type 1 error.
	Method	Cochran-Mantel-Haenszel
	Comments

3. Secondary Outcome

Title	Time to Onset of Severe (WHO Grade 3 or 4) Oral Mucositis
Description	Time to onset of severe (WHO Grade 3 or 4) oral mucositis (OM) was analyzed using the Kaplan-Meier procedure. Participants without an assessed event by the end of the acute OM evaluation phase were censored at the date of last assessment for severe OM.
Time Frame	Up to 15 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Placebo	Palifermin
Arm/Group Description	Participants received a single IV dose of placebo three days before the start of radiotherapy, and then 7 once weekly placebo doses during a 7-week radiotherapy/chemotherapy course.	Participants received a single intravenous dose of palifermin at 180 μg/kg three days before the start of radiotherapy, and then 7 once weekly palifermin doses at the same dose level during a 7-week radiotherapy/chemotherapy course.
Measure Participants	94	94
Median (Inter-Quartile Range) [days]	35.0	47.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Palifermin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0261
	Comments
	Method	Stratified Log-Rank test
	Comments	Stratified by disease stage (III versus IV) and primary anatomical tumor location (oral cavity / oropharynx vs. nasopharynx vs. hypopharynx / larynx).
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.6603
	Confidence Interval	(2-Sided) 95%; 0.4546 to 0.9592
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio of palifermin over placebo based on Stratified Cox proportional hazard model.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Palifermin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1566
	Comments	Adjusted p-value was based on Hochberg procedure to control for the Type 1 error.
	Method	Stratified Log-Rank test
	Comments

4. Secondary Outcome

Title	Number of Participants With Xerostomia at Month 4 (Grade 2 or Higher)
Description	The number of participants with grade 2 or higher xerostomia (dryness of the oral mucosa) at the Month 4 visit, graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v3.0 Dry Mouth/Xerostomia scale.
Time Frame	Month 4

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Placebo	Palifermin
Arm/Group Description	Participants received a single IV dose of placebo three days before the start of radiotherapy, and then 7 once weekly placebo doses during a 7-week radiotherapy/chemotherapy course.	Participants received a single intravenous dose of palifermin at 180 μg/kg three days before the start of radiotherapy, and then 7 once weekly palifermin doses at the same dose level during a 7-week radiotherapy/chemotherapy course.
Measure Participants	94	94
Yes	57 60.6%	37 39.4%
No	19 20.2%	31 33%
Unknown	18 19.1%	26 27.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Palifermin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0463
	Comments	Generalized Cochran-Mantel-Haenszel test for general association. Participants having no assessment were assumed to have the event.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by disease stage (III versus IV) and primary anatomical tumor location (oral cavity / oropharynx vs. nasopharynx vs. hypopharynx / larynx).
Method of Estimation	Estimation Parameter	Chi-Square Statistic
	Estimated Value	3.9715
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Palifermin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2314
	Comments	Adjusted p-value was based on Hochberg procedure to control for the Type 1 error.
	Method	Cochran-Mantel-Haenszel
	Comments

5. Secondary Outcome

Title	Patient-Reported Mouth and Throat Soreness Score
Description	The average patient-reported mouth and throat soreness (MTS) score as reported on question 3 of the Oral Mucositis Weekly Questionnaire for Head and Neck Cancer [OMWQ-HN]): "How much mouth and throat soreness did you experience in the past 24 hours?" Participants answered on a scale from 0 (no soreness) to 4 (extreme soreness). For each participant, an average patient-reported mouth and throat soreness score was calculated by dividing the sum of the MTS scores at each assessment by the total number of assessments.
Time Frame	Assessed twice a week for up to 15 weeks.

Outcome Measure Data

Analysis Population Description

The Patient Reported Outcome-evaluable analysis set included all randomized patients with a valid Baseline assessment for MTS question 3 of the OMWQ-HN and either: At least 1 completed assessment each week for MTS up to withdrawal/Week 8, whichever came first, or 70% or greater overall compliance for MTS until withdrawal/Week 8.

Arm/Group Title	Placebo	Palifermin
Arm/Group Description	Participants received a single IV dose of placebo three days before the start of radiotherapy, and then 7 once weekly placebo doses during a 7-week radiotherapy/chemotherapy course.	Participants received a single intravenous dose of palifermin at 180 μg/kg three days before the start of radiotherapy, and then 7 once weekly palifermin doses at the same dose level during a 7-week radiotherapy/chemotherapy course.
Measure Participants	88	89
Mean (Standard Deviation) [units on a scale]	1.86 (0.65)	1.66 (0.73)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Palifermin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0712
	Comments	Generalized Cochran-Mantel-Haenszel test for mean score difference using modified ridit score
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by disease stage (III versus IV) and primary anatomical tumor location (oral cavity / oropharynx vs. nasopharynx vs. hypopharynx / larynx).
Method of Estimation	Estimation Parameter	Chi-Square Statistic
	Estimated Value	3.2548
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Palifermin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2849
	Comments	Adjusted p-value was based on Hochberg procedure to control for the Type 1 error.
	Method	Cochran-Mantel-Haenszel
	Comments

6. Secondary Outcome

Title	Total Dose of Opioid Analgesics Used for Mucositis Within 15 Weeks
Description	The total dose of opioid analgesics (mg of intravenous [IV] morphine equivalents) used by all participants. Participants with at least one reported administration of opioid analgesic (parenteral, peroral or transdermal) were considered to have received opioid analgesics. The total dose of opioid analgesics is the sum of all opioid analgesic administrations that have been converted to morphine equivalents.
Time Frame	Up to 15 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Placebo	Palifermin
Arm/Group Description	Participants received a single IV dose of placebo three days before the start of radiotherapy, and then 7 once weekly placebo doses during a 7-week radiotherapy/chemotherapy course.	Participants received a single intravenous dose of palifermin at 180 μg/kg three days before the start of radiotherapy, and then 7 once weekly palifermin doses at the same dose level during a 7-week radiotherapy/chemotherapy course.
Measure Participants	94	94
Mean (Standard Deviation) [mg of IV morphine equivalents]	1219.55 (1769.29)	1243.31 (2700.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Palifermin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2384
	Comments	Generalized Cochran-Mantel-Haenszel test for mean score difference using modified ridit score.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by disease stage (III versus IV) and primary anatomical tumor location (oral cavity / oropharynx vs. nasopharynx vs. hypopharynx / larynx).
Method of Estimation	Estimation Parameter	Chi-Square Statistic
	Estimated Value	1.3901
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Palifermin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6835
	Comments	Adjusted p-value was based on Hochberg procedure to control for the Type 1 error.
	Method	Cochran-Mantel-Haenszel
	Comments

7. Secondary Outcome

Title	Number of Participants With Unplanned Breaks in Cisplatin Chemotherapy Treatment
Description	Cisplatin was administered on Days 1, 22, and 43. An unplanned break in cisplatin refers to a delay of ≥ 5 days from the scheduled Day 22 or Day 43 cisplatin administration or a discontinuation of cisplatin for any reason.
Time Frame	During the 7 weeks of chemotherapy treatment

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Placebo	Palifermin
Arm/Group Description	Participants received a single IV dose of placebo three days before the start of radiotherapy, and then 7 once weekly placebo doses during a 7-week radiotherapy/chemotherapy course.	Participants received a single intravenous dose of palifermin at 180 μg/kg three days before the start of radiotherapy, and then 7 once weekly palifermin doses at the same dose level during a 7-week radiotherapy/chemotherapy course.
Measure Participants	94	94
Number [participants]	42 44.7%	49 52.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Palifermin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3417
	Comments	Generalized Cochran-Mantel-Haenszel test for general association
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by disease stage (III versus IV) and primary anatomical tumor location (oral cavity / oropharynx vs. nasopharynx vs. hypopharynx / larynx).
Method of Estimation	Estimation Parameter	Chi-Square Statistic
	Estimated Value	0.9039
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Palifermin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6835
	Comments	Adjusted p-value was based on Hochberg procedure to control for the Type 1 error.
	Method	Cochran-Mantel-Haenszel
	Comments

8. Secondary Outcome

Title	Number of Participants With Unplanned Breaks in Radiotherapy
Description	Participants with a duration of 5 days or more without an administration of radiotherapy or who discontinue radiotherapy prior to completion of planned radiotherapy were considered to have an unplanned break in radiotherapy.
Time Frame	During the 7 weeks of radiotherapy

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Placebo	Palifermin
Arm/Group Description	Participants received a single IV dose of placebo three days before the start of radiotherapy, and then 7 once weekly placebo doses during a 7-week radiotherapy/chemotherapy course.	Participants received a single intravenous dose of palifermin at 180 μg/kg three days before the start of radiotherapy, and then 7 once weekly palifermin doses at the same dose level during a 7-week radiotherapy/chemotherapy course.
Measure Participants	94	94
Number [participants]	11 11.7%	13 13.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Palifermin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9587
	Comments	Generalized Cochran-Mantel-Haenszel test for general association.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by disease stage (III versus IV) and primary anatomical tumor location (oral cavity / oropharynx vs. nasopharynx vs. hypopharynx / larynx).
Method of Estimation	Estimation Parameter	Chi-Square Statistic
	Estimated Value	0.0027
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Palifermin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9587
	Comments	Adjusted p-value was based on Hochberg procedure to control for the Type 1 error.
	Method	Cochran-Mantel-Haenszel
	Comments

Adverse Events

Time Frame	Approximately 8 weeks
Adverse Event Reporting Description	The table of Other Adverse Events summarizes non-serious occurrences of adverse events that exceeded a 5% frequency in either treatment arm.
Arm/Group Title	Placebo		Palifermin
Arm/Group Description	Participants received a single intravenous (IV) dose of placebo three days before the start of radiotherapy, and then 7 once weekly placebo doses during a 7-week radiotherapy/chemotherapy course.		Participants received a single intravenous dose of palifermin at 180 μg/kg three days before the start of radiotherapy, and then 7 once weekly palifermin doses at the same dose level during a 7-week radiotherapy/chemotherapy course.
All Cause Mortality
	Placebo		Palifermin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Palifermin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/91 (27.5%)		35/94 (37.2%)
Blood and lymphatic system disorders
Agranulocytosis	0/91 (0%)		1/94 (1.1%)
Anaemia	2/91 (2.2%)		0/94 (0%)
Febrile neutropenia	2/91 (2.2%)		2/94 (2.1%)
Haemoglobinaemia	0/91 (0%)		1/94 (1.1%)
Leukopenia	1/91 (1.1%)		1/94 (1.1%)
Neutropenia	0/91 (0%)		1/94 (1.1%)
Pancytopenia	0/91 (0%)		1/94 (1.1%)
Cardiac disorders
Cardiac failure	1/91 (1.1%)		2/94 (2.1%)
Cardio-respiratory arrest	1/91 (1.1%)		0/94 (0%)
Ear and labyrinth disorders
Hypoacusis	1/91 (1.1%)		1/94 (1.1%)
Gastrointestinal disorders
Diarrhoea	1/91 (1.1%)		0/94 (0%)
Dysphagia	2/91 (2.2%)		5/94 (5.3%)
Nausea	1/91 (1.1%)		2/94 (2.1%)
Odynophagia	1/91 (1.1%)		0/94 (0%)
Oral pain	0/91 (0%)		1/94 (1.1%)
Pancreatitis necrotising	0/91 (0%)		1/94 (1.1%)
Stomatitis	2/91 (2.2%)		1/94 (1.1%)
Vomiting	2/91 (2.2%)		3/94 (3.2%)
General disorders
Asthenia	0/91 (0%)		1/94 (1.1%)
General physical health deterioration	0/91 (0%)		2/94 (2.1%)
Mucosal inflammation	1/91 (1.1%)		4/94 (4.3%)
Hepatobiliary disorders
Hepatic cirrhosis	0/91 (0%)		1/94 (1.1%)
Hepatitis	1/91 (1.1%)		0/94 (0%)
Portal vein thrombosis	0/91 (0%)		1/94 (1.1%)
Immune system disorders
Hypersensitivity	0/91 (0%)		1/94 (1.1%)
Infections and infestations
Bronchitis	1/91 (1.1%)		0/94 (0%)
Bronchitis acute	0/91 (0%)		1/94 (1.1%)
Bronchopneumonia	0/91 (0%)		1/94 (1.1%)
Candidiasis	1/91 (1.1%)		0/94 (0%)
Catheter related infection	0/91 (0%)		1/94 (1.1%)
Catheter site infection	0/91 (0%)		2/94 (2.1%)
Clostridial infection	0/91 (0%)		1/94 (1.1%)
Colitis pseudomembranous	1/91 (1.1%)		1/94 (1.1%)
Infected epidermal cyst	0/91 (0%)		1/94 (1.1%)
Laryngitis	1/91 (1.1%)		0/94 (0%)
Pharyngitis	1/91 (1.1%)		0/94 (0%)
Pneumonia	3/91 (3.3%)		2/94 (2.1%)
Pulmonary sepsis	0/91 (0%)		1/94 (1.1%)
Sepsis	1/91 (1.1%)		2/94 (2.1%)
Urinary tract infection	1/91 (1.1%)		0/94 (0%)
Injury, poisoning and procedural complications
Alcohol poisoning	1/91 (1.1%)		0/94 (0%)
Device occlusion	0/91 (0%)		1/94 (1.1%)
Injury asphyxiation	0/91 (0%)		1/94 (1.1%)
Lumbar vertebral fracture	0/91 (0%)		1/94 (1.1%)
Post procedural haemorrhage	0/91 (0%)		1/94 (1.1%)
Tracheostomy malfunction	0/91 (0%)		1/94 (1.1%)
Investigations
Blood bilirubin abnormal	0/91 (0%)		1/94 (1.1%)
Blood creatinine abnormal	0/91 (0%)		1/94 (1.1%)
Blood creatinine increased	0/91 (0%)		2/94 (2.1%)
Blood lactate dehydrogenase abnormal	0/91 (0%)		1/94 (1.1%)
Blood phosphorus decreased	0/91 (0%)		1/94 (1.1%)
Blood potassium decreased	0/91 (0%)		1/94 (1.1%)
Blood sodium abnormal	0/91 (0%)		1/94 (1.1%)
Gamma-glutamyltransferase abnormal	0/91 (0%)		1/94 (1.1%)
Hepatic enzyme increased	1/91 (1.1%)		0/94 (0%)
Platelet count decreased	0/91 (0%)		1/94 (1.1%)
Weight decreased	1/91 (1.1%)		5/94 (5.3%)
White blood cell count decreased	0/91 (0%)		1/94 (1.1%)
Metabolism and nutrition disorders
Dehydration	9/91 (9.9%)		4/94 (4.3%)
Diabetes mellitus	0/91 (0%)		1/94 (1.1%)
Food intolerance	0/91 (0%)		1/94 (1.1%)
Hyperglycaemia	0/91 (0%)		1/94 (1.1%)
Hypoglycaemia	0/91 (0%)		1/94 (1.1%)
Hyponatraemia	0/91 (0%)		1/94 (1.1%)
Malnutrition	3/91 (3.3%)		0/94 (0%)
Musculoskeletal and connective tissue disorders
Neck pain	0/91 (0%)		1/94 (1.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Laryngeal neoplasm	0/91 (0%)		1/94 (1.1%)
Peritoneal carcinoma	0/91 (0%)		1/94 (1.1%)
Tumour haemorrhage	0/91 (0%)		1/94 (1.1%)
Nervous system disorders
Convulsion	0/91 (0%)		1/94 (1.1%)
Headache	0/91 (0%)		1/94 (1.1%)
Syncope	2/91 (2.2%)		2/94 (2.1%)
Syncope vasovagal	1/91 (1.1%)		0/94 (0%)
Psychiatric disorders
Delirium	1/91 (1.1%)		0/94 (0%)
Depression suicidal	1/91 (1.1%)		0/94 (0%)
Psychotic disorder due to a general medical condition	0/91 (0%)		1/94 (1.1%)
Renal and urinary disorders
Renal failure	4/91 (4.4%)		1/94 (1.1%)
Renal failure acute	2/91 (2.2%)		1/94 (1.1%)
Respiratory, thoracic and mediastinal disorders
Cryptogenic organizing pneumonia	1/91 (1.1%)		0/94 (0%)
Dyspnoea	1/91 (1.1%)		2/94 (2.1%)
Laryngeal oedema	2/91 (2.2%)		1/94 (1.1%)
Pharyngeal inflammation	0/91 (0%)		1/94 (1.1%)
Pharyngeal oedema	1/91 (1.1%)		0/94 (0%)
Pharyngolaryngeal pain	1/91 (1.1%)		0/94 (0%)
Pneumonia aspiration	2/91 (2.2%)		1/94 (1.1%)
Pneumonitis	0/91 (0%)		1/94 (1.1%)
Respiratory distress	0/91 (0%)		1/94 (1.1%)
Respiratory failure	1/91 (1.1%)		0/94 (0%)
Stridor	1/91 (1.1%)		0/94 (0%)
Vascular disorders
Deep vein thrombosis	0/91 (0%)		1/94 (1.1%)
Hypertension	0/91 (0%)		1/94 (1.1%)
Other (Not Including Serious) Adverse Events
	Placebo		Palifermin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	81/91 (89%)		89/94 (94.7%)
Blood and lymphatic system disorders
Anaemia	32/91 (35.2%)		21/94 (22.3%)
Leukopenia	11/91 (12.1%)		21/94 (22.3%)
Neutropenia	6/91 (6.6%)		10/94 (10.6%)
Thrombocytopenia	6/91 (6.6%)		2/94 (2.1%)
Ear and labyrinth disorders
Tinnitus	7/91 (7.7%)		11/94 (11.7%)
Gastrointestinal disorders
Constipation	24/91 (26.4%)		31/94 (33%)
Diarrhoea	14/91 (15.4%)		7/94 (7.4%)
Dry mouth	5/91 (5.5%)		9/94 (9.6%)
Dyspepsia	4/91 (4.4%)		5/94 (5.3%)
Dysphagia	19/91 (20.9%)		27/94 (28.7%)
Nausea	42/91 (46.2%)		46/94 (48.9%)
Odynophagia	5/91 (5.5%)		9/94 (9.6%)
Oesophagitis	0/91 (0%)		5/94 (5.3%)
Oral pain	3/91 (3.3%)		9/94 (9.6%)
Vomiting	24/91 (26.4%)		24/94 (25.5%)
General disorders
Asthenia	5/91 (5.5%)		4/94 (4.3%)
Fatigue	20/91 (22%)		21/94 (22.3%)
Malaise	1/91 (1.1%)		5/94 (5.3%)
Oedema peripheral	4/91 (4.4%)		6/94 (6.4%)
Pyrexia	19/91 (20.9%)		16/94 (17%)
Infections and infestations
Candidiasis	14/91 (15.4%)		11/94 (11.7%)
Oral candidiasis	11/91 (12.1%)		17/94 (18.1%)
Oral fungal infection	6/91 (6.6%)		5/94 (5.3%)
Injury, poisoning and procedural complications
Radiation skin injury	13/91 (14.3%)		25/94 (26.6%)
Investigations
Blood creatinine increased	4/91 (4.4%)		7/94 (7.4%)
Weight decreased	26/91 (28.6%)		25/94 (26.6%)
Metabolism and nutrition disorders
Anorexia	10/91 (11%)		12/94 (12.8%)
Dehydration	12/91 (13.2%)		10/94 (10.6%)
Hypokalaemia	8/91 (8.8%)		19/94 (20.2%)
Hypomagnesaemia	3/91 (3.3%)		5/94 (5.3%)
Nervous system disorders
Dizziness	5/91 (5.5%)		3/94 (3.2%)
Dysgeusia	7/91 (7.7%)		18/94 (19.1%)
Headache	5/91 (5.5%)		10/94 (10.6%)
Psychiatric disorders
Anxiety	8/91 (8.8%)		9/94 (9.6%)
Depression	3/91 (3.3%)		5/94 (5.3%)
Insomnia	10/91 (11%)		11/94 (11.7%)
Respiratory, thoracic and mediastinal disorders
Cough	13/91 (14.3%)		16/94 (17%)
Dysphonia	8/91 (8.8%)		11/94 (11.7%)
Dyspnoea	5/91 (5.5%)		6/94 (6.4%)
Pharyngolaryngeal pain	22/91 (24.2%)		20/94 (21.3%)
Skin and subcutaneous tissue disorders
Alopecia	1/91 (1.1%)		6/94 (6.4%)
Dermatitis	10/91 (11%)		4/94 (4.3%)
Rash	4/91 (4.4%)		9/94 (9.6%)
Skin hyperpigmentation	1/91 (1.1%)		5/94 (5.3%)
Vascular disorders
Flushing	0/91 (0%)		6/94 (6.4%)
Hypertension	4/91 (4.4%)		5/94 (5.3%)

Limitations/Caveats

[Not Specified]

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