Trial to Evaluate Palifermin in the Reduction of Acute Graft Versus Host Disease in Patients With Hematologic Malignancies Undergoing Allogeneic Marrow/Peripheral Blood Progenitor Cell (PBPC) Transplantation

• Sponsor: Swedish Orphan Biovitrum (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00189488
• Collaborator: Amgen (Industry)
• Enrollment: 155
• Arms: 2
• Duration (Months): 92

Study Details

Study Description

Brief Summary

The main purpose of this study is to evaluate the effect of palifermin versus placebo in the reduction of severe acute graft versus host disease (GVHD) and severe oral mucositis.

Condition or Disease	Intervention/Treatment	Phase
Graft Versus Host Disease; Hematologic Malignancies	Drug: Palifermin; Drug: Placebo; Other: Conditioning Regimen; Procedure: Allogeneic stem cell transplant; Drug: Methotrexate	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 155 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled Trial to Evaluate Palifermin (rHuKGF) in the Reduction of Acute Graft Versus Host Disease in Subjects With Hematologic Malignancies Undergoing Allogeneic Marrow/PBPC Transplantation
• Study Start Date: Dec 1, 2005
• Actual Primary Completion Date: Nov 1, 2008
• Actual Study Completion Date: Aug 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Palifermin Palifermin 60 μg/kg administered daily on 3 consecutive days prior to the day of start of the conditioning regimen and 180 μg/kg administered once prior to transplant and at least 96 hours from last palifermin dose of 60 μg/kg. Participants received conditioning therapy starting at least 24 hours after the last 60 μg dose of palifermin. Allogeneic stem cell transplant occurred on Day 0. Methotrexate dosing began at least 24 hours after the 180 μg/kg dose of palifermin on Days 1, 3, 6 and (planned) 11 administration (toxicity allowing) at doses of 15, 10, 10 and 10 mg/m^2 respectively.	Drug: Palifermin; Administered as an intravenous (IV) bolus.; Other Names: Recombinant human keratinocyte growth factor (rHuKGF) Kepivance ; Other: Conditioning Regimen; Each participant received 1 of the following conditioning regimens: Cyclophosphamide (Cy) / total body irradiation (TBI) with and without etoposide (VP-16) TBI/VP-16 Melphalan (Mel)/TBI (TBI regimens must include fully ablative doses ie > 1100 cGy; sequence of chemotherapy/radiation (CT/RT) flexible) Busulfan (Bu)/Cy Bu/Mel (non-TBI but fully ablative regimens/doses [Mel dose > 140 mg/m^2]) Fludarabine (Flu)/Mel (non-TBI but fully ablative regimens/doses [Mel dose > 140 mg/m^2]); Procedure: Allogeneic stem cell transplant; Allogeneic marrow/peripheral blood progenitor cell transplantation; Drug: Methotrexate
Placebo Comparator: Placebo Placebo to palifermin 60 μg/kg administered daily on 3 consecutive days prior to the day of start of the conditioning regimen and placebo to palifermin 180 μg/kg once prior to transplant and at least 96 hours from previous placebo to palifermin 60 μg/kg dose. Participants received conditioning therapy starting at least 24 hours after the last 60 μg/kg dose of placebo to palifermin. Allogeneic stem cell transplant occurred on Day 0. Methotrexate dosing began at least 24 hours after the dose of placebo to palifermin 180 μg/kg on Days 1, 3, 6 and (planned) 11 administration (toxicity allowing) at doses of 15, 10, 10 and 10 mg/m^2 respectively.	Drug: Placebo; Administered as an intravenous (IV) bolus.; Other: Conditioning Regimen; Each participant received 1 of the following conditioning regimens: Cyclophosphamide (Cy) / total body irradiation (TBI) with and without etoposide (VP-16) TBI/VP-16 Melphalan (Mel)/TBI (TBI regimens must include fully ablative doses ie > 1100 cGy; sequence of chemotherapy/radiation (CT/RT) flexible) Busulfan (Bu)/Cy Bu/Mel (non-TBI but fully ablative regimens/doses [Mel dose > 140 mg/m^2]) Fludarabine (Flu)/Mel (non-TBI but fully ablative regimens/doses [Mel dose > 140 mg/m^2]); Procedure: Allogeneic stem cell transplant; Allogeneic marrow/peripheral blood progenitor cell transplantation; Drug: Methotrexate

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Severe (Grade 3 and 4) Acute Graft Versus Host Disease (GVHD) [From transplant (Day 0) until Day 100]

   GVHD was graded using the modified Keystone Criteria weekly during the first 2 months after stem cell infusion, then every other week until Day 100. Severity was determined clinically (based on physical exam and laboratory serum values) and from biopsies of affected organs whenever possible. The degree of GVHD in individual organs was scored by at least 2 assessors. Grade 3 GVHD = total bilirubin 3.1 - 15.0 mg/dL or ≥ 1000 mL/day diarrhea or severe abdominal pain with/without ileus. Grade 4 GVHD = skin involvement with bullous formation or total bilirubin > 15.0 mg/dL.

Secondary Outcome Measures

1. Number of Participants With Grade 2 to 4 Acute Graft Versus Host Disease (GVHD) [From transplant (Day 0) until Day 100]

   GVHD was graded using the modified Keystone Criteria weekly during the first 2 months after stem cell infusion, then every other week until Day 100. Severity was determined clinically (based on physical exam and laboratory serum values) and from biopsies of affected organs whenever possible. The degree of GVHD in individual organs was scored by at least 2 assessors. Grade 2 GVHD = > 50% skin involvement or total bilirubin 2.0 - 3.0 mg/dL or 500 - 999 mL/day diarrhea, or persistent nausea with histologic evidence. Grade 3 GVHD = total bilirubin 3.1 - 15.0 mg/dL or ≥ 1000 mL/day diarrhea or severe abdominal pain with/without ileus. Grade 4 GVHD = skin involvement with bullous formation or total bilirubin > 15.0 mg/dL.

2. Number of Participants With Day 11 Methotrexate Graft Versus Host Disease Prophylaxis Administration [Day 11]

   Low dose methotrexate is widely used in regimens to prophylax against acute GVHD. Methotrexate was administered on days 1, 3, 6 and 11 (toxicity allowing) at doses of 15, 10, 10 and 10 mg/m^2, respectively.

3. Number of Participants With Severe (Grade 3 or 4) Oral Mucositis [From transplant (Day 0) until Day 100]

   Oral cavity assessments were performed by a trained assessor using the World Health Organization (WHO) oral toxicity scale. Daily oral mucositis assessments were performed: while participants were hospitalized, including the day of discharge (maximum until day 28); after discharge until the oral mucositis grade returns to a WHO grade ≤ 2. The WHO oral toxicity criteria are: 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.

4. Duration of Severe Oral Mucositis (WHO Grade 3 and 4) [From transplant (Day 0) until Day 100]

   The duration of severe oral mucositis was calculated as the number of days from the onset of severe mucositis (first time a WHO grade of 3 or 4 was observed) to the last day when severe mucositis was observed. If oral mucositis assessments were recorded as missed visits immediately prior to or immediately after severe mucositis was recorded, the missed visits were considered to be severe oral mucositis.

5. Number of Participants With Parenteral or Transdermal Opioid Analgesic Use [From transplant (Day 0) until Day 100]

   Includes nonprophylactic intravenous opioid analgesics (fentanyl, morphine, morphine sulphate, hydromorphone, meperidine) and transdermal opioid analgesics (fentanyl patch) for the indication of oral mucositis and dysphagia.

6. Duration of Hospitalization [From transplant (Day 0) until Day 100]

   Duration of hospitalization was defined as the number of days a participant stayed in hospital (hospitalized) during the period starting from the day of the transplant (Day 0) to the 100th day following the transplant.

7. Area Under the Curve (AUC) of Mouth and Throat Soreness Score [The first day of study drug administration through Day 28.]

   The modified Oral Mucositis Daily Questionnaire (OMDQ) is a self-reported tool that evaluates overall health, mouth and throat soreness (MTS) and activity limitations due to MTS. The modified OMDQ was completed once daily beginning with the first day of study drug administration through day 28. The area under the curve of mouth and throat soreness score was assessed from the question "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).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Subjects with hematologic malignancies (including myelodysplastic syndromes [MDS]) who are considered eligible for Cyclophosphamide (Cy)/Total Body Irradiation(TBI) +/- Etoposide (VP-16); Total Body Irradiation(TBI)/ Etoposide(VP-16); Melphalan(Mel) / Total Body Irradiation(TBI); Busulfan(Bu)/ Cyclophosphamide(Cy); Busulfan(Bu)/ Melphalan (Mel); or Fludarabine(Flu)/ Melphalan(Mel) conditioning therapy with allogeneic stem cell support

• Subjects with a 6/6 Human Leukocyte Antigen (HLA)-matched family member or unrelated donor who would provide donor marrow/ peripheral progenitor stem cells. [For unrelated matched donors, molecular typing of class I and class II is mandatory]

• Karnofsky Performance Status >= 70%

• 18 years of age or older at time of informed consent

• Before any study-specific procedure, the appropriate written informed consent must be obtained

Exclusion Criteria:

• Cancer other than Non-Hodgkin's lymphoma, Hodgkin's disease, acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, myelodysplastic syndrome or multiple myeloma (except: adequately treated basal cell carcinoma of the skin)

• Prior autologous or allogeneic bone marrow or peripheral blood stem cell transplantation

• Previous use of palifermin

• Current active infection (including human immunodeficiency virus (HIV) and hepatitis) or oral mucositis

• Congestive heart failure as defined by New York Heart Association class III or IV

• Graft T-cell depletion for Graft-versus-host disease (GVHD) prophylaxis

• Inadequate renal function (serum creatinine > 1.5x the upper limit of normal per the institutional guidelines or clearance < 40 ml/min adjusted for age)

• Inadequate liver function (total bilirubin > 1.5x the upper limit of normal, aspartate aminotransferase (AST) > 3x upper limit of normal and/or alanine aminotransferase (ALT) > 3x upper limit of normal per the institutional guidelines)

• Inadequate pulmonary function as measured by a corrected DLCO (diffusing capacity of the lung for carbon monoxide lung function test) <50% of predicted

• Subject is currently enrolled in or has not yet completed at least 30 days since ending other investigational device or drug trial(s), or subject is receiving other investigational agent(s)

• Subject of child-bearing potential is evidently pregnant (e.g. positive human chorionic gonadotropin- HCG test) or is breast feeding during Part A of the study

• Subject or partner of subject is not using or refuses to use adequate contraceptive precautions during Part A of the study

• Subject has known sensitivity to any of the products to be administered during dosing including Escherichia coli-derived products

• Subject was previously randomized into this study

• Subject will not be available for follow-up assessments

• Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures

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: NCT00189488
• Other Study ID Numbers: 20040213; NCT00964899
• First Posted: Sep 19, 2005
• Last Update Posted: Sep 15, 2014
• Last Verified: Sep 1, 2014

• Keywords provided by Swedish Orphan Biovitrum: Hematological Malignancies; Graft-versus-host-disease; Oral Mucositis; Allogeneic Transplantation
• Additional relevant MeSH terms: Neoplasms; Hematologic Neoplasms; Graft vs Host Disease; Methotrexate

Study Results

Participant Flow

Arm/Group Title	Placebo	Palifermin
Arm/Group Description	Placebo to 60 μg/kg palifermin administered daily on 3 consecutive days prior to the day of start of the conditioning regimen and placebo to 180 μg/kg palifermin once prior to transplant and at least 96 hours from the previous placebo dose. Participants received conditioning therapy starting at least 24 hours after the last 60 μg/kg dose of placebo to palifermin. Allogeneic stem cell transplant occurred on Day 0. Methotrexate dosing began at least 24 hours after the dose of placebo to palifermin 180 μg/kg on Days 1, 3, 6 and (planned) 11 administration (toxicity allowing) at doses of 15, 10, 10 and 10 mg/m^2 respectively.	Palifermin 60 μg/kg administered daily on 3 consecutive days prior to the day of start of the conditioning regimen and 180 μg/kg administered once prior to transplant and at least 96 hours from last palifermin dose of 60 μg/kg. Participants received conditioning therapy starting at least 24 hours after the last 60 μg dose of palifermin. Allogeneic stem cell transplant occurred on Day 0. Methotrexate dosing began at least 24 hours after the 180 μg/kg dose of palifermin on Days 1, 3, 6 and (planned) 11 administration (toxicity allowing) at doses of 15, 10, 10 and 10 mg/m^2 respectively
Period Title: Overall Study
STARTED	78	77
Received Palifermin/Placebo	75	76
COMPLETED	63	55
NOT COMPLETED	15	22

Baseline Characteristics

Arm/Group Title	Placebo	Palifermin	Total
Arm/Group Description	Placebo to 60 μg/kg palifermin administered daily on 3 consecutive days prior to the day of start of the conditioning regimen and placebo to 180 μg/kg palifermin administered once, prior to transplant and at least 96 hours from the previous placebo dose.	Palifermin 60 μg/kg administered daily on 3 consecutive days prior to the day of start of the conditioning regimen and 180 μg/kg administered once prior to transplant and at least 96 hours from last palifermin dose of 60 μg/kg.	Total of all reporting groups
Overall Participants	78	77	155
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	42.2 (10.5)	40.4 (12.1)	41.3 (11.3)
Sex: Female, Male (Count of Participants)
Female	29 37.2%	37 48.1%	66 42.6%
Male	49 62.8%	40 51.9%	89 57.4%
Race/Ethnicity, Customized (participants) [Number]
White or Caucasian	67 85.9%	65 84.4%	132 85.2%
Black or African American	4 5.1%	3 3.9%	7 4.5%
Hispanic or Latino	4 5.1%	5 6.5%	9 5.8%
Asian	2 2.6%	3 3.9%	5 3.2%
Native Hawaiian or Other Pacific Islander	1 1.3%	0 0%	1 0.6%
Other	0 0%	1 1.3%	1 0.6%
Type of diagnosis (participants) [Number]
Leukemia - all types	62 79.5%	55 71.4%	117 75.5%
Acute lymphoblastic leukemia	15 19.2%	17 22.1%	32 20.6%
Acute myelogenous leukemia	34 43.6%	29 37.7%	63 40.6%
Chronic lymphocytic leukemia	7 9%	3 3.9%	10 6.5%
Chronic myelogenous leukemia	6 7.7%	6 7.8%	12 7.7%
Hodgkin's disease	0 0%	1 1.3%	1 0.6%
Non-Hodgkin's lymphoma	6 7.7%	9 11.7%	15 9.7%
Multiple Myeloma	1 1.3%	0 0%	1 0.6%
Myelodysplastic Syndrome	9 11.5%	12 15.6%	21 13.5%
Donor type (participants) [Number]
Related Family Member	46 59%	45 58.4%	91 58.7%
Unrelated	32 41%	32 41.6%	64 41.3%
Donor source (participants) [Number]
Marrow	17 21.8%	18 23.4%	35 22.6%
Peripheral blood progenitor cell(s)	61 78.2%	59 76.6%	120 77.4%
Prior radiotherapy (participants) [Number]
Yes	3 3.8%	4 5.2%	7 4.5%
No	75 96.2%	73 94.8%	148 95.5%

Outcome Measures

1. Secondary Outcome

Title	Number of Participants With Grade 2 to 4 Acute Graft Versus Host Disease (GVHD)
Description	GVHD was graded using the modified Keystone Criteria weekly during the first 2 months after stem cell infusion, then every other week until Day 100. Severity was determined clinically (based on physical exam and laboratory serum values) and from biopsies of affected organs whenever possible. The degree of GVHD in individual organs was scored by at least 2 assessors. Grade 2 GVHD = > 50% skin involvement or total bilirubin 2.0 - 3.0 mg/dL or 500 - 999 mL/day diarrhea, or persistent nausea with histologic evidence. Grade 3 GVHD = total bilirubin 3.1 - 15.0 mg/dL or ≥ 1000 mL/day diarrhea or severe abdominal pain with/without ileus. Grade 4 GVHD = skin involvement with bullous formation or total bilirubin > 15.0 mg/dL.
Time Frame	From transplant (Day 0) until Day 100

Outcome Measure Data

Analysis Population Description

Primary Analysis Set (consisting of all randomized participants) with GVHD assessments.

Arm/Group Title	Placebo	Palifermin
Arm/Group Description	Placebo to 60 μg/kg palifermin administered daily on 3 consecutive days prior to the day of start of the conditioning regimen and placebo to 180 μg/kg palifermin administered once, prior to transplant and at least 96 hours from the previous placebo dose.	Palifermin 60 μg/kg administered daily on 3 consecutive days prior to the day of start of the conditioning regimen and 180 μg/kg administered once prior to transplant and at least 96 hours from last palifermin dose of 60 μg/kg.
Measure Participants	72	74
Yes	29 37.2%	43 55.8%
No	43 55.1%	31 40.3%

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	0.034
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Adjusted for the stratification factors (TBI use, matched donor type, and source of donor cells) using the Cochran-Mantel-Haenszel weights.
Method of Estimation	Estimation Parameter	Adjusted Treatment Difference (%)
	Estimated Value	-17.9
	Confidence Interval	(2-Sided) 95%; -33.4 to -2.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference between treatment groups in the percentage of participants with Grade 2 to 4 acute GVHD, adjusted for the stratification factors (TBI use, matched donor type, and source of donor cells) using the Cochran-Mantel-Haenszel weights.

2. Primary Outcome

Title	Number of Participants With Severe (Grade 3 and 4) Acute Graft Versus Host Disease (GVHD)
Description	GVHD was graded using the modified Keystone Criteria weekly during the first 2 months after stem cell infusion, then every other week until Day 100. Severity was determined clinically (based on physical exam and laboratory serum values) and from biopsies of affected organs whenever possible. The degree of GVHD in individual organs was scored by at least 2 assessors. Grade 3 GVHD = total bilirubin 3.1 - 15.0 mg/dL or ≥ 1000 mL/day diarrhea or severe abdominal pain with/without ileus. Grade 4 GVHD = skin involvement with bullous formation or total bilirubin > 15.0 mg/dL.
Time Frame	From transplant (Day 0) until Day 100

Outcome Measure Data

Analysis Population Description

Primary Analysis Set (consisting of all randomized participants) with GVHD assessments. Efficacy analyses were according to randomized treatment assignment.

Arm/Group Title	Placebo	Palifermin
Arm/Group Description	Placebo to 60 μg/kg palifermin administered daily on 3 consecutive days prior to the day of start of the conditioning regimen and placebo to 180 μg/kg palifermin administered once, prior to transplant and at least 96 hours from the previous placebo dose.	Palifermin 60 μg/kg administered daily on 3 consecutive days prior to the day of start of the conditioning regimen and 180 μg/kg administered once prior to transplant and at least 96 hours from last palifermin dose of 60 μg/kg.
Measure Participants	72	74
Yes	12 15.4%	12 15.6%
No	60 76.9%	62 80.5%

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	0.929
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Adjusted for the stratification factors (TBI use, matched donor type, and source of donor cells) using the Cochran-Mantel-Haenszel weights.
Method of Estimation	Estimation Parameter	Adjusted Difference (%)
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 95%; -11.0 to 12.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference between treatment groups in the percentage of participants with severe GVHD, adjusted for the stratification factors (TBI use, matched donor type, and source of donor cells) using the Cochran-Mantel-Haenszel weights.

3. Secondary Outcome

Title	Number of Participants With Day 11 Methotrexate Graft Versus Host Disease Prophylaxis Administration
Description	Low dose methotrexate is widely used in regimens to prophylax against acute GVHD. Methotrexate was administered on days 1, 3, 6 and 11 (toxicity allowing) at doses of 15, 10, 10 and 10 mg/m^2, respectively.
Time Frame	Day 11

Outcome Measure Data

Analysis Population Description

Primary Analysis Set

Arm/Group Title	Placebo	Palifermin
Arm/Group Description	Placebo to 60 μg/kg palifermin administered daily on 3 consecutive days prior to the day of start of the conditioning regimen and placebo to 180 μg/kg palifermin administered once, prior to transplant and at least 96 hours from the previous placebo dose.	Palifermin 60 μg/kg administered daily on 3 consecutive days prior to the day of start of the conditioning regimen and 180 μg/kg administered once prior to transplant and at least 96 hours from last palifermin dose of 60 μg/kg.
Measure Participants	78	77
Yes	56 71.8%	60 77.9%
No	22 28.2%	17 22.1%

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	0.352
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Adjusted for the stratification factors (TBI use, matched donor type, and source of donor cells) using the Cochran-Mantel-Haenszel weights.
Method of Estimation	Estimation Parameter	Adjusted Treatment Difference (%)
	Estimated Value	-6.5
	Confidence Interval	(2-Sided) 95%; -19.4 to 6.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference between treatment groups in the percentage of participants with Day 11 Methotrexate GVHD, adjusted for the stratification factors (TBI use, matched donor type, and source of donor cells) using the Cochran-Mantel-Haenszel weights.

4. Secondary Outcome

Title	Number of Participants With Severe (Grade 3 or 4) Oral Mucositis
Description	Oral cavity assessments were performed by a trained assessor using the World Health Organization (WHO) oral toxicity scale. Daily oral mucositis assessments were performed: while participants were hospitalized, including the day of discharge (maximum until day 28); after discharge until the oral mucositis grade returns to a WHO grade ≤ 2. The WHO oral toxicity criteria are: 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	From transplant (Day 0) until Day 100

Outcome Measure Data

Analysis Population Description

Primary Analysis Set

Arm/Group Title	Placebo	Palifermin
Arm/Group Description	Placebo to 60 μg/kg palifermin administered daily on 3 consecutive days prior to the day of start of the conditioning regimen and placebo to 180 μg/kg palifermin administered once, prior to transplant and at least 96 hours from the previous placebo dose.	Palifermin 60 μg/kg administered daily on 3 consecutive days prior to the day of start of the conditioning regimen and 180 μg/kg administered once prior to transplant and at least 96 hours from last palifermin dose of 60 μg/kg.
Measure Participants	78	77
Yes	57 73.1%	62 80.5%
No	16 20.5%	13 16.9%
Unknown	5 6.4%	2 2.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Palifermin
	Comments	Participants with "Unknown" incidence are treated as "Yes" when constructing the differences, 95% confidence intervals and p-value.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.675
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Adjusted for the stratification factors (TBI use, matched donor type, and source of donor cells) using the Cochran-Mantel-Haenszel weights.
Method of Estimation	Estimation Parameter	Adjusted Treatment Difference (%)
	Estimated Value	-2.6
	Confidence Interval	(2-Sided) 95%; -14.2 to 9.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference between treatment groups in the percentage of participants with severe oral mucositis, adjusted for the stratification factors (TBI use, matched donor type, and source of donor cells) using the Cochran-Mantel-Haenszel weights.

5. Secondary Outcome

Title	Duration of Severe Oral Mucositis (WHO Grade 3 and 4)
Description	The duration of severe oral mucositis was calculated as the number of days from the onset of severe mucositis (first time a WHO grade of 3 or 4 was observed) to the last day when severe mucositis was observed. If oral mucositis assessments were recorded as missed visits immediately prior to or immediately after severe mucositis was recorded, the missed visits were considered to be severe oral mucositis.
Time Frame	From transplant (Day 0) until Day 100

Outcome Measure Data

Analysis Population Description

Primary Analysis Set

Arm/Group Title	Placebo	Palifermin
Arm/Group Description	Placebo to 60 μg/kg palifermin administered daily on 3 consecutive days prior to the day of start of the conditioning regimen and placebo to 180 μg/kg palifermin administered once, prior to transplant and at least 96 hours from the previous placebo dose.	Palifermin 60 μg/kg administered daily on 3 consecutive days prior to the day of start of the conditioning regimen and 180 μg/kg administered once prior to transplant and at least 96 hours from last palifermin dose of 60 μg/kg.
Measure Participants	78	77
Mean (Standard Deviation) [days]	8.1 (6.8)	7.8 (6.7)

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	0.953
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Adjusted for the stratification factors (TBI use, matched donor type, and source of donor cells) using the Cochran-Mantel-Haenszel weights.
Method of Estimation	Estimation Parameter	Adjusted Treatment Difference
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 95%; -1.5 to 2.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted for the stratification factors (TBI use, matched donor type, and source of donor cells) using the Cochran-Mantel-Haenszel weights.

6. Secondary Outcome

Title	Number of Participants With Parenteral or Transdermal Opioid Analgesic Use
Description	Includes nonprophylactic intravenous opioid analgesics (fentanyl, morphine, morphine sulphate, hydromorphone, meperidine) and transdermal opioid analgesics (fentanyl patch) for the indication of oral mucositis and dysphagia.
Time Frame	From transplant (Day 0) until Day 100

Outcome Measure Data

Analysis Population Description

Primary Analysis Set

Arm/Group Title	Placebo	Palifermin
Arm/Group Description	Placebo to 60 μg/kg palifermin administered daily on 3 consecutive days prior to the day of start of the conditioning regimen and placebo to 180 μg/kg palifermin administered once, prior to transplant and at least 96 hours from the previous placebo dose.	Palifermin 60 μg/kg administered daily on 3 consecutive days prior to the day of start of the conditioning regimen and 180 μg/kg administered once prior to transplant and at least 96 hours from last palifermin dose of 60 μg/kg.
Measure Participants	78	77
Yes	50 64.1%	48 62.3%
No	28 35.9%	29 37.7%

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	0.797
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Adjusted for the stratification factors (TBI use, matched donor type, and source of donor cells) using the Cochran-Mantel-Haenszel weights.
Method of Estimation	Estimation Parameter	Adjusted Treatment Difference (%)
	Estimated Value	2.0
	Confidence Interval	(2-Sided) 95%; -12.5 to 16.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference between treatment groups in the percentage of participants with opioid analgesic use, adjusted for the stratification factors (TBI use, matched donor type, and source of donor cells) using the Cochran-Mantel-Haenszel weights.

7. Secondary Outcome

Title	Duration of Hospitalization
Description	Duration of hospitalization was defined as the number of days a participant stayed in hospital (hospitalized) during the period starting from the day of the transplant (Day 0) to the 100th day following the transplant.
Time Frame	From transplant (Day 0) until Day 100

Outcome Measure Data

Analysis Population Description

Primary analysis set

Arm/Group Title	Placebo	Palifermin
Arm/Group Description	Placebo to 60 μg/kg palifermin administered daily on 3 consecutive days prior to the day of start of the conditioning regimen and placebo to 180 μg/kg palifermin administered once, prior to transplant and at least 96 hours from the previous placebo dose.	PaPalifermin 60 μg/kg administered daily on 3 consecutive days prior to the day of start of the conditioning regimen and 180 μg/kg administered once prior to transplant and at least 96 hours from last palifermin dose of 60 μg/kg.
Measure Participants	78	77
Mean (Standard Deviation) [days]	36.1 (20.8)	42.2 (25.1)

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	0.186
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Adjusted for the stratification factors (TBI use, matched donor type, and source of donor cells) using the Cochran-Mantel-Haenszel weights.
Method of Estimation	Estimation Parameter	Adjusted Treatment Difference
	Estimated Value	-5.5
	Confidence Interval	(2-Sided) 95%; -12.7 to 1.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted for the stratification factors (TBI use, matched donor type, and source of donor cells) using the Cochran-Mantel-Haenszel weights.

8. Secondary Outcome

Title	Area Under the Curve (AUC) of Mouth and Throat Soreness Score
Description	The modified Oral Mucositis Daily Questionnaire (OMDQ) is a self-reported tool that evaluates overall health, mouth and throat soreness (MTS) and activity limitations due to MTS. The modified OMDQ was completed once daily beginning with the first day of study drug administration through day 28. The area under the curve of mouth and throat soreness score was assessed from the question "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).
Time Frame	The first day of study drug administration through Day 28.

Outcome Measure Data

Analysis Population Description

Primary analysis set

Arm/Group Title	Placebo	Palifermin
Arm/Group Description	Placebo to 60 μg/kg palifermin administered daily on 3 consecutive days prior to the day of start of the conditioning regimen and placebo to 180 μg/kg palifermin administered once, prior to transplant and at least 96 hours from the previous placebo dose.	Palifermin 60 μg/kg administered daily on 3 consecutive days prior to the day of start of the conditioning regimen and 180 μg/kg administered once prior to transplant and at least 96 hours from last palifermin dose of 60 μg/kg.
Measure Participants	78	77
Mean (Standard Deviation) [MTS score * days]	43.0 (26.3)	47.7 (26.2)

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	0.219
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Adjusted for the stratification factors (TBI use, matched donor type, and source of donor cells) using the Cochran-Mantel-Haenszel weights.
Method of Estimation	Estimation Parameter	Adjusted Treatment Difference
	Estimated Value	-4.1
	Confidence Interval	(2-Sided) 05%; -12.2 to 4.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted for the stratification factors (TBI use, matched donor type, and source of donor cells) using the Cochran-Mantel-Haenszel weights.

Adverse Events

Time Frame	125 Days
Adverse Event Reporting Description	The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events. Two participants were randomized to the Placebo arm but received palifermin inadvertently and were summarized in Palifermin arm.
Arm/Group Title	Placebo		Palifermin
Arm/Group Description	Placebo to 60 μg/kg palifermin administered daily on 3 consecutive days prior to the day of start of the conditioning regimen and placebo to 180 μg/kg palifermin administered once, prior to transplant and at least 96 hours from the previous placebo dose.		Palifermin 60 μg/kg administered daily on 3 consecutive days prior to the day of start of the conditioning regimen and 180 μg/kg administered once prior to transplant and at least 96 hours from last palifermin dose of 60 μg/kg.
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	40/73 (54.8%)		50/78 (64.1%)
Blood and lymphatic system disorders
Febrile neutropenia	0/73 (0%)		2/78 (2.6%)
Neutropenia	0/73 (0%)		1/78 (1.3%)
Pancytopenia	0/73 (0%)		2/78 (2.6%)
Thrombocytopenia	0/73 (0%)		1/78 (1.3%)
Cardiac disorders
Angina pectoris	1/73 (1.4%)		0/78 (0%)
Atrial fibrillation	0/73 (0%)		2/78 (2.6%)
Cardiac failure congestive	1/73 (1.4%)		1/78 (1.3%)
Sinus tachycardia	0/73 (0%)		1/78 (1.3%)
Tachycardia	1/73 (1.4%)		1/78 (1.3%)
Ventricular arrhythmia	1/73 (1.4%)		0/78 (0%)
Ventricular fibrillation	0/73 (0%)		1/78 (1.3%)
Gastrointestinal disorders
Abdominal pain	3/73 (4.1%)		1/78 (1.3%)
Caecitis	0/73 (0%)		1/78 (1.3%)
Diarrhoea	3/73 (4.1%)		2/78 (2.6%)
Gastritis	0/73 (0%)		1/78 (1.3%)
Nausea	4/73 (5.5%)		4/78 (5.1%)
Oesophagitis	0/73 (0%)		1/78 (1.3%)
Oral pain	1/73 (1.4%)		0/78 (0%)
Pneumatosis intestinalis	1/73 (1.4%)		0/78 (0%)
Vomiting	3/73 (4.1%)		2/78 (2.6%)
General disorders
Asthenia	0/73 (0%)		1/78 (1.3%)
Face oedema	0/73 (0%)		1/78 (1.3%)
Fatigue	0/73 (0%)		1/78 (1.3%)
Mucosal inflammation	0/73 (0%)		2/78 (2.6%)
Multi-organ failure	0/73 (0%)		3/78 (3.8%)
Oedema peripheral	0/73 (0%)		1/78 (1.3%)
Pyrexia	10/73 (13.7%)		10/78 (12.8%)
Hepatobiliary disorders
Hepatic function abnormal	0/73 (0%)		1/78 (1.3%)
Immune system disorders
Graft versus host disease	12/73 (16.4%)		17/78 (21.8%)
Graft versus host disease in liver	0/73 (0%)		1/78 (1.3%)
Immunodeficiency	0/73 (0%)		1/78 (1.3%)
Transplant rejection	1/73 (1.4%)		1/78 (1.3%)
Infections and infestations
Bacteraemia	5/73 (6.8%)		2/78 (2.6%)
Bacterial infection	0/73 (0%)		1/78 (1.3%)
Catheter related infection	0/73 (0%)		2/78 (2.6%)
Catheter sepsis	0/73 (0%)		1/78 (1.3%)
Cellulitis	1/73 (1.4%)		0/78 (0%)
Central line infection	0/73 (0%)		1/78 (1.3%)
Cytomegalovirus infection	2/73 (2.7%)		1/78 (1.3%)
Enterobacter infection	1/73 (1.4%)		0/78 (0%)
Enterococcal bacteraemia	0/73 (0%)		1/78 (1.3%)
Enterococcal infection	2/73 (2.7%)		0/78 (0%)
Escherichia infection	0/73 (0%)		1/78 (1.3%)
Febrile infection	0/73 (0%)		1/78 (1.3%)
Gastroenteritis viral	0/73 (0%)		1/78 (1.3%)
Herpes simplex	0/73 (0%)		1/78 (1.3%)
Influenza	0/73 (0%)		1/78 (1.3%)
Mycobacterial infection	1/73 (1.4%)		0/78 (0%)
Neutropenic sepsis	1/73 (1.4%)		0/78 (0%)
Pneumonia	3/73 (4.1%)		2/78 (2.6%)
Pneumonia aspergillus	0/73 (0%)		1/78 (1.3%)
Pneumonia cytomegaloviral	1/73 (1.4%)		0/78 (0%)
Pneumonia klebsiella	1/73 (1.4%)		0/78 (0%)
Pneumonia respiratory syncytial viral	0/73 (0%)		1/78 (1.3%)
Pneumonia staphylococcal	1/73 (1.4%)		1/78 (1.3%)
Pseudomonas infection	0/73 (0%)		1/78 (1.3%)
Rectal abscess	0/73 (0%)		1/78 (1.3%)
Respiratory tract infection	0/73 (0%)		1/78 (1.3%)
Sepsis	1/73 (1.4%)		5/78 (6.4%)
Septic shock	1/73 (1.4%)		1/78 (1.3%)
Sinusitis	2/73 (2.7%)		0/78 (0%)
Staphylococcal bacteraemia	1/73 (1.4%)		0/78 (0%)
Staphylococcal infection	3/73 (4.1%)		4/78 (5.1%)
Staphylococcal sepsis	0/73 (0%)		1/78 (1.3%)
Tooth abscess	1/73 (1.4%)		0/78 (0%)
Injury, poisoning and procedural complications
Medical device pain	0/73 (0%)		1/78 (1.3%)
Skin laceration	0/73 (0%)		1/78 (1.3%)
Therapeutic agent toxicity	1/73 (1.4%)		0/78 (0%)
Tooth fracture	0/73 (0%)		1/78 (1.3%)
Investigations
Atrial natriuretic peptide increased	0/73 (0%)		1/78 (1.3%)
Blood creatinine increased	1/73 (1.4%)		0/78 (0%)
Blood culture	0/73 (0%)		1/78 (1.3%)
Cytomegalovirus antigen positive	1/73 (1.4%)		0/78 (0%)
Cytomegalovirus test	0/73 (0%)		2/78 (2.6%)
Weight decreased	1/73 (1.4%)		0/78 (0%)
Metabolism and nutrition disorders
Anorexia	0/73 (0%)		2/78 (2.6%)
Decreased appetite	0/73 (0%)		1/78 (1.3%)
Dehydration	1/73 (1.4%)		1/78 (1.3%)
Electrolyte imbalance	0/73 (0%)		1/78 (1.3%)
Hypernatraemia	1/73 (1.4%)		0/78 (0%)
Hypovolaemia	1/73 (1.4%)		0/78 (0%)
Malnutrition	0/73 (0%)		1/78 (1.3%)
Oral intake reduced	0/73 (0%)		1/78 (1.3%)
Musculoskeletal and connective tissue disorders
Flank pain	0/73 (0%)		1/78 (1.3%)
Musculoskeletal chest pain	0/73 (0%)		1/78 (1.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia	1/73 (1.4%)		3/78 (3.8%)
Lung neoplasm	1/73 (1.4%)		0/78 (0%)
Lymphoma	0/73 (0%)		1/78 (1.3%)
Non-Hodgkin's lymphoma	1/73 (1.4%)		2/78 (2.6%)
Tumour lysis syndrome	1/73 (1.4%)		0/78 (0%)
Nervous system disorders
Cerebral haematoma	0/73 (0%)		1/78 (1.3%)
Convulsion	2/73 (2.7%)		3/78 (3.8%)
Dizziness	0/73 (0%)		1/78 (1.3%)
Haemorrhage intracranial	0/73 (0%)		1/78 (1.3%)
Reversible posterior leukoencephalopathy syndrome	0/73 (0%)		1/78 (1.3%)
Syncope	1/73 (1.4%)		2/78 (2.6%)
Unresponsive to verbal stimuli	1/73 (1.4%)		0/78 (0%)
Psychiatric disorders
Disorientation	1/73 (1.4%)		0/78 (0%)
Mental status changes	0/73 (0%)		1/78 (1.3%)
Renal and urinary disorders
Cystitis haemorrhagic	2/73 (2.7%)		1/78 (1.3%)
Renal failure acute	2/73 (2.7%)		5/78 (6.4%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	1/73 (1.4%)		1/78 (1.3%)
Acute respiratory failure	0/73 (0%)		1/78 (1.3%)
Apnoea	1/73 (1.4%)		0/78 (0%)
Asthma	1/73 (1.4%)		0/78 (0%)
Cryptogenic organizing pneumonia	0/73 (0%)		1/78 (1.3%)
Dyspnoea	2/73 (2.7%)		2/78 (2.6%)
Epistaxis	0/73 (0%)		1/78 (1.3%)
Hypoxia	3/73 (4.1%)		1/78 (1.3%)
Idiopathic pneumonia syndrome	1/73 (1.4%)		0/78 (0%)
Lung infiltration	1/73 (1.4%)		1/78 (1.3%)
Pneumonitis	1/73 (1.4%)		2/78 (2.6%)
Pneumothorax	0/73 (0%)		1/78 (1.3%)
Pulmonary alveolar haemorrhage	1/73 (1.4%)		1/78 (1.3%)
Pulmonary cavitation	0/73 (0%)		1/78 (1.3%)
Pulmonary congestion	0/73 (0%)		1/78 (1.3%)
Pulmonary embolism	0/73 (0%)		1/78 (1.3%)
Pulmonary microemboli	1/73 (1.4%)		0/78 (0%)
Respiratory distress	2/73 (2.7%)		1/78 (1.3%)
Respiratory failure	1/73 (1.4%)		1/78 (1.3%)
Sleep apnoea syndrome	1/73 (1.4%)		0/78 (0%)
Skin and subcutaneous tissue disorders
Dermatitis exfoliative	0/73 (0%)		1/78 (1.3%)
Exfoliative rash	1/73 (1.4%)		0/78 (0%)
Rash macular	1/73 (1.4%)		0/78 (0%)
Rash maculo-papular	0/73 (0%)		1/78 (1.3%)
Vascular disorders
Deep vein thrombosis	0/73 (0%)		1/78 (1.3%)
Haematoma	1/73 (1.4%)		1/78 (1.3%)
Hypotension	1/73 (1.4%)		1/78 (1.3%)
Superior vena caval occlusion	0/73 (0%)		1/78 (1.3%)
Thrombosis	1/73 (1.4%)		0/78 (0%)
Venoocclusive disease	0/73 (0%)		2/78 (2.6%)
Other (Not Including Serious) Adverse Events
	Placebo		Palifermin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	71/73 (97.3%)		77/78 (98.7%)
Blood and lymphatic system disorders
Anaemia	14/73 (19.2%)		13/78 (16.7%)
Febrile neutropenia	24/73 (32.9%)		24/78 (30.8%)
Neutropenia	4/73 (5.5%)		2/78 (2.6%)
Pancytopenia	5/73 (6.8%)		7/78 (9%)
Thrombocytopenia	14/73 (19.2%)		13/78 (16.7%)
Cardiac disorders
Bradycardia	4/73 (5.5%)		3/78 (3.8%)
Tachycardia	16/73 (21.9%)		20/78 (25.6%)
Ear and labyrinth disorders
Tinnitus	4/73 (5.5%)		0/78 (0%)
Endocrine disorders
Cushingoid	4/73 (5.5%)		2/78 (2.6%)
Eye disorders
Conjunctival haemorrhage	1/73 (1.4%)		4/78 (5.1%)
Dry eye	5/73 (6.8%)		5/78 (6.4%)
Vision blurred	9/73 (12.3%)		9/78 (11.5%)
Gastrointestinal disorders
Abdominal discomfort	4/73 (5.5%)		3/78 (3.8%)
Abdominal distension	4/73 (5.5%)		10/78 (12.8%)
Abdominal pain	27/73 (37%)		34/78 (43.6%)
Abdominal pain upper	4/73 (5.5%)		6/78 (7.7%)
Abdominal tenderness	5/73 (6.8%)		1/78 (1.3%)
Constipation	29/73 (39.7%)		16/78 (20.5%)
Diarrhoea	65/73 (89%)		64/78 (82.1%)
Dry mouth	13/73 (17.8%)		11/78 (14.1%)
Dyspepsia	12/73 (16.4%)		16/78 (20.5%)
Dysphagia	10/73 (13.7%)		6/78 (7.7%)
Flatulence	6/73 (8.2%)		4/78 (5.1%)
Gastrooesophageal reflux disease	6/73 (8.2%)		3/78 (3.8%)
Haemorrhoids	3/73 (4.1%)		5/78 (6.4%)
Nausea	70/73 (95.9%)		71/78 (91%)
Oesophagitis	2/73 (2.7%)		7/78 (9%)
Oral pain	6/73 (8.2%)		9/78 (11.5%)
Paraesthesia oral	1/73 (1.4%)		4/78 (5.1%)
Proctalgia	7/73 (9.6%)		4/78 (5.1%)
Tongue coated	2/73 (2.7%)		7/78 (9%)
Tongue disorder	0/73 (0%)		6/78 (7.7%)
Vomiting	53/73 (72.6%)		53/78 (67.9%)
General disorders
Asthenia	18/73 (24.7%)		15/78 (19.2%)
Catheter site pain	9/73 (12.3%)		8/78 (10.3%)
Chills	13/73 (17.8%)		7/78 (9%)
Face oedema	3/73 (4.1%)		6/78 (7.7%)
Fatigue	47/73 (64.4%)		54/78 (69.2%)
Generalised oedema	2/73 (2.7%)		5/78 (6.4%)
Mucosal inflammation	8/73 (11%)		12/78 (15.4%)
Oedema	11/73 (15.1%)		9/78 (11.5%)
Oedema peripheral	30/73 (41.1%)		26/78 (33.3%)
Pain	11/73 (15.1%)		6/78 (7.7%)
Pyrexia	33/73 (45.2%)		34/78 (43.6%)
Hepatobiliary disorders
Hyperbilirubinaemia	2/73 (2.7%)		4/78 (5.1%)
Jaundice	2/73 (2.7%)		4/78 (5.1%)
Immune system disorders
Graft versus host disease	17/73 (23.3%)		13/78 (16.7%)
Infections and infestations
BK virus infection	3/73 (4.1%)		4/78 (5.1%)
Bacteraemia	9/73 (12.3%)		11/78 (14.1%)
Candidiasis	2/73 (2.7%)		8/78 (10.3%)
Catheter site infection	4/73 (5.5%)		1/78 (1.3%)
Clostridial infection	4/73 (5.5%)		3/78 (3.8%)
Cytomegalovirus viraemia	2/73 (2.7%)		4/78 (5.1%)
Enterococcal infection	4/73 (5.5%)		5/78 (6.4%)
Folliculitis	5/73 (6.8%)		2/78 (2.6%)
Oral candidiasis	2/73 (2.7%)		9/78 (11.5%)
Pneumonia	1/73 (1.4%)		4/78 (5.1%)
Staphylococcal infection	6/73 (8.2%)		10/78 (12.8%)
Upper respiratory tract infection	4/73 (5.5%)		1/78 (1.3%)
Urinary tract infection	2/73 (2.7%)		8/78 (10.3%)
Injury, poisoning and procedural complications
Contusion	5/73 (6.8%)		3/78 (3.8%)
Investigations
Blood bilirubin increased	0/73 (0%)		4/78 (5.1%)
Blood creatinine increased	4/73 (5.5%)		1/78 (1.3%)
Cytomegalovirus test	3/73 (4.1%)		6/78 (7.7%)
Weight decreased	8/73 (11%)		6/78 (7.7%)
Metabolism and nutrition disorders
Anorexia	26/73 (35.6%)		26/78 (33.3%)
Decreased appetite	15/73 (20.5%)		12/78 (15.4%)
Dehydration	4/73 (5.5%)		2/78 (2.6%)
Fluid overload	3/73 (4.1%)		5/78 (6.4%)
Fluid retention	4/73 (5.5%)		2/78 (2.6%)
Hyperglycaemia	8/73 (11%)		16/78 (20.5%)
Hyperkalaemia	8/73 (11%)		2/78 (2.6%)
Hypervolaemia	4/73 (5.5%)		2/78 (2.6%)
Hypocalcaemia	3/73 (4.1%)		5/78 (6.4%)
Hypokalaemia	13/73 (17.8%)		11/78 (14.1%)
Hypomagnesaemia	25/73 (34.2%)		18/78 (23.1%)
Hypophosphataemia	4/73 (5.5%)		3/78 (3.8%)
Musculoskeletal and connective tissue disorders
Arthralgia	11/73 (15.1%)		10/78 (12.8%)
Back pain	20/73 (27.4%)		18/78 (23.1%)
Bone pain	6/73 (8.2%)		2/78 (2.6%)
Muscle spasms	5/73 (6.8%)		5/78 (6.4%)
Muscular weakness	8/73 (11%)		5/78 (6.4%)
Musculoskeletal chest pain	7/73 (9.6%)		6/78 (7.7%)
Myalgia	2/73 (2.7%)		5/78 (6.4%)
Neck pain	5/73 (6.8%)		3/78 (3.8%)
Pain in extremity	15/73 (20.5%)		15/78 (19.2%)
Pain in jaw	5/73 (6.8%)		3/78 (3.8%)
Shoulder pain	7/73 (9.6%)		7/78 (9%)
Nervous system disorders
Dizziness	21/73 (28.8%)		14/78 (17.9%)
Dysgeusia	8/73 (11%)		6/78 (7.7%)
Headache	38/73 (52.1%)		46/78 (59%)
Lethargy	4/73 (5.5%)		4/78 (5.1%)
Neuropathy peripheral	6/73 (8.2%)		2/78 (2.6%)
Paraesthesia	4/73 (5.5%)		3/78 (3.8%)
Sinus headache	4/73 (5.5%)		1/78 (1.3%)
Tremor	17/73 (23.3%)		10/78 (12.8%)
Psychiatric disorders
Anxiety	20/73 (27.4%)		18/78 (23.1%)
Confusional state	13/73 (17.8%)		6/78 (7.7%)
Depression	11/73 (15.1%)		10/78 (12.8%)
Hallucination	8/73 (11%)		5/78 (6.4%)
Insomnia	29/73 (39.7%)		28/78 (35.9%)
Renal and urinary disorders
Dysuria	9/73 (12.3%)		10/78 (12.8%)
Haematuria	11/73 (15.1%)		12/78 (15.4%)
Pollakiuria	4/73 (5.5%)		3/78 (3.8%)
Renal failure	6/73 (8.2%)		6/78 (7.7%)
Renal failure acute	1/73 (1.4%)		5/78 (6.4%)
Reproductive system and breast disorders
Vaginal haemorrhage	3/73 (4.1%)		5/78 (6.4%)
Respiratory, thoracic and mediastinal disorders
Cough	22/73 (30.1%)		26/78 (33.3%)
Dyspnoea	14/73 (19.2%)		16/78 (20.5%)
Dyspnoea exertional	5/73 (6.8%)		3/78 (3.8%)
Epistaxis	17/73 (23.3%)		13/78 (16.7%)
Hiccups	4/73 (5.5%)		10/78 (12.8%)
Hypoxia	6/73 (8.2%)		6/78 (7.7%)
Nasal congestion	4/73 (5.5%)		6/78 (7.7%)
Pharyngolaryngeal pain	14/73 (19.2%)		8/78 (10.3%)
Pleural effusion	3/73 (4.1%)		11/78 (14.1%)
Pulmonary oedema	4/73 (5.5%)		2/78 (2.6%)
Rhinorrhoea	5/73 (6.8%)		1/78 (1.3%)
Sinus congestion	6/73 (8.2%)		3/78 (3.8%)
Wheezing	4/73 (5.5%)		3/78 (3.8%)
Skin and subcutaneous tissue disorders
Alopecia	4/73 (5.5%)		1/78 (1.3%)
Blister	4/73 (5.5%)		3/78 (3.8%)
Dermatitis	4/73 (5.5%)		0/78 (0%)
Dry skin	14/73 (19.2%)		7/78 (9%)
Ecchymosis	3/73 (4.1%)		4/78 (5.1%)
Erythema	17/73 (23.3%)		11/78 (14.1%)
Night sweats	4/73 (5.5%)		1/78 (1.3%)
Petechiae	9/73 (12.3%)		4/78 (5.1%)
Pruritus	20/73 (27.4%)		20/78 (25.6%)
Rash	27/73 (37%)		35/78 (44.9%)
Rash erythematous	4/73 (5.5%)		3/78 (3.8%)
Skin hyperpigmentation	2/73 (2.7%)		4/78 (5.1%)
Swelling face	1/73 (1.4%)		10/78 (12.8%)
Vascular disorders
Flushing	5/73 (6.8%)		4/78 (5.1%)
Hypertension	25/73 (34.2%)		29/78 (37.2%)
Hypotension	13/73 (17.8%)		6/78 (7.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits sponsor a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Sponsor may remove confidential information, but authors have final control and approval of publication content. For multi-center studies, investigator agrees not to publish any results before the first multi-center publication.