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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00434161
Recruitment Status : Completed
First Posted : February 12, 2007
Results First Posted : March 10, 2015
Last Update Posted : March 30, 2015
Sponsor:
Information provided by (Responsible Party):
Swedish Orphan Biovitrum

Brief Summary:
The purpose of this study was to evaluate the efficacy and effect of palifermin on the incidence of oral mucositis in subjects with multiple myeloma receiving Melphalan followed by autologous peripheral blood stem cell transplantation. Amendment 01 (April 07) introduced three cataract assessments to be carried out at Screening, Month 6 and Month 12 in response to FDA and EMEA follow up measures.

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: Palifermin before only Drug: Placebo Drug: Palifermin before and after Phase 3

Detailed Description:

This was a double-blind, placebo-controlled, randomized, multicenter Phase IIIb study of palifermin given before and after dose chemotherapy (total 6 doses) or before dose chemotherapy only (total 3 doses), in subjects with Multiple Myeloma (MM)receiving high dose melphalan (chemotherapy), in a 1-day schedule, followed by autologous Peripheral Blood Stem Cell Transplantation (PBSCT).

All subjects were to be followed for disease progression, second primary tumors, additional malignancies and survival for up to 10 years.

Planned: 275 subjects, in fact, 281 subjects were randomized. Randomized: 115 subjects to palifermin pre/post-CT, 109 subjects to palifermin pre-CT and 57 subjects to placebo Analyzed: 281 subjects in the full analysis set, 277 subjects in the safety subset.

Efficacy Oral cavity assessment, patient reported outcome (PRO) questionnaires (Oral Mucositis Daily Questionnaire [OMDQ], Functional Assessment of Cancer Therapy Esophageal [FACT-E], European Quality of Life Utility Scale [EQ 5D], Mucositis Chronic Symptoms Questionnaire [MCSQ]).

Safety Physical examination (including body temperature), concomitant medications, transfusions, vital signs, laboratory assessments (hematology, chemistry), cataract assessments, adverse events (AEs).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 281 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Supportive Care
Official Title: A Double-Blind, Randomized, Placebo-controlled Study of Two Different Schedules of Palifermin for Reduction in Severity of Oral Mucositis in Subjects With Multiple Myeloma Receiving Melphalan Followed by Autologous Blood Stem Cell Transplantation
Study Start Date : December 2006
Actual Primary Completion Date : March 2009
Actual Study Completion Date : May 2012

Resource links provided by the National Library of Medicine

Drug Information available for: Palifermin

Arm Intervention/treatment
Active Comparator: Palifermin before only
Subjects received palifermin before-high dose chemotherapy (total 3 doses) and matched placebo after-high dose chemotherapy (total 3 doses)
Drug: Palifermin before only
One bolus IV injection at 60 μg/kg/day, on Days 6, 5 & 4 days before-high dose chemotherapy and one bolus IV injection at 60 μg/kg/day of matched placebo on days 0, 1 & 2 days after-high dose chemotherapy. Minimum of 4 days between before-chemotherapy and after-transplantation dosing.
Other Name: Kepivance

Placebo Comparator: Placebo (suger pill)
Subjects received matched placebo before- and after-high dose chemotherapy
Drug: Placebo

One bolus IV injection at 60 μg/kg/day of matched placebo on Days 6, 5 & 4 (before-high dose chemotherapy) and on Days 0, 1 & 2 (after-high dose chemotherapy).

Minimum of 4 days between pre-chemotherapy and post-transplantation dosing.


Active Comparator: Palifermin before and after
Subjects received palifermin before- and after-high dose chemotherapy (total of 6 doses)
Drug: Palifermin before and after

One bolus IV injection at 60 μg/kg/day, on Days 6, 5 & 4 (before-high dose chemotherapy) and on Days 0, 1 & 2 (after-high dose chemotherapy).

Minimum of 4 days between before-chemotherapy and after-transplantation dosing.

Other Name: Kepivance




Primary Outcome Measures :
  1. Maximum Severity of Oral Mucositis (World Health Organization (WHO) Grades 0/1, 2, 3, or 4) [ Time Frame: at Day 32 ]

    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.


  2. Incidence of Cataract Development or Progression at Month 12. [ Time Frame: 12 months ]
    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).


Secondary Outcome Measures :
  1. Incidence Ulcerative Mucositis (WHO Grades 2, 3, and 4) [ Time Frame: at Day 32 ]

    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.


  2. Duration of Ulcerative Mucositis (WHO Grades 2, 3, and 4) [ Time Frame: at Day 32 ]

    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.


  3. The Area Under the Curve (AUC) Was Calculated From the Patient-reported Outcome Mouth and Throat Soreness (MTS) Score. [ Time Frame: at Day 32 ]

    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.


  4. Incidence of Cataract Development or Progression (Change of ≥0.3 in Lens Opacities Classification System III (LOCS III Score)) at Month 6. [ Time Frame: 6 Months ]
    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).

  5. Incidence of an Increase Posterior Subcapsular Cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO) at Month 6 and 12 [ Time Frame: at Month 6 and Month 12 ]

    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.


  6. Change From Baseline in Posterior Subcapsular (P), Cortical (C) Cataract and Nuclear Opalescence (NO) on the Lens Opacities Classification System III (LOCS III) Scale at Months 6. [ Time Frame: Months 6 ]

    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.


  7. Change From Baseline in Posterior Subcapsular (P), Cortical (C) Cataract and Nuclear Opalescence (NO) on the Lens Opacities Classification System III (LOCS III) Scale at Months 12. [ Time Frame: Months 12 ]

    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.


  8. Incidence of a Decreased From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by a Change of 10 Letters on the ETDRS (Early Termination Diabetic Retinopathy Study) at 4 Meters at Months 6 [ Time Frame: Months 6 ]
    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).

  9. Incidence of a Decreased From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by a Change of 10 Letters on the ETDRS (Early Termination Diabetic Retinopathy Study) at 4 Meters at Months 12. [ Time Frame: Month 12 ]
    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).

  10. Incidence of Adverse Events and Laboratory Abnormalities [ Time Frame: at Day 32 ]
    Incidence of Adverse Events CTCAE grade 3 or higher reported

  11. Overall Survival [ Time Frame: During long-term follow up phase (maximum of 10 years) ]
    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.

  12. Progression Free Survival [ Time Frame: During long-term follow up phase (maximum of 10 years) ]
    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.

  13. Time Death or Disease Progression [ Time Frame: During long-term follow up phase (maximum of 10 years) ]
    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.

  14. Incidence of Second Primary Malignancies or Other Malignancies [ Time Frame: During long-term follow up phase (maximum of 10 years) ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Multiple myeloma (MM) subjects scheduled to receive high-dose Melphalan in a one day schedule followed by autologous peripheral blood progenitor cell (PBSCT)
  • Body Mass Index (BMI) ≤ 35
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, or an ECOG status of 3 if the reason for a status of 3 is exclusively due to MM (e.g. pathological fracture)
  • Functional hematopoietic, hepato-renal and pulmonary systems
  • Subjects at minimum with a baseline best corrected visual acuity (BCVA) of 20/40, (6/12 or 0.5 on the decimal scale) or better using the ETDRS chart in one eye
  • Subject at minimum with one eye with a natural, intact lens
  • Subject who has a LOCS III score at baseline of P < 1.0, C < 2.0 and NO < 2.0 in at least one eye
  • Women in child bearing potential must have a negative pregnancy test

Exclusion Criteria:

  • Presence or history of any other malignancy (other than curatively treated basal cell or squamous cell carcinoma of the skin, in situ cervical carcinoma, or other surgically cured malignancy, without evidence of disease for > 3 years
  • Prior autologous or allogeneic transplants
  • Prior treatment with palifermin, or other fibroblast or keratinocyte growth factors
  • Receiving dialysis
  • History of cataract surgery in both eyes
  • Incapable of being responsive to mydriatic agents
  • History of other ocular disease (e.g., macular degeneration, glaucoma, corneal disease) that would make assessment of visual status difficult
  • Subject is scheduled to undergo cataract surgery
  • Subject with any disease, that in the opinion of the ophthalmologist, could adversely effect the subject's vision during the course of the study
  • Currently active oral mucositis infection
  • Positive for HIV, hepatitis B or C
  • Subject is unable or unwilling to follow with study procedures
  • Subject is pregnant or is breast feeding
  • Subject has not agreed to use adequate contraceptive precautions

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00434161


Locations
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Germany
Universitatsklinikum Leipzig
Leipzig, Germany
Sponsors and Collaborators
Swedish Orphan Biovitrum
Investigators
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Study Director: Kristina Timdahl, MD Swedish Orphan Biovitrum AB
Principal Investigator: Dietger Niederwieser, Professor Universitatsklinikum Leipzig, Leipzig, Germany

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Responsible Party: Swedish Orphan Biovitrum
ClinicalTrials.gov Identifier: NCT00434161    
Obsolete Identifiers: NCT00964925
Other Study ID Numbers: 20050219
First Posted: February 12, 2007    Key Record Dates
Results First Posted: March 10, 2015
Last Update Posted: March 30, 2015
Last Verified: March 2015
Keywords provided by Swedish Orphan Biovitrum:
Palifermin
KGF
Clinical Trial
Oncology
Oral Mucositis
Multiple Myeloma
Cataract
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Mucositis
Stomatitis
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Mouth Diseases
Stomatognathic Diseases