Brain Edema, Brain Tumor
Conditions
Keywords
peritumoral brain edema, edema, malignant brain tumor, astrocytoma, brain tumor, dexamethasone, Decadron
Brief summary
The purpose of this study is to compare the safety and efficacy of XERECEPT® to dexamethasone (Decadron) a common treatment for symptoms of brain swelling (edema). This study is specifically aimed at patients who require chronic high doses of dexamethasone to manage symptoms.
Detailed description
XERECEPT® is not a potential treatment for cancer, but may reduce the edema associated with tumors and as a result, decrease neurological symptoms.
Interventions
DRUGhCRF
hCRF ; open-label dexamethasone that the patient is currently taking
DRUGplacebo hCRF
placebo hCRF 2mg/day and open-label dexamethasone that they are taking
Sponsors
Neurobiological Technologies
Celtic Pharma Development Services
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed diagnosis of a primary malignant brain tumor or, if metastatic, documentation and histology (if available) of primary source of cancer. * Patient must have 1 or more qualifying steroid-associated side effect(s) at Baseline. * Patient has required administration of dexamethasone to control symptoms of peritumoral edema for at least 30 days. * Stable dexamethasone dose of 4-24 mg/day for at least 14 days prior to Baseline. * Need for administration of dexamethasone to treat peritumoral brain edema (referenced above) has been documented by MRI or comparable diagnostic technology within 21 days of Baseline. * Karnofsky score of \> 50 at Screening and Baseline. * Capable of self-administration of subcutaneous injections twice daily for 12 weeks, or availability of assistance from caregiver. * Ability to provide written informed consent or, if unable to provide, have a legal guardian or representative provide written informed consent. * For women of childbearing potential: a negative serum pregnancy test at Screening. * Must be 18 years of age or older
Exclusion criteria
* Ongoing or anticipated need for surgery, radiosurgery or radiation therapy or the introduction of new chemotherapeutic regime within the first 5 weeks of study enrollment. Treatment with pre-study chemotherapy may continue. * Concurrent enrollment in any other investigational drug or device study, or plan to enroll in such a study during the first 5 weeks of treatment. * Systemic steroid use for any indication other than peritumoral brain edema. * Use or intended use of dexamethasone as an anti-emetic during Screening or Study * Non-compliance with dexamethasone or anticonvulsant therapy. * Clinical signs and symptoms of cerebral herniation. * Serious concomitant cardiovascular, pulmonary, renal, gastrointestinal or endocrine metabolic disease which could put the patient at unusual risk for study participation. * Confounding previous or concurrent neurological disorders that would interfere with adequate clinical evaluation. * Clinically significant head injury or chronic seizure disorder, if the condition results in functional impairment or is likely to interfere with evaluations. (Maintenance anticonvulsant therapy is allowed.) * Central nervous system infection. * Pregnancy, breastfeeding and/or refusal to practice birth control while in study, for women of childbearing potential. * Any conditions that are considered contraindications for patients to receive niacin, e.g. liver disease (with LFTs \> 3 times the upper limit of the norm),active peptic ulcer, arterial hemorrhage, asthma and known hypersensitivity to niacin.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Proportion of Patients in Each Treatment Group Who Are Responders at Week 2 and Continue to be Responders at Week 5 | Prospective | The primary efficacy endpoint was the proportion of patients in each treatment group who were Responders at Week 2 and who continued to be Responders at Week 5. Responders were defined as study patients who demonstrated the following: * 50% or greater reduction in dexamethasone dose relative to Baseline * Overall 10-Item Neurological Examination Score unchanged or lower compared to Baseline * Karnofsky Score unchanged or increased relative to Baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Proportion of Patients in Each Treatment Group Who Are Responders at Week 2 and Who Continue to be Responders at Weeks 5 and 8 | Prospective | • The proportion of patients in each treatment group who were Responders at Week 2 and who continued to be Responders at Weeks 5 and 8. |
| Change From Baseline in the 10-Item Neurological Examination Score at Weeks 2, 5, 8 12 and 16 (or Early Discontinuation) | Prospective | Change from Baseline in the 10-Item Neurological Examination Score at Weeks 2, 5, 8, 12 (or Early Study Drug Discontinuation), and 16 (or 4-week follow-up visit). Each item is scored from 0 (normal) to 4 (severely abnormal) except for speech (0-3) for a total range of 0-39. Total score for each patient was the sum of each item score. Change is calculated as the follow-up score minus the baseline score; a negative value indicates improvement. |
| Change From Baseline in the Karnofsky Performance Score | Prospective | Change from Baseline in the Karnofsky Performance Score at Weeks 2, 5, 8, 12 and 16.The Karnofsky score runs from 100 to 0, where 100 is perfect health and 0 is death. Although practitioners occasionally assign performance scores in between standard intervals of 10 as follows: 100 - Normal; no complaints; no evidence of disease. 90 - Able to carry on normal activity; minor signs or symptoms of disease. 80 - Normal activity with effort; some signs or symptoms of disease. 70 - Cares for self; unable to carry on normal activity or to do active work. 60 - Requires occasional assistance, but is able to care for most of his personal needs. 50 - Requires considerable assistance and frequent medical care. 40 - Disabled; requires special care and assistance. 30 - Severely disabled; hospital admission is indicated although death not imminent. 20 - Very sick; hospital admission necessary; active supportive treatment nec |
| Percent of Patients in Each Treatment Group Achieving 50% Reduction in Dexamethasone Usage Relative to Baseline by Week 2 Without Deterioration in Neurological Function as Measured by the 10-Item Neurological Exam and the KPS | Prospective | — |
| Change From Baseline in Myopathy Assessment Results at Week 12 (or Early Study Drug Discontinuation) and Week 16 (or 4-week Follow-up Visit) | Prospective | Myopathy, using Kendall Myopathy Scale, was assessed at Baseline, Week 12 (or upon Early SDD), and at the post-treatment 4-week follow-up visit (Week 16 and/or any unscheduled 4-week Follow-up). The Kendall Myopathy Scale is a 10 point scale where 10 represents holding test position against strong pressure (best) and 0 represents no contraction palpable (worst). |
| Maximum Percent Reduction in Dexamethasone Usage Relative to Baseline Achieved During the Study | Prospective | The maximum reduction in dexamethasone usage at any time during the study. Dexamethasone dosage was assessed at Weeks 0, 2, 5, 8, 12 and 16. |
| Number of Patients Who Discontinued Study Drug Prior to the End of Week 5 | Prospective | Numbers of patients who discontinued prior to the Week 5 assessment |
| Change From Baseline in the FACT-Br Quality of Life Results | Prospective | The FACT-Br Quality of Life Questionnaire was self-administered at Baseline, Weeks 5 and 12 (or upon Early SDD), and at the post-treatment 4-week follow-up visit (Week 16 and/or any unscheduled 4-week Follow-up).FACT-Br is a reliable and valid 50-item measure that includes FACT-G (27 items) and a brain subscale (23 items) to assess health-related quality of life in brain tumor patients. Each inventory question is scored from 0 (worst possible QOL) to 4 (best possible QOL) |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| hCRF Patients will take hCRF (XERECEPT) 2mg/day and open label-dexamethasone they are currently taking. | 100 |
| Placebo Patient will receive placebo hCRF and any open-label dexamethasone that they are currently taking | 100 |
| Total | 200 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 11 | 9 |
| Overall Study | Death | 3 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Patient deterioration | 29 | 39 |
| Overall Study | Physician Decision | 4 | 1 |
| Overall Study | Protocol Violation | 1 | 5 |
| Overall Study | Withdrawal by Subject | 5 | 5 |
Baseline characteristics
| Characteristic | hCRF | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 11 Participants | 13 Participants | 24 Participants |
| Age, Categorical Between 18 and 65 years | 89 Participants | 87 Participants | 176 Participants |
| Age, Continuous | 51.9 years STANDARD_DEVIATION 11.8 | 52.7 years STANDARD_DEVIATION 11.6 | 52.3 years STANDARD_DEVIATION 11.7 |
| Region of Enrollment Australia | 3 participants | 3 participants | 6 participants |
| Region of Enrollment Canada | 7 participants | 15 participants | 22 participants |
| Region of Enrollment New Zealand | 0 participants | 1 participants | 1 participants |
| Region of Enrollment United States | 90 participants | 81 participants | 171 participants |
| Sex: Female, Male Female | 43 Participants | 43 Participants | 86 Participants |
| Sex: Female, Male Male | 57 Participants | 57 Participants | 114 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 99 / 101 | 97 / 99 |
| serious Total, serious adverse events | 46 / 101 | 40 / 99 |
Outcome results
Primary
The Proportion of Patients in Each Treatment Group Who Are Responders at Week 2 and Continue to be Responders at Week 5
The primary efficacy endpoint was the proportion of patients in each treatment group who were Responders at Week 2 and who continued to be Responders at Week 5. Responders were defined as study patients who demonstrated the following: * 50% or greater reduction in dexamethasone dose relative to Baseline * Overall 10-Item Neurological Examination Score unchanged or lower compared to Baseline * Karnofsky Score unchanged or increased relative to Baseline
Time frame: Prospective
Population: Intent to Treat Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| hCRF | The Proportion of Patients in Each Treatment Group Who Are Responders at Week 2 and Continue to be Responders at Week 5 | 57 participants |
| Placebo | The Proportion of Patients in Each Treatment Group Who Are Responders at Week 2 and Continue to be Responders at Week 5 | 46 participants |
Secondary
Change From Baseline in Myopathy Assessment Results at Week 12 (or Early Study Drug Discontinuation) and Week 16 (or 4-week Follow-up Visit)
Myopathy, using Kendall Myopathy Scale, was assessed at Baseline, Week 12 (or upon Early SDD), and at the post-treatment 4-week follow-up visit (Week 16 and/or any unscheduled 4-week Follow-up). The Kendall Myopathy Scale is a 10 point scale where 10 represents holding test position against strong pressure (best) and 0 represents no contraction palpable (worst).
Time frame: Prospective
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| hCRF | Change From Baseline in Myopathy Assessment Results at Week 12 (or Early Study Drug Discontinuation) and Week 16 (or 4-week Follow-up Visit) | Week 16 | 0.0 Scores on a scale | Standard Deviation 2.7 |
| hCRF | Change From Baseline in Myopathy Assessment Results at Week 12 (or Early Study Drug Discontinuation) and Week 16 (or 4-week Follow-up Visit) | Week 12 | 0.1 Scores on a scale | Standard Deviation 2.8 |
| Placebo | Change From Baseline in Myopathy Assessment Results at Week 12 (or Early Study Drug Discontinuation) and Week 16 (or 4-week Follow-up Visit) | Week 12 | -0.2 Scores on a scale | Standard Deviation 2.2 |
| Placebo | Change From Baseline in Myopathy Assessment Results at Week 12 (or Early Study Drug Discontinuation) and Week 16 (or 4-week Follow-up Visit) | Week 16 | -0.3 Scores on a scale | Standard Deviation 2.5 |
Secondary
Change From Baseline in the 10-Item Neurological Examination Score at Weeks 2, 5, 8 12 and 16 (or Early Discontinuation)
Change from Baseline in the 10-Item Neurological Examination Score at Weeks 2, 5, 8, 12 (or Early Study Drug Discontinuation), and 16 (or 4-week follow-up visit). Each item is scored from 0 (normal) to 4 (severely abnormal) except for speech (0-3) for a total range of 0-39. Total score for each patient was the sum of each item score. Change is calculated as the follow-up score minus the baseline score; a negative value indicates improvement.
Time frame: Prospective
Population: Intent to Treat population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| hCRF | Change From Baseline in the 10-Item Neurological Examination Score at Weeks 2, 5, 8 12 and 16 (or Early Discontinuation) | Week 5 | 0.2 Scores on a scale | Standard Deviation 2.9 |
| hCRF | Change From Baseline in the 10-Item Neurological Examination Score at Weeks 2, 5, 8 12 and 16 (or Early Discontinuation) | Week 12 | 0.1 Scores on a scale | Standard Deviation 3.1 |
| hCRF | Change From Baseline in the 10-Item Neurological Examination Score at Weeks 2, 5, 8 12 and 16 (or Early Discontinuation) | Week 8 | 0.3 Scores on a scale | Standard Deviation 3.1 |
| hCRF | Change From Baseline in the 10-Item Neurological Examination Score at Weeks 2, 5, 8 12 and 16 (or Early Discontinuation) | Last Visit | 0.1 Scores on a scale | Standard Deviation 3.1 |
| hCRF | Change From Baseline in the 10-Item Neurological Examination Score at Weeks 2, 5, 8 12 and 16 (or Early Discontinuation) | Week 2 | -0.1 Scores on a scale | Standard Deviation 2.3 |
| Placebo | Change From Baseline in the 10-Item Neurological Examination Score at Weeks 2, 5, 8 12 and 16 (or Early Discontinuation) | Last Visit | 0.8 Scores on a scale | Standard Deviation 3.4 |
| Placebo | Change From Baseline in the 10-Item Neurological Examination Score at Weeks 2, 5, 8 12 and 16 (or Early Discontinuation) | Week 2 | -0.1 Scores on a scale | Standard Deviation 2.7 |
| Placebo | Change From Baseline in the 10-Item Neurological Examination Score at Weeks 2, 5, 8 12 and 16 (or Early Discontinuation) | Week 5 | 0.4 Scores on a scale | Standard Deviation 3 |
| Placebo | Change From Baseline in the 10-Item Neurological Examination Score at Weeks 2, 5, 8 12 and 16 (or Early Discontinuation) | Week 8 | 0.5 Scores on a scale | Standard Deviation 3.3 |
| Placebo | Change From Baseline in the 10-Item Neurological Examination Score at Weeks 2, 5, 8 12 and 16 (or Early Discontinuation) | Week 12 | 0.7 Scores on a scale | Standard Deviation 3.4 |
Secondary
Change From Baseline in the FACT-Br Quality of Life Results
The FACT-Br Quality of Life Questionnaire was self-administered at Baseline, Weeks 5 and 12 (or upon Early SDD), and at the post-treatment 4-week follow-up visit (Week 16 and/or any unscheduled 4-week Follow-up).FACT-Br is a reliable and valid 50-item measure that includes FACT-G (27 items) and a brain subscale (23 items) to assess health-related quality of life in brain tumor patients. Each inventory question is scored from 0 (worst possible QOL) to 4 (best possible QOL)
Time frame: Prospective
Population: Intent to Treat; LOCF
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| hCRF | Change From Baseline in the FACT-Br Quality of Life Results | Week 5 | 0.6 Scores on a scale | Standard Deviation 17.5 |
| hCRF | Change From Baseline in the FACT-Br Quality of Life Results | Week 12 | -1.8 Scores on a scale | Standard Deviation 20.3 |
| hCRF | Change From Baseline in the FACT-Br Quality of Life Results | Week 16 | 01.7 Scores on a scale | Standard Deviation 20.9 |
| Placebo | Change From Baseline in the FACT-Br Quality of Life Results | Week 5 | -2.2 Scores on a scale | Standard Deviation 15.8 |
| Placebo | Change From Baseline in the FACT-Br Quality of Life Results | Week 12 | -1.9 Scores on a scale | Standard Deviation 20.3 |
| Placebo | Change From Baseline in the FACT-Br Quality of Life Results | Week 16 | -5.9 Scores on a scale | Standard Deviation 20.9 |
Secondary
Change From Baseline in the Karnofsky Performance Score
Change from Baseline in the Karnofsky Performance Score at Weeks 2, 5, 8, 12 and 16.The Karnofsky score runs from 100 to 0, where 100 is perfect health and 0 is death. Although practitioners occasionally assign performance scores in between standard intervals of 10 as follows: 100 - Normal; no complaints; no evidence of disease. 90 - Able to carry on normal activity; minor signs or symptoms of disease. 80 - Normal activity with effort; some signs or symptoms of disease. 70 - Cares for self; unable to carry on normal activity or to do active work. 60 - Requires occasional assistance, but is able to care for most of his personal needs. 50 - Requires considerable assistance and frequent medical care. 40 - Disabled; requires special care and assistance. 30 - Severely disabled; hospital admission is indicated although death not imminent. 20 - Very sick; hospital admission necessary; active supportive treatment nec
Time frame: Prospective
Population: Intent to Treat population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| hCRF | Change From Baseline in the Karnofsky Performance Score | Week 5 | -2.1 Scores on a scale | Standard Deviation 9.6 |
| hCRF | Change From Baseline in the Karnofsky Performance Score | Week 12 | -3.4 Scores on a scale | Standard Deviation 10.1 |
| hCRF | Change From Baseline in the Karnofsky Performance Score | Week 8 | -3.2 Scores on a scale | Standard Deviation 10.3 |
| hCRF | Change From Baseline in the Karnofsky Performance Score | Last Visit | -3.5 Scores on a scale | Standard Deviation 10.1 |
| hCRF | Change From Baseline in the Karnofsky Performance Score | Week 2 | -0.5 Scores on a scale | Standard Deviation 7.4 |
| Placebo | Change From Baseline in the Karnofsky Performance Score | Last Visit | -3.6 Scores on a scale | Standard Deviation 10.2 |
| Placebo | Change From Baseline in the Karnofsky Performance Score | Week 2 | -2.2 Scores on a scale | Standard Deviation 8.5 |
| Placebo | Change From Baseline in the Karnofsky Performance Score | Week 5 | -2.6 Scores on a scale | Standard Deviation 8.8 |
| Placebo | Change From Baseline in the Karnofsky Performance Score | Week 8 | -3.2 Scores on a scale | Standard Deviation 9 |
| Placebo | Change From Baseline in the Karnofsky Performance Score | Week 12 | -3.3 Scores on a scale | Standard Deviation 10.1 |
Secondary
Maximum Percent Reduction in Dexamethasone Usage Relative to Baseline Achieved During the Study
The maximum reduction in dexamethasone usage at any time during the study. Dexamethasone dosage was assessed at Weeks 0, 2, 5, 8, 12 and 16.
Time frame: Prospective
Population: Intent to Treat population; baseline observation carried forward
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| hCRF | Maximum Percent Reduction in Dexamethasone Usage Relative to Baseline Achieved During the Study | -62.7 Percent dexamethasone dose reduction | Standard Deviation 21.8 |
| Placebo | Maximum Percent Reduction in Dexamethasone Usage Relative to Baseline Achieved During the Study | -51.4 Percent dexamethasone dose reduction | Standard Deviation 21.5 |
Secondary
Number of Patients Who Discontinued Study Drug Prior to the End of Week 5
Numbers of patients who discontinued prior to the Week 5 assessment
Time frame: Prospective
Population: Intent to Treat population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| hCRF | Number of Patients Who Discontinued Study Drug Prior to the End of Week 5 | 29 participants |
| Placebo | Number of Patients Who Discontinued Study Drug Prior to the End of Week 5 | 39 participants |
Secondary
Percent of Patients in Each Treatment Group Achieving 50% Reduction in Dexamethasone Usage Relative to Baseline by Week 2 Without Deterioration in Neurological Function as Measured by the 10-Item Neurological Exam and the KPS
Time frame: Prospective
Population: Intent to Treat Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| hCRF | Percent of Patients in Each Treatment Group Achieving 50% Reduction in Dexamethasone Usage Relative to Baseline by Week 2 Without Deterioration in Neurological Function as Measured by the 10-Item Neurological Exam and the KPS | 78 participants |
| Placebo | Percent of Patients in Each Treatment Group Achieving 50% Reduction in Dexamethasone Usage Relative to Baseline by Week 2 Without Deterioration in Neurological Function as Measured by the 10-Item Neurological Exam and the KPS | 62 participants |
Secondary
The Proportion of Patients in Each Treatment Group Who Are Responders at Week 2 and Who Continue to be Responders at Weeks 5 and 8
• The proportion of patients in each treatment group who were Responders at Week 2 and who continued to be Responders at Weeks 5 and 8.
Time frame: Prospective
Population: Intent to Treat Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| hCRF | The Proportion of Patients in Each Treatment Group Who Are Responders at Week 2 and Who Continue to be Responders at Weeks 5 and 8 | Week 2 | 78 participants |
| hCRF | The Proportion of Patients in Each Treatment Group Who Are Responders at Week 2 and Who Continue to be Responders at Weeks 5 and 8 | Week 5 | 62 participants |
| hCRF | The Proportion of Patients in Each Treatment Group Who Are Responders at Week 2 and Who Continue to be Responders at Weeks 5 and 8 | Week 8 | 57 participants |
| Placebo | The Proportion of Patients in Each Treatment Group Who Are Responders at Week 2 and Who Continue to be Responders at Weeks 5 and 8 | Week 2 | 62 participants |
| Placebo | The Proportion of Patients in Each Treatment Group Who Are Responders at Week 2 and Who Continue to be Responders at Weeks 5 and 8 | Week 5 | 48 participants |
| Placebo | The Proportion of Patients in Each Treatment Group Who Are Responders at Week 2 and Who Continue to be Responders at Weeks 5 and 8 | Week 8 | 42 participants |