Malignant Glioma
Conditions
Keywords
malignant glioma, glioblastoma multiforme, quality of life, naltrexone
Brief summary
To compare the effects of low dose naltrexone (LDN) versus placebo on quality of life in high grade glioma patients undergoing standard chemoradiation
Detailed description
The proposed study is a placebo-controlled, randomized clinical trial. Potential participants will be identified via clinical protocol chart review of patients scheduled to attend their predetermined follow-up consultations at The Preston Robert Tisch Brain Tumor Center (PRT-BTC) at Duke University Medical Center after evaluation of treatment for newly diagnosed high grade gliomas. We will identify high grade glioma patients that will receive standard chemoradiation (radiotherapy with daily temozolomide dosed at 75 mg/m2). After obtaining written informed consent, all participants will be scheduled for baseline study assessments before starting radiotherapy. Patients will be randomized to receive either placebo or low dose naltrexone (LDN) dosed at 4.5 mg orally to be taken every evening before going to bed. Patients will be assessed at the following time points: 1. Baseline (before chemoradiation), 2. After chemoradiation (approximately 8 weeks from initial assessment), 3. Two months after standard chemoradiation (approximately 16 weeks after initial assessment), and 4. Four months after standard chemoradiation (approximately 24 weeks after initial assessment). Treatment with LDN or placebo will begin on first day of chemoradiation and will be continued for a total of 16 weeks from initial assessment. Last assessment at 24 weeks will occur 8 weeks after discontinuation of LDN or placebo. All visits will be linked to patients' clinical management visits. All testing will be performed at PRT-BTC and at Duke University Medical Center. The following procedures will be obtained at each assessment visit: 1. Complete a six-minute walk test. The exercise test is designed to determine how far the subject can walk in six minutes. This test will take place at the PRT-BTC at Duke University Medical Center with appropriate medical supervision. 2. Blood testing that will be performed as part of each clinic visit. Approximately 10 milliliters or 2 teaspoons of blood will be drawn at each visit. This will not be additional blood work, but rather the standardized blood work that the subject will need for evaluation associated with radiation and chemotherapy treatments. We will ask the subject to complete the following tests/questionnaires: 1. Neurocognitive testing: this testing will be performed using a computer program called CNS Vital Signs®. This program consists of verbal and visual memory tests, attention tests, reasoning tests, and speed of processing tests. The subject will use a laptop computer to complete these tests. No previous exposure to computers or computer testing is needed to complete the test. 2. Computerized Questionnaires: Four questionnaires will be presented using a computerized program. These will include Medical Outcomes Survey (MOS), Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), and Zung Self-Rating Depression Scale (ZSDS). MOS assesses general health, well-being, and quality of life. ESS asks about level of sleepiness while PSQI asks about sleep quality. Finally, ZSDS will evaluate feelings of depression and sadness. 3. Beck depression inventory (BDI): This questionnaire asks questions about the subject's levels of sadness, changes in the subject's mood, sleeping and eating patterns, the subject's level of interest in activities, thoughts and feelings the subject is having and the subject's level of concentration. This is a pen and paper questionnaire. 4. Functional Assessment of Cancer Therapy-Brain (FACT-BR) scale: This questionnaire asks questions about physical, function, emotional, and social well-being. This is a pen and paper questionnaire. 5. Functional Assessment of Cancer Therapy-Fatigue (FACIT-F) scale: This questionnaire asks questions about fatigue. This is a pen and paper questionnaire. 6. Functional Assessment of Cancer Therapy-Cognition (FACT-Cog) scale: This questionnaire asks questions about your thinking and ability to do memory, attention, and reasoning activities. This is a pen and paper questionnaire.
Interventions
DRUGLDN
Randomized patients received 4.5 mg low dose naltrexone (LDN) to be taken every night before bed.
DRUGPlacebo
Randomized patients received placebo to be taken every night before bed.
Sponsors
Katy Peters
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* written informed consent prior to beginning specific protocol procedures * histologically proven high-grade glioma * planned treatment with concurrent radiotherapy and daily oral temozolomide (with or without Avastin) * ≥ 18 years of age * Karnofsky performance index ≥ 70% * must be able to ambulate unassisted for 6 minutes safely * The Preston Robert Tisch Brain Tumor Center (PRT-BTC) neuro-oncologist's approval * hematocrit ≥ 29%, hemoglobin ≥ 9, absolute neutrophil count (ANC) ≥ 1,500 cells/microliter, platelets ≥ 100,000 cells/microliter * serum creatinine \< 1.5 times upper limit of normal, serum glutamic oxaloacetic transaminase (SGOT) \< 2.5 times upper limit of normal and bilirubin \< 2.0 times upper limit of normal * if sexually active, patients will take contraceptive measures for the duration of the treatments * Women of childbearing potential must have a negative serum pregnancy test within 48 hours prior to administration of study drug
Exclusion criteria
* prior therapy with naltrexone or naloxone * co-medication that may interfere with study results, e.g. opioids, * known hypersensitivity to any component of naltrexone * pregnant (positive pregnancy test) or lactating
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effects of Low-dose Naltrexone Versus Placebo on Change in Quality of Life (QoL) in High-grade Glioma Patients Undergoing Standard Chemoradiation From Baseline | Baseline and 16 weeks | The difference in QoL scores between the 3rd QoL measurement (approximately 16 weeks from initial assessment) and the initial baseline assessment are reported. QoL instruments included are listed below. Higher scores indicate more favorable outcomes unless otherwise indicated. * Functional Assessment of Cancer Therapy-Brain (FACT-Br) measures general QoL reflecting symptoms associated with brain malignancies (range 0-132) * Functional Assessment of Chronic Illness Therapy (FACIT-F) measures level of fatigue during patients' usual daily activities (range 0-52) * Epworth Sleepiness Scale measures level of daytime sleepiness. Note that higher scores indicate a greater level of sleepiness (range 0-24) * Medical Outcomes Survey (MOS) measures QoL including physical, mental and general health via 8 domains (range 0-100 for each domain) * Zung Self-Rating Depression Scale quantifies the depressed status of a patient. Lower scores indicate more favorable outcome (range 20-80) A difference |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effects of Low-dose Naltrexone Versus Placebo on Change in Functional Capacity From Baseline | Baseline and 16 weeks | Patients completed the 6-minute walk test (6MWT) at each QoL measurement assessment. The 6 minute walk test is a measure of functional capacity in which the distance that a patient can quickly walk on a flat, hard surface in a period of 6 minutes is measured. The mean difference in distance traveled (in meters) between the 3rd QoL measurement (approximately 16 weeks from initial assessment) and the initial baseline assessment are reported. A difference greater than 0 indicates an increase in distance traveled, while a difference less than 0 indicates a decrease. |
| Effects of Low-dose Naltrexone Versus Placebo on Change in Neurocognitive Function From Baseline | Baseline and 16 weeks | Patients completed neurocognitive testing at each QoL measurement assessment. Neurocognitive function was measured via a computerized neurocognitive test battery called CNS Vital Signs. The battery consists of 7 tests that assess verbal and visual memory, finger tapping, symbol digit coding, the Stroop Test, a test of shifting attention, and continuous performance. The battery provides scores over 9 domains with higher scores indicating better performance. Scores were normalized to a standard score mean of 100 and standard deviation of 15 using a normative sample. The mean difference in score in each domain between the 3rd QoL measurement (approximately 16 weeks from initial assessment) and the initial baseline assessment are reported. A difference greater than 0 indicates an increase in mean score, while a difference less than 0 indicates a decrease in mean score. |
Countries
United States
Participant flow
Pre-assignment details
Patients were randomized to either low dose naltrexone (LDN) or placebo and were followed for 24 weeks. A patient is defined as completing the study if they completed the Quality of Life (QoL) assessments at 24 weeks.
Participants by arm
| Arm | Count |
|---|---|
| Naltrexone Randomized patients received 4.5 mg naltrexone to be taken every night before bed. | 54 |
| Placebo Randomized patients received placebo to be taken every night before bed. | 56 |
| Total | 110 |
Baseline characteristics
| Characteristic | Naltrexone | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 55.6 years STANDARD_DEVIATION 11 | 56.7 years STANDARD_DEVIATION 11.3 | 56.2 years STANDARD_DEVIATION 11.1 |
| Sex: Female, Male Female | 23 Participants | 25 Participants | 48 Participants |
| Sex: Female, Male Male | 31 Participants | 31 Participants | 62 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 51 / 54 | 54 / 56 |
| serious Total, serious adverse events | 12 / 54 | 17 / 56 |
Outcome results
Primary
Effects of Low-dose Naltrexone Versus Placebo on Change in Quality of Life (QoL) in High-grade Glioma Patients Undergoing Standard Chemoradiation From Baseline
The difference in QoL scores between the 3rd QoL measurement (approximately 16 weeks from initial assessment) and the initial baseline assessment are reported. QoL instruments included are listed below. Higher scores indicate more favorable outcomes unless otherwise indicated. * Functional Assessment of Cancer Therapy-Brain (FACT-Br) measures general QoL reflecting symptoms associated with brain malignancies (range 0-132) * Functional Assessment of Chronic Illness Therapy (FACIT-F) measures level of fatigue during patients' usual daily activities (range 0-52) * Epworth Sleepiness Scale measures level of daytime sleepiness. Note that higher scores indicate a greater level of sleepiness (range 0-24) * Medical Outcomes Survey (MOS) measures QoL including physical, mental and general health via 8 domains (range 0-100 for each domain) * Zung Self-Rating Depression Scale quantifies the depressed status of a patient. Lower scores indicate more favorable outcome (range 20-80) A difference
Time frame: Baseline and 16 weeks
Population: This analysis only includes those patients who completed both the initial QOL assessments and the 16 week QoL assessments, and thus number of participants may not match those reported in the participant flow module, which reports number of participants completing the trial at 24 weeks.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Low Dose Naltrexone (LDN) | Effects of Low-dose Naltrexone Versus Placebo on Change in Quality of Life (QoL) in High-grade Glioma Patients Undergoing Standard Chemoradiation From Baseline | FACT-Brain Trial Outcome Index (TOI) | -3.73 Scores on a Scale | Standard Deviation 22.85 |
| Low Dose Naltrexone (LDN) | Effects of Low-dose Naltrexone Versus Placebo on Change in Quality of Life (QoL) in High-grade Glioma Patients Undergoing Standard Chemoradiation From Baseline | FACIT-Fatigue | -4.22 Scores on a Scale | Standard Deviation 11.07 |
| Low Dose Naltrexone (LDN) | Effects of Low-dose Naltrexone Versus Placebo on Change in Quality of Life (QoL) in High-grade Glioma Patients Undergoing Standard Chemoradiation From Baseline | Epworth Sleepiness Scale | 3.47 Scores on a Scale | Standard Deviation 4.37 |
| Low Dose Naltrexone (LDN) | Effects of Low-dose Naltrexone Versus Placebo on Change in Quality of Life (QoL) in High-grade Glioma Patients Undergoing Standard Chemoradiation From Baseline | MOS - Physical Functioning | -5.54 Scores on a Scale | Standard Deviation 34.41 |
| Low Dose Naltrexone (LDN) | Effects of Low-dose Naltrexone Versus Placebo on Change in Quality of Life (QoL) in High-grade Glioma Patients Undergoing Standard Chemoradiation From Baseline | MOS - Role Limitations due to Physical Health | 0 Scores on a Scale | Standard Deviation 51.71 |
| Low Dose Naltrexone (LDN) | Effects of Low-dose Naltrexone Versus Placebo on Change in Quality of Life (QoL) in High-grade Glioma Patients Undergoing Standard Chemoradiation From Baseline | MOS - Role Limitations due to Emotional Issues | 2.69 Scores on a Scale | Standard Deviation 49.31 |
| Low Dose Naltrexone (LDN) | Effects of Low-dose Naltrexone Versus Placebo on Change in Quality of Life (QoL) in High-grade Glioma Patients Undergoing Standard Chemoradiation From Baseline | MOS - Energy/Fatigue | -6.22 Scores on a Scale | Standard Deviation 29.8 |
| Low Dose Naltrexone (LDN) | Effects of Low-dose Naltrexone Versus Placebo on Change in Quality of Life (QoL) in High-grade Glioma Patients Undergoing Standard Chemoradiation From Baseline | MOS - Emotional Well Being | 3.5 Scores on a Scale | Standard Deviation 21.4 |
| Low Dose Naltrexone (LDN) | Effects of Low-dose Naltrexone Versus Placebo on Change in Quality of Life (QoL) in High-grade Glioma Patients Undergoing Standard Chemoradiation From Baseline | MOS - Social Functioning | 1.34 Scores on a Scale | Standard Deviation 32.38 |
| Low Dose Naltrexone (LDN) | Effects of Low-dose Naltrexone Versus Placebo on Change in Quality of Life (QoL) in High-grade Glioma Patients Undergoing Standard Chemoradiation From Baseline | MOS - Pain | 10.41 Scores on a Scale | Standard Deviation 27.12 |
| Low Dose Naltrexone (LDN) | Effects of Low-dose Naltrexone Versus Placebo on Change in Quality of Life (QoL) in High-grade Glioma Patients Undergoing Standard Chemoradiation From Baseline | MOS - General Health | -13.38 Scores on a Scale | Standard Deviation 17.8 |
| Low Dose Naltrexone (LDN) | Effects of Low-dose Naltrexone Versus Placebo on Change in Quality of Life (QoL) in High-grade Glioma Patients Undergoing Standard Chemoradiation From Baseline | Zung Depression Scale | 0.86 Scores on a Scale | Standard Deviation 11.15 |
| Placebo | Effects of Low-dose Naltrexone Versus Placebo on Change in Quality of Life (QoL) in High-grade Glioma Patients Undergoing Standard Chemoradiation From Baseline | MOS - General Health | -12.11 Scores on a Scale | Standard Deviation 19.82 |
| Placebo | Effects of Low-dose Naltrexone Versus Placebo on Change in Quality of Life (QoL) in High-grade Glioma Patients Undergoing Standard Chemoradiation From Baseline | FACT-Brain Trial Outcome Index (TOI) | -6.06 Scores on a Scale | Standard Deviation 21.72 |
| Placebo | Effects of Low-dose Naltrexone Versus Placebo on Change in Quality of Life (QoL) in High-grade Glioma Patients Undergoing Standard Chemoradiation From Baseline | MOS - Energy/Fatigue | -4.61 Scores on a Scale | Standard Deviation 29.76 |
| Placebo | Effects of Low-dose Naltrexone Versus Placebo on Change in Quality of Life (QoL) in High-grade Glioma Patients Undergoing Standard Chemoradiation From Baseline | FACIT-Fatigue | -4.1 Scores on a Scale | Standard Deviation 13.41 |
| Placebo | Effects of Low-dose Naltrexone Versus Placebo on Change in Quality of Life (QoL) in High-grade Glioma Patients Undergoing Standard Chemoradiation From Baseline | MOS - Pain | 2.39 Scores on a Scale | Standard Deviation 24.92 |
| Placebo | Effects of Low-dose Naltrexone Versus Placebo on Change in Quality of Life (QoL) in High-grade Glioma Patients Undergoing Standard Chemoradiation From Baseline | Epworth Sleepiness Scale | 0.81 Scores on a Scale | Standard Deviation 3.45 |
| Placebo | Effects of Low-dose Naltrexone Versus Placebo on Change in Quality of Life (QoL) in High-grade Glioma Patients Undergoing Standard Chemoradiation From Baseline | MOS - Emotional Well Being | -1.89 Scores on a Scale | Standard Deviation 15.64 |
| Placebo | Effects of Low-dose Naltrexone Versus Placebo on Change in Quality of Life (QoL) in High-grade Glioma Patients Undergoing Standard Chemoradiation From Baseline | MOS - Physical Functioning | -3.42 Scores on a Scale | Standard Deviation 29.75 |
| Placebo | Effects of Low-dose Naltrexone Versus Placebo on Change in Quality of Life (QoL) in High-grade Glioma Patients Undergoing Standard Chemoradiation From Baseline | Zung Depression Scale | 3.54 Scores on a Scale | Standard Deviation 8.48 |
| Placebo | Effects of Low-dose Naltrexone Versus Placebo on Change in Quality of Life (QoL) in High-grade Glioma Patients Undergoing Standard Chemoradiation From Baseline | MOS - Role Limitations due to Physical Health | 20.39 Scores on a Scale | Standard Deviation 41.86 |
| Placebo | Effects of Low-dose Naltrexone Versus Placebo on Change in Quality of Life (QoL) in High-grade Glioma Patients Undergoing Standard Chemoradiation From Baseline | MOS - Social Functioning | 7.87 Scores on a Scale | Standard Deviation 41.57 |
| Placebo | Effects of Low-dose Naltrexone Versus Placebo on Change in Quality of Life (QoL) in High-grade Glioma Patients Undergoing Standard Chemoradiation From Baseline | MOS - Role Limitations due to Emotional Issues | 12.3 Scores on a Scale | Standard Deviation 56.11 |
Secondary
Effects of Low-dose Naltrexone Versus Placebo on Change in Functional Capacity From Baseline
Patients completed the 6-minute walk test (6MWT) at each QoL measurement assessment. The 6 minute walk test is a measure of functional capacity in which the distance that a patient can quickly walk on a flat, hard surface in a period of 6 minutes is measured. The mean difference in distance traveled (in meters) between the 3rd QoL measurement (approximately 16 weeks from initial assessment) and the initial baseline assessment are reported. A difference greater than 0 indicates an increase in distance traveled, while a difference less than 0 indicates a decrease.
Time frame: Baseline and 16 weeks
Population: This analysis only includes those patients who completed both the initial 6MWT assessments and the 16 week assessments, and thus number of participants may not match those reported in the participant flow module, which reports number of participants completing the trial at 24 weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Naltrexone (LDN) | Effects of Low-dose Naltrexone Versus Placebo on Change in Functional Capacity From Baseline | 13.43 Meters | Standard Deviation 113.7 |
| Placebo | Effects of Low-dose Naltrexone Versus Placebo on Change in Functional Capacity From Baseline | -6.42 Meters | Standard Deviation 136.73 |
Secondary
Effects of Low-dose Naltrexone Versus Placebo on Change in Neurocognitive Function From Baseline
Patients completed neurocognitive testing at each QoL measurement assessment. Neurocognitive function was measured via a computerized neurocognitive test battery called CNS Vital Signs. The battery consists of 7 tests that assess verbal and visual memory, finger tapping, symbol digit coding, the Stroop Test, a test of shifting attention, and continuous performance. The battery provides scores over 9 domains with higher scores indicating better performance. Scores were normalized to a standard score mean of 100 and standard deviation of 15 using a normative sample. The mean difference in score in each domain between the 3rd QoL measurement (approximately 16 weeks from initial assessment) and the initial baseline assessment are reported. A difference greater than 0 indicates an increase in mean score, while a difference less than 0 indicates a decrease in mean score.
Time frame: Baseline and 16 weeks
Population: This analysis only includes those patients who completed both the initial CNS Vital Signs assessments and the 16 week assessments, and thus number of participants may not match those reported in the participant flow module, which reports number of participants completing the trial at 24 weeks.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Low Dose Naltrexone (LDN) | Effects of Low-dose Naltrexone Versus Placebo on Change in Neurocognitive Function From Baseline | Processing Speed | -0.71 Scores on a Scale | Standard Deviation 24.72 |
| Low Dose Naltrexone (LDN) | Effects of Low-dose Naltrexone Versus Placebo on Change in Neurocognitive Function From Baseline | Cognitive Flexibility | 3.62 Scores on a Scale | Standard Deviation 23.14 |
| Low Dose Naltrexone (LDN) | Effects of Low-dose Naltrexone Versus Placebo on Change in Neurocognitive Function From Baseline | Verbal Memory | -0.1 Scores on a Scale | Standard Deviation 28.22 |
| Low Dose Naltrexone (LDN) | Effects of Low-dose Naltrexone Versus Placebo on Change in Neurocognitive Function From Baseline | Complex Attention | 7.33 Scores on a Scale | Standard Deviation 32.07 |
| Low Dose Naltrexone (LDN) | Effects of Low-dose Naltrexone Versus Placebo on Change in Neurocognitive Function From Baseline | Reaction Time | -7.24 Scores on a Scale | Standard Deviation 29.61 |
| Low Dose Naltrexone (LDN) | Effects of Low-dose Naltrexone Versus Placebo on Change in Neurocognitive Function From Baseline | Psychomotor Speed | -0.76 Scores on a Scale | Standard Deviation 13 |
| Low Dose Naltrexone (LDN) | Effects of Low-dose Naltrexone Versus Placebo on Change in Neurocognitive Function From Baseline | Visual Memory | -8.38 Scores on a Scale | Standard Deviation 19.05 |
| Low Dose Naltrexone (LDN) | Effects of Low-dose Naltrexone Versus Placebo on Change in Neurocognitive Function From Baseline | Executive Functioning | 3.9 Scores on a Scale | Standard Deviation 23.17 |
| Low Dose Naltrexone (LDN) | Effects of Low-dose Naltrexone Versus Placebo on Change in Neurocognitive Function From Baseline | Memory | -5.38 Scores on a Scale | Standard Deviation 24.03 |
| Placebo | Effects of Low-dose Naltrexone Versus Placebo on Change in Neurocognitive Function From Baseline | Executive Functioning | 7.56 Scores on a Scale | Standard Deviation 22.87 |
| Placebo | Effects of Low-dose Naltrexone Versus Placebo on Change in Neurocognitive Function From Baseline | Memory | -0.24 Scores on a Scale | Standard Deviation 17.63 |
| Placebo | Effects of Low-dose Naltrexone Versus Placebo on Change in Neurocognitive Function From Baseline | Processing Speed | 7.32 Scores on a Scale | Standard Deviation 19.17 |
| Placebo | Effects of Low-dose Naltrexone Versus Placebo on Change in Neurocognitive Function From Baseline | Reaction Time | -8.64 Scores on a Scale | Standard Deviation 17.03 |
| Placebo | Effects of Low-dose Naltrexone Versus Placebo on Change in Neurocognitive Function From Baseline | Verbal Memory | 2 Scores on a Scale | Standard Deviation 17.29 |
| Placebo | Effects of Low-dose Naltrexone Versus Placebo on Change in Neurocognitive Function From Baseline | Visual Memory | -2.24 Scores on a Scale | Standard Deviation 19.32 |
| Placebo | Effects of Low-dose Naltrexone Versus Placebo on Change in Neurocognitive Function From Baseline | Cognitive Flexibility | 7.44 Scores on a Scale | Standard Deviation 22.12 |
| Placebo | Effects of Low-dose Naltrexone Versus Placebo on Change in Neurocognitive Function From Baseline | Complex Attention | 6.24 Scores on a Scale | Standard Deviation 18.84 |
| Placebo | Effects of Low-dose Naltrexone Versus Placebo on Change in Neurocognitive Function From Baseline | Psychomotor Speed | 4.72 Scores on a Scale | Standard Deviation 11.6 |