Regional Research Partnership

The BTFC recently made a $50,000 grant to Duke University, to help fund a project by Dr. Katy Peters. 

Effects of Low-Dose Naltrexone on Quality of Life in High-Grade Glioma Patients: A

Placebo, Double-Blind Randomized Controlled Trial

A. Specific Aims

Individuals who are diagnosed with high-grade gliomas (HGGs) are immediately confronted

with two serious health issues. First, there is a new diagnosis of cancer that will require serious

therapies such as brain surgery, brain irradiation, and chemotherapy. Secondly, they face the

symptoms and signs of neurological dysfunction. Having both immediate oncologic and

neurological concerns is unique to brain tumor patients such that they have more challenges in

their search for a positive and productive quality of life (QOL). In fact, when compared to

matched patients with other types of cancer, HGG patients exhibit more dysfunction with

physical function, neurocognition, and QOL.

are few options to improve QOL, functional capacity, and neurocognition during the course of

treatment for newly diagnosed HGG.

approaches, are needed to treat and evaluate multi-dimensional aspects of QOL. Naltrexone is

a commonly used opioid antagonist, but in very low doses, its action can increase the

expression of opioid receptors and increase met-enkephalin and

signaling changes and endogenous compounds can decrease inflammation, improve mood, and

improve well-being.

as multiple sclerosis and fibromyalgia and has been shown to improve QOL.

is well-tolerated at this lower dosage. In light of its utility in other neurological disorders, we

have embarked on a study to evaluate LDN and its effects on QOL in HGG patients. In this

grant proposal, we have designed a placebo-controlled, double-blind randomized trial of 72

newly diagnosed postsurgical HGG patients to evaluate if LDN in comparison to placebo can

improve QOL during standard chemoradiation and adjuvant chemotherapy.

likely have farther reaching implications on how we measure QOL and improve QOL in all

cancer patients that are undergoing treatment.

Primary Aim

AIM:

QOL in HGG patients.

We hypothesize that QOL will be improved in newly diagnosed HGG patients when taking LDN

in comparison to placebo.

Secondary Aims

AIM 1:

HGG patients.

We hypothesize that functional capacity in newly diagnosed HGG patients will differ depending

on whether the patient is on LDN or placebo.

AIM 2:

patients.

We hypothesize that neurocognition in newly diagnosed HGG patients will differ depending on

whether the patient is on LDN or placebo.

AIM 3:

We hypothesize that LDN will be safe and well-tolerated therapy in HGG patients.

B. Background

Primary brain tumors represent 1% of all diagnosed cancers.

newly diagnosed high-grade gliomas (HGGs) involves surgical resection followed by

temozolomide concurrently with and after radiotherapy. Before and during treatment for HGG,

adult patients experience a decline in perceived quality of life (QOL).

concept that encompasses the multidimensional well-being of a person and reflects an

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individual’s overall satisfaction with life.”

dysfunction, whether cognitive or physical, fatigue associated with treatment, symptoms such as

nausea and anorexia associated with treatment, and other common symptoms such as

insomnia, seizures, and headaches all have negative impacts on QOL. Overall functionality

and QOL are particular important in brain tumor patients since they experience more

dysfunction than age-matched controls with non-small lung cancer patients.

prospective study by Budrukkar and colleagues on QOL in brain tumor patients, they found that

QOL, as rated by questionnaire scores, was low before initiating any type of treatment.

Factors associated with poorer QOL included poor performance status, illiteracy, and more

aggressive nature of tumors.

neurocognition such that HGG patients with better physical function and better neurocognitive

function reported having higher levels of QOL.

symptoms and signs are interrelated and should not be studied alone such that cognitive

decline/dysfunction was associated with increased fatigue and poorer performance status.

During concurrent chemoradiation, brain tumor patients experience a decline in relative QOL

particularly due to fatigue and changes in cognition.

not be studied alone, but in concert with neurocognition and physical function. Because of this,

we have designed a multidimensional approach to look at the subjective aspects of QOL and

objective findings in physical function and neurocognition.

For subjective QOL measures, we have utilized multiple standardized questionnaires to

evaluate issues with fatigue, cognition, physical function, sleep, and mood. The Functional

Assessment of Cancer Therapy-Brain (FACT-Br) has been used extensively and has been

documented to identify key QOL problems for brain tumor patients.

questionnaires include Functional Assessment of Cancer Therapy-Fatigue, Functional

Assessment of Cancer Therapy-Cognition, Beck Medical Outcomes Survey, Epworth

Sleepiness Scale, Pittsburgh Sleep Quality Index and Zung Self-Rating Depression Scale.

Since these are subjective measures, we have also employed objective measures of physical

function and neurocognition using six-minute walk test and neurocognitive testing with CNS

Vital Signs®, respectively. These measurements have been validated and are being used

extensively in our research in not only brain tumor patients but also in patients with other forms

of cancer.

In a recent published study in the Journal of Neuro-Oncology, physical fitness using the

6- minute walk test and QOL using patient-reported outcomes were obtained in recurrent highgrade

glioma patients. This study revealed that patients that had very poor physical fitness as

objectively measured with the 6-minute walk test had poorer patient-reported QOL measures in

comparison to patients with better performance on the 6-minute walk test.

walk test is a validated and useful test in determining functional capacity in GBM patients and

correlates with patient-reported QOL. In a recent article by Jones, Peters, and colleagues, we

examined objective physical functioning and patient-reported QOL, fatigue, and cognitive

function in low grade glioma and HGG patients.

surgery to 6 months after surgery. Again, changes in physical functioning were associated with

similar changes in patient-reported QOL, fatigue, and cognitive function measures. Additionally

findings showed that three distinct sets of patients could be delineated based on their physical

functioning. These results point further to a necessity for interventions to improve QOL in HGG

patients during their treatment course.

Interventions to improve QOL in brain tumor patients have included stimulants such as

methylphenidate and modafinil. Clinical trials with methylphenidate in brain tumor patients

undergoing radiation therapy were discontinued in early stages because interim analysis did not

show any evidence of effectiveness.

QOL in brain tumor patients, but the study was not placebo-controlled.

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approaches and more clinical studies are needed to evaluate interventions in regards brain

tumor patient QOL.

Naltrexone is orally semisynthetic opiate antagonist that has been licensed by the FDA

for the treatment of heroin and alcohol addiction. Doses for this treatment are usually in the

range of 50 mg to 100 mg. The main role of naltrexone is to counteract the effects of opioids

by blocking opiate receptors.

less than 5 mg/day), works much differently than naltrexone at higher, conventional doses.

The proposed mechanism for LDN is that by transiently inhibiting opioid receptors it stimulates

the expression of mu, delta, and epsilon opioid receptors, circulating met-enkephalin and

endorphins.

energy, mood, and well-being. There has been recent interest in the use of LDN for the

treatment of fatigue in other neurological conditions such as multiple sclerosis and fibromyalgia.

In a single-blind, crossover study in fibromyalgia patients, LDN was shown to lower symptoms

of fatigue and stress.

included vivid dreaming in two subjects and transient insomnia and nausea in one subject.

Three pilot trials have been performed in multiple sclerosis and its effects on QOL.

most recent study by Cree and colleagues, they evaluated eighty multiple sclerosis patients in a

single-center, double-masked, placebo-controlled crossover study. In self-reported QOL

measures, LDN (at dose of 4.5 mg orally nightly) improved scores significantly in several

different scales. In particular, outcomes on the Medical Outcomes Survey were significantly

improved with 3.3-point increase at 8 week for LDN in comparison to placebo. Most common

toxicities were vivid dreaming as seen in seven placebo patients and ten LDN patients. Other

adverse events include sinus infection (1 in LDN group), anorexia (1 in LDN group), insomnia (1

in placebo group), flu-like symptoms (1 in placebo group), and fatigue (2 in LDN group and 1 in

placebo group). Moreover, this treatment was deemed easily tolerated while multiple sclerosis

patients were on disease modifying therapies such as interferon-

this information, LDN is a provocative agent with little to no toxicity that can positively impact

QOL in patients with neurological disease. Therefore, we have designed a clinical trial to

explore this possibility in brain tumor patients.

In this pilot clinical trial, we will test the effectiveness of LDN in improving QOL in HGG

patients that are receiving standard chemoradiation. The primary objective of this pilot study is

to compare patient-reported measures of QOL in HGG patients on either LDN or placebo.

Using a multidimensional approach, secondary measures will include functional capacity (as

measured by the six-minute walk test) and neurocognitive function (as measured by CNS Vital

Signs®). Safety of LDN in this population will also be a secondary outcome with standard

monitoring with complete blood counts with differential and comprehensive metabolic panels.

This data will be used to design large studies in regards to cancer-related QOL and the use of

LDN.

C. Experimental Design/Brief Methods of Procedure

C.1 Setting and Patient Participants

The proposed study will be conducted at the Preston Robert Tisch Brain Tumor Center

(PRT-BTC) at Duke. All subjects will be patients that will be undergoing standard

chemoradiation with radiotherapy and daily oral temozolomide for the treatment of high-grade

glioma.

Inclusion criteria for this study are:

1) Written informed consent prior to beginning specific protocol procedures

2) Histologically proven high-grade glioma

3) Planned treatment with concurrent radiotherapy and daily oral temozolomide

4)

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5) Karnofsky performance index >70%

6) No documented cardiac or pulmonary disease

7) No contraindications to six-minute walk test

8) Primary neuro-oncologist approval

9) Hematocrit

10) Serum creatinine < 1.5 times upper limit of normal, serum SGOT < 2.5 times upper

limit of normal and bilirubin < 2.0 times upper limit of normal

11) If sexually active, patients will take contraceptive measures for the duration of the

treatments.

Exclusion criteria for this study are:

1) Prior therapy with naltrexone or naloxone

2) Co-medication that may interfere with study results; e.g opioids

3) Known hypersensitivity to any component of naltrexone

4) Pregnant (positive pregnancy test) or lactating

5) Life expectancy of < 12 weeks.

C.2 Study Design and Procedures

The proposed study is a placebo-controlled, double-blind randomized clinical trial.

Potential participants will be identified via clinical protocol chart review of patients scheduled to

attend their pre-determined follow-up consultations at PRT-BTC 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 LDN dosed at 4.5 mg orally to be taken every evening before going to bed. Patients will be

assessed at the following timepoints:

1. Baseline (before chemoradiation)

2. After chemoradiation (approximately 8 weeks from initial assessment)

3. 2 months after standard chemoradiation (approximately 16 weeks after initial

assessment),

4. 4 months after standard chemoradiation (approximately 24 weeks after initial

assessment). (See Figure 1 for study design)

Treatment with LDN or placebo will begin on first day of chemoradiation and will be

continued for a total of 16 weeks. Last assessment at 24 weeks will occur 8 week after

discontinued 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. LDN and

placebo will be compounded and distributed by the Duke University Compounding Pharmacy

(Durham, NC).

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C.3 Assessments

Quality of Life

(FACT-BR) scale. The FACT-BR (version 4) contains subscales for physical (7-items),

functional (7-items), emotional (6-items), and social/family (7-items) well-being. In addition, this

instrument contains an 23-item brain cancer subscale (BCS) which assess symptoms

commonly reported by brain cancer patients.

13-item Fatigue Scale using the Functional Assessment of Cancer Therapy-Fatigue (FACITFatigue)

subscale, version 4.

Functional Assessment of Cancer Therapy-Cognition (FACT-Cog) subscale.

subscales for perceived cognitive impairments (20 items), comments from others (4 items),

perceived cognitive abilities (9 items), and impact of quality of life (4 items). Using CNS Vital

Signs, we have included the following batteries: Medical Outcomes Survey (MOS), Epworth

Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), and Zung Self-Rating

Depression Scale (ZSDS). These questionnaires will be computerized and delivered as part of

the cognitive testing. They will be viewed and completed after the neurocognitive testing

portion. MOS is a 36-item scale using to assess general health, well-being, and quality of life,

and we will be using the short form for this assessment.

assess sleepiness.

item scale used to assess self-rating of depression.

used to evaluate for underlying depressive symptoms. We will used the revised version (BDI-II)

and the scores will range from 0 (no depression) to 63 (severe depression).

21 questions in regards to mood symptoms and is multiple-choice and self-reported.

Figure 1: Study Design. Yellow areas are for standard chemoradiation time and orange areas are

for adjuvant chemotherapy. A1, A2, A3, and A4 are indicative of assessments and number.

(XRT=irradiation, mg=milligrams, po=orally, qhs=at night)

Peters_Katherine 2010

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Functional capacity

instructed to walk at their fastest pace and to cover the longest possible distance over 6 minutes

under supervision of an American College of Sports Medicine certified exercise specialist.

Distance walked will be determined in a measured corridor and performed according to ATS

guidelines. Oxyhemoglobin saturation (SpO

using pulse oximetry (BCI, Hand-Held Pulse Oximeter, Waukesha, WN).

Neurocognitive testing

computerized battery CNS Vital Signs®.

verbal and visual memory, finger tapping, symbol digit coding, the Stroop Test, a test of shifting

attention, continuous performance test. Verbal memory test will assess verbal learning,

memory for words, immediate recall, and delayed recall. Visual memory tests will assess visual

learning, memory for geometric shapes, immediate recall, and delayed recall. Finger tapping

test will assess motor speed and fine motor control. Symbol digit coding test will evaluate

complex attention, visual-perceptual speed, and information processing speed. Stroop Test will

assess executive function, simple and choice reaction time, speed-accuracy trade-off,

information processing speed, and inhibition/ disinhibition. Shifting attention test will assess

executive function, reaction time, and information processing speed. Continuous performance

test will assess sustained attention and choice reaction time. Normative data is available for

this testing through CNS Vital Signs® and patients’ performance will be compared to this

normative data.

Medical and Demographic Information

(e.g., education, employment, smoking status). Medical information will be abstracted from

medical records and study questionnaires.

Monitoring for adverse events will be included along with routine testing with

comprehensive metabolic panel, complete blood cell counts with differential, and thyroid

function testing including thyroid stimulating hormone and free thyroxine.

C.4 Location and facilities:

PRT-BTC at Duke is an internationally known center for the treatment of primary brain

tumors. Each week, we see approximately 12 to 20 new primary brain tumor patients in our

outpatient clinic with a majority of those being newly diagnosed HGG. Because of the

excellence and experience of

service for the PRT-BTC has approximately 5 to 6 newly diagnosed primary brain tumor patients

that will be undergoing surgery at Duke University Medical Center every week. All of the

testing has been designed to be amendable to the inpatient and outpatient setting. The QOL

questionnaires, neurocognitive testing, and 6-minute walk testing are all easily performed at the

bedside, on the clinical ward, or in the clinic outpatient setting. Because of our resources, in

particular multitude of patients, inpatient services, and outpatient services, we feel that this

study can be performed successfully at the PRT-BTC.

C.5. Study Personnel and Expertise

I,

Surgery) am a board-certified neurologist with a background in cognitive neuroscience and

neuro-oncology. My unique backgrounds in both neurology and cancer biology (PhD work from

Stanford University) provide me with the appropriate criteria to author and lead this study. As

one of the new attending for the PRT-BTC, I work with world-renown clinician scientists in

neuro-oncology such as

continuation of collaboration with

Radiation Oncology) who is a preeminent exercise scientist and Director of the Cancer

Survivorship Center at Duke. I have written several protocols with

will continue to benefit from his knowledge and support.

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aforementioned colleagues, I have been able to design an innovated study to evaluate,

for the first time, at the use of LDN in HGG and how it impacts QOL during

chemoradiation.

C.6 Timeline

The focus of the time line will be initially on patient recruitment in the first 5 months and will

shift to data collection and patient follow-up in the later months. Because of our patient volume,

we anticipate recruiting and randomizing 72 patients within 5 months. Essentially, this will be

approximately 15 patients recruited per month for the study. Because the study time is 24

weeks total we will need to complete recruitment by month 5. Therefore, all data collection and

follow-up information will be obtained at month 11. This will be suitable for data analysis in

month 12. Reporting of finding will include communication to granting organization, professional

meetings, and likely publication.

12 Months

Months 1-5 Months 6-11 Month 12

Patient Recruitment/Data Collection Data Collection Final Data

Months 6-11 Analysis

Follow-up on Patients

D. Statistical Analysis

Seventy-two (72) patients newly diagnosed with high-grade glioma will be randomized

with equal probability to receive either LDN or placebo with standard chemoradiation treatment

consisting of temozolomide, radiotherapy, and possibly bevacizumab. Randomization will be

stratified by the inclusion of bevacizumab in the chemoradiation treatment plan. Though this

study is comparative, the goal of this randomized double-blinded pilot study is to determine

whether LDN is worthy of further investigation, and not to make definitive statements about its

effectiveness relative to placebo. Though the basis for sample size determination will focus on

treatment differences in QOL at week 16 as measured by FACT-Br, other factors such as

treatment differences in QOL at week 8 and treatment differences in cognition and fatigue at all

follow-up assessments will be considered in the final decision-making.

The universal importance of a half standard deviation change or difference has been

previously reported for health-related quality of life measures.

detect a half standard deviation difference in QOL scores measured at week 16.

Being a phase II study, there is a need to constrain the sample size requirements at the

expense of either an increased false negative or false positive rate. As proposed by Ratain and

Sargent, a false-positive rate of 0.2 will be used to test this hypothesis.

patients per arm in this screening study, the power of a 1-tailed two-sample t-test conducted at

the 0.2 level of significance to detect a half standard deviation difference in QOL scores

measured at week 16 is 90% (SAS 9.2, Cary, NC). Assuming that approximately 10% of

patients withdraw from study participation prior to week 16 assessment, approximately 66

patients are expected to provide a week 16 assessment. With 33 patients per arm, the test

described above will have approximately 88% power to detect the noted difference.

Descriptive statistics (e.g. means and standard deviations) will be used to summarize

within-group changes from baseline in each patient-reported outcome and cognition scale and

subscale at each follow-up assessment. Analysis of covariance will be used to compare groups

with respect to changes between baseline and week 16 in each of these subscales, with the

baseline measure included as a covariate. Generalized linear models for repeated measures

which accounts for correlations among serial measurements obtained from the same patient will

be used to compare treatment patterns of response over time in cognition and patient-reported

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outcomes from questionnaires. Adjustments to the intended analysis plan will be made if

patients withdraw from study participation before the completion of the week 16 assessment.

Options include a focus on repeated measures obtained during the first 8 weeks, as well as

more complicated models such as pattern mixture models. An intent-to-treat philosophy will be

followed in all analyses.

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