Feasibility Study of Modified Atkins Ketogenic Diet in the Treatment of Newly Diagnosed Malignant Glioma
Phase: NA
Conditions: Glioblastoma
Sponsor: University of Cincinnati

MAD/KD protocol revision date 18MAR2020– Page 1
STUDY NUMBER: UCCI-BRAIN-16-01
STUDY TITLE: 
Feasibility Study of Modified Atkins Ketogenic Diet in the Treatment of 
Newly Diagnosed Malignant Glioma
PRINCIPAL INVESTIGATOR:  Rekha Chaudhary, MD
                                                Adjunct-Associate Professor of Medicine
                                                Division of Hematology/Oncology
3125 Eden Avenue
Cincinnati, Ohio 45267
                                                Telephone:  513-558-2119
Fax:  513-558-2124
             
Rekha.chaudhary@uc.edu
CO- INVESTIGATORS
Tammy Ward, RD, CSO, LD
Clinical RD, Specialist in Oncology Nutrition
University of Cincinnati Cancer Institute
Barrett Cancer Center Room 2039
234 Goodman Street 
Cincinnati, Ohio 45219
Telephone: 513-584-4508
Fax: 513-584-6949
Tammy.Ward@uchealth.com
STATISTICIAN:
Jeffrey Welge, PhD
Research Associate Professor of Psychiatry
Department of Psychiatry and Behavioral Neuroscience
University of Cincinnati Academic Health Center
PO Box 670559
Cincinnati, Ohio 45267-0559
Telephone: 513-558-0856
Fax: 513-558-0877
jeffrey.welge@uc.edu
SUPPORT: UC Brain Tumor Center John C Tew Endowed Chair Fund
AGENT: Temozolomide
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SCHEMA:
1. Diagnosis of High Grade Glioma (-28 days)
2. Pretreatment Visit 1:  Meet with Physician and/or Nurse Practitioner (NP) for 
chemotherapy teaching. (day -28 to day -7)
a.
Check lipid profile, complete metabolic panel, complete blood count with 
differential (CBC with diff), and hemoglobin A1C
b. Take medical history concerning pancreatitis, recent cholecystectomy or 
gallbladder dysfunction, diabetes, dairy allergies and/or lactose intolerance, in-
born errors of metabolism 
c.
Obtain informed consent
d. Obtain tissue from biopsy or resection
3. Pretreatment Visit 2:  Meet with Nurse Practitioner for chemotherapy teaching (day -28 to 
day -7)
a.
Laboratory Correlatives
i. Serum beta-hydroxybutyrate (BHB)
ii. Complete metabolic panel, fasting serum glucose and insulin 
iii. Vital signs, height, body weight, waist circumference
iv. Platelet mitochondrial labs
v. Neurocognitive testing (See Appendix VI)
vi. Quality of Life (FACT-Br) survey (See Appendix I)
vii. MRI planning scan 
4. Pretreatment Visit 3:  Meet with registered RD (RD) for nutritional education concerning 
carbohydrate restricted diet (Modified Atkins Diet (MAD)) (day -28 to day -7)
a.
Diet education consultation with RD – 1.5 hours. Distribute week 1 food diary 
with education concerning completion (Appendix II)
b. Confirm above histories and labs 
c.
Random assignment to MAD ketogenic diet with radiation therapy day -7 
5. Radiation/Chemotherapy commences (Day 0-Day 42)
a.
Collect daily food diaries
b. Weekly visits with NP/MD
i. Serum BHB
ii. Complete metabolic panel, fasting serum glucose and insulin levels
iii. Vital signs, body weight, waist circumference 
iv. Quality of Life (FACT-Br) survey (See Appendix I)
c.
Weekly telephone contact with RD to address diet related concerns 
6. Radiation and temozolomide treatment terminated
a.
Continued MAD until MRI (Day 43-70)
7. MRI and post-treatment visit #1 (approximately Day 70)
a.
Meet with RD 
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i. If patient wishes to discontinue research diet, RD will instruct patient on 3-
day titration back to pre-study carbohydrate intake levels.
ii. If patient wishes to continue longer term discuss supplement use to prevent 
nutritional deficiencies from long-term diet.
b. Meet with attending physician 
i. Review MRI findings
ii. Review post-intervention maintenance chemotherapy 
iii. Laboratory Correlatives
i.
Lipid profile, complete metabolic panel, complete blood count 
with differential (CBC with diff), and hemoglobin A1C
ii.
Serum BHB
iii.
Fasting serum glucose and insulin 
iv.
Vital signs, body weight, waist circumference
v.
Platelet mitochondrial Labs
iv. Adverse Events
v. Performance Status
vi. Quality of life (FACT-Br) survey (See Appendix 1)
vii. Neurocognitive testing (See Appendix VI)
8. MRI and Ppost-treatment visit #2 (approximately day 126-154 after post-treatment MRI)
a.
Meet with attending physician 
i. Review MRI findings
ii. Review post-intervention maintenance chemotherapy 
iii. Laboratory Correlatives
i.
Lipid profile, complete metabolic panel, complete blood count 
with differential (CBC with diff) and hemoglobin A1C
ii.
Serum beta-hydroxybutyrate
iii.
Fasting serum glucose and insulin 
iv.
Vital signs, body weight, waist circumference
v.
Platelet Mitochondrial Labs
iv. Performance Status
v. Quality of life (FACT-Br) survey (See Appendix 1)
vi. Neurocognitive testing (See Appendix VI)
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1. OBJECTIVES
1.1. Hypothesis/Rationale of the Study:  Modified Atkins diet (MAD) concurrent with 
radiation therapy will produce ketosis and improve outcomes in patients with 
malignant gliomas due to increased sensitivity of the tumors to radiation therapy. 
1.2. Primary Objectives
1.2.1. Assessment of feasibility of inducing ketosis with MAD concurrent with 
radiation therapy by measuring serum beta-hydroxybuterate
1.2.2. Assessment of fasting glucose and insulin levels with MAD concurrent with 
radiation therapy 
1.2.3. Assessment of compliance with MAD concurrent with radiation therapy
1.3. Secondary Objectives
1.3.1. Assessment of 6-month progression-free survival in patients with high-grade 
gliomas with MAD concurrent with radiation therapy as compared to historical 
controls
1.3.2. Safety of MAD concurrent with radiation and chemotherapy therapy
1.4. Exploratory Objectives
1.4.1. Assessment of QOL changes with MAD concurrent with radiation therapy
1.4.2. Assessment of cognitive function changes with MAD concurrent with radiation 
therapy
1.4.3. Assessment of 2-year survival of patients with high-grade primary brain 
neoplasms with MAD concurrent with radiation therapy as compared to historical 
controls
1.4.4.  Assessment of mitochondrial respiration in peripheral platelets and correlate 
with cognitive findings
2. BACKGROUND
2.1. Malignant Gliomas: Malignant gliomas are among the most virulent tumors. High-
grade gliomas are divided into Grade III gliomas (including anaplastic astrocytoma, 
anaplastic oligodendroglioma, and anaplastic oligoastrocytomas) and Grade IV which 
are termed Glioblastoma Multiforme (GBM). GBM is the most common primary 
brain tumor and the most aggressive. The five-year survival for GBM is dismal and 
multiple treatment modalities have been unsuccessful.  Stupp et ali defined the 
standard of care in 2005 with the combination of temozolomide and radiation therapy 
increasing the 2-year survival with this regimen from 10.3% in the radiation only arm 
to 26.5% in the combination arm. This has defined the standard of care but still just 
3% of patients are surviving at 5 years.
2.2. Ketone metabolism: Gliomas cells in contrast to normal glial cells rely on glucose 
and glycolysis for division and survival. Normal glial cells can survive on ketones 
alone but it is hypothesized that glioma cells cannot utilize ketone bodies as energy 
substrate.ii The Akt/phosphoinositide 3-kinase (PI3K)/mammalian target of 
rapamycin (mTOR) (AKT/PIK3/MTOR) pathway has been implicated in the 
inhibition of cell death and is activated by glucose and glycolysis. This pathway is 
found in many gliomas.iii Ketone metabolism has been used to control childhood 
epilepsy for many years and this is thought to be through inhibition of the 
AKT/PIK3/MTOR pathway and other mechanisms.iv Abdelwahab implanted mice 
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with malignant glioma cells to study the effect of ketosis on survival and glioma 
control. The mice had a modest increase in survival with ketone metabolism as 
compared to control mice not on the ketogenic diet. However, when radiation was 
added to the treatment (with or without the ketogenic diet) there was a significant 
increase in survival so much so that tumor cells could no longer be detected in the 
ketogenic arm. The mice were switched to a non-ketogenic diet after 101 days and no 
signs of recurrence were seen for over 200 days in the radiation and ketogenic diet 
arm.v 
Ketone bodies may act as a radiation sensitizing agent and this would explain the 
significantly increased survival in the mice that received the ketogenic diet with 
radiation as compared to the mice that received the ketogenic diet alone. 
Caloric restriction is also important in glioma control.   Seyfried et al. injected mice 
with CT-2A glioma cells. Mice were placed on a caloric restriction diet or a regular 
diet with and without ketone body supplementation. The ketone supplemented diet 
alone did not predict increased overall survival. Caloric restriction was an important 
contributor to decrease in tumor size and increase in overall survival.  Caloric 
restriction inhibits the insulin growth factor-1 pathway (IGF-1) pathway and therefore 
inhibits tumor growth. Combined caloric restriction and serum ketosis achieved 
greater tumor control and mouse survival.vi Seyfried, however, conducted this study 
without radiation. From this data, our hypothesis is that both decreased glucose and 
ketosis in conjunction with radiation are necessary to produce tumor reduction in 
gliomas.  
There is limited data in humans with ketogenic diets and cancer but because of the 
preliminary data in mice of the effect of ketones and radiation on gliomas and the 
retrospective data in humans with glioblastoma that hyperglycemia  decreases 
survival, vii there are multiple on-going trials.  Champ et al. retrospectively studied 6 
patients with glioblastoma on the ketogenic diet.  The six patients had lower blood 
glucose and higher ketone levels than their counterparts and tolerated the diet well.viii 
Nebeling et al studied two pediatric patients with anaplastic astrocytoma (high grade 
gliomas) and found that the diet was tolerated and safe.  The two patients had 
significant decreases in glucose, increases in ketone levels and decreases in glucose 
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uptake on FDG-PET.ix Again given the retrospective nature of these studies, it is 
difficult to draw any unbiased conclusions from this data.  
2.3.
Modified Atkins Diet (MAD): The form of the KD used in pediatric epilepsy is 
composed of a 4:1, fat to carbohydrate plus protein ratio. However, the modified 
Atkins diet (MAD) (<20 grams of carbohydrates per day) produces ketosis and has 
been used in the treatment of adults with epilepsy with the same efficacy. Notably, 
there is better compliance with the MAD than with the traditional KD.  Many studies 
have also shown improved  tolerability the MAD in the adult population as compared 
to the traditional ketogenic diet .x
2.4.
Cognitive Outcomes: We have shown in older adults with Mild Cognitive 
Impairment (MCI), a risk condition for Alzheimer’s disease, that dietary ketosis 
achieved through carbohydrate restriction, improves memory performance (Fig 1). 
Figure 1. 
Pre- and 
post-intervention 
memory performances for low and high carbohydrate participants with MCI as 
measured by the Verbal Paired Associate Learning Test, F(1,20) = 6.45, p = 0.01, 
Cohen’s f = 0.26 (Krikorian et al. 2012).  
In addition to these improvements in memory performance in older adults, we 
observed preliminary indications that dietary ketosis is associated with enhanced 
neuronal integrity and increased bioenergetic function in pre- and post-dietary 
intervention studies using proton magnetic resonance imaging (1H MRS) in older 
adults with MCI (Krikorian et al. 2014; Fig 2).  
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Figure 2. Effect and trends indicating increased myo-inositol, N-acetyl-aspartate, and 
creatine + phosphocreatine in older adults with MCI following six weeks of 
nutritional ketosis induced by carbohydrate restriction.
In addition, our colleague, Dr. Patrick Sullivan at the University of Kentucky, has 
developed a method to assess platelet mitochondrial function and demonstrated 
significant changes in mitochondrial function in blood platelets preceding changes in 
brain mitochondrial function in a trichloroethylene (TCE) rodent model. 
Mitochondrial respiratory capacity in platelets isolated from animals (n=3-5/group) 
that had been exposed to TCE (1000 mg/kg, oral gavage daily) was assessed for 
different periods (1 hour to 7 days). Chronic TCE exposure induces a Parkinsonian 
disease state. (Fig 3). In addition, wild type (WT) mice and mice overexpressing 
human wild type alpha synuclein (aSyn), a pathological factor in Parkinson’s disease 
neuropathology, under the Thy1 promoter (Thy1-aSyn) were placed on a ketogenic or 
control diet. Mitochondrial respiration was measured in mitochondria isolated from 
the striatum from mice fed a ketogenic or standard diet for 28 days. Thy1-aSyn mice 
fed a standard diet displayed significantly diminished mitochondrial efficiency 
compared to WT mice on the standard diet and Thy1-aSyn mice fed the ketogenic 
diet displayed mitochondrial efficiency rates similar to WT mice (Fig 4). 
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TCE Exposure
% Control Respiration Capacity
1 hr
1 Day
3 Day
4 Day
7 Day
0
50
100
150
200
Vehicle
TCE
*
*
*
Figure 3. TCE exposure reduces mitochondrial function in a progressive manner. In 
contrast, measurable change in brain mitochondria requires two weeks of chronic 
exposure. Thus, the peripheral measure may function as an early marker brain 
mitochondrial dysfunction in animal and human PD. Bars = means +SD
Figure 4: Mitochondria were isolated from striatum and oxygen consumption rate (OCR) 
was measured in WT and Thy1-aSyn mice at 3m of age and 28 days on a ketogenic or 
standard diet. Mitochondrial oxygen consumption is significantly reduced in Thy1-aSyn 
mice fed a standard diet but not in Thy1-aSyn mice fed a ketogenic diet. N=3 in each 
condition, * Represents p<0.05, ANOVA
Very recently, we obtained data demonstrating enhanced peripheral platelet mitochondrial 
efficiency through nutritional ketosis in overweight, middle-aged individuals with memory 
complaints, factors that confer greater risk for late-life dementia. Figure 5 shows 
preliminary data from four participants randomized to either the higher carbohydrate or 
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lower carbohydrate ketogenic protocols. Platelet assays from participants randomized to the 
low carbohydrate arm exhibited enhanced state III respiration and uncoupling.
Baseline
Final
0
0.5
1
1.5
2
Higher carb
Higher carb
Low carb
Low carb
Change, state III respiration
Percent deviation from baseline
Baseline
Final
0
0.5
1
1.5
2
Higher carb
Higher carb
Low carb
Low carb
Change, uncoupling
Percent deviation from baseline
These preliminary studies demonstrate our ability to administer the carbohydrate-
restricted, ketogenic diet with research participants and the efficacy of this intervention 
with respect to neurocognitive function. Further, in collaboration with Dr. Sullivan, we 
have shown in animal and, more recently in humans, that this intervention influences 
mitochondrial function favorably.
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3.
STUDY DESIGN
3.1. This is a single arm feasibility study.
3.2. Study Diet:  Patients will be screened for study eligibility and written informed 
consent will be obtained prior to enrollment.  Patients will meet with the registered 
dietitian (RD) one to four weeks prior to initiation of concurrent radiation and 
chemotherapy.  At that visit, the RD will provide education on all aspects of MAD 
including meal planning and daily food diary completion (Appendix II). The diet will 
begin approximately 7 days prior to the initiation of concurrent radiation and 
chemotherapy and the patient will continue the study diet until the first post-radiation 
MRI, a time period of approximately 10 weeks. We will obtain blood to assess serum 
BHB, fasting insulin and glucose, and other chemistries as well as body weight 
weekly, according to the standard of care, while on chemotherapy and radiation 
therapy. Participants will receive weekly phone calls from the RD to address any 
questions or concerns the patient may have regarding the MAD and daily food diary.  
A food diary (Appendix II) will be used to assess adherence during the 10-week 
period. All macronutrient intake from food diaries will be entered by study agent into 
nutrient analysis software. This macronutrient breakdown will be utilized to identify 
potential problematic macronutrient intake which may be preventing patient from 
achieving ketosis.  This is available online as well.
3.2.1. Temozolomide and radiation will be given according to the standard protocol 
described by Stupp et al.i Patients will receive 75 mg/m2 of temozolomide 
concurrent with radiation therapy at standard dose.  The dose of radiation and/or 
chemotherapy and/or steroid may be modified by the attending physician based 
on clinical indications.  
3.2.2. Correlative platelet mitochondrial studies will be drawn on the pre-treatment 
visit #2, the post-treatment visit #1 and the post-treatment visit #2.    Patients are 
already having blood drawn at these visits as standard of care.  This sample will 
be transported within 6 hours to the laboratory Dr. Matthew Skelton at Cincinnati 
Children’s Hospital Medical Center for assessment of mitochondrial respiration 
in the platelets.  
3.2.3. QOL studies will be done at the pre-treatment visit #2, pre-treatment visit #3, 
weekly during chemotherapy and radiation, at the post-treatment visit #1 and then 
at post-treatment visit #2
3.2.4. Neurocognitive testing will be performed at the pre-treatment visit #2, at the 
post-treatment visit #1 and then at post-treatment visit #2
3.3. Number of Participants: Thirty evaluable patients will be enrolled.  Because this is a 
feasibility study, ECOG performance status and MGMT methylation which are both 
predictors of survival will be recorded but not used for stratification.  
4. PATIENT SELECTION
4.1.  Inclusion Criteria
4.1.1. Patients must have a histologically confirmed primary malignant glioma 
(Grade III (1p/19q intact) or Grade IV tumor).  Patients can have a 
radiographically confirmed diagnosis if biopsy is not possible, but this must be 
approved by the primary investigator.  
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4.1.2.  No uncontrolled infection or other active malignancy or chronic systemic 
immune therapy.
4.1.3. Age > 18 years.
4.1.4. ECOG performance status < 3 (see Appendix A).
4.1.5. Life expectancy > three months.
4.1.6. Ability to understand and willingness to sign a written informed consent 
document. 
4.1.7. Patients can be on an investigational study but will not be eligible if the 
investigational drug is given during the intervention 
4.1.8. Physician must have the intent to treat with the Stupp Protocol.  
(http://www.nejm.org/doi/full/10.1056/NEJMoa043330)
4.1.9. Patient must be on steroid dose of dexamethasone < 8 mg at study entry.
4.1.10. Adequate renal function, defined as follows: Serum creatinine < institutional ULN 
within 14 days prior to registration.  Creatinine clearance (CC) ≥ 60 ml/min within 14 
days prior to registration determined by 24- hour collection or estimated by Cockcroft-
Gault formula: CCr male = [(140 – age) x (wt in kg)] [(Serum Cr mg/dl) x (72)]; CCr 
female = 0.85 x (CrCl male)
4.1.11. Adequate hepatic function defined as follows:  Total bilirubin < 2 x institutional 
ULN within 14 days prior to registration; AST or ALT < 3 x institutional ULN within 
14 days prior to registration.
4.2.  Exclusion Criteria:  The presence of any of the following will exclude a patient from 
study enrollment.
4.2.1. Patients who are pregnant
4.2.2. Patients with a genetic disorder of fat metabolism.
4.2.3. Patients with IDDM or Type 2 diabetes diagnosed with a hemoglobin A1C>6.4
4.2.4. Patients who are allergic to dairy or lactose intolerance
4.2.5. Patients with known inborn errors of metabolism of primary carnitine 
deficiency, carnitine palmitoyltransferase I or II deficiency, carnitine translocase 
deficiency, beta-oxidation defects, pyruvate carboxylase deficiency and 
porphyria.
4.2.6. Patients with pancreatic insufficiency or history of pancreatitis within last 5 
years
4.2.7. Patients with gallbladder dysfunction or disease
4.2.8. Decompensated congestive heart failure
4.3. Inclusion of Women and Minorities:  Men, women and members of all races and 
ethnic groups are eligible for this trial.
5.
REGISTRATION 
5.1. To register a patient, the following documents should be completed by the research 
nurse or data manager and faxed (Fax 513-584-5680) or emailed to the UCCC CTO 
Study Coordinator:
5.1.1. Signed patient consent form
5.1.2. Eligibility Screening Worksheet and registration form 
5.1.3. HIPAA authorization form
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6. TREATMENT PLAN
6.1. Modified Atkins Diet (MAD) education and treatment plan: The modified Atkins 
diet (MAD) approximates a diet with a 1:1 ratio of macronutrients: 1 part fat to 1 part 
protein and carbohydrate combined. It is referred to as “modified” because it is lower 
in carbohydrate content (< 20 net grams/day) than the original Atkins diet used for 
weight loss. In the MAD, fat and protein are not limited; however, protein intake may 
be assessed and limited if a patient is not able to achieve and/or maintain ketosis with 
< 20gm net carb intake as documented per daily food diary.  Intake of protein in 
excess of that required for normal cell maintenance/repair can enter gluconeogenic 
pathways resulting in increases in serum glucose. A registered dietitian (RD), 
specially trained in managing ketogenic diets, will provide diet education and 
monitoring of diet-related side effects of the patients throughout the study period of 
10 weeks, as per the schema. As part of this education, the RD will provide 
recommendations for meal planning and preparation, grocery shopping, completion of 
daily food diary and education related to management of potential adverse effects of 
the study diet.
6.1.1. Diet adherence: Diet adherence will be carefully monitored via daily 
patient/caregiver-generated food diary and ability to achieve and maintain 
ketosis. Weekly phone contact with RD will aid in ensuring compliance to the 
study diet by addressing any questions/concerns the patient and/or caregivers 
may have regarding any aspect of the study diet/processes. Body weight will be 
recorded each week for the first six weeks. 
6.1.2. Diet-related adverse effects: Weight loss is common during the initiation 
period due to the diuretic effect of the diet.  Electrolytes will be monitored 
weekly, oral hydration and adequate sodium intake encouraged, and caloric 
intake adjusted as needed. Constipation can be managed pharmaceutically with 
carbohydrate-free stool softeners and/or laxatives. Dietary modifications such as 
adequate oral liquid intake and increases in fiber-containing low carbohydrate 
vegetables may be necessary.
6.1.3.  The patient will be educated on concomitant over-the-counter and prescription  
medications that could prevent the patient from attaining ketosis because of their 
carbohydrate content.  See appendix VII
6.2.  Duration of Therapy: In the absence of treatment delays due to adverse events, 
treatment may continue for 10-11 weeks or until one of the following criteria applies:
6.2.1. Intercurrent illness that prevents further administration of treatment
6.2.2. Unacceptable adverse treatment related toxicity, NCI CTC AE version 4.0. 
Grade 3 or 4 that fails to recover to baseline or < Grade 3 in the absence of 
treatment within 4 weeks
6.2.3. General or specific changes in the patient’s condition that render the patient 
unable or unsuited for further participation in the judgment of the investigator, 
6.2.4. Patient decision to withdraw from treatment (partial consent) or from the study 
(full consent),
6.2.5. Pregnancy during the course of the study for a childbearing participant.
6.2.6. Death.
6.3. Duration of Follow Up
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6.3.1. Patients will be followed for toxicity for 14 days after treatment has been 
discontinued or until progression/death, whichever occurs first
7. DOSING DELAYS / DOSE MODIFICATIONS
7.1. If serum ketosis is not obtained (BHB >0.5 mM), the RD will review the daily food 
diary (Appendix II) to determine if the calculation of net carbohydrate intake is 
accurate and to modify the diet to obtain ketosis.   
7.2. If patient develops Grade 3 or Grade 4 toxicity determined to be related to the diet 
then patient will be removed off diet.  Toxicity can be determined by research 
coordinator, primary investigator or co-investigator.
7.3   If patient has a fasting glucose level >90 mg/dl, it will precipitate an evaluation of 
dietary intake and/or medical issues (i.e. infection).  
7.4  If patient is admitted to the hospital while on study/diet, compliance with the diet will 
be up to the admitting physician and the patient.  If the admission is secondary to the 
diet/protocol, this will be documented as a serious adverse event and the diet will be 
discontinued to till patient returns to Grade 1 level and then the diet can be resumed.  
If the patient has a second serious adverse event from the protocol, then the patient 
will be permanently removed from the diet.   Please see section 6.2
8. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENT
8.1. Adverse Events and Potential Risks with Dose Modifications
8.2. Modified Atkins Diet
8.2.1. Immediate short-term potential adverse effectsxi
8.2.1.1.
Constipation
8.2.1.2.
Exacerbation of gastroesophageal reflux disease
8.2.1.3.
Fatigue
8.2.1.4.
Food refusal
8.2.1.5
Dehydration
8.3.1.6
Nausea
8.4.1.7 
Mild increase in total cholesterol
8.3. Definitions 
8.4.1. Adverse Event: An adverse event (AE) is any unfavorable or unintended 
event, physical or psychological, associated with a research study, which causes 
harm or injury to a research participant as a result of the participant’s 
involvement in a research study. The event can include abnormal laboratory 
findings, symptoms, or disease associated with the research study. The event does 
not necessarily have to have a causal relationship with the research, any risk 
associated with the research, the research intervention, or the research 
assessments. Adverse events may be the result of the interventions and 
interactions used in the research; the collection of identifiable private information 
in the research; an underlying disease, disorder, or condition of the subject; 
and/or other circumstances unrelated to the research or any underlying disease, 
disorder, or condition of the subject. 
8.4.2. Serious Adverse Events: A serious adverse event (SAE) is any adverse 
experience occurring at any dose that results in any of the following outcomes: 
8.4.2.1.
Results in death. 
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8.4.2.2.
Is a life-threatening adverse experience. The term life-threatening in 
the definition of serious refers to an adverse event in which the subject was 
at risk of death at the time of the event.  It does not refer to an adverse event 
which hypothetically might have caused death if it were more severe.
8.4.2.3.
Requires inpatient hospitalization or prolongation of existing 
hospitalization.  Any adverse event leading to hospitalization or 
prolongation of hospitalization will be considered as Serious, UNLESS at 
least one of the following expectations is met:
8.4.2.3.1.
The admission results in a hospital stay of less than 24 hours OR
8.4.2.3.2.
The admission is pre-planned (e.g., elective or scheduled 
surgery arranged prior to the start of the study) OR
8.4.2.3.3.
The admission is not associated with an adverse event (e.g., 
social hospitalization for purposes of respite care.
8.4.2.3.4.
However it should be noted that invasive treatment during any 
hospitalization may fulfill the criteria of “medically important” and as 
such may be reportable as a serious adverse event dependent on 
clinical judgment.  In addition where local regulatory authorities 
specifically require a more stringent definition, the local regulation 
takes precedent. 
8.4.2.4.
Results in persistent or significant disability/incapacity.  The definition 
of disability is a substantial disruption of a person’s ability to conduct 
normal life’s functions.
8.4.2.5.
Is a congenital anomaly/birth defect. 
8.4.2.6.
Is an important medical event.  Important medical events that may not 
result death, be life-threatening, or require hospitalization may be 
considered a serious adverse experience when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this 
definition.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood 
disease or disorders, or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. The 
development of a new cancer is always considered an important medical 
event.
8.4.Adverse Event Evaluation: The investigator or designee is responsible for ensuring 
that all adverse events (both serious and non-serious) observed by the clinical team or 
reported by the subject which occur after the subject has signed the informed consent 
are fully recorded in the subject’s medical records. Source documentation must be 
available to support all adverse events. A laboratory test abnormality considered 
clinically relevant (e.g., causing the subject to withdraw from the study, requiring 
treatment or causing apparent clinical manifestations, result in a delay or dose 
modification of study treatment, or judged relevant by the investigator), should be 
reported as an adverse event.  
8.5.1. The investigator or sub-investigator (treating physician if applicable) will 
provide the following for all adverse events (both serious and non-serious):
8.5.1.1.
Event term (as per CTCAE)
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8.5.1.2.
Description of the event
8.5.1.3.
Date of onset and resolution
8.5.1.4.
Expectedness of the toxicity
8.5.1.5.
Grade of toxicity 
8.5.1.6.
Attribution of relatedness to the investigational agent- (this must be 
assigned by an investigator, sub-investigator, or treating physician)
8.5.1.7.
Action taken as a result of the event, including but not limited to; no 
changes, dose interrupted, reduced, discontinued, etc. or action taken with 
regard to the event, i.e. no action or other intervention, etc.
8.5.2. Descriptions and grading scales found in the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4 will be utilized for AE reporting. 
8.5.2.1.
An expected adverse event is an event previously known or 
anticipated to result from participation in the research study or any 
underlying disease, disorder, or condition of the subject. The event is 
usually listed in the Investigator Brochure, consent form or research 
protocol. 
8.5.2.2.
An unexpected adverse event is an adverse event not previously 
known or anticipated to result from the research study or any underlying 
disease, disorder, or condition of the subject. 
8.5.2.3.
Attribution is the relationship between an adverse event or serious 
adverse event and the study drug.  Attribution will be assigned as follows:
8.5.2.3.1.
Definite – The AE is clearly related to the study drug.
8.5.2.3.2.
Probable – The AE is likely related to the study drug.
8.5.2.3.3.
Possible – The AE may be related to the study drug.
8.5.2.3.4.
Unlikely – The AE is doubtfully related to the study drug.
8.5.2.3.5.
Unrelated – The AE is clearly NOT related to the study drug.
8.5.2.4.
Protocol must specify if attribution is required for individual 
components of the treatment regimen or the treatment regimen as a whole.
8.5. ALL SAE attributed to the MAD will reported to the DSMB. 
8.6  Data and Safety Monitoring Board:    Any new significant finding that may affect the 
patient’s willingness to continue in the study will be shared with patients. Immediately after the 
study is approved and before the first patient is enrolled, investigators will meet, develop and 
finalize all measurements/variables for the study. Each patient, once being enrolled, will be 
provided a unique id from the study and their personal information, such as name, SSN, address, 
phone number and DOB, will be de-identified whenever necessary to the researchers. Data entry 
will be monitored regularly by the “Data Safety Monitoring Board” which is an independent 
group of experts who will advise the study investigators. The members of the DSMB serve in 
an individual capacity and provide their expertise and recommendations. Membership consists 
of persons independent of the investigators and any conflict of interest with the trial. Written 
documentation attesting to absence of conflict of interest is required. The DSMB includes 
experts in or representatives of the fields of relevant clinical expertise, and biostatistics. The 
DSMB will be provided feedback on a regular basis, including findings from adverse-event 
reports, and recommendations derived from data and safety monitoring, and members of the 
DSMB will have no personal or financial stake in the study.  Interim reports will be prepared at 
least twice each year by the PI with the help of the study coordinator 1 month prior to DSMB 
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meeting for DSMB review.  These reports will contain information about the accrual rate with 
projected completion date for the accrual phase, exclusion rates and reasons, pretreatment 
characteristics of patients accrued, compliance rate of treatment delivered with respect to the 
protocol prescription, and the frequency and severity of adverse events.  All serious adverse 
events will be reported by the PI to the DSMB and IRB within 24 hours of knowledge of the 
occurrence.   HIPAA confidentiality will be maintained during the phases of the trial including 
monitoring, preparation of interim results, review, and response to monitoring 
recommendations.  Exceptions may be made under circumstances where there are serious 
adverse events or when it is deemed appropriate for patient safety.  The DSMB will function in 
an advisory capacity and recommendations that emanate from monitoring activities will be 
reviewed by the responsible official (the principal investigator) and addressed. 
8.6.2 Responsibility of the DSMB:  To approve the initiation of this clinical trial. After this 
approval and at periodic intervals during the course of the trial, the DSMB 
responsibilities are to periodically review and evaluate the accumulated study data for 
participant safety, study conduct and progress, and when appropriate, efficacy. Make 
recommendations to the study investigators and regulatory agencies (IRB, IBC, FDA, 
etc.) concerning the continuation, modification, or termination of the trial. 
8.6.3   Responsibility of the PI:  It is the responsibility of the study PI to ensure that the 
DSMB is apprised of all new safety information relevant to the study. This includes 
providing the DSMB with a copy of the study protocol in advance as well as providing 
all IRB/Regulatory Protocol revisions and all safety data reports.
8.6.4 Serious Adverse Events:  (Please see section 8.4 for definitions of adverse events.) All 
serious and related adverse events will be reported immediately to the Chair and other 
members of the DSMB by the study sponsor or designee. The decision to meet by 
teleconference or on site to discuss the adverse event will be left to the discretion of 
the members of the DSMB. If the DSMB determines that the study procedures present 
a greater risk than expected, the board may recommend to the P.I. and the IRB that the 
study enrollment be suspended pending further evaluation.
8.6.4.1 Written Reports: Written reports should be sent to DSMB members prior to the 
meeting and should allow sufficient time for review. Written reports may consist 
of 2 separate parts:
8.6.4.2 Open Session Report: This report provides information on study conduct, such as 
accrual, appropriate demographic representation, baseline characteristics, protocol 
compliance, site performance, quality control, currency of follow-up. General 
(ungrouped) adverse events and toxicity issues will be included in the open report. 
Open Session reports will be distributed at least a week prior to a scheduled meeting 
to DSMB members, study investigators and other appropriate persons as directed 
by the DSMB.
8.6.4.3 Closed Session Report: This report may contain data on study outcomes, including 
safety data and efficacy data. Closed session reports are distributed on the same 
schedule, but only to DSMB members, the chairman of the IRB, and others as 
designated by the DSMB Chair. This report is confidential and marked accordingly.
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8.6.4.4 Verbal Report: At the conclusion of the DSMB meeting, the DSMB should discuss 
its findings and recommendations with the study investigator and sponsor (or 
sponsor designee). The DSMB will issue a written summary report that identifies 
topics discussed by the DSMB and describes their individual findings, overall 
safety assessment and recommendations. The report should conclude with a 
recommendation to continue or terminate the study. The DSMB Chair or designee 
is responsible for drafting, circulating and obtaining approval from other DSMB 
members within 2 weeks of the meeting.
8.6.4.5 A final summary report: will be forwarded to the Study Sponsor and PI. The UCCI 
Regulatory Coordinator will forward the summary report to regulatory authorities 
as a part of the annual report unless immediate action is required.
8.6.4.6 Closed Session Report (optional): The DSMB may also prepare confidential 
minutes that include details of closed session discussions. These meeting minutes 
are to be held in strict confidence and only accessible to DSMB members until such 
a time when the study is closed or the DSMB recommends early termination or in 
the event the minutes are requested by the FDA for participant safety reasons or for 
regulatory purposes.
8.6.4.7 Immediate Action Report: The DSMB Chair will notify the PI  directly of any 
findings of a serious and immediate nature or recommendations to discontinue all 
or part of the trial. The report will be submitted to UCCI Regulatory Coordinator 
for appropriate dissemination to regulatory authorities. This will be done in order 
to identify significant adverse event trends, missing and incorrect inputs, and other 
outliers. A log file will be created and record any change/modification of data 
inputs for purpose of future inspection. Data files will be safely stored in the server 
of the cancer clinical trials office, with authorized access to researchers and staffs 
only; and protected by double firewalls from both UC Health and the University of 
Cincinnati Information Technology (UCIT). All active study patients are reviewed 
at the weekly study team meeting. Confidentiality will be maintained as much as 
possible, consistent with applicable regulations. Names of participants or 
identifying material will not be released without patient permission, except when 
such release is required by law. No patient’s name or identifying information will 
be released in any publication or presentation. Records are maintained according to 
current legal requirements, and are made available for review according to the 
requirements of the Food and Drug Administration (FDA) or other authorized user, 
only under guidelines established by the Federal Privacy Act.
9. CORRELATIVE / SPECIAL STUDIES/ LABS
9.1. B-hydroxybutyrate: It is necessary to obtain measures of ketone bodies to determine 
that the diet is producing the desired biological effect. In addition, this is one method 
to assess patient compliance.  Serum BHB is a quantitative measure of ketosis that is 
less dependent on hydration status than other measures. In addition, the level of serum 
ketosis will be correlated with treatment outcome. It is speculative if the level of 
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ketosis as based on low, moderate or high will correlate with the treatment outcomes 
of treatment response, PFS 6 and overall survival.  
9.2. Blood glucose: Measurement of blood glucose is necessary in patients on a low 
carbohydrate diet in order to monitor for hypoglycemia (< 70mg/L) for patient safety. 
In addition, serum glucose is known to be a prognostic factor for survival in GBM. 
The level of blood glucose will be correlated with treatment outcome. Every attempt 
will be made to obtain glucose levels fasting.
9.3. Blood insulin: Insulin is expected to be inversely related to beta-hydroxybutyrate. 
Insulin also will be important to measure, as reductions of insulin, a proliferative 
hormone, may be important mechanistically in the benefit associated with the 
nutritional intervention. Further, in our preliminary studies with older adults with 
MCI, insulin level was inversely related to cognitive performance. Insulin levels have 
been important in in IGF-1 pathway and therefore are important in addition to the 
fasting glucose levels.  Every attempt will be made to obtain insulin levels fasting.  
9.4. Complete Metabolic Panel: This is already monitored weekly for treatment of gliomas 
with temozolomide and radiation.  However will be important to monitor for 
hyponatremia and increased creatinine indicating dehydration.   CO2 will also be 
measured on this test and will determine if lactate levels need to be drawn to check for 
acidosis.
9.5. Imaging: MRI tumor imaging will be performed before radiation as a pre-planning scan, 
and 4 weeks after completion of radiation. Then MRI’s will be done  as per treating physician 
recommendations. The treatment planning MRI  will occur as clinically ordered. The prior 
diagnostic MRI examination with contrast and the concurrent imaging for treatment planning 
will be employed in selecting the two locations. For the two locations, we will interrogate a) 
the solid portion of the tumor and b) a control region without tumor, preferably within the 
thalamus (left hemisphere preference; right hemisphere if tumor involvement within the left). 
9.6. Neurocognitive Assessment:  We will administer measures of attention, working
memory, long-term memory, speed of processing, depression and anxiety prior to initiation 
of intervention and at termination of intervention.  This is to determine effect of 
intervention on cognition and mood.
9.7.Peripheral Platelet Mitochondrial function: Whole blood will be obtained pre-treatment 
visit #2, post-treatment visit #1 and post-treatment visit #2. Patients are already having 
blood drawn at these visits as standard of care. This sample will be transported within 
hours to the laboratory of Dr. Matthew Skelton at Cincinnati Children’s Hospital 
Medical Center for assessment of mitochondrial respiration in the platelets. Our 
preliminary data has shown that this measure responds to the institution of nutritional 
ketosis, and we would expect to observe enhanced state III respiration and uncoupling 
at termination of the intervention
10.  MEASUREMENT OF EFFECT 
10.1.
Although response is not the primary endpoint of this trial, patients with 
measurable disease will be assessed by standard criteria. In addition to a baseline 
scan, confirmatory scans will also be obtained.  Response and progression will be 
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evaluated in this study using RANO (radiographic assessment in neuro-oncology) 
criteria.  (http://neurooncology.ucla.edu/pub/20231676.pdf)
10.2.
Definitions
10.2.1. Quality of Life (QOL):  QOL will be assessed using the FACT-Br QOL tool.  
See Appendix I.  QOL scores pre-intervention will be compared to post 
intervention-QOL score.  QOL will also be obtained at the post-treatment visit #2 
to assess if termination of intervention decreased QOL score.  We understand that 
there are many variables that can affect QOL during this time other than the 
intervention.
10.2.2. Two-year survival (2YS):  Duration of survival will be defined as the number 
of months from diagnosis to death due to any cause.
10.2.3. 6-month progression free survival (6moPFS): will be defined as the percentage 
of patients without progression (defined below) at 6 months. 
10.2.4. Ketosis:  Will be defined as serum BHB > 0.5 mM
10.2.5. Compliance: Dietary adherence is assessed by review of the daily food diary 
(Appendix II) serum ketone levels. 
10.3.
Methods for Evaluation of Measurable Disease: All baseline evaluations 
should be performed as closely as possible to the beginning of treatment.  MRI 
imaging techniques that can be used to determine progression are:
10.3.1. T2-weighted MRI, Fluid-attenuated, inversion-recovery (FLAIR) MRI
10.3.2. Diffusion-weighted imaging (DWI)
10.3.3. T1 pre-contrast MRI
10.3.4. Perfusion including dynamic-contrast-enhanced (DCE) followed by dynamic-
susceptibility- contrast (DSC) MRI
10.3.5. T1 post-contrast axial and coronal images
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10.4.
Response Criteria
10.4.1. Evaluation of target lesions will use the Radiographic Assessment in Neuro-
oncology (RANO) criteria.  See Appendix V will be defined as by RANO 
criteria.
10.4.1.1.
>5 mm increase in maximal diameter, as well as ≥ 25% increase in the 
sum of the products of the progressing 
10.4.1.2.
Significant increase in T2/FLAIR non-enhancing lesion compared with 
baseline (post-chemoradiation) or best response after initiation of therapy, 
not caused by comorbid events (e.g., radiation therapy, demyelination, 
ischemic injury, infection, seizures, postoperative changes, or other 
treatment effects) 
10.4.1.3.
Clear progression of non-measurable disease
10.4.1.4.
Any new lesion 
10.5
Statistics 
10.5.1 Ketosis will be defined as  serum BHB > 0.05 mM throughout 6-
week period of radiation and chemotherapy.  We hope to find that in our given 
sample of 30 patients at least 50% will meet this criteria.  We will compute a 
95% confidence interval for this rate to estimate the likely range in the target 
population.  A 10% increase in glutamate within the tumor on the post-RT MRI  
as compared to the pre-RT MRI will be considered evidence that the tumor is 
using ketones as fuel by the conversion to glutamate.  
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APPENDIX I:  Hematology Oncology Quality of Life Survey – FACT-Br 
(Version 4)
Patient MRN: 
  
Patient Name:
  
Date/Time of Visit: ___________________________________
Patient DOB: _______________
Below is a list of statements that other people with your illness have said are important. Please circle 
one (1) number per line indicating your response as it applies to the past 7 days.
N
o
t
 
a
t
 
a
l
l
A
 
l
i
t
t
l
e
 
b
i
t
S
o
m
e
-
w
h
a
t
Q
u
i
t
e
 
a
 
b
i
t
V
e
r
y
 
m
u
c
h
PHYSICAL WELL-BEING
I have a lack of energy
0
1
2
3
4
I have nausea
0
1
2
3
4
Because of my physical condition, I have trouble meeting 
the needs of my family
0
1
2
3
4
I have pain
0
1
2
3
4
I am bothered by side effects of treatment
0
1
2
3
4
I feel ill
0
1
2
3
4
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I am forced to spend time in bed
0
1
2
3
4
SOCIAL/FAMILY WELL-BEING
I feel close to my friends
0
1
2
3
4
I get emotional support from my family
0
1
2
3
4
I get support from my friends
0
1
2
3
4
My family has accepted my illness
0
1
2
3
4
I am satisfied with family communication about my illness
0
1
2
3
4
I feel close to my partner (or the person who is my main 
support)
0
1
2
3
4
Regardless or you current level of sexual activity, please answer the following question, If you 
prefer not to answer it, please mark this box
and go to the next section.
I am satisfied with my sex life
0
1
2
3
4
EMOTIONAL WELL-BEING
I feel sad
0
1
2
3
4
I am satisfied with how I am coping with my illness
0
1
2
3
4
I am losing in the fight against my illness
0
1
2
3
4
I feel nervous
0
1
2
3
4
I worry about dying
0
1
2
3
4
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I worry that my function will get worse
0
1
2
3
4
FUNCTIONAL WELL-BEING
I am able to work (include work from home)
0
1
2
3
4
My work (include work at home) is fulfilling
0
1
2
3
4
I am able to enjoy life
0
1
2
3
4
I have accepted my illness
0
1
2
3
4
I am sleeping well
0
1
2
3
4
I am enjoying the things I usually do for fun
0
1
2
3
4
I am content with the quality of my life right now
0
1
2
3
4
ADDITIONAL CONCERNS
I am able to concentrate
0
1
2
3
4
I have had seizures (convulsions)
0
1
2
3
4
I can remember new things
0
1
2
3
4
I get frustrated that I cannot do the things I used to
0
1
2
3
4
I am afraid of having a seizure (convulsion)
0
1
2
3
4
I have trouble with my eyesight
0
1
2
3
4
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I feel independent
0
1
2
3
4
N
I have trouble hearing
0
1
2
3
4
I am able to find the right word(s) to say what I mean
0
1
2
3
4
I have difficulty expressing my thoughts
0
1
2
3
4
I am bothered by the change in my personality
0
1
2
3
4
I am able to make decisions and take responsibility
0
1
2
3
4
I am bothered by my drop in my contribution to the family
0
1
2
3
4
I am able to put my thoughts together
0
1
2
3
4
I need help caring for myself (bathing, dressing, eating, 
etc.)
0
1
2
3
4
I am able to put my thoughts into action
0
1
2
3
4
I am able to read like I used to
0
1
2
3
4
I am able to write like I used to
0
1
2
3
4
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I am able to drive a vehicle (my car, truck, etc.)
0
1
2
3
4
I have trouble feeling sensations in my arms, hands, or legs
0
1
2
3
4
I have weakness in my arms or legs
0
1
2
3
4
I have trouble with coordination
0
1
2
3
4
I get headaches
0
1
2
3
4
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APPENDIX II:  Food diary 
AP
Meal
Food and Beverage 
Description
Amount
Total Carb 
(grams)
_
Total Fiber 
(grams)
=
Net Carbs 
(grams)
Total Net Carbs
Date:
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APPENDIX III:  ECOG Performance Status Scale
ECOG Performance Status Scale
Grade
Descriptions
0
Normal activity.  Fully 
active, able to carry on all 
pre-disease performance 
without restriction.
1
Symptoms, but 
ambulatory.  Restricted in 
physically strenuous 
activity, but ambulatory 
and able to carry out work 
of a light or sedentary 
nature (e.g., light 
housework, office work).
2
In bed <50% of the time.  
Ambulatory and capable of 
all self-care, but unable to 
carry out any work 
activities.  Up and about 
more than 50% of waking 
hours.
3
In bed >50% of the time.  
Capable of only limited 
self-care, confined to bed 
or chair more than 50% of 
waking hours.
4
100% bedridden.  
Completely disabled.  
Cannot carry on any self-
care.  Totally confined to 
bed or chair.
5
Dead.
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APPENDIX IV
Pre-
Treatment 
Visit #1
Pre-
Treatment 
Visit #2
Pre-
Treatm
ent Visit 
#3
Temodar 
plus 
radiation 
therapy 
(RT)
Temodar 
and 
RT 
completed
Post-
Treatment 
Visit #1
Post-
Treatment 
Visit #2
D-28 to 
day -7
-28 to day 
-7
  D-28 
to day -
7
Day 0-42
Day42
Appx. Day 
70
2-3 months 
after PTV1
Weekly
Daily
Informed 
Consent
X
Medical 
History
X
X
X
X
Concomitant 
Medications
/ Treatments
X
X
X
X
X
Physical 
Exam
X
X
X
X
Vital 
Signs/Weigh
t/
Waist 
Circumferen
ce
X
X
X
X
X
 Lipid 
profile, CBC 
with diff, 
hemoglobin 
A1C, 
X
X
Serum BHB
X
X
X
X
Complete 
Metabolic 
Panel, 
fasting 
glucose, 
fasting 
insulin
X
X
X
X
Platelet 
Mitochondri
al Labs
X
X
X
MRI
X
X
X 
Food diary 
X
X
X
Pre-
Treatment 
Visit #1
Pre-
Treatment 
Visit #2
Pre-
Treatm
Temodar 
plus 
radiation 
Temodar 
and 
RT 
completed
Post-
Treatment 
Visit #1
Post-
Treatment 
Visit #2
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ent Visit 
#3
therapy 
(RT)
D-28 to 
day -7
-28 to day 
-7
  D-28 
to day -
7
Day 0-42
Day42
Appx. Day 
70
2-3 months 
after PTV1
Weekly
Daily
Adverse 
Events
X
X
X
Performance 
Status
X
X
X
X
Quality of 
Life (FACT-
BR)
X
X
X
X
Neurocognit
ive Testing
X
      X
X
RD Consult 
(initial in 
person and 
then via 
phone)
X
X
Treatment
MAD
X
X
X
X
Temodar 
and RT 
(Stupp)
X
X
 
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APPENDIX V 
RANO Criteria for Response Assessment using MRI
From: Wen 2010. Response 
Criteria 
Complete Response 
Requires all of the following: complete 
disappearance of all enhancing measurable 
and non-measurable disease sustained for at 
least 4 weeks; no new lesions; stable or 
improved non-enhancing (T2FLAIR) lesions; 
patients must be off corticosteroids (or on 
physiologic replacement doses only); and 
stable or improved clinically. Note: Patients 
with non-measurable disease only cannot have 
a complete response; the best response 
possible is stable disease. 
Partial Response 
Requires all of the following:≥ 50% decrease 
compared with baseline in the sum of products 
of perpendicular diameters of all measurable 
enhancing lesions sustained for at least 4 
weeks; no progression of non-measurable 
disease; no new lesions; stable or improved 
non-enhancing (T2/FLAIR) lesions on same or 
lower dose of corticosteroids compared with 
baseline scan; the corticosteroid dose at the 
time of the scan evaluation should be no 
greater that the dose at the time of baseline 
scan; and stable or improved clinically. Note: 
Patients with non-measurable disease only 
cannot have a partial response; the best 
response possible is stable disease. 
Stable Disease 
Requires all of the following: does not qualify 
for complete response, partial response, or 
progression; stable non-enhancing 
(T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared with baseline scan. 
In the event that the corticosteroid dose was 
increased for new symptoms and signs without 
confirmation of disease progression on 
neuroimaging, and subsequent follow-up 
imaging show that this increase in 
corticosteroids was required because of 
disease progression, the last scan considered to 
show stable disease will be the scan obtained 
when the corticosteroid dose was equivalent to 
the baseline dose. 
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Progressive Disease 
Defined by any of the following: ≥ 25% 
increase in the sum of the products of maximal 
perpendicular diameters of enhancing tumor(s) 
compared to the smaller of pre-SL-701 
baseline or best response following initiation 
of SL-701; New measureable contrast-
enhancing lesion(s) defined as lesion(s) that 
measure at least 1 cm in at least 2 planes; 
Significant clinical decline not attributable to 
co-morbid event or change in concurrently 
administered medication. 
NOTE: All measurable and non-measurable lesions must be assessed using the same techniques 
as at baseline. Abbreviation: FLAIR, fluid-attenuated inversion recovery
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APPENDIX VI
GBM cognitive protocol (repeated three times)
1) Demographic, personal information
a) Academic and Medical History Questionnaire
2) Executive ability, working memory, attention
a) Delis Kaplan Executive Function System, Trails subtest 
b) Porteus Maze Test [revised version]
c) Verbal Primary Memory with Interference 
d) Auditory Verbal Sequencing Test
e) Corsi Block-Tapping Task 
3) Lexical Access
a)  Controlled Oral Word Production (phonological & categorical constraints)
b)  Boston Naming Test
4) Secondary (long-term) memory
a)   Memory Impairment Screen
b)  Verbal Paired Associate Learning
c)  California Verbal Learning Test-II 
d) Spatial Paired Associate Learning 
5) Mood
a) Beck Depression Inventory
b)  Beck Anxiety Inventory
6) Cognitive Symptoms  
a) Dysexecutive Questionnaire
b) Everyday Memory Questionnaire
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APPENDIX VII
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APPENDIX VIII
Modified Ketogenic Diet Guidelines
The modified ketogenic diet (MKD) is a diet that reduces the amount of carbohydrates you eat 
so that your body will begin burning primarily fat, instead of carbs, for energy.  This diet is very 
low in carbohydrates, high in fat and moderate in protein.
When your body breaks down the carbohydrates found in food it makes a product called 
glucose. Glucose, commonly known as blood sugar, is the main source of energy for the body. 
The focus of the ketogenic diet is to shift your metabolism to use fat as the main source of 
energy. When your body breaks down fat it makes products known as ketones. When your body 
is using ketones for energy it is said that you are in “ketosis”.
The goal of this diet is to get your body into ketosis and keep it there. Your doctor will monitor 
your level of ketosis by checking your blood for ketones. This will help you and your team know 
if you are following the diet properly. You may also monitor yourself via urine Ketostix. Your 
dietitian will explain their use.
Some individuals lose weight when they start this diet. It will be important to monitor this 
because it can indicate loss of lean muscle mass as well as loss of crucial vitamins and minerals 
important to maintaining your energy throughout treatment. 
The guidelines below are designed to help you be successful in acquiring and maintaining 
ketosis.
1.  Eat either three regular-sized meals per day or four to five smaller meals. Do not skip 
meals or go more than six waking hours without eating.
2. Eat no more than 20 grams of NET carbs per day. Try to eat a wide variety of vegetables 
including lettuce-based salads. This will help you get more vitamins and minerals for 
overall health, but also fiber needed to feel full longer and aid in preventing constipation. 
Remember, carb counts of various vegetables are different so be sure to check them. Use 
measuring cups, measuring spoons, and food scales for measuring all foods to ensure 
accuracy.
3. At each meal, including breakfast, eat 4 to 6 ounces of protein foods, including poultry, 
beef, lamb, pork, veal, fish and shellfish, eggs, and cheese; you may count 1 egg as 1 
ounce of protein. There is no need to trim fat from meat or the skin from poultry, but it is 
fine if you prefer to. Just add a splash of olive or avocado oil or a pat of butter to your 
meal to replace the fat.
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4. There is no restriction on fat.  Enjoy butter, olive and avocado oils, canola oil, and seed 
and nut oils and mayonnaise.  Aim for 1 tablespoon of oil on a salad or other vegetables, 
or a pat of butter.  Cook foods in just enough oil to ensure that they don’t burn.  Or spritz 
the pan with a mist of oil.
5. Use spices and herbs to flavor foods.  Get creative with meals and snacks to keep interest 
in the food you are eating. You will be given resources to find recipes appropriate for 
your diet.
6. This diet can cause constipation. Make sure you drink plenty of water, eat all of the 
recommended salad greens and vegetables, and let your doctor and/or dietitian know if 
you are becoming constipated. Occasionally, a medication bowel regimen is necessary.
7. Cheese can be a good source of fat and protein; however, cheeses such as cottage and 
ricotta have higher net carbs, so please remember to measure these carefully. Also, 
cheese can cause constipation – limit your daily intake to 4 ounces or less.
8. Acceptable sweeteners include sucralose (Splenda), saccharine (Sweet’N Low), stevia 
(SweetLeaf or Truvia). Have no more than three packets a day and count each one as 1 
gram of carbs. These sweeteners themselves contain no carbs; however, the fillers they 
are packaged with to prevent caking do contain a little bit of carbohydrates. If you 
purchase a bulk container of these sweeteners, check the nutrition facts label for net 
carb content; they are not all the same.
9. To satisfy your sweet tooth you can have sugar-free gelatin desserts. There are resources 
for recipes within this educational packet that will give you more ideas.
10.  Each day, drink at least eight 8-ounce portions of approved beverages: water, club soda, 
herb teas, or coffee (caffeinated in moderation). This will prevent dehydration and 
electrolyte imbalances. In this count, you may include two cups of broth (not low 
sodium), one in the morning and one in the afternoon.
11.  Don’t starve yourself and don’t skimp on fats.
12.  Don’t assume that any food is low in carbs. Always read the labels on packaged 
whole foods being certain to note the serving size.
13.  When dining out, be on guard for hidden carbs. Gravies and sauces are usually made 
with flour or cornstarch. Sugar is found in many commercial salad dressings and may 
be in coleslaw and other deli salads. Avoid breaded foods.  Some restaurant websites 
have nutritional information posted; you should consider looking at these ahead of 
time to better manage your carb intake.
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Where Are Carbohydrates Found?
Carbohydrates (carbs) are found in many, but not all, of the foods that we eat. 
Carbohydrates are found in foods that contain both natural and added sugars. The following 
foods and food groups have carbohydrates in them:
Grains: Any food made from wheat, rice, oats, cornmeal, barley, or white and wheat flour. 
Examples include white and wheat bread, hot and cold breakfast cereals, most types of pasta 
noodles, couscous, quinoa, etc. These foods contain many carbs and should not be eaten 
while following the diet. Ask your dietitian for examples of substitutions of these foods that 
can be included in the diet.
Fruits: All fruits have a natural form of sugar. Some fruits are higher in carbs than others. 
For example, one banana has more carbohydrates than one serving of raspberries. Very 
small portions of some fruit can be included in the diet.
Dairy: Milk and some dairy products contain a natural form of sugar (carb) called lactose. 
Cow’s milk, most yogurt brands, pudding, and ice cream are examples of dairy foods that 
contain too many carbs and should not be included in the diet.  Most cheeses, heavy cream, 
whipped cream, plain Greek yogurt, sour cream, and cottage cheese have less carbs. 
Portions of unsweetened versions of soy milk, almond milk, and/or cashew milk can be 
included in the diet.
Vegetables: All vegetables contain carbohydrates. Some vegetables contain more than 
others. “Non-starchy” vegetables contain minimal carbs and should be included in the diet. 
Examples of non-starchy carbs include spinach, green beans, asparagus, and salad greens. 
“Starchy” vegetables include dried beans, peas, corn, potatoes, and sweet potatoes. They 
contain many carbs and should not be included in the diet.
Desserts: Foods made with flour and sugar contain carbs and should not be eaten while on 
the diet. This includes cookies, cakes, pies, ice cream, candies, etc. Even foods labeled as 
“sugar free” have some carbs. Ask your dietitian how to satisfy your sweet tooth.
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Common Carb Foods
Cheese/Dairy: You may have up to 4 oz cheese per day. Most cheeses will have approximately 1 
gram of carb per ounce. An ounce is about the size of an individually wrapped slice of American 
cheese or string cheese.
Type
Serving Size
Net Carbs
Blue Cheese
1 oz
0.7
Cheddar
1 oz.
0.9
Cottage cheese, 4% milkfat
½ cup
3.6
Cream Cheese
1 oz
1.6
Feta
1 oz
1.2
Gouda
1 oz
0.6
Heavy cream
1 tbsp
0.4
Mozzarella, part skim
1 oz
1.6
Parmesan, grated
1 tbsp
0.7
Ricotta cheese, part skim
½ cup
6.4
Sour cream
1 tbsp
0.6
Swiss
1 oz
0.6
Salad Garnishes/herbs/spices:  If topping your salad with cheese, see above net carb table. 
Below is a list of commonly used foods, herbs, and spices used on many types of salads. Salad 
dressings have a wide variation in carb content -always check the nutrition facts label for serving 
size and net carbs.
Type
Serving Size
Net Carbs
Basil
1 tbsp
0.0
Cayenne pepper
1 tbsp
0.0
Cilantro
1 tbsp
0.0
Dill
1 tbsp
0.0
Garlic
1 clove
0.9
Ginger
1 tbsp chopped root
1.0
Pepper
1 tbsp
0.0
Rosemary
1 tbsp
0.0
Sage
1 tbsp
0.0
Tarragon
1 tbsp
0.0
Oregano
1 tbsp
0.0
Vegetables: You should eat 12 to 15 net carbs a day of vegetables. This should be ~ 6 cups of 
salad greens and ~ 2 cups cooked vegetables (depending on net carb content). Choosing a wide 
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variety of vegetables will not only add variety to your diet but provide important vitamins and 
minerals needed for optimal health.
Type
Serving Size/Prep
Net Carbs
Acorn squash
½ cup, cooked
10.4
 Alfalfa sprouts
½ cup
0.0
Artichoke, whole
½ medium, boiled
3.8
Arugula
½ cup
0.2
Asparagus
6 medium spears, cooked
1.9
Avocado, black skinned
½ raw
1.3
Bamboo shoots
½ cup, boiled
1.2
Beets
½ cup, cooked
6.8
Bok Choy
½ cup, cooked
0.7
Broccoli
½ cup cooked
3.0
Broccoli
½ cup raw
1.8
Brussels sprouts
½ cup cooked
3.5
Cabbage, green or red
½ cup cooked 
2.7
Cabbage, green or red
½ cup raw
1.1
Carrots
1 raw, large (8”)
4.9
Carrots
½ cup, cooked
4.1
Cauliflower
½ cup cooked
1.2
Celery
1 stalk, med (8”)
0.6
Chard, Swiss
½ cup
1.8
Chicory greens
½ cup raw
0.1
Chives
1 tbsp
0.0
Collard greens
½ cup cooked
1.6
Cucumber
½ cup raw
0.9
Daikon radish
½ cup, cooked
1.3
Eggplant
½ cup, cooked
3.1
Endive
½ cup
0.0
Escarole
½ cup raw
0.2
Fennel
½ cup, raw
1.9
Green beans
½ cup, cooked
2.9
Jicama
½ cup, raw
2.5
Kale
½ cup, cooked
2.4
Kohlrabi
½ cup, cooked
4.6
Kohlrabi
½ cup, raw
1.8
Leeks
½ cup, raw
5.5
Lettuce, average
1 cup
1.0
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Mushrooms
½ cup, raw
1.1
Okra
½ cup, cooked
1.6
Olives, green or black
5 each
0.1
Onion
¼ cup, chopped, raw
2.2
Peas, green
¼ cup, cooked
2.4
Peppers, green or red
½ cup, raw
1.8
Pepper, green or red
½ cup, cooked
3.8
Potato, white
1 baked, small (2 ½”)
27.0
Pumpkin
¼ cup, cooked
2.3
Radicchio
½ cup, raw 
0.7
Radish
1 each, medium (¾” to 1”)
0.1
Rhubarb
½ cup, raw
1.7
Sauerkraut
½ cup, canned
0.9
Spaghetti squash
½ cup, cooked
3.9
Spinach
½ cup, cooked
1.2
Spinach
1 cup, raw
0.4
Summer squash
½ cup, cooked
2.4
Sweet potato
½ cup, cooked
17.4
Tomato
1 med (2 ½”), raw
3.3
Turnips
½ cup, cooked
2.4
Water chestnuts
½ cup, canned
6.8
Fruits:  Fruits are a good source of vitamins, minerals, and fiber; however, they are also high in 
carbohydrates. Be sure to measure serving sizes accurately.
Type
Serving Size
Net Carbs
Apple
½ whole, small (2 ¾”)
8.5
Banana
1 small
20.5
Blueberries
¼ cup
4.5
Cantaloupe
¼ cup
2.8
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Cherries
¼ cup
4.8
Grapefruit
½ whole, medium (4”)
8.9
Grapes, red or green
¼ cup
6.5
Guava
1 medium
4.9
Kiwi
1 medium
9.0
Lemon juice
¼ cup
4.0
Lime juice
¼ cup
4.9
Mango
¼ cup
5.5
Peach
1 whole, medium (2 ½”)
12.1
Plum
1 whole, medium (2 ½”)
6.6
Raspberries
¼ cup
1.7
Strawberries
¼ cup
2.4
Watermelon
½ cup
5.4
Legumes: Legumes can be used minimally to add color and texture to a combination meal. 
Type
Serving size/Prep
Net Carbs
Black beans
¼ cup, canned, drained
5.8
Garbanzo beans
¼ cup, canned, drained
10.3
Great northern beans
¼ cup, canned, drained
10.5
Kidney beans
¼ cup, canned drained
10.6
Lentils
¼ cup, cooked
6.1
Lima beans
¼ cup, cooked
7.8
Navy beans
¼ cup, cooked
7.1
Pinto beans
¼ cup, cooked
10.2
Nuts and seeds: Nuts and seeds have a healthy amount of fiber and fat. They can be used on 
salads, in recipes, and as an easy in-between meal snack. Nuts and seeds also contain important 
minerals as well as antioxidants.
Type
Serving size
Net Carbs
Almonds
1 oz (23 kernels)
2.6
Brazil nuts
1 oz (6 kernels)
1.2
Cashews
1 oz (18 kernels)
7.6
Sunflower seeds, shelled
1 oz 
1.7
Macadamias
1 oz (10-12 kernels)
1.2
Pecans
1 oz (19 halves)
1.2
Pistachios, shelled
1 oz. (49 kernels)
5.1
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Walnuts
1 oz (14 kernels)
2.0
Find Recipes:
http://www.charliefoundation.org/resources-tools/resources-2/find-recipes
http://www.atkins.com/recipes
Book: Modified Keto Cookbook: Quick, Convenient Great Tasting Recipes  ISBN: 978-1-936303-
77-9 
Calculating Net Carbs
Keeping your net carb intake at or below 20 grams per day is vital to reaching and maintaining 
ketosis. Therefore, it is important that you understand how to determine how many net grams 
are in each serving of the foods you eat.  You can calculate this by reading the nutrition facts 
labels present on packaged food containers.  The label will tell you how many servings there are 
in the container and how many grams of total carbohydrates and fiber are in each serving. 
Subtract the grams of fiber from total carbs to get the net carb amount.
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1. Find how many servings are in the   
container and what the serving size 
is.
2. Total Carbohydrate minus Dietary 
Fiber equals Net Carb per Serving:
8g – 3g = 5g Net Carbs per ½ cup
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