Feasibility and Efficacy of a Well-Formulated Ketogenic Diet in Delaying Progression of Polycystic Kidney Disease in Patients at Risk for Rapid Progression
Phase: NA
Conditions: Polycystic Kidney Disease
Sponsor: Ohio State University

Feasibility and Efficacy of a Well-
Formulated Ketogenic Diet in delaying 
progression of Polycystic Kidney Disease 
in patients at risk for Rapid Progression 
 
 
The Ohio State University 
 
 
IRB Approval 7 January 2024 
 
 
 
 
IRB# 2024H0258 
 

Clinical Study Protocol 
 
Study Title: “Feasibility and Efficacy of a Well-Formulated Ketogenic Diet in delaying 
progression of Polycystic Kidney Disease in patients at risk for Rapid Progression” 
 
Principal Investigator: Rima Kang 
Co-Investigators: Yuchi Han, Orlando Simonetti, Jeff Volek, Brad Rovin, Arunark 
Kolipaka, Qing Wu 
Key Personnel: Madison Kackley, Teryn Bedell, Catherine Saenz 
 
SUMMARY AND BACKGROUND  
 
ADPKD is the fourth most common cause of chronic kidney disease and accounts for 5% 
of patients with kidney failure [1]. It is the fourth most common cause for end stage renal disease 
(ESRD) which typically occurs in the sixth decade of life [17].  ADPKD affects more than 
600,000 Americans and 12.5 million people worldwide [2].   
 
ADPKD is characterized by the predisposition to cyst formation and enlargement.  The 
progressive development and enlargement of cysts leads to fibrosis of the renal parenchyma and 
eventually ESRD [1]. The glomerular filtration rate (GFR) remains stable for many decades due 
to compensatory hyperfiltration.  Therefore, it is imperative to utilize alternative prognostic 
biomarkers to assess progression to end stage renal disease (ESRD).   
 
Due the genetic heterogeneity in ADPKD, there is significant phenotypic variability with 
regard to progression to ESRD.  Therefore, it is critical to use biomarkers to assess patients’ risk 
of progression to initiate early renal protective measures and therapeutics to delay progression.  
Factors that suggest rapid progression include hypertension onset ≤ age 35, urologic events such 
as hemorrhagic cysts or infection ≤ age 35, multiple family members with ESRD ≤ age 55, or 
PKD 1 mutations if genetics are known.  Other objective measures of rapid progression include 
total kidney volume growth ≥ 5% per year (on 3 measurements done at least 6 months apart), 
GFR decline ≥ 2.5 ml/min/year over 5 years and Mayo Imaging Classification of Class 1C-1E.  
The Mayo Imaging Classification is used in patients with “typical” ADPKD in which individuals 
have bilateral, diffuse cystic disease.  It is a validated calculator for measurement of height-
adjusted total kidney volume (htTKV) and predicts trajectory of GFR and time to ESRD [1].  At 
present, Tolvaptan, a vasopressin V2 antagonist, is the only US Food and Drug Administration 
(FDA) approved drug for slowing progression of ADPKD in individuals at risk for rapid 
progression.  However, Tolvaptan is associated with significant aquaretic effects and requires 
frequent lab monitoring for liver toxicity, making it challenging to prescribe.   
Lifestyle interventions such as ketogenic diet have shown promise in animal models, yet 
long-term studies in humans are lacking.  We propose that ketogenic diet will slow htTKV 
growth and thus slow disease progression.  Furthermore, it may prove beneficial and reduce need 
for Tolvaptan, which is associated with significant side effects and financial burden or act as an 
alternative therapy for those who cannot or chose not to take Tolvaptan. 
 
Background: 
 
Autosomal dominant Polycystic Kidney Disease (ADPKD) is the most common genetic 
cause for ESRD.  It is critical to assess individuals at high risk for disease progression in order to 
implement kidney protective measures early in disease course.   

At present, caloric restriction is the only dietary intervention that has shown benefit with 
regard to disease progression in this unique population [2].  Animal models suggest metabolic 
reprogramming contributes to cystic epithelial proliferation and cyst growth [4].  The metabolic 
alteration in the cystic cell epithelia resembles that of cancer cells, known at the “Warburg 
Effect”.  Thus, glucose serves as the primary source of fuel in highly proliferative cystic cells, 
which consequently shift to aerobic glycolysis as opposed to oxidative phosphorylation through 
the tricarboxylic acid (TCA) cycle.  In the former pathway, glucose is preferentially converted to 
lactate.  The glycolytic products shift to anabolic pathways such as the Pentose Phosphate 
pathway that sustain cell proliferation and growth via reduction in AMP-activated protein kinase 
(AMPK) and  upregulation of mammalian target of rapamycin (mTOR).  This was demonstrated 
in Pkd1 knockout mice.  Furthermore, glucose deprivation led to reduced cystic cell proliferation 
[8].  Interestingly, 2-deoxyglucose (2DG), a molecule that inhibits glycolysis, restored normal 
levels of AMPK and acetyl-CoA carboxylase, reducing increase in total kidney volume [9].  
Because of decreased glycolytic activity with administration of 2DG, activation of AMPK 
inhibits mTOR, which downstream inhibits cell proliferation and cyst growth [10]. 
  Oxidative phosphorylation relies on fatty acid oxidation (FAO) for generation of ATP; 
impaired FAO is another hallmark in the abnormal metabolic pathways of ADPKD and leads to 
increased mitochondrial damage.  In cystic cells, mitochondria no longer function as the energy 
sources, but supply the intermediates for anabolic pathways [10].  Additionally, glutamine is 
catabolized to α-ketoglutarate, which switches the TCA cycle in the opposite direction and 
produces acetyl-CoA for fatty acid biosynthesis.  Mitochondrial function is thought to be 
mediated by the polycystins.  Polycystin-1 (PC-1) and polycystin-2 (PC-2) are membrane 
proteins encoded by PKD1 and PKD2 genes.  From a metabolic standpoint, PC-1 and PC-2 are 
present in the mitochondria-associated endoplasmic reticulum membranes.  Abnormal polycystin 
proteins in the setting of ADPKD lead to reduced calcium-dependent oxidative phosphorylation 
and thus switching to the glycolytic pathway [7].  The abnormal pathways are depicted in Figure 
1. 

 
Figure 1 
 
  Animal models have shown slowed disease progression with diet interventions such as 
fasting and ketogenic diet, meant to diminish available glucose [7].  Metabolic pathways are 
under investigation as potential targets for both dietary and pharmacologic interventions.  
Ketosis improves the phenotype in mouse models of ADPKD, including reduction in fibrosis, 
reduced kidney and cyst size, and improvement in creatinine clearance.  The proposed 
mechanism involves a switch from glucose metabolism to fat oxidation.  The switch leads to 
activation of AMPK and induces peroxisome proliferator activated receptor α (PPARα) [6].  
Activation of PPARα increases fatty acid utilization and oxidative phosphorylation [10].  
Additionally, ketosis inhibits mTOR (a known modulator of cyst cell proliferation and fluid 
secretion).  Β-hydroxy-butyrate (BHB) elevation and ketogenic diet was shown to reduce cysts 
number and size in rat models [5].  This supports a theory that cystic cells are unable to utilize 
ketone bodies as a source of energy, and therefore use glucose as their main source of energy 
[12].  Ketosis inhibits STAT3 signaling to reduce cyst growth and fibrosis [16].  Figure 2 
illustrates ketogenic diet effect. 
 

 
Figure 2 
 
STUDY SYNOPSIS 
Title 
Feasibility and Efficacy of a Well-Formulated 
Ketogenic Diet in delaying progression of 
Polycystic Kidney Disease in patients at risk 
for Rapid Progression 
Study Design 
Phase 1 open label single arm dietary 
intervention study 
Study Center 
The Ohio State University 

Primary Objective 
Renal MRI (non-contrast) measures of total 
kidney volume to assess disease progression, 
cyst growth/progression, and stiffness/fibrosis 
Secondary Objective 
Urine microalbumin, eGFR, body mass  and 
composition 
Number of Subjects 
20 patients 
 
 
Inclusion Criteria 
1. Age 18-65 years old 
2. Diagnosis of ADPKD by imaging 
and/or genetic testing 
3. GFR ≥ 25 mg/dl 
4. Patients at risk for rapid progression 
of ADPKD: Mayo Class 1C-1E along 
with any other high risk features 
including early decline in GFR, 
hypertension onset ≤ 35 years of age, 
urologic events ≤ 35 years of age, 
PKD 1 truncating mutation and 
PROPKD score of 4 or higher as 
determined by the treating physician 
5. No changes of medications within the 
last three months.   
6. Able to comply with dietary 
intervention 
7. Ability to sign informed consent 
Exclusion Criteria 
1. Patients currently being treated with 
Tolvaptan 
2. Diagnosed with diabetes. 
3. Pregnancy 
4. Contraindications to MRI 
5. Ketogenic diet within the last three 
months 
6. Severe kidney disease with GFR < 25 
mg/dl 
7. Unable to purchase food for the diet 
intervention 
8. Gastrointestinal disorders that will 
interfere with diet intervention 
9. Chronic alcohol or drug abuse 
 
 
Target Population: 
Patients with Class 1C-1E Mayo Clinic Imaging Class by MRI with assessment of high risk 
to progress to ESRD.  This may include early onset hypertension ≤ 35 years of age, first urologic 

event (hematuria or urinary tract infection) ≤ 35 years of age, and/or family history of rapid 
progression to ESRD by about age 55. 
 
 
Study Duration: 
12 months 
 
OUTCOMES 
Study Endpoints: Change in total kidney volume (TKV) from baseline to 1 year to assess 
disease progression.  Change in albuminuria and GFR. 
 
Primary Objective: The primary Objective will be to determine htTKV at baseline and 1 
year after ketogenic diet intervention. 
 
Secondary Objectives: The secondary endpoints will be measurement of GFR and 24-h 
urine microalbumin. 
 
RESEARCH STRATEGY  
This is a prospective study to determine ketogenic diet effect on htTKV, GFR, 
microalbuminuria.  This is a single-center study of 20 patients with ADPKD and deemed high 
risk for progression to ESRD.  This determined by combination of features of ADPKD and 
htTKV as assessed by prior computed tomography (CT) or MRI.  Patients will be recruited from 
the Polycystic Kidney Disease (PKD) Clinic at Ohio State University Wexner Medical Center.  
Enrolled patients will have MRI for htTKV, urinary studies, blood tests at baseline, 6 months, 
and 52 weeks.  Blood for GFR will be assessed three times over the course of the study including 
baseline, 6 months, and 1 year.  Participants will follow ketogenic diet for 52 weeks.  The Volek 
Lab Nutrition Team will manage the ketogenic diet.  
 
METHODS 
Description of Ketogenic Diet: 
The goal of the KD will be to achieve a state of nutritional ketosis in each person as defined as 
blood BHB ≥0.5 mM. Typical BHB in a person consuming a well-formulated KD are between 0.5 
and 4 mM. We will target BHB levels of >1 mM in participants in the KD, which are expected to 
be an order of magnitude higher than concentrations observed at baseline.  
Baseline to Week 6: Participants will be provided a personalized ketogenic plan with up to 3 
ready-to-eat “ketogenic-appropriate” meals per day and supplemental snacks in order to offset 
participant food costs, ensure nutrient quality, and facilitate adherence.  In addition, natural low-
carbohydrate/high-fat snacks, sources of fat, and electrolytes will be provided to meet caloric 
needs. This may include shelf stable items such as high-quality fats/salad dressings, salmon & 
sardine packets, jerky, cheese whisps, nuts and seeds. The quantity and content of these provided 
foods will vary from participant to participant based on caloric needs and personal preference. 
Weeks 7-52: Participants will transition to a free-living ketogenic diet.  They will be 
provided ongoing personalized support, coaching, and education by the Volek Lab Team to 
facilitate dietary compliance.  

 
The ketogenic diet intervention will start after all baseline testing is complete. Each participant 
may require slightly different levels of coaching depending on their baseline knowledge and 
individual situation. Thus, the intensity of engagement may vary across participants. The ketogenic 
diet will follow general principles with the aim to achieve blood ketones >0.5 mM, which will 
require most participants to consume <50 g/day carbohydrate and ~1.5 g/kg reference weight 
protein. Fat will comprise the remaining calories with an emphasis on monounsaturated and 
saturated sources from whole foods. A wide range of foods will be incorporated including non-
starchy vegetables, fruits (berries, olives, tomatoes, lemons/limes), meats (beef, chicken, pork, 
fish, lamb), nuts and seeds, oils (olive, canola, coconut), cheese, butter, cream, eggs, and fatty fish 
(salmon, sardines). Nutritional ketosis is associated with natriuresis that will lead to sodium and 
fluid loss if the extra sodium excreted is not compensated by individualized intakes. If untreated, 
the resultant hypovolemia can manifest in side effects and adrenal stress (often mis-characterized 
as ‘keto-flu’) that disrupts body fluid, electrolyte, and mineral status. Thus, slightly higher sodium 
and potassium intakes are required to offset the natriuresis, which will be achieved through the 
provision of broth/LMNT electrolyte packs and appropriate food sources and cooking methods.  
 
MRI Imaging protocol for htTKV: 
Patients will undergo investigational Magnetic Resonance Imaging for assessment of Total 
Kidney Volume at baseline and 1 year of study participation. MRI specific safety screening will 
be performed by a qualified imaging team member prior to the imaging session. Patients will be 
prepared for imaging by the imaging team member and imaging will be completed over the 
abdominal area, imaging will last no more than one hour. Studies will be carried out using FDA 
approved 0.55T, 1.5T, or 3T MRI units. Imaging sequences will include 2D T2-weighted Turbo 
Spin Echo and 3D T1-weighted fat-water separated sequences. Intravenous contrast agent will 
not be administered. Images of the abdomen and kidneys will be analyzed in order to calculate 
height-adjusted TKV according to established practices of the Mayo Imaging Classification [1].  
 
The presence of pre- and post-treatment MRI and laboratory tests for comparing kidney size is 
crucial for evaluating the effectiveness of the treatment. However,  there is a potential for inter 
and intra-observer bias in the measurement of kidney size. To address this issue, several steps 
and strategies can be implemented: 
Standardized Protocols: Develop standardized protocols for measuring kidney size that all 
observers must adhere to. These protocols should include specific guidelines for image 
acquisition, positioning of patients, and measurement techniques. 
Training and Calibration: We have ensured that that all observers receive comprehensive 
training on the measurement techniques and protocols, prior to the study. This training includes 
both theoretical and hands-on components. Additionally, periodic calibration sessions can be 
organized to minimize observer variability. 
Quality Control Checks: We will regularly monitor the quality and consistency of 
measurements throughout the study. If significant variability is observed, additional training and 
calibration sessions should be conducted. 
Interpretation Guidelines: We have developed clear guidelines for interpreting the MRI and 
lab results. This can help standardize the assessment of improvement in kidney size, reducing the 
risk of bias in interpretation. 
 

 
Documentation and Audit Trails: Maintain detailed documentation of all measurements, 
protocols, and observer assignments. This information can be audited to ensure compliance and 
identify any potential sources of bias. 
 
Table 1 | Table of Study Procedures.  
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
MRI Imaging 
X 
 
 
 
 
X 
Medical History 
Questionnaire 
X 
X 
X 
X 
X 
X 
Vitals and 
Physical Exam 
X 
X 
X 
X 
X 
X 
Blood Draw 
X 
X 
X 
X 
X 
X 
Body 
Composition 
(DXA) 
X 
X 
 
 
 
X 
 
 
Study Procedures: 
Serological Assessment and Health monitoring 
Visit 1(Baseline):  
- 
Record patient’s medical history, including extrarenal manifestations 
- 
Medications 
- 
Pregnancy history if applicable 
- 
Vitals 
- 
Physical Exam 
- 
Patients will undergo MRI non-contrast for evaluation of htTKV 
- 
Blood will be drawn for baseline assessment of GFR, urine osmolality, and urine 
microalbumin to creatinine ratio 
- 
Blood samples will be saved for metabolomics analysis  
- 
Body composition will be assessed by dual-energy x-ray absorptiometry (DXA) 
- 
Finger Stick BHB: Finger sticks will be taken daily in the morning, by the participant to 
determine ketone and glucose levels in a fasted state. Measurements will be reported daily 
in RedCap or Qualtrics. 
CGM/CKM: Continuous Glucose Monitoring (CGM) and Continuous Ketone Monitoring 
(CKM) will be performed. This involves applying a sensor patch on the back of the arm to 
measure metabolites in interstitial fluid. The sensor can capture data for 2-weeks. 
 
Visit 2 (6 Weeks): 
- 
Same procedures in visit 1, except no MRI will be done at this visit. 
 
Visit 3 (3 months): 
- 
Same procedures in visit 1, except no MRI or DXA Scan will be done at this visit. 
 
Visit 4 (6 months):  

- 
Same procedures in visit 1, except no MRI will be done at this visit. 
 
Visit 5 (9 months): 
- 
Same procedures in visit 1, except no MRI or DXA Scan will be done at this visit. 
 
 
Visit 6 (12 months): Same procedures in visit 1. 
- 
Medications 
Vitals 
- 
Physical Exam 
- 
Patients will undergo MRI non-contrast for evaluation of htTKV 
- 
Blood will be drawn for assessment of GFR, urine osmolality, and urine microalbumin to 
creatinine ratio 
- 
Payment of $500 
 
For testing at the PAES building in the Kinesiology Laboratory, subjects will arrive at the lab in 
the morning after an overnight fast. We will test for hydration, measure height and body mass, and 
then have participants complete surveys followed by resting blood pressure. A phlebotomist will 
obtain blood samples from a forearm vein in subjects after sitting for 10-min. Appropriate sample 
tubes will be used for EDTA, sodium heparin, or serum for different analytes. A serum tube will 
be sent to Quest Diagnostics to assess standard chemistry panel (liver enzymes, kidney function, 
lipids, etc.).  
Serum and plasma will be immediately centrifuged and aliquoted into tubes and stored at -80°C 
until subsequent analyses. Samples will be thawed only once for analysis and assayed in duplicate 
for ketones, glucose, and insulin, which will be used to calculate an index of insulin resistance, 
and HbA1c. Extra serum and plasma will be archived for future analysis of biomarkers that may 
provide insight into novel associations with depression.  
We will determine body composition from a single whole-body scan using dual-energy x-ray 
absorptiometry (iDXA, Lunar Corporation, Madison, WI). Total time for this visit will be 
approximately 1-2 hours.   
DATA ANALYSIS AND STATISTICAL METHODS 
The study will focus on percent change for TKV, albuminuria, and GFR pre and post the 
ketogenic dietary intervention.  We will collect the following data for each patient including age, 
sex, race, baseline medications, BMI, albuminuria, GFR, and blood pressure.  The univariate 
analysis will include the above variables and use analysis of variance to assess changes at 
baseline and at 12 months.  Based on the univariate analysis, we will perform linear regression.  
Ketogenic diet administration will be forced into the model.  Other variables will be chosen 
based on strength of the univariate analysis.  Our outcome of interest will be percent change in 
TKV, albuminuria, and GFR. In regard to MR Imagining, we will utilize a statistical method to 
account for observer variability. Statistical techniques such as intra-class correlation coefficients 
(ICC) can quantify the level of agreement between different observers and help correct for any 
bias. 
 
 

 
STUDY MONITOTRING 
 
Diet Monitoring Protocol for Polycystic Kidney Disease (PKD) Study 
 
The dietary guidelines for PKD closely align with CKD recommendations, emphasizing 
personalized sodium intake, starting at ~2300mg/day. In a well-formulated ketogenic diet, 
sodium levels may decrease due to reduced sodium-rich food consumption and the natriuretic 
effect of decreased carbohydrate intake. To address this, our dietary approach includes an 
additional 1-2 g/day of sodium, with adequate fluid intake to prevent hypovolemia and 
associated keto-flu symptoms. Recognizing individual variations, we aim to personalize sodium 
intakes within a general range of 1500-2300mg/day. 
 
Monitoring Strategies: 
 
Tailored Sodium Adjustment: 
• Dietetics team to tailor sodium intake based on individual needs. 
• Ongoing monitoring for signs of keto-flu, edema, rapid weight changes, and blood 
pressure variations. 
 
Study Design Checkpoints: 
• Incorporate consistent 24-hour dietary recalls and habitual dietary assessments. 
• Regular check-ins with a registered dietitian for personalized support and adjustments. 
• Education provided for recognizing high or low sodium responses. 
 
Communication with Nutritionist: 
• Participants to engage with a trained nutritionist for ongoing communication. 
• Participants encouraged to share adherence to the dietary approach and address any 
questions or concerns. 
 
Objective and Subjective Markers: 
• Daily monitoring of blood ketones levels to assess ketosis. 
• Address deviations individually with appropriate diet counseling and support. 
Dietary Assessments: 
 
• Submission of both acute (24-hour) and more habitual (30-day) diet assessments. 
• Analysis of dietary data to ensure adherence and inform necessary adjustments. 
 
Clinical Collaboration: 
• Reinforce education on signs and symptoms associated with sodium balance. 
• Work closely with clinicians to maintain consistent messaging and promptly address 
emerging issues. 
 
This comprehensive monitoring protocol integrates various strategies to ensure effective tracking 
and management of the dietary approach for individuals with PKD. Regular communication, 

objective markers, and collaboration with healthcare professionals contribute to a thorough 
assessment of diet adherence and individualized support throughout the study. 
 
Monitoring Plan for Polycystic Kidney Disease (PKD) Ketogenic Diet Intervention Study 
 
Objective: 
The primary objective of this monitoring plan is to oversee and ensure the safety of study 
participants and the integrity of data collected during the Polycystic Kidney Disease (PKD) 
ketogenic diet intervention study. The primary marker of disease progression will be total kidney 
volume assessed via MRI. 
 
Information to be Evaluated: 
 
Patient Safety: 
 
Adverse events related to the ketogenic diet, if any. 
Monitoring of vital signs, kidney function, and electrolyte levels. 
Compliance with dietary recommendations and any potential side effects. 
 
Data Integrity: 
 
Accuracy and consistency of MRI measurements of total kidney volume. 
Proper documentation of patient data and dietary adherence. 
 
Monitoring Personnel: 
 
Principal Investigator (PI): The PI will have overall responsibility for the study and will lead 
the monitoring efforts. 
 
Key Personnel : The study coordinator will assist in data collection, ensure compliance with the 
study protocol, and report any issues to the PI. 
 
Timing of Monitoring: 
Monitoring will be conducted at the following time points: 
 
Baseline: Prior to enrollment, each participant's medical history, kidney function, and MRI scans 
will be assessed. 
 
Regular Intervals: During the study, participants will be monitored regularly. This includes 
assessments of dietary adherence (weekly by Key Personnel), vital signs, anthropometrics, blood 
work and glomerular filtration rate (GFR) will be used for monitoring disease progression at the 
specified intermediate time points (Baseline, Week 6 and Month 3, Month 6, Month 9, Month 
12), and kidney function (Baseline, Month 12 via MRI). 
 
Adverse Event Reporting: Any adverse events related to the ketogenic diet or the study 
protocol will be monitored continuously and reported promptly. 

 
Decisions and Actions: 
 
Data Review Meetings: The study team will conduct regular data review meetings to assess the 
safety and progress of participants. This will involve a review of adverse events, dietary 
adherence, and MRI results. 
 
Stopping Criteria: The study will include predefined stopping criteria to protect participant 
safety. If severe adverse events related to the ketogenic diet occur or if there is a significant 
worsening of kidney function, the study may be halted early. 
 
 
Reporting: All monitoring findings, decisions, and actions will be documented in a monitoring 
report. Serious adverse events will be promptly reported to the Institutional Review Board (IRB) 
and relevant regulatory authorities, as required. Detailed Adverse enevt monitoring can be found 
below.  
 
Participant Withdrawal: If participants wish to withdraw from the study, they will be allowed 
to do so at any time without prejudice. 
 
Early Termination: 
We anticipate that participants will follow the diet plan as closely as possible to ensure the 
study's success. In the event of a more than twofold increase in serum creatinine, reaching Stage 
II acute kidney injury, we may consider early termination from the study. However, we 
recognize that individual differences, especially in creatinine levels related to protein intake, may 
occur. Therefore, decisions about early termination will be made in consultation with a 
physician. Subsequent visits will involve careful consideration of the rate of increase in serum 
creatinine, allowing the physician to determine whether continued participation is safe and 
advisable for the participant's health. Our top priority is the well-being of each participant, and 
any decisions about early termination will be made with their best interests in mind. 
 
Conclusion: 
This monitoring plan for the PKD ketogenic diet intervention study is designed to ensure 
participant safety and maintain data integrity throughout the study. Regular assessments, 
reporting mechanisms, and decision-making criteria are in place to address unanticipated 
problems and make informed decisions regarding study continuation or termination. 
 
Adverse Event Monitoring 
An AE is defined as any untoward medical occurrence in an investigation participant following written 
informed consent that does not necessarily have a causal relationship with the study product. An AE can 
be any unfavorable or unintended sign (including an abnormal finding), symptom, or disease temporally 
associated with the use of an investigational product, whether or not related to the investigational product. 
This includes any occurrence that is new in onset or aggravated in severity or frequency from the baseline 
condition, or abnormal results of diagnostic procedures (including laboratory test abnormalities).  
 

Some side effects or GI symptoms could occur as an outcome of these dietary interventions; side effects 
listed in the beverage tolerability questions and reported will not be categorized as AEs but recorded as 
study outcomes. Side effects, outside of what is expected as a result of study product consumption, 
reported by participants and judged by the Investigators as medically relevant events and related to study 
product will be recorded as AEs.   
 
Events should be considered AEs if they: 
• 
Result in discontinuation from the study, 
• 
Require treatment or any other therapeutic intervention, 
• 
Require further diagnostic evaluation (excluding a repetition of the same procedure to confirm the 
abnormality), 
• 
Are associated with clinical signs or symptoms judged by the Investigator to have a significant 
clinical impact. 
 
Grading and Severity 
The Investigator will evaluate all AEs with respect to their severity, and record the outcome and action 
taken on the AE study documents . AEs will be graded as: 
 
Mild:  
 Awareness of symptoms but easily tolerated  
Moderate:   
 Discomfort enough to interfere with but not prevent daily activity 
Severe:          Unable to perform usual activity 
 
Relationship 
The Investigator will also judge the likelihood that the AE was related to the study beverage and 
document this on the appropriate study documents as: 
 
NOT 
RELATED 
This category applies to those adverse experiences which, after careful 
consideration, are clearly and incontrovertibly due to extraneous causes 
(disease, environment, etc.). 
UNLIKELY 
 
In general, this category can be considered applicable to those experiences 
that after careful medical consideration at the time they are evaluated, are 
judged to be, unlikely related to the study beverage. 

POSSIBLY 
 
This category applies to those adverse experiences for which, after careful 
medical consideration at the time they are evaluated, a connection with the 
study beverage administration appears possible but cannot be ruled out with 
certainty. 
PROBABLY 
 
This category applies to those adverse experiences that, after careful medical 
consideration at the time they are evaluated, are felt with a high degree of 
certainty to be related to the study beverage.  
DEFINITELY 
 
This category applies to those adverse experiences which, the Investigator 
feels are incontrovertibly related to the study beverage.  
Appropriate therapeutic action and follow-up measures will be performed by the Investigator in 
accordance with appropriate medical practice standard of care.    
 
Serious Adverse Event Definition/Qualification 
A SAE is defined as an AE that results in any of the following outcomes: 
• 
Death (note that death is the outcome of a SAE and the cause of death should be listed as the AE), 
• 
Life-threatening event, 
• 
In-patient hospitalization or prolongation of existing hospitalization, 
• 
A persistent or significant disability/incapacity, 
• 
Congenital anomaly or birth defect, 
• 
Any other important medical event that may not result in death, be life-threatening, or require 
hospitalization, may be considered a SAE when, based upon appropriate medical judgment, the 
event may jeopardize the participant and may require medical or surgical intervention to prevent 
one of the outcomes listed above.   
 
In the event of a SAE, the participant may be dropped from the study if the Investigator deems it 
necessary. 
 
Serious Adverse Event Reporting Instructions 
If in the opinion of the Investigator the event meets the criteria of a SAE the following procedures will be 
followed: 
• 
The Investigator will notify Institutional Review Board (IRB) of the SAE within the 
parameters and timeframe specified under the IRB Standard Operating Procedures (SOP). 
An initial report followed promptly by a complete report will be forwarded to the IRB, 
when applicable. 
• 
If a participant is hospitalized or hospitalization is prolonged due to the SAE, the hospital 
discharge summary will be obtained if possible. 

• 
If a death occurs and an autopsy is performed, a copy of the autopsy report will be 
obtained if possible.  
• 
All efforts must be undertaken to obtain follow-up information promptly. 
 
Recording of Adverse Events 
All AEs (AE or SAE) will be recorded on the AE study documents. For participants who have an ongoing 
AE at their final study visit, follow-up information will be captured in the AE eCRF page which will be 
completed after 30 days.   
 
Serious Adverse Event Follow-Up 
For all ongoing SAEs occurring during the study, the Investigator must submit follow-up reports 
regarding the participant’s subsequent course. All SAEs that are ongoing at the end of the study or upon 
discontinuation of the participant’s participation must be followed until either: 
• 
The event resolves, or 
• 
The event/condition has stabilized (e.g., in the case of persistent impairment), or 
• 
The event returns to baseline, if a baseline value is available, or 
• 
The participant dies, or 
• 
The event can be attributed to other than the study beverage, or to other than the study 
conduct. 
 
Safety and Adverse Events via MRI 
An adverse event is defined as illness, signs or symptoms that worsen over the course of the 
study.  Abnormal lab tests, if deemed by the investigator to have resulted from ketogenic diet 
intervention, would be considered an adverse event.  If the abnormal lab results lead to 
symptoms, further diagnostic tests, or withdrawal from the study, they are considered adverse 
events. 
MRI at 0.55 Tesla, 1.5 Tesla, or 3 Tesla is considered a minimal risk procedure. There are no 
additional safety risks associated with the investigational MRI imaging.  For patients receiving 
investigational 3 Tesla MRI (or lower field strength) imaging, the associated risks are the same 
as those that would normally be encountered in a standard of care MRI examination, and they are 
as follows: 
 
Magnetic Resonance Imaging devices use three different types of electromagnetic fields that 
may pose potential risks to subjects undergoing MRI examinations. These are static magnetic 
fields, time varying magnetic field gradients, and radiofrequency (RF) electromagnetic fields. 
 
1) Static magnetic fields exert forces on magnetic objects and induct electric currents in any 
conductive material, imposing two main risk categories: 
a) Dislodgement or malfunction of medical implants or metallic foreign objects. 
b) Current induction in tissue and subsequent alteration of physiologic function. 
 
The FDA has classified MRI up to 8 Tesla as Non-Significant Risk. 

 
In addition, subjects may be harmed by  
• 
Loud noise from the MRI device. 
• 
Some subjects may experience mild transient vertigo and/or metallic taste when they are 
being moved into the MRI system.  
• 
Subjects may experience discomfort from the blood pressure cuff and finger clamp from 
the pulse-oximeter. Some subjects may experience feelings of being closed in if they are 
claustrophobic. 
• 
Long-term effects of high field MRI are not known at this time. 
 
Risk from static, time varying magnetic field gradients and radiofrequency fields are at or 
below the FDA limits and thus risks are identical to standard field strength MRI units.  
 
All above listed known effects of exposure to static magnetic fields, switched magnetic field 
gradients and RadioFrequency are transient, i.e. vertigo, spontaneous visual light perceptions, 
metallic taste, peripheral nerve stimulation as well as RF heating will end once exposure to the 
fields is ended. Based on this, cumulative effects are not expected, however long-term effects are 
not known at this time.  
 
To minimize risks from the static magnetic field as with standard MRI, the following 
subjects will be excluded from this study (see MRI Safety Screening Forms for further details): 
- 
Subjects who have any type of bioimplant activated by mechanical, electronic, or 
magnetic means (e.g., cochlear implants, pacemakers, neurostimulators, biostimulators, 
electronic infusion pumps, etc.). 
- 
Subjects who have any type of ferromagnetic bioimplant that could potentially be 
displaced or damaged.  
- 
Subjects who have cerebral aneurysm clips. 
- 
Subjects who may have shrapnel imbedded in their bodies (such as from war wounds), 
metal workers and machinists (potential for metallic fragments in or near the eyes), severe car 
accident victims. 
 
Because effects of high field MRI are not known at this time also excluded are: 
- 
Subjects who have permanent tattoo (e.g., eye liner) (may contain metallic coloring). 
 
Also excluded are subjects incapable of giving informed written consent 
- 
Subjects who cannot adhere to the experimental protocols for any reason, or have an 
inability to communicate with the researcher. 
- 
Subjects who have limited mental ability to give informed consent, mentally retarded, 
altered mental status, mental disability, confusion, or psychiatric disorders. 
- 
Prisoners 
 
 
To minimize discomfort we will also exclude subjects who exhibit noticeable anxiety and/or 
claustrophobia or who exhibit severe vertigo when they are moved into the MRI system. 
All subjects will be given ear protection to prevent risks from loud noise. 
 
CONDUCT OF THE STUDY 

1. Ethics and Regulatory Considerations  
This study will be conducted according to Good Clinical Practice Guidelines, the Declaration of Helsinki 
(2004) and United State Code of Federal Regulation Title 21. Signed written informed consent for 
participation in the study will be obtained from all participants before protocol-specific procedures are 
carried out. Participants will be informed of their right to withdraw from the study at any time. Participants 
will be informed that their participation in the study is completely voluntary, personal information will be 
both coded with a study ID to preserve anonymity.  
 
2. Institutional Review Board  
The Investigator will ensure that an appropriately constituted IRB, in compliance with the requirements of 
21 CFR 56, reviews and approves the clinical study. Before the study is started, the Investigator will forward 
copies of the protocol and consent form for this study to the IRB for review and approval. IRB approval 
must refer to the study by exact protocol title and number, identify the documents reviewed, and state the 
date of review. The IRB must be informed of all subsequent protocol amendments. No alterations, 
modifications to IRB-approved documents, including the protocol, protocol summary, consent form, 
recruitment materials and questionnaires will be allowed. The IRB must also be informed of all SAEs and 
of unexpected AEs as outlined in the IRB’s SOPs or reporting guidelines.  
 
3. Informed Consent and Protected Health Information  
The study will be explained verbally as well as on the informed consent document. Each participant will be 
given ample opportunity to inquire about details of the study and to read and understand the consent form 
before signing it. It will be made clear that participants can withdraw from the study at any time.  
 
Each participant’s signed informed consent document must be kept on file by the Investigator. The 
participant should receive a copy of the informed consent document. A participant may not be admitted to 
the study unless informed consent of the participant (or his/her legally authorized representative) has been 
obtained.  
 
4. Participant Confidentiality  
The Investigator is responsible for ensuring that participants’ anonymity will be maintained. For all the data 
collected over the course of the study for each participant (i.e., records, biological samples and 
questionnaires) a unique subject identifier (i.e., a code) will be assigned and used instead of the subject’s 
name. The code for each participant which links the subject name with their identifier will only be available 
to research personnel. Electronic CRFs or other documents will identify participants by initials, number, or 
code, and not by name. The Investigator will keep a separate log showing codes, names, and addresses. 
Any records that contain the subject’s name and identifier will either be stored in the Kinesiology file 
storage room in a file cabinet (locked) or protected on a computer via password protection on the individual 
digital file and password protection on the computer the file(s) are stored on. All other records that contain 
the subject identifier only will also be kept in either a file cabinet in our locked file storage room or on a 
password protected computer. Subject names will never be used in any presentation or publication resulting 

from this study. The records will be maintained until the data are published and up to a maximum of ten 
years after the completion of the study. All records or biological data obtained after signing of the informed 
consent (including the screening visit, even for subjects that are not eligible for participation in the study) 
are treated with the same confidentiality safety measures as those subjects who qualify. Any information 
obtained during the prescreening for participants that were not eligible will be deleted 
 
5. Withdrawal of Participants from the Study  
Participants may be removed from the study for any of the following reasons:  
• 
A participant requests discontinuation;  
• 
The Investigator initiates removal for medical or compliance reasons;  
• 
Occurrence of any AE or condition that could, in the Investigator’s opinion, interfere with the 
evaluation of the effect of the study beverage or put the participant at undue risk.  
 
It is understood by all concerned that an excessive rate of withdrawals can render the study uninterpretable, 
therefore, unnecessary withdrawal of participants should be avoided. Should a participant decide to 
withdraw, all efforts will be made to complete and report observations as thoroughly as possible. In the 
event that a participant is withdrawn from the study, the reason for the withdrawal will be documented in 
the eCRF.  
 
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