Symptoms of Polycystic Ovarian Syndrome Ameliorated by Keto-Adaptation Pilot
Phase: NA
Conditions: PCOS (Polycystic Ovary Syndrome)
Sponsor: Ohio State University

 
Version date: 10/14/2025 
 
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Title:  
Symptoms of Polycystic Ovarian Syndrome Ameliorated by 
Responses of Keto-Adaptation  
Short title: 
 
SPARK 
 
PI: 
 
 
 
Madison Kackley, PhD, CSCS 
Research Scientist, Department of Human Sciences 
The Ohio State University 
305 Annie & John Glenn Ave 
Columbus, OH 43210 
Office: 614-247-9650| kackley.19@osu.edu 
 
Co-PI/External Collaborator: 
 
 
 
Teryn Bedell, MS, RD, LD, Co-I 
 
 
 
Senior Research Dietician  
The Ohio State University 
305 Annie & John Glenn Ave 
Columbus, OH 43210 
Office: 614-292-4788 | bedell.387@osu.edu  
 
Jeff S. Volek, PhD, RD 
Professor, Department of Human Sciences 
The Ohio State University 
305 Annie & John Glenn Ave 
Columbus, OH 43210 
Office: 614-688-1701 | volek.1@osu.edu 
 
Loriana Soma,  MD 
Physician, Obtetrics and Gynocology 
The Ohio State University Wexner Medical Center 
395 W 12th Ave 
Columbus, OH 43210 
Office: 614-293-3069 | loriana.soma@osumc.edu 
 
 
 

 
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ABBREVIATIONS 
BHB 
Beta hydroxybutyrate 
KD 
Ketogenic Diet 
FSH 
Follicle Stimulating Hormone 
LBM 
Lean body mass 
LH 
Luteinizing hormone  
PCOS 
Polycystic Ovarian Syndrome 
DEXA 
Dual-Energy X-ray Absorptiometry 
mL 
milliliters 
mg 
Milligrams 
h 
Hour 
ANOVA 
Analysis of variance 
AE 
Adverse event 
USG 
Urine Specific Gravity  
yr 
Year 
 
 
 

 
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STUDY SYNOPSIS 
 
 
 
Study Title 
Symptoms of PCOS Ameliorated by Responses to Keto-
adaptation  
Short Title 
SPARK 
Study Design 
A 12-week randomized, 2 arm intervention  testing responses 
to ketogenic diet intervention vs mixed diet with exogenous 
ketone supplement in women diagnosed with PCOS. 
Study Participants 
• Women diagnosed with PCOS between ages 18-40 
Planned Study 
Period 
August 2024-August 2025 
OUTCOMES 
Primary 
Changes in anovulatory status in women with PCOS 
 
Secondary 
•  Changes in reproductive hormones such as 
progesterone, estrogen, LH, FSH 
• Analysis of potential predictive metabolic baseline 
characteristics 
• Differences in blood metabolites (metabolic and 
lipids). 
 
Exploratory 
• Examine cardiovascular function and ovarian 
morphology using magnetic resonance imaging (MRI).  

 
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SUMMARY AND BACKGROUND  
Proposed research aims to examine the effects of ketogenic intervention on metabolic 
outcomes and ovulatory regulation in women with PCOS. We expect to demonstrate the 
novel role of low-carbohydrate, ketogenic intervention in regulating metabolic and 
reproductive health in PCOS-diagnosed women. Finding a therapeutic strategy that 
simultaneously ameliorates multiple PCOS symptoms is crucial due to the absence of a 
known cure. The ketogenic diet has proven safe and effective in various 
endocrinopathies, with or without weight loss. This study will provide foundational 
recommendations for PCOS-diagnosed women, irrespective of their specific 
symptomologies. 
 
Impact of a Low-Carbohydrate, Ketogenic Approach. A well-formulated ketogenic diet 
(ketogenic diet) is a nutrient-dense lifestyle characterized by increasing blood ketones 
into a safe, therapeutic range of nutritional ketosis (0.5–4.0 mM beta-hydroxybutyrate; R-
βHB)5. Ketosis is rapidly inducible (~3-5 days)6 with non-starchy vegetables as primary 
carbohydrate source (20–50 g/day), moderate protein intake (1.2–1.6 g/kg BW/day), and 
sufficient lipids for energy and satiety. Sustained ketosis positively modulates blood 
parameters during weight-loss6–11 and weight-maintenance 12,13. Ketogenic diets show 
promise for metabolic reversal and endocrine improvement in women14, with studies 
indicating enhancements in glycemic control, insulin sensitivity, cholesterol profiles, 
hormonal profiles, and androgens. Further research is needed to understand ketogenic 
diets' impact on female physiology, especially pre-menopausal outcomes. In our previous 
work, a eucaloric low-carbohydrate, ketogenic approach was more effective in reversing 
metabolic syndrome compared to moderate- and high-carbohydrate diets13. We 
discovered a robust difference in circulating lipoproteins and fatty acid composition after 
the low-carbohydrate diet. Circulating saturated fat in both triglycerides and phospholipids 
were significantly lower in the groups with lower carbohydrate intake. Decreasing 
carbohydrate intake led to an increase in peak LDL diameter and a decrease in the 
concentration of small, atherosclerotic LDL particles 
(Figure 1). The positive effects of these markers 
may prove efficacious in decreasing dyslipidemia, 
both determinant factors of hyperandrogenism 
condition in women diagnosed with PCOS15.  
Ketogenic Interventions in PCOS. The PCOS 
literature overwhelmingly supports weight-loss as an 
effective strategy to manage symptoms, however 
ketogenic diet interventions in PCOS sustained over 
longer durations provide even greater additional 
benefits. A 12-week pilot trial revealed that a 
ketogenic diet with no pharmaceutical assistance 
can regulate menses positively, and to the same 
extent as a mixed diet with pharmaceutically-treated 
PCOS, whereas the glucose control and body weight 
changes favored the ketogenic diet16. A single-arm, 
Figure 1 | Changes in Peak LDL 
Diameter  
BL, Baseline; LC, Low carbohydrate; MC, 
Moderate Carbohydrate; HC, High 
Carbohydrate 

 
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12-week trial conducted in 14 women with PCOS also revealed that the ketogenic diet is 
a feasible, non-pharmacological intervention to improve body weight, body composition, 
insulin-sensitivity, cardiometabolic risk, and female-specific circulating hormones11. 
Lastly, a 24-week single-arm study examining the ketogenic diet effects on metabolic and 
endocrine parameters enrolled 11 women with PCOS – 5 completing all study details 
(~45% retention) – who demonstrated positive reductions in testosterone, luteinizing 
hormone: follicle stimulating hormone, and fasting insulin by the end of the diet8. However, 
the presence of menses does not confirm ovulatory function, which is a primary concern 
for women battling PCOS. Currently, no studies confirm the potential for reversing the 
anovulation that burdens women with PCOS who are desperately trying to conceive. 
 
Women with PCOS are at an increased risk of cardiovascular complications, such as 
endothelial dysfunction and subclinical atherosclerosis, making precise cardiovascular 
measurements critical for early detection and management of potential risks (Al-Kassas 
et al., 2023). Similarly, MRI offers unparalleled accuracy in assessing ovarian morphology 
key diagnostic features of PCOS, without exposure to ionizing radiation (Wang et al., 
2022). Integrating MRI for these evaluations enables a comprehensive understanding of 
the systemic and reproductive manifestations of PCOS, fostering improved diagnostic 
accuracy and the development of targeted interventions. Magnetic Resonance Imaging 
(MRI) provides a non-invasive and highly detailed modality to evaluate both 
cardiovascular function and ovarian morphology in women with PCOS. Optional baseline 
and post-intervention MRI measurements will be conducted to observe these trends.  
 
As the hormone dynamics could shift when an individual is on a ketogenic intervention, 
testing will be moved to biweekly to capture these changes. These changes are already 
in effect in the SPARK001 participant in the study. 
 
IMPACT   
Our intent is to produce preliminary feasibility and efficacy data to inform the design of a 
future fully-powered, clinical trial that will examine whether ketogenic dietary 
intervention strategies are  effective in ameliorating multiple adverse signs and 
symptoms in women with an incurable endocrinopathy. Thus, providing evidence 
suggesting this approach as a safe and effective treatment intervention in women 
diagnosed with PCOS. 
 
OUTCOMES 
Primary  
Changes in anovulatory status in women with PCOS 
Secondary 
• Changes in reproductive hormones such as progesterone, estrogen, LH, FSH 
• Analysis of potential predictive metabolic baseline characteristics 
• Differences in blood metabolites (metabolic and lipids). 
Exploratory  

 
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• Examine cardiovascular function using magnetic resonance imaging (MRI)  
• Examine ovarian morphology through MRI. 
PARTICIPANTS 
This study aims to recruit 40 female participants between the ages of 18 to 40yr who 
have been diagnosed with PCOS. Each participant must meet all the inclusion criteria 
and none of the exclusion criteria at screening in order to participate. 
 
Inclusion criteria: 
• Female 
• Ages 18 – 40 years 
• Participant is willing and able to comply with all study procedures including the 
following prior to Test Day: fasting (>10 h; water only), no alcohol (>24 h), no  
exercise (>24 h), no acute illness and controlled feeding before the Test Day, 
maintain diet, exercise, medication, and supplement habits throughout the study.  
• Participants with PCOS symptoms including oligomenorrhea-anovulation or 
spontaneous intermenstrual periods.  
• BMI >18kg/m 
• Participant understands the study procedures and signs forms providing informed 
consent to participate in the study. 
• Must have access to smart phone, computer or tablet to access diet.  
Exclusion criteria: 
• Participant follows a low-carbohydrate diet (<30% energy from carbohydrate) 
• Participant has non-PCOS etiologies of anovulation, menopause or the removal 
of the ovaries. 
• Participant has history of type 1 diabetes 
• Participant has loss of 10% bodyweight in the last 6 months 
• Participant is pregnant or breast feeding  
• Participant has a condition the Investigator believes would interfere with his 
ability to provide informed consent. 
 
Sample Size. In our pilot trial with a sample size of 20 participants in each intervention, 
we acknowledge the limitations in statistical power due to the small sample. However, for 
this pilot trial we plan to recruit 40 participants to investigate the effects on ovulation. The 
results of this pilot trial will provide initial insights, but it is essential to acknowledge the 
limitations imposed by the small sample size. 
 
Recruitment: 
Recruitment will occur through well-established methods at OSU which include word of 
mouth, ResearchMatch database, social media engagement and flyers. 
 

 
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METHODS  
 
Study overview:  
Figure 2 | Study schematic, showing timeline for a study day.   
 
Study Procedures 
Study Day 
Screening 
Test Day  
Daily 
Visit to Study Center 
X 
X 
 
Informed consent 
X 
 
 
Medical intake questionnaire, diet 
assessment, anthropometrics1 
X 
 
 
Body Composition Scan2 
 
X 
 
Basal Body Temperature 3 
 
 
X 
Urine based Ovulation predication 
test4 
 
 
X 
Fingerstick Measurements5 
 
 
X 
Hydration Status 6 
 
X 
 
Whole blood collection7 
 
X 
 
Surveys 8 
 
X 
 
Cardiovascular and Ovarian MRI9 
 
X 
 
1. Medical intake questionnaire and diet assessment questionnaire are attached in 
Appendix . Anthropometric data will include: Hip and Waist circumference, BMI, 
height and weight. 
2. Lean Body Mass and fat mass assessments will be done by DXA measurement at 
weeks 0 and 8.  
3. Participants will also be provided with an intravaginally inserted OvuCore Sensor that 
is designed for measuring core body temperature which rises as progesterone is 

 
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releases. Participants will insert these monitors before sleep and wear them throughout 
the night 
4. Participants will be provided with urine ovulation predictor kit testing strips to use during 
the duration of the study as a tertiary predictor of potential ovulation 
5. Daily fasting glucose/ketones will be assessed using capillary finger stick lancing. A 
small drop of blood (i.e., the size of a grain of rice) will be obtained once daily, while 
fasting, using enzymatic strips fitted for a handheld analyzer (KetoMojo). All the data 
will be stored in the device’s internal memory until retrieved by the study team during 
test visits.  
6. Prior to blood collection, participants will be asked to completely void their bladder. And 
hydration status will be determined via urine specific gravity (USG) reporting <1.025. 
Urine will be tested for pregnancy status.  
7. Blood samples will be collected according to the schedule in Figure 2.  
8. Participants will complete a menstrual history survey and Ferriman-Gallwey index 
survery biweekly. 
9. Optional assessment of cardiovascular function using MRI at weeks 0 and 12. 
 
Screening Visit: Participants that meet the initial qualifying criteria will visit the study 
center for a screening meeting. The participant and a member of the research team will 
meet in a private office to discuss the informed consent form. The informed consent form 
will be provided to the participant for their review, the study will be described in full detail 
and any questions the interested participant has will be encouraged and responded to. If 
they choose to participate in the study, they will be asked to sign the consent form 
providing written consent. The participant will be informed that even though they signed 
the consent form, their participation in the study is dependent on anthropometric 
measures and diet and medical questionnaire answers to determine if they meet the study 
criteria.  
 
If the participant provides consent, they will be provided with questionnaires including 
Automated Self-administered 24-hour Dietary Assessment Tool (ASA24®), and medical 
history. All collected samples and data will be coded to maintain participant anonymity. 
Height and weight will be collected. If the participant is eligible for the study and is still 
interested in participating then they will be scheduled to return to the study center for the 
testing visit. 
 
Testing Day: 
Participants will report to the study center in the morning of the Test Day. Compliance 
with pre-test instructions (fasted > 10h, no alcohol >24h, no exercise >24h, consumed 
pre-test food) will be confirmed by the Investigator. Participants will complete a baseline 
menstrual history and Ferriman-Gallwey index survey. Participants will be asked to 
completely void their bladder and a sample will be analyzed for hydration status. 
Participants with samples reading greater > 1.025 USG will be asked to drink 160z of 
water and retest again in 30 minutes.  Urine will be tested for pregnancy status; a positive 

 
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test would exclude participant from the study. At the same time as all whole blood 
samples, we will also collect capillary blood samples from a finger for real-time analysis 
of blood BHB and glucose concentration, using lancing device, commercially available 
test strips and a handheld monitor (KetoMojo, CA, USA). Body composition will be 
determined at each study visit by dual-energy x-ray absorptiometry (iDXA, Lunar 
Corporation, Madison, WI). One whole body scan will quantify lean and fat mass using 
encore software and visceral fat quantification will be calculated using the new CoreScan 
software. 
 
Sample Processing and Analysis 
Blood Processing: Whole blood collected through the IV cannula will be processed to 
plasma (EDTA tubes) or serum (clot activator serum collection tubes) and then snap 
frozen in liquid nitrogen or dry ice for storage prior to analysis (details below). We will 
collect capillary blood samples for real-time analysis of blood BHB and glucose 
concentration, using commercially available test strips and a handheld monitor 
(KetoMojo, CA, USA), this will also allow comparison of ketone values obtained via 
different methods.  
 
Blood Sample Analytical Methods:  
• Capillary glucose and ketone concentrations will be obtained from a finger stick 
using a handheld device (KetoMojo, USA).  
• Serum hormone markers (progesterone, estradiol, FSH, LH) will be analyzed using 
commercially available Elecsys kits on cobas e 411(Roche, Indianapolis IN).   
 
OvuSense Basal Body Temperature Tracking: To validate whether a ketogenic diet 
intervention is pivotal in reversing anovulatory status, participants enrolled will begin 
tracking their menstrual cycle with the OvuSense cycle tracking phone application daily. 
The OvuSense application is specifically targeted for participants with PCOS and is 
proven to be hypersensitive to the abnormal or absent ovulatory patterns of this condition. 
Participants will also be provided with an intravaginally inserted OvuCore Sensor that is 
designed for measuring core body temperature which rises as progesterone is releases. 
Participants will insert these monitors before sleep and wear them throughout the night. 
The true core temperature, which typically occurs during sleep, will automatically populate 
to the application and aid in predicting and confirming ovulation. This data will be shared 
with and downloaded by the research staff to an encrypted and secure research study 
laptop. 
Ovulation Predictor Kit:  each participant will be provided with a Per manufacturer’s 
literature, patients were instructed to dip the wand into a sample of the first urine in the 
morning for 15 seconds. If two color bands are visible, and the test band is as dark or 

 
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darker than the control band, this is predictive of a positive LH surge which may predict 
ovulation. The participant will take a picture of the stick and upload to the OvuSense 
menstrual cycle tracking application.  
Satiety Visual Analogue Scale: We will use a 3-item visual analogue scale, that assesses 
hunger, fullness and desire to eat by participant’s marking on a line anchored at either 
end with ‘not at all’ and ‘extremely.’ Distance along the line is measured in mm.   
Body Composition:  Two, 7-minute whole-body scan will be conducted to assess lean-
body mass and fat mass changes pre- to post-diet. 
 
Optional Cardiovascular and Ovarian Magnetic Resonance Imaging: Magnetic 
resonance imaging (MRI) will be performed using a 3 Tesla system (MAGNETOM 
Prisma, Siemens Healthcare, Germany) to assess cardiovascular function, adipose 
tissue distribution, and ovarian morphology in women with PCOS. For cardiovascular 
and adipose measurements, chemical shift imaging will be used to generate proton 
density fat fraction (PDFF) maps, enabling quantification of fat content in liver, skeletal 
muscle, myocardium, visceral adipose tissue, subcutaneous fat, and epicardial fat. 
Subjects will undergo brief breath-hold scans (20–60 seconds) for liver, abdominal fat, 
and skeletal muscle assessments, as well as ECG-gated scans for myocardial and 
epicardial fat evaluation. Participants will not be required to be fasted for this procedure.  
 
For ovarian assessment, MRI will be used to evaluate ovarian morphology, including 
follicle count and distribution, without ionizing radiation. All image data will be analyzed 
post-scan using specialized software, including in-house tools for adipose quantification 
and ImageJ for fat fraction and ovarian measurements. The same protocol will be 
repeated after the 12-week intervention period. 
 
Diet Intervention. 
Participants will be randomized into either a ketogenic diet arm or a mixed diet with ketone 
ester arm. During the first 2 weeks, participants will be provided food meeting either the 
Ketogenic diet requirements, or mixed diet (following the USDA dietary macronutrient 
recommendations) at a caloric level estimated at 100% of energy requirements. The 
participants randomized into the Mixed diet arm will also receive a ketone ester 
supplement. This will be provided throughout the study. Energy requirements will be 
determined using a combination of information obtained from testing including habitual 
diet assess through an NIH sponsored food frequency questionnaire (e.g., DHQ-III which 
will be sent to the participants email) , body mass and composition, and formulas (e.g., 
Harris-Benedict) that consider sex, age, height and activity patterns. 
 
All participants will be provided all their meals and snacks selected to meet all calorie 
needs via individualized pre-ordered groceries and/or prepared food for the first 2 weeks 
of the diet. We have established the infrastructure for conducting controlled feeding 
studies for other funded research including development and implementation of 7-day 

 
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rotational menus, hybrid feeding approaches (providing groceries), and use of ready-
made meal services (Pangea Keto, Factor, Fresh and Lean). After the initial 2 weeks, and 
until completion of the 8-week intervention, the participants will not be supplied with all 
their food but will continue to receive educational materials, recipe guides and dietitian 
consultation as needed. Participants will have 24-hour access to the dietetic team to 
answer questions. After the initial 2 weeks, participants will switch to a self-guided dietary 
approach. Adherence will be prospectively evaluated throughout the study period. 
Subjects will be asked to use the meter each morning and to submit the results to the 
research team through a secure KetoMojo provider/consumer sharing application. 
Results will be recorded by a member of the research team. Levels of ketosis and glucose 
will be monitored daily. Participants will be asked to maintain levels of ketones that are 
equal or greater than 0.5mmol/L. 
 
DATA ANALYSIS AND STATISTICAL METHODS 
 
Statistical Plan: To evaluate the impact of the ketogenic diet intervention on menstrual 
cycle regularity in women with PCOS, we have the following data analysis plan:  
1) Descriptive Analysis: We will provide concise summaries of menstrual cycle attributes 
such as cycle length, variability, and ovulation status for participants at baseline.  
2) Menstrual Cycle Regularity Assessment: Survival analysis techniques, including 
Kaplan-Meier curves and log-rank tests, will be employed to compare the timeframe 
required to establish regular menstrual cycles (21-35 days range). Observations censored 
due to drop-outs or non-occurrences of events will be appropriately handled.  
3) Ovulation Pattern Analysis: We will utilize logistic regression analysis to assess the 
effect of the ketogenic diet on the incidence of ovulation in PCOS women, considering 
each cycle as an independent statistical unit. This analysis will offer quantifiable insights 
into the probability of ovulation in the study population, considering potential confounders 
like age, BMI, and initial menstrual cycle characteristics.  
4) Effect Size Estimation: Hazard ratios and their confidence intervals will be calculated 
to quantify the influence of the ketogenic diet on attaining regular menstrual cycles.  
Primary 
Changes in anovulatory status in women with PCOS 
 
Secondary 
•  Changes in reproductive hormones such as 
progesterone, estrogen, LH, FSH 
• Analysis of potential predictive metabolic baseline 
characteristics 
• Differences in blood metabolites (metabolic and 
lipids). 
Exploratory 
• Examine cardiovascular function and ovarian 
morphology using magnetic resonance imaging (MRI).  

 
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5) Significance Testing: The proportion of participants achieving regular menstrual cycles 
in each diet group will be compared using appropriate statistical tests such as the chi-
square test.  
Through this robust analytical strategy, we aim to unravel the influence of a ketogenic 
dietary intervention on menstrual cycle regularity and ovulation patterns in women with 
PCOS, thereby providing a compelling narrative around the potential benefits of a 
ketogenic diet. 
 
 
STUDY MONITOTRING 
Concomitant Medication/Supplements and Treatment 
All concomitant medications/supplements used 1 months prior to Screening Visit  and 
during the study will be reported to the study personnel for assessment and recorded in 
the participant’s study documents.  
 
Radiation 
This study comprises two, whole-body DXA scans, eight-weeks apart. This radiation 
exposure is not necessary for medical care and is for research purposes only. The total 
amount of radiation is about 78 mrem and is approximately equivalent 95 days of 
exposure to natural background radiation. This procedure involves minimal risk and is 
necessary to obtain the research information about changes in lean body mass, fat mass, 
and bone density (i.e., 3-compartment assessment model). 
 
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: 

 
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• 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.    
 

 
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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: 

 
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• 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. 
 
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 deidentified 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  
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.  
 

 
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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.  
 
 
 

 
Version date: 10/14/2025 
 
17
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