The Effect of Lysulin on Glycemic Control and Advanced Glycation in Inadequately Controlled Type 2 Diabetes Mellitus: a Double Blinded Placebo Controlled Study
Phase: NA
Conditions: Type 2 Diabetes
Sponsor: Juraj Koska

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Protocol 05/06/2020  
The Effect of Lysulin on Glycemic Control and Advanced Glycation in Inadequately   
Controlled Type 2 Diabetes Mellitus: A Double blinded Placebo Controlled Study   
Sponsor: Lysulin Inc., San Diego, CA   
PI: Juraj Koska, PhD   
Co-PI Peter Reaven, MD   
Phoenix VA Health Care System   
650 E Indian School Rd, AZ 85012   
602 277 5551 x7685 juraj.koska@va.gov   
   
   
  
 

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Protocol 05/06/2020  
PROTOCOL SYNOPSIS   
Protocol Title:   
The Effect of Lysulin on Glycemic Control and Advanced Glycation in   
Inadequately Controlled Type 2 Diabetes Mellitus: A Double blinded Placebo 
Controlled Study   
Site Numbers & Names:   Phoenix VA Health Care System   
Research Hypothesis:   
Dietary supplement (Lysulin™) reduces blood glucose, hemoglobin A1c and 
Advanced Glycation Endproducts in individuals with inadequately controlled 
type 2 diabetes.   
Study Schema:   
Drugs / Doses /   
Length of Treatment)   
Lysulin 3,330 mg/d (two 555mg tablets TID) x 12 weeks   
Study Objectives:   
• 
Primary:   
• 
Secondary:   
The primary objective is to determine whether 12 weeks of treatment with 
Lysulin, compared to placebo, causes a reduction from baseline in the plasma 
levels of glucose, hemoglobin A1c (HbA1c) and Advanced Glycation   
End products (AGEs) in patients with inadequately controlled type 2 diabetes 
mellitus. Secondary objectives include determining whether 12 weeks of 
treatment with Lysulin increases beta-cell function as measured by plasma 
Cpeptide levels.    
Study Design   
This is a randomized, prospective, double-blind study. Randomization to Lysulin 
and placebo will be in a 1:1 fashion.   
Accrual Goal: (Total  
number of 
subjects)   
60 subjects for the successful completion of 56 subjects   
Accrual Rate: 
(Number of subjects 
expected per month)   
15 subjects/month   
Correlative Studies:   
(PK/PD, etc.)   
N/A    
Inclusion Criteria:   
 
 
 
 
1. 
Signed written informed consent   
2. 
Able to communicate meaningfully with the investigator and legally 
competent to provide informed written consent    
3. 
Men and women, ages 21-75 years    
4. 
Diabetes, with HbA1c ≥ 7.5 % and < 10% within 6 weeks of screening   
5. 
Stable dose of insulin (<20% change in units) 6 weeks prior to 
enrollment   
Exclusion Criteria:   
1)  Sex and Reproductive Status   
a) Women of child-bearing potential who are unwilling or unable to use 
an acceptable method to avoid pregnancy for the entire study period.   
b) Women who are pregnant or breastfeeding   

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2)  Target Disease Exceptions   
a) Gastrointestinal disease (including gastrectomy, chronic pancreatitis, 
bariatric surgery and gastroparesis)   
b) Hepatic disease (ALT, AST >2.5 times the upper limit of normal)   
c) Kidney disease (GFR ≤50 mL/min)   
d) Hypertension (blood pressure >160/95 mmHg) at screening for the 
mean of three consecutive readings performed in a sitting position after 
a 5-minute resting period. If treatment for hypertension has recently   
 
been initiated, subjects must be clinically stable for 4 weeks prior to 
screening.   
e) Cardiac disease (myocardial infarction within past 6 months, clinically 
significant arrhythmia, unstable angina, uncontrolled congestive heart 
failure, or coronary artery bypass surgery within 1 year or expected to 
require coronary bypass surgery within 12 months of study entry)   
3) Medical History and Concurrent Diseases   
a) Type 1 diabetes mellitus   
b) Active malignancy other than basal cell or squamous cell skin cancer 
(cancers in remission or stable and not receiving active therapy 
permitted)   
c) Significant clinical allergic rhinitis or asthma, regularly requiring inhaled 
corticosteroids and/or antihistamines   
d) Chronic inflammatory disease (e.g. Rheumatoid arthritis)   
4) Additional Laboratory Test Findings   
a) Hemoglobin <12 g/dl in men, <11 g/dl in women   
5) Allergies and Adverse Drug Reactions   
History of a serious hypersensitivity reaction to compounds containing lysine, 
such as anaphylaxis, angioedema, or exfoliative skin conditions.   
6) Prohibited Treatments and/or Therapies   
a) Regular use of supplements containing lysine, zinc or vitamin C for the 
last 3 months   
b) Current or expected treatment with any of the following medications at 
screening: systemic glucocorticoids (for >2 weeks), antineoplastic 
agents, transplant medications, drugs for weight loss or anti-retroviral 
medications   
c) Treatment with antihistamines or inhaled corticosteroids within 3 months 
prior to screening   
d) Start or change of hormonal replacement therapy within 3 months prior 
to screening   
7) Other Exclusion Criteria   
a) Prisoners, or subjects who are involuntarily incarcerated   
b) Subjects who are compulsorily detained for treatment of either a 
psychiatric or physical (e.g., infectious disease) illness   
c) Currently abusing alcohol or drugs, or have a history of alcohol or drug 
abuse that in the investigator’s opinion could cause the subject to be 
non-compliant; or have a general history of non-compliance with 
medications   
d) Any acute febrile illness within 2 weeks of screening with a temperature  
≥ 100°F   

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Protocol 05/06/2020  
Criteria for Evaluation:  
Efficacy, safety, stopping 
rules, etc.)   
Study participation will be stopped for adverse effects at the discretion of the study 
investigator. Subjects may stop study participation at any time and for any reason. 
Enrollment may be stopped due to futility or efficacy by interim analysis.   
Statistical analysis:   
A linear mixed effects model will be used to evaluate treatment-induced 
endpoints. The models will be fit for sequential values of the response variable 
(including the baseline measurement).   
Statistical power:   
54 participants will be required to complete the study to detect a of 0.7% points 
reduction in HbA1c and 19 mg/dl reduction in fasting plasma glucose levels with 
80% power at the alpha level of 0.05. This corresponds to SDs for HbA1c 0.9% 
points and fasting glucose 25 mg/dl.   
   
   
BACKGROUND AND SIGNIFICANCE   
Type 2 diabetes mellitus (T2DM) is a progressive disease and is associated with long term 
microvascular complications such as retinopathy, nephropathy, and neuropathy as well as 
cardiovascular morbidity and mortality. There is direct link between the levels of glycemia and the 
development of diabetes complications1,2. Glucose lowering trials conducted in type 1 diabetes 
(T1D) and in new onset type 2 diabetes (T2D) patients supported the concept that improving 
glucose control was an effective method to reduce diabetes microvascular complications 3,4. 
Although individually these trials did not show statistically significant reductions in cardiovascular 
disease (CVD), observational follow-up of these trials suggested improved glycemic control 
reduces cardiovascular outcomes and may reduce mortality5,6. In contrast intensive glycemic 
control for up to 6 years has at best only modestly reduced the development of CVD and renal 
disease in people with longstanding, inadequately controlled T2D7-11. To achieve adequate 
glycemic control in patients with chronic T2D frequently requires combination of diabetes agents 
at increasing dosage resulting in increasing risk of side effects, including hypoglycemia, weight 
gain, edema and changes in blood lipid profile, that may counteract the benefactor effects of 
glucose lowering. Another explanation for the modest and slow benefit of glucose lowering on 
diabetes complication, is that chronic hyperglycemia has built up a legacy of vascular and kidney 
injury which is not easily or rapidly resolved12. This may in part be due to increased tissue levels 
of advanced glycation end-products (AGEs) that formed by the non-enzymatic glycosylation of 
reducing sugars to amino-groups of proteins, lipoproteins or nucleic acids13,14. Multiple clinical and 
epidemiological studies indicate an association between AGEs/glycoxidation products diabetes 
complications15-24. We have recently demonstrated that several plasma “free” AGEs from a panel 
measured by LC-MS predicted long-term progression of coronary and carotid atherosclerosis in 
a subset of participants of the Veterans Affairs Diabetes Trial (VADT) 25. Increases in several AGEs 

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also appeared to predict incident CVD events in the same VADT subset as well as in a small 
subcohort of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) 26.   
Given the importance of chronic hyperglycemia and AGEs in the development of diabetes 
complications, there has been substantial interest in treatments that in addition to improving 
glucose control may also rapidly AGE levels. LysulinTM is a nutraceutical tablet which contains the 
essential amino acid lysine, a micronutrient zinc and vitamin C as the active ingredients, together 
with other standard excipients (Lysulin Inc, San Diego, CA) (www.lysulin.com). When 
supplemented separately, all 3 ingredients reduced blood glucose in both animal models as well 
as humans with T2D27-30. The mechanisms of action appear to include improvement of both major 
mechanisms of T2D, insulin sensitivity and insulin secretion27-30. Importantly, lysine also reduced 
AGE formation31,32. To support the glucose-lowering efficacy of Lysulin, preliminary single-arm 
study in patients with T2D reported a significant, on average 10% (or 0.9 percent point) reduction 
in HbA1c after 12 weeks of treatment with 3.3 g daily LysulinTM. Given its minimal toxic profile due 
to natural character of all ingrediencies, the addition of Lysulin TM to current diabetes agents may 
improve glycemia in parallel with reducing dosage and variety of diabetes medications resulting 
in lower risk of side effects.   
   
HYPOTHESIS    
Administration of LysulinTM for 12 weeks will improve glycemic control in T2D patients with 
inadequate glycemic control. LysulinTM may also reduce AGE levels and increase beta-cell 
function.   
   
STUDY APPROACH    
Trial Overview: This will be a 3-month, randomized, placebo-controlled, double-blinded trial that 
tests the effects of LysulinTM on glycemic control and AGEs levels in blood, and renal function in   
T2D patients, when added to the usual care for glycemic control in a standard primary care setting.  
Trial Design: 60 patients with Type 2 DM with inadequate glycemic control will be randomly 
allocated in blocks for 3 months to LysulinTM (1,110 mg TID, i.e. 3.3 g/day) or matching placebo. 
Fasting plasma glucose and HbA1c will be measured at baseline and then at week 6 and week 
12 (visit windows at week 6 and 12 visits will be -7/+3 days). Plasma AGEs, creatinine and 
Cpeptide levels will be determined at baseline and at the end of the study. Lipid levels will be 
measured at baseline, week 6 and at the end of study.  

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Inclusion criteria: Age 21-75 years, Type 2 diabetes mellitus, HbA1c ≥7.5 % and <10.0% within 6 
weeks of the screening visit treated non-pharmacologically with diet or stable doses of oral 
antihyperglycemic agents with or without insulin, stable body weight (< 5% change in last 3 
months). Patients on insulin therapy will to be on a stable dose, i.e. < 20% variation in insulin 
units, 6 weeks prior to the study.    
Exclusion criteria: Type 1 DM, current or recent use of supplements containing lysine, zinc or 
vitamin C, uncontrolled hypertension (blood pressure ≥160/90 mmHg), kidney disease (serum 
creatinine GFR ≤50 mL/min, major illness, severe gastrointestinal disease, pregnancy, liver 
function tests > 2.5 times normal values in the past 3 months, currently abusing alcohol or drugs, 
or have a history of alcohol or drug abuse that in the investigator’s opinion could cause the subject 
to be non-compliant; or have a general history of non-compliance with medications.   
Study Visits Schedule: All visits will be performed in the Clinical Research Center (CRC) at the 
Phoenix VA. Completion of the entire study will involve up 3-4 visits to the CRC. After initial visit 
for obtaining of informed consent and screening, qualified patients will undergo a baseline testing 
(on the same day as screening visit or on a separate day), including blood collection for baseline 
measurements, and will be randomized to treatment (LysulinTM or matching placebo). Study 
medication will be dispensed to the subject in a double-blinded fashion by Phoenix VA research 
pharmacist. Subjects will be instructed to take two tablets orally with breakfast, lunch and dinner. 
They will return to the CRC for clinical evaluation and blood draws after 6 and 12 weeks (final 
visit). Subjects will be instructed to not make major lifestyle modifications, including changes to 
their diet or exercise, during their study participation. At least one phone call contact will take 
place between interim visits to ensure medication is being taken appropriately and to help address 
any study related questions. At each visit a comprehensive assessment of side effects, medication 
compliance/competency and concurrent medical history will be obtained and entered into the 
database. Additional brief visits may occur as needed to ensure participant comfort/competency 
with treatment.   
Study endpoints:    
Primary: Fasting plasma glucose and HbA1c concentrations   
Secondary: Fasting plasma AGEs, C-peptide concentrations and lipid measurements  
Recruitment Approach: Participants will be recruited utilizing VA electronic medical records to 
identify potential candidates meeting inclusion criteria, as well as from the Phoenix VA primary 
care, specialty and women’s clinics, community diabetes clinics, ads in VA newsletters and flyers, 

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permission to be contacted forms, on hold message, social media, clinic list, BISL, list of A1c 
results from lab, and through VINCI.    
Diabetes care during the study: The research team will provide diet and exercise guidance at 
baseline and review at subsequent study visits, and monitor side effects, medication changes or 
general health issues of all subjects. We will notify relevant PCP providers of study activity to 
avoid unnecessary diabetes medication changes during the study. Addition of diabetes agents 
will be discouraged, but of course supported if clinically indicated. However, general and diabetes 
healthcare and routine lab tests will be conducted by the PCP as warranted. With hypoglycemia, 
excessive hyperglycemia or other adverse events - we will work with the participant and/or primary 
care team to evaluate/change contributory diet or behavior and/or reduce/modify other diabetes 
medications as appropriate.   
Biochemical analyses: Plasma glucose, HbA1c, creatinine and all safety screening will be 
measured at the VAMC clinical laboratory using established automated methods. Plasma 
Cpeptide levels will be measured by commercial ELISA kit in the VAMC research laboratory. 
AGEs will be measured by LC-MS/MS utilizing internal stable heavy isotope substituted standards 
(Preventage Healthcare technology) if initial data analysis indicates Lysulin had a rapid and 
favorable effect on HbA1c values.   
Data Handling:  All participants will be given non-identifying study IDs and all case report forms 
and samples are labeled with this information. The code for these IDs is stored in locked files in 
the locked office of the project manager. Only approved VA research employees will have access 
to study samples and data.   
Statistical Analysis Plan: Univariate numerical and graphical procedures will be used to explore 
distributional characteristics and dependence structure of measured variables. Data 
transformations (e.g., logarithm) may be used to improve distributional characteristics and/or to 
improve linearity of relationships between response and covariates. A linear mixed effects model 
will be used to evaluate treatment-induced endpoints (glucose, HbA1c, AGEs, C-peptide). This 
approach allows the inclusion of potential covariates, and explicitly accounts for repeated 
measurements on each patient (and patient-to-patient variability). We will fit models to all 
sequential values of the response variable (including the baseline measurement), rather than 
computing a change score. This structure allows statistically efficient evaluation of treatment 
effects33 and allows modeling of differential treatment effects for patients with varying initial 
glycemic control.    

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Power Calculation: 54 participants will be required to complete the study to detect a of 0.7% points 
reduction in HbA1c and 19 mg/dl reduction in fasting plasma glucose levels with 80% power at 
the alpha level of 0.05. This was based on SDs for HbA1c=0.9% points and fasting glucose=25 
mg/dl from our previous study in patients with > 5 years duration of type 2 diabetes 34.   
Interim analysis: Using a 2-stage group sequential trial design, an interim analysis will be 
performed by an independent statistician after completing first 28 participants, i.e. 14 per group. 
The sample size for interim analyses as well as the boundary values for the treatment effect were 
computed by SEQDESIGN procedure of SAS v9.4. The SEQTEST procedure will compare the 
test statistic with the boundary values at the interim stage so that the study can be stopped to 
reject or accept the null hypothesis. If the interim analysis will indicate futility, the enrollment of 
new patients will be discontinued. All active participants will complete the study as planned.   
Ethical considerations: The study is testing a potential benefit of a diabetes supplement and is not 
providing a direct clinical benefit to the research subject.  Participation in the study will be voluntary 
and won’t affect standard of care. The VA has very strict research guidelines regarding clinical 
research. All protocols receive IRB, safety, scientific and privacy committee reviews and approval 
before being initiated. Audits of all studies are conducted by the compliance officer on annual 
basis: these include consent audits; case report form audits and other study conduct activity. All 
studies and their adverse events are also reviewed annually by the IRB. The study will be 
conducted in accordance with the Declaration of Helsinki, all local and national VA policies, and 
adhere to ICH GCP guidelines.   
Payment Schedule: Study participants will be reimbursed $15 for screening visit and $25 for each 
completed study visit for up $115 for the whole study.    
Reporting of Adverse Events: There is a VA policy for reporting serious adverse events, 
unexpected/unanticipated adverse events, and standard adverse events. Depending on the 
category of the event, it is reported within 5 days or annually to the IRB.    
The sponsor-investigator will be responsible for reporting of all serious adverse events (SAE), 
unexpected/unanticipated adverse events, and standard adverse events to the appropriate 
authority and independent ethics committee/institutional review boards based upon federal 
regulations and local/IRB policies.   
If the SAE or problem is UNANTICIPATED (i.e., it reflects a RISK that is NEW or GREATER than 
previously known) then this would be reported more rapidly and within the required local expedited 

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policy time frame but if the AE or problem was ANTICIPATED, this would be reported in 
accordance to the local policy (e.g., which may be an AE reported at continuing review).   
   
  
Adverse Event Definitions   
Adverse Event (AE): An AE is any undesirable medical event occurring to a subject in a clinical 
trial, if related to the trial product(s). This includes events reported from the first trial related activity 
after the subject has signed the informed consent and until post treatment follow-up period as 
defined in the protocol. The following should not be recorded as AEs, if recorded as medical 
history/concomitant illness on the CRF at screening:   
• 
Pre-planned procedure, unless the condition for which the procedure was planned has    
worsened from the first trial related activity after the subject has signed the informed 
consent   
• 
Pre-existing conditions found because of screening procedures   
Clinical Laboratory Adverse Event: A clinical laboratory AE is any clinical laboratory abnormality 
regarded as clinically significant i.e. an abnormality that suggests a disease and/or organ toxicity 
and is of a severity, which requires active management, (i.e. change of dose, discontinuation of 
trial product, more frequent follow-up or diagnostic investigation).   
Serious Adverse Event (SAE): A serious AE is an experience that at any dose results in any of 
the following:   
• 
Death   
• 
A life-threatening* experience   
• 
In-patient hospitalization or prolongation of existing hospitalization   
• 
A persistent or significant disability/incapacity   
• 
A congenital anomaly/birth defect   
• 
Important medical events that may not result in death, be life-threatening*, or required 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgement, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.   

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Unanticipated (Unexpected) Adverse events: The terms “unanticipated” and “unexpected” refer to 
an event or problem in VA research that is new or greater than previously known in terms of 
nature, severity, or frequency, given the procedures described in protocol-related documents and 
the characteristics of the study population.   
  
Serious unanticipated problems involving risks to subjects or others include:   
(1) 
Interruptions of subject enrollments or other research activities due to concerns about the 
safety, rights, or welfare of human research subjects, research staff, or others.   
(2) 
Any work-related injury to personnel involved in human research, or any research-related 
injury to any other person, that requires more than minor medical intervention (i.e., basic first aid), 
requires extended surveillance of the affected individual(s), or leads to serious complications or 
death.   
Serious Adverse Drug Reaction (SADR):  An adverse drug reaction (ADR) is an adverse event 
for which a causal relationship (Possible/Probable relation) between the study drug and the 
occurrence of the event is suspected. The ADR should be classified as serious if it meets one or 
more of the seriousness criteria.    
Non-Serious Adverse Event: A non-serious AE is any AE which does not fulfil the definition of an 
SAE.   
Severity Assessment Definitions:   
• Mild: Transient symptoms, no interference with the subject’s daily activities   
• Moderate: Marked symptoms, moderate interference with the subject’s daily activities   
• Severe: Considerable interference with the subject’s daily activities, unacceptable   
Related AE or a Related Problem: A “related” AE or a “related” problem in VA research is an AE 
or problem that may reasonably be regarded as caused by, or probably caused by, the research.   
Collection, Recording and Reporting of Adverse Events: All events meeting the definition of an 
adverse event must be collected and reported from the first trial related activity after the subject 
has signed the informed consent and until the end of the post-treatment follow-up period as stated 
in the protocol.    
Follow-up of Adverse Events: During and following a subject’s participation in a clinical trial, the 
sponsor-investigator and institution will provide adequate medical care to the study subject for 

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any study-related adverse events, including clinically significant laboratory values related to the 
study as per local VA policy.    
All adverse events classified as serious or severe or possibly/probably related to the trial product 
must be followed until the subject has recovered, is recovering, or the condition has reached a 
new stable condition, and all queries have been resolved according to local VA policy.    
Pregnancy: Study subjects will be instructed to notify the sponsor-investigator immediately if 
they become pregnant. Pregnancy complications should be recorded as adverse event(s). If the 
infant has a congenital anomaly/birth defect this must be reported and followed up as a serious 
adverse event.   
Overdose: An overdose is defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important. All occurrences of overdose 
must be reported as an SAE.   
Timeline: We anticipate completion of study about 8 months after recruiting the first patient.   
Implications and Future Directions: If successful, this study may provide support for adding Lysulin 
or comparable supplements as add-on treatment in T2D. However, definitive confirmation of these 
findings and a more thorough exploration of the relevant signaling events will be needed and could 
be effectively pursued using animal and cell models. Future long-lasting RCT will be needed to 
establish whether these types of supplements provide long-term improvement of glycemic control 
and reduce the risk of diabetes complications.   
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