Safety and Efficacy of KH-1 for Stimulating Autophagy in Non-diabetic Adults With Elevated Blood Glucose Concentration

A Randomized, Double-blind, Placebo-controlled, Proof-of-concept Study to Evaluate the Safety and Efficacy of the Test Product KH-1 for Stimulating Autophagy in Non-diabetic Adults With Elevated Blood Glucose Concentration

Aging significantly impacts overall health and is a risk factor for developing diabetes. An estimated 50% of U.S. adults aged ≥65 years were reported to have prediabetes (defined as having a fasting glucose concentration of 100-125 mg/dl) in 2005-2008. The Centers for Disease Control and Prevention (CDC) has stated that in the United States, 88 million people (one in every 3 Americans) are currently classified as prediabetic, emphasizing the importance of preventative measures and early intervention to manage and reduce the risk of progression to diabetes. Additionally, an estimated 430 million individuals worldwide are expected to have prediabetes by 2030. Dietary supplementation of polyamines, spermidine in particular, have been touted to have beneficial health effects such as increasing life span and mitigating impacts of aging. Spermidine and spermine are polyamines that are being increasingly investigated for their ability to slow the aging process by inducing autophagy. Nevertheless, literature on these topics is scarce and results from trials have been inconclusive; therefore further research is needed. The novel nutraceutical KH-1, comprised of spermidine, spermidine derivatives and probiotics, is examined in this trial of healthy volunteers aged 18 years or over. This study evaluates KH-1 for its safety and its effect on glucose homeostasis. This study measures the effects of KH-1 on biomarkers for inflammation, cardiovascular disease, insulin sensitivity, and those important for autophagy. A qualitative assessment of the effect of KH-1 on well-being is also examined.

Study Overview

• Status: Completed
• Conditions: PreDiabetes; Aging
• Intervention / Treatment: Dietary supplement: KH-1; Other: Placebo

Detailed Description

Prediabetes is the intermediate state and precursor that can lead to an eventual diagnosis of diabetes. The presence of an elevated hemoglobin A1c (HbA1c), as well as insulin resistance with concomitant β-cell dysfunction is a strong indicator of prediabetes. Dietary and lifestyle changes are the most effective methods to control and prevent prediabetes, but maintenance of these changes is often difficult. Pharmaceutical options are indicated for treatment of diabetes rather than prevention of prediabetes, however many are associated with side effects. Therefore, a safe and effective alternative to prevent disease in metabolically dysregulated individuals is necessary.

The novel nutraceutical KH-1 is comprised of spermidine, amino acids, and a probiotic. This nutraceutical may offer a promising strategy for managing prediabetes.

This study is a double-blinded randomized controlled trial with 48 healthy volunteers to test the efficacy and safety of the novel nutraceutical KH-1. A total of 48 participants will be randomized in a double-blinded fashion, with 24 participants in each study group (KH-1 vs. placebo). After screening and randomization, participants will consume their assigned study product for 3 months, after which all participants will be assigned to consume the KH-1 for the remaining 3 months in an open-label fashion. Upon arrival at the clinic at the screening visit, participants will review the informed consent form (ICF), and if they agree to participate in the study, will sign and date the ICF, complete a brief screening, provide demographic information, and take part in other study activities indicated to be done on the screening visit. Participants who complete the screening process and qualify to continue are randomized to receive either the KH-1 or placebo in a 1:1 ratio for the first 3 months and assigned a unique randomization code. After the first 3 months, all participants will take KH-1. Participants will be instructed on the use of the nutraceutical product/placebo, according to label instructions. Participants will self-administer the study product at home and compliance will be assessed and documented at each visit. Venous blood samples will be collected at Week 0, Week 12 and Week 24 and analysed for biomarkers of glucose regulation and metabolism, cardiovascular health, inflammatory and autophagy biomarkers. Haematology and biochemistry parameters will be measured at screening, week 0, week 12 and week 24. A qualitative health questionnaire will be completed at 3 in-clinic visits and physical measurements to assess safety of the nutraceutical.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Memphis, Tennessee, United States, 38119
      • LifeDoc Research, PLLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Healthy adult participants who are at least 50 years of age (inclusive) at the time of signing the informed consent form.
2. Have a body mass index (BMI) between 25.0 to 45.0 kg/m2 (inclusive).
3. In good general health and good oral health (no active or uncontrolled diseases, infections or conditions).
4. Impaired glucose metabolism evidence by either fasting glucose of 100 to 125 mg/dL at screening or an HbA1c between 5.7 and 6.4%.
5. Female participants of childbearing potential (i.e., participants who are not surgically sterilized or not post-menopausal (defined as amenorrhea for greater than 1 year), or transgendered males with retained ovaries and uterus) must agree to use a medically approved method of birth control for at least one month prior (or three months prior in the case of oral or long-acting injective contraceptives) to the first dose of study product and throughout the study, or abstain from heterosexual intercourse throughout the duration of the study and have a negative urine pregnancy result at baseline. For males of reproductive potential: use of condoms, abstinence from heterosexual intercourse, or other methods to ensure that their partners (if able) do not become pregnant during the course of the study.
6. Willing and able to agree to the requirements and restrictions of this study, be willing to give voluntary consent, be able to understand and read the questionnaires, and carry out all study-related procedures.

Exclusion criteria:

1. Participant has a medical history of uncontrolled hypertension (i.e., ≥160 mmHg systolic and/or ≥100 mmHg diastolic)
2. Participant has a medical history of heart disease and/or cardiovascular disease, kidney disease (dialysis or renal failure), hepatic impairment or disease, or Type 1 or Type 2 diabetes.
3. Participant has a medical history of unstable thyroid disease, previously diagnosed major affective disorder, psychiatric disorder that required hospitalization in the year prior to screening, immune disorder (i.e., HIV/AIDS), or a history of cancer (except localized skin cancer without metastases or in situ cervical cancer) within 5 years prior to screening visit.
4. Female participants who are lactating, pregnant, or planning to become pregnant during the study.
5. Have a known intolerance, sensitivity, or allergy to any of the study products or their ingredients, or any of the excipients used in the formulation.
6. Have a known intolerance, sensitivity, or allergy to milk.
7. Unable to be prescribed at least one of the antibiotics outlined in the study protocol.
8. Any condition or abnormality that, in the opinion of the Investigator, would compromise the safety of the participant or the quality of the study data.
9. Currently taking dietary supplements other than vitamins (a 14-day washout period prior to baseline/Visit 2 would be permitted).
10. Taking any prescription medication at the time of randomization that is known to impact blood sugar and or blood sugar metabolism, as per Principal Investigator's (PI) discretion.
11. Use of certain medications in timeframes defined in the study protocol (Ampicillin, Gentamicin, Kanamycin, Streptomycin, Erythromycin, Clindamycin, Tetracycline, Chloramphenicol, Potassium sparing diuretics, Nitroglycerin and other nitrates, antidiabetic/Blood sugar lowering medications, any blood thinning medications (i.e., anticoagulant/antiplatelet drugs), antidepressants (use is permitted if dosage is maintained throughout the study), anxiolytics, antipsychotics , anticholinergics/antispasmodics, calcium-channel blockers (use is permitted if dosage is maintained throughout the study), Opioids.
12. Use of supplements dietary supplements/food/drink within 2 weeks or 7 half-lives (whichever is longer) prior to baseline and for the duration of the study, including foods/drinks rich in probiotics or prebiotics (e.g., yogurt, sauerkraut, kombucha) or synbiotics, Any herbs and supplements with hypoglycemic potential, any herbs or supplements that induce weight loss, any blood sugar lowering herbs or supplements, any blood thinning herbs or supplements
13. History of alcohol or substance abuse in the 12 months prior to screening.
14. Receipt or use of an investigational product in another research study within 28 days prior to baseline/Visit 2.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: KH-1; Three capsules containing spermidine and amino acids. One stick packet containing probiotics.	Dietary supplement: KH-1; 3 capsules and one stick packet consumed daily around the same time
Placebo Comparator: Placebo; Three capsules containing hypromellose, hypromellose acetate succinate, purified water, pigments and gellen gum. One stick packet containing microcrystalline cellulose.	Other: Placebo; 3 capsules and one stick packet consumed daily around the same time

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin resistance	Between placebo and test product, change from baseline to 3 months in fasting insulin	3 months
Insulin resistance	Between placebo and test product, change from baseline to 3 months in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)	3 months
Insulin Resistance	Between placebo and test product, change from baseline to 3 months Oral Glucose Tolerance Test (OGTT)- derived indices of insulin dynamics	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Long-term effect on Insulin Resistance	Within-group change from baseline to 3 months for fasting insulin	3 months
Long-term effect on Insulin Resistance	Within-group change from baseline to 6 months for fasting insulin	6 months
Long-term effect on Insulin Resistance	Within-group change from baseline to 3 months for HOMA-IR	3 months
Long-term effect on Insulin Resistance	Within-group change from baseline to 6 months for HOMA-IR	6 months
Long-term effect on Insulin resistance	Within-group change from baseline to 3 months for OGTT-derived indices	3 months
Long-term effect on Insulin Resistance	Within-group change from baseline to 6 months for OGTT-derived indices	6 months
Post-prandial Glycemic Response	Between placebo and test product, change from baseline to 3 months in area under the glucose concentration (AUC) post-OGTT	3 months
Post-prandial Glycemic Response	Within-group change from baseline to 3 months in area under the glucose concentration (AUC) post-OGTT	3 months
Post-prandial Glycemic Response	Within-group change from baseline to 6 months in area under the glucose concentration (AUC) post-OGTT	6 months
Post-prandial Glycemic Response	Between placebo and test product, change from baseline to 3 months in 2-hour post-prandial glucose	3 months
Post-prandial Glycemic Response	Within-group change from baseline to 3 months in 2-hour post-prandial glucose	3 months
Post-prandial Glycemic Response	Within-group change from baseline to 6 months in 2-hour post-prandial glucose	6 months
Glycemic Control	Between placebo and test product, change from baseline to 3 months in fasting glucose	3 months
Glycemic Control	Within-group change from baseline to 3 months in fasting glucose	3 months
Glycemic Control	Within-group change from baseline to 6 months in fasting glucose	6 months
Glycemic Control	Between placebo and test product, change from baseline to 3 months in HbA1c	3 months
Glycemic Control	Within-group change from baseline to 3 months in HbA1c	3 months
Glycemic Control	Within-group change from baseline to 6 months in HbA1c	6 months
β-cell Function	Between placebo and test product, change from baseline to 3 months in oral disposition index (DI) calculated by the ratio of the insulinogenic index over fasting insulin	3 months
β-cell Function	Within-group change from baseline to 3 months in oral DI	3 months
β-cell Function	Within-group change from baseline to 6 months in oral DI	6 months
Cardiovascular Biomarkers	Between placebo and test product, change from baseline to 3 months in fasting triglycerides (TG)	3 months
Cardiovascular Biomarkers	Within-group change from baseline to 3 months in fasting TG	3 months
Cardiovascular Biomarkers	Within-group change from baseline to 6 months in fasting TG	6 months
Cardiovascular Biomarkers	Between placebo and test product, change from baseline to 3 months in fasting total cholesterol	3 months
Cardiovascular Biomarkers	Within-group change from baseline to 3 months in fasting total cholesterol	3 months
Cardiovascular Biomarkers	Within-group change from baseline to 6 months in fasting total cholesterol	6 months
Cardiovascular Biomarkers	Between placebo and test product, change from baseline to 3 months in fasting low-density lipoprotein (LDL)	3 months
Cardiovascular Biomarkers	Within-group change from baseline to 3 months in fasting LDL	3 months
Cardiovascular Biomarkers	Within-group change from baseline to 6 months in fasting LDL	6 months
Cardiovascular Biomarkers	Between placebo and test product, change from baseline to 3 months in high-density lipoprotein (HDL)	3 months
Cardiovascular Biomarkers	Within-group change from baseline to 3 months in HDL	3 months
Cardiovascular Biomarkers	Within-group change from baseline to 6 months in HDL	6 months
Inflammatory Biomarkers	Between placebo and test product, change from baseline to 3 months in high-sensitivity C-reactive protein (hs-CRP)	3 months
Inflammatory Biomarkers	Within-group change from baseline to 3 months in hs-CRP	3 months
Inflammatory Biomarkers	Within-group change from baseline to 6 months in hs-CRP	6 months
Inflammatory Biomarkers	Between placebo and test product, change from baseline to 3 months in tumor necrosis factor (TNF)-alpha	3 months
Inflammatory Biomarkers	Within-group change from baseline to 3 months in TNF-alpha	3 months
Inflammatory Biomarkers	Within-group change from baseline to 6 months in TNF-alpha	6 months
Inflammatory Biomarkers	Between placebo and test product, change from baseline to 3 months in interleukin-6 (IL-6)	3 months
Inflammatory Biomarkers	Within-group change from baseline to 3 months in IL-6	3 months
Inflammatory Biomarkers	Within-group change from baseline to 6 months in IL-6	6 months
Autophagy	Between placebo and test product, change from baseline to 3 months in Beclin-1	3 months
Autophagy	Within-group change from baseline to 3 months in Beclin-1	3 months
Autophagy	Within-group change from baseline to 6 months in Beclin-1	6 months
Immunity Biomarkers	Between placebo and test product, change from baseline to 3 months in Cluster of Differentiation (CD) 3	3 months
Immunity Biomarkers	Within-group change from baseline to 3 months in CD3	3 months
Immunity Biomarkers	Within-group change from baseline to 6 months in CD3	6 months
Immunity Biomarkers	Between placebo and test product, change from baseline to 3 months in CD4	3 months
Immunity Biomarkers	Within-group change from baseline to 3 months in CD4	3 months
Immunity Biomarkers	Within-group change from baseline to 6 months in CD4	6 months
Immunity Biomarkers	Between placebo and test product, change from baseline to 3 months in CD8	3 months
Immunity Biomarkers	Within-group change from baseline to 3 months in CD8	3 months
Immunity Biomarkers	Within-group change from baseline to 6 months in CD8	6 months
Immunity Biomarkers	Between placebo and test product, change from baseline to 3 months in CD25	3 months
Immunity Biomarkers	Within-group change from baseline to 3 months in CD25	3 months
Immunity Biomarkers	Within-group change from baseline to 6 months in CD25	6 months
Overall Patient Health	Between placebo and test product, change from baseline to 3 months in Patient Health Questionnaire scores	3 months
Overall Patient Health	Within-group change from baseline to 3 months in Patient Health Questionnaire scores	3 months
Overall Patient Health	Within-group change from baseline to 6 months in Patient Health Questionnaire scores	6 months
Overall Quality of Life	Between placebo and test product, change from baseline to 3 months in RAND-36 questionnaire scores	3 months
Overall Quality of Life	Within-group change from baseline to 3 months in RAND-36 questionnaire scores	3 months
Overall Quality of Life	Within-group change from baseline to 6 months in RAND-36 questionnaire scores	6 months
Stress	Between placebo and test product, change from baseline to 3 months in Perceived Stress Scale (PSS) scores	3 months
Stress	Within-group change from baseline to 3 months in PSS scores	3 months
Stress	Within-group change from baseline to 6 months in PSS scores	6 months
Systolic Blood Pressure (SBP)	Change from baseline to 6 months in SBP (mmHg)	6 months
Diastolic Blood Pressure (DBP)	Change from baseline to 6 months in DBP (mmHg)	6 months
Heart Rate	Change from baseline to 6 months in heart rate (beats per minute)	6 months
Weight	Change from baseline to 6 months in weight (kg)	6 months
Percent Body Fat	Change from baseline to 6 months in percent body fat (%)	6 months
Body Mass Index (BMI)	Change from baseline to 6 months in BMI (kg/m2)	6 months
Whole Blood Hemoglobin	Change from baseline in fasting whole blood hemoglobin (g/dL)	6 months
Whole Blood Hematocrit	Change from baseline in fasting whole blood hematocrit (%)	6 months
Whole Blood Red Blood Cell Count	Change from baseline in fasting whole blood red blood cell count (x10^6/uL)	6 months
Whole Blood Red Blood Cell Distribution Width	Change from baseline in fasting whole blood red blood cell distribution width (%)	6 months
Whole Blood Mean Corpuscular Volume	Change from baseline in fasting whole blood mean corpuscular volume (fL)	6 months
Whole Blood Mean Corpuscular Hemoglobin	Change from baseline in fasting whole blood mean corpuscular hemoglobin (pg)	6 months
Whole Blood Mean Corpuscular Hemoglobin Concentration	Change from baseline in fasting whole blood mean corpuscular hemoglobin concentration (g/dL)	6 months
Whole Blood White Blood Cells	Change from baseline in fasting whole blood white blood cells (x10^3/uL)	6 months
Whole Blood Neutrophils	Change from baseline in fasting whole blood neutrophils (cells/uL)	6 months
Whole Blood Basophils	Change from baseline in fasting whole blood basophils (cells/uL)	6 months
Whole Blood Eosinophils	Change from baseline in fasting whole blood eosinophils (cells/uL)	6 months
Whole Blood Lymphocytes	Change from baseline in fasting whole blood lymphocytes (cells/uL)	6 months
Whole Blood Monocytes	Change from baseline in fasting whole blood monocytes (cells/uL)	6 months
Whole Blood Mean Platelet Volume	Change from baseline in fasting whole blood mean platelet volume (fL)	6 months
Whole Blood Platelet Count	Change from baseline in fasting whole blood platelet count (x10^9/L)	6 months
Serum Creatinine	Change from baseline in fasting serum creatinine (umol/L)	6 months
Serum Blood Urea Nitrogen	Change from baseline in fasting serum blood urea nitrogen (mg/dL)	6 months
Serum Alkaline Phosphatase (ALP)	Change from baseline in fasting serum ALP (U/L)	6 months
Serum Asparatate Transaminase (AST)	Change from baseline in fasting serum AST (U/L)	6 months
Serum Alanine Transaminase (ALT)	Change from baseline in fasting serum ALT (U/L)	6 months
Serum Albumin	Change from baseline in fasting serum albumin (g/dL)	6 months
Serum Total Protein	Change from baseline in fasting serum total protein (g/dL)	6 months
Serum Chloride	Change from baseline in fasting serum chloride (mmol/L)	6 months
Serum Sodium	Change from baseline in fasting serum sodium (mmol/L)	6 months
Serum Potassium	Change from baseline in fasting serum potassium (mmol/L)	6 months
Serum Calcium	Change from baseline in fasting serum calcium (mg/dL)	6 months
Serum Urea	Change from baseline in fasting serum urea (mg/dL)	6 months
Incidence of Adverse Events	Number of participants with adverse events	6 months

Collaborators and Investigators

• Sponsor: Kalin Health, LLC
• Collaborators: Nutrasource Pharmaceutical and Nutraceutical Services, Inc.
• Investigators: Principal Investigator: Pedro Velasquez, MD, LifeDoc Research, PLLC

Study record dates

Study Major Dates

• Study Start (Actual): December 20, 2021
• Primary Completion (Actual): June 8, 2023
• Study Completion (Actual): June 8, 2023

Study Registration Dates

• First Submitted: May 31, 2024
• First Submitted That Met QC Criteria: May 31, 2024
• First Posted (Actual): June 6, 2024

Study Record Updates

• Last Update Posted (Actual): June 6, 2024
• Last Update Submitted That Met QC Criteria: May 31, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Probiotic; Autophagy; Spermidine; Elevated Blood Glucose
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperglycemia
• Other Study ID Numbers: K02-21-01-T0012

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No