A Phase 2 Study of Cyclo-Z in Subjects With Type 2 Diabetes

Study Overview
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Brief Summary
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This is a double-blind, randomized, placebo-controlled, parallel-group comparison study to evaluate the efficacy and safety of Cyclo-Z vs. placebo in adult subjects with type 2 diabetes. Approximately 20 clinical sites may be utilized in the United States so that approximately 300 subjects (a potential 20% screening failure rate) may be screened for total 28-week study period (2 weeks for screening, 24 weeks for treatment, and 2 weeks for safety follow-up).

Detailed Description
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Insulin degrading enzyme (IDE) is a zinc-containing enzyme that regulates degradation of internalized insulin and the maintenance of insulin sensitivity. Diabetic animals and humans are zinc deficient due to impaired intestinal zinc absorption and hyperzincuria. If endosomal IDE levels are inadequate, undigested insulin will remain in the cytosol and prevent insulin signal transduction. Cyclo-Z enhances IDE synthesis and stimulates insulin degradation. Although Cyclo (his-pro) (CHP) or zinc alone are somewhat effective in the control of blood glucose metabolism, based on the available literature and previous background studies, it is hypothesized that the combination of CHP and zinc in Cyclo-Z work synergistically to ameliorate insulin resistance in diabetic and obese subjects mainly by stimulating IDE synthesis.

Official Title
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A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 2 Study to Evaluate the Efficacy and Safety of Cyclo-Z in Subjects With Type 2 Diabetes

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Cyclo-Z
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females aged 18 or older. Subjects diagnosed with type 2 diabetes mellitus (DM) according to the American Diabetes Association (ADA) criteria. Subjects treated with stable doses of insulin and/or other hypoglycemic agent(s) for type 2 diabetes mellitus for at least 2 months prior to randomization and who agree to stay on stable doses of anti-diabetes agents during the study. Subjects whose fasting blood glucose levels are reasonably stable for at least 2 months prior to randomization and during the 2-week screening period. Subjects who have Hemoglobin A1c levels of 7.5 to 10.0 % at Screening and a fasting plasma glucose less than 310 mg/dL. Subjects who can give written informed consent. Subjects who are willing and able to monitor their blood glucose concentrations with a home glucose monitor (before breakfast and 2 hours after dinner). Female subjects must be either: Surgically sterile (i.e., have had bilateral tubal ligation, hysterectomy, or bilateral oophorectomy) at least 6 months before randomization, or Post-menopausal for at least 12 months prior to Screening, or If of childbearing potential and sexually active, must agree to use adequate contraception from Screening to completion of the study. Exclusion Criteria: Subjects who have any significant DM-related end-organ damages. Subjects who have a history of diabetic ketoacidosis or hyperosmolar non-ketotic coma. Subjects who have any disease likely to limit life span and/or increase risks of interventions such as: Carotid B-mode ultrasound test results indicating clinically significant stenosis in the common carotid arteries requiring intervention by angioplasty or resection. Cancer treatment in the past 5 years, with the exception of cancers which have been cured, and carry a good prognosis. Infectious disease: HIV positivity, active tuberculosis, or pneumonia. Subjects with evidence of clinically significant cardiovascular or cerebrovascular disease, including (but not limited to): Hospitalization for the treatment of heart disease in the past 12 months. New York Heart Association Functional Class > 2. Left bundle branch block on ECG at Screening. Third degree atrioventricular block on ECG at Screening. Stroke or transient ischemic attack in the past 12 months. Subjects with uncontrolled hypertension with average systolic blood pressure of ≥ 160 mmHg or diastolic blood pressure ≥ 95 mmHg at Screening and Baseline. Subjects with pulse rate ≥ 95 beats per minute at Screening and Baseline. Subjects who have or had any of the following conditions related to gastrointestinal disease: Chronic hepatitis or cirrhosis. Episode of alcoholic hepatitis or pancreatitis. Inflammatory bowel disease or irritable bowel syndrome. Significant abdominal surgery (e.g., gastrectomy, gastric bypass) in the past 2 months. Serum creatinine ≥ 1.5 mg/dL for males or ≥ 1.4 mg/dL for females. Hemoglobin ≤ 12 g/dL for males or ≤ 10 g/dL for females. Subjects who have chronic obstructive airway disease or asthma requiring daily inhaled corticosteroid therapy or home use oxygen. Subjects who have any of the following conditions or behaviors likely to affect the conduct of the study: Weight loss of > 10% in the past 6 months. Unable to walk without assisted device. Major psychiatric disorder which would impede conduct of the research. Excessive alcohol intake (i.e., more than 2 drinks/day). Use of illicit drugs or drugs of abuse. Subjects who take any of the following medications: Psychoactive agents such as monoamine oxidase inhibitors and antidepressants (e.g., lithium, Prozac, Zoloft, Serzone, Paxil, Effexor). Any insulin sensitizers (thiazolidinediones - TZDs) such as Avandia, Actos or Duvie, etc. Subjects with any other clinically significant and/or unexplained abnormalities that, in the opinion of the Investigator, could impact the subject's ability to fully participate in or complete the study. Female subjects who have a positive serum pregnancy test at Screening, plan a pregnancy during study period, or are breast feeding.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Subject will be assigned to either 6 mg Cyclo-Z, 15 mg Cyclo-Z or placebo for the duration of study treatment.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose A<br>Cyclo-Z containing 23 mg zinc plus 6 mg CHP | Drug: Cyclo-Z<br>* Cyclo (His-Pro) and zinc<br>* Other names: CHP plus zinc;|
| Experimental: Dose B<br>Cyclo-Z containing 23 mg zinc plus 15 mg CHP | Drug: Cyclo-Z<br>* Cyclo (His-Pro) and zinc<br>* Other names: CHP plus zinc;|
| Placebo Comparator: Dose C<br>Placebo | Other: Placebo<br>* Matching placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Glycosylated Hemoglobin (HbA1c) from Baseline at Week 24 | Change in HbA1c from Day 1 to Week 24 | Day 1 to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in HbA1c over time | Change in HbA1c over 24 weeks | Day 1 to 24 weeks | 
| Change from Baseline in fasting plasma glucose (FPG) levels over time | Change in FPG levels over 24 weeks | Day 1 to 24 weeks | 
| Change from Baseline in plasma insulin over time | Change in plasma insulin over 24 weeks | Day 1 to 24 weeks | 
| Proportion of subjects achieving HbA1c goal of < 7.0% at Week 24 | Percent of subjects who achieved HbA1c of <7% at Week 24 | Day 1 to 24 weeks | 
| Proportion of subjects achieving HbA1c goal of < 6.5% at Week 24 | Percent of subjects who achieved HbA1c of <6.5% at Week 24 | Day 1 to 24 weeks | 
| Proportion of subjects with decrease in HbA1c of ≥ 0.5% from Baseline at Week 24 | Percent of subjects who achieved HbA1c decrease at Week 24 of ≥ 0.5% from Day 1 | Day 1 to 24 weeks | 
| Proportion of subjects with decrease in HbA1c of ≥ 1.0% from Baseline at Week 24 | Percent of subjects who achieved HbA1c decrease at Week 24 of ≥ 1.0% from Day 1 | Day 1 to 24 weeks |