Development of A Novel Anti-Hyperglycemic Agent

The purpose of this clinical trial is to test the effectiveness and safety of a new anti-diabetes drug (Cyclo-Z) for the prevention and treatment of Type 2 diabetes. This study will determine dose-dependent efficacy and safety of this new drug for the treatment of human diabetes. The Food and Drug Administration has granted approval for the use of this investigational product to be used in a study (FDA approval IND #: 61,897). This new drug is thought to work by increasing the amount of zinc in your body, which in turn should improve your sugar metabolism. If this study successfully proves that Cyclo-Z is effective for the treatment of diabetes and is without significant side effects, a large, multi-center study of diabetic patients will then be performed.

We have demonstrated that a cyclic dipeptide Cyclo (his-pro) plus zinc (Cyclo-Z) treatment improved clinical conditions of diabetes in various animal models and a phase 1 clinical trial. The main objective of this study is to demonstrate that this product is safe and effective for the treatment of human diabetes.

Research Plan This is a randomized, double blinded, placebo-controlled, and parallel study. In this study, we will recruit 120 hypoglycemic drug na ve type 2 diabetic patients and randomize them into 4 groups of 30 subjects each to compare the effects of a Cyclo-Z capsule containing CHP 0 (placebo), 3 mg (minimally effective), 9 mg (optimally effective), or 15 mg (no-additional effect) plus 20 mg zinc on diabetic symptoms in a 12-week trial period. The primary outcome of this study is improvement of hemoglobin A1c; secondary outcomes are fasting blood glucose, 2 hours postprandial glucose and glucose tolerance test. Safety will be assessed by the presence of severe adverse events (SAEs), adverse events (AEs), any changes of vital signs, physical exams, blood hematology, chemistry, liver, renal, thyroid function tests, urine analysis and zinc, copper levels.

Clinical Significance The proposed study has a direct impact on veteran's healthcare service. The applicant has obtained two types of US and international patent approvals for preventing and treating human diabetes and obesity with Cyclo-Z. One patent application for Alzheimer's disease treatment has just been approved. These patent rights are now assigned to the DVA. Based on our background studies and observation we anticipate the proposed Phase 2a clinical trials will prove that Cyclo-Z treatment is safe and effective for the treatment of human diabetes and we will be able to present a new class of anti-diabetes drug to improve healthcare of both the VA diabetic patients and the general public.

• Drug: Cyclo-Z
  Cyclo-Z is a cyclic dipeptide Cyclo (his-pro) plus zinc that may lower blood glucose
• Drug: Placebo
  Placebo control

• Placebo Comparator: Arm 1
  Placebo control
  Intervention: Drug: Placebo
• Experimental: Arm 2
  Active medication
  Intervention: Drug: Cyclo-Z
• Experimental: Arm 3
  Active medication efficacy dose
  Intervention: Drug: Cyclo-Z
• Experimental: Arm 4
  Active medication high dose
  Intervention: Drug: Cyclo-Z

Inclusion Criteria:

1. History of type 2 diabetes mellitus who are na ve to hypoglycemic treatment, inadequately controlled by diet and exercise alone or oral medications.
2. Hemoglobin A1c level of 6.5 % to 8.0 % inclusive. Subjects not taking hypoglycemic drugs with HgbA1c of 6.0% to 6.5% must have a diagnosis of DM.
3. Fasting blood glucose levels reasonably stable for at least 2 months or during the two-week lead-in-period.
4. Ethnicity: All ethnic groups.
5. Gender: Both men and women.
6. Female with reproductive potential must not be pregnant or lactating, and using reliable contraception methods.
7. Age >18 years old.

Exclusion Criteria:

1. Taking insulin.
2. History of diabetic ketoacidosis or hyper osmolar non-ketotic coma.

3. Diabetes Mellitus related end-organ damage:

   • Evidence of diabetic autonomic and peripheral neuropathy
   • Diabetic proliferative retinopathy, based on eye exam by ophthalmologist
   • Diabetes nephropathy defined by > 500 mg/24 hour urinary albumin excretion

4. Any disease likely to limit life span and/or increase risks of interventions:

   • Screening carotid B-mode ultrasound indicating clinically significant stenos in the common carotid arteries requiring intervention by angioplasty or resection.
   • Cancer treatment in the past 5 years, with the exception of cancers that have been cured, and carry a good prognosis.
   • Infectious disease: HIV positivity, active tuberculosis, or pneumonia.

5. Cardiovascular disease:

   • Hospitalization for treatment of heart disease in the past 12 months.
   • New York Heart Association Functional Class > 2.
   • Left Bundle branch block on EKG.
   • Third degree atrioventricular block on EKG.
   • Uncontrolled hypertension with average systolic blood pressure of > 160 mmHg on two screening visits and diastolic blood pressure > 95 mmHg on two screening visit.
   • Pulse rate > 95 beats per minute on both screening visits.
   • Stroke or transient ischemic attack in the past 12 months.

6. Gastrointestinal disease:

   • Chronic hepatitis or cirrhosis.
   • Episode of alcoholic hepatitis or alcoholic pancreatitis.
   • Inflammatory bowel disease requiring treatment in the past 12 months.
   • Recent or significant abdominal surgery (e.g. gastrectomy, gastric bypass).
7. Renal disease: Serum creatinine > 1.5 mg/dL for men, and > 1.4 mg/dL for women.

8. Lung disease:

   • Chronic obstructive airway disease or asthma requiring daily therapy.
   • Use of home oxygen.
9. Anemia: Hematocrit of < 36.0% in men or < 33% in women.

10. Conditions or behaviors likely to affect the conduct of the study

    • Unable or unwilling to give informed consent.
    • Unable to communicate with the clinic staff.
    • Unwilling to accept treatment assignment by randomization.
    • Weight loss of > 10% in the past 6 months.
    • Unable to walk without any assisted device.
    • Major psychiatric disorder which would impede conduct of the research.
    • Excessive alcohol intake (more than 2 drinks/day)

11. Medications

    • Psychoactive agents such as Monoamine oxidase inhibitors and Antidepressive agents (lithium, prozac, zoloft, serzone, paxil, efflexor)
    • Systemic use of glucocorticoids steroids within previous 6 weeks.