Pilot Study to Assess the Effects of Hepatic Ultrasound Insonification on Subjects With T2DM

This research study is being done to evaluate the effect of hepatic ultrasound insonification on whole-body insulin sensitivity and evaluate the safety and tolerability of hepatic ultrasound insonification in subjects with Type 2 Diabetes Mellitus (T2DM). "Insonify/insonification" is defined as applying to an area or an object carefully-controlled sound waves, typically as in ultrasound imaging. GE Research is sponsoring this research study. The purpose of this research study is to:

* Evaluate the effect of liver ultrasound waves on changes from baseline in whole-body insulin sensitivity
* Test the safety and tolerability of liver ultrasound waves in subjects with Type 2 Diabetes Mellitus
* Evaluate the effect of liver ultrasound waves on change from baseline in glucose tolerance and insulin secretion
* Evaluate the effect of liver ultrasound waves on glucose metabolism

Insulin sensitivity refers to how sensitive the body's cells are in response to insulin.

Glucose tolerance refers to the body's ability to handle (tolerate) glucose. Insulin secretion is a process in which the body releases insulin in response to glucose levels in the blood becoming elevated.

The study device used in this study is cleared for use by the United States Food and Drug Administration (FDA) for ultrasound diagnostic exams, however it has not been tested or approved specifically for modulation of metabolism in people with diabetes. The use of the study device in this study is investigational and is considered a Non-Significant Risk (NSR).

This was an open label, exploratory pilot study to assess the effects of hepatic ultrasound insonification on glucometabolic parameters in subjects with T2DM through selective hepatic ultrasound of the porta hepatis region of the liver utilizing pulsed ultrasound. The study was to consist of 1 cohort comprising up to 15 subjects. Dropouts and withdrawals could have been replaced until the anticipated number of subjects completed the study. Finally, the study consisted of one cohort with 36 subjects enrolled, including 20 screen failures, 15 subjects that completed the study (1 completer had an incorrect infusion parameter and was removed from clamp analysis), and 1 subject that was discontinued at the discretion of the Investigator. As this was an exploratory, open-label study, no randomization or blinding was performed and no-unblinding codes were required.

The study included a Screening Period, Observational Period 1, 3 consecutive days of hepatic ultrasound insonification, and Observational Period 2. Each Observational Period was divided into an In-house Period and an Outpatient Visit (OPV). The Screening Period was performed up to 28 days prior to the first In-house Period. For eligible subjects with a body mass index (BMI) \> 35.0 and ≤ 40.0 kg/m2 and/or a waist circumference \> 40 and ≤ 45 inches, an ultrasound examination was added to confirm eligibility, and the Screening Period was extended to at least 30 days. The first Observational Period lasted approximately 2-weeks (Days -1 to 14). On the morning of Day -1, subjects checked into the clinic for a 3-day In-house Period; subjects may have been released from the clinic on Day 2. Subjects were contacted via telephone every other day until the next In-house Period. On Day 8, subjects checked into the clinic for an OPV. On Day 15, subjects checked into the clinic in fasting conditions for a 4-day In-house Period. Insonifications were performed on three consecutive days (Days 15, 16 and 17). Subjects may have been released from the clinic on Day 18. The second Observational Period lasted 11 days (Days 18 to 28). Subjects were contacted via telephone every other day until the Follow-up Visit. On Day 22, subjects checked into the clinic for the OPV. The Follow-up Visit was performed on Day 28.

Eligibility Criteria:
Inclusion Criteria:

1. Male or female subjects with type 2 diabetes ≥ 12 months.
2. Age ≥ 21 and ≤ 75 years.
3. Stable treatment with diet and exercise or stable treatment with metformin monotherapy. Stable treatment is defined as no change in treatment during the last 3 months.
4. HbA1c \> 6.5% and\< 10% by local laboratory analysis (one retest is permitted with the result of the last test being conclusive).
5. Body Mass Index (BMI) ≥ 18 to ≤ 35.0 kg/m2.
6. Waist circumference ≤ 40 inches (≤ 102 cm).
7. Considered generally healthy upon completion of medical history, physical examination and biochemical investigations as judged by the Principal Investigator.
8. Female subjects must be non-pregnant and non-lactating and have a negative serum pregnancy test at Screening. Females may be surgically sterile, postmenopausal or of child-bearing potential. Females of childbearing potential must be using an acceptable method of birth control.
9. Ability to provide written informed consent.

Exclusion Criteria:

1. History or current diagnosis with T1DM or T2DM subjects on insulin or other injectable therapies not allowed for this study (as listed in table of Prohibited Medication below).
2. A subject who is already indicated for medication escalation of their current diabetic therapy, or, who based upon study entry criteria, would be indicated for medication escalation during the course of the study (as assessed by the qualified Principal Investigator).
3. A subject who has diabetic complications, i.e., acute proliferative retinopathy or maculopathy, severe gastroparesis, and/or severe neuropathy, in particular autonomic neuropathy, as judged by the Principal Investigator.
4. Recurrent severe hypoglycemia (more than 1 event ≤ 6 month) or hypoglycemic unawareness or recent severe ketoacidosis (hospitalization ≤ 6 month), as judged by the Principal Investigator.
5. Persistent systolic blood pressure \> 150 mm Hg and/or diastolic blood pressure \> 95 mm Hg at screening. (Subjects may be re-checked once on the same day).
6. Treatment with antihypertensive medication is not allowed, unless antihypertensive medication is given on a stable dose for at least 2 months prior to screening.
7. Subjects with a clinically significant history or active disease of any of the following body systems: pulmonary, neurological (including dementia, neurodegenerative disease, movement disorder, spinal disorders), pancreatic (including pancreatitis), immunological or systemic inflammatory (including systemic lupus erythematosus \[SLE\], rheumatoid arthritis \[RA\]), dermatological, endocrine, genitourinary or hematological (including sickle cell anemia or other anemia syndromes, monocytosis, thrombocytopenia).
8. Subjects with a history or clinically active malignancy (history of basal cell carcinoma \[BCC\] is allowed).
9. History or current diagnosis of cardiac dysrhythmias or heart disease, defined as symptomatic heart failure (New York Heart Association class III or IV), myocardial infarction, unstable angina requiring medication.
10. Transient ischemic attack \[TIA\], cerebral infarct, or cerebral hemorrhage.
11. Invasive cardiovascular procedure, such as coronary artery bypass graft surgery (CABG), or angioplasty/percutaneous coronary intervention (PCI) within 6 months of screening.
12. PHistory of or presence of clinically significant ECG findings (e.g., QTcF \> 450 msec for males, QTcF \> 470 msec for females, LBBB) at Screening, or cardiac arrhythmia requiring medical or surgical treatment within 6 months prior to screening.
13. History of renal disease or abnormal kidney function tests at Screening (glomerular filtration rate \[GFR\] \< 60 mL/min/1.73m2 as estimated using the MDRD equation).
14. History or clinically significant active hepatic disease or clinically significant abnormal hepatic function tests at Screening suggestive of hepatic impairment (e.g., ALT and/or AST \>2 x ULN), total bilirubin \> 1 x ULN).
15. Subjects with a history or presence of any psychiatric disorder that, in the opinion of the Principal Investigator, might confound the results of the trial or pose additional risk in administering the investigational product to the subject.
16. Personal or family history of hypercoagulability or thromboembolic disease, including deep vein thrombosis and/or pulmonary embolism (PE)
17. History of surgical treatment for obesity (bariatric surgery, gastric banding, etc.) or any other gastrointestinal surgery (including appendectomy, cholecystectomy), any malabsorption disorder, severe gastroparesis, any GI procedure for weight loss (including LAP-BAND®), as well as clinically significant gastrointestinal disorders (e.g. peptic ulcers, severe GERD) at Screening.
18. History of any major surgery within 3 months prior to screening.
19. Any nerve stimulation study or implanted stimulator, including previously or currently implanted vagus nerve stimulator, previously or currently implanted spinal cord stimulator, other implanted electronic medical device, such as implanted pacemaker or cardioverter/defibrillator (AICD) or history of seizures.
20. Diagnosis of sleep apnea.
21. Participation in an investigational study within 30 days of screening or 5 half-lives within the last dose of any investigational product given during the investigational study, whichever is longer.
22. Current use of any drugs (other than current treatment for diabetes mellitus) that are known to interfere with glucose or insulin metabolism as stated below in table prohibited medication.
23. Thyroid hormone use is not allowed unless medication is given on a stable dose for at least 3 months prior to screening.
24. Chronic use of acetaminophen, and inability to wash-out and abstain from use during the study, as it would interfere with the CGMS assessment.
25. Subject is unable to tolerate adhesive tape or has any unresolved adverse skin reaction in the area of the sensor placement.
26. Implanted pacemaker or cardioverter/defibrillator (AICD).
27. Daily use of more than 5 cigarettes/day or equivalent use of any tobacco- or nicotine-containing product (such as, but not limited to vaping, transdermal nicotine patch, nicotine gum use, etc.) within 4 weeks prior to screening. Subjects must be able to abstain from any tobacco or nicotine containing products during confinement period.
28. Any use of marijuana within 4 weeks prior to screening and positive test at screening.
29. History of any active infection, except mild viral disease, such as common cold, within 30 days prior to screening.
30. History of any recent traumatic injury, including intracerebral hemorrhage and visceral injury.
31. History of alcohol or illicit drug abuse as judged by the Principal Investigator within past 12 months or positive test at screening. Any use of alcohol within 4 days prior to baseline assessment. Subjects must be able to abstain from any alcohol during confinement period.
32. Known history or positive test for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV Ab), human immunodeficiency virus type 1 (HIV-1) or type 2 (HIV-2)
33. Donation or loss of \> 500 mL of blood or blood product within 56 days prior to screening
34. Mental incapacity, unwillingness or language barriers precluding adequate understanding and to follow verbal commands during the ultrasound session or cooperation.
35. An abdominal ultrasound scan or exam within 1 month prior to screening and/or any pre-planned ultrasound examinations during the study, or the need to participate in any unplanned outside ultrasound procedures during study.