Study of HDV Insulin Versus Insulin in Type 1 Diabetes Subjects (ISLE-1)

This will be a Phase 2b, multicenter, randomized, double blind, titration clinical study,
evaluating the efficacy and safety in the HDV Insulin Lispro Group versus Insulin Lispro
Group in patients with type 1 diabetes over a 26 week treatment period. The patients will be
randomized using a centrally allocated randomization scheme to 1 of the 2 treatment arms in
an overall 2:1 scheme (HDV Insulin Lispro: Insulin Lispro). Both arms will receive the
randomized treatment in combination with glargine or detemir.

SCREENING (Visit 1, Week -4 to -1) Patients will arrive for Screening following an 8 hour
fast. During Screening, patients will sign the informed consent form, be reviewed for
inclusion/exclusion, and provide medical history, concomitant medications, and demographics.
They will have a brief physical exam and provide vital signs. Safety
hematology/chemistry/urinalysis (with liver enzymes) will include infectious serology, and
serum pregnancy test for women of childbearing potential. An ECG will be performed and
patients will provide samples for HbA1c determination.

Patients taking lispro/glargine or lispro/detemir at the time of Screening and who meet all
eligibility criteria will proceed to Visit 2 (Week -1).

TREATMENT PERIOD Visit 1a (Week -2) will be required only if a patient must convert to lispro
prior to Visit 3 (Week 0, randomization). Patients taking non-lispro/glargine or
non-lispro/detemir or using an insulin pump will be converted to lispro/glargine or
lispro/detemir (respectively) using equivalent insulin units, then proceed to Visit 2 (Week
-1) after 1 week on the new regimen. At Visit 2 (Week -1), patients will receive the CGM and
be trained on its use. Patients will also have their first Mixed Meal Tolerance Test (MMTT)
during Visit 2 (Week -1) accompanied by monitoring of blood ketones pre- and post-ingestion.
CGM and MMTT will be repeated at Visits 9 (Week 12) and 14 (Week 25). A diary, glucose meter,
and supplies will also be provided at Visit 2 (Week -1). Patients will be instructed on how
to perform self-monitored blood glucose measurements (SMBG). During Visit 3 (Week 0),
eligible patients will be randomized by IWRS to either treatment arm (Test Group or Control
Group) and baseline data will be collected. All visits will include progress reviews and
safety procedures. Safety hematology/chemistry/ urinalysis at Visits 2 (Week -1), 10 (Week
13), 14 (Week 25) and 16 (Week 27) will include liver enzymes. At Visits 6 (Week 5) and 12
(Week 19), liver enzymes will be the only chemistry safety tests performed. The only
chemistry safety tests performed at Visits 2 (Week -1), 9 (Week 12), and 14 (Week 25) will be
blood ketones; these will be measured at baseline and 3 hours after the MMTT. HbA1c will be
measured at Visits 3 (Week 0), 4 (Week 1), 7 (Week 7), 10 (Week 13), 12 (Week 19), and 15
(Week 26). Fasting blood glucose will be measured at Visits 3 (Week 0), 10 (Week 13), and 15
(Week 26). An in-clinic urine pregnancy test will be performed at all visits for women of
childbearing potential. MRI will be performed at Visits 3 (Week 0) and 14 (Week 25) for
approximately 20% of patients in each treatment arm. MRI may also be performed on a
case-by-case basis in the event of abnormal liver enzyme results. Patients will receive
weekly telephone calls from the PI or a designee to discuss insulin dosing and titration.

FOLLOW-UP Visit 16 (Week 27) is a safety follow-up visit which will include a physical exam.
Safety hematology/chemistry/ urinalysis (including liver enzymes) will include a urine
pregnancy test for women of childbearing potential.

Concomitant medications, vital signs, and adverse events will be recorded throughout the
entire study period.

Inclusion Criteria:

1. Men and women ≥ 18 yrs. of age

2. Clinical diagnosis of Type 1 diabetes mellitus for at least 12 months

3. Body Mass Index (BMI) ≤ 35 Kg/m2

4. Basal insulin includes insulin Glargine or insulin Detemir

5. Patient should be using bolus insulin defined as 2 to 4 doses of regular human insulin
or rapid-acting analog at meals

6. HbA1c ≥ 7.0% and ≤ 10.5%

7. Fasting C-peptide ≤ 0.5 pmol/mL

8. Willingness to adhere to protocol and perform all required tests

9. Willing and able to review and sign the Informed Consent Form.

10. If child bearing age, must use acceptable form of birth control (ligation, 2 forms of
birth control)

11. Willing to wear CGM devices and complete diaries.

Exclusion Criteria:

1. Total daily insulin dose ≥ 1.5 IU/kg/day.

2. History of recent blood transfusions (within previous 3 months), hemoglobinopathies,
or any other conditions that effect HbA1c measurements

3. Evidence of serious complications of diabetes (eg, Symptomatic autonomic neuropathy)

4. Patients who are selected to but are unwilling or unable to participate in the MRI
evaluation subset. (These patients may still participate in the non-MRI subset).

5. Significant cardiovascular dysfunction or history within 12 months of Screening, eg,
congestive heart failure (New York Heart Association Class III or IV), or clinically
significant arrhythmia, myocardial infarction, cardiac surgery; history of valvular
heart disease including mild or greater aortic insufficiency, or moderate or greater
mitral insufficiency; recurrent syncope, transient ischemic attacks, or
cerebrovascular accident

6. Impaired liver function with elevated enzymes > 50% above the normal range at
Screening. Patients with elevated liver enzymes may have the test repeated only at
Visit 2 on a case-by-case basis at the request of the PI.

7. Creatinine level > 2 mg/dL for men, and > 1.8 mg/dL for women at Screening.

8. Patient on low carbohydrate diet, such as Atkins Diet

9. History of Adrenal supplementation within 3 years of Screening.

10. History of unawareness or SEVERE recurrent hypoglycemia, defined as a patient who is
unaware of symptoms of hypoglycemia, or due to autonomic dysfunction, has no inherent
warnings of hypoglycemia, and therefore requires outside assistance to rectify any
episodes of hypoglycemia

11. Patients treated with systemic corticosteroids (Sporadic use of inhaled,
intraarticular, and topical corticosteroids is not considered systemic).

12. Patients with triglyceride levels ≥500 mg/dL at Screening.

13. Patients with a history of cancer within the past 5 years, excluding basal or squamous
cell carcinoma localized to the skin.

14. Epilepsy or other physical or medical conditions which could result in non-compliance
with the study.

15. Participation in a clinical trial or use of an investigational drug within 30 days
prior to admission to this study

16. Unwilling to discontinue use of an insulin pump for the duration of the study.

17. Women who are pregnant, nursing, or planning to become pregnant during the course of
the study.

18. Patients on NPH as their basal insulin.

19. Positive history of hepatitis A (within 12 months of Screening), or a positive history
of hepatitis B, hepatitis C, or HIV at Screening.

20. History of drug addiction and/or alcohol abuse within 12 months of Screening.