Phase 2, Randomized, Open-Label, Crossover, PD/PK Study of a Novel Pram-Insulin Co-Formulation in Adults With T1D

A Phase 2, Single-Dose, Randomized, Open-Label, Active-Controlled, Crossover, Pharmacodynamic, and Pharmacokinetic Comparative Study of a Novel Pramlintide-Insulin Co-Formulation in Adults With Type 1 Diabetes Mellitus

This is a randomized, open-label, active-controlled, single-dose, 3-treatment, 3-period, 3-way crossover, comparative PD and PK inpatient study in adults with T1D. The study comprises 5 visits: Screening (Visit 1), Treatment Periods (Visits 2 - 4), and Follow-Up (Visit 5).

The primary objective of this study is to evaluate the PD properties of a single dose of PRAM9 compared to single doses of regular insulin and regular insulin plus pramlintide (co-administered as separate injections) in adults with T1D. The secondary objectives of this study are to evaluate the safety and PK profiles of a single dose of PRAM9 compared to single doses of regular insulin and regular insulin plus pramlintide (co-administered as separate injections) in adults with T1D. During each treatment period subjects will receive a single SC dose of PRAM9, regular insulin, or co-administered regular insulin plus pramlintide.

Inclusion Criteria:

1. Understands the study procedures, alternative treatment available, and risks involved with the study, and voluntarily agrees to participate by giving written informed consent
2. Male or non-pregnant, non-lactating female diagnosed with T1D for at least 24 months prior to Screening.
3. Aged 18 to 64 years of age, inclusive
4. On a stable insulin regimen for 21 days prior to Screening (no greater than ± 20% variability in total daily dose)
5. Have a plasma C-peptide level < 0.6 ng/mL at Screening
6. Have an HbA1c < 10% at Screening
7. Body mass index (BMI) in the range of ≥ 18 to ≤ 35 kg/m2 at Screening
8. For women of childbearing potential, there is a requirement for a negative urine pregnancy test at Screening and for agreement to use contraception throughout the study and for 7 days after the last dose of study drug. Acceptable contraception includes birth control pill/patch/vaginal ring, Depo-Provera® (medroxyprogesterone acetate), Norplant® System (levonorgestrel), an intra-uterine device (IUD), the double barrier method (the woman uses a diaphragm and spermicide and the man uses a condom), or abstinence.
9. Fasting Serum triglyceride concentration < 200 mg/dL

Exclusion Criteria:

1. Currently being treated with pramlintide or has discontinued pramlintide within 21 days of Screening
2. Currently using an insulin pump
3. Has renal insufficiency (serum creatinine <3.0 mg/dL) or end-stage renal disease requiring renal replacement therapy
4. Has hepatic disease, including serum ALT or AST ≥3 times the upper limit of normal (ULN)
5. Has hepatic synthetic insufficiency (serum albumin <3.0 g/dL)
6. Has a hematocrit value that is exclusionary: Female <35.5% and Male <38.3%
7. Has a hemoglobin value that is exclusionary: Female <11.5 g/dL and Male <12.5 g/dL
8. Has out-of-range systolic or diastolic BP readings at Screening (systolic BP <90 or >150 mm Hg or diastolic BP <50 or >100 mm Hg)
9. Has clinically significant ECG abnormalities at Screening
10. Has congestive heart failure, NYHA Class III or IV
11. Has history of myocardial infarction, unstable angina, or revascularization within 6 months prior to Screening
12. Has history of a cerebrovascular accident in 6 months prior to Screening with major neurological deficits
13. Has active malignancy within 5 years prior to Screening (exception: basal cell or squamous cell skin cancers)
14. Has had major surgical operation within 60 days prior to Screening or planned surgical operation during the study
15. Has a seizure disorder (other than with suspected or documented hypoglycemia)
16. Has a current bleeding disorder, treatment with anticoagulants, or platelet count <50 ×10^9/L
17. Has a history of allergies or significant hypersensitivity to pramlintide or any pramlintide-related products or to any of the excipients in the investigational formulation
18. Has a history of positive test result for hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV)
19. Has a concurrent illness not controlled by a stable therapeutic regimen
20. Tests positive for drugs of abuse at Screening. Subjects testing positive for tetrahydrocannabinol (THC) at Screening or reporting active marijuana use will be allowed to participate in the study at the discretion of the investigator.
21. Has active substance or alcohol abuse (>21 drinks/week for males or >14 drinks/week for females)
22. Has participated in other studies involving administration of an investigational drug within 30 days or 5 half-lives prior to Screening (whichever is longer) or during participation in the current study
23. There is any reason the investigator deems exclusionary
24. Has donated blood within 8 weeks prior to Screening.