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

Phase 2

Completed

Conditions: Diabetes Mellitus, Type 1
Insulin-dependent Diabetes Mellitus

Interventions: Drug: PRAM9
Drug: Regular Insulin + Pramlintide
Drug: Regular Insulin

Registration Number: NCT04074317

Lead Sponsor: Xeris Pharmaceuticals

Brief Summary: 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).

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 18

Inclusion Criteria

Understands the study procedures, alternative treatment available, and risks involved with the study, and voluntarily agrees to participate by giving written informed consent
Male or non-pregnant, non-lactating female diagnosed with T1D for at least 24 months prior to Screening.
Aged 18 to 64 years of age, inclusive
On a stable insulin regimen for 21 days prior to Screening (no greater than ± 20% variability in total daily dose)
Have a plasma C-peptide level < 0.6 ng/mL at Screening
Have an HbA1c < 10% at Screening
Body mass index (BMI) in the range of ≥ 18 to ≤ 35 kg/m2 at Screening
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.
Fasting Serum triglyceride concentration < 200 mg/dL

Exclusion Criteria

Currently being treated with pramlintide or has discontinued pramlintide within 21 days of Screening
Currently using an insulin pump
Has renal insufficiency (serum creatinine <3.0 mg/dL) or end-stage renal disease requiring renal replacement therapy
Has hepatic disease, including serum ALT or AST ≥3 times the upper limit of normal (ULN)
Has hepatic synthetic insufficiency (serum albumin <3.0 g/dL)
Has a hematocrit value that is exclusionary: Female <35.5% and Male <38.3%
Has a hemoglobin value that is exclusionary: Female <11.5 g/dL and Male <12.5 g/dL
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)
Has clinically significant ECG abnormalities at Screening
Has congestive heart failure, NYHA Class III or IV
Has history of myocardial infarction, unstable angina, or revascularization within 6 months prior to Screening
Has history of a cerebrovascular accident in 6 months prior to Screening with major neurological deficits
Has active malignancy within 5 years prior to Screening (exception: basal cell or squamous cell skin cancers)
Has had major surgical operation within 60 days prior to Screening or planned surgical operation during the study
Has a seizure disorder (other than with suspected or documented hypoglycemia)
Has a current bleeding disorder, treatment with anticoagulants, or platelet count <50 ×10^9/L
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
Has a history of positive test result for hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV)
Has a concurrent illness not controlled by a stable therapeutic regimen
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.
Has active substance or alcohol abuse (>21 drinks/week for males or >14 drinks/week for females)
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
There is any reason the investigator deems exclusionary
Has donated blood within 8 weeks prior to Screening.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Regular Insulin to PRAM9 to Regular Insulin+pramlintide	Regular Insulin	Regular Insulin (Humulin®) to Xeris pramlintide + insulin co-formulation (PRAM9) to Regular Insulin+pramlintide (Symlin® pen) as separate SC injections to Regular Insulin
Regular Insulin+pramlintide to Regular Insulin to PRAM9	PRAM9	Regular Insulin (Humulin®)+pramlintide (Symlin® pen) as separate SC injections to Xeris pramlintide + insulin co-formulation (PRAM9) to Regular Insulin to Xeris pramlintide + insulin co-formulation (PRAM9)
PRAM9 to Regular Insulin+pramlintide to Regular Insulin	PRAM9	Xeris pramlintide + insulin co-formulation (PRAM9) to Regular Insulin (Humulin®)+pramlintide (Symlin® pen) as separate SC injections to Regular Insulin
PRAM9 to Regular Insulin to Regular Insulin+pramlintide	PRAM9	Xeris pramlintide + insulin co-formulation (PRAM9) to Regular Insulin (Humulin®) to Regular Insulin+pramlintide (Symlin® pen) as separate SC injections
PRAM9 to Regular Insulin to Regular Insulin+pramlintide	Regular Insulin	Xeris pramlintide + insulin co-formulation (PRAM9) to Regular Insulin (Humulin®) to Regular Insulin+pramlintide (Symlin® pen) as separate SC injections
Regular Insulin+pramlintide to PRAM9 to Regular Insulin	Regular Insulin	Regular Insulin (Humulin®)+pramlintide (Symlin® pen) as separate SC injections to Xeris pramlintide + insulin co-formulation (PRAM9) to Regular Insulin
PRAM9 to Regular Insulin+pramlintide to Regular Insulin	Regular Insulin	Xeris pramlintide + insulin co-formulation (PRAM9) to Regular Insulin (Humulin®)+pramlintide (Symlin® pen) as separate SC injections to Regular Insulin
Regular Insulin to Regular Insulin+pramlintide to PRAM9	Regular Insulin + Pramlintide	Regular Insulin (Humulin®) to Regular Insulin+pamlintide (Symlin® pen) as separate SC injections to PRAM9
Regular Insulin to Regular Insulin+pramlintide to PRAM9	Regular Insulin	Regular Insulin (Humulin®) to Regular Insulin+pamlintide (Symlin® pen) as separate SC injections to PRAM9
PRAM9 to Regular Insulin to Regular Insulin+pramlintide	Regular Insulin + Pramlintide	Xeris pramlintide + insulin co-formulation (PRAM9) to Regular Insulin (Humulin®) to Regular Insulin+pramlintide (Symlin® pen) as separate SC injections
Regular Insulin+pramlintide to PRAM9 to Regular Insulin	Regular Insulin + Pramlintide	Regular Insulin (Humulin®)+pramlintide (Symlin® pen) as separate SC injections to Xeris pramlintide + insulin co-formulation (PRAM9) to Regular Insulin
Regular Insulin to PRAM9 to Regular Insulin+pramlintide	Regular Insulin + Pramlintide	Regular Insulin (Humulin®) to Xeris pramlintide + insulin co-formulation (PRAM9) to Regular Insulin+pramlintide (Symlin® pen) as separate SC injections to Regular Insulin
Regular Insulin+pramlintide to Regular Insulin to PRAM9	Regular Insulin	Regular Insulin (Humulin®)+pramlintide (Symlin® pen) as separate SC injections to Xeris pramlintide + insulin co-formulation (PRAM9) to Regular Insulin to Xeris pramlintide + insulin co-formulation (PRAM9)
PRAM9 to Regular Insulin+pramlintide to Regular Insulin	Regular Insulin + Pramlintide	Xeris pramlintide + insulin co-formulation (PRAM9) to Regular Insulin (Humulin®)+pramlintide (Symlin® pen) as separate SC injections to Regular Insulin
Regular Insulin+pramlintide to Regular Insulin to PRAM9	Regular Insulin + Pramlintide	Regular Insulin (Humulin®)+pramlintide (Symlin® pen) as separate SC injections to Xeris pramlintide + insulin co-formulation (PRAM9) to Regular Insulin to Xeris pramlintide + insulin co-formulation (PRAM9)
Regular Insulin to Regular Insulin+pramlintide to PRAM9	PRAM9	Regular Insulin (Humulin®) to Regular Insulin+pamlintide (Symlin® pen) as separate SC injections to PRAM9
Regular Insulin to PRAM9 to Regular Insulin+pramlintide	PRAM9	Regular Insulin (Humulin®) to Xeris pramlintide + insulin co-formulation (PRAM9) to Regular Insulin+pramlintide (Symlin® pen) as separate SC injections to Regular Insulin
Regular Insulin+pramlintide to PRAM9 to Regular Insulin	PRAM9	Regular Insulin (Humulin®)+pramlintide (Symlin® pen) as separate SC injections to Xeris pramlintide + insulin co-formulation (PRAM9) to Regular Insulin

Primary Outcome Measures

Name	Time	Method
Area Under the Curve 0-180 Minutes for Plasma Glucose >180 mg/dL	0-180 minutes following administration of study drug	The PD effects on plasma glucose levels were compared among the treatment arms as defined by AUC0-180 (mg/dL \* minutes) for plasma glucose \>180 mg/dL

Secondary Outcome Measures

Name	Time	Method
Plasma Glucose Cmax	Up to 360 minutes following administration of study drug	The maximum measured glucose concentrations over the time span.
Insulin Tmax	Up to 360 minutes following administration of study drug	The time to maximum measured insulin concentrations.
Plasma Glucose Tmax	Up to 360 minutes following administration of study drug	The time to maximum measured glucose concentrations.
Pramlintide Tmax	Up to 360 minutes following administration of study drug	The time to maximum measured pramlintide concentrations.
Mean Proportional Time for Plasma Glucose Levels	Up to 360 minutes following administration of study drug	The mean proportional times were evaluated for the following Plasma Glucose Levels: \>180 mg/dL, \>250 mg/dL, \<54 mg/dL, and \<70 The mean proportional times evaluated for each Plasma Glucose Level were during the following post-study drug injection periods: 0 to 90 minutes, 0 to 180 minutes, 0 to 360 minutes
Area Under the Concentration (AUC) Curve for Plasma Glucose	Up to 360 minutes following administration of study drug	AUC0-t (mg/dL\*minutes) for plasma glucose X mg/dL, in which X = (\>180 mg/dL, \>250 mg/dL) and t = 90, 180, and 360 minutes
Pramlintide Cmax	Up to 360 minutes following administration of study drug	The maximum measured pramlintide concentrations (arithmetic mean).
Insulin Cmax	Up to 360 minutes following administration of study drug	The maximum measured insulin concentrations (arithmetic mean)
Insulin Area Under the Concentration (AUC) Curve	Up to 360 minutes following administration of study drug	The insulin area under the concentration time curve after study drug administration.
Mean Proportional Time After Glucose Challenge for Plasma Glucose Levels Between 126 to 180 mg/dL	During 40 to 180 minutes post-injection of study drug	The mean proportional times to plasma glucose levels between 126 to 180 mg/dL following a glucose challenge administered 30 minutes post study drug administration.
Area Over the Concentration (AOC) Curve for Plasma Glucose	Up to 360 minutes following administration of study drug	AOC0-t (mg/dL\*minutes) for plasma glucose X mg/dL, in which X = \<54 mg/dL and \<70 mg/dL and t = 90, 180, and 360 minutes
Pramlintide Area Under the Concentration (AUC) Curve	Up to 360 minutes following administration of study drug	The pramlintide area under the concentration time curve after study drug administration (arithmetic mean).