Multi-Center, double blind, active comparator controlled multiple dose safety, tolerability and efficacy study

This is a double blind, active comparator controlled multiple dose safety, tolerability and efficacy study comparing HDV insulin lispro with insulin lispro in 40 Type 1 Diabetes Mellitus Subjects with Good Glycemic Control, with specific focus on time in range (70-180 mg/dL). Subjects will be screened and then monitored with one week of baseline CGM. They will then be randomized to one of two treatment groups: (A) six weeks of treatment with HDV-lispro (B) six weeks of treatment with insulin lispro diluted with sterile water alone.

All subjects will use insulin glargine or insulin degludec for basal insulin coverage throughout the trial. Fasting glucose goals will be 70-120 mg/dL, with recommendations for dosage adjustments made twice weekly according to a simple dosing algorithm based on mean fasting glucose values during the previous 3-4 days.

Subjects will receive standard diabetes education refresher training at the beginning of the trial, including review of insulin dose administration and titration, carbohydrate counting (or other dietary planning as deemed appropriate by the investigator), avoidance of hypoglycemia, and management of exercise and stress.

Post meal (60-90 min after start of meal) goals will be <140 mg/dL. A test meal study (standardized liquid test meal) to be conducted at the beginning of treatment (baseline study) and at the end of the six week treatment period (treatment comparison study). Subjects will also perform blinded continuous glucose monitoring during 4 weeks of study (i.e weeks 1,3,5 and 7 of study)

Throughout study, subjects will be asked to perform frequent self-monitoring of blood glucose (SMBG), at least 6 times per day (before and 60-90 minutes after each meal) during 3 or more days of each week. This will serve as data for therapeutic decision-making as well as for data collection.

Inclusion Criteria:

1. Male or female of age 18 to 65 years, inclusive. Females of child-bearing potential must use a standard and effective means of birth control for the duration of the study
2. T1DM ≥12 months
3. C-peptide <0.6 ng/mL (single retest allowed)
4. Treatment with rapid analog insulin for the previous 6 months and willing to use insulin vial and syringe to deliver rapid acting insulin during the study
5. Currently using either insulin glargine (U100 only) or insulin degludec for basal insulin therapy for at least 4 weeks prior to study
6. Not using insulin pump delivery systems during the previous 3 months
7. Familiarity with continuous glucose monitoring (CGM) technology; subjects need to be not currently using CGM; subjects will NOT use unblinded CGM during the treatment period of the trial
8. Willingness to use insulin lispro as the analog bolus insulin during the study period
9. BMI ≥18.0 kg/m2 and ≤35.0 kg/m2
10. 6.9%≤A1C≤7.9% (single retest allowed)

Exclusion Criteria:

1. Known or suspected allergy to any component of any of the study drugs in this trial.
2. A patient who has unstable proliferative retinopathy or maculopathy, and/or severe neuropathy, in particular autonomic neuropathy, as judged by the Investigator
3. As judged by the investigator, clinically significant active disease of the gastrointestinal, cardiovascular (including a history of arrhythmia or conduction delays on ECG), hepatic, neurological, renal, genitourinary, or hematological systems, or uncontrolled hypertension (diastolic blood pressure ≥ 100 mmHg and/or systolic blood pressure ≥ 160 mmHg after 5 minutes in the supine position).
4. History of any illness or disease that in the opinion of the Investigator might confound the results of the trial or pose additional risk in administering the study drugs to the patient.
5. As judged by the Investigator, clinically significant findings in routine laboratory data
6. Use of drugs that may interfere with the interpretation of trial results or are known to cause clinically relevant interference with insulin action, glucose utilization, or recovery from hypoglycemia
7. Use of oral anti-diabetic or non-insulin anti-diabetic injection therapies (e.g. SGLT-2 inhibitors, pramlintide, GLP-1 agonists, etc.) during the 4 weeks prior to randomization
8. Current smokers; if a former smoker, no tobacco products (inhaled, oral or buccal) for the previous 3 months
9. Use of e-cigarettes or other nicotine-containing products for the previous 3 months
10. Current addiction to alcohol or substances of abuse as determined by the Investigator.
11. Pregnancy, breast-feeding, the intention of becoming pregnant, or not using adequate contraceptive measures (adequate contraceptive measures consist of sterilization, intra-uterine device [IUD], oral or injectable contraceptives, barrier methods or abstinence as per investigator discretion).
12. Mental incapacity, unwillingness, or language barriers precluding adequate understanding or cooperation in this study
13. Symptomatic gastroparesis.
14. Receipt of any investigational drug within 4 weeks of Visit 2 in this study
15. Any condition (intrinsic or extrinsic) that in the judgment of the Investigator will interfere with trial participation or evaluation of data

Not planned

All subjects, investigators, monitors, sponsor and sponsor representatives are blinded to the treatment group and treatment to patients are randomized. The group randomizing the subjects, the pharmacist preparing the drug, the party shipping the drug are unblinded but do not have contact with the blinded parties. An unblinded monitor will monitor any activities performed by unblinded parties.