Evaluation of Pharmacokinetics , Safety, Tolerability and Pharmacodynamics of Biocon Insulin Tregopil

Multi-centre, open label, multiple ascending dose trial in patients with type 1 diabetes mellitus

This is a Phase 1, open-label, multiple dose trial with two parts in patients with type 1 diabetes mellitus (T1DM). Part 1 consists of four cohorts with multiple ascending doses of insulin Tregopil and comprises a sentinel dosing design. Part 2 consists of a randomised, 2-treatment, crossover design with mixed meal tests (MMTs) of different compositions followed by parallel design titrated treatment period. Both parts include dosing during an in-house period and during a subsequent outpatient period.

Eligibility Criteria:
Inclusion Criteria (key criteria):

1. Male or female patient with diabetes mellitus type 1 on insulin therapy for at least 1 year before screening
2. Age between 18 and 64 years, both inclusive.
3. Body Mass Index (BMI) between 18.5 and 29.0 kg/m2, both inclusive.
4. Body weight between 60 kg and 100 kg, both inclusive and a stable weight +/- 5% for at least 3 months prior to screening (evaluated by patient history or medical history documents).
5. Beta-N-1-deoxy fructosyl haemoglobin (HbA1c) between 6.5 to 9%, both inclusive.
6. Total insulin dose of \< 1.2 (I)U/kg/day.
7. Daily dose of prandial insulin analogues or regular human insulin not exceeding 70% of total daily insulin dose at screening.
8. Fasting C-peptide \<= 0.20 nmol/L.
9. Daily dose of prandial insulin analogues or regular human insulin of at least 21 (I)U per day at screening.
10. Stable basal-bolus insulin regimen for at least 3 months prior to screening (stable as per Investigator's discretion).
11. Patients with experience in insulin titration and self-treatment of hypoglycemic events.
12. Considered generally healthy (apart from conditions associated with T1DM) upon completion of medical history and screening safety assessments including safety lab results, as judged by the Investigator.

Exclusion Criteria(key criteria):

1. Use of continuous subcutaneous insulin infusion (CSII) in the last 3 months prior to screening.
2. History of multiple and/or severe allergies to drugs or foods or a history of severe anaphylactic reaction.
3. History of autoimmune disorders other than T1DM as judged clinically relevant by the Investigator (obtained by patient history), except a stable thyroid disorder treated with a stable dose of thyroxin.
4. Hospitalization for diabetic ketoacidosis during the previous 6 months.
5. More than one episode of severe hypoglycemia (as per American Diabetes Association classification) with seizure, coma or requiring assistance of another person during the past 6 months.
6. Hypoglycemic unawareness (defined as individuals with a score of 3 or more \[reduced awareness and intermediate awareness\] as assessed by the Clarke score).
7. Presence of clinically significant acute gastrointestinal (GI) symptoms (e.g. nausea, vomiting, heartburn or diarrhea) within 2 weeks prior to dosing, as judged by the investigator.
8. Presence of chronic GI disorders or conditions known to significantly alter the absorption of orally administered drugs or significantly alter upper GI or pancreatic function, as judged by the Investigator.
9. Patient with previous gastrointestinal surgery, except patients that underwent uncomplicated surgical procedures such as appendectomy, hernia surgery, biopsies, as wells as colonic- and gastric endoscopy.
10. Treatment with glucagon-like peptide 1 (GLP-1) receptor agonists within the last 12 weeks prior to screening visit.
11. The use of any prescribed medication that would interfere with trial endpoints or the safe completion of the trial procedures like e.g. warfarin, indomethacin or systemic non-selective ß-blocker, as judged by the investigator.
12. Any clinically significant abnormality in ECG or safety laboratory tests (liver function, renal function, hematology, urinalysis or any other laboratory result judged as clinically relevant by the investigator) at screening.
13. Clinically significant cardiovascular and/or cerebrovascular disease within 12 months before Screening, as judged by the Investigator.
14. Active proliferative retinopathy as confirmed by ophthalmoscopy / retinal photography examination performed (by a qualified person as per local legislation) within 6 months prior to screening.
15. Renal impairment with estimated Glomerular Filtration Rate (eGFR) \< 60 mL

    * min/1.73m2 as defined by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI).
16. History of severe form of neuropathy or clinically significant cardiac autonomic neuropathy (CAN).
17. Patients who needed systemic (oral, intravenous, intramuscular) glucocorticoid therapy within 4 weeks prior to the screening visit OR expected of requiring during the study period.
18. Patients who have undergone pancreatectomy or pancreas/islet cell transplant or had any significant pancreatic disease that affects safety of the patient.
19. Inability or unwillingness to refrain from smoking and use of nicotine substitute products one day before and during the study.
20. Patients refusing/not capable to consume three major meals per day on routine basis.
21. If female, pregnancy or breast-feeding.
22. Women of childbearing potential who are not using a highly effective contraceptive method.
23. Men with non-pregnant partner(s) of childbearing potential not willing to use male contraception (condom) in addition to a highly effective contraceptive method until one month after last dosing.
24. Men of childbearing potential not willing to refrain from sperm donation for the duration of the study and for one month following last dose of study drug.
25. Men with pregnant partner not willing to use male contraception (condom) until one month after last dosing, in order to avoid exposure of the embryo/foetus to seminal fluid.
26. Patients unwilling to avoid heavy machinery work, driving within specified post dose interval during the study treatment period