Clinical trial NCT04141423: Evaluation of Pharmacokinetics , Safety, Tolerability and Pharmacodynamics of Biocon Insulin Tregopil
Official title: An Open Label, Multiple Ascending Dose Trial in Patients With T1DM to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Insulin Tregopil and to Evaluate the Postprandial Glucose Control With Different Meal Types in Comparison With Insulin Aspart
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Type 1 Diabetes Mellitus (T1DM)
Keywords: Oral Insulin
Lead sponsor: Biocon Limited
Sponsor class: INDUSTRY
Collaborators: name: Profil Institut für Stoffwechselforschung GmbH
name: Juvenile Diabetes Research Foundation
First posted: 2019-10-28
Enrollment: 55
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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

Detailed description: 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

Primary outcomes:
measure: Adverse events (AEs)
timeFrame: Between screening (up to Day -21) and End of study ( up to Day 6)
measure: Laboratory safety parameters
timeFrame: Between screening (up to Day -21) and End of study ( up to Day 6)
measure: Physical examination
timeFrame: Between screening (up to Day -21) and End of study ( up to Day 6)
measure: Vital signs, clinically
timeFrame: Between screening (up to Day -21) and End of study ( up to Day 6)
measure: Hypoglycaemic events
timeFrame: Between screening (up to Day -21) and End of study ( up to Day 6)
measure: Hyperglycaemia events
timeFrame: Between screening (up to Day -21) and End of study ( up to Day 6)
measure: Electrocardiograms
timeFrame: Between screening (up to Day -21) and End of Treatment ( up to Day 6)
measure: Adverse events (AEs)
timeFrame: Day of screening to Day 20 (Diary) and During follow up Via (Telephone)
measure: Hypoglycaemic events
timeFrame: Day of screening to Day 20 (Diary) and During follow up Via (Telephone)
measure: Hyperglycaemia events
timeFrame: Day of Run-in to Day 20 (Diary) and During follow up Via (Telephone)
measure: Laboratory safety parameters
timeFrame: Day of screening and Day 20
measure: Physical examination
timeFrame: Day of screening, Dosing day 1 and Day 20
measure: Vital signs
timeFrame: Day of screening, Day1-6 and Day 20)
measure: Electrocardiograms
timeFrame: Day of screening and Day 20
measure: Anti-insulin Tregopil antibodies
timeFrame: Day -1 and Day 20
Secondary outcomes:
measure: Pharmacokinetics (PK) endpoint-Area under the insulin concentration curve(AUCins).
timeFrame: 0 to 1 hour
measure: PK endpoint-Area under the insulin concentration curve(AUCins).
timeFrame: 0 to 2 hour
measure: PK endpoint-Area under the insulin concentration curve(AUCins).
timeFrame: 0 to 3 hour
measure: PK endpoint-Area under the insulin concentration curve(AUCins).
timeFrame: 0 to 4 hour
measure: PK endpoint-Area under the insulin concentration curve(AUCins).
timeFrame: Time zero to the last measurable concentration (6 hours)
measure: PK endpoint-Area under the insulin concentration curve(AUCins).
timeFrame: Day 1, Day 2, Day 6
measure: PK endpoint-time to maximum observed insulin concentration (tmax)
timeFrame: Day 1, Day 2, Day 6
measure: PK endpoint-terminal elimination half-life calculated
timeFrame: Day 1, Day 2, Day 6
measure: PK endpoint-Area under the insulin concentration curve in the intended dosing interval (AUCins)
timeFrame: Day 1, Day 2, Day 6
measure: PK endpoint-Insulin concentration at the end of treatment (Ctrough)
timeFrame: Day 1, Day 2, Day 6
measure: PK endpoint-Insulin concentration in plasma, tlag (lag time)
timeFrame: Day 1, Day 2, Day 6
measure: pharmacodynamics (PD) Endpoints-Area under the plasma glucose concentration excursion from baseline (pre-meal) in the indicated time intervals on Day 1, 2 and 6 mixed meal tests
timeFrame: 0-1 hour
measure: PD Endpoints-Area under the plasma glucose concentration excursion from baseline (pre-meal) in the indicated time intervals
timeFrame: 0-2 hour
measure: PD Endpoints-Area under the plasma glucose concentration excursion from baseline (pre-meal) in the indicated time intervals
timeFrame: 0-3 hour
measure: PD Endpoints-Area under the plasma glucose concentration excursion from baseline (pre-meal) in the indicated time intervals
timeFrame: -10 min-6 hour
measure: PD Endpoints-Area under the plasma glucose concentration excursion from baseline (pre-meal) in the indicated time intervals
timeFrame: 0-6 hour
measure: PD Endpoints-Area under the plasma glucose concentration curve in the indicated time intervals
timeFrame: 0-1 hour
measure: PD Endpoints-Area under the plasma glucose concentration curve in the indicated time intervals
timeFrame: 0-2 hour
measure: PD Endpoints-Area under the plasma glucose concentration curve in the indicated time intervals
timeFrame: 0-3 hour
measure: PD Endpoints-Area under the plasma glucose concentration curve in the indicated time intervals
timeFrame: 0-4 hour
measure: PD Endpoints-Area under the plasma glucose concentration curve in the indicated time intervals
timeFrame: 0-6 hour
measure: PD Endpoints-minimum plasma glucose concentration in the indicated time intervals
timeFrame: 0-1 hour
measure: PD Endpoints-minimum plasma glucose concentration in the indicated time intervals
timeFrame: 0-2 hour
measure: PD Endpoints-minimum plasma glucose concentration in the indicated time intervals
timeFrame: 0-3 hour
measure: PD Endpoints-minimum plasma glucose concentration in the indicated time intervals
timeFrame: 0-4 hour
measure: PD Endpoints-minimum plasma glucose concentration in the indicated time intervals
timeFrame: 0-6 hour
measure: PD Endpoints-maximal plasma glucose concentration in the indicated time intervals
timeFrame: 0-2 hour
measure: PD Endpoints-maximal plasma glucose concentration in the indicated time intervals
timeFrame: 0-4 hour
measure: PD Endpoints-maximal plasma glucose concentration in the indicated time intervals
timeFrame: 0-6 hour
measure: PD Endpoints-maximal plasma glucose observed sampling period
timeFrame: -10 min-6 hour
measure: PD Endpoints- ΔGmin minimum postprandial plasma glucose increment, absolute and percent
timeFrame: 0-6 hour
measure: PD Endpoints- time to onset of action; time to decrease in PG of 5 mg/dL from baseline
timeFrame: 0 hour
measure: Duration of action;
timeFrame: 0- 6 hour
measure: Continuous glucose monitoring (CGM) profile
timeFrame: 6 days
measure: PK Endpoints- Maximum concentration recorded ( Day 1, 2,3,4,5,6,20)
timeFrame: 0-4 hours
measure: PK Endpoints-Area under the insulin concentration curve ( Day 1, 2,3,4,5,6,20)
timeFrame: 0-1 hours
measure: PK Endpoints-Area under the insulin concentration curve ( Day 1, 2,3,4,5,6,20)
timeFrame: 0-2 hours
measure: PK Endpoints-Area under the insulin concentration curve ( Day 1, 2,3,4,5,6,20)
timeFrame: 0-4 hours
measure: PK Endpoints-Area under the insulin concentration curve ( Day 1, 2,3,4,5,6,20)
timeFrame: 0-6 hours
measure: PK Endpoints-Area under the insulin concentration curve ( Day 1, 2,3,4,5,6,20)
timeFrame: 0-last
measure: PK Endpoints-Area under the insulin concentration curve ( Day 1, 2,3,4,5,6,20)
timeFrame: 0-∞
measure: PK Endpoints- terminal elimination half-life calculated ( Day 1, 2,3,4,5,6,20)
timeFrame: Day 1, Day 2,Day 3,Day 4, Day5, Day 6, Day 20
measure: PK endpoint-time to maximum observed insulin concentration (tmax) ( Day 1, 2,3,4,5,6,20)
timeFrame: Day 1, Day 2,Day 3,Day 4, Day5, Day 6, Day 20
measure: PK Endpoints-Area under the insulin concentration curve ( Day 1, 2,3,4,5,6, 20)
timeFrame: Day 1, Day 2,Day 3,Day 4, Day5, Day 6, Day 20
measure: PK endpoint-Insulin concentration at the end of treatment ( Day 1, 2,3,4,5,6, 20)
timeFrame: Day 1, Day 2,Day 3,Day 4, Day5, Day 6, Day 20
measure: PD Endpoints-Area under the plasma glucose concentration excursion from baseline (pre-meal) in the indicated time intervals ( Day 1, 2,3,4,5,6, 20)
timeFrame: 0-1 hours
measure: PD Endpoints-Area under the plasma glucose concentration excursion from baseline (pre-meal) in the indicated time intervals ( Day 1, 2,3,4,5,6, 20)
timeFrame: 0-2 hours
measure: PD Endpoints-Area under the plasma glucose concentration excursion from baseline (pre-meal) in the indicated time intervals ( Day 1, 2,3,4,5,6, 20)
timeFrame: 0-3 hours
measure: PD Endpoints-Area under the plasma glucose concentration excursion from baseline (pre-meal) in the indicated time intervals ( Day 1, 2,3,4,5,6, 20)
timeFrame: 0-4 hours
measure: PD Endpoints-Area under the plasma glucose concentration excursion from baseline (pre-meal) in the indicated time intervals ( Day 1, 2,3,4,5,6,20)
timeFrame: 0-6 hours
measure: PD Endpoints-Area under the plasma glucose concentration excursion from baseline (pre-meal) in the indicated time intervals ( Day 1, 2,3,4,5,6, 20)
timeFrame: 0-1 hours
measure: PD Endpoints-Area under the plasma glucose concentration excursion from baseline (pre-meal) in the indicated time intervals ( Day 1, 2,3,4,5,6, 20)
timeFrame: 0-3 hours
measure: PD Endpoints-Area under the plasma glucose concentration excursion from baseline (pre-meal) in the indicated time intervals ( Day 1, 2,3,4,5,6, 20)
timeFrame: 0-4 hours
measure: PD Endpoints-minimum plasma glucose concentration in the indicated time intervals ( Day 1, 2,3,4,5,6, 20)
timeFrame: 0-1 hours
measure: PD Endpoints-minimum plasma glucose concentration in the indicated time intervals ( Day 1, 2,3,4,5,6,20)
timeFrame: 0-3 hours
measure: PD Endpoints-minimum plasma glucose concentration in the indicated time intervals ( Day 1, 2,3,4,5,6, 20)
timeFrame: 0-4 hours
measure: PD Endpoints-maximal plasma glucose concentration in the indicated time intervals ( Day 1, 2,3,4,5,6, 20)
timeFrame: 0-4 hours
measure: PD Endpoints -minimal PG concentration in observed sampling period ( Day 1, 2,3,4,5,6, 20)
timeFrame: 0 - 6 hours
measure: PD Endpoints - maximal PG concentration in observed sampling period ( Day 1, 2,3,4,5,6, 20)
timeFrame: 0 - 6 hours
measure: PD Endpoints - CGM profile
timeFrame: Day 1 to 20
Other outcomes:
Locations:
city: Mainz
country: Germany
facility: Profil Mainz GmbH & Co. KG Malakoff-Passage,Rheinstraße 4C D-55116
Study officials:
affiliation: Profil Institut für Stoffwechselforschung GmbH Hellersbergstraße 9 (Acting as Coordinating Investigator)
name: Ulrike Hövelmann, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Profil Institut für Stoffwechselforschung GmbH Hellersbergstraße 9
name: Leona Plum Mörschel, MD
role: PRINCIPAL_INVESTIGATOR
References: