Effect of Dosing Time and Meal on IN-105 (Insulin Tregopil) PK and PD

Study Overview
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Brief Summary
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A study to evaluate the PK and PD of oral IN-105 (Insulin Tregopil) w.r.t. time of dosing prior to meal, duration between meals and type of meal .

Detailed Description
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A Phase 1, Randomized, Placebo Controlled, Crossover Trial in Type 2 Diabetes Patients to evaluate the effect of pre-meal dosing time, inter-meal interval and meal composition on the PK and PD of IN-105 (Insulin Tregopil), an oral insulin; conducted in 3 sequential cohorts in an adaptive manner .

Official Title
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To Assess the Pharmacokinetics and Pharmacodynamics of IN-105 in Relation to the Pre-meal Dosing Time, Between-meal Interval and Type of Meal - A Phase 1, Three Cohort, Randomized, Placebo Controlled, Crossover Trial in Type 2 Diabetes Patients

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: IN-105 (Insulin Tregopil)
* Other: Placebo comparator


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient should have an established diagnosis of T2DM per ADA 2013 criteria for at least 1 year prior to screening and are on metformin treatment for at least a month before screening. Body mass index (BMI) of 18.5 to 40.00 kg/m2, both inclusive Glycosylated hemoglobin (HbA1c) ≤ 9.5%. Hemoglobin ≥9.0 g/dL. No clinically significant abnormality in the ECG at screening. Fasting plasma glucose levels less than 140 mg/dL at screening. The patient should be ready to give a written and signed informed consent before starting any protocol-specific procedures. Exclusion Criteria: History of hypersensitivity to insulins or insulin analogues. Evidence of the following (either due to improper diabetes control or due to secondary complications following diabetes). History of ≥2 episodes of severe hypoglycemia within 6 months before screening or history of hypoglycemia unawareness as judged by the investigator. History of ≥1 episodes of hyperglycemic hyperosmolar state or emergency room visits for uncontrolled diabetes leading to hospitalization in the 6 months prior to screening. History of limb amputation as a complication of diabetes during his/her lifetime or any vascular procedure during the 1 year prior to screening. History of diabetic foot or diabetic ulcers in the past 1 year prior to screening. History of severe form of neuropathy or cardiac autonomic neuropathy (determined when obtaining patient history). Presence of any of the following: Serological evidence of human immunodeficiency virus (HIV), hepatitis B (HBsAg) or hepatitis C infection at screening. Any clinically significant abnormality in the safety laboratory tests conducted at screening. Impaired hepatic function at screening [alanine transaminase (ALT) or aspartate aminotransferase (AST) value >2 times the upper limit of the reference range and/or serum bilirubin 1.5 times the upper limit of the reference range] which investigator considers clinically significant. Evidence of clinically significant chronic renal disease (e.g. nephrotic syndrome, diabetic nephropathy) as assessed by the investigator at screening History or use of the following: Patients on OADs other than metformin for previous three months prior to screening. Patients who have received ≥14 consecutive days of oral, intravenous, or inhaled glucocorticoid therapy within the past 1 year or have received steroids by any route within 4 weeks immediately preceding screening visit (intra-nasal, intra ocular, and topical steroid use is allowed). Receipt of another investigational drug in the 4 weeks prior to screening, or within 5 half-lives of the another investigational drug at screening visit (whichever is longer), or scheduled for another investigational drug during the current study period.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: 3 Cohorts Cohort 1: 5 periods, 4 treatments and 5 sequences with a partial replicate crossover design Cohort 2: 6 periods, 6 treatments and 6 sequences in a cross-over design Cohort 3: 6 periods, 6 treatments and 6 sequences in a cross over design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IN-105 (Insulin Tregopil)<br>Cohort1: Treatments A, B, and C: IN-105 administered at 30, 20 or 10 minutes before the ADA meal, respectively; Treatment D: Placebo administered at 20 minutes before the ADA meal. Cohort 2: Treatments A, B, and C: IN-105 administered at 4, 5, and 6 hours after the previous ADA meal, respectively; Treatments D, E, and F: Placebo administered at 4, 5, and 6 hours after the previous ADA meal, respectively. Cohort 3: For the first meal, IN-105 30 mg administered at the optimal pre meal time determined from Cohort 1 with ADA meal (Treatments A and D) or high fat meal (Treatments B and E) or high fiber meal (Treatments C or F). | Drug: IN-105 (Insulin Tregopil)<br>* 15 mg strength tablets for oral use used at a dose of 30 mg<br>|
| Placebo Comparator: Placebo tablet<br>Cohort1: Treatments A, B, and C: IN-105 administered at 30, 20 or 10 minutes before the ADA meal, respectively; Treatment D: Placebo administered at 20 minutes before the ADA meal. Cohort 2: Treatments A, B, and C: IN-105 administered at 4, 5, and 6 hours after the previous ADA meal, respectively; Treatments D, E, and F: Placebo administered at 4, 5, and 6 hours after the previous ADA meal, respectively. Cohort 3: For the first meal, IN-105 30 mg administered at the optimal pre meal time determined from Cohort 1 with ADA meal (Treatments A and D) or high fat meal (Treatments B and E) or high fiber meal (Treatments C or F). | Other: Placebo comparator<br>* Placebo tablet for oral use<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration-time curve (AUC0-last) will be assessed (Cohort 1) | Area under the plasma concentration-time curve (AUC0-last; from dosing time to 180 minutes post meal, extrapolated) after single dose administration in the 30 ,20 and 10 minute pre-meal dosing groups | from dosing time to 180 minutes post meal, extrapolated | 
| The maximum observed plasma drug concentration (Cmax) will be assessed (Cohort 1) | The maximum observed plasma drug concentration after single dose administration (Cmax) | from dosing time to 180 minutes post meal | 
| Glucose AUC0-t will be assessed (Cohort 1) | Glucose AUC0-t [AUC both above and below the baseline values] | from dosing time to 180 minutes post meal | 
| Glucose concentration (Cmin) will be assessed (Cohort 1) | Minimum observed glucose concentration (Cmin) | from dosing time to 180 minutes post meal | 
| Glucose concentration (Tmin) will be assessed (Cohort 1) | Time of minimum observed glucose concentration (Tmin) | from dosing time to 180 minutes post meal | 
| Area under the plasma concentration-time curve (AUC0-last) will be assessed (Cohort 2) | Area under the plasma concentration-time curve (AUC0-last; time of dosing to 180 minutes post dose, extrapolated) after single dose administration in morning and afternoon in the 4, 5 and 6 h inter-meal interval groups. | time of dosing to 180 minutes post dose,extrapolated | 
| The maximum observed plasma drug concentration (Cmax) will be assessed. (Cohort 2) | The maximum observed plasma drug concentration after single dose administration (Cmax) | time of dosing to 180 minutes post dose | 
| Glucose AUC0-t will be assessed (Cohort 2) | Glucose AUC0-t [AUC both above and below the baseline values] | time of dosing to 180 minutes post dose | 
| Glucose concentration (Cmin) will be assessed (Cohort 2) | Minimum observed glucose concentration (Cmin) | time of dosing to 180 minutes post dose | 
| Glucose concentration (Tmin) will be assessed (Cohort 2) | Time of minimum observed glucose concentration (Tmin) | time of dosing to 180 minutes post dose | 
| Area under the plasma concentration-time curve (AUC0-last) will be assessed (Cohort 3) | Area under the plasma concentration-time curve (AUC0-last) for high-fat, high-fibre and ADA meal groups after single dose administration in morning and afternoon | time of dosing to 180 minutes post dose,extrapolated | 
| The maximum observed plasma drug concentration (Cmax) will be assessed (Cohort 3) | The maximum observed plasma drug concentration after single dose administration (Cmax) | time of dosing to 180 minutes post dose | 
| Glucose AUC0-t will be assessed (Cohort 3) | Glucose AUC0-t [AUC both above and below the baseline values] | time of dosing to 180 minutes post dose | 
| Glucose concentration (Cmin) will be assessed. (Cohort 3) | Minimum observed glucose concentration (Cmin) | time of dosing to 180 minutes post dose | 
| Glucose concentration (Tmin) will be assessed. (Cohort 3) | Time of minimum observed glucose concentration (Tmin) | time of dosing to 180 minutes post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | An adverse event is any untoward medical event including hypoglycemia that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. | Through study completion, approximately 3 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dosing time, Oral insulin, Insulin concentration, Prandial insulin, Post Prandial Glucose (PPG)