Clinical trial NCT02470637: Single Dose Clamp Study to Evaluate Concentration-time Profile and Metabolic Activity of 3 Dose Levels of Afrezza and 3 Dose Levels of Insulin Lispro in Patients With Type 1 Diabetes Mellitus
Official title: A Randomized, Controlled, 6-treatment, 6-sequence, 6-period Cross-over Dose Response Study of 3 Single Doses of Afrezza Inhaled Technosphere Insulin and of 3 Single Doses of SC Insulin Lispro in Patients With Diabetes Mellitus Type 1 Using the Euglycemic Clamp Technique
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Type 1 Diabetes Mellitus
Lead sponsor: Mannkind Corporation
Sponsor class: INDUSTRY
First posted: 2015-06-12
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: Primary Objective:

To assess the dose-response pattern of the glucose consumption (GIR-AUC0-end) of 3 different single doses of Afrezza inhaled Technosphere insulin and of 3 single doses of subcutaneous (SC) insulin lispro in a euglycemic clamp setting.

Secondary Objectives:

To assess the dose proportionality of insulin exposure (INS-AUClast) of 3 different single doses of Afrezza inhaled Technosphere insulin and of 3 single doses of SC insulin lispro in a euglycemic clamp setting.

To assess the pharmacodynamic (PD) characteristics of 3 different single doses of Afrezza inhaled Technosphere insulin and of 3 single doses of SC insulin lispro in a euglycemic clamp setting.

To assess the pharmacokinetic (PK) characteristics of 3 different single doses of Afrezza inhaled Technosphere insulin and of 3 single doses of SC insulin lispro in a euglycemic clamp setting.

To assess the safety and tolerability of 3 different single doses of Afrezza inhaled Technosphere insulin.

Detailed description: The total study duration for one patient is approximately 6.7 to 22.7 weeks (minimum to maximum duration, excluding screening). The duration of the study includes a screening period of 3 to 28 days (D -28 to D -3), 6 treatment periods of 1 or 2 days each (1 overnight stay), a washout period of 7 to 28 days (preferentially 7 days between consecutive dosing), and an end-of-study visit of 7 to 14 days after the last study drug administration.

Eligibility criteria: Inclusion criteria :

* Male or female patients, between 18 and 65 years of age, inclusive, with diabetes mellitus type 1 for more than one year, as defined by the American Diabetes Association.
* Total insulin dose of \<1.0 U/kg/day.
* Body weight between 50.0 and 95 kg, inclusive, body mass index between 18.5 and 29 kg/m², inclusive.
* Fasting serum C-peptide \<0.3 nmol/L.
* Glycohemoglobin (HbA1c) ≤75 mmol/mol (≤9%).
* Stable insulin regimen for at least 2 months prior to study (with respect to safety of the patient and scientific integrity of the study).
* Certified as otherwise healthy for type 1 diabetes mellitus patient by assessment of medical history and physical examination (cardiovascular system, chest and lungs, thyroid, abdomen, nervous system, skin and mucosae, and musculoskeletal system), unless the Investigator considers any abnormality to be clinically irrelevant and not interfering with the conduct of the study (with respect to safety of the subject and scientific integrity of the study).
* Having given written informed consent prior to undertaking any study-related procedure.
* Non-smoking at least for the last 6 months before screening (to be confirmed by urine cotinine \<500 µg/L).
* Pulmonary function test at screening: forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) \>70% of the individual prediction according to the equation of the Third National Health and Nutrition Examination Survey (NHANES III).

Exclusion criteria:

* Severe hypoglycemia resulting in coma/seizures or requiring assistance of another person, and/or hospitalization for diabetic ketoacidosis in the last 6 months before screening visit.
* Frequent severe headaches and/or migraine, recurrent nausea and/or vomiting (more than twice a month).
* Presence or history of drug hypersensitivity, or allergic disease diagnosed and treated by a physician.
* History or presence of drug or alcohol abuse (alcohol consumption more than 40 g per day).
* If female, pregnancy (defined as positive beta-human chorionic gonadotropin \[β-hCG\] blood test), breastfeeding at screening and before any treatment periods (defined as positive β-hCG urine test).
* Any medication (including St John's Wort) within 14 days before inclusion or within 5 times the elimination half-life or PD half-life of the medication, with the exception of insulins, thyroid hormones, lipid-lowering, and antihypertensive drugs and if female with the exception of hormonal contraception or menopausal hormone replacement therapy; any vaccination within 28 days before inclusion.
* Presence or history of any acute or chronic obstructive bronchopulmonary disease including chronic obstructive pulmonary disease, asthma, and cancer.
* Upper respiratory tract infection within 8 weeks before screening.
* Known hypersensitivity to insulin lispro or Afrezza Technosphere insulin and excipients.
* Inability, in the opinion of the Principal Investigator or a designee, to adequately inhale Afrezza powder.
* Any history or presence of deep leg vein thrombosis or a frequent appearance of deep leg vein thrombosis in first-degree relatives (parents, siblings, or children).
* The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Primary outcomes:
measure: Assessment of PD parameter: Area under the glucose infusion rate curve within 24 hours after administration of the investigational medicinal product or until administration of rescue insulin (GIR-AUC0-end)
timeFrame: 24 hours
Secondary outcomes:
measure: Assessment of PD parameters: Maximum smoothed glucose infusion rate (GIRmax)
timeFrame: 24 hours
measure: Assessment of PD parameters: Time to GIRmax (GIR-Tmax)
timeFrame: 24 hours
measure: Duration of blood glucose control (time to elevation of smoothed blood glucose profile above different prespecified clamp levels)
timeFrame: 24 hours
measure: Assessment of PK parameters: Area under the baseline-corrected serum insulin concentration-time curve over 24 hours or until administration of rescue insulin (INS-AUClast)
timeFrame: 24 hours
measure: Assessment of PK parameters: Baseline-corrected maximum serum concentration (INS-Cmax)
timeFrame: 24 hours
measure: Assessment of PK parameters: Time to INS-Cmax (INS-Tmax)
timeFrame: 24 hours
measure: Assessment of PK parameters: Area under the concentration-time curve (INS-AUClast)
timeFrame: 24 hours
measure: Number of patients with adverse events
timeFrame: Up to 2 days
Other outcomes:
Locations:
city: Neuss
country: Germany
facility: Investigational Site Number 276001
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: Grant M, Heise T, Baughman R. Comparison of Pharmacokinetics and Pharmacodynamics of Inhaled Technosphere Insulin and Subcutaneous Insulin Lispro in the Treatment of Type 1 Diabetes Mellitus. Clin Pharmacokinet. 2022 Mar;61(3):413-422. doi: 10.1007/s40262-021-01084-0. Epub 2021 Nov 13.