| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045242 |
| E.1.2 | Term | Type II diabetes mellitus |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The objectives of this trial are to determine the safety and pharmacological response of MKC253 (GLP-1/Technosphere®) Inhalation Powder in adult male and postmenopausal female subjects with type 2 diabetes mellitus.
The primary objective of this trial is to evaluate the effect of MKC253 Inhalation Powder on post-prandial glucose concentrations, expressed as Area Under the Glucose Concentration-Time Curve (AUC), following a standardized meal. |
|
| E.2.2 | Secondary objectives of the trial |
1. Adverse effects on safety variables, including reported adverse events (AE), vital signs, physical examinations, clinical laboratory tests, pulmonary function tests (PFT) and electrocardiograms (ECG);
2. Insulin, C-peptide, glucagon (at limited time points) and GLP-1 concentrations (of active, and at limited time points total GLP-1) and Areas Under the Concentration-Time Curves, as well as the maximum post-prandial glucose, insulin and C-peptide excursions from baseline during the pre-treatment to post-treatment interval for each standardized meal;
3. Time of gastric emptying (T½ and Tlag from the % dose recovered/hour and cumulative % dose curves) as measured by 13C-carbon dioxide clearance when 13C-octanoate is administered with the meal;
4. Additional PK parameters of plasma GLP-1 include: time of maximum (tmax) plasma GLP-1; maximum (Cmax) plasma GLP-1; and plasma GLP-1 half-life (t1/2). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Males and postmenopausal or surgically sterile females ≥ 18 and ≤ 70 years of age with Type 2 Diabetes Mellitus. (Post-menopausal is defined as > 24 months amenorrhea; for subjects with amenorrhea < 5 years menopause should be confirmed by FSH testing).
2. Male subjects, unless surgically sterilized, must be prepared to use effective contraceptive measures to prevent the pregnancy of partner, from screening until 14 days after the end of dosing.
3. Diabetes managed on a stable regimen of diet and exercise within the preceding 8 weeks and/or metformin and/or a sulfonylurea or meglitinide or alpha glucosidase inhibitors, without any dose adjustments within the preceding 8 weeks. For subjects taking both metformin and sulfonylurea, meglitinide, or alpha glucosidase inhibitor, one or both oral agents must be ≤ half the maximal allowable dose as cited in the product label.
4. HbA1c ≥ 6.2% to ≤ 8.5%.
5. Fasting C-peptide ≥ 0.5 ng/mL.
6. On the last 3 days of the washout period (Days -3, -2, and -1) a fasting blood glucose (FBG) by finger stick ≤ 13.5 mmol/L.
7. Body Mass Index (BMI) of ≤ 32 kg/m2.
8. Smoking Status and Urine Cotinine Test:
• Non-smoker (includes cigarettes, cigars and pipe) for ≥ the preceding 6 months;
• Negative urine Cotinine Test, defined as ≤ 100 ng/mL;
9. PFTs:
• Forced Expiratory Volume in 1 second (FEV1)/Forced Vital Capacity (FVC) ≥ Lower
Limit of Normal (LLN) National Health and Nutrition Examination Survey (NHANES) III at Screening;
• FEV1 ≥ 70% of Predicted (NHANES III) at Screening ;
• TLC ≥ 80% predicted (ITS);
• Single-breath carbon monoxide diffusing capacity of the lung (DLCO) (uncorrected)
≥ 70% of Predicted (Miller); and
10. Written Informed Consent. |
|
| E.4 | Principal exclusion criteria |
1. Exposure to any investigational medications or devices within the previous 90 days prior to trial entry or participation in another clinical trial while participating in this trial.
2. Allergy or known hypersensitivity to any of the drugs to be used in the trial or a history of hypersensitivity to TIP, GLP-1, exenatide, or to drugs with a similar chemical structure.
3. Use of any prescription medication within 90 days prior to screening, other than allowed anti-diabetic therapy, that has not been approved by the PI and Sponsor. The use of alpha blockers, antihypertensives, proton pump inhibitors and cholesterol medication as comedications is allowed throughout the study.
4. Treatment with any type of anti-diabetic therapy other than metformin, sulfonylurea, meglitinide and alpha glucosidase inhibitors within the preceding 12 weeks [ie, thiazolinediones (TZDs), dipeptidyl dipeptidase inhibitors (DPP-IV), Symlin (pramlintide acetate) and or Byetta (exenatide)].
5. Serum creatinine above Upper Limit of Normal (ULN) as defined by the laboratory.
6. Known symptomatic gastrointestinal disease (GI) disease that may predispose to nausea and/or vomiting (eg, peptic ulcer disease, gastritis or gastric emptying disorder) or any other disorder that may predispose to nausea and/or vomiting (eg, vestibular disorders).
7. Clinically significant disease including, but not limited to:
o History of significant psychiatric or neurological disease including seizure disorder and major depression.
o Cardiovascular, cerebrovascular or peripheral vascular disease or uncontrolled hypertension. (Such as subjects with hypertension who are not medically monitored and treated)
o Cancer (other than excised cutaneous basal cell carcinoma) or history of benign lung neoplasms.
o History of active acute or chronic hepatic disease including any history of Hepatitis B, Hepatitis C, or autoimmune liver disease or positive Hepatitis B or C serology on screening laboratories.
o History of HIV disease or HIV positive on screening laboratories.
o History of systemic autoimmune or collagen vascular disease.
8. Current or previous chemotherapy or radiation therapy that may result in pulmonary toxicity.
9. Any abnormalities on screening, hematology, or chemistry laboratory studies, defined as outside of the normal range of the reference laboratory (unless discussed with and approved by the Medical Monitor).
10. Current drug or alcohol abuse, or a history of drug or alcohol abuse that in the opinion of the PI would make the subject an unsuitable candidate for participation in the clinical trial. An herbal or dietary regimen that in the opinion of the PI would make the subject an unsuitable candidate for participation in the clinical trial.
11. Unable and/or unlikely to comprehend and/or follow the trial protocol.
12. A lack of compliance with medication or procedures that in the PI’s opinion may affect the clinical trial data or the subject’s safety and which precludes the subject from further participation in the clinical trial.
13. Any other condition that in the opinion of the PI makes the subject unsuitable for the clinical trial, or could limit the validity of the informed consent and/or impair the subject’s ability to participate in the trial.
14. Significant improvement in pre- to post-bronchodilator spirometry (defined as an increase of 12% AND 200 mL in either FVC OR FEV1).
15. History of chronic obstructive pulmonary disease (COPD), including but not limited to, asthma and/or any other clinically important pulmonary disease, confirmed by pulmonary function testing or radiologic findings.
16. Inability to perform PFT maneuvers meeting recommended American Thoracic Society (ATS) standards of acceptability and repeatability criteria.
17. Active respiratory infection [subject may return after 30 days from resolution for Visit 1 (Screening)]; if respiratory infection manifests after Visit 1 (Screening) but prior to Visit 1 PFTs, subject will be considered a screen failure. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| AUC0-240 min post-prandial plasma glucose. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 1 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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