E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Male or female nonsmoking patients 18 years of age or older who have had type 1 diabetes mellitus for at least 24 months at study entry and are taking at least 2 or 3 preprandial injections per day for at least 2 months, have FEV1 and DLCO >70% predicted, and have an HbA1c less or equal 11.0% at screening. |
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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 | 10045228 |
E.1.2 | Term | Type I diabetes mellitus |
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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 primary objective of this study is to test the hypothesis that preprandial HIIP is noninferior to preprandial injectable insulin (insulin lispro) with respect to mean change in HbA1c from baseline to endpoint of 6 months in patients with type 1 diabetes. A noninferiority margin of 0.4% for HbA1c will be used. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are: 1) To compare preprandial HIIP with preprandial injectable insulin (insulin lispro) in patients with type 1 diabetes who have been treated for 6 months with respect to the following: •8-point self-monitored blood glucose (SBGM) •proportion of patients who have an HbA1c less or equal 6.5% and <7.0% •insulin dose requirements •insulin antibody binding levels •FEV, FVC, and TLC •diffusing capacity of the lung for carbon monoxide (DLCO) •pulmonary symptoms using the Pulmonary Symptoms Questionnaire (PSQ) •safety as assessed by adverse events, episodes of hypoglycemia •body weight •patient-reported outcomes questionnaires. 2) To assess inhaler reliability in patients randomized to treatment with HIIP. 3) To assess the pharmacokinetics (PK) of HIIP administered preprandially in a subgroup of patients. The exploratory objective of this study is to explore the secondhand smoking effects on clinical correlates.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients are eligible to be included in the study only if they meet all of the following criteria at screening or otherwise as described below: [1] male and female patients who are 18 years of age or older [2] patients who have type 1 diabetes for at least 24 months’ duration at study entry and meet the disease diagnostic criteria as defined by the World Health Organization (WHO) [3] patients who have an HbA1c ≤11%; • If the HbA1c criterion is not met at the first screening visit, the patient may undergo retest of HbA1c once within a 3-month period. If less than 1 month has passed since the initial screening, only the HbA1c test will be repeated. If more than 1 month but less than 3 months have passed, the entire screening panel will be repeated, except for cotinine. • One retest may occur as long as the screening period for the study is still ongoing at the time of the retest. [4] patients who are on an insulin regimen involving 2 or 3 preprandial injections per day for at least 2 months (Patients who are on a regimen that includes premix insulin are appropriate candidates. Patients on insulin pump therapy within the previous 2 months are not appropriate candidates.) [5] patients who are nonsmokers for at least 6 months prior to the study and intend to continue nonsmoking for the duration of the study. Serum cotinine level must be <20 ng/mL at screening; [6] female patients who are not breastfeeding, and if female patients are of childbearing potential they must: test negative for pregnancy at the time of screening • intend not to become pregnant during the study • agree to use a reliable method of birth control during the study. [7] patients who are able to perform pulmonary function testing, according to guidelines from the American Thoracic Society (ATS 1995) [8] patients who have PFTs graded as “A,” “B,” or “C” in quality and satisfy all of the following criteria for PFTs: • DLCO >70% of predicted • FEV1/FVC >lower limit of normal and FEV1 >70% predicted • Patients should be able to perform at least 3 acceptable FEV1, FVC, and DLCO maneuvers. • If the grade for FEV1, FVC, or DLCO is “D” or “F,” then the patient may retest within a 4-week period. • Retesting may occur as long as the screening period for the study is still ongoing at the time of the retest. [9] patients who have a chest x-ray with no evidence of clinically significant pulmonary abnormalities in the opinion of the investigator (Scarring due to inactive tuberculosis is not exclusionary.) [10] patients who have signed and dated the informed consent document. |
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E.4 | Principal exclusion criteria |
Patients will be excluded from the study if they meet any of the following criteria at screening: [1] patients who are investigative site personnel directly affiliated with the study, or are immediate family of investigative site personnel directly affiliated with the study. [2] patients who are employed by Lilly or Alkermes. Immediate family of Lilly employees may participate in Lilly-sponsored clinical trials, but are not permitted to participate at a Lilly facility. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted. [3] patients who have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry [4] patients who have previously completed or withdrawn from this study or have previously received any form of inhaled insulin [5] patients who require a daily total insulin dosage greater than 150 U at screening [6] patients who have a current or past history of asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, alpha-1 antitrypsin deficiency, or other clinically relevant pulmonary disease that in the opinion of the investigator would preclude participation in the study due to safety concerns, or confound data interpretation [7] patients who have a history of lung transplantation [8] patients who are diagnosed with pneumonia (on clinical or radiological grounds) in the 3 months prior to screening [9] patients who have obvious clinical signs or symptoms of liver disease, acute or chronic hepatitis, or alanine aminotransaminase/serum glutamic pyruvic transaminase (ALT/SGPT) greater than 3 times the upper limit of the reference range [10] patients who have a history of renal transplantation, are currently receiving renal dialysis, or have a serum creatinine >2.0 mg/dL (177 µmol/L) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy: The primary efficacy measure is the HbA1c change from baseline to 6 months. The secondary measures of the study are as follows: 8-point SBGM profiles (blood glucose measurements before and 2 hours after the start of the morning, midday, and evening meals, blood glucose measurements at bedtime and 3 a.m.); and proportion of patients who achieve or maintain an HbA1c ≤6.5% and <7.0%; daily insulin dose requirements (total, preprandial, and basal insulin). Exploratory measures will include second-hand smoking questions.
HIIP Delivery System: Insulin inhaler reliability will be assessed by laboratory assessment of inhalers returned for patient complaint.
Safety Measures: Insulin antibody levels (cross-reactive antibodies, insulin-specific antibodies, lispro-specific antibodies, antibody classes); change from baseline in pulmonary function tests (FEV1, FVC, TLC, DLCO); change from baseline in cough and other pulmonary symptoms using the PSQ; hypoglycemic episodes; treatment-emergent adverse events; laboratory tests; vital signs (body temperature, systolic blood pressure, diastolic blood pressure, pulse rate, and respiratory rate); and body weight. Pharmacokinetic: Serum free immunoreactive insulin (IRI) concentrations in up to 5 blood samples collected from a subgroup of approximately 120 patients in the HIIP treatment group at Visits 5 and 6. Visit 5 includes the consumption of a standard meal.
Health Outcomes: Patient-reported general well-being, diabetes-associated symptoms, diabetes treatment satisfaction, and evaluation of insulin delivery systems using the 12-item Well-Being Questionnaire (W-BQ12); the Cognitive Distress, Fatigue, Hyperglycemia, and Hypoglycemia Subscales of the Diabetes Symptom Checklist-Revised (DSC-R); the Diabetes Treatment Satisfaction Questionnaire Status Version (DTSQs); and the Insulin Delivery System Questionnaire (IDSQ), respectively.
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
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) | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
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 | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
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
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The end of the trial is the last visit of the last subject undergoing the trial. |
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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 | 18 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 18 |