| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| 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 the study is to demonstrate non-inferiority of an insulin regimen using insulin glargine as the basal insulin with Exubera as the mealtime insulin, compared to a regimen using insulin glargine as the basal insulin and insulin lispro as the mealtime insulin in terms of glycemic control (HbA1c) after 52 weeks of treatment with each treatment regimen. |
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| E.2.2 | Secondary objectives of the trial |
| Secondary objectives of the study include durability of glycemic control additional measurements of glycemic control (fasting plasma glucose - FPG, postprandial glucose - PPG), hypoglycemia, body weight and body mass index changes, patient reported outcomes as well as the safety of both treatment regimens, each after 52 weeks of treatment with each treatment regimen. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1- Exploratory Study Comparing the 24-Hour Glucose Profiles of EXUBERA (Inhaled Insulin) with Subcutaneous Insulin Lispro Therapy in Adult Subjects with Type 1 Diabetes Mellitus, 18.08.06, final 3
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| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the trial:
1. Diagnosis: Subjects with type 1 diabetes mellitus, as defined by the American
Diabetes Association (Diabetes Care 2005 28: S37-42), for more than one year.
2. Subjects who have not participated in a prior inhaled insulin clinical trial.
3. Age: ≥ 18 years.
4. Current Therapy: For the 2 months prior to screening, subjects must have been on a stable insulin regimen involving at least 3 injections daily of insulin or an insulin
analogue (i.e., no change in the type(s) of insulin or in the schedule of injections; dose changes are acceptable).
5. Screening (week-4) HbA1c between 5.5% and 9.0% inclusive.
6. Fasting plasma C-peptide ≤ 0.20 nmol/L.
7. Body Mass Index ≤ 30. (BMI = Weight[kg] ÷ {Height[m]}2
8. Subjects must have documentation of an ophthalmologic exam within 1 year of
screening demonstrating no active proliferative retinopathy requiring treatment during the study. Documentation must be obtained prior to randomization.
9. Subjects must be able to demonstrate the ability to adequately perform spirometry
tests.
10. Subjects willing to perform specified home blood glucose monitoring and otherwise to comply with study protocol requirements.
11. The investigator will be responsible for obtaining written informed consent prior to the subject participating in the study.
12. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures. |
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| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the trial:
1. Pregnant or lactating females, or females planning to become pregnant during the
study. Females of childbearing potential must have a negative pregnancy test at screening and be using a medically accepted contraception method such as systemic hormones (birth control pills, hormonal implant device), intra-uterine device, barrier
method (diaphragm with intravaginal spermicide, cervical cap, male or female condom). Females who become pregnant or who are unable or unwilling to maintain
adequate contraception for the duration of the study will be withdrawn from the study.
2. Donation of blood or receipt of blood transfusion during the 12 weeks prior to the
screening visit, for the duration of the study, or for 30 days after completion of the study.
3. Use of any other investigational drug during the two months prior to screening and for the duration of the study.
4. Subjects on insulin pump treatment as part of their MDI regime during the 2 months prior to screening.
5. Subjects with “brittle” diabetes or a predisposition to severe hypoglycemia — i.e., 2 or more severe hypoglycemic episodes within the past 6 months, or any hospitalization or emergency room visit due to poor diabetic control within the past 6
months. Similarly, during the baseline run-in period, any subject with more than one
severe hypoglycemic episode or any hospitalization or emergency room visit due to poor diabetic control will be excluded from randomization. Severe hypoglycemia is defined in section 8.13.2 (SAFETY REPORTING, Other Safety Parameters, Hypoglycemia).
6. Pulmonary Conditions:
• FEV1, defined as FEV1 <70% of predicted.
• Significant pulmonary diseases including:
• History of poorly-controlled, unstable or severe asthma.
• Severe (GOLD stage III or IV) chronic obstructive pulmonary disease (COPD).
• Any other significant respiratory disease which in the opinion of the investigator would impair absorption of inhaled insulin.
7. Any smoking within the last 6 months prior to the screening visit. Smoking is not
permitted at any time during this study.
8. Metabolic Conditions:
a. Significant hypoglycemia risk e.g. several episodes of hypoglycemia unawareness within past 6 months, known adrenal insufficiency, symptomatic autonomic neuropathy.
b. Current chronic inhaled or systemic corticosteroid treatment likely to be of metabolic effect (prednisone equivalent >2 mg/day); intercurrent treatment at a
higher dose is allowed if treatment duration does not exceed 2 weeks.
c. Patients with celiac disease
9. Active Liver disease; ALT ≥ 2.0 times the upper limit of normal reference range for
the central lab at screening. Evidence within the preceding six months of hepatic dysfunction e.g., AST or ALT 2.0 times or more of the upper limit of normal or hepatic disease, e.g., hepatitis, jaundice, cirrhosis.
10. Cardiovascular conditions:
a. Significant cardiovascular dysfunction and/or history including hospitalization
within the preceding six months, e.g., congestive heart failure or serious arrhythmia, myocardial infarction, cardiac surgery, recurrent syncope, transient ischemic attacks or cerebrovascular accident.
b. Poorly-controlled hypertension (systolic blood pressure >180 mmHg, diastolic
blood pressure >110 mmHg) on two readings (sitting).
c. Abnormal screening ECG:
• predominant rhythm other than normal sinus;
• A-V block greater than first degree;
• resting heart rate > 100 or < 50 bpm.
• The principal investigator, or other designated physician at each site, will be
responsible for deciding the clinical significance of any abnormal ECG
findings.
11. Kidney disease:
a. History of renal transplantation or current renal dialysis.
b. Clinical nephrotic syndrome, or renal dysfunction or disease, e.g., serum creatinine ≥ 1.5 mg/dl (≥ 133 µmol/L) in males and ≥ 1.4 mg/dl (≥ 124 µmol/L) in females and/or BUN > 50 mg/dl.
12. Psychological
a. History of substance abuse/dependence or alcoholism within the past 5 years.
b. Psychiatric disorders that would interfere with the patient’s ability to complete the
study.
13. Neurological
a. Seizure disorder.
b. Significant gastroparesis or orthostatic hypotension (autonomic neuropathy).
c. Cerebrovascular accident in the previous 6 months to screening
14. Any current malignancy except:
a. those ≥ 5 years ago without recurrence.
b. excised basalioma or squamous cell cancer.
15. Clinically significant abnormalities on screening laboratory evaluation (unless
discussed with and approved by a Pfizer clinician).
16. Clinically significant major organ system disease such as
a. Active infection (e.g., HIV, Hepatitis), or history of severe infection, during the 30 days prior to screening.
b. Any concurrent illness other than diabetes mellitus not controlled by a stable
therapeutic regimen.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1- The primary efficacy endpoint is the change in % HbA1c from baseline (average of week –1 and week 0 HbA1c values) to week 52. Change from baseline in HbA1c between the two arms will be compared following adjustment according to baseline HbA1c values.
2- Secondary endpoints (reported at all post-baseline visits up to and including Week 52 where relevant data was captured; see Schedule of Activities for further detail) include:
• Hypoglycemic event rates during the entire study (see protocol section 6.3.2.3 for definitions of hypoglycemia):
• Non-severe hypoglycemic event rates.
• Total and severe hypoglycemic event rates in subjects who attain HbA1c levels less
than 6.5%, less than 7%, less than 8% and those who fail with HbA1c levels greater
than or equal to 8% at the end of the study.
• Percentage of subjects with an HbA1c < 8 %,< 7%, <6.5%, and ≥ 8% at 24 weeks and at the end of study/early termination.
• Percentage of subjects with ≥0.5, ≥0.7 and ≥1.0% absolute reduction in HbA1c levels at the end of the study from baseline levels
• Percentage of subjects who attain target FPG values 4.0-6.5 mmol/l (72-117 mg/dl) at each evaluation
• Change in fasting plasma glucose from baseline to endpoint and change in fasting and post-prandial blood glucose from baseline to endpoint based on glucometer data and in-hospital assessments
• Change from baseline to week 52 in fasting lipids
• Change from baseline to week 52 in body weight and body mass index
• Change in insulin antibody levels and body weight from baseline to endpoint.
• Change in basal and prandial insulin doses from baseline to endpoint.
• Blood glucose values determined by home blood glucose monitoring (HBGM).
• Change from baseline in subject reported health state, quality of life, preference and diabetes treatment satisfaction.
• Change from baseline to week 24 in glucose uptake into thigh muscle as assessed by 18FDG PET in a subset of patients.
• Change from baseline to week 24 in postprandial and fasting glucose metabolism as assessed by infusion of stable isotopes in a subset of patients.
• Variability in a 24 – hour glucose profile assessed at baseline, at week 24 and at week 52 in a subset of patients
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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 | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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.8.5.1 | Number of sites anticipated in the EEA | 35 |
| 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 |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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