| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with type 1 diabetes mellitus and many patients with type 2 diabetes mellitus require daily use of insulin for the maintenance of normal glucose homeostasis. At present, insulin can be delivered only by injection. The availability of noninjectable routes of insulin administration may eliminate a barrier to effective therapy and improve the quality of life for many patients with diabetes. |
|
| MedDRA Classification |
| 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 the glycemic control achieved with preprandial HIIP is noninferior to that achieved with injectable insulin, as measured by mean change from baseline to endpoint in hemoglobin A1c (HbA1c) after approximately 12 months, in patients with diabetes and chronic obstructive pulmonary disease (COPD) or asthma. A noninferiority margin of 0.4% for HbA1c will be used. |
|
| E.2.2 | Secondary objectives of the trial |
1) To compare effects of preprandial HIIP and injectable insulin after approximately 12 months, in patients with diabetes and COPD and/or asthma on:
- FEV1, FVC, total lung capacity, DLCO before inhalation of bronchodilator
- change in FEV1, FVC 30, and DLCO 30 minutes after inhalation of bronchodilator
- safety assessed by insulin antibody titers, adverse events, episodes of hypoglycemia
- safety using serial chest x-rays
- safety assessed by St. George’s Respiratory Questionnaire
- safety assessed by Six-Minute Walk Test with Borg CR10 Scale
- 8-point self blood glucose monitoring profiles
- insulin dose requirements
2) To explore proportion of patients that require conversion to basal/bolus therapy to achieve an HbA1c <7.5% after at least six months of treatment.
3) To assess insulin inhaler reliability in patients randomized to treatment with HIIP
4) To explore impact of HIIP on peak flow and peak flow variability in the subgroup of patients with asthma |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
- Male or female patients who are 18 years of age or older
- Patients who have had either:
. type 1 diabetes mellitus for at least 24 months duration at study entry and meet the disease diagnostic criteria as defined by the World Health Organization (WHO). Patients must have been on an insulin regimen involving basal insulin plus two or three preprandial injections per day for at least two months.
or
. type 2 diabetes mellitus who are already taking insulin or are appropriate candidates for insulin therapy, as judged by the investigator . Patients must have had diabetes mellitus for at least six months duration at study entry and meet the disease diagnostic criteria as defined by the WHO.
- Patients with diabetes who have an HbA1c <11% at screening
. type 2 patients not currently being treated with insulin must also have an HbA1c >6.5%.
. if the HbA1c criterion is not met at the first screening visit, the patient may undergo retest of HbA1c once within a three-month period.
- Patients who are nonsmokers for at least six months prior to the study and agree to remain nonsmokers for the duration of the study. Serum cotinine level must be <20 ng/mL at screening.
- Patients must have one or more of the following:
. chronic obstructive pulmonary disease (COPD) based on: previous diagnosis of COPD, emphysema, or chronic bronchitis; or the opinion of the investigator as judged by signs and symptoms consistent with COPD.
- asthma based on: previous diagnosis; or the opinion of the investigator as judged by signs and symptoms consistent with asthma.
Additionally, if patients are being treated for pulmonary symptoms, the treatment regimen should not have changed during the two months prior to Visit 1.
- Female patients who are not breastfeeding and if female patients are of childbearing potential (not surgically sterilized and between menarche and one year postmenopausal), they test negative for pregnancy at the time of screening and intend not to become pregnant during the study.
and
- Patients who have signed and dated the informed consent document
- Patients who are able to perform pulmonary function testing, according to guidelines from the American Thoracic Society (ATS) (1995)
- Patients who have PFTs graded as “A,” “B,” or “C” in quality and satisfy all of the following criteria for locally read PFTs:
. FEV1 >50% of predicted
. FVC >50% of predicted
. DLCO >50% of predicted
. patients should be able to perform at least three acceptable FVC, FEV1, and DLCO maneuvers, two of which are reproducible.
- Patients have a chest x-ray without evidence of clinically significant pulmonary abnormalities (including severe bullous disease), in the opinion of the investigator. |
|
| E.4 | Principal exclusion criteria |
- Patients who are investigator site personnel directly affiliated with the study, or are immediate family of investigator site personnel directly affiliated with the study.
- Patients who are employed by Lilly or Alkermes (that is, employees, temporary contract workers, or designees responsible for the conduct of the study). Immediate family of Lilly employees may participate in Lilly-sponsored clinical trials, but are not permitted to participate at a Lilly facility.
- 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
- Patients who have previously completed or withdrawn from this study or any study investigating any form of inhaled insulin.
- Patients who are taking a thiazolidinedione (TZD) dose greater than rosiglitazone 4 mg daily or pioglitazone 30 mg daily. In countries where the combination of the TZD and insulin is not approved, patients taking any TZD at study entry will be excluded.
- Patients who require a total daily insulin dosage greater than 150 U at screening
- Patients who have had a lower respiratory infection in the six months prior to screening, evidenced by diagnosed pneumonia (on clinical or radiologic grounds)
- 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 three times the upper limit of the reference range.
- Patients who have a history of renal transplantation, are currently receiving renal dialysis, or have a serum creatine >2.0 mg/dL (177 μmol/L) if not on metformin; or have a serum creatinine >1.5 mg/dL (132 μmol/L) for males or >1.4 mg/dL (123 μmol/L) for females if on metformin at study entry.
- Patients who have a history of angina, myocardial infarction (MI), or Functional Capacity Class III/IV cardiac disease within the six months prior to study entry
- Patients who have had >2 episodes of severe hypoglycemia during the six months prior to study entry.
- Patients who have had >1 hospitalization or emergency room visit due to poor diabetic control during the six months prior to study entry
- Patients who have a history of lung cancer
- Patients who have a history of lung transplantation
- Patients who have an active malignancy, other than basal cell or squamous cell skin cancer.
- Patients who:
. are currently taking chronic systemic glucocorticoid therapy
. have required treatment with systemic glucocorticoid therapy on more than one occasion within the six months prior to screening
. have had any systemic glucocorticoid therapy within one month prior to screening.
Exceptions include topical, nasal, inhaled, or intra-articular preparations, or physiologic replacement therapy for Addison’s Disease or hypopituitarism, all of which are permitted.
- Patients who have a current or past history of 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
- Patients who are unable to complete the Six-Minute Walk Test
- Patients who have been hospitalized for exacerbations of COPD or asthma within the past six months
- patients who require oxygen supplementation
- Patients who have any other condition (including known drug abuse, alcohol abuse, or psychiatric disorder) that, in the opinion of the investigator, precludes the patient from following and completing the protocol
- Patients who fail to satisfy the investigator of suitability to participate for any other reason. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcomes of this study will be the efficacy measure HbA1c change from baseline to endpoint and the assessment of HIIP effects on important safety parameters. |
|
| 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 | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| 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) | Yes |
| 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.8.5 | 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 |
|
| 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
| |
| 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 months | 18 |
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