| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Male or non pregnant female nonsmoking patients, 18 years of age or older: have had type 2 diabetes mellitus for at least 6 months, and have been treated with one or more oral antihyperglycemic medications for at least 6 weeks (12 weeks for thiazolidinediones [TZDs]), and are insulin-naïve as defined in the protocol, have HbA1c >7.0% and ≤10.5%, and FEV1 and DLCO >70% of predicted value
|
|
| 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 | 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 primary objective of this study, in suboptimally-controlled insulin-naïve individuals
with type 2 diabetes, is to demonstrate that a simple approach for adding HIIP to oral antihyperglycemic medication can achieve, within 6 months, glycemic control similar to a more aggressive approach.
The two treatment regimens algorithms (Algorithm A versus Algorithm B) will be
compared with respect to mean change in HbA1c from baseline to endpoint (6 months).
Noninferiority with respect to HbA1c will be concluded if the upper limit of the 95% confidence interval for the treatment difference (Algorithm A – Algorithm B) is less than 0.4%.
|
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are:
1) To compare the two dose titration algorithm groups with respect to the following:
• mean change in HbA1c from baseline to 2 months, and 3 months
• daily insulin dose requirements
• time to maximum dose; time to 90% maximum dose; and time to achievement of 75% of SBGM targets
• the proportion of patients achieving HbA1c <7% and, in a separate analysis, achieving HbA1c ≤6.5%
• 8-point SBGM profile, 4-point SBGM profile, and total number of blood glucose measurements per week
• hypoglycemia
• patient-reported energy; fatigue and cognitive distress symptoms; diabetes treatment satisfaction; and evaluation of the insulin delivery system
• treatment-emergent adverse events
• safety as assessed by insulin antibody levels; pulmonary function testing (PFT)
and diffusing capacity of the lung for carbon monoxide (DLCO); Pulmonary Symptoms Questionnaire (PSQ); body weight.
2) To assess inhaler reliability.
|
|
| 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 indicated below:
[1] male or female patients who are 18 years of age or older,
[2] patients who have had type 2 diabetes mellitus, based on the disease diagnosis criteria (Section 4.1.1), for at least 6 months’ duration at study entry,
[3] patients who have been treated with the following regimen:
• one or more oral antihyperglycemic medications on a stable dose for at
least 6 weeks (12 weeks for thiazolidinediones [TZDs]),
AND
• have been on insulin for 14 days or less throughout life and have not taken
insulin within 6 months,
AND
• are candidates for insulin therapy, in the opinion of the investigator.
[4] patients who have HbA1c >7.0% and ≤10.5% at screening:
[5] 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,
and
• agree to use a reliable method of birth control during the study.
[6] patients who are nonsmokers, have not smoked for >6 months prior to
entering the study, and agree not to smoke (cigars, cigarettes, or pipes)
or use smokeless tobacco for the duration of 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 pulmonary function tests (PFT):
• DLCO >70% of predicted
• FEV1/FVC > lower limit of normal and FEV1 >70% predicted
• Patients should be able to perform at least three acceptable FEV1, FVC, and DLCO maneuvers
[9] patients who have a chest x-ray (posteroanterior and lateral views) without evidence of clinically significant pulmonary abnormalities, in the opinion of the investigator
[10]patients who have signed and dated the informed consent document. |
|
| E.4 | Principal exclusion criteria |
Patients will be excluded from the study if they meet any of the following criteria:
[11] are investigative site personnel directly affiliated with the study, and/or
their immediate families.
[12] patients are Lilly employees or are employed by Alkermes. Immediate family of Lilly or Alkermes employees may participate in Lilly-sponsored clinical trials, but are
not permitted to participate at a Lilly facility.
[13] 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,
[14] patients who have previously received any form of inhaled insulin, or have completed or discontinued from this study,
[15] patients who are taking a TZD dose greater than what is indicated in
combination with insulin according to the TZD label in the respective
country. In countries where the combination of the TZD and insulin
is not approved, patients taking any TZD at study entry will be
excluded.
[16] patients who have had more than two episodes of severe hypoglycemia
during the 6 months prior to study entry
[17] patients who have had more than one hospitalization or emergency room visit due to poor diabetic control during the 6 months prior to study entry,
[18] patients who have had pneumonia in the 3 months prior to screening, on clinical or radiologic grounds,
[19] patients who have received systemic glucocorticoid therapy within the 3 months prior to study entry (topical preparations, nasal preparations, intra-articular administration, as well as physiologic replacement for Addison’s Disease and hypopituitarism are permitted),
[20] 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,
[21] 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) if not on metformin; or if on metformin at study entry, have a serum creatinine above what is contraindicated in the metformin label in the respective country (for example, in the United States, ≥1.5 mg/dL [132 µmol/L] for males or ≥1.4 mg/dL [123 µmol/L] for females),
[22] patients who have a history of angina, myocardial infarction (MI), or Functional Capacity Class III/IV cardiac disease (as defined by the New York Heart Association within the 6 months prior to study entry,
[23] patients who have an active or untreated malignancy, or have been in
remission from a clinically significant malignancy (other than basal cell or squamous cell skin cancer, in situ carcinoma of the cervix, or in situ prostate cancer) for less than 5 years,
[24] patients who have a current or past history of lung cancer,
[25] patients who have a history of lung transplantation,
[26] 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,
[27] patients who are taking or have taken exenatide (Byetta™) or other incretin mimetics that are not approved for use with insulin during the prior 8 weeks,
[28] patients who have any other condition (including reported drug abuse, alcohol abuse, or psychiatric disorder) that, in the opinion of the investigator, precludes the patient from following and completing the protocol,
[29] 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) |
Efficacy:
The primary efficacy outcome is the mean change in HbA1c from baseline to endpoint.
An analysis of covariance (ANCOVA) model will be used to establish the noninferiority
of Algorithm A to Algorithm B.
In addition to the primary efficacy analysis of HbA1c for noninferiority, the following
outcomes will be analyzed for efficacy with all observed data and no imputations:
• mean change in HbA1c from baseline and observed HbA1c values at 2 months, 3 months, and 6 months
• proportion of patients who have an HbA1c ≤6.5% and <7.0%
• daily insulin dose (individual preprandial HIIP dose, total daily HIIP dose)
• time to maximum dose; time to 90% maximum dose; and time to achievement of 75% of SBGM targets
• SBGM level:
o 8-point SBGM
o 4-point SBGM
Furthermore, descriptive statistics such as rate of inhaler complaint will be presented for assessment of insulin inhaler reliability.
Health Outcome/Quality of Life Analyses will be measured using questionnaires to assess PROs: the W-BQ12, DSC-R subscales, IDSQ, and DTSQS.
Safety:
Safety measures include drug exposure, pulmonary function tests, change from baseline in cough and other pulmonary symptoms using the PSQ, vital signs, body weight, hypoglycemic episodes, adverse events, and insulin antibody levels. Exposure to HIIP for each algorithm during the treatment period will be calculated for each patient and summarized by treatment group. |
|
| 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 | 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) | Information not present in EudraCT |
| 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) | Information not present in EudraCT |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| 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 | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Two active treatment dose algorithms are studied |
|
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| 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 | Yes |
| 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
|
| The end of the trial is the last visit of the last patient undergoing the trial. For any patients who completed visit 6, a follow up after 2 weeks will be conducted. |
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
Print
