| 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; have had type 2 diabetes mellitus for at least 6 months at study entry and have been treated with one or more oral antihyperglycemic medications on a stable dose for at least 6 weeks (3 months for thiazolidinediones [TZDs]) and once-daily insulin glargine for at least 4 months, have FEV1 and DLCO >70% predicted, and have an HbA1c between 7.5% and 9.5% at screening. |
|
| 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 compare, in patients who at study entry have
type 2 diabetes not optimally controlled by one or more oral antihyperglycemic
medications plus once-daily insulin glargine, a regimen including mealtime HIIP without
insulin glargine (“HIIP only” group) versus a regimen including intensified insulin
glargine without mealtime HIIP (“intensified glargine” group), with respect to mean
change in HbA1c from baseline to endpoint (24 weeks). Superiority with respect to
HbA1c will be concluded if the upper limit of the 95% confidence interval for the
treatment difference (“HIIP only” minus “intensified glargine”) is less than zero.
Noninferiority will be concluded if this upper limit is less than 0.4%, but greater than orequal to 0.0%. |
|
| E.2.2 | Secondary objectives of the trial |
| Please refer to protocol for full secondary objectives. Space does not allow full text. |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| 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] Are male or female who are 18 years of age or older,
[2] 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] Have been treated with the following regimen:
• one or more oral antihyperglycemic medications on a stable dose
for at least 6 weeks (3 months for thiazolidinediones [TZDs])
AND
• once-daily insulin glargine for at least 4 months
[4] Have HbA1c ≥7.5 and ≤10.5% at screening
• 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 except
cotinine will be repeated.
• Retesting may occur as long as the screening period for the study is
still ongoing at the time of the retest.
•Patients who were screened for this study prior to the approval of protocol amendment b and who failed to meet this inclusion criterion due to an HbA1c of > 9.5% may be rescreened if the screening HbA1c was also ≤ 10.5%.
[5] If female, are not breastfeeding
AND
If female and of childbearing potential (not surgically sterilized and
between menarche and 1 year postmenopause), must
• test negative for pregnancy at the time of screening based on a
urine or serum test,
• intend not to become pregnant during the study,
• agree to use a reliable method of birth control (for example, use of
oral contraceptives or Norplant®; a reliable barrier method of birth
control [diaphragms with contraceptive jelly; cervical caps with
contraceptive jelly; condoms with contraceptive foam; intrauterine
devices]; partner with vasectomy) during the study.
[6] Are nonsmokers, have not smoked for at least 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. Serum cotinine
level must be <20 ng/mL at screening.
• If the patient is a nonsmoker for a period of ≥6 months, and the
serum cotinine level is ≥20 and ≤100 ng/mL, the patient may
undergo retesting of serum cotinine once within 4 weeks.
• Retesting may occur as long as the screening period for the study is
still ongoing at the time of the retest.
[7] Are able to perform pulmonary function testing, according to
guidelines from the American Thoracic Society (ATS) (1995),
[8] Have PFTs graded as “A,” “B,” or “C” in quality (see Section 6.3.3.1)
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 three acceptable FEV1,
FVC, and two acceptable DLCO maneuvers, two of which are
reproducible (within 0.20 L for FEV1 and FVC; and within
2.5 standard DLCO units for DLCO).
o If the patients are not able to meet the reproducibility criteria
for FEV1, FVC, or DLCO maneuvers, they may return for retest
within a 4-week period as described in Section 6.3.3.1.
o If the grade for FEV1, FVC, or DLCO is “D” or “F,” then the
patients may return for retest as described in Section 6.3.3.1.
o Retesting may occur as long as the screening period for the
study is still ongoing at the time of the retest.
[9] Have a chest x-ray without evidence of clinically significant
pulmonary abnormalities (including severe bullous disease), in the
opinion of the investigator. (Scarring due to inactive tuberculosis is
not exclusionary.) If an x-ray has been performed no more than
6 months before Visit 1, it will not have to be repeated, provided the
investigational site reviews a record of the results by Visit 2.
[10] 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. Immediate family is defined as a
spouse, parent, child, or sibling, whether biological or legally adopted.
[12] Are Lilly or Alkermes employees,
[13] 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 completed or withdrawn from this study
or any study investigating any form of inhaled insulin and took one or
more doses of inhaled insulin, or have previously taken any form of
inhaled insulin,
[15] Are taking a TZD dose greater than what is indicated in combination
with insulin according to the TZD label in the respective country (for
example, in the United States, rosiglitazone greater than 4 mg daily or
pioglitazone greater than 45 mg daily is not currently indicated). In the UK, patients who are on a TZD and glargine at study entry may be enrolled, if the patient is classified as NYHA I, and has been stable (from a cardiovascular perspective) while on this medication combination. In other
countries where the combination of the TZD and insulin is not
approved, patients taking any TZD at study entry will be excluded.
[16] Have had more than two episodes of severe hypoglycemia during the
6 months prior to study entry (see Section 5.9 for information about
severe hypoglycemia),
[17] Have had more than one hospitalization or emergency room visit due
to poor diabetic control during the 6 months prior to study entry,
[18] Have had a lower respiratory infection in the 3 months prior to
screening, evidenced by diagnosed pneumonia (on clinical or
radiologic grounds),
[19] 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] Have obvious clinical signs or symptoms of liver disease, acute or
chronic active hepatitis, or alanine aminotransaminase/serum glutamic
pyruvic transaminase (ALT/SGPT) greater than three times the upper
limit of the reference range,
[21] 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] Have a history of angina, myocardial infarction, or Functional Capacity Class II,III/IV cardiac disease (patients taking a TZD), Functional
Capacity Class III/IV cardiac disease (patients not taking a TZD) (as defined by the New York
Heart Association [Attachment IDBA.5]) within the 6 months prior to
study entry.
[23] 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] Have a current or past history of lung cancer,
[25] Have a history of lung transplantation,
[26] Have a current diagnosis 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] Are taking or have taken exenatide (Byetta™) within 6 weeks,
[28] Require more than 150 U/day of insulin glargine,
[29] 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,
[30] 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 efficacy measure is the difference in the change in mean HbA1c from
baseline to endpoint (24 weeks) between the “HIIP only” and “intensified glargine”
groups.
The following secondary efficacy measures will be collected at the times shown in
Attachment IDBA.1 (Study Schedule).
The secondary measures of the study are as follows:
• To compare “HIIP only” versus “intensified glargine,” “HIIP + intensified
glargine” versus “intensified glargine,” and “HIIP + intensified glargine”
versus “HIIP only,” in patients who have been treated for 24 weeks and 52
weeks with respect to the following parameters:
o mean change in HbA1c from baseline to various timepoints (including
comparison for change in HbA1c from baseline to endpoint for “HIIP
+ intensified glargine” versus “intensified glargine,” “HIIP +
intensified glargine” versus “HIIP only”, and “intensified glargine
only” and “HIIP only” groups),
o 8-point SMBG profiles (blood glucose measurements before and
2 hours after the start of the morning, midday, and evening meals, and
blood glucose measurements at bedtime and at 3 a.m.),
o 2-hour blood glucose excursions (the difference between the preprandial and
the 2-hour postprandial blood glucose values) for the morning, midday, and
evening meals (based on 8-point SMBG data),
o proportion of patients who achieve or maintain an HbA1c <6.5% and, in
separate analysis, <7.0%,
o proportion of patients who require rescue therapy,
o insulin dose requirements (total) for days when 8-point profiles are
performed. Additionally, in the “HIIP + intensified glargine” and
“intensified glargine” groups, basal insulin dose requirements will be
compared. In the “HIIP + intensified glargine” and the “HIIP only”
groups, prandial insulin dose requirements will be compared.
o standard fasting lipid profile (high-density lipoprotein cholesterol [HDL-C],
total cholesterol, triglycerides, and low-density lipoprotein cholesterol
[LDL-C]),
o patient-reported evaluation of insulin delivery system satisfaction, lifestyle
impact of insulin delivery system, ease of dosing; diabetes treatment
satisfaction; energy, positive well-being, negative well-being; fatigue,
cognitive distress symptoms, hyperglycemia symptoms, hypoglycemia
symptoms; perceived effectiveness; willingness to continue current insulin
system (Section 6.2),
• In patients randomized to either group using HIIP, insulin inhaler
reliability as assessed by laboratory assessment of inhalers returned for
patient complaint. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| 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) | Yes |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Diabetes oral treatment combinations and Lantus (insulin glargine) |
|
| 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 | 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
|
| The end of the trial is 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 10 |
| 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 | 10 |
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