Exubera Large Simple Trial To Evaluate Long-Term Pulmonary And Cardiovascular Safety

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the long-term pulmonary and cardiovascular safety of Exubera in routine clinical practice.

Detailed Description
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Pfizer announced in October 2007 that it would stop marketing Exubera. At that time, Pfizer committed to continued marketing until it returned the licensing rights for the technology to Nektar. Following the announcement, enrollment was halted. Subjects already enrolled and receiving treatment at the time of the halt in enrollment could continue in the study in accordance with the protocol. Nektar, the company from which Pfizer licensed Exubera, announced on April 9, 2008 that it had stopped its search for a new marketing partner. Accordingly, there will be no commercial availability of Exubera. As a result, an amendment was filed on April 16, 2008 specifying that all subjects randomized to Exubera had to be transitioned to usual diabetes care, and all study subjects followed for serious adverse events for 6 months. In accordance with this amendment, study A2171069 was terminated on April 29, 2009. Neither safety nor efficacy reasons were the cause of the study termination.

Official Title
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An International, Multicenter, Large Simple Trial To Evaluate The Long-Term Pulmonary And Cardiovascular Safety Of Exubera In Patients With Diabetes Mellitus

Conditions
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Diabetes Mellitus

Intervention / Treatment
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* Drug: Randomization to Exubera (insulin human [rDNA origin] inhalation powder) or Usual Diabetes Care
* Drug: Randomization to Exubera (insulin human [rDNA origin] inhalation powder) or Usual Diabetes Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eligible for receiving Exubera treatment based on the approved local label Exclusion Criteria: Pregnant or lactating Have a progressive fatal disease or a life expectancy that prohibits them from participating in a five-year research study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exubera<br> | Drug: Randomization to Exubera (insulin human [rDNA origin] inhalation powder) or Usual Diabetes Care<br>* Subjects are randomized to use Exubera. Following initial use of randomized treatment, physicians and subjects are free to change regimens and dosing based on subject response to assigned treatment (as consistent with routine practice). Enrolling physicians are provided with the approved local label for Exubera to guide prescribing and treatment decisions.<br>|
| Active Comparator: Usual Diabetes Care<br> | Drug: Randomization to Exubera (insulin human [rDNA origin] inhalation powder) or Usual Diabetes Care<br>* Subjects are randomized to use usual diabetes care. Following initial use of randomized treatment, physicians and subjects are free to change regimens and dosing based on subject response to assigned treatment (as consistent with routine practice).<br>* Other names: Non-Exubera;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Decline in Forced Expiratory Volume (FEV1) Exceeding 20% From Baseline | Persistent decline in FEV1 exceeding 20% from baseline: observed decline in FEV1 exceeding 20% from baseline, 3 months after a confirmed decline (2 consecutive declines within 1 month) in FEV1 exceeding 20% from baseline. Second pulmonary function test (PFT) that confirmed decline was to occur within 14-42 days of the decline. Persistence: PFT that established persistence was to occur within 60-120 days of the confirming (2nd) decline. Index Visit: date subject had final Scheduled spirometry; was to occur within 2 months of Institutional Review Board/Ethics approval of April 2008 amendment. | Baseline, Month 6, Year 1, Year 2, Index Visit | 
| Supplemental Definition of Decline in Forced Expiratory Volume in One Second (FEV1): Number of Subjects | Confirmed FEV1 decline: any two consecutive declines that are >= 14 days apart. The pulmonary function test that established persistence occured >= 60 days after the initial decline. A confirmed decline: any two consecutive declines ≥ 14 days apart. The third PFT that established persistence was to occur ≥ 60 days after the initial decline. Index Visit: date the subject had his/her final scheduled spirometry was to occur within 2 months of Institutional Review Board/Ethics approval of April 2008 amendment. | Baseline, Month 6, Year 1, Year 2, Index Visit | 
| Time to Persistent Decline in FEV1 Exceeding 20% From Baseline | Elapsed time, in days, from the start of subject's participation in the study to the first reading of FEV1 that is: 20% or more below the subject's latest pre-study measurement, subsequently confirmed as a >20% decline [(baseline observed value minus visit observed value)/by baseline observed value *100], and assessed as persistent as defined by protocol process. Censoring time: elapsed time, in days, from the start of a subject's participation in the study to latest valid FEV1 measurement for the particular analysis set of interest. Cox proportional hazards model to estimate treatment effect. | Baseline to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Change from Baseline: mean of value of observed forced expiratory volume in the first second of forced exhalation [FEV1] in liters [L] at observation minus Baseline value. Index Visit: date subject had final scheduled spirometry; was to occur within 2 months of Institutional Review Board/Ethics approval of April 2008 amendment. | Baseline, Week 26, Week 52, Week 104, Index Visit | 
| Pulmonary Serious Adverse Event (SAE) Composite: SAEs of Asthma, Chronic Obstructive Pulmonary Disease (COPD), Pneumonia, or Acute Bronchitis | Endpoint committee adjudicated the endpoint based on review of medical and hospital records, and results were classified using standard criteria. Definite: definite pneumonia, definite COPD, or definite asthma; possible: possible pneumonia, possible COPD, possible asthma, probable obstructive lung disease not otherwise specified or probable acute bronchitis; definite or possible: either definite or possible; insufficient: insufficient data. | Baseline through End of Study | 
| Time to Event for Pulmonary Serious Adverse Event (SAE) Composite: SAEs of Asthma, Chronic Obstructive Pulmonary Disease (COPD), Pneumonia, or Acute Bronchitis | Elapsed time, in days, from the start of a subject's participation in the study to the date of the first report of an event subsequently confirmed (according to protocol definition) as meeting the criteria for pulmonary SAE composite. Censoring time: elapsed time, in days, from the start of a subject's participation in the study to the latest contact with the subject for the particular analysis set of interest. Cox proportional hazards model to estimate treatment effect. | Baseline to 5 years | 
| All-cause Mortality: Number of Deaths | Endpoint committee adjudicated the endpoint based on review of medical and hospital records, and results were classified using standard criteria (confirmation of deaths by blinded adjudicator(s) through medical records or death certificates). Patients meeting the endpoint All Cause Mortality after adjudication by the endpoint committee. | Baseline through End of Study | 
| Time to Event: All-cause Mortality | Time to all-cause mortality: elapsed time, in days, from the start of a subject's participation in the study to the date of the event subsequently confirmed (according to protocol definition) as meeting the criteria for all-cause mortality. Censoring time: elapsed time, in days, from the start of a subject's participation in the study to the latest contact with the subject for the particular analysis set of interest. Cox proportional hazards model to estimate treatment effect. | Baseline to 5 years | 
| Cardiovascular SAE Composite: SAEs of Cardiovascular Mortality, Non-fatal Myocardial Infarction (MI), or Non-fatal Stroke | Endpoint committee adjudicated based on review of medical/hospital records; results classified using standard criteria. Definite: definite MI or stroke; Possible: possible MI or stroke; Other (non-MI, non-stroke): other cardiovascular event (non-MI, non-stroke); Definite or possible: either definite or possible or both; Insufficient: insufficient data; Death from cardiovascular or cerebrovascular: cardiovascular or cerebrovascular event; Definite or possible or death from cardiovascular or cerebrovascular: either definite or possible or both or cardiovascular or cerebrovascular event. | Baseline through End of Study | 
| Time to Event for Cardiovascular Serious Adverse Event (SAE) Composite: SAEs of Cardiovascular Mortality, Non-fatal Myocardial Infarction, or Non-fatal Stroke | Elapsed time, in days, from the start of a subject's participation in the study to the date of the first event subsequently confirmed (according to protocol definition) as meeting the criteria for cardiovascular SAE composite. Censoring time: elapsed time, in days, from the start of a subject's participation in the study to the latest contact with the subject for the particular analysis set of interest. Cox proportional hazards model to estimate treatment effect. | Baseline to 5 years | 
| Allergic Response Serious Adverse Event (SAE) Composite: SAEs of Anaphylaxis, Angioedema, Generalized Allergic Reaction, or Allergic Bronchospasm | Endpoint committee adjudicated the endpoint based on review of medical and hospital records, and results were classified using standard criteria. Definite or possible: anaphylaxis, angioedema/urticaria, bronchospasm or possible allergic reaction not otherwise specified (NOS); Insufficient: insufficient data. | Baseline through End of Study | 
| Time to Event for Allergic Response Serious Adverse Event (SAE) Composite, Including: SAEs of Anaphylaxis, Angioedema, Generalized Allergic Reaction, or Allergic Bronchospasm | Elapsed time, in days, from the start of a subject's participation in the study to the date of the first event subsequently confirmed (according to protocol definition) as meeting the criteria for allergic response. Censoring time: elapsed time, in days, from the start of a subject's participation in the study to the latest contact with the subject for the particular analysis set of interest. Cox proportional hazards model to estimate treatment effect. | Baseline to 5 years | 
| Change in Glycosylated Hemoglobin (HbA1c) From Baseline | Baseline HbA1c: the latest determination prior to beginning study participation. Change from Baseline: HbA1c at observation (falling within the time window associated with a given analysis set) minus the baseline value. | Baseline, Month 6, Year 1, Year 2, Index Visit | 
| Change in Glycosylated Hemoglobin (HbA1c) From Baseline | Baseline HbA1c taken as the latest determination prior to beginning study participation. Change = on-study value (for measurements falling within the time window associated with a given analysis set) minus the baseline value. Linear model with terms for treatment, baseline HbA1c, time on study, and subject within treatment. | Baseline to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Large Simple Trial