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

• ClinicalTrials.gov Identifier: NCT00359801
• Recruitment Status: Completed
• First Posted: August 2, 2006
• Results First Posted: January 27, 2010
• Last Update Posted: February 2, 2010
• Sponsor: Pfizer
• Information provided by: Pfizer

Tracking Information

• First Submitted Date: July 31, 2006
• First Posted Date: August 2, 2006
• Results First Submitted Date: December 22, 2009
• Results First Posted Date: January 27, 2010
• Last Update Posted Date: February 2, 2010
• Study Start Date: July 2006
• Actual Primary Completion Date: December 2008 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 22, 2009)

• Number of Subjects With Decline in Forced Expiratory Volume (FEV1) Exceeding 20% From Baseline [ Time Frame: Baseline, Month 6, Year 1, Year 2, Index Visit ]
  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.
• Supplemental Definition of Decline in Forced Expiratory Volume in One Second (FEV1): Number of Subjects [ Time Frame: Baseline, Month 6, Year 1, Year 2, Index Visit ]
  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.
• Time to Persistent Decline in FEV1 Exceeding 20% From Baseline [ Time Frame: Baseline to 5 years ]
  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.

• Original Primary Outcome Measures (submitted: July 31, 2006): Persistent decline in FEV1 exceeding 20% from baseline, defined as an observed decline in FEV1 exceeding 20% from baseline, 3 months after a confirmed decline in FEV1 exceeding 20% from baseline.

Current Secondary Outcome Measures (submitted: January 29, 2010)

• Change From Baseline in Forced Expiratory Volume in One Second (FEV1) [ Time Frame: Baseline, Week 26, Week 52, Week 104, Index Visit ]
  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.
• Pulmonary Serious Adverse Event (SAE) Composite: SAEs of Asthma, Chronic Obstructive Pulmonary Disease (COPD), Pneumonia, or Acute Bronchitis [ Time Frame: Baseline through End of Study ]
  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.
• Time to Event for Pulmonary Serious Adverse Event (SAE) Composite: SAEs of Asthma, Chronic Obstructive Pulmonary Disease (COPD), Pneumonia, or Acute Bronchitis [ Time Frame: Baseline to 5 years ]
  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.
• All-cause Mortality: Number of Deaths [ Time Frame: Baseline through End of Study ]
  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.
• Time to Event: All-cause Mortality [ Time Frame: Baseline to 5 years ]
  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.
• Cardiovascular SAE Composite: SAEs of Cardiovascular Mortality, Non-fatal Myocardial Infarction (MI), or Non-fatal Stroke [ Time Frame: Baseline through End of Study ]
  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.
• Time to Event for Cardiovascular Serious Adverse Event (SAE) Composite: SAEs of Cardiovascular Mortality, Non-fatal Myocardial Infarction, or Non-fatal Stroke [ Time Frame: Baseline to 5 years ]
  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.
• Allergic Response Serious Adverse Event (SAE) Composite: SAEs of Anaphylaxis, Angioedema, Generalized Allergic Reaction, or Allergic Bronchospasm [ Time Frame: Baseline through End of Study ]
  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.
• Time to Event for Allergic Response Serious Adverse Event (SAE) Composite, Including: SAEs of Anaphylaxis, Angioedema, Generalized Allergic Reaction, or Allergic Bronchospasm [ Time Frame: Baseline to 5 years ]
  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.
• Change in Glycosylated Hemoglobin (HbA1c) From Baseline [ Time Frame: Baseline, Month 6, Year 1, Year 2, Index Visit ]
  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.
• Change in Glycosylated Hemoglobin (HbA1c) From Baseline [ Time Frame: Baseline to 5 years ]
  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.

Original Secondary Outcome Measures (submitted: July 31, 2006)

• Pulmonary serious adverse event (SAE) composite, including: SAEs of asthma,
• chronic obstructive pulmonary disease (COPD), pneumonia, or acute bronchitis
• All-cause mortality
• Cardiovascular SAE composite, including: SAEs of cardiovascular mortality,
• non-fatal myocardial infarction, or non-fatal stroke
• Allergic response SAE composite, including: SAEs of anaphylaxis, angioedema,
• generalized allergic reaction, and allergic bronchospasm
• Change in HbA1c from baseline

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Exubera Large Simple Trial To Evaluate Long-Term Pulmonary And Cardiovascular Safety
• Official Title: An International, Multicenter, Large Simple Trial To Evaluate The Long-Term Pulmonary And Cardiovascular Safety Of Exubera In Patients With Diabetes Mellitus
• Brief Summary: The purpose of this study is to evaluate the long-term pulmonary and cardiovascular safety of Exubera in routine clinical practice.
• Detailed Description: 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.
• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Diabetes Mellitus

Intervention

• Drug: Randomization to Exubera (insulin human [rDNA origin] inhalation powder) or Usual Diabetes Care
  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.
• Drug: Randomization to Exubera (insulin human [rDNA origin] inhalation powder) or Usual Diabetes Care
  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).
  Other Name: Non-Exubera

Study Arms

• Experimental: Exubera
  Intervention: Drug: Randomization to Exubera (insulin human [rDNA origin] inhalation powder) or Usual Diabetes Care
• Active Comparator: Usual Diabetes Care
  Intervention: Drug: Randomization to Exubera (insulin human [rDNA origin] inhalation powder) or Usual Diabetes Care

Publications *

• Gatto NM, Bracken MB, Kolitsopoulos F, Duggan WT, Koch GG, Wise RA, Jackson NC. Pulmonary and cardiovascular safety of inhaled insulin in routine practice: The Exubera Large Simple Trial (VOLUME). Contemp Clin Trials Commun. 2019 Aug 13;18:100427. doi: 10.1016/j.conctc.2019.100427. eCollection 2020 Jun.
• Kolitsopoulos FM, Gatto NM, Sweetland K, Bracken MB, Jackson N. Implications of product withdrawal on a post-approval pragmatic trial: The VOLUME study experience. Contemp Clin Trials Commun. 2019 Oct 28;16:100477. doi: 10.1016/j.conctc.2019.100477. eCollection 2019 Dec.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 22, 2009): 1976
• Original Enrollment (submitted: July 31, 2006): 5300
• Actual Study Completion Date: April 2009
• Actual Primary Completion Date: December 2008 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Germany, Puerto Rico, Sweden, United Kingdom, United States

Administrative Information

• NCT Number: NCT00359801
• Other Study ID Numbers: A2171069
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Director, Clinical Trial Disclosure Group, Pfizer, Inc.
• Study Sponsor: Pfizer
• Collaborators: Not Provided

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: September 2009