Case Study: Exubera VOLUME Study design

Question 1

Background

Answer 1

• Inhaled insulin for patients with diabetes
• Novel route of administration
• Approved in 2006 for treatment of T1 and T2 diabetes in US and EU
• RCT established efficacy and safety in select patients under tight control
• There was concern about effect on lungs (pulmonary function and lung cancer), and limited data on long term outcomes of patients with large declines in FEV1 so regulators requested post-marketing study of risk of large declines in pulmonary function

Question 2

Spirometry testing schedule

Answer 2

• Scheduled FEV at baseline and month 6, year 1, year 2, etc.
• Triggered FEV at month 6 (repeat if there is 15-20% decline from baseline)
• Stopping rule (if >20% decline from baseline is confirmed (discontinue exubera)

Question 3

What kind of study was the VOLUME study and what was the rationale?

Answer 3

-They chose a Large Simple Trial and the rationale was that there was a large potential for confounding due to contraindications and a concern that there would be very few patients on EXU with these conditions

Question 4

Study question

Answer 4

Designed to evaluate if long term use of exubera in routine clinical practice was associated with an increased risk of serious outcomes

Question 5

Study Design

Answer 5

-5300 patients with diabetes randomized
-1:1 randomization with EXUBERA or non-EXUBERA (standard of care) groups
-Post approval, open label study, used marketed drug
-FU of 5 years
Spirometry testing required in both groups
-all other care was routine

Question 6

Study Design (-contd-)

Answer 6

• Patients visit enrolling physician
• eligibility criteria based on exubera label
• patient randomly assigned to treatment group
• spirometry measurements per protocol done
• Outcome: persistent decline of FEV1 (>20% from baseline) or not

Question 7

Primary objective

Answer 7

Compare those randomized to EXU and non-EXU to estimate RR of a persistent decline in FEV1 exceeding 20& from baseline

Question 8

Definition of primary endpoint

Answer 8

• Baseline FEV measurement
• decline >20% from baseline at any follow up = discontinue use, but if there is persistent decline throughout FU = primary endpoint
• at the end of 5 years, those not contributing to primary endpoint include patients who: never had a decline >20%, had >20% decline that was unconfirmed, had >20% decline confirmed but not persistent

Question 9

Secondary Objective

Answer 9

Compare those randomized to exubera and non-exubera to estimate: RR of pulmonary serious adverse events (SAEs), all cause mortality, cardiovascular SAEs, allergic reaction SAEs, change in HbA from baseline at specified time points

Question 10

Inclusion criteria

Answer 10

Eligible to receive exubera treatment based on approved local label

• 18 years or older
• evidence of informed consent
• wiling to provide information of another contact
• comply with scheduled visits, and laboratory test

Question 11

Exclusion criteria

Answer 11

-pregnant or lactating
-have progressive fatal disease that prevents 5 year study
-medical or psychological condition that prevents 5 year study
Have participated in any other studies involving study drugs within 30 days prior to entry
-previously enrolled in the study

Question 12

Spirometry measurement

Answer 12

Collected per routine practice and was not standardized

Question 13

Difference between VOLUME Study and LST

Answer 13

VOLUME required patient visits, while regular LST does not and it had softer endpoints, while LST has hard endpoints