pramlintide acetate safety review dragos roman md center for drug evaluation and research
TRANSCRIPT
Pramlintide AcetateSafety Review
Dragos Roman MD
Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research
Pramlintide Acetate Safety Review Outline
• Phase 3 Trials
– Motor vehicle accident (MVA)-related events
• Serious adverse events (SAEs) associated with hypoglycemia (type 1 diabetes)
– Other accident/injury-related events
• Assisted hypoglycemia
Pramlintide Acetate Safety Review Outline
• Phase 3 Trials
– Motor vehicle accident (MVA)-related events
• Serious adverse events (SAEs) associated with hypoglycemia (type 1 diabetes)
– Other accident/injury-related events
• Assisted hypoglycemia
Phase 3 Clinical Trials
• Long-term controlled studies in patients with type 1 diabetes:– 137-121 1 year
– 137-112 1 year
– 137-117 6 months
• Long-term controlled studies in patients with type 2 diabetes:– 137-122 1 year
– 137-123 6 months
– 137-111 1 year
Phase 3 Clinical Trials (Type 1 Diabetes)
Pramlintide Placebo
Total Population 1179 538
Completed Trial 781 (66%) 403 (75%)
Withdrew(all reasons)
398 (34%) 135 (25%)
Withdrew(adverse events)
214 (18%) 31 (6%)
First Month Nausea-Related Withdrawals -Type 1 Diabetes
0
1
2
3
4
5
6
7
137-121 137-117 137-112 All studies
PramlintidePlacebo
% withdrawals
Phase 3 Clinical Trials (Type 2 Diabetes)
Pramlintide Placebo
Total Population 1273 420
Completed Trial 968 (76%) 321 (76%)
Withdrew(all reasons)
305 (24%) 99 (24%)
Withdrew(adverse events)
117 (9%) 31 (7%)
First Month Nausea-Related Withdrawals -Type 2 Diabetes
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
137-122 137-123 All studies
PramlintidePlacebo
% withdrawals
Pramlintide Acetate-Safety Review Outline
• Phase 3 Trials
– Motor vehicle accident (MVA)-related events
• Serious adverse events (SAEs) associated with hypoglycemia (type 1 diabetes)
– Other accident/injury-related events
• Assisted hypoglycemia
Assisted Hypoglycemia: Definition
• Hypoglycemic event that requires:
– oral carbohydrates
– glucagon
– IV glucose
Assisted Hypoglycemia-Type 1 Diabetes Phase 3 Trials: First Month Incidence
0
2
4
6
8
10
12
14
137-121 137-117 137-112 All studies
PramlintidePlacebo
% patients
Assisted Hypoglycemia-Type 1 Diabetes Phase 3 Trials: End of the First Month to The
End of the Trial Incidence
0
5
10
15
20
25
137-121 137-117 137-112 Allstudies
1stmonth
PramlintidePlacebo
% patients
Change in HbA1c: Study 137-121Type 1 Diabetes
Assisted Hypoglycemia-Type 1 Diabetes Phase 3 Trials: Summary
• Pramlintide therapy is associated with a two fold increase in incidence of assisted hypoglycemia when compared to placebo, during the first month of treatment.
Assisted Hypoglycemia-Type 1 Diabetes Phase 3 Trials: Summary
• The difference in incidence of assisted hypoglycemia between pramlintide and placebo groups persists following the first month of treatment albeit to a lower extent.
• This decrease in hypoglycemic events associated with pramlintide takes place in the context of prior nausea-related patient withdrawals and waning drug efficacy.
Assisted Hypoglycemia-Type 2 Diabetes Phase 3 Trials: First Month Incidence
0
0.5
1
1.5
2
2.5
3
137-122 137-123 All studies
PramlintidePlacebo
% patients
Assisted Hypoglycemia-Type 2 Diabetes Phase 3 Trials: End of the First Month to The
End of the Trial Incidence
0
1
2
3
4
5
6
7
8
9
137-122 137-123 All studies 1st month
PramlintidePlacebo
% patients
Assisted Hypoglycemia-Type 2 Diabetes Phase 3 Trials: Summary
• Pramlintide therapy is associated with a three fold increase in incidence of assisted hypoglycemia when compared to placebo, during the first month of treatment.
Assisted Hypoglycemia-Type 2 Diabetes Phase 3 Trials: Summary
• The difference in incidence of assisted hypoglycemia between pramlintide and placebo groups wanes following the first month of treatment.
• This decrease takes place in the context of prior nausea-related patient withdrawals although to a lower extent than in type 1 diabetes.
Assisted Hypoglycemia: Summary
• The incidence of assisted hypoglycemia was higher during the type 1 and type 2 diabetes trials when compared to controls during both time intervals analyzed.
• Hypoglycemia associated with pramlintide was, however, more common in type 1 diabetes patients.
Pramlintide Acetate Safety Review Outline
• Phase 3 Trials
– Motor vehicle accident (MVA)-related events
• Serious adverse events (SAEs) associated with hypoglycemia (type 1 diabetes)
– Other accident/injury-related events
• Assisted hypoglycemia
Serious Adverse Events-Definition
• Death
• Life-threatening
• Hospitalization
• Disability
Deaths Possibly Related to Hypoglycemia
• A 48-year-old male with a 12-year history of type 1 diabetes mellitus with a prior history of “diabetes-related seizures“ died during a nocturnal hypoglycemic seizure (pramlintide 30µg QID).
• 35-year-old male with a 6-year history of type 1 diabetes mellitus died in a motor vehicle accident within 24 hours from the beginning of the trial. “Food was present in the stomach at the post-mortem examination, indicating that the subject had eaten lunch prior to the event.” (pramlintide 90 µg TID).
Pramlintide Acetate Safety Review Outline
• Phase 3 Trials
– Motor vehicle accident (MVA)-related events
• Serious adverse events (SAEs) associated with hypoglycemia (type 1 diabetes)
– Other accident/injury-related events
• Assisted hypoglycemia
Hypoglycemia and Accidents-Type 1 Diabetes
• Motor vehicle accident (MVA)-related events.
• Automobile-related adverse events with no motor vehicle accident reported.
• Other accident/injury-related events (e.g. falls, fractures, lacerations).
MVAs and Automobile-Related Adverse Events-Type 1 Diabetes (All Clinical
Development Program)Pramlintide Placebo
Total Number ofSubjects
2573 904
MVAs(total)
28 (1.8%) 7 (0.66%)
MVAs(with hypoglycemia)
17 (0.66%) 2 (0.22%)
Automobile-relatedHypoglycemic Events(no MVAs)
8 (0.31%) 0
Driving-Related Events Associated With Hypoglycemia -Phase 3 Trials (Type 1
Diabetes)
Treatment Group
Pramlintide Placebo
Total Numberof Subjects
1179 538
Subjects withEvents
18 (1.53%) 2 (0.37%)
Driving-Related Events Associated With Hypoglycemia - Type 1 Diabetes:
Conclusion
• Pramlintide use in addition to insulin is associated with a four fold increase in driving-related events in type 1 diabetes patients.
Other Accidents and Injuries-Type 1 Diabetes (All Clinical Development Program)
Pramlintide Placebo
Total Number of Subjects 2573 904
All Subjects with Events 197 (7.65%) 53 (5.86%)
Subjects with Events andHypoglycemia
10 (0.39%) 2 (0.22)
Other Accidents and Injuries-Phase 3 Trials (Type 1 Diabetes)
Treatment Group
Pramlintide Placebo
Total Numberof Subjects
1179 538
Subjects withEvents(Number and %)
9 (0.76%) 1 (0.18%)
Other Accidents and Injuries- Type 1 Diabetes: Conclusion
• Pramlintide use in addition to insulin is associated with a four fold increase in non-MVA injuries in type 1 diabetes patients.
Severe Hypoglycemia:Labeling Question
• Do we know how to initiate safely pramlintide treatment and avoid the risk of first month hypoglycemia in both patients with type 1 and type 2 diabetes?
Severe Hypoglycemia:Labeling Question
Sponsor’s suggestions:“Initiate treatment with 30 µg or 60 µg of pramlintide per dose in type 1 diabetics and 120 µg per dose in type 2 diabetics”.
FDA comments:
All above doses have been shown to be associated with a two fold increased risk of assisted hypoglycemia during the phase 3 trials.
Severe Hypoglycemia:Labeling Question
Sponsor’s suggestions:“In clinical practice it would be prudent to reduce the patient’s insulin dose, particularly the short-acting insulin administered preprandially by 10-20% at the time of initiation of pramlintide therapy.”
FDA comments:
While such an approach seems prudent it has not been tested in a clinical trial and its potential usefulness remains unknown.
Accidents Associated With Hypoglycemia-Labeling Question
• How can one prevent the four fold risk of driving-related events and the four fold risk of non-MVA injuries associated with hypoglycemia observed in the type 1 diabetes trials?
Time of Driving-Related Events vs HbA1c
4
5
6
7
8
9
10
11
12
0 2 4 6 8 10 12
Months
Hg
bA
1c (
%)
= pramlintide= placebo
SummaryPramlintide therapy results in a small but statistically significant reduction in HbA1c.
This reduction is associated with a two fold increase of severe hypoglycemia during the first month of treatment.
In addition, a four fold increase in hypoglycemia- associated MVAs and non-MVA trauma, was observed in patients with type 1 diabetes.