# Presentation: 531181

## Pramlintide AcetateSafety ReviewDragos Roman MD

**Center for Drug Evaluation and Research**

**Notes:**
The purpose of this presentation is to discuss solely the major safety issues that are associated with the use of pramlintide in the treatment of patients with type 1 and type 2 diabetes.
Our review process has covered extensively a vast majority of the safety information submitted to the Agency. While a few areas are still under review, the only important safety signal we have come across so far is severe hypoglycemia.
Therefore the focus of this safety review is the severe hypoglycemia as it has been observed during the long-term controlled pramlintide studies.

## 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

**Notes:**
In this presentation I will cover the following topics:
First I will briefly describe some of the features of the phase 3 clinical trials in order to provide an understanding of the clinical context during which severe hypoglycemia occurs.
Second, I will discuss two distinct aspects of severe hypoglycemia: assisted hypoglycemia, defined as any hypoglycemic event requiring another person’s help for treatment 
, and Serious Adverse Events (SAEs) associated with hypoglycemia in type 1 diabetes. 
As an extension of the SAE category I will discuss motor vehicle accidents associated with hypoglycemia and other types of trauma and injuries associated with hypoglycemia as they occur during the phase 3  type 1 diabetes trials.

## 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

**Notes:**
Both assisted hypoglycemia and SAEs associated with hypoglycemia will be discussed in the context of the long term-controlled phase 3 clinical trials.

## 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

**Notes:**
Among the 51 studies which constitute the pramlintide clinical program the phase 3 studies allow the most extensive side by side comparison between the pramlintide and placebo treatments, both in terms of duration (up to one year) and number of patients (over 2000).

From the start I would like to make the following clarification: in this presentation pramlintide treatment will always mean pramlintide injection plus insulin injection, and placebo treatment will always mean placebo injection plus insulin injection.

## Phase 3 Clinical Trials (Type 1 Diabetes)

**Notes:**
Shown here is a cumulative summary of the phase 3 type 1 diabetes trials:
-enrolled in the study
-subject randomization ratio 3:1
-only 75 completed the trial and an even lower number 66
-withdrawals were higher in the pramlintide group 
-there was a 3 fold difference over placebo
An adverse event with unusually high frequency resulting in early withdrawals in the pramlintide treatment group was nausea.

## First Month Nausea-Related Withdrawals -Type 1 Diabetes

- % withdrawals

**Notes:**
Shown here is  the frequency of nausea-related withdrawals during the 1st month of treatment in the type 1diabetes trials:
	-Y axis
	-Yellow bars
	-blue bars
	-individual studies and all studies
It is quite striking that nausea-related withdrawals occur across all studies many times over placebo. 
On the average there is a 17 fold ratio between % of nausea-related withdrawals in the pramlintide group and the placebo group respectively).
The net effect of this occurrence is the early preferential loss in the trial of patients sensitive to the effects of pramlintide.

## Phase 3 Clinical Trials (Type 2 Diabetes)

**Notes:**
Shown here is the cumulative summary of the phase 3 type 2 diabetes trials:
-same number enrolled in the study
-same subject randomization ratio 3:1
-only 76% completed the trial but equal proportion in both groups
-withdrawals were equal between treatment groups 
-but there were more withdrawals due to adverse events in the pramlintide group 9% vs 7%
Nausea was also a reason for first month withdrawals during the type 2 diabetes trials albeit to a lesser extent.

## First Month Nausea-Related Withdrawals -Type 2 Diabetes

- % withdrawals

**Notes:**
This slide displays the frequency of nausea-related withdrawals during the 1st month of the phase 3 type 2 diabetes trials:
	-Y axis; It should be noticed that the values on the Y axis are smaller than in the previous slides shown for type 1 diabetes patients.
	-Yellow bars
	-blue bars
	-individual studies and all studies
Overall, a two fold difference between pramlintide and placebo nausea-related withdrawals is present..
First month nausea-related withdrawals are 4 times less frequently than during the type 1 trials.

## 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

**Notes:**
With this general information in mind about the phase 3 trials I would like to move on and discuss one of the aspects of severe hypoglycemia: assisted hypoglycemia.

## Assisted Hypoglycemia: Definition

- Hypoglycemic event that requires:
- oral carbohydrates
- glucagon
- IV glucose

**Notes:**
Assisted hypoglycemia has been defined as any episode of hypoglycemia requiring the help of another individual for treatment: oral, glucagon, glucose/

This definition of severe hypoglycemia has been applied consistently in all three 1 diabetes trials, and in two of the three type 2 diabetes trials.

Analysis of the time of occurrence of assisted hypoglycemia during the phase 3 trials has been presented to the Agency stratified by 2 time intervals: assisted hypoglycemia occurring during the first month of the trial and assisted hypoglycemia following the end of the first month up to the completion of the trial.

## Assisted Hypoglycemia-Type 1 Diabetes Phase 3 Trials:  First Month Incidence

- % patients

**Notes:**
Shown here is the incidence of subjects who experienced assisted hypoglycemia during the first month of pramlintide treatment in the type 1 diabetes.
	Y axis is % of patients with at least one episode of hypoglycemia
	Yellow bars
	Blue bars
	The data for individual studies and all studies combined
One can observe consistently a two fold difference in incidence between pramlintide and placebo.
Individual and combined studies.
A different picture emerges though after the first month.

## Assisted Hypoglycemia-Type 1 Diabetes Phase 3 Trials:  End of the First Month to The End of the Trial Incidence

- % patients

**Notes:**
This slide depicts the incidence of assisted hypoglycemia after the end of the first month and up to the completion of the trial.
Y,yellow,blue 
Individual studies and all studies combined.
 It should be noticed that the Y scale values are different than those shown in the previous slide. Therefore I included the pram-to-plac. comparison as observed during the first month of the trial in pale colors.
 In contrast to the first month of teatment the difference in incidence between pramlintide and placebo is less obvious but still present. 
It should be noted that the incidence is cumulative for 11 months in studies 121, 112 and 5 months for 117.

When we contemplate this particular slide we need to keep two things in mind:
	-the patient population observed here is not the patient population which started the trial.  As shown previously the first month of pram treatment is associated with 17 fold higher withdrawal ratio in the pram group.  Therefore subjects sensitive to the drug discontinue early.
	-2nd: the occurrence of hypoglycemia has to be looked at in the context of efficacy.

## Change in HbA1c: Study 137-121Type 1 Diabetes

**Notes:**
Shown here are the HbA1c changes during a representative type 1 diabetes trial: study 121.
Y=mean change of HbA1c from baseline 
X is time in the trial
HbA1c changes in the placebo group are shown at the top
HbA1c changes in the pramlintide group for a variety of doses are shown at the bottom.
The first month of treatment which is associated with a two fold increase in assisted hypoglycemia also has a more pronounced drop in HbA1c
The remainder of the trial is associated with both a waning of Hg A1c benefit as well a decreased incidence of assisted hypo.

## 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

- % patients

**Notes:**
Some similarities to the type 1 diabetes trials are present during the type 2 diabetes phase 3 studies.
Shown here is the incidence of subjects who experienced assisted hypoglycemia during the first month of pramlintide treatment in the type 2 diabetes.
Y
X
orange
blue
Individual studies and all studies. 
The first month of treatment is associated with a 3 fold increase in assisted hypo over placebo overall.

It should be noted that the incidence is lower compared to the type 1 diabetes trials. (3% vs 13%).

## Assisted Hypoglycemia-Type 2 Diabetes  Phase 3 Trials:  End of the First Month to The End of the Trial Incidence

- % patients

**Notes:**
Shown here is the incidence of assisted hypo. in type 2 diabetes trials following the first month of treatment.
 Y ,,Yellow ,Blue Individual and combined 
It should be noticed that the Y scale values are different than those shown in the previous slide. Therefore I included the pram-to-plac. comparison as observed during the first month of the trial in pale colors.
When one observes assisted hypoglycemia for the rest of the trial duration in type 2 diabetes the differences in assisted hypoglycemia incidence is minimal and inconsistent between trials.
1 year study 122: no difference
6 month study 123: 2 fold difference
overall: a small difference is present 
One should keep in mind that the incidence is cumulative for 11 months for 122 and for 5 months for 123.
We also need to keep in mind that the 1st month nausea withdrawals were higher for the pramlintide group and also interpret the hypoglycemia in the context of decreasing efficacy with time.

## 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.

**Notes:**
And finally we should remember:

## 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

**Notes:**
SAEs are defined as adverse events that result

## 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).

**Notes:**
We feel that the presence of food in the stomach is a fact of significant concern when one of the major effects of pramlintide is a delay ingastric emptying.

An additional patient, 31 years of age with no other past medical history except for type 1 diabetes also died in the pramlintide treatment group.  Although his death was hypothesized to have been due to an alcohol problem the evidence is inconsistent and circumstantial.

## 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

**Notes:**
During the review process the observation was made that SAEs associated with hypoglycemia occurred 2-3 times more frequently during the pramlintide treatment over placebo in the type 1 diabetes trials.
In search for a possible explanation the patients narratives were reviewed in detail.
As a reminder, patient narratives are brief descriptions of the events and circumstances which lead to a subject’s withdrawal from the study, death or or life-threatening events.
A total of 20 Motor vehicle accidents and other driving-related events occurring in conjunction with hypoglycemia were thus identified along with several different injuries.
Therefore the Agency has requested an analysis of all MVAs and trauma occurring in association with hypoglycemia during the pramlintide clinical program.

## 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).

**Notes:**
These events have been presented to us in the following categories:
1st category: MVAs-related events. This is a self-explanatory category and involves a patient behind the wheel loosing control of the car with a subsequent collision.
2nd category is: Automobile-related adverse events with no motor vehicle accident reported.  As this title suggests this is a less specific category: it may involve a patient behind the wheel who is able to stop in time before a collision occurs, or an event taking place in the car in the parking lot, or an event occurring at about the time when the patient is entering or leaving the car.

3rd category : other accident/injury-related events.  This category includes a whole range of non-MVA related trauma such as falls, fractures, lacerations.

## MVAs and Automobile-Related Adverse Events-Type 1 Diabetes (All Clinical Development Program)

**Notes:**
Shown here are the MVAs and the automobile related adverse events presented for the entire pramlintide clinical program.
MVA with and without hypoglycemia.
Automobile related: all associated with hypoglycemia.
Before going any further it should be noted that these events have been collected from the entire clinical program including for instance patients in uncontrolled studies and pre-phase 3 studiess.  This analysis does not allow a direct pramlintide to placebo comparison.
Total numbers
Hypoglycemia (3:1)
None in the automobile category.
We feel that both categories represent in essence different facets of the same range of events of hypoglycemia in the context of the driving activity and that they should be analyzed together.  
In such a analysis: 25 to 2.
As I mentioned before a balanced analysis of these events should involve the pramlintide to placebo comparison limited to the phase 3 controlled studies.

## Driving-Related Events Associated With Hypoglycemia -Phase 3 Trials (Type 1 Diabetes) 

**Notes:**
Such an analysis is presented in this slide as driving-related events associated with hypoglycemia  in the phase 3 type 1 diabetes trials.
Total number
Subjects with hypoglycemia
Analysis of the details pertaining to the placebo subjects has allowed us to make the observation that one of the placebo subjects experienced an MVA three days after the termination of the study and we feel that the number of placebo patients with a driving-related event is limited to one.
Irrespective, there is a four fold difference between the two groups.
It should be kept in mind that these driving-related events have not been actively ascertained during any of the clinical trials and they may be grossly underestimated.

## 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)

**Notes:**
Shown here is a summary of the non-Mva or “other accidents and injuries” which occurred during the type 1 diabetes pramlintide clinical program.
Again, it should be noted that these events have been collected from the entire clinical program including uncontrolled studies and pre-phase 3 studies.  This analysis does not allow a direct pramlintide to placebo comparison.
Total number
Subjects with hypoglycemia.
We have identified at least 2 more patients in the data base who fit this category:
137-121-5030: fall and facial laceration and 
137-117-6303: fell from a tree, broken elbow
Number should be 12.

## Other Accidents and Injuries-Phase 3 Trials (Type 1 Diabetes)

**Notes:**
As I mentioned before a balanced analysis of these events should involve the pramlintide to placebo comparison limited to the phase 3 controlled studies.

## 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?

**Notes:**
I would like to finish with 2 labeling safety questions

## 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?

## = pramlintide

- = placebo

**Notes:**
This is a particularly difficult question as illustrated by this slide.
Shown here is the time distribution of all driving related events associated with hypoglycemia during the phase 3 type 1 diabetes trials.
Shown on the y axis is the Hb A1c at the time when the event took place.
Yellow blue purple
Several troublesome observations are noted:
 although 1st month clustering 2/3 of events occur during the duration of the whole trial and at a whole range of HbA1c level.
Prediction of which subject will experience such an event appears impossible. The events appear unpredictable.

## Summary

**Pramlintide 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.**