The Current Status of Vagus Nerve Stimulation VNS

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The Current Status of Vagus Nerve Stimulation
(VNS)

• Lauren Marangell M.D.
• Brown Foundation Chair, Psychopharmacology of
  Mood Disorders
• Associate Professor of Psychiatry
• Baylor College of Medicine

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Objective Discuss the long-term efficacy
and safety data for the use of vagus nerve
stimulation in treatment-resistant mood disorders
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Disclosure

• The VNS device is manufactured by Cyberonics,
  Inc. Dr. Marangell has received research support,
  consulting fees and speaking fees from
  Cyberonics. The data presented are from studies
  funded by Cyberonics.

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Off Label Use

• The use of VNS for depression and other
  psychiatric indications in the United States is
  currently investigational
• VNS Therapy is approved for medically refractory
  partial-onset seizures, ages 12 and up.
• The US FDA has stated that VNS Therapy is
  approvable for treatment-resistant mood
  disorders.

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Vagus Nerve Stimulation (VNS)

• Pulse generator implanted in left chest wall
  area, connected to leads attached to left vagus
  nerve
• Outpatient procedure

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VNS Therapy Programming

• Telemetric wand attached to a PC
• ON/OFF cycle is programmable
• Typical cycle
• 30 sec ON
• 5 min OFF

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Rationale for InvestigatingVNS Therapy in
Depression

• Improved mood among patients receiving VNS
  Therapy for the treatment of epilepsy1,2
• Anatomy and Physiology
• Stimulating the vagus nerve produces effects on
  norepinephrine and serotonin3
• Brain imaging studies have shown that VNS Therapy
  modulates blood flow or metabolism in many areas
  of the brain that are implicated in
  neuropsychiatric disorders4
• Huge unmet need

1Harden CL, et al. Epilepsy Behav.
20001(2)93-99 2Elger G, et al. Epilepsy Res.
200042(2-3)203-210 3Rutecki P. Epilepsia.
199031(suppl 2)S1-S6 4Henry TR, et al.
Epilepsia. 199839(9)983-990.
E-4
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Pilot Study Design (D01, 4 site)
Acute Study 12 weeks
ScreeningandBaseline
StimulationAdjustment
Fixed DoseVNS
Recovery
Long-term Study
ImplantDay 0
2 weeks
2 weeks
8 weeks
Rush AJ, et al. Biol Psychiatry.
200047276-286. Sackeim HA, et al.
Neuropsychopharmacology. 200125713-728.
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Pilot Study HRSD28 Response and Remission Rates
Over 2 Years (LOCF)
1LOCF for patients completing at least 1 visit
beyond 12 months of long-term follow up
Remission defined as HRSD28 ?10
Evaluable LOCF
Rush et al. Presented at the 43rd Annual New
Clinical Drug Evaluation Unit Meeting, 2003Boca
Raton, Florida.
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Pivotal Study Design (D02, 21 sites)
VNS Therapy Group
StimulationAdjustment
Fixed Dose VNS
Long-term Study
2 weeks
8 weeks
Implant
Randomize Recovery
Baseline
45 days
2 weeks
Sham Stimulation Group
PMA-S Submission, October 2003
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Types of Outcome Analyses
PMA-S Submission, October 2003 D-02 Long-Term
Statistical Plan
E-13
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Pivotal Study Baseline Demographics
Data not available for 1 patient in the control
group
PMA-S Submission, October 2003
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Pivotal Study Acute Results(12 Weeks)
IDS-SR30
PMA-S Submission, October 2003
Evaluable Observed
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Pivotal Study Long-Term Design
VNS Therapy Treatment Group Sham-Control
Crossover Group
End of Acute Study
1-year post implant
Quarterly Visits Until Study Termination or FDA
Approval
Monthly Visits for 1 Year of VNS Therapy
For acute non-responders, the protocol
recommended changing VNS parameters first, and
then adjusting medications
PMA-S Submission, October 2003
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Pivotal Study Long-Term Response
Response defined as ?50 reduction in HRSD24,
MADRS, IDS-SR30 compared with pre-stimulation
baseline
PMA-S Submission, October 2003
Evaluable Observed and LOCF
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Pivotal Study Long-Term Remission
Remission HRSD24 raw score ?9 MADRS raw score
?10 IDS-SR raw score ?14
Evaluable Observed and LOCF
PMA-S Submission, October 2003
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Pivotal Study Long Term IDS-SR Sustained
Response
PMA-S Submission Amendment, September 2004
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Pivotal Study Long Term HRSD24 Sustained
Response
PMA-S Submission Amendment, September 2004
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Average IDS for D-02 Patients With and Without an
ARR Increase
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D-02/D-04 Comparison Study
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D-04 An Observational Study of Long-Term
Outcomes in TRD

• 13 total study sites, including 12 from D-02
• Similar study enrollment criteria with D-02
• Similar age and sex distribution with D-02
• Similar level of treatment resistance with D-02
• Similar clinical characteristics
• Subjects received treatment as usual in the
  community with ratings at the site

PMA-S Submission, October 2003
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Comparison Study Patient Populations are
Comparable
PMA-S Submission, October 2003
Evaluable Observed
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Comparison Study Analyses

• Primary Efficacy Analyses
• Repeated measures linear regression analyses on
  raw IDS-SR30 scores over 12 months of
  stimulation
• Secondary Efficacy Analyses
• Additional IDS-SR analyses (raw scores, R, CR,
  ?)
• HRSD24 (raw score ?, R, CR, ?)
• HRSD6 (raw score ?, ?)
• CGI-I
• 9 subscale totals from the MOS SF-36
• Medication use

PMA-S Submission, October 2003/D-02/D-04
Comparison Statistical Analysis Plan
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Propensity Score

• To control for D-02 and D-04 differences in
  patient and disease characteristics, a propensity
  score was incorporated in the primary efficacy
  analysis
• Used to adjust for non-random treatment
  assignment
• Confirmed that differences were few and did not
  account for the difference in efficacy outcomes

Executive Summary, PMA-S Submission, October 2003
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Statistical Significance Demonstrated for
Primary Comparison Study Analysis
PMA-S Submission, October 2003
Evaluable Analysis
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Comparison Study 12-Month IDS-SR30Response and
Remission Rates
D-02 Observed n180, LOCF n204 D-04 Observed
n112, LOCF n124
PMA-S Submission, October 2003
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Secondary AnalysesCategorical Outcomes at 12
Months
PMA-S Submission, October 2003
Evaluable Observed
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Difference in Outcomes Between D-02 / D-04 Not
Attributable to

• Baseline features because results hold with and
  without propensity adjustments
• Medication changes (D-02 had fewer than D-04)
• Placebo response is time-limited and does not
  grow over time
• Different slopes in D-02, D-04 after 3 months
• Different time-to-response curves

Executive Summary, PMA-S Submission, October 2003
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Comparison Study Summary

• Comparable, highly treatment-resistant groups at
  baseline
• Statistically significant result favoring
  adjunctive VNS therapy group on primary analysis
  (plt0.001)
• Statistical significance in both evaluable and
  ITT analyses
• Differences confirmed by secondary analyses using
  multiple outcome measures

Executive Summary, PMA-S Submission, October 2003
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Medical Management in Comparison Study

• Medication use was essentially the same between
  D-02 and D-04 patients
• D-04 patients actually had more medication
  changes than D-02 patients
• Among D-02 patients, non-responders had more
  medication changes than responders

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D-02 Responders Had Significantly Fewer
Antidepressant Medication Changes
Percent of Patients with Additions or Increases
in Antidepressant Medications
Compared with D-02 Responders Two D-04
patients had no medication data
PMA-S Submission, October 2003
Evaluable LOCF
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Concomitant Mood Disorder Treatments Taken During
the Study
Evaluable LOCF
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Long-Term Safety Profile Improvement

• Minimal new side effects after 3 months
• Majority of side effects mild or moderate in
  severity initially
• Decreased incidence over time
• Accommodation

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Side Effects Typically Diminish Over Time
125
100
03 Months
3-6 Months
6-9 Months
9-12 Months
75
Number of Patients Reporting Event
50
25
0
Pain
Nausea
Dyspnea
Neck Pain
Headache
Dysphagia
Pharyngitis
Paresthesia
Laryngismus
Voice Alteration
Cough Increased
Side effects shown are those that occurred at an
incidence gt5 during the first 3 months of VNS
PMA-S Submission October 2003
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Safety
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Depression Studies Safety Overview

• Side effects are mainly stimulation-related and
  typically decrease over time
• Low rate of treatment-related discontinuation
• No signal for treatment-related emergence of
  suicidal ideation/behavior
• Emergent mania/hypomania within range expected
  for effective antidepressant
• Overall, VNS therapy was well-tolerated and safe

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Conclusions

• Improvements observed with adjunctive VNS therapy
  are largely sustained during long-term treatment
• VNS therapy is well-tolerated and safe in
  depression clinical trials and clinical use in
  epilepsy
• VNS therapy has additional device-related
  benefits vs standard-of-care treatments