Stewart J. Tepper, MD l 1 Neuromodulation and Headache Disorders Stewart J. Tepper, MD Professor of...

Stewart J. Tepper, MD l 1

Neuromodulation and Headache Disorders

Stewart J. Tepper, MD Professor of Medicine (Neurology)

Cleveland Clinic Lerner College of Medicine

Co-Director of Research

Neurological Center for Restoration

Neurological Institute

Cleveland Clinic

Disclosures for 2015• Grants/Research Support (no personal compensation):

– Alder, Allergan/MAP, Amgen, ATI, ElectroCore, eNeura, GSK, Labrys/Teva, Pernix, Optinose/Avanir/Otsuka

• Consultant:

– Acorda, Allergan, Amgen, ATI, Avanir, Depomed, Impax, Pfizer, Teva, Zosana,

• Speakers Bureau:

– Allergan, Depomed, Impax, Pernix, Teva

• Advisors Board:

– Allergan/MAP, Amgen, ATI, Avanir, Dr. Reddy’s, Lilly, Merck, Labrys/Teva, Pfizer

• Stock options:

– ATI

• Royalties:

– University of Mississippi Press, Springer


Neuromodulation and Headache Outline

• Overview

• FDA approved:o Transcranial magnetic stimulator for acute treatment of migraine w/aura

(SpringTMS)- Phase 4 in selected centers

o Transcutaneous supraorbital neurostimulation (tSNS) for prevention of migraine (CEFALY)- available

• Not FDA approved:– Non-invasive vagal nerve stimulator (nVNS, gammaCore)

– Sphenopalatine ganglion stimulation (SPG, PULSANTE)

– Occipital Nerve Stimulation (ONS)

– Deep Brain Stimulation (DBS)


Clinical Plan is to Work Up from the Bottom, Least Invasive, Most Convenient, to Maximally Invasive

Maximally invasive

•Deep brain Stimulation (DBS)

Minimally invasive

•Occipital Nerve Stimulation (ONS)

•SPG Stimulation

Noninvasive

•tSNS

•Transcranial Magnetic Stim (TMS)

•nVNS


Neuromodulation for migraine: FDA approved

• Transcranial magnetic stimulator for acute treatment of migraine with aura (SpringTMS)

• Transcutaneous supraorbital neurostimulation (tSNS) for prevention of migraine (CEFALY)


Non-invasive FDA Approved Neuromodulation2. Transcranial Magnetic Stimulation (TMS)

• TMS is able to disrupt rat cortical spreading depression

• TMS modifies excitability of cortical areas• Effect may also be thalamocortical inhibition• sTMS = single pulse• rTMS = repetitive (trains) • 1Hz=inhibitory, 10Hz=excitatory

Holland et al. Cephalalgia. 2009;29(Suppl 1):22.

Andreou et al. Headache. 2010;50(Suppl 1):58.

Summary of TMS Prevention Randomized Controlled Trials (RCTs) Authors N Methods Results Comments

Brighina et al. 2004.

11 Hi-f 10 hz rTMS NS

Teepker et al. 2010.

27 Low-f rTMS NS

Misra et al. 2013.

100 Hi-f 10 hz rTMS60 CM, 28 MOH, MO & MA, >4 attacks/mo, no preventive meds

Positive1-month:↓ HA f↓ VAS severity↓ Disability

One patient withdrawn due to drowsiness

Conforto et al. 2014.

18 Hi-f 10 hz rTMS forCM

NS ↓ HA f >50% in sham group


• N=164 (82 sham); 2 pulses 30 sec apart within 1 hour of aura onset

• 2 h pain-free (PF): 39% TMS vs 22% sham (p=0.0179)

• Sustained 2-24 h PF: 29% TMS vs 16% sham (p=0.0405)

• Sustained 2-48 h PF: 27% TMS vs 13% sham (p=0.0327)

• AEs rare: sinusitis, aphasia, vertigo, dizziness

Therapeutic gain = 17%

sTMS RCT for Acute treatment of M W/Aura (≥30% of attacks)

8

SpringTMS

Lipton et al. Lancet Neurol. 2010;9:373-80.

Transcranial Magnetic Stimulation (TMS)Acute Level of Evidence is B, Prevention U

• CE mark in the EU 2013 for single pulse TMS

• FDA approved sTMS on Dec 13, 2013 for “acute treatment of pain associated with migraine with aura” with 2 pulses / 24 hours

• The FDA approved sTMS through a “de novo premarket review pathway …for some low- to moderate-risk medical devices”

• For Acute treatment:– One Class 1 RCT (Lipton et al), for acute treatment of migraine with aura

– Level B, Probably Effective, based on one Class 1 study, but it is FDA approved already

• For prevention of migraine, Level U, 4 RCTs with conflicting data:– One positive RCT (Misra et al), 3 negative RCTs

• Future RCTs need to be on dose ranging, MO, prevention, and AEs

• Phase 4 studies underway at selected centers in US and UK

Neuromodulation for migraine: FDA approved

• Transcranial magnetic stimulator for acute treatment of migraine with aura (SpringTMS)

• Transcutaneous supraorbital neurostimulation (tSNS) for prevention of migraine (CEFALY)


tSNS RCT PREMICE Trial • 67 patients randomized to verum (n = 34) and sham (n = 33)

• Episodic migraine wwo aura, with ≥2 attacks/month, no prevention for 3 mos, 30 day baseline using paper diaries

• 3 months of 20 minutes/day device vs sham (90 sessions)

• Adverse events “none” yet all subjects experienced “strong paresthesias”

• Primary outcomes in third month:1. Change in monthly migraine days in run-in vs third month: not significant

2. ≥ 50% reduction in migraine days/month: (+) for 38.2%

Stewart J. Tepper, MD l 11 Schoenen et al. Neurology 2013;80;697-704.

Change in HA days (NS)P = 0.054

50% Responder RatesP = 0.023

More on the tSNS

• One setting with 2 ramping intensities

• Cost: $349 plus $35 for shipping, not generally covered by insurance

• Prescription must accompany each order

• 3 pack of electrodes is $25, with an additional $5 for shipping

• Each electrode pad lasts between 15 and 30 sessions

• The company accepts only Visa, Mastercard, and PayPal

• It can be returned within 60 days

• tSNS received FDA approval March 2014 for minimal risk device: 1 RCT

• Level of Evidence: Level B, probably effective, based on 1 RCT

Stewart J. Tepper, MD l 12 Tepper D. Headache 2014;54:1415-6.

Neuromodulation

• FDA approved:o Transcranial magnetic stimulator for acute treatment of migraine w/aura (SpringTMS)- Phase 4 in

selected centers


o Not FDA approved:

–Non-invasive vagal nerve stimulator (nVNS, gammaCore)– Sphenopalatine ganglion stimulation (SPG, PULSANTE)

– Occipital Nerve Stimulation (ONS)



Trigemino-cervical complex

spinal cord

LPBMedial

parabrachialnuclei

N. tractussolitarius

Pain inhibition

Parabrachial Complex

14

VagusnerveVagusnerve

Sensory-discriminative

aspects of pain

Emotional &autonomic

dimensions of pain

Thalamus

Other limbic regions

Somato-sensory cortex

AmygdalaHypothalamus

Frontal cortex

Attentionarousal

CCourtesy of Jean Schoenen and Stephen Silberstein, MD

Afferent limb

+

• gammaCore by electroCore Medical, LLC is a handheld, patient-controlled nVNS device

–Produces a uniform electric field across the surface of the electrodes

–Selectively stimulates low-threshold myelinated afferent A fibers, but not higher-threshold C fibers

–Delivers 90-second stimulations that can be used repeatedly

15

Development of a Non-Invasive Vagus Nerve Stimulator (nVNS)

Prevention of Chronic Migraine (EVENT) Study RCT

Author Methods Results Comments

Silberstein et al. 2014 (abstract).

CM sham controlled RCT followed by OLE; Two 90 sec pulses TID

NS at 2 mos -With nVNS:15% had ↓≥50% during RCT -Clinically meaningful & progressive ↓HA days during OLE

Silberstein et al. Headache 2014;54:1426-7 (Abstracts LBP19, 21).

• Two 90 second stimulations TID• No effect observed with sham,

no significant difference from nVNS (-2.0 vs -0.1; P=.1821)

Two 90 second stimulations TID

-2.0 -0.1

17

nVNS Duration on Headache Days per Month: The Longer Used, the Better

Ch

ang

e F

rom

Bas

elin

e in

Nu

mb

er o

f H

ead

ach

e D

ays

per

28

Day

s O

ver

Tim

e

0 Months 2 Months 4 Months

6 Months

nVNS Treatment Duration

Silberstein et al. Headache 2014;54:1426-7 (Abstracts LBP19, 21).Data presented as mean change from baseline. Post hoc analysis of the pooled per-protocol populations.

*P<.05 vs baseline (0 months)†P<.01 vs baseline (0 months)

*

*†

Cluster RCTs nVNS

Authors N Methods Results Comments

Gaul et al. EHMTIC 2014.

Silberstein et al.AHS 2015

93

150

CCHPrevention: SOC + nVNS vs SOC (no placebo), then OLE w/nVNS + SOC

ECH & CCHAcute, sham controlled

Positive ↓CH attacks/wk from baseline;-50% responder rate-↓ rescue meds & O2, compared with SoC

NS15 min response rate

-↓Longer treatment duration associated w/ even better -↓CH attacks fFew nVNS AEs

Positive for 2° endpoint, sustained response

Gaul. EHMTIC meeting, Copenhagen, Sept 2014.

Adverse Events nVNS

• AEs are transient, and for the most part, very mild

• Most common AEs:• Mild to moderate neck pain (local discomfort)• Mild skin reaction to gel• Worsening of pain• Oropharyngeal pain• Paresthesias• Facial twitching/spasms


Peripheral Handheld Non-invasive Vagal Nerve Stimulator(nVNS) for Migraine: Level U; for Cluster, Level C or U

One RCT for Prevention of Chronic Migraine1, negative for primary endpoint, showed increasing benefit over continued use, Level U, inadequate or conflicting data

One RCT for Prevention of Cluster Headache2, positive for primary endpoint, Level C (no placebo)

One RCT for Acute Treatment of Cluster Headache3, negative for primary endpoint, positive for secondary endpoint, Level U

Already approved with CE mark in the EU; also approved in Canada, may be filing for US approval in 2015

.1. Silberstein et al. Headache 2014;54:1426-7 (Abstracts LBP19, 21).2. Gaul. EHMTIC meeting, Copenhagen, Sept 2014. 3. Silberstein et al. AHS scientific meeting, June 2015.

Neuromodulation for migraine

• FDA approved:o Transcranial magnetic stimulator for acute treatment of migraine w/aura (SpringTMS)- Phase 4 in

selected centers


o Not FDA approved:– Non-invasive vagal nerve stimulator (nVNS, gammaCore)

–Sphenopalatine ganglion stimulation (SPG, PULSANTE)– Occipital Nerve Stimulation (ONS)




The Sphenopalatine Ganglion (SPG)

Stewart J. Tepper, MD l 23 Lance and Goadsby. Mechanism and Management of Headache. Elsevier:2005.

SPG Innervations: Sympathetic postganglionic pathways pass through the SPG without synapsing;Parasympathetics synapse in SPG

The SPG is the final switching station for cluster and migraine

Burstein,Jakubowski. J Comp Neurol 2005;493:9-14.

Sphenopalatine ganglion [SPG]

SSN

Post/InferiorHypothalamus

Edvinsson, Goadsby. Cephalalgia 1994;14:320-7.

SPG Stimulation Therapy with Implanted System• Miniaturized implant stimulates the SPG

• Change of paradigm - Wirelessly powers and controls the neurostimulator with no external batteries or wires

• Implanted through the mouth

• On-demand, patient-controlled therapy

• Rechargeable through USB port

• Internet connected

• On / Off Button, Programmable Up / Down Buttons (amplitude adjustment)

25Schoenen et al. Cephalalgia 2013;33: 816–830.

Efficacy of the Implanted SPG Stimulator(PULSANTE)


• Randomized, controlled, blinded, prospective multi-center study

• Minimum 4 attacks/week, dissatisfied with current treatment

• Random insertion of placebo & subthreshold stimulation study design

• Initial 28 patient results published in Cephalalgia 2013, another 11 recruited subsequently

• Final N = 38 patients; 769 cluster attacks treated presented at IHC Boston June 2013

End of Experimental PeriodAnalyses

1. Attack Pain relief at 15 minutes2. Attack frequency % change vs.

baseline

Start of Long-Term Follow-Up (LTFU) Period Analyses

1. Patient Satisfaction Survey2. HIT-6 headache disability change vs.

baseline3. SF-36v2 quality of life change vs.

baseline4. Preventive meds usage vs. baseline

Pathway CH-1 Study: SPG Stimulation for the Treatment of Chronic Cluster Headache

Schoenen et al. Cephalalgia 2013; 33(Supplement 8):101-102. Schoenen et al. Cephalalgia 2013;33: 816–830.

The SPG stimulator worked acutely, preventively, or bothN=38 patients at end of experimental period, 769 attacks analyzed)

Acute treatment: 55% of attacks with pain relief 15 minutes vs 6% sham

Preventive effect: 42% of patients had 89% decreased attack frequency

Stewart J. Tepper, MD l 28 Schoenen et al. Cephalalgia 2013;33: 816–830. Schoenen et al. Cephalalgia 2013; 33 (Supplement 8):101-102.

Responders:–Pain relief in ≥ 50% of evaluable, treated attacks–≥ 50% reduction in attack frequency vs. baseline–Or both

SPGS Responder Rates (RR) for Cluster, RCT CH-1 through 24 months

68% Overall RRN = 28 patients

29

Experimental period18 Months Post Implant


36%Acute

12%Both39%

Frequency

25%Acute

7%Both36%

Frequency

May A. EHMTIC 2014.Jensen R. IHC 2015.

24 Months Post Implant


45%Acute

30%Frequency

15%Both

• The system is well tolerated

• Safety evaluated in 99 cluster patients (Pathway CH-1 & Registry studies)

• Most common surgical side effects occur within 30 days of the surgery and are mild and temporary:

– 67% experience sensory disturbances– 47% experience pain and/or swelling– Peri-operative AEs resolved within avg. 90 days

• Does lead motion interfere with jaw motion? No

• After insertion, no scars and the device cannot be seen

• Adverse events and side effects similar to those reported in other oral procedures

30Schoenen et al. Cephalalgia 2013;33:816-30; Hillerup et al. ICOMS, Barcelona, October 2013. Hillerup et al. (Poster) Presented at the 4th EHMTIC, Sept. 2014.

Safety profile

Circling back to the mechanism of action: is the SPG Stimulator Inhibiting or Activating SPG Parasympathetic Output?


Is the SPG Stimulator Inhibiting or Activating SPG Parasympathetic Output?• Hypotheses: Information block on outflow; Stimulation depletes

neurotransmitters, resulting in ↓outflow

• Study: Low frequency SPG neurostimulation induces immediate cluster-like headache attacks w/autonomic symptoms: activates

• High frequency SPG neurostimulation terminates cluster attacks : inhibits outflow

• This study is a dramatic confirmation of the pathophysiology of the device and how SPG stimulation affects cluster

Stewart J. Tepper, MD l 32 Schytz et al. Cephalalgia 2013; 33:831–841.

Hyper-activation and Neurotransmitter depletion

Information block on outflow


SPG Stimulation from Implant Inhibits Outflow

Level of Evidence Implanted SPG stimulation for Cluster: For primary acute endpoint: Level B, probably effective For additional preventive endpoint: Level C, possibly effective

• Cluster RCT showed both acute and preventive efficacy, one RCT, CH-11

• Implanted ATI SPG stimulator (brand name Pulsante) has a CE Mark in Europe & is reimbursed for implant in several countries including Germany and Denmark as first-line treatment for CCH based on the RCT and open-label f/u2-4

• >200 Chronic and Episodic Cluster patients implanted in Europe, with about 2/3 of them responding, some remitting

• US pivotal RCT, CH-2, is underway and implanting patients at multiple sites

• Once approved in the US, we would use non-invasive neuromodulation first (assuming that works); then, some level of medication failure would be necessary before proceeding to SPG implantation

Schoenen et al. Cephalalgia 2013;33: 816–830; Schoenen et al. Cephalalgia 2013; 33 (Supplement 8):101-102; Lainez et al. Cephalalgia 2013;33 (Supplement 8): 103-104.Jensen et al. presented at World Congress of Neurology, Vienna, Austria, Sept 22, 2013.

Neuromodulation for migraine

• FDA approved:o Transcranial magnetic stimulator for acute treatment of migraine w/aura (SpringTMS)-

Phase 4 in selected centers


o Not FDA approved:– Non-invasive vagal nerve stimulator (nVNS, gammaCore)

– Sphenopalatine ganglion stimulation (SPG, PULSANTE)

–Occipital Nerve Stimulation (ONS) – Deep Brain Stimulation (DBS)


ONS for Chronic Migraine: 3 trials, Level U, Conflicting or Inadequate Data

3 studies, 3 different systems, none reached 1°endpoint, all had methodologic problems, all Class III at best

– Lipton et al1, abstract only –1° endpoint: ↓ migraine days/month not significant @ 12 wks vs sham

– Saper et al2: no primary endpoint pre-specified; adjustable stimulation, no sham group (vs medical management)–39% had ≥ 50% decreased frequency or

≥ 50% decreased severity

– Silberstein et al3: no blinding–negative for primary endpoint, responder rate for ≥ 50% decrease in

mean daily VAS at 12 weeks

– Decrease of ≥ 30%, HA days, disability, & pain relief achieved

1. Lipton et al. Cephalalgia 2009; 29 (Supplement 1): 30. 2. Saper et al. Cephalalgia 2011; 41: 271–285.3. Silberstein et al. Cephalalgia 2012; 32: 1165–1179.

Invasive Neuromodulation,

In Development

Occipital Nerve Stimulation


ONS Multicenter RCT for CH is underway • ICON study: Prospective, double-blind, parallel group multi-center

international RCT for CCH prevention between two different ONS stimulations: high (100%) and low (30%) amplitude

• High vs. low stimulation design, instead of on vs. off design, should minimize unblinding due to paresthesias

• They hypothesize a dose response relationship

• Until this is completed, no RCTs for evidence: It appears to work about 60% of the time in case series but has unclassifiable evidence

• Level U for Cluster, Inadequate data so far

Stewart J. Tepper, MD l 38 Wilbrink et al. Cephalalgia 2013;33:1238–1247.

• Electrode migration

• Can be very frequent, and more common when placed by anesthesia rather than neurosurgeon• Mobility of cervical region• Electrode type

• AEs: intolerance to paresthesias, cable discomfort, muscular spasm

• Infection

• Battery depletion: high intensities increase cost

ONS: main adverse effects

• In 2014, the EU rescinded the CE Mark for the St Jude Genesis ONS device, presumably because of these issues

Invasive Neuromodulation for Cluster headache in development

Hypothalamic deep brain stimulation (DBS)


DBS implanted in ipsilateral posterior hypothalamus

DBS in CH: Summary of Case Series

• Magis and Schoenen summarized 14 case series published from 2005-20131,2

• 65 patients have been implanted with a mean of 2.8 years follow-up

• Pain Free: 20/65 (31%)

• # of patients with ≥50% decrease in HA f or intensity: 23/35 (35%)

• Therefore, 66% improved

• Leone et al’s follow-up was 17 patients, 8.7 years, sustained significant improvement in 6/17 (35%)

42 days mean to effectiveness

Turning off stimulator blind to patient: clusters recur, then stop when turned back on

Magis and Schoenen. Lancet Neurol 2012; 11:708-19.Magis. EHMTIC, 2014.Leone et al. Pain. 2013;154:89-94.

Deep Brain Stimulation for Cluster Headache

• Adverse events: • Oculomotor disturbance & vertigo • Infections• Sleep disorders• Intracerebral hemorrhage: 2/64 cases (1 fatal) = 3%• One death in Belgium; TIAs, strokes, hemorrhages described

• No RCTs for evidence: It works but has unclassifiable case series evidence

• Level U, Inadequate data so far

Levels of EvidenceNon-invasive

•tSNS (Cephaly): Level B for Preventive Treatment Episodic Migraine, FDA-approved

•sTMS (SpringTMS): Level B for Acute Treatment Episodic Migraine with aura, FDA-approved

•rTMS: Level U for Prevention of Migraine

•nVNS (gammaCore) [Approved in EU and Canada]:

– Level U for Acute and Level C for Preventive Treatment of Cluster

– Level U for Migraine

Minimally invasive

•Implantable SPG Stimulator (Pulsante) [Approved in EU]:

– Level B for Acute Treatment of Cluster

– Level C for Preventive Treatment of Cluster

Invasive

•Occipital Nerve Stimulation: Level U for Cluster and Migraine

•Deep Brain Stimulation: Level U for Cluster


The Future will be real soon

• Very soon, we might try non-invasive neuromodulation before drugs or O2 for acute and preventive treatment of cluster and migraine, if nVNS works

• Minimally invasive neuromodulation such as the SPG stimulator would come after non-invasive neuromodulation, and after some, but not excessive medication failures

• Significantly invasive neuromodulation would wait until multiple and significant medication failures

• Once nVNS and sTMS are widely available, trials of these (and, sometimes tSNS) for migraine may precede drugs. This could be in 2015 for many centers!


Thank you for your attention!

Stewart J. Tepper, MD l 1 Neuromodulation and Headache Disorders Stewart J. Tepper, MD Professor of...

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