Neurostimulation 2016

Transcription

1 Neurostimulation 2016 Stephen D Silberstein, MD Jefferson Headache Center Thomas Jefferson University Hospital Philadelphia, PA 1

2 Neuromostimulation Occipital Nerve Stimulation (ONS) Transcranial Magnetic Stimulation (TMS) Frontal Nerve Stimulation Vagal nerve stimulation (VNS) Sphenopalatine ganglion stimulation (SPGS)

3 Trigemino-Cervical Complex Anatomical Convergence Pain perception PAG stop Central 2 nd -order neuron (trigeminal cervical complex) ONS

4 ONS: Randomized Sham-Controlled Studies For Chronic Migraine: Design Elements Study Control Trial Primary Endpoint ONSTIM N=60 PRISM N=139 Preset stim 1 min/day Medical managed None BUT intraoperative testing for adequate paresthesia coverage 1 s on / 90 m off Yes; 5-10d active and sham trial None Migraine days per month at week 12 St Jude N=157 No stimulation Yes; only those with >50% pain relief enrolled Responder rate (>50% VAS)

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6 ONSTIM: Mean Percent Reduction in Headache Days Per Month From Baseline to Month 3 P=0.566 P=0.132 P=0.058 Adjustable stim Preset stim Medical Mgt Ancillary N=75 Saper, JR et al. Cephalalgia 2010;31(3)

7 ONSTIM: Responder Rate Responder rate = > 50% reduction in headache days/mo or >3 point reduction in overall pain intensity (VAS) P=1.0 P=0.032* P=0.003* 0% Adjustable stim Preset stim Medical Mgt Ancillary N=75 Saper, JR et al. Cephalalgia 2010;31(3)

8 Silberstein SD, et al. Cephalalgia 2012;32(16) :

9 Primary Endpoint: Significant difference at 50% reduction in pain AND 10% differential at the 95% CI % reduction from baseline Control Group % responders (n=52) Active Group % responders (n=105) p-value 1 met protocol objective (>10% dif.) 2 10,0% 30,8% 56,2% 0,003 Yes 20,0% 19,2% 40,0% 0,009 Yes 30,0% 17,3% 35,2% 0,020 Yes 40,0% 15,4% 25,7% 0,0143 No 50,0% 13,5% 17,1% 0,553 No Silberstein SD, Dodick DW, Saper JR, et al. Cephalalgia 2012;32(16) :

10 Headache Days (Secondary Endpoint) Visit Control Group (n=52) Active Group (n=105) P-Value Baseline Mean (± std) 20,1 (± 7,2) 22,4 (± 6,9) 0,049 Week 12 Mean Change 1-3,0 (14,9%) -6,1 (27,2%) 0,008 Difference (95% CI) -3,1 (-5,4, -0,8) Silberstein SD, Dodick DW, Saper JR, et al. Cephalalgia 2012;32(16) :

11 12-Week Outcome Migraine days/month [change from baseline] PRISM: Primary Endpoint: No Significant Change From Baseline in Migraine Days/Month at 12 Weeks Intent-to-Treat (n=139) Modified ITT (n=125) 0 Baseline [days/month] ±8.0 ±7.3 Baseline [days/month] ±7.9 ± ± ±8.2 Control Treatment ± ±8.7 P=0.26 P=0.29 Lipton RB, et al. Presented at IHC 2009

12 ONS: Adverse Event Rate

13 Neuromostimulation Occipital Nerve Stimulation (ONS) Transcranial Magnetic Stimulation (TMS) Frontal Nerve Stimulation Vagal nerve stimulation (VNS) Sphenopalatine ganglion stimulation (SPGS)

14 Transcranial Magnetic Stimulation stms Repetitive TMS low frequency : INHIBITS high frequency : EXCITES

15 Single Pulse TMS (stms) Disrupts CSD Modifies Cortical Excitability Holland et al. Cephalalgia. 2009;29(Suppl 1):22. Andreou et al. Headache. 2010;50(Suppl 1):58.

16 Single Pulse Transcranial Magnetic Stimulation for Acute Treatment of Migraine With aura Portable device developed to facilitate early self-treatment at home 201 aura patients randomized in double- blind, parallel group, sham controlled study at 16 U.S. headache centers Lipton RB et al. Lancet Neurology 2010;9:

17 Multicenter, randomized, double-blind, sham-controlled stms N=82, sham N=82 Migraine with aura 1-8 migraine attacks per month Instructed to treat as soon as possible after the onset of migraine aura and always within 1 hour of aura onset 2 consecutive pulses per attack Rescue drugs permitted 2h after treatment Lipton RB et al. Lancet Neurology 2010;9:

18 Pain-free Response at 2, 24 and 48 hours 1 0 outcome: 2 hour pain free 39% vs 22%, p< % Therapeutic gain 17% 22% 29% 27% AEs minimal and mild 5% stms vs. 2% sham 16% 13% Lipton RB et al. Lancet Neurology 2010;9:

19 TMS Adverse Events Adverse Event Type Number of Patients With at least 1AE Number of Patients With at least 1 TRAE Sham N = 99 TMS N = (9.1%) 14 (13.7%) 2 (2.0%) 5 (4.9%) AEs Leading to Withdrawal 0 0 Serious Adverse Events (SAEs) 0 1 (1%) Optic Neuritis Treatment-related SAEs 0 0 Lipton RB, Dodick DW, Silberstein SD et al. Lancet Neurol 2010; 9:

20 UK Pilot: Open Label Experience (Demographics) Migraine Features # of Patients # of Attacks Treated Migraine with aura Migraine without aura Of these: Episodic Chronic Daily 4 53 N= 98 patients prescribed Goadsby PJ, et al. EHMTIS London, Sept 2012

21 stms Open Label Study: Pulsed BID and PRN Reduction Acute Medicine Days Reduction Migraine Days MO MA Migraine wo aura Migraine w/aura Time 0 wks 6 wks 12 wks / 0 wks 6 wks 12 wks N=29 patients Bhola et al. AHS Scientific Meeting, June 2015.

22 eneura SpringTMS Post-Market Observational U.S. Study of Migraine (The ESPOUSE Study) MULTI-CENTER, PROSPECTIVE, NON-RANDOMIZED, SINGLE ARM, OPEN LABEL, POST- MARKET, OBSERVATIONAL STUDY TO EVALUATE THE USE OF THE ENEURA, SPRINGTMS SYSTEM IN REDUCTION OF MIGRAINE HEADACHE SYMPTOMS SITE Mayo Clinic Arizona Jefferson Headache Center UCLA Headache Research and Treatment Program Mid-Atlantic Permanente Medical Group (Kaiser) Stanford Headache Program The Cleveland Clinic Center for Headache and Pain Montefiore Headache Center (MAB site) INVESTIGATOR Amaal J. Starling, MD Michael J. Marmura, MD Andrew Charles, MD Ejaz A. Shamim MD Nada Ahmad Hindiyeh, MD Stewart Tepper, MD Matthew S. Robbins, MD

23 Patient Selection Criteria Inclusion Criteria 18 to 65 years of age Migraine w/wo aura 4-25 headache days per month; minimum of 5 completely headachefree days/month) Headache Day: 4 hours of headache which at any point resulted in moderate to severe pain Exclusion Criteria Epilepsy or history of seizure. Metal-containing implants Concurrent use of other neurostimulation devices No change in preventive medications past 2 months Extracranial nerve blocks within past 3 months Botox within past 4 months

24 ESPOUSE Treatment Protocol Daily: 4 Pulses each morning and evening 2 consecutive pulses wait 15 minutes and repeat the 2 consecutive pulses. As needed: Treat an acute attack 3 consecutive pulses at the onset of migraine pain, wait 15 minutes. If needed, treat with additional 3 pulses, wait 15 minutes If needed, treat with additional 3 pulses Patients may rescue with acute medication 30 minutes after the first three pulses are delivered

25 ESPOUSE Study Subject Accountability Flow Chart Patients consented to enroll in study 263 Patients completing baseline (BL) diary Patients who were confirmed eligible to participate and received a device Patients who began treatment Completed BL diary Deemed Eligible Safety Data Set Patients eligible based on definition of headache day Patients who completed 3 months of treatment Patients who completed 3 months of treatment per protocol 1 47 patients were not included in the Full Analysis Set because they did not meet the inclusion criteria of at least 4 headache days 2 Definition of Headache Day = 4 hours of pain which at any point during the 4 hour period resulted in moderate to severe pain 132 1, Full Analysis Set (FAS) Completed Cases (CC) Per Protocol (PP)

26 Mean Reduction of Headache Days from Baseline Primary Effectiveness Endpoint: Mean Reduction in Headache Days Baseline = 9.07 Days Full Analysis Set (FAS) Per Protocol (PP) Performance Goal = P<

27 Safety: Adverse Events No Serious AEs Adverse Event n % Lightheadedness 8/ Tingling 7/ Tinnitus 7/ Dizziness 6/ Headache 5/ Worsened head pain 5/ Scalp discomfort 5/ Any reported adverse event 62/

28 Practical Implications for Clinicians Promising non-drug treatment option that is safe and well tolerated Acute and prophylactic studies in migraine without aura underway FDA approved for acute treatment of migraine with aura

29 Neuromostimulation Occipital Nerve Stimulation (ONS) Transcranial Magnetic Stimulation (TMS) Frontal Nerve Stimulation Vagal nerve stimulation (VNS) Sphenopalatine ganglion stimulation (SPGS)

30 Supraorbital TNS Schoenen J et al. Neurology 2013;80:

31 Supraorbital TNS Double-blind, sham-controlled trial, n=67 Stimulation 250 µs, 60 Hz, 16 ma, 20 min / day 3 months Verum Sham P-value Decrease in mean migraine days % responder rate 38.1% 12.1% 0.023* Verum 0.023* Sham Schoenen J et al, Neurology 2013

32 Supraorbital Supraorbital Transcutaneous TNS: AEs Stimulation AEs Reported by >1 Patient (40-day trial period) Patients (N) AEs (%) Patients (%) Do not like the feeling and want to discontinue use Sleepiness Headache Reversible forehead skin irritation Insomnia Feeling of fatigue Forehead paresthesia for several minutes post-session Feeling of stress during the session Allergic skin reaction Dental pain during the session or at the beginning Inability to keep eyes open during sessions Feeling of contusion on the forehead during a few days Magis D et al. J Headache Pain ,313 renters Mean 58.2 day rental 46.6% unsatisfied, returned device

33 Neuromostimulation Occipital Nerve Stimulation (ONS) Transcranial Magnetic Stimulation (TMS) Frontal Nerve Stimulation Vagal nerve stimulation (VNS) Sphenopalatine ganglion stimulation (SPGS)

34 VNS: An Evolving Field Much I wanted to review But never enough time I have written what I would have said!

35 The Vagus Nerve (VN) Cranial Nerve X Latin: wandering Longest cranial nerve Innervates neck, thorax and abdomen Reaches colon 35

36 GammaCore (ElectroCore ) Handheld, patient-controlled Uniform electric field Low-voltage 1-ms bursts of 5kHz sine waves repeated at 25hz. Maximum: 30 V and 60 ma Stimulates low-threshold A fibers, not high-threshold efferent C fibers Recommended preventive Rx: Two 120-second stimulations TID.

37 VNS Clinical Trial Overview: Cluster Study Principal Investigator Size (N) Format Status Royal Free Hospital Goadsby 21 patients GC-002 (PREVA) Gaul 97 patients CH-US-01 (ACT 1) Silberstein 150 patients Open-label case series, prevention and acute use Open-label, SoC comparator study; prevention Double-blind, RCT, active sham, acute Neurology 2015 Cephalalgia 2015 AHS 2015 GC-003 (ACT 2) Goadsby 102 patients Double-blind, RCT, active sham, acute In Preparation Abbreviations: RCT, randomized controlled trial; SoC, standard of care. 37

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39 PREVA Study Overview Randomly assigned treatment groups had matched demographics and baseline characteristics nvns stimulations twice daily and as needed for rescue Baseline Phase Randomised Phase Open-label Phase Standard of Care (N=114) Standard of Care Plus nvns (N=48) Standard of Care (N=49) Standard of Care Plus nvns (N=90) 2 weeks 4 weeks 4 weeks 39

40 Characteristic Demographics and Baseline Characteristics SoC Plus nvns (n=48) Control (n=49) Age, y, mean (SD) 45.4 (11.0) 42.3 (11.0) Sex, n (%) Male 34 (71) 33 (67) Time since onset of chronic CH disorder, y, mean (SD) a 4.7 (3.9) 5.0 (3.7) CH attack duration, min, mean (SD) With acute pharmacologic medications/oxygen b 27.4 (19.8) 29.3 (29.9) Without acute pharmacologic medications/oxygen c 95.2 (57.7) (66.8) Number of CH attacks in the 4 weeks before enrolment, mean (SD) c 67.3 (43.6) 73.9 (115.8) Abbreviations: CH, cluster headache; nvns, non-invasive vagus nerve stimulation; SD, standard deviation; SoC, standard of care. a Data were missing for 2 subjects in the control group. b Data were missing for 1 subject in the control group. c Data were missing for 1 subject in the SoC plus nvns group.

41 Mean Change in the Number of CH Attacks per Week Change in the Number of CH Attacks/ Week Baseline Versus the Last 2 Weeks of Randomised Phase (ITT) 0 SoC Plus nvns (n=45) Control (n=48) P=0.02 Δ=3.9 Abbreviations: CH, cluster headache; ITT, intent-to-treat; nvns, non-invasive vagus nerve stimulation; SoC, standard of care. Values are presented as unadjusted means and were calculated from all subjects with evaluable data. P value corresponds to the difference in the change from baseline between treatment groups from an analysis of variance.

42 50% Treatment Response Rate (%) 50% Treatment Response Rate 80 SoC Plus nvns Control % Δ= 31.7% (p<0.001) 48.6% Δ= 40.1% (p<0.001) % 8.5% n=45 n=48 n=37 n=47 ITT Population mitt Population Abbreviations: ITT, intent-to-treat; mitt, modified intent-to-treat; nvns, non-invasive vagus nerve stimulation; SoC, standard of care. Analysis of response rate was performed on the ITT population (defined as subjects who had 1 efficacy recording in the headache diary after randomization), the mitt population (defined as subjects who had measurable observations across the study phases being compared); subjects with incomplete data were designated as treatment failures. Small n values represent the number of observations included in the analyses.

43 Attack Frequency Over Time * p<0.02 vs SoC alone No. of Attacks per Week (Mean ± 95% CI) Treatment Week Abbreviations: CH, cluster headache; CI, confidence interval; mitt, modified intent-to-treat; nvns, non-invasive vagus nerve stimulation; SoC, standard of care.

44 Expanded Response Rates SoC Alone (n=48) SoC+nVNS (n=45) Patients (%) Responder Rate a Abbreviations: ITT, intent-to-treat; nvns, non-invasive vagus nerve stimulation; SoC, standard of care. a Proportion of patients with the specified percentage decrease in attack frequency from baseline to the end of the randomized phase.

45 nvns Conclusions Significant improvement compared with SoC Reduced frequency of CH attacks per week Associated with significantly higher proportion of patients who achieved 50% reduction in CH attacks per week versus SoC Reduced use of rescue medication, including sumatriptan and oxygen, compared with SoC Safe and generally well tolerated, with few reported devicerelated AEs Continued use of nvns associated with sustained clinical effects 45

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47 Study Overview Two-phase, randomized, sham-controlled prospective study of nvns for CH Double-blind phase (up to 1 month or until 5 CH attacks were treated) Open-label phase (3 months) Study population Episodic CH or chronic CH according to the International Classification of Headache Disorders criteria enrolled subjects; 133 subjects in the ITT population (ie, all randomly assigned subjects who treated 1 CH attack) Acute treatment Three consecutive 2-minute stimulations to the right side of the neck at the onset of premonitory symptoms or pain Only 1 CH attack could be treated during a 12-hour period 1. Headache Classification Subcommittee of the International Headache Society. Cephalalgia. 2004;24(suppl 1):

48 Study Design and Patient Disposition Assessed for Eligibility N=172 Subjects Enrolled N= Subjects failed screening a - 16 Did not meet entry criteria - 6 Declined to participate - 2 Other nvns Group Sham Group nvns n=73 Randomized Phase 1 Month Sham n=77 14 Discontinuations - 3 Nonadherence - 8 No CH/CH ended - 2 Lost to follow-up - 1 Other ITT n=60 ITT n=73 8 Discontinuations - 2 Nonadherence - 1 No CH/CH ended - 3 Lost to follow-up - 2 Other 17 Discontinuations - 1 AEs - 3 No CH/CH ended - 8 Lack of efficacy - 1 Lost to follow-up - 4 Other nvns n=59 nvns n=42 ITT n=45 Open-label Phase 3 Months End of Study ITT n=59 nvns n=69 nvns n=58 11 Discontinuations - 1 No CH/CH ended - 6 Lack of efficacy - 2 Lost to follow-up - 2 Other a Some subjects failed screening for >1 reason. 3

49 Primary End Point: 1 st Attack 15 Minutes (ITT) All Subjects Episodic CH Chronic CH

50 Secondary End Point Proportion of Subjects With a Sustained Treatment Response (60 Min/No Rescue) All Subjects Episodic CH Chronic CH 9

51 Summary of Results (Double-blind Phase) End Point Response rate Sustained treatment response rate Pain intensity Responder for 50% of treated attacks Pain free for 50% of treated attacks Duration of first attack Change in attack duration Rescue medication use in the first hour after the first attack All Subjects (n=150) NS (P=0.1) SIG (P=0.04) NS (P=0.4) NS (P=0.41) NS (P=0.33) NS (P=0.25) SIG (P=0.03) NS (P=0.15) ech Cohort (n=101) SIG (P=0.008) SIG (P=0.008) NS (P=1.0) SIG (P=0.04) SIG (P=0.04) NS (P=0.21) SIG (P=0.03) NS (P=0.53) cch Cohort (n=49) NS (P=0.48) NS (P=1.0) NS (P=0.2) NS (P=0.19) NS (P=0.36) NS (P=0.82) NS (P=0.69) NS (P=0.13) 12

52 Safety and Tolerability Incidence of AEs/ADEs (All Treated Subjects) nvns (n=73) Sham (n=77) 1 AE, No. (%) 18 (24.7) 31 (40.3) 1 Serious AE, No. (%) 1 (1.4) a,b 0 1 ADE, No. (%) 11 (15.1) 24 (31.2) ADEs Occurring in 5% of Subjects in Any Treatment Group, n (%) Application site reactions Burning/tingling/soreness/stinging 2 (2.7) 7 (9.1) Skin irritation/redness/erythema 0 9 (11.7) Musculoskeletal disorders Lip or facial drooping/pulling/twitching 8 (11) 0 Nervous system disorders Dysgeusia/metallic taste 0 7 (9.1) a Serious AE of cluster headache. b Serious AEs were not considered related to the study device. c Serious AEs included cluster headache (1 occurrence; 1 subject); cluster headache as well as multiple left extremity deep vein thromboses, abdominal aortic aneurysm, pneumonia, anasarca, acute respiratory failure, and urethral trauma (1 occurrence each in the same subject); mesenteric ischemia (1 occurrence; 1 subject); herniated disk (1 occurrence; 1 subject); and ureteral calculus (1 occurrence; 1 subject) 13

53 Conclusions Large RCT of a therapeutic intervention for cluster Examined acute response, sustained relief, safety and tolerability Significant and meaningful benefit in ech (34.2% vs. 10.6%; p=0.008) Not significant in cch (13.6% vs. 23.1%; p=0.48) Impacted total population (26.7% vs. 15.1%; p=0.1) Safe and well tolerated New treatment option with benefit profile in ech 14

54 Clinical Trial Overview: Migraine Study PI N/attacks Format Primary Findings Status Acute Treatment Episodic Migraine Goadsby 27/80 OL, MC 33.3% PF, 62.9% PR (mildsevere) Cephalalgia 2014 HFEM & CM Barbanti 18/131 OL, MC CM Moscato 22/79 OL, SC 39.6% PF, 64.6% PR (mildsevere) 44% improvement in mean pain 2 hr Journal of Headache and Pain /2015 AHS, EHMTIC, IHS CM & MOH Rainero 15/362 OL, SC 33.4% PF AAN 2014 EM Tassorelli 300 Preventive Treatment EM/CM (Acute and Prev.) CM (EVENT) MM/MRM DB, sham controlled RCT Kinfe 20/225 OL, SC Silberstein Grazzi 59/8 months 56/3 months EM Diener 425 Double-blind, sham controlled, pilot RCT OL, MC DB, sham controlled RCT 39.4% (p<0.001) reduction in headache days; Met safety endpoint, 2 day (ns) reduction in HA days at 2 months 33% decrease in monthly MM/MRM days per month > 200 enrolled, Sep. 16 Journal of Headache and Pain 2015 Neurology 2016 Journal of Headache and Pain, In-Press >350 enrolled as of Sep. 16 Abbreviations: MOH, medication-overuse headache; RCT, randomized controlled trial. HFEM, high frequency episodic migraine; CM, chronic migraine; EM, episodic migraine; OL, open label; DB, double blind; SC, single-center; MC, multi-center; PF, Pain Freedom (2hr); PR, Pain Relief (2hr); MM/MRM, menstrual/menstrually related migraine

55 Chronic Migraine Headache Prevention With Non-invasive Vagus Nerve Stimulation The EVENT Study

56 Study Overview and Design Run-in Phase 4 weeks Randomized Phase 8 weeks Open-label Extension 6 months Run-in nvns Sham control Open-label nvns Randomization (1:1) Patients had chronic migraine with or without aura Prophylactic treatment (comparative and extension phases) - Two 2-minute stimulations (nvns or sham) administered to the right side of the neck 3 times per day (6 stimulations total per day) Abbreviation: nvns, non-invasive vagus nerve stimulation.

57 Demographics and Baseline Characteristics Characteristic nvns (n=30) Sham (n=29) Age, mean (SD), y 40.5 (14.2) 38.8 (11.1) BMI, mean (SD), kg/m (5.3) 31.6 (9.8) Headache days reported during baseline, mean (SD) 20.8 (5.0) 22.3 (4.9) Females, n (%) 26 (87) 27 (93) Race, n (%) Caucasian 26 (87) 25 (86) Black 3 (10) 0 Other 1 (3) 4 (14) Abbreviations: BMI, body mass index; SD, standard deviation.

58 Change From Baseline in the # of Headache Days Reduction in Number of Headache Days Mean Change From Baseline in Number of Headache Days per 28 Days a Randomized Open-label Baseline Month 2 Month 4 Month 6 Month *P<0.05 vs baseline a Imputation for missing data was performed using the last observation carried forward. ITT Population. b Received open-label nvns after month b Sham (n=29) nvns (n=30) -3.6

59 Treatment Response Response was defined as a 50% decrease from baseline in the number of headache days per 28 days. Per Protocol Completer Population. a 2-, 4-, and 6-month completers were from the 59 subjects initially randomized to either nvns or sham treatment. b 8-month completers were from the 30 subjects initially randomized to nvns treatment.

60 Conclusions: nvns Prophylactic Use Safe, well tolerated in chronic migraine(cm) patients Compared with sham device, nvns had greater reductions in mean headache days Longer treatment duration associated with increased benefits: fewer headache days and improved treatment response Improved outcomes with longer treatment may result from neuroplastic change in the brain state; further research required to substantiate this nvns may offer CM patients clinical benefit without exposure to additional pharmacologic Rx Health Canada approved, CE mark in the EU, approved by NICE in the UK, and currently under consideration by US FDA

61 Neuromostimulation Occipital Nerve Stimulation (ONS) Transcranial Magnetic Stimulation (TMS) Frontal Nerve Stimulation Vagal nerve stimulation (VNS) Sphenopalatine ganglion stimulation (SPGS)

62 The Sphenopalatine Ganglion (SPG) Edvinsson, Goadsby. Cephalalgia 1994;14: Burstein,Jakubowski. J Comp Neurol 2005;493:9-14

63 SPG Stimulation with Implanted System Miniaturized implant stimulates SPG Wirelessly powers and controled: no external batteries or wires Implanted through mouth On-demand, patient-controlled therapy with remote controller Rechargeable through USB port, internet connected On / Off Button, Programmable Up / Down Buttons (amplitude adjustment) Schoenen et al. Cephalalgia 2013;33:

64 SPG Stimulation Acute, Preventive, or Both In Large EU RCT N=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 Schoenen et al. Cephalalgia 2013;33: Schoenen et al. Cephalalgia 2013; 33 (Supplement 8):

65 Pain is a more terrible lord of mankind than even death itself. -Albert Schweitzer 65