Upper Airway Stimulation for Obstructive Sleep Apnea Background, Mechanism and Clinical Data Overview Seth Hollen RPSGT 21 May 2016 1
Conflicts of Interest Therapy Support Specialist, Inspire Medical Systems 2
Learning Objectives Introduction to Upper Airway Stimulation (UAS) Clinical Evidence of UAS Indications and Contra-indications for UAS Understand mechanism of action for UAS Understand the titration process for UAS 3
Upper Airway Stimulation Inspire II Systems Physician Programmer Implantable Pulse Generator Stimulation Lead Respiratory Sensing Lead 4 Patient Remote
Feasibility of Hypoglossal Nerve Stimulation Augmented muscle tone Without causing arousals Immediately stabilized airway Improved Oxygenation Schwartz et al, Arch Oto Head Neck Surg 2001 5
Mechanism of Action: Multi-level Effect Palate Tongue- Base Strohl et al, AJRCCM 2013 abstract Increased airway at palate and tongue-base Increased airway size with increasing stimulation energy Safiruddin et al, ERJ 2015
100% Mechanism of Action: Site of Obstruction 80.9% Exclusion of complete concentric collapse (CCC) at palate for improved response AP Collapse Concentric Collapse Vanderveken et al, J Clin Sleep Med 2013 7
Mechanism of Action: Hypoglossal Nerve Stimulation Styloglossus (SG) Hyoglossus (HG) Inferior Longitudinal Stimulation Site: Medial branch of the hypoglossal nerve, activates only protrusors (genioglossus, geniohyoid), distal to retractors (styloglossus and hyoglossus) Geniohyoid (GH) Thyrohyoid Stimulation Site Hypoglossal Nerve (XII) Genioglossus (GG) Mu and Sanders 2010 8
Palatoglossal Coupling 9
Upper Airway Stimulation Effect EEG EMG Nasal Therm Chest Abdm SaO 2 No Stimulation Stimulation Active 10
Inspire Clinical Evidence Development Inspire 1 Inspire 2&3 2 Inspire 2 & 3 Inspire STAR Proof of Principle Feasibility Study Trials Feasibility Studies Pivotal Trial (Phase 3) 8 patients @ 4 centers 22 patients @ 4 centers 12 patients @ 7 centers 126 patients @ 22 centers 2001 2009/10 2010/11 2012 /13 First in man Patient selection Implant technique Safety / Efficacy Safety / Efficacy / FDA approval 1 publication 1 peer reviewed publications 2 peer reviewed publications N Eng J Med (Jan 9, 2014) FDA full approval in May 2014
Inspire Phase III Pivotal Study The STAR Trial (n=126) Study Design Key Patient Selection Criteria Prospective, multi-center single-arm trial with a randomized, controlled therapy withdrawal phase Inclusion: CPAP failure or intolerant Moderate to severe OSA Exclusion BMI > 32 kg/m 2 Complete concentric collapse at the level of soft palate Significant central sleep apnea Study Endpoints Primary Endpoints at 12 months AHI and ODI reductions Secondary Endpoints at 12 months Quality of life questionnaires Randomized withdrawal effect Strollo et al, New Engl J Med, 2014 12
Study Design and Rationale Pre 1-mo 12-mo 18-mo ON Implant Therapy activation and titration period OFF 1-week randomized withdrawal period Every 6-mo Long-term follow-up Use objective measures of OSA severity (AHI and ODI) for primary efficacy endpoint Long-term follow up at 12/18 months to evaluate sustained effect Randomized controlled withdrawal phase to confirm therapy effects 13
Study Patient Demographics Characteristics Values Age, years 54.5 ± 10.2 Male sex no. (%) 105 (83%) Race White no. (%) 122 (97%) Body-mass index 28.4 ± 2.6 AHI mean ± SD (range) 32.0 ± 11.8 (13.3 65.1) UPPP no. (%) 22 (17%) Mean ± SD 14
Implantation Procedure General anesthesia, sterile technique Average 2.5 hours duration Same day or second discharge Resume normal diet first day, restricted arm motion first week Maurer et al, Operative Techniques in Otolaryngology, 2012 15
Medain Pain VAS (mm) Post-implant Pain Visual Analog Scale 100 90 80 70 60 50 40 30 20 10 0 Typical Pain after UPPP 30 13 2 0 0 0 Implant 1-Week 1-Month 2-Month 6-Month 12-Month Average post-op pain for UPPP ranges from 46 to 79 mm at one day post-op, and 55 to 88 mm at one week post-op (Troell, RJ 2000 and Rombaux, P 2003) Inspire STAR data presented at the FDA Panel Review, 2014 16
Safety Summary Serious adverse events were rare (1.58%) IPG repositioning to address discomfort (N=2) Time-limited tongue weakness related to surgical procedure and incision pain Stimulation side effects included discomfort and tongue abrasion and were resolved by reprogramming or therapy acclimatization Side effects did not affect overall therapy use 17
Median AHI Median ODI Reduced OSA severity 35 30 25 20 15 10 5 0 29.3 Baseline p < 0.0001 25.4 p < 0.0001 9.0 Month-12 30 25 20 68% reduction 70% reduction 15 10 5 0 Baseline 7.4 Month-12 N = 126 N = 124 N = 126 N = 124 Therapy significantly reduced OSA severity Strollo et al, New Engl J Med, January 2014 18
Median FOSQ Score Median ESS Score 19 Improved Quality of Life Measures Increased daytime functioning Reduced daytime sleepiness 20 19 18 17 16 15 14 13 12 Normal > 17.9 18.2 14.6 Baseline Month-12 p < 0.0001 p < 0.0001 12 11.0 10 Normal < 10 8 6.0 6 4 2 0 Baseline Month-12 N = 126 N = 123 N = 126 N = 123
Therapy randomization demonstrated the therapy effect is due to stimulation First 46 consecutive participants with a therapy response were randomized 1:1 to therapy maintenance or therapy withdrawal for 1 week after 12-month visit PSG was repeated after 1 week, and compared against the 12-month The therapy withdrawal group had a significant increase in AHI while maintenance group remained low Strollo et al, New Engl J Med, 2014 20
AHI (Events/hr) Therapy Withdrawal and Reactivation 40 35 30 25 20 15 10 5 Maintenance ('ON') Group * * Withdrawal ('OFF') Group # ## * * * 0 Baseline 12 Month RCT 18 Month Mean and S.E. *p<0.05 vs. baseline; # p<0.05 vs. 12 month ; ## p<0.05 vs. RCT. Woodson et al, Otolaryngology Head and Neck Surgery, 2014 21
Median FOSQ Score Median ESS Score Median AHI Median ODI Long-term Outcome at 18 months 35 30 25 20 15 10 5 0 20 19 18 17 16 15 14 13 12 29.3 30 25 25.4 20 15 9.0 9.7 10 7.4 8.6 5 0 Baseline Month-12 Month-18 Baseline Month-12 Month-18 N = 126 N = 124 N = 121 N = 126 N = 124 N = 121 12 11.0 18.2 18.4 10 8 6.0 6.0 6 14.6 4 2 0 Baseline Month-12 Month-18 Baseline Month-12 Month-18 N = 126 N = 123 N = 123 N = 126 N = 123 N = 123 Strollo et al, SLEEP 2015
SLEEP meeting 2015, Seattle 23 36 Month Follow Up
Nightly Use (%) Self-report Nightly Use 100% 80% 86% 81% 81% 60% 40% 20% 0% 12 Month N = 124 24 Month N = 117 36 Month N = 108 24
Self and Partner-Report Snoring 100% 80% 60% 40% 20% 0% 24% 24% 30% 11% 11% Self Report Snoring 1% 3% 2% 9% 10% 33% 37% 53% 49% Baseline (n = 123) 12M (n = 120) M36 (n=108) No or Soft Snoring increased from 17% to 85% 100% 90% 80% 70% 60% 50% 40% 30% 20% 30% 24% 29% 5% 3% 2% 3% 7% 14% 38% 36% 48% 44% 10% 11% 0% 6% Baseline (n = 108) 12M (n = 103) M36 (n=97) No snoring Soft snoring Loud snoring Very intense snoring Partner leaves room reduced from 30% to 5% Partner Report Snoring Bed partner leaves room 25
Mortality and CV Risks associated with Severe OSA AHI < 5 AHI 30 AHI 5-15 AHI 15-30 AHI 30 AHI 30 1. Young et al, SLEEP 2008, Wisconsin Sleep Cohort 2. Marin et al, Lancet 2005, Spanish Sleep Network 26
Multi-disciplinary Longitudinal Management Sleep ENT ENT Sleep Sleep/ ENT Screen Implant Activation/ Titration Long-term 1-3 month Annual Screen: Consultation Sleep study DISE Office Visit and In-lab PSG: Activation Home use and acclimatization In-lab sleep titration Office Visit: Battery Usage Therapy Adjustment
Amplitude (volts) 28 Titration Basic Algorithm Arousal Threshold Therapeutic Amplitude Range 30 minutes in the patient s preferred sleep position with minimum occurrence of events, preferably with REM sleep observed 10 min Reduce amplitude by 0.1 to 0.2 volts if stimulation causes persistent arousals or is poorly tolerated Start at: FT - 0.2 V Increase amplitude by 0.1 to 0.2 volts if 5 obstructive apneas or hypopneas or loud, unambiguous snoring Time (minutes) *Adapted from current practice guidelines established for CPAP titration by the American Academy of Sleep Medicine, ref: Journal of Clinical Sleep Medicine, Vol. 4, No 2, 2008
29 Titration Stimulation Artifact chin EMG signal stimulation artifact flow cannula signal inhalation
30 Titration Acute Flow Changes (Flow Effect) flow without stimulation flow with stimulation Look for increases in airflow associated with stimulation, as shown here (usually seen in the PTAF)
31 Titration Minimum Therapeutic Amplitude When therapy is turned on at therapeutic amplitude, you may see a dramatic effect. In this case, breathing, respiratory effort and SaO2 immediately stabilize.
32 Titration Increasing Stimulation Strength Increasing the stimulation strength is similar to increasing CPAP pressure. As stimulation strength is increased, airway patency is also increased. 1.5V 1.6V 1.7V
33 Case Study University of Alabama Birmingham Pre-Implant and Implant Baseline AHI = 49/hour BMI = 26.1 Implanted without any adverse events Titration Titrated in the laboratory to an AHI of 3.0/hour Incoming amplitude of 2.2 volts, titrated to 2.6 volts for therapeutic efficacy
34 Case Study University of Alabama Birmingham Tongue Motion
Case Study University of Alabama Birmingham 35
36 Upper Airway Stimulation Clinical Evidence Map Safety and Effectiveness Pivotal study: safety and efficacy 1 Feasibility studies 2,3 Randomized withdrawal study 4 Long-term outcome at 18- and 24-month 5,6 Cost effectiveness analysis 7 Mechanism of Action Multi-level effects 8 Patient selection 9 Clinical Practice Standardized implant techniques 10 Device programming 5 19 peer reviewed publications supporting upper airway stimulation for OSA 1. Strollo et al 2014; 2. Schwartz et al 2001; 3. Van de Heyning 2012; 4. Woodson et al 2014; 5. Strollo et al 2015; 6. Soose et al (under review) 2015; 7. Pietzsch et al 2015; 8. Safirudin et al 2014; 9. Vanderveken et al 2013; 10. Maurer et al 2012