Obstructive Sleep Apnea
Conditions
Keywords
tongue, surgery, neurostimulation, hypoglossal nerve, upper airway stimulation
Brief summary
The purpose of this clinical trial is to demonstrate long-term safety and efficacy of the Inspire system. The Inspire Upper Airway Stimulation (UAS) therapy is intended to treat moderate-to-severe obstructive sleep apnea by improving airway patency through stimulation of the hypoglossal nerve. Study objectives include demonstrating that the Inspire system improves key indices of sleep apnea in a pre-specified percentage of patients.
Detailed description
The STAR trial is a multicenter, prospective trial that includes a randomized controlled therapy withdrawal study. The primary and secondary endpoint data were collected during an in-laboratory sleep study 12 months after the device implant and were compared against the baseline sleep studies. Following the 12-month visit, 46 consecutive responding subjects were randomized 1:1 to either a therapy maintenance group (ON group) or a therapy withdrawal group (OFF group). A subsequent sleep study of the two randomized groups was conducted and results were compared between the two groups. In addition, quality of life questionnaires were administered at baseline and at the 12-month visit to further assess the effectiveness of Inspire therapy. The STAR trial was conducted at 15 clinical sites in the United States and 7 in Europe. Of the 126 implanted subjects in the STAR trial, 87 or 69% were implanted in the United States. The remaining 39 subjects or 31% were implanted in Europe. The STAR trial subjects were evaluated prior to implant to ensure the following: 1) that their pre-implant AHI (as scored during an in-laboratory sleep study prior to implant) was between 20 and 50 events per hour, 2) that any AHI contribution from central or mixed sleep apnea was less than 25%, 3) that subjects did not have primarily lateral OSA (defined as limited sleep apnea when lying on their side), and 4) that the subjects did not have a complete concentric collapse at the level of the soft palate while observed during a drug-induced sleep endoscopy (DISE). After successful pre-implant screening, the subjects were implanted with the Inspire system. The subjects were allowed to recover for 1 month following surgery, at which time a second in-laboratory sleep study was conducted without activating the Inspire device. The results of this 1-month sleep study were averaged with the results of the pre-implant sleep study, and the average is defined as the subject's baseline. The Inspire device is programmable in order to optimize a subject's response to therapy. The initial device settings are programmed in an office setting. Additional adjustments are made during an overnight sleep study whereby real time review of the polysomnogram (PSG) is available to aid in device setting adjustments during the 2 and 6-month visit. At the 12-month in-laboratory sleep study, no device adjustments were allowed as this sleep study was the primary endpoint sleep study. Furthermore, no device adjustments were allowed at the 13-month sleep study which was the randomized controlled therapy withdrawal sleep studies. Blinding was not possible during the study since the stimulation therapy evokes a physiological response in the subjects. However, the primary endpoints were based on the objective measures of AHI and oxygen desaturation index (ODI) which were collected during an overnight sleep study using PSG. The sleep studies were all scored by an independent core lab in order to minimize assessment bias. Furthermore, the sleep study results, as well as all other clinical results, were 100% source data verified by the Inspire clinical monitoring team.
Interventions
Inspire Upper Airway Stimulation System, is a permanent, implantable therapy device, which consists of three implantable components: IPG, stimulation lead, and a sensing lead. In additional the patient receives a remote to activate the therapy.
Sponsors
Inspire Medical Systems, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
22 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Likely suffer moderate-to-severe OSA based on history and physical * Have failed or have not tolerated CPAP treatment * Willing and capable of providing informed consent * Willing and capable to have stimulation hardware permanently implanted, and to use the patient programmer to activate the stimulation * Willing and capable to return for all follow-up visits and sleep studies, including the evaluation procedures and filling out the questionnaires
Exclusion criteria
* Body Mass Index limits * Surgical resection or radiation therapy for cancer or congenital malformations in the larynx, tongue, or throat * Significant co-morbidities making the patient unable or inappropriate to participate in the trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Apnea Hypopnea Index | 12 months | Demonstrate at least a 50% responder rate at the 12-month follow-up visit. An Inspire therapy AHI responder was defined as a subject who experienced at least a 50% reduction in AHI from baseline and had an AHI of less than 20 at the 12-month follow-up. |
| Oxygen Desaturation Index | 12 months | Demonstrate at least a 50% responder rate at the 12-month follow-up visit. An Inspire therapy ODI responder was defines as a subject who experienced at least a 25% reduction in ODI from baseline. |
| Safety | 12 months | The primary safety objective of this pivotal trial was to evaluate safety via a description of all reported adverse events. Per the IDE-approved protocol, no formal statistical hypothesis was tested as part of the safety assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change Epworth Sleepiness Scale (ESS) From Baseline to 12 Months | Baseline and 12 months | The Epworth Sleepiness Scale (ESS) is a validated instrument that rates a subject's daytime sleepiness. Like the FOSQ, it is a quality of life measure that is commonly used in clinical evaluation and management of OSA. Scores range from 0 to 24, with lower scores indicating greater functioning. An ESS score of less than 10 is considered to be the cutpoint for normal subjective sleepiness. |
| AHI for the Randomized Controlled Therapy (RCT) Withdrawal Study | 12 Months | The AHI difference between the 12-month PSG study and the 13-Month PSG study in the therapy maintenance group will be compared to the AHI difference in the therapy withdrawal group. The objective was to demonstrate that AHI increase in the therapy withdrawal group (therapy=OFF) is greater than any AHI change in the active therapy group (therapy=ON). AHI is the number of apneas or hypopneas recorded during a sleep study per hour of sleep; this is calculated by dividing the number of AHI events by the number of hours of sleep. |
| Percentage Sleep Time at SaO2 < 90% | 12 months | The percentage of time spent with oxygen saturation below 90% has been an increasingly utilized surrogate for morbidity risk in sleep apnea populations. The SaO2 secondary endpoint in this study was determined by the time below an SaO2 level of 90% during the 12-month PSG study compared to that at baseline (average of screening and 1-month PSG studies). The objective was to demonstrate a decrease in the percentage of sleep time with an SaO2 level below 90% at 12 months. |
| Modified Intent to Treat - AHI Responder Rate for All Implanted Subjects | 12 months | The intent-to-treat (ITT) analysis for the primary endpoint included all patients who underwent an implant. A modified ITT analysis was conducted to include the subjects who did not completed the 12-month follow-up sleep study also. The ITT analysis was to calculate the AHI responder rate based on the subjects included in the analysis as described below. An Inspire therapy AHI responder was defined as a subject who experienced at least a 50% reduction in AHI from baseline and had an AHI of less than 20 at their last visit. The following subjects were included: * All implanted subjects who had AHI data collected at both baseline and 12-months follow-up. * All implanted subjects who had baseline data but no 12-month data, and had their last data values carried forward, provide they had a least 6-month AHI data. * Any implanted subject who did not have 12-month data available due to therapy failure (e.g., study withdrawal will be included in the analsys as a treatment failure. |
| Change in FOSQ From Baseline to 12 Months | Baseline and 12 months | The Functional Outcomes Sleep Questionnaire (FOSQ) is a validated instrument that assesses the effect of a subject's daytime sleepiness on activities of ordinary living. It is a quality of life measure that is commonly used in the clinical evaluation and management of OSA. This self-administered instrument consists of 30 questions divided into 5 domains: activity level, vigilance, intimacy, general productivity and social outcome. Scores range from 5 to 20, with higher scores indicating greater functioning. Change in FOSQ was calculated by subtracting the baseline score from the 12-month score. |
Countries
Belgium, France, Germany, Netherlands, United States
Participant flow
Recruitment details
Between 10 Nov 2010 and 15 Feb 2012, 25 clinical sites enrolled 929 subjects into the study. A total of 803 subjects were withdrawn from the study as they were not eligible and did not receive an implant.126 subjects from 22 clinical sites were implanted the UAS system (3 clinical sites enrolled subjects but did not attempt or implant a device).
Pre-assignment details
126 subjects were implanted with the Inspire therapy. At 12 months, the first 46 therapy responders were randomized 1:1 to either therapy ON (maintenance) or therapy OFF (withdrawal) for one week. Those who were in the withdrawal group returned to full therapy after one week of therapy being turned off.
Participants by arm
| Arm | Count |
|---|---|
| Inspire Therapy Study subjects continue to use Inspire therapy
Inspire Upper Airway Stimulator: The stimulator is surgically positioned subcutaneously near the clavicle in the upper chest, and connects to a stimulation lead (around a hypoglossal nerve) and a sensing lead (in the chest). The stimulation contracts a patient's upper airway muscles to maintain airway patency, with the intent to keep the airway open during inspiration. | 126 |
| Total | 126 |
Baseline characteristics
| Characteristic | Inspire Therapy |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 16 Participants |
| Age, Categorical Between 18 and 65 years | 110 Participants |
| Age, Continuous | 54.5 years STANDARD_DEVIATION 10.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 123 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 122 Participants |
| Region of Enrollment Belgium | 4 participants |
| Region of Enrollment France | 2 participants |
| Region of Enrollment Germany | 11 participants |
| Region of Enrollment Netherlands | 22 participants |
| Region of Enrollment United States | 87 participants |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 105 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 107 / 126 |
| serious Total, serious adverse events | 13 / 126 |
Outcome results
Primary
Apnea Hypopnea Index
Demonstrate at least a 50% responder rate at the 12-month follow-up visit. An Inspire therapy AHI responder was defined as a subject who experienced at least a 50% reduction in AHI from baseline and had an AHI of less than 20 at the 12-month follow-up.
Time frame: 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Inspire Therapy | Apnea Hypopnea Index | 66 percentage of subjects responding |
Primary
Oxygen Desaturation Index
Demonstrate at least a 50% responder rate at the 12-month follow-up visit. An Inspire therapy ODI responder was defines as a subject who experienced at least a 25% reduction in ODI from baseline.
Time frame: 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Inspire Therapy | Oxygen Desaturation Index | 75 percentage of subjects responding |
Primary
Safety
The primary safety objective of this pivotal trial was to evaluate safety via a description of all reported adverse events. Per the IDE-approved protocol, no formal statistical hypothesis was tested as part of the safety assessment.
Time frame: 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Inspire Therapy | Safety | 494 Events Reported |
Secondary
AHI for the Randomized Controlled Therapy (RCT) Withdrawal Study
The AHI difference between the 12-month PSG study and the 13-Month PSG study in the therapy maintenance group will be compared to the AHI difference in the therapy withdrawal group. The objective was to demonstrate that AHI increase in the therapy withdrawal group (therapy=OFF) is greater than any AHI change in the active therapy group (therapy=ON). AHI is the number of apneas or hypopneas recorded during a sleep study per hour of sleep; this is calculated by dividing the number of AHI events by the number of hours of sleep.
Time frame: 12 Months
Population: The first 46 responders to the Inspire therapy at 12 months were randomized 1:1 to either the Therapy Maintenance Group (ON) or the Therapy Withdrawal Group (OFF). A subsequent sleep study of the two randomized groups was conducted and results were compared between the two groups.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Inspire Therapy | AHI for the Randomized Controlled Therapy (RCT) Withdrawal Study | 12.0 events per hour |
| Withdrawal | AHI for the Randomized Controlled Therapy (RCT) Withdrawal Study | 16.4 events per hour |
Secondary
Change Epworth Sleepiness Scale (ESS) From Baseline to 12 Months
The Epworth Sleepiness Scale (ESS) is a validated instrument that rates a subject's daytime sleepiness. Like the FOSQ, it is a quality of life measure that is commonly used in clinical evaluation and management of OSA. Scores range from 0 to 24, with lower scores indicating greater functioning. An ESS score of less than 10 is considered to be the cutpoint for normal subjective sleepiness.
Time frame: Baseline and 12 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Inspire Therapy | Change Epworth Sleepiness Scale (ESS) From Baseline to 12 Months | 4.7 units on a scale |
Secondary
Change in FOSQ From Baseline to 12 Months
The Functional Outcomes Sleep Questionnaire (FOSQ) is a validated instrument that assesses the effect of a subject's daytime sleepiness on activities of ordinary living. It is a quality of life measure that is commonly used in the clinical evaluation and management of OSA. This self-administered instrument consists of 30 questions divided into 5 domains: activity level, vigilance, intimacy, general productivity and social outcome. Scores range from 5 to 20, with higher scores indicating greater functioning. Change in FOSQ was calculated by subtracting the baseline score from the 12-month score.
Time frame: Baseline and 12 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Inspire Therapy | Change in FOSQ From Baseline to 12 Months | 2.9 units on a scale |
Secondary
Modified Intent to Treat - AHI Responder Rate for All Implanted Subjects
The intent-to-treat (ITT) analysis for the primary endpoint included all patients who underwent an implant. A modified ITT analysis was conducted to include the subjects who did not completed the 12-month follow-up sleep study also. The ITT analysis was to calculate the AHI responder rate based on the subjects included in the analysis as described below. An Inspire therapy AHI responder was defined as a subject who experienced at least a 50% reduction in AHI from baseline and had an AHI of less than 20 at their last visit. The following subjects were included: * All implanted subjects who had AHI data collected at both baseline and 12-months follow-up. * All implanted subjects who had baseline data but no 12-month data, and had their last data values carried forward, provide they had a least 6-month AHI data. * Any implanted subject who did not have 12-month data available due to therapy failure (e.g., study withdrawal will be included in the analsys as a treatment failure.
Time frame: 12 months
Population: Implanted subjects
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Inspire Therapy | Modified Intent to Treat - AHI Responder Rate for All Implanted Subjects | 83 Number of subjects responding to therapy |
Secondary
Percentage Sleep Time at SaO2 < 90%
The percentage of time spent with oxygen saturation below 90% has been an increasingly utilized surrogate for morbidity risk in sleep apnea populations. The SaO2 secondary endpoint in this study was determined by the time below an SaO2 level of 90% during the 12-month PSG study compared to that at baseline (average of screening and 1-month PSG studies). The objective was to demonstrate a decrease in the percentage of sleep time with an SaO2 level below 90% at 12 months.
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inspire Therapy | Percentage Sleep Time at SaO2 < 90% | 2.5 Percentage of Sleep Time SaO2 <90% | 95% Confidence Interval 11.1 |