James M. Andry, MD,* Eric Powell, PhD,* Courtney Whitney, MD,** Christopher J. Miller, MS,*** Kohl Hames, MS **** and Bruce R. Bowman, ScD****

*Sleep Therapy & Research Center, San Antonio, Texas USA
**Whitney Sleep Center, Plymouth MN
***NAMSA, Minneapolis, MN
****Somnetics International, New Brighton, MN

 

BACKGROUND

Clinicians may be reluctant to prescribe newly developed sleep therapy devices without assurance of their performance.¹ This is especially true with APAP devices that use sophisticated algorithms for detecting apnea and hypopnea and precursors to apnea and hypopnea, such as flow-limited breathing and snoring. Some APAP devices have been shown to have limitations in identifying sleep disordered breathing (SDB)^2-11 or exhibit inaccuracies in reporting SDB from compliance reports.11 Consequently, clinical evaluations are warranted anytime a new, unproven device enters the market. This clinical investigation was designed to demonstrate that the performance of the Transcend Auto was equivalent to a well established, commercially available APAP device.

The Transcend Auto provides auto titrating positive airway pressure to support treatment of obstructive sleep apnea. The device is 5.1” x 3.5” x 2.8” (15.4 cm x 8.9 cm x 7.0 cm), weighs less than one pound (450 g), and supports a variety of power sources. A mini-AB USB port provides direct data exchange to a computer via a USB data cable. The interface allows the clinician to configure the Transcend Auto operating parameters and allows the patient to view and email therapy and compliance data to the clinician. The Transcend Auto offers an adjustable ramp feature and relieves pressure during expiration (EZEX), when configured by the clinician to do so. Transcend Auto automatically compensates for altitude; measures airflow; and, coupled with pressure sensing, monitors breathing and adjusts pressure according to a proprietary algorithm. The device is able to react to indicators of airway obstruction, including apnea, hypopnea, flow-limited breathing, and snoring events, by increasing pressure. Similarly, the Transcend Auto determines when normal breathing is occurring and reduces pressure to a level that maintains upper airway patency.

MATERIALS AND METHODS

Study Subjects

Patients greater than 30 kg, over 18 years of age, previously diagnosed with obstructive sleep apnea with AHI ≥15 per hour, and compliant using CPAP or APAP were potential study candidates. Patients were excluded from the study if any one of the following criteria was met: diagnosis of central or mixed sleep apnea (≥1 event per hour); current diagnosis of cardiovascular disease, asthma, or diabetes unless stable on medication for a minimum of 3 months; current diagnosis of moderate or severe chronic obstructive pulmonary disease (COPD) or restrictive pulmonary disease; non-ambulatory status; recent major surgery; use of hypnotic drugs for insomnia that was not at a stable dose for at least 30 days.

Study Design

This study was a prospective, randomized, 2×2 crossover trial to investigate whether the performance of the Transcend Auto was substantially equivalent to REMstar Auto, a representative predicate for commercially available positive airway pressure devices. Substantial equivalence was assessed by comparing the two devices’ SDB parameters assessed through manually scored PSG. Secondly, compliance reported SDB parameters from the two devices were compared to PSG to assess accuracy of device reporting. Patients underwent two full-night sleep studies in one of two randomized orders, Transcend Auto followed by REMstar Auto or REMstar Auto followed by Transcend Auto. The Sponsor and PSG scorer were blinded to treatment group throughout the course of the study. The protocol and the informed concent were reviewed and aproved by a regional Institutional Review Board (IRB)

Study Procedure

Minimum pressures were set to the same value for REMstar Auto and Transcend Auto devices based on how the patient used his/her home PAP device. If the patient normally used CPAP with ramp, the minimum pressure was set to the same pressure as their home device starting ramp pressure. If the patient normally used CPAP without ramp, the minimum pressure was set to 6 cm H2O below therapy pressure if their therapy pressure was between 14 and 20 cm H2O; 4 cm H2O below therapy pressure if therapy pressure was between 8 and 13.9 cm H2O; and at 4 cm H2O if therapy pressure was between 4 and 7.9 cm H2O. If the patient normally used APAP at home, the minimum pressure was set to 2 cm H2O below the minimum pressure of their home APAP. Maximum pressure was always set to 20 cm H2O.

Humidifiers were not used during treatment with either device and expiratory pressure relief features were set to off or zero. Each device was set on automatic mode and allowed to titrate therapy pressure during the entire night. The patient used the mask and headgear that they currently used for treatment at home. Mask leak was monitored throughout the night. If the unintentional leak exceeded approximately 24 L/min beyond the intentional leak, the technician adjusted the mask so that the unintentional leak was below approximately 24 L/min.

Patients were instrumented according to the guidelines published by the AASM Adult Obstructive Sleep Apnea Task Force for PSG testing, and included EEG, EOG, EMG, pulse oximetry, body position, snoring, chest, and abdominal belts.¹² Airflow and pressure were output from devices and recorded on the PSG system.

Patients were removed from the study if the patient was found to have central or mixed sleep apnea (≥1 event per hour), the subject withdrew consent, or the subject did not comply with the protocol. The minimum amount of sleep time for a successful sleep study was five hours. If sleep time was less than five hours, the subject was asked to undergo a repeat sleep study on a subsequent night or the patient was withdrawn from the study.

Study Data

At the conclusion of each night’s study, the compliance data stored in each APAP device was downloaded and entered into a secure, validated database. The PSGs were sent to a central laboratory for manual scoring using standardized criteria as specified by AASM for apnea and hypopnea to calculate AHI.¹² All PSGs were scored by the same Ph.D. credentialed individual, who was blinded to treatment device.

Data on airflow, average pressure, and 90% pressure were recorded from device reports. Desaturation index, arousal index, respiratory event related arousal (RERA) index, and periodic leg movement (PLM) index were from central lab scoring of the PSG.

To assure the quality of clinical data, standardized data controls were used for case report form (CRF) design, monitoring, data entry and verification, and archiving. Further, steps were taken to minimize potential sources of bias from affecting study outcomes, such as recruiting subjects from various geographical locations, using a common protocol at all sites, and having PSG scoring performed by a single individual at a central laboratory blinded to treatment device.

Analysis

The primary population for analysis was the modified intent-to-treat (mITT) population, which comprised all subjects who successfully completed both sleep studies and had no evidence of central or mixed apnea.

The primary objective for this study was to compare the efficacy of the two devices as measured by the central laboratory-scored AHI from the PSG. The statistical test for substantial equivalence was a test of non-inferiority (or substantial equivalence) of Transcend Auto to REMstar Auto at a pre-defined non-inferiority margin of 6.9.¹³ Statistical analysis for this test was conducted using a mixed model in SAS version 9.3.¹⁴

Secondary objectives for this study included comparison of AHI, apnea index (AI), and hypopnea index (HI) measured by Transcend Auto and REMstar Auto compliance reports to PSG as well as comparison of average pressure delivered by each device as reported by the compliance reports downloaded from the respective device. T-tests were used to test for differences between the central lab-scored PSG and device output measures of apnea hypopnea index (AHI), apnea index (AI) and hypopnea index (HI). Crossover models were used to compare PSG measures between devices.

RESULTS

Patient Demographics

Forty-one (41) patients provided informed consent and were enrolled in the study with thirty-five (35) subjects included in the modified ITT population and the primary analysis. Six patients were excluded from the modified ITT analysis for the following reasons: central apnea index ≥1.0 on baseline titration PSG or during study nights, loss to follow-up, or less than the required 5 hours of sleep time.

The mean age of mITT subjects was 50±9 years with 69% males. The average BMI was 37±9 with baseline AHI of 50±28. Average duration of use of CPAP was 12±20 months with minimum use of 1.5 months.

Comparison of PSG measures:

Table 1 shows the mean differences, confidence intervals, and p-values from crossover models along with device-specific means, standard deviations, and ranges. The mean AHI was 2.1±2.0 (range, 0.2 to 9.1) and 2.0±2.4 (range, 0.0 to 9.0) for Transcend Auto and REMstar Auto, respectively. The mean difference in AHI between the devices was 0.1 (95% CI, -0.6 to 0.9). The test for non-inferiority (i.e., substantial equivalence) of the Transcend Auto to the REMstar Auto was statistically significant (p<0.0001), indicating the devices were comparable in therapy efficacy.

Transcend Auto attained a statistically significant lower average therapy pressure than REMstar Auto (p=0.004).

Other respiratory PSG measures, including RERA Index, Desaturation Index, Respiratory Disturbance Index, Arousal Index, and Periodic Leg Movement Index were not significantly different between devices (Table 1).

Comparison of Residual Sleep-Disordered Breathing Measures from Compliance Reports Results shown in Table 2 indicate little evidence of clinically significant bias in either the Transcend Auto or the REMstar Auto in reporting of AI and HI compared to manual scoring of the PSG. Two subjects’ device data for the REMstar Auto data were not recorded due to device malfunction, so device data are presented for those subjects with data.

REMstar Auto tended to overestimate the true AI by 1 event/hour on average while the Transcend Auto compared more favorably to PSG score. REMstar Auto tended to underestimate HI by 0.2 events per hour while Transcend Auto tended to overestimate HI by 0.7 events per hour. AHI was overestimated by 0.9 and 0.7 events per hour by REMstar Auto and Transcend Auto, respectively.

CONCLUSION

This randomized crossover study of Transcend Auto successfully met the primary endpoint of non-inferiority to REMstar Auto in AHI (p<0.0001), so the devices were shown to be substantially equivalent. Other measured PSG parameters were not statistically significantly different. Transcend Auto average pressure was lower than REMstar Auto (p=0.004). Clinicians and patients can be assured that Transcend Auto is safe and effective in treating OSA with the potential to provide equivalent therapy at a lower average therapy pressure, which could allow greater comfort for the patient.

ACKNOWLEDGEMENTS

The sponsor acknowledges the assistance of the central scoring lab, Sleep Therapy & Research Center, San Antonio, TX, and other study site labs, Whitney Sleep Center, Plymouth, MN, and Northwind Lung Specialists and Sleep Center,
Coon Rapids, MN.

REFERENCES

1. Brown LK. Autotitrating CPAP: how shall we judge safety and efficacy of a “black box”? Chest 2006; 130:312–314.
2. Lafond C, Sériès F. Influence of nasal obstruction on auto-CPAP behavior during sleep in sleep apnea/hypopnea syndrome.
   Thorax 1998; 53:780–783.
3. Husain AM Evaluation and comparison of Tranquility and AutoSet T autotitrating CPAP machiones. J Clin Neurophysiol 2003;20(4):291–295.
4. Kessler R, Weitzenblum E, Chaouat A, et al. Evaluation of unattended automatic titration to determine therapeutic continuous positive airway pressure in patients with obstructive sleep apnea. Chest 2003 123(3):704–710.
5. Stammnitz A, Jerrentrup A, Penzel T, et al. Automatic CPAP titration with dirrerent self-setting devices in patients with obstructive sleep apnea. Eur Respir J 2004 24(2) 273–278.
6. Nolan GM, Ryan S, O’Connor TM, et al. Comparison of three auto-adjusting positive pressure devices in patients with sleep apnea. Eur Respir J 2006;28(1):159–164.
7. Sériès F, Plante J, Lacasse Y. Reliability of home CPAP titration with different automatic CPAP devices. Resir Res 2008; 9; 56.
8. Rodenstein D. Determination of therapeutic continuous positive airway pressure for obstructive sleep apnea using automatic titration: promises not fulfilled. Chest 2008; 133:595–597
9. Torre-Bouscoulet L, Meza Vargus MS, Castorena-Maldonado A,et al. Autoadjusting positive pressure trial in adults with sleepapnea assessed by simple diagnostic approach. J Clin Sleep Med 2008; 341–347.
10. Mulgrew AT, Lawati NA, Ayas NT, et al. Residual sleep apnea on polysomnography after 3 months of CPAP therapy: clinical implications, predictors and patterns. Sleep Med 2010; 11: 119–125.
11. Denotti AL, Wong KH, Dungan GC, et al. Residula sleepdisordered breathing during autotitrating continuous positive airway pressure therapy. Eur Respir J 2012; 39:1391–1397.
12. Iber C, et al. The AASM Manual for the Scoring of Sleep and Associated Events. The American Academy of Sleep Medicine, 2007.
13. Smith I, Lasserson TJ. Pressure modification for improving usage of continuous positive airway pressure machines in adults with obstructive sleep apnea. Cochrane Database Syst Rev 2009; 4:CD00353.
14. Grizzle, JE, The two-period change-over design and its use in clinical trials. Biometrics, 1965 (21), 461–480.