Evaluation of the System One RemStar Auto A-Flex for the Treatment of OSA

Obstructive Sleep Apnoea
Obstructive Sleep Apnoea (OSA) is the most common form of sleep-disordered
breathing (SDB), affecting approximately 2% of women and 4% of men (1). It is
generally characterised by persistent loud snoring and repetitive partial
(hypopnoea) and full (apnoea) collapse of the upper airway during sleep. Each
collapse of the upper airway lasts for at least 10 seconds and is terminated by
an arousal response leading to broken sleep and excessive daytime sleepiness.
OSA severity is commonly assessed by using the Apnoea/Hypopnoea Index (AHI)
which indicates the number of upper airway events that occur per hour of sleep.
The majority of European physicians would describe obstructive sleep apnoea as
being clinically significant if the patient*s AHI was >= 15 with symptoms such
as snoring and excessive daytime sleepiness.

Untreated OSA increases the risk of falling asleep while doing routine tasks
resulting in an increased incidence of workplace accidents (2) and motor
vehicle collisions while driving (3;4). OSA can also reduce quality of life (5)
and increase the risks of developing other long term health risks such as
stroke (6), heart rhythm abnormalities (7), high blood pressure (8) and type 2
diabetes (9).

Polysomnography
Polysomnography (PSG) with electroencephalographic sleep staging, oximetry and
respiratory monitoring is the *gold standard* for the diagnosis of SDB and to
conduct a CPAP titration. Polysomnography refers to the collective process of
monitoring and recording physiologic data related to sleep and wakefulness plus
respiration.

Continuous Positive Airways Pressure Therapy
Continuous Positive Airway Pressure (CPAP) is the first-line medical therapy
for treatment of OSA, with multiple studies documenting its effectiveness in
decreasing the associated morbidity and mortality of Obstructive Sleep
Disordered Breathing. This therapy is very effective in reducing the frequency
and number of apnoeas and hypopnoeas, improving sleep quality as well as the
symptoms of daytime sleepiness. CPAP prevents partial and complete airway
obstruction by stabilising the upper airway, acting as a pneumatic splint to
maintain UA patency during sleep. A blower unit produces controlled
positive-pressure airflow that is introduced through the nasal passage, holding
the soft tissue of the uvula and soft palate and the soft pharyngeal tissue in
the upper airway in position so the airway remains open. Typically, CPAP is
applied via a patient interface such as a nasal mask, oronasal mask or nasal
pillows.

With proper patient compliance, CPAP therapy can effectively eliminate sleep
disordered breathing (SDB)/OSA in addition to improving daytime hypersomnolence
and alertness, and improve the overall quality of the patient*s life. Patients
who are not able to comply with CPAP therapy may be offered Bi-Level therapy,
an alternative mode of treatment to improve compliance with positive airway
pressure therapy.
Continuous Positive Airways Pressure Titration
The goal of polysomnography testing and titration in a sleep lab is to identify
an effective pressure that will prevent apnoea, hypopnoea, snoring and
respiratory effort - related arousals in all body positions and sleep stages.
Attended sleep studies allow the technician to adjust the pressure to meet
changes in body position and sleep stage and to intervene for mask leaks or
persistent hypoxemia after airway patency is restored.

There are disadvantages to performing CPAP titration in the sleep lab using
full polysomnography as this technique is labour intensive and can lead to long
scheduling delays. Some patients, especially those in rural areas, may not have
easy access to a standard sleep lab. For other patients, an optimal pressure
effective in all situations cannot be identified in a single study night.
Auto-titrating CPAP devices, which vary the delivered pressure during the night
in response to periods of apnoea and hypopnoea during sleep, are an alternative
means of finding the optimal pressure levels required for treatment.

These devices are designed to increase pressure as needed to maintain airway
patency and then to decrease pressure if no event is detected over a set period
of time. Because the minimum effective pressure is delivered (auto adjusting),
the mean pressure is often lower than the optimal fixed CPAP pressure (10).
This lower pressure could increase acceptance and adherence with chronic
positive pressure treatment. Most automatic PAP (APAP) units have the ability
to store pressure vs. time data and many can also record leak, apnoea and
hypopnoea information. This information can be transferred to a computer and
analysed quickly to provide both summary information and more detailed pressure
and leak versus time plots on selected nights. A maximum pressure or a pressure
thought satisfactory for the majority of the time as the optimal effective CPAP
level for chronic treatment could then be chosen. This effective pressure level
(Peff) of CPAP for a given individual varies in relation to a number of
factors: ingestion of alcohol and other sedative drugs, body position while
sleeping, sleep stages, and even the course of CPAP itself, which may result in
decrease of (Peff) itself (11).

Continuous Positive Airways Pressure Intolerance
Clinical effectiveness of CPAP therapy requires nightly use. Resistance to and
intolerance of CPAP poses a serious limitation to its use. Failure to comply
with treatment has been reported to be high, with approximately 25% of patients
completely abandoning therapy during the first year treatment (12). Most
problems associated with nasal CPAP relate to issues of rhinitis, nasal
congestion, mask discomfort, claustrophobia and difficulty adjusting to the
pressure, especially during expiration (10).. Regardless of actual improvement
in the apnoea/hypopnoea index (AHI), it is the patient*s perception of their
improvement that increases compliance. If the patient feels that CPAP is
beneficial for them they are understandably more likely to comply with the
treatment. Those patients who are most compliant seem to be the most
symptomatic and have a greater awareness of the beneficial effects of CPAP.
Under these conditions, patients seem to use CPAP for the optimal length of
time, regardless of the side effects linked to the treatment (11).

Preliminary Clinical Data
A number of small studies were performed during the development of Philips
Respironics new Sleep Therapy Platform that are relevant to the APAP device
that will be investigated in this study. First, a user preference validation
trial including 284 existing CPAP patients were transitioned onto Philips
Respironics new Sleep Therapy Platform (55 used the APAP device) and
demonstrated that 79% of the surveyed subjects rated the new device as
equivalent or superior on noise, cleaning, usability, ease of transport, and
overall preference to their current device.

Preliminary comparisons of the new auto algorithm were made with the previous
auto algorithm (M-Series, Philips Respironics) in a 20 subject study in which
patients were randomised to receive each algorithm on consecutive nights with
full PSG recordings. Data from 16 completed subjects showed no statistically
significant difference between the new and previous algorithm for all sleep
variables.

Device Mean SD p-value
New auto algorithm AHI 2.9 ±3.4 0.079
Previous auto algorithm AHI 3.2 ± 3.4
New auto algorithm 90% PP 10.4 ± 2.3
0.422
New auto algorithm 90% PP 10.8 ± 3.3

Furthermore, when comparing the advanced event detection capabilities of the
new auto algorithm to similar manually scored events on consecutively measured
PSGs, a strong significant correlation between the algorithm derived Obstructed
Apnoea Index, Clear Apnoea Index and PSG scored events was demonstrated.

Finally an in lab comparison was performed of the obstructed and clear apnoea
detection capabilities of the new auto algorithm. Nineteen participants with
Sleep Disordered Breathing were studied overnight with full PSG. Scored PSG
Obstructive and central apnoeas identified using standard criteria were
compared to obstructed airway and closed airway apnoeas identified by the new
auto algorithm. The Obstructed Apnoea Indices showed an intra-class
correlation coefficient of 0.976, and the Central / Clear Apnoea Indices showed
an intra-class correlation coefficient of 0.728. The algorithm-detected Clear
Apnoea Indices were also compared to *specialised scoring* Clear Apnoea Indices
on the PSG (where the scorer had been trained to consider the effect of the
pressure pulses when classifying events), with an intra-class correlation
coefficient of 0.968.


Justification for the Study
In addition to the clinically-proven auto-titrating algorithm inherited from
the our previous auto device, Philips Respironics new Sleep Therapy System also
has the ability to distinguish obstructed and clear airway apnoea, and detect
RERA and Cheyne-Stokes respiration. The successful detection of these events
is integral to the efficacy of the auto algorithm and accordingly the ability
of the new auto algorithm to effectively treat patients with OSA. Thus, the
ability of this new system to reliably detect these events needs to be
evaluated in an adequately powered study.

Compare the performance of the Philips Respironics Sleep Therapy Auto System to
a fixed CPAP device for the treatment of OSA and validate its event detection
capabilities.

Double blind, randomised, crossover study.

Before signing the consent form for this study, the details of the subjects*
participation will be fully explained to them. Subjects will be instructed that
they will be trialling a positive airways pressure device with two different
modes, without being given any further information about the modes. The PSG
technician will alter machine setting using PC Direct software with the screen
turned away from the patient.

Following the standard education and acclimatisation program of the centre, in
which subjects will undergo a daytime CPAP session at a constant pressure of 4
cm H2O using several different interface models so that an appropriate
interface can be selected, eligible subjects will complete a CPAP titration
study with full PSG monitoring. CPAP shall start with a value of 4cmH2O and be
increased in 1cmH2O increments to the point where disordered breathing,
including hypopnoeas, RERAs, snoring, and flow limitations, are eliminated.
Respironics* Integrated heated humidifier will be used if needed and set to an
initial setting of 2. During the course of the night, this setting can be
changed to optimise participant comfort. This study shall be interpreted by the
co-investigator to determine the optimal CPAP setting. A successful titration
will be defined as an AHI < 10.0 /h under the determined optimal pressure.
Subjects in whom CPAP does not adequately treat OSA during the titration will
be excluded.

Following the CPAP titration study, subjects will be randomly assigned to one
night of APAP and one night of fixed CPAP delivered by the Philips Respironics
Sleep Therapy Auto System on consecutive nights in the Sleep Laboratory by the
PSG technician with full PSG monitoring. The therapeutic pressure from the CPAP
titration study will be applied on the fixed CPAP night and the APAP system
will be allowed to determine the PAP level on the auto night.These studies
should be performed within 14 days of the CPAP determination study.
Humidification will be standardised at the level from the CPAP determination
study. The same interface will also be used on each occasion.

At the conclusion of the subject*s participation in this study, they will be
treated for their sleep disordered breathing condition per their physicians*
instructions

Subjects will be randomly assigned to one night of APAP and one night of fixed
CPAP delivered by the Philips Respironics Sleep Therapy Auto System on
consecutive nights in the Sleep Laboratory using full PSG monitoring.

We believe that the risks of providing positive airway pressure therapy with
the Philips Respironics Sleep Therapy System are no greater than the risks
encountered with other PAP devices. We believe that no significant risks will
be posed to the subjects participating in this protocol, as the study is non
invasive and will be conducted in a standard sleep laboratory and monitored by
trained clinical staff. The PAP equipment has been tested to ensure safety.
Should the auto CPAP equipment not perform as designed, therapy could increase
or / and decrease more than desired. This effect could be uncomfortable or
awaken the subject.

Additionally, a trained sleep technician / technologist will always be present
monitoring the subject while the device is in use. The sleep technician /
technologist will intervene should any problems be identified. The patient can
also easily remove their interface device should it become uncomfortable or
make breathing difficult. Rarely there may be skin irritation in response to
the tape used to attach some of the electrodes. Other potential side effects of
PAP therapy may include: ear discomfort, conjunctivitis, skin abrasions due to
non-invasive interfaces and gastric distension (aerophagia), all of which are
quite uncommon. Thus, we believe that the risks and discomfort associated with
participation in this study are minimal.

There are a number of minor risks and hazards associated with the
investigational device that do not differ from other positive airways pressure
devices that provide positive pressure ventilation and/or its accessories
(i.e., nasal masks, tubing, etc.). These include:
• pneumothorax*
• nasal passage irritation or dryness
• irritation of the eyes
• headaches
• upper airway contamination
• re-breathing of expired air if the mask is worn and the unit is not powered up
• hypotension secondary to a decrease in cardiac output

(*Note: the occurrence of a pneumothorax will be considered a serious adverse
device effect, but has never been reported during studies of this type.)

Potential Benefits - Subjects will receive no direct benefit from participating
in this study.