<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03011762</url>
  </required_header>
  <id_info>
    <org_study_id>ZCP2013_01</org_study_id>
    <nct_id>NCT03011762</nct_id>
  </id_info>
  <brief_title>Feasibility and Predictive Accuracy of an In-Home Computer Controlled Mandibular Positioner in Identifying Favorable Candidates for Oral Appliance Therapy</brief_title>
  <official_title>Feasibility and Predictive Accuracy of an In-Home Computer Controlled Mandibular Positioner in Identifying Favorable Candidates for Oral Appliance Therapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Zephyr Sleep Technologies</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Zephyr Sleep Technologies</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Sleep apnea is a condition in which the throat air passage closes during sleep and repeatedly&#xD;
      interrupts breathing. The standard treatment of sleep apnea is air pressure applied to the&#xD;
      nose, so-called nasal CPAP, but it is not suitable for all patients. Another treatment is to&#xD;
      use a dental appliance while asleep. In this treatment, an appliance covers the upper and&#xD;
      lower teeth and acts to pull the jaw forward, which opens the throat passage. This allows the&#xD;
      patient to breathe normally.&#xD;
&#xD;
      Dental appliance treatment does not work effectively in all patients. In order to identify&#xD;
      those in whom dental appliance therapy will be effective, the study sponsor has invented the&#xD;
      remotely controlled mandibular positioner, MATRx. The MATRx is an FDA cleared motorized&#xD;
      dental appliance which is used overnight in hospital sleep studies and works by pulling the&#xD;
      jaw outward under the control of a technician.&#xD;
&#xD;
      In order to eliminate the need for an overnight in hospital sleep study, the sponsor has&#xD;
      invented a new device that allows for the identification of individuals who are suitable&#xD;
      candidates for dental appliance therapy from the comfort of the home. Like with MATRx,&#xD;
      participants will sleep with a motorized mandibular positioner in place. But, it is&#xD;
      controlled by a computer, rather than a sleep technician, making it a computer controlled&#xD;
      mandibular positioner (CCMP). The feasibility and predictive accuracy of multi night testing&#xD;
      using the CCMP will be evaluated through participation in this study.&#xD;
&#xD;
      The sponsor has carried out two previous research trials leading to the development of the&#xD;
      CCMP. The first established the predictive accuracy of the remotely controlled mandibular&#xD;
      positioner at identifying candidates suitable for oral appliance therapy and their effective&#xD;
      therapeutic setting. The second established the accuracy of the algorithms used by the CCMP&#xD;
      to similarly identify successful candidates in a clinical setting. No significant problems&#xD;
      were identified in conjunction with our previous research protocol, and no significant risks&#xD;
      were identified. This third protocol is to establish the feasibility and accuracy of the CCMP&#xD;
      when used in the home setting.&#xD;
&#xD;
      The trial will utilize data collected over a series of nights to formulate a prediction of&#xD;
      therapeutic outcome with an oral appliance. The prediction will be tested by comparing the&#xD;
      degree of airway obstruction without treatment (from data collected prior to the study) to&#xD;
      the degree of airway obstruction with oral appliance therapy. A custom fit oral appliance&#xD;
      will be provided to participants as part of the trial.&#xD;
&#xD;
      The purpose of the study is to test the predictive accuracy of the CCMP in identifying&#xD;
      favorable candidates for oral appliance therapy and in determining an efficacious protrusive&#xD;
      position. Another purpose is to evaluate the convenience and possibility of carrying out a&#xD;
      multi-night CCMP study in the home.&#xD;
&#xD;
      There are no known risks or side effects to the CCMP studies, to the home studies, or to the&#xD;
      oral appliance therapy. It is possible that participants will have some discomfort during the&#xD;
      nights of the CCMP studies but this will be transient and not cause any long term damage.&#xD;
      Participants may experience soreness of the teeth or jaw joint during adjustment of the oral&#xD;
      appliance by the dentist. There is no risk of jaw dislocation or problems with the&#xD;
      temporomandibular joint (TMJ).&#xD;
&#xD;
      Participants will have the benefit of receiving a dental appliance for treating their sleep&#xD;
      apnea at no charge. This will be supplied to participants by a dentist who is an expert in&#xD;
      this field. Participation in the study will also allow the further development and ultimately&#xD;
      commercialization of the CCMP device which may help individuals who have sleep apnea.&#xD;
&#xD;
      Dental appliance therapy is just one of two therapies for sleep apnea. If participants choose&#xD;
      not to have the dental appliance therapy, they may wish to try nasal continuous positive&#xD;
      airway pressure. Participants may withdraw at any time during the study without compromising&#xD;
      their health care in any way. To withdraw, participants should simply notify one of the&#xD;
      physicians or the research assistant. If the sponsor obtains new information that might&#xD;
      affect an individual's willingness to participate in the study, they will be informed&#xD;
      immediately.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      I. BACKGROUND AND SIGNIFICANCE&#xD;
&#xD;
      Obstructive sleep apnea (OSA) is a common disease that carries significant risks for&#xD;
      cardiovascular disease, mortality, and economic costs. Almost thirty years ago, initial&#xD;
      population studies found the prevalence of OSA to be five to nine per cent of the adult&#xD;
      population. Excess body weight is a risk factor for the development of OSA, and the recent&#xD;
      rise in prevalence of obesity has led to revised estimates of OSA prevalence, now at&#xD;
      seventeen per cent of the adult population. OSA is poorly recognized clinically; currently&#xD;
      85% of apneics remain undiagnosed and untreated.&#xD;
&#xD;
      OSA derives fundamentally from structural abnormalities of the pharynx that cause pharyngeal&#xD;
      narrowing or closure during sleep and produce recurrent apneas and hypopneas. During&#xD;
      wakefulness compensatory neuromuscular reflexes protect the pharynx from collapse. These&#xD;
      reflexes are lost during sleep, leaving the collapsible human pharynx susceptible to&#xD;
      narrowing or closure. Nasal continuous positive airway pressure (CPAP), comprised of an air&#xD;
      generator and nose mask, is the standard therapy for OSA. CPAP delivers positive pressure to&#xD;
      the pharyngeal lumen, thereby dilating it and eliminating obstruction. While this therapy is&#xD;
      highly efficacious, it is cumbersome and its effectiveness is compromised by a relatively low&#xD;
      adherence rate. Adherence depends on the methods used to initiate therapy and on the severity&#xD;
      of OSA, being higher in subjects with more severe hypoxemia and excessive daytime sleepiness.&#xD;
      In current practice, CPAP adherence rate appears to approximate fifty per cent.&#xD;
&#xD;
      The only currently available alternative to CPAP is oral appliance (OA) therapy. Oral&#xD;
      appliances maintain patency of the airway during sleep by stabilizing and protruding the&#xD;
      mandible and/or the tongue. The most commonly used type of OA is a custom-made mandibular&#xD;
      repositioner (MR) which protrudes the mandible. Mandibular protrusion in paralyzed subjects&#xD;
      dilates both the velopharynx and the oropharynx. In clinical practice, a specialist dentist&#xD;
      fabricates a custom-fitted appliance covering upper and lower teeth. The appliance is then&#xD;
      empirically adjusted to progressively protrude the mandible until a therapeutic end-point is&#xD;
      reached. OA therapy is better accepted by the OSA subject than nasal CPAP, and self-reported&#xD;
      adherence rates are high. Unfortunately, OA therapy is not uniformly effective in OSA.&#xD;
      Reported effectiveness ranges from 50 to 70 percent, and our recent study found a 58% percent&#xD;
      success rate. In short, two therapies are currently available for treating OSA, and each has&#xD;
      its own shortcomings: 1) CPAP is efficacious but not uniformly tolerated by subjects; and 2)&#xD;
      OAT is not highly efficacious but is better tolerated than CPAP.&#xD;
&#xD;
      II. CURRENT STATUS OF MEDICAL PRACTICE&#xD;
&#xD;
      Because of the uncertainties regarding use of OA therapy for treating OSA, current practices&#xD;
      in North America focus primarily on the use of nasal CPAP. Virtually all subjects found to&#xD;
      have OSA receive a trial of nasal CPAP. If they prove non-adherent with this therapy, they&#xD;
      may then be offered OA therapy. The American Academy of Sleep Medicine recommends OA therapy&#xD;
      as a CPAP alternative in subjects with OSA of mild to moderate severity. However, lacking a&#xD;
      valid test for clinically selecting subjects with OSA who will have a favorable response to&#xD;
      OA therapy, reimbursement for OA therapy is usually provided only for apneics who fail CPAP.&#xD;
&#xD;
      The effectiveness of OA therapy could be improved by screening OSA subjects and prospectively&#xD;
      identifying those suitable for this therapy. Unfortunately, at the present time, a method for&#xD;
      selecting favorable candidates for OA therapy is lacking. Moreover, even if a subject were&#xD;
      known to be a favorable candidate, the dentist currently has no way to determine the target&#xD;
      therapeutic protrusive position. Studies of the passive pharynx indicate that the response of&#xD;
      the pharynx to mandibular protrusion is 'dose dependent'; incremental mandibular protrusion&#xD;
      produces corresponding pharyngeal enlargement. However, clinical experience shows that&#xD;
      excessive mandibular protrusion is undesirable, producing side effects, such as, pain and&#xD;
      tooth movement that lead to discontinuation of therapy. In some cases, over-protrusion can&#xD;
      worsen OSA. Current practice is for the dentist to progressively protrude the mandible until&#xD;
      a symptomatic response occurs, and then reassess the subject to determine if OSA has&#xD;
      resolved. Thus, prospective identification of suitable candidates and of a target protrusive&#xD;
      position would greatly facilitate treatment of OSA with OA.&#xD;
&#xD;
      Owing largely to its association with excess body weight, obstructive sleep apnea (OSA) has&#xD;
      become arguably the most prevalent chronic non-communicable disease in industrialized&#xD;
      societies, assuming that obesity is not classified a disease. In addition to impairing&#xD;
      quality of life, OSA conveys an increased risk of cardiovascular disease and vehicular&#xD;
      accidents. Finally, the majority of apneics remain undiagnosed and untreated. Thus, OSA has&#xD;
      all the hallmarks of a major public health problem, affecting all age groups and increasing&#xD;
      in epidemic proportions. Unfortunately, current medical practices seem ill suited to dealing&#xD;
      with the challenges posed by OSA.&#xD;
&#xD;
      Perhaps the most unsettling aspect of present medical practices relates to the cumbersome,&#xD;
      uninviting and expensive methods currently used to diagnose and treat the disease. Common&#xD;
      clinical experience indicates that individuals often resist undergoing the standard&#xD;
      diagnostic test, an overnight in-hospital polysomnogram, because of the extensive attachments&#xD;
      to the body surface and because, if OSA is present, continuous positive airway pressure&#xD;
      (CPAP) will be administered during the latter half of the night. In other words, as public&#xD;
      awareness of sleep apnea has increased so also has the negative impression of current testing&#xD;
      and treatment. Any effective solution to the public health challenges posed by sleep apnea&#xD;
      will have to consider the need for less cumbersome and off-putting clinical methods. In other&#xD;
      words, the current approach to OSA, i.e., overnight polysomnogram plus CPAP, simply will not&#xD;
      deal with the problem.&#xD;
&#xD;
      While simpler, less expensive home monitoring appears to be gaining acceptance of sleep&#xD;
      physicians, CPAP continues to be virtually the only therapy offered to most patients, despite&#xD;
      the low adherence rated documented in numerous studies. The dominant alternative, at the&#xD;
      present time, is mandibular repositioner (MR) therapy, using a custom fitted dental appliance&#xD;
      that protrudes the mandible during sleep. Despite overwhelming patient preference for OA over&#xD;
      CPAP, only 5% of patients diagnosed with OSA receive this therapy. The likely reason for the&#xD;
      physician bias in favor CPAP therapy is that it is benign and highly efficacious. OA therapy,&#xD;
      while similarly benign, is efficacious in only 50-70% of unselected cases. Thus, the&#xD;
      clinician prefers prescribing the more reliable therapy, having less concern about the low&#xD;
      adherence rate. To summarize, current practice of diagnosis and treatment of OSA in North&#xD;
      America emphasizes expensive in-hospital testing and initiation of a therapy which is&#xD;
      difficult for many patients to accept and use regularly.&#xD;
&#xD;
      III. NEW TECHNOLOGIES&#xD;
&#xD;
      The proposed research evaluates new technology that could contribute to ameliorating the&#xD;
      difficulties outlined above by allowing accurate selection of patients for OA therapy using a&#xD;
      test that is performed in the home. This home technology is, in turn, derived from a device&#xD;
      that Zephyr Sleep Technologies has invented, developed and now have brought to market, called&#xD;
      remotely controlled mandibular positioner (RCMP).&#xD;
&#xD;
      In order to have a more convenient and less expensive method for selecting favorable&#xD;
      candidates for OA therapy, Zephyr Sleep Technologies has developed a companion technology for&#xD;
      use in the home. Like the RCMP, the patient sleeps with the motorized mandibular positioner&#xD;
      in place. However, the position of the mandibular protruder is controlled by a computer,&#xD;
      rather than a sleep technician, making it a computer controlled mandibular positioner (CCMP).&#xD;
      As in the RCMP study, respiratory airflow and oxygen saturation are recorded, and the CCMP&#xD;
      accurately detects apneas and hypopneas in real time. However, bioelectric signals necessary&#xD;
      for sleep staging are not recorded. The CCMP protrudes the mandible when apneas or hypopneas&#xD;
      are detected. In addition, it conducts proactive testing, moving the mandible and evaluating&#xD;
      the effect on airflow. Using both types of information, the controller decides whether or not&#xD;
      to move the mandible, in which direction, and by how much. Finally, Zephyr Sleep Technologies&#xD;
      has developed an analytical algorithm that examines the response of the moving apnea hypopnea&#xD;
      index (AHI, the sum of apneas and hypopneas per unit time) to mandibular protrusion and makes&#xD;
      a prediction of therapeutic success with OA.&#xD;
&#xD;
      The CCMP uses the same motorized mandibular protruder used for the MATRx product. The motor&#xD;
      is enclosed in a housing which is attached to the upper and lower appliances. The movement of&#xD;
      the linear actuator exerts a force on the lower jaw to either protrude or retrude it. A&#xD;
      series of dental trays for upper and lower teeth have been fabricated. This allows a close&#xD;
      fitting of the tray to the subject's teeth so that a minimum amount of tray material occupies&#xD;
      the inner surface of the teeth. A highly flexible, thin wire connects the motor in the&#xD;
      mandibular protruder to a controller on a bedside table which, in turn, is connected to a&#xD;
      laptop computer. As well, an input signal box on the bedside table is connected to two naris&#xD;
      catheters that are positioned in the patient's nose and a commercially available finger&#xD;
      oximeter. The input signal box is connected to the laptop and these two signals (oxygen&#xD;
      saturation and airflow) are used by the computer algorithms to decide how to move the&#xD;
      mandible. The MATRx controller receives commands from the computer that cause it to protrude&#xD;
      or retrude the mandible in small, defined steps. The controller also has a wired output&#xD;
      connection to the input box of computer, continuously providing the computer with information&#xD;
      regarding the position of the mandible. The limits of excursion by the actuator are set by&#xD;
      the technician in the software, according to the full retrusion and full protrusion values&#xD;
      noted by the dentist. Thus, the computer can move the mandible only between predefined limits&#xD;
      during the CCMP study. The signal box also receives input signals from a microphone and a&#xD;
      position sensor mounted on the mandibular positioner as well as an input from a force&#xD;
      transducer inside the positioner.&#xD;
&#xD;
      IV. STUDY PROCEDURES&#xD;
&#xD;
      Participants will receive a two night in-home cardio-pulmonary evaluation during sleep using&#xD;
      the Snore Sat Recorder. The results will provide baseline data. Prior to the in-home CCMP&#xD;
      study, the subject will be assessed by the dental co-investigator to ensure suitability for&#xD;
      the trial and use of the device. They will then be fitted with an upper and a lower dental&#xD;
      tray by the dental co-investigator. The dentist fills each tray with a silicone impression&#xD;
      material and applies them to the upper and lower teeth. The relative position of upper and&#xD;
      lower trays is documented by the numerical reading from a linear scale imprinted on the&#xD;
      sliding strut of the lower tray. The subject moves the mandible to the rest position, the&#xD;
      most retruded position, and the most protruded position. The scale is read by the dentist at&#xD;
      each position. The data collected is provided to the research coordinator and will be input&#xD;
      into the device to control the range of protrusion tested by the device.&#xD;
&#xD;
      The clinical coordinator will visit the subject in the home during the day of the first night&#xD;
      test and set up the computer equipment and mandibular positioner. To attach the subject's&#xD;
      dental trays, the upper and lower trays are clipped to the actuator housing with the actuator&#xD;
      piston fully retracted. The maximum allowable protrusive position as determined by the&#xD;
      dentist will be entered in the computer to prevent excessive protrusion of the mandible. The&#xD;
      computer controls movement of the linear actuator in protrusive or retrusive directions in&#xD;
      increments of 0.2 mm through the keyboard on the computer. The position of the actuator is&#xD;
      connected as an input to the computer. Just prior to starting the study, the subject will lie&#xD;
      supine in bed and insert the dental trays into the mouth with the trays in the rest position.&#xD;
&#xD;
      The clinical coordinator will also provide the subject with full instruction on how to use&#xD;
      the device during the study. The subject will be instructed to properly insert the trays,&#xD;
      connected to the mandibular positioner, in the mouth. The subject will also learn to apply&#xD;
      the finger oximeter probe, and the naris cannula. The subject will be taught how to start the&#xD;
      CCMP test, pause it and terminate it at the end of the study. At bedtime, the subject will&#xD;
      apply the naris cannula and the probe, insert the tray in the mouth and initiate the CCMP&#xD;
      study by the appropriate command on the laptop. The subject then falls asleep, and as apneas&#xD;
      and/or hypopneas appear, the computer will protrude the mandible from rest position in 0.2 mm&#xD;
      steps. Once all respiratory disturbances are eliminated (absence of apneas, hypopneas),&#xD;
      proactive testing is performed in which the mandible is protruded or retruded 0.6 mm. If the&#xD;
      latter causes a decrease in peak inspiratory airflow or if the former causes an increase in&#xD;
      this variable, the mandible is protruded 0.6 mm, and so on. The following morning, the&#xD;
      subject will awaken and remove the oral appliance, terminate the CCMP program and transmit&#xD;
      the night's data to the server by a mouse click on a send button. The subject will complete a&#xD;
      Device Satisfaction Questionnaire each morning.&#xD;
&#xD;
      The data from the first night titration will be retrieved and automatically analyzed to judge&#xD;
      the efficaciousness of the mandibular protrusion in eliminating pharyngeal obstruction and to&#xD;
      identify the effective target protrusive position that will be required for successful&#xD;
      therapy. If the predicted success criterion is not met, the subject is tentatively predicted&#xD;
      to be a therapeutic failure, and a target of 90% of full protrusion is selected. After the&#xD;
      analysis has been completed, the clinical coordinator will return to the subject's home and&#xD;
      set the target position for the second night CCMP study.&#xD;
&#xD;
      During the home visit prior to the second night study, the clinical coordinator will discuss&#xD;
      with the subject his/her experience during the first night, and will carefully inquire&#xD;
      regarding any discomfort or problems the subject may have experienced. The coordinator sets&#xD;
      the CCMP for the Refinement and Verification program and enters the appropriate target&#xD;
      distance. At bedtime the subject prepares for the study as on the first night.&#xD;
&#xD;
      The CCMP algorithm moves the mandible to the target position and holds it there for the&#xD;
      entire night, if the moving AHI (i.e. AHI for the time after the target is reached, initially&#xD;
      measured over at least 2 hr) remains below 10 hr-1, ±0.6 mm. Otherwise the computer will&#xD;
      protrude the mandible in 0.2 mm steps and repeat the test at a higher protrusive level. The&#xD;
      following morning, the subject will awaken and remove the oral appliance, terminate the CCMP&#xD;
      program and transmit the night's data to the Zephyr server by a mouse click on a send button.&#xD;
      The subject will complete the Device Satisfaction Questionnaire.&#xD;
&#xD;
      The computer calculates an AHI for the full night. The results from the first and second&#xD;
      night titration studies will be provided to a sleep physician who will review the results and&#xD;
      refine the prediction to arrive at a final prediction of therapeutic outcome and target&#xD;
      protrusive setting.&#xD;
&#xD;
      The target protrusive position determined from the analysis of the combined titration studies&#xD;
      will then be sent to the dentist. For patients predicted to be a success, the minimum&#xD;
      effective position will be provided. For patients predicted to be a failure, the scale&#xD;
      reading at 70 percent of maximum protrusion will serve as a sham target value. The dentist&#xD;
      will be blinded to whether the CCMP test results were &quot;positive&quot; or &quot;negative&quot;. The subject&#xD;
      will be referred to the dental co-investigator, and fitted with a custom oral appliance at no&#xD;
      cost while blinded to the results of the CCMP studies.&#xD;
&#xD;
      Follow-up portable cardio-pulmonary monitoring will be performed on two consecutive nights&#xD;
      with the oral appliance at target protrusive distance. If the AHI is greater than 10 hr-1,&#xD;
      the subject will be referred to the dental co-investigator for further mandibular protrusion.&#xD;
      This adjustment will be performed in a minimum period of 3 weeks. The subject will be&#xD;
      retested and the therapy judged successful according to the criteria outlined above. If the&#xD;
      AHI is greater than 10hr-1, once maximum clinical protrusion of the mandible has been&#xD;
      achieved, the OA therapy will be considered a failure.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>November 2012</start_date>
  <completion_date type="Actual">October 2016</completion_date>
  <primary_completion_date type="Actual">October 2016</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Predictive Accuracy</measure>
    <time_frame>4 weeks</time_frame>
    <description>Following the CCMP test, individuals will undergo a home sleep test to determine if the prediction made by the device was accurate (i.e. therapeutic responder or non-responder to oral appliance therapy).</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">202</enrollment>
  <condition>Sleep Apnea, Obstructive</condition>
  <arm_group>
    <arm_group_label>Computer Controlled Mandibular Positioner</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>All study participants will undergo the computer controlled mandibular positioner test.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Computer controlled mandibular positioner</intervention_name>
    <description>Participants in this arm will complete the computer controlled mandibular positioner test. The study participant, study dentist, and PI are all blinded to the outcome of the CCMP test. Those participants predicted to experience therapeutic success with OAT will have their oral appliance set at the predicted protrusive level; those participants predicted to experience therapeutic failure will have their oral appliance set at a default position. Outcome home sleep tests with the oral appliance in place will be used to determine the accuracy of the prediction.</description>
    <arm_group_label>Computer Controlled Mandibular Positioner</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Aged between 21 and 80 yrs&#xD;
&#xD;
          2. Obstructive sleep apnea (AHI &gt; 10hr-1)&#xD;
&#xD;
          3. Body mass index less than 40 kg/m2&#xD;
&#xD;
          4. Neck circumference less than 50 cm&#xD;
&#xD;
          5. Absence of severe oxyhemoglobin desaturation during sleep as indicated by a mean value&#xD;
             of oxygen saturation (SaO2) greater than 90 percent&#xD;
&#xD;
          6. Mandibular range of motion greater than 5 mm&#xD;
&#xD;
          7. Adequate dentition (10 upper and 10 lower teeth)&#xD;
&#xD;
          8. Ability to understand and provide informed consent&#xD;
&#xD;
        Subjects will be recruited from the population of subjects seen by the PI or other sleep&#xD;
        physicians at the out-patient clinic of the Foothills Medical Center Sleep Disorders Center&#xD;
        (Calgary, Canada), and by the dental co-investigator at the Snore Centre (Calgary, Canada).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Inability to breathe comfortably through the nose&#xD;
&#xD;
          2. Central Sleep Apnea&#xD;
&#xD;
          3. Anticipated change in medical therapy that could alter the severity of OSA during the&#xD;
             protocol&#xD;
&#xD;
          4. Anticipated change in body weight (5% or more) during the protocol&#xD;
&#xD;
          5. Symptomatic, non-respiratory sleep disorder, e.g., restless leg syndrome or chronic&#xD;
             insomnia&#xD;
&#xD;
          6. Severe respiratory disorder(s) other than sleep disordered breathing&#xD;
&#xD;
          7. Loose teeth or advanced periodontal disease&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <verification_date>June 2018</verification_date>
  <study_first_submitted>January 3, 2017</study_first_submitted>
  <study_first_submitted_qc>January 3, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 5, 2017</study_first_posted>
  <last_update_submitted>June 25, 2018</last_update_submitted>
  <last_update_submitted_qc>June 25, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">June 27, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sleep Apnea, Obstructive</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03011762
org study id: ZCP2013_01
nct id: NCT03011762
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Sleep apnea is a condition in which the throat air passage closes during sleep and repeatedly
      interrupts breathing. The standard treatment of sleep apnea is air pressure applied to the
      nose, so-called nasal CPAP, but it is not suitable for all patients. Another treatment is to
      use a dental appliance while asleep. In this treatment, an appliance covers the upper and
      lower teeth and acts to pull the jaw forward, which opens the throat passage. This allows the
      patient to breathe normally.

      Dental appliance treatment does not work effectively in all patients. In order to identify
      those in whom dental appliance therapy will be effective, the study sponsor has invented the
      remotely controlled mandibular positioner, MATRx. The MATRx is an FDA cleared motorized
      dental appliance which is used overnight in hospital sleep studies and works by pulling the
      jaw outward under the control of a technician.

      In order to eliminate the need for an overnight in hospital sleep study, the sponsor has
      invented a new device that allows for the identification of individuals who are suitable
      candidates for dental appliance therapy from the comfort of the home. Like with MATRx,
      participants will sleep with a motorized mandibular positioner in place. But, it is
      controlled by a computer, rather than a sleep technician, making it a computer controlled
      mandibular positioner (CCMP). The feasibility and predictive accuracy of multi night testing
      using the CCMP will be evaluated through participation in this study.

      The sponsor has carried out two previous research trials leading to the development of the
      CCMP. The first established the predictive accuracy of the remotely controlled mandibular
      positioner at identifying candidates suitable for oral appliance therapy and their effective
      therapeutic setting. The second established the accuracy of the algorithms used by the CCMP
      to similarly identify successful candidates in a clinical setting. No significant problems
      were identified in conjunction with our previous research protocol, and no significant risks
      were identified. This third protocol is to establish the feasibility and accuracy of the CCMP
      when used in the home setting.

      The trial will utilize data collected over a series of nights to formulate a prediction of
      therapeutic outcome with an oral appliance. The prediction will be tested by comparing the
      degree of airway obstruction without treatment (from data collected prior to the study) to
      the degree of airway obstruction with oral appliance therapy. A custom fit oral appliance
      will be provided to participants as part of the trial.

      The purpose of the study is to test the predictive accuracy of the CCMP in identifying
      favorable candidates for oral appliance therapy and in determining an efficacious protrusive
      position. Another purpose is to evaluate the convenience and possibility of carrying out a
      multi-night CCMP study in the home.

      There are no known risks or side effects to the CCMP studies, to the home studies, or to the
      oral appliance therapy. It is possible that participants will have some discomfort during the
      nights of the CCMP studies but this will be transient and not cause any long term damage.
      Participants may experience soreness of the teeth or jaw joint during adjustment of the oral
      appliance by the dentist. There is no risk of jaw dislocation or problems with the
      temporomandibular joint (TMJ).

      Participants will have the benefit of receiving a dental appliance for treating their sleep
      apnea at no charge. This will be supplied to participants by a dentist who is an expert in
      this field. Participation in the study will also allow the further development and ultimately
      commercialization of the CCMP device which may help individuals who have sleep apnea.

      Dental appliance therapy is just one of two therapies for sleep apnea. If participants choose
      not to have the dental appliance therapy, they may wish to try nasal continuous positive
      airway pressure. Participants may withdraw at any time during the study without compromising
      their health care in any way. To withdraw, participants should simply notify one of the
      physicians or the research assistant. If the sponsor obtains new information that might
      affect an individual's willingness to participate in the study, they will be informed
      immediately.
I. BACKGROUND AND SIGNIFICANCE

      Obstructive sleep apnea (OSA) is a common disease that carries significant risks for
      cardiovascular disease, mortality, and economic costs. Almost thirty years ago, initial
      population studies found the prevalence of OSA to be five to nine per cent of the adult
      population. Excess body weight is a risk factor for the development of OSA, and the recent
      rise in prevalence of obesity has led to revised estimates of OSA prevalence, now at
      seventeen per cent of the adult population. OSA is poorly recognized clinically; currently
      85% of apneics remain undiagnosed and untreated.

      OSA derives fundamentally from structural abnormalities of the pharynx that cause pharyngeal
      narrowing or closure during sleep and produce recurrent apneas and hypopneas. During
      wakefulness compensatory neuromuscular reflexes protect the pharynx from collapse. These
      reflexes are lost during sleep, leaving the collapsible human pharynx susceptible to
      narrowing or closure. Nasal continuous positive airway pressure (CPAP), comprised of an air
      generator and nose mask, is the standard therapy for OSA. CPAP delivers positive pressure to
      the pharyngeal lumen, thereby dilating it and eliminating obstruction. While this therapy is
      highly efficacious, it is cumbersome and its effectiveness is compromised by a relatively low
      adherence rate. Adherence depends on the methods used to initiate therapy and on the severity
      of OSA, being higher in subjects with more severe hypoxemia and excessive daytime sleepiness.
      In current practice, CPAP adherence rate appears to approximate fifty per cent.

      The only currently available alternative to CPAP is oral appliance (OA) therapy. Oral
      appliances maintain patency of the airway during sleep by stabilizing and protruding the
      mandible and/or the tongue. The most commonly used type of OA is a custom-made mandibular
      repositioner (MR) which protrudes the mandible. Mandibular protrusion in paralyzed subjects
      dilates both the velopharynx and the oropharynx. In clinical practice, a specialist dentist
      fabricates a custom-fitted appliance covering upper and lower teeth. The appliance is then
      empirically adjusted to progressively protrude the mandible until a therapeutic end-point is
      reached. OA therapy is better accepted by the OSA subject than nasal CPAP, and self-reported
      adherence rates are high. Unfortunately, OA therapy is not uniformly effective in OSA.
      Reported effectiveness ranges from 50 to 70 percent, and our recent study found a 58% percent
      success rate. In short, two therapies are currently available for treating OSA, and each has
      its own shortcomings: 1) CPAP is efficacious but not uniformly tolerated by subjects; and 2)
      OAT is not highly efficacious but is better tolerated than CPAP.

      II. CURRENT STATUS OF MEDICAL PRACTICE

      Because of the uncertainties regarding use of OA therapy for treating OSA, current practices
      in North America focus primarily on the use of nasal CPAP. Virtually all subjects found to
      have OSA receive a trial of nasal CPAP. If they prove non-adherent with this therapy, they
      may then be offered OA therapy. The American Academy of Sleep Medicine recommends OA therapy
      as a CPAP alternative in subjects with OSA of mild to moderate severity. However, lacking a
      valid test for clinically selecting subjects with OSA who will have a favorable response to
      OA therapy, reimbursement for OA therapy is usually provided only for apneics who fail CPAP.

      The effectiveness of OA therapy could be improved by screening OSA subjects and prospectively
      identifying those suitable for this therapy. Unfortunately, at the present time, a method for
      selecting favorable candidates for OA therapy is lacking. Moreover, even if a subject were
      known to be a favorable candidate, the dentist currently has no way to determine the target
      therapeutic protrusive position. Studies of the passive pharynx indicate that the response of
      the pharynx to mandibular protrusion is 'dose dependent'; incremental mandibular protrusion
      produces corresponding pharyngeal enlargement. However, clinical experience shows that
      excessive mandibular protrusion is undesirable, producing side effects, such as, pain and
      tooth movement that lead to discontinuation of therapy. In some cases, over-protrusion can
      worsen OSA. Current practice is for the dentist to progressively protrude the mandible until
      a symptomatic response occurs, and then reassess the subject to determine if OSA has
      resolved. Thus, prospective identification of suitable candidates and of a target protrusive
      position would greatly facilitate treatment of OSA with OA.

      Owing largely to its association with excess body weight, obstructive sleep apnea (OSA) has
      become arguably the most prevalent chronic non-communicable disease in industrialized
      societies, assuming that obesity is not classified a disease. In addition to impairing
      quality of life, OSA conveys an increased risk of cardiovascular disease and vehicular
      accidents. Finally, the majority of apneics remain undiagnosed and untreated. Thus, OSA has
      all the hallmarks of a major public health problem, affecting all age groups and increasing
      in epidemic proportions. Unfortunately, current medical practices seem ill suited to dealing
      with the challenges posed by OSA.

      Perhaps the most unsettling aspect of present medical practices relates to the cumbersome,
      uninviting and expensive methods currently used to diagnose and treat the disease. Common
      clinical experience indicates that individuals often resist undergoing the standard
      diagnostic test, an overnight in-hospital polysomnogram, because of the extensive attachments
      to the body surface and because, if OSA is present, continuous positive airway pressure
      (CPAP) will be administered during the latter half of the night. In other words, as public
      awareness of sleep apnea has increased so also has the negative impression of current testing
      and treatment. Any effective solution to the public health challenges posed by sleep apnea
      will have to consider the need for less cumbersome and off-putting clinical methods. In other
      words, the current approach to OSA, i.e., overnight polysomnogram plus CPAP, simply will not
      deal with the problem.

      While simpler, less expensive home monitoring appears to be gaining acceptance of sleep
      physicians, CPAP continues to be virtually the only therapy offered to most patients, despite
      the low adherence rated documented in numerous studies. The dominant alternative, at the
      present time, is mandibular repositioner (MR) therapy, using a custom fitted dental appliance
      that protrudes the mandible during sleep. Despite overwhelming patient preference for OA over
      CPAP, only 5% of patients diagnosed with OSA receive this therapy. The likely reason for the
      physician bias in favor CPAP therapy is that it is benign and highly efficacious. OA therapy,
      while similarly benign, is efficacious in only 50-70% of unselected cases. Thus, the
      clinician prefers prescribing the more reliable therapy, having less concern about the low
      adherence rate. To summarize, current practice of diagnosis and treatment of OSA in North
      America emphasizes expensive in-hospital testing and initiation of a therapy which is
      difficult for many patients to accept and use regularly.

      III. NEW TECHNOLOGIES

      The proposed research evaluates new technology that could contribute to ameliorating the
      difficulties outlined above by allowing accurate selection of patients for OA therapy using a
      test that is performed in the home. This home technology is, in turn, derived from a device
      that Zephyr Sleep Technologies has invented, developed and now have brought to market, called
      remotely controlled mandibular positioner (RCMP).

      In order to have a more convenient and less expensive method for selecting favorable
      candidates for OA therapy, Zephyr Sleep Technologies has developed a companion technology for
      use in the home. Like the RCMP, the patient sleeps with the motorized mandibular positioner
      in place. However, the position of the mandibular protruder is controlled by a computer,
      rather than a sleep technician, making it a computer controlled mandibular positioner (CCMP).
      As in the RCMP study, respiratory airflow and oxygen saturation are recorded, and the CCMP
      accurately detects apneas and hypopneas in real time. However, bioelectric signals necessary
      for sleep staging are not recorded. The CCMP protrudes the mandible when apneas or hypopneas
      are detected. In addition, it conducts proactive testing, moving the mandible and evaluating
      the effect on airflow. Using both types of information, the controller decides whether or not
      to move the mandible, in which direction, and by how much. Finally, Zephyr Sleep Technologies
      has developed an analytical algorithm that examines the response of the moving apnea hypopnea
      index (AHI, the sum of apneas and hypopneas per unit time) to mandibular protrusion and makes
      a prediction of therapeutic success with OA.

      The CCMP uses the same motorized mandibular protruder used for the MATRx product. The motor
      is enclosed in a housing which is attached to the upper and lower appliances. The movement of
      the linear actuator exerts a force on the lower jaw to either protrude or retrude it. A
      series of dental trays for upper and lower teeth have been fabricated. This allows a close
      fitting of the tray to the subject's teeth so that a minimum amount of tray material occupies
      the inner surface of the teeth. A highly flexible, thin wire connects the motor in the
      mandibular protruder to a controller on a bedside table which, in turn, is connected to a
      laptop computer. As well, an input signal box on the bedside table is connected to two naris
      catheters that are positioned in the patient's nose and a commercially available finger
      oximeter. The input signal box is connected to the laptop and these two signals (oxygen
      saturation and airflow) are used by the computer algorithms to decide how to move the
      mandible. The MATRx controller receives commands from the computer that cause it to protrude
      or retrude the mandible in small, defined steps. The controller also has a wired output
      connection to the input box of computer, continuously providing the computer with information
      regarding the position of the mandible. The limits of excursion by the actuator are set by
      the technician in the software, according to the full retrusion and full protrusion values
      noted by the dentist. Thus, the computer can move the mandible only between predefined limits
      during the CCMP study. The signal box also receives input signals from a microphone and a
      position sensor mounted on the mandibular positioner as well as an input from a force
      transducer inside the positioner.

      IV. STUDY PROCEDURES

      Participants will receive a two night in-home cardio-pulmonary evaluation during sleep using
      the Snore Sat Recorder. The results will provide baseline data. Prior to the in-home CCMP
      study, the subject will be assessed by the dental co-investigator to ensure suitability for
      the trial and use of the device. They will then be fitted with an upper and a lower dental
      tray by the dental co-investigator. The dentist fills each tray with a silicone impression
      material and applies them to the upper and lower teeth. The relative position of upper and
      lower trays is documented by the numerical reading from a linear scale imprinted on the
      sliding strut of the lower tray. The subject moves the mandible to the rest position, the
      most retruded position, and the most protruded position. The scale is read by the dentist at
      each position. The data collected is provided to the research coordinator and will be input
      into the device to control the range of protrusion tested by the device.

      The clinical coordinator will visit the subject in the home during the day of the first night
      test and set up the computer equipment and mandibular positioner. To attach the subject's
      dental trays, the upper and lower trays are clipped to the actuator housing with the actuator
      piston fully retracted. The maximum allowable protrusive position as determined by the
      dentist will be entered in the computer to prevent excessive protrusion of the mandible. The
      computer controls movement of the linear actuator in protrusive or retrusive directions in
      increments of 0.2 mm through the keyboard on the computer. The position of the actuator is
      connected as an input to the computer. Just prior to starting the study, the subject will lie
      supine in bed and insert the dental trays into the mouth with the trays in the rest position.

      The clinical coordinator will also provide the subject with full instruction on how to use
      the device during the study. The subject will be instructed to properly insert the trays,
      connected to the mandibular positioner, in the mouth. The subject will also learn to apply
      the finger oximeter probe, and the naris cannula. The subject will be taught how to start the
      CCMP test, pause it and terminate it at the end of the study. At bedtime, the subject will
      apply the naris cannula and the probe, insert the tray in the mouth and initiate the CCMP
      study by the appropriate command on the laptop. The subject then falls asleep, and as apneas
      and/or hypopneas appear, the computer will protrude the mandible from rest position in 0.2 mm
      steps. Once all respiratory disturbances are eliminated (absence of apneas, hypopneas),
      proactive testing is performed in which the mandible is protruded or retruded 0.6 mm. If the
      latter causes a decrease in peak inspiratory airflow or if the former causes an increase in
      this variable, the mandible is protruded 0.6 mm, and so on. The following morning, the
      subject will awaken and remove the oral appliance, terminate the CCMP program and transmit
      the night's data to the server by a mouse click on a send button. The subject will complete a
      Device Satisfaction Questionnaire each morning.

      The data from the first night titration will be retrieved and automatically analyzed to judge
      the efficaciousness of the mandibular protrusion in eliminating pharyngeal obstruction and to
      identify the effective target protrusive position that will be required for successful
      therapy. If the predicted success criterion is not met, the subject is tentatively predicted
      to be a therapeutic failure, and a target of 90% of full protrusion is selected. After the
      analysis has been completed, the clinical coordinator will return to the subject's home and
      set the target position for the second night CCMP study.

      During the home visit prior to the second night study, the clinical coordinator will discuss
      with the subject his/her experience during the first night, and will carefully inquire
      regarding any discomfort or problems the subject may have experienced. The coordinator sets
      the CCMP for the Refinement and Verification program and enters the appropriate target
      distance. At bedtime the subject prepares for the study as on the first night.

      The CCMP algorithm moves the mandible to the target position and holds it there for the
      entire night, if the moving AHI (i.e. AHI for the time after the target is reached, initially
      measured over at least 2 hr) remains below 10 hr-1, ±0.6 mm. Otherwise the computer will
      protrude the mandible in 0.2 mm steps and repeat the test at a higher protrusive level. The
      following morning, the subject will awaken and remove the oral appliance, terminate the CCMP
      program and transmit the night's data to the Zephyr server by a mouse click on a send button.
      The subject will complete the Device Satisfaction Questionnaire.

      The computer calculates an AHI for the full night. The results from the first and second
      night titration studies will be provided to a sleep physician who will review the results and
      refine the prediction to arrive at a final prediction of therapeutic outcome and target
      protrusive setting.

      The target protrusive position determined from the analysis of the combined titration studies
      will then be sent to the dentist. For patients predicted to be a success, the minimum
      effective position will be provided. For patients predicted to be a failure, the scale
      reading at 70 percent of maximum protrusion will serve as a sham target value. The dentist
      will be blinded to whether the CCMP test results were "positive" or "negative". The subject
      will be referred to the dental co-investigator, and fitted with a custom oral appliance at no
      cost while blinded to the results of the CCMP studies.

      Follow-up portable cardio-pulmonary monitoring will be performed on two consecutive nights
      with the oral appliance at target protrusive distance. If the AHI is greater than 10 hr-1,
      the subject will be referred to the dental co-investigator for further mandibular protrusion.
      This adjustment will be performed in a minimum period of 3 weeks. The subject will be
      retested and the therapy judged successful according to the criteria outlined above. If the
      AHI is greater than 10hr-1, once maximum clinical protrusion of the mandible has been
      achieved, the OA therapy will be considered a failure.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Other
masking: None (Open Label)
measure: Predictive Accuracy
time frame: 4 weeks
description: Following the CCMP test, individuals will undergo a home sleep test to determine if the prediction made by the device was accurate (i.e. therapeutic responder or non-responder to oral appliance therapy).
arm group label: Computer Controlled Mandibular Positioner
arm group type: Other
description: All study participants will undergo the computer controlled mandibular positioner test.
intervention type: Device
intervention name: Computer controlled mandibular positioner
description: Participants in this arm will complete the computer controlled mandibular positioner test. The study participant, study dentist, and PI are all blinded to the outcome of the CCMP test. Those participants predicted to experience therapeutic success with OAT will have their oral appliance set at the predicted protrusive level; those participants predicted to experience therapeutic failure will have their oral appliance set at a default position. Outcome home sleep tests with the oral appliance in place will be used to determine the accuracy of the prediction.
arm group label: Computer Controlled Mandibular Positioner
criteria: 
gender: All
minimum age: 21 Years
maximum age: 80 Years
healthy volunteers: No
responsible party type: Sponsor
mesh term: Sleep Apnea, Obstructive
sharing ipd: No