<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/NCT04449133</url>
  </required_header>
  <id_info>
    <org_study_id>2019-004917-15</org_study_id>
    <nct_id>NCT04449133</nct_id>
  </id_info>
  <brief_title>Study of AD128 Versus Placebo in Obstructive Sleep Apnea</brief_title>
  <official_title>Crossover, Double-blind, Phase 2 Study of AD128 Versus Placebo in Obstructive Sleep Apnea</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Istituto Auxologico Italiano</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>YGHEA, CRO Division of Ecol Studio spa</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>STM Pharma PRO srl</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Apnimed Inc.</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Istituto Auxologico Italiano</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Obstructive Sleep Apnea (OSA) is the most common and serious of the sleep disorders.&#xD;
      Long-term, OSA is associated with increased morbidity and mortality, with a number of adverse&#xD;
      cardiovascular, neurocognitive, metabolic, and daytime functioning consequences. No drugs are&#xD;
      currently approved for OSA treatment.&#xD;
&#xD;
      This is a randomized, double blind, placebo controlled, cross-over, inpatient phase 2&#xD;
      clinical trial to examine the efficacy and the safety of a fixed dose level of AD128 in&#xD;
      patients with OSA.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 3, 2020</start_date>
  <completion_date type="Actual">October 31, 2020</completion_date>
  <primary_completion_date type="Actual">October 30, 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <intervention_model_description>Patients who meet the eligibility criteria will be assigned alternatively to the the treatment with a AD128 or matching placebo. After 7 days of treatment and a washout period, the patients will crossover to the other arm for 7 days.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Apnea-Hypopnea Index (AHI)</measure>
    <time_frame>From the screening/baseline to the last day of treatment (7 days after the start of each treatment period).</time_frame>
    <description>The percentage change of mean AHI will be compared between treatment groups.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>AHI decrease ≥50%</measure>
    <time_frame>From screening/baseline to the last day of treatment (7 days after the start of each treatment period).</time_frame>
    <description>The proportion of patients with AHI decrease ≥50% will be calculated.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AHI&lt;15/hour</measure>
    <time_frame>From screening/baseline to the last day of treatment (7 days after the start of each treatment period).</time_frame>
    <description>The number of patients with AHI &lt;15/hour measured during the inpatient night Polysomnography will be compared between treatment groups.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Epworth Sleepiness Scale (ESS)</measure>
    <time_frame>From screening/baseline to the last day of treatment (7 days after the start of each treatment period).</time_frame>
    <description>The ESS is a self-administered questionnaire which measures the daytime sleepiness. The ESS score can range from 0 to 24. The change will be measured in terms of difference from baseline and between treatment groups.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Karolinska Sleepiness Scale (KSS)</measure>
    <time_frame>From screening/baseline to the last day of treatment (7 days after the start of each treatment period).</time_frame>
    <description>The KSS is a self-reported 9-points scale which measure the subjective level of sleepiness at a particular time during the day. The change will be measured in terms of difference from baseline and between treatment groups.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient Global Impression of OSA Severity (PGI-S)</measure>
    <time_frame>From screening/baseline to the last day of treatment (7 days after the start of each treatment period).</time_frame>
    <description>The PGI-S is a single question asking the patient to rate on a scale, ranging from 0 to 4, the severity of the OSA condition at that time.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Psychomotor Vigilance Test (PVT)</measure>
    <time_frame>From screening/baseline to last day of treatment (7 days after the start of each treatment period).</time_frame>
    <description>PVT is a chronometric measure of a patient's reaction time to a visual stimulus. PVT reaction times/lapses and failures to react will be measured. The change will be measured in terms of difference from baseline and between treatment groups.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Oxygen Desaturation Index (ODI) 3%</measure>
    <time_frame>From screening/baseline to last day of treatment (7 days after the start of each treatment period).</time_frame>
    <description>The number of times per hour of sleep that the blood's oxygen level drops by 3% from baseline will be measured by means of a CE marked oximeter capable of nightly recording and storage of data for the entire at-home period. The change in mean value from baseline will be compared between treatment groups.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in total time with Oxygen Saturation (SaO2) &lt;90%</measure>
    <time_frame>From screening/baseline to last day of treatment (7 days after the start of each treatment period).</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in mean SaO2</measure>
    <time_frame>From screening/baseline to last day of treatment (7 days after the start of each treatment period).</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in minimum SaO2</measure>
    <time_frame>From screening/baseline to last day of treatment (7 days after the start of each treatment period).</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in arousal index</measure>
    <time_frame>From screening/baseline to last day of treatment (7 days after the start of each treatment period).</time_frame>
    <description>The number of arousals will be registered during the polysomnography and reported as a frequency per hour of sleep. The change in mean value from baseline will be compared between treatment groups.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in periodic limb movement</measure>
    <time_frame>From screening/baseline to last day of treatment (7 days after the start of each treatment period).</time_frame>
    <description>The number of periodic limb movements will be measured during the polysomnography. The change in mean value from baseline will be compared between treatment groups.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Oxygen Desaturation Index 4%</measure>
    <time_frame>For the entire at home treatment period: days 1-7 (before crossover) and days 15-20 (after crossover)</time_frame>
    <description>The number of times per hour of sleep that the blood's oxygen level drops by 4% or more from baseline will be measured by means of a CE marked oximeter capable of nightly recording and storage of data. The average numbers will be compared between treatment groups.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse Events (AE)</measure>
    <time_frame>From screening/baseline to 4 weeks after last day of treatment.</time_frame>
    <description>All adverse events occurring to patients after recruitment in the study will be recorded. The total number of AEs, their severity and their seriousness will be compared between treatment groups.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Obstructive Sleep Apnea</condition>
  <arm_group>
    <arm_group_label>Treatment Group 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>AD128 for 7 days, then, after a wash-out period of 7-10 days, placebo for 7 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Treatment Group 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Placebo for 7 days, then, after a wash-out period of 7-10 days, AD128 for 7 days</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AD128</intervention_name>
    <description>Oral administration of two capsules before sleep for 7 days.</description>
    <arm_group_label>Treatment Group 1</arm_group_label>
    <arm_group_label>Treatment Group 2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Oral administration of two capsules before sleep for 7 days.</description>
    <arm_group_label>Treatment Group 1</arm_group_label>
    <arm_group_label>Treatment Group 2</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients who are able to understand the nature of the study and to give free informed&#xD;
             consent&#xD;
&#xD;
          -  AHI ≥ 15 on screening/baseline PSG&#xD;
&#xD;
          -  Any of the following conditions should be met:&#xD;
&#xD;
               1. Documented prior PSG within 1 year demonstrating AHI of 15 or higher&#xD;
&#xD;
               2. Documented Continuous Positive Airway Pressure (CPAP) intolerance or poor&#xD;
                  compliance (compliance is defined as self-reported use of CPAP 4 hours per night&#xD;
                  for 70% of nights) or CPAP-naïve.&#xD;
&#xD;
               3. Patients who have been using CPAP at least 4 hours nightly for at least 70% of&#xD;
                  the nights are eligible only if CPAP is not used for 2 weeks prior to the&#xD;
                  screening/study baseline PSG.&#xD;
&#xD;
          -  Epworth Sleepiness Scale (ESS) score ≥ 4 for patients not using CPAP&#xD;
&#xD;
          -  Previous surgical treatment for OSA is allowed if ≥ 1 year prior to enrollment.&#xD;
&#xD;
          -  BMI between 18.5 and 40.0 kg/m2, inclusive&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of narcolepsy.&#xD;
&#xD;
          -  Clinically significant craniofacial malformation.&#xD;
&#xD;
          -  Clinically significant cardiac disease or hypertension requiring more than 3&#xD;
             medications for control.&#xD;
&#xD;
          -  Clinically significant neurological disorder, including epilepsy/convulsions&#xD;
&#xD;
          -  History of schizophrenia, schizoaffective disorder or bipolar disorder according to -&#xD;
             Diagnostic and Statistical Manual of Mental Disorders-V (DSM V) or International&#xD;
             Classification of Disease X edition criteria.&#xD;
&#xD;
          -  History of attempted suicide or suicidal ideation within 1 year prior to screening, or&#xD;
             current suicidal ideation.&#xD;
&#xD;
          -  Positive history for abuse of drugs or substance use disorder as defined in DSM-V&#xD;
             within 12 months prior to Screening Visit.&#xD;
&#xD;
          -  A significant illness or infection requiring medical treatment in the past 30 days.&#xD;
&#xD;
          -  Clinically significant cognitive dysfunction.&#xD;
&#xD;
          -  Untreated narrow angle glaucoma.&#xD;
&#xD;
          -  Women who are pregnant or nursing.&#xD;
&#xD;
          -  History of using oral or nasal devices for the treatment of OSA may enroll as long as&#xD;
             the devices are not used during participation in the study.&#xD;
&#xD;
          -  History of using devices to affect participant sleeping position for the treatment of&#xD;
             OSA, e.g. to discourage supine sleeping position, may enroll as long as the devices&#xD;
             are not used during participation in the study.&#xD;
&#xD;
          -  History of oxygen therapy.&#xD;
&#xD;
          -  Use of medications from the list of disallowed concomitant medications.&#xD;
&#xD;
          -  Treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors, or monoamine oxidase&#xD;
             inhibitors (MAOI) or linezolid within 14 days of the start of treatment, or&#xD;
             concomitant with treatment.&#xD;
&#xD;
          -  Use of another investigational agent within 30 days or 5 half-lives, whichever is&#xD;
             longer, prior to dosing.&#xD;
&#xD;
          -  Central apnea index &gt; 5/hour on baseline PSG&#xD;
&#xD;
          -  Any condition that in the investigator's opinion would present an unreasonable risk to&#xD;
             the participant, or which would interfere with their participation in the study or&#xD;
             confound study interpretation.&#xD;
&#xD;
          -  Patients considered by the investigator, for any reason, unsuitable candidates to&#xD;
             receive AD128 treatment or unable or unlikely to understand or comply with the dosing&#xD;
             schedule or study evaluations.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Elisa Perger, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Istituto Auxologico Italiano</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Istituto Auxologico Italiano,Ospedale San Luca</name>
      <address>
        <city>Milano</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>September 2021</verification_date>
  <study_first_submitted>June 23, 2020</study_first_submitted>
  <study_first_submitted_qc>June 23, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 26, 2020</study_first_posted>
  <last_update_submitted>September 21, 2021</last_update_submitted>
  <last_update_submitted_qc>September 21, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">September 27, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Obstructive Sleep Apnea</keyword>
  <keyword>Apnea Hypopnea Index</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Apnea</mesh_term>
    <mesh_term>Sleep Apnea Syndromes</mesh_term>
    <mesh_term>Sleep Apnea, Obstructive</mesh_term>
  </condition_browse>
  <pending_results>
    <submitted>June 6, 2022</submitted>
    <returned>March 17, 2023</returned>
  </pending_results>
  <!-- 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/NCT04449133
org study id: 2019-004917-15
nct id: NCT04449133
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Obstructive Sleep Apnea (OSA) is the most common and serious of the sleep disorders.
      Long-term, OSA is associated with increased morbidity and mortality, with a number of adverse
      cardiovascular, neurocognitive, metabolic, and daytime functioning consequences. No drugs are
      currently approved for OSA treatment.

      This is a randomized, double blind, placebo controlled, cross-over, inpatient phase 2
      clinical trial to examine the efficacy and the safety of a fixed dose level of AD128 in
      patients with OSA.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: Patients who meet the eligibility criteria will be assigned alternatively to the the treatment with a AD128 or matching placebo. After 7 days of treatment and a washout period, the patients will crossover to the other arm for 7 days.
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Change in Apnea-Hypopnea Index (AHI)
time frame: From the screening/baseline to the last day of treatment (7 days after the start of each treatment period).
description: The percentage change of mean AHI will be compared between treatment groups.
measure: AHI decrease ≥50%
time frame: From screening/baseline to the last day of treatment (7 days after the start of each treatment period).
description: The proportion of patients with AHI decrease ≥50% will be calculated.
measure: AHI<15/hour
time frame: From screening/baseline to the last day of treatment (7 days after the start of each treatment period).
description: The number of patients with AHI <15/hour measured during the inpatient night Polysomnography will be compared between treatment groups.
measure: Change in Epworth Sleepiness Scale (ESS)
time frame: From screening/baseline to the last day of treatment (7 days after the start of each treatment period).
description: The ESS is a self-administered questionnaire which measures the daytime sleepiness. The ESS score can range from 0 to 24. The change will be measured in terms of difference from baseline and between treatment groups.
measure: Change in Karolinska Sleepiness Scale (KSS)
time frame: From screening/baseline to the last day of treatment (7 days after the start of each treatment period).
description: The KSS is a self-reported 9-points scale which measure the subjective level of sleepiness at a particular time during the day. The change will be measured in terms of difference from baseline and between treatment groups.
measure: Patient Global Impression of OSA Severity (PGI-S)
time frame: From screening/baseline to the last day of treatment (7 days after the start of each treatment period).
description: The PGI-S is a single question asking the patient to rate on a scale, ranging from 0 to 4, the severity of the OSA condition at that time.
measure: Change in Psychomotor Vigilance Test (PVT)
time frame: From screening/baseline to last day of treatment (7 days after the start of each treatment period).
description: PVT is a chronometric measure of a patient's reaction time to a visual stimulus. PVT reaction times/lapses and failures to react will be measured. The change will be measured in terms of difference from baseline and between treatment groups.
measure: Change in Oxygen Desaturation Index (ODI) 3%
time frame: From screening/baseline to last day of treatment (7 days after the start of each treatment period).
description: The number of times per hour of sleep that the blood's oxygen level drops by 3% from baseline will be measured by means of a CE marked oximeter capable of nightly recording and storage of data for the entire at-home period. The change in mean value from baseline will be compared between treatment groups.
measure: Change in total time with Oxygen Saturation (SaO2) <90%
time frame: From screening/baseline to last day of treatment (7 days after the start of each treatment period).
measure: Change in mean SaO2
time frame: From screening/baseline to last day of treatment (7 days after the start of each treatment period).
measure: Change in minimum SaO2
time frame: From screening/baseline to last day of treatment (7 days after the start of each treatment period).
measure: Change in arousal index
time frame: From screening/baseline to last day of treatment (7 days after the start of each treatment period).
description: The number of arousals will be registered during the polysomnography and reported as a frequency per hour of sleep. The change in mean value from baseline will be compared between treatment groups.
measure: Change in periodic limb movement
time frame: From screening/baseline to last day of treatment (7 days after the start of each treatment period).
description: The number of periodic limb movements will be measured during the polysomnography. The change in mean value from baseline will be compared between treatment groups.
measure: Oxygen Desaturation Index 4%
time frame: For the entire at home treatment period: days 1-7 (before crossover) and days 15-20 (after crossover)
description: The number of times per hour of sleep that the blood's oxygen level drops by 4% or more from baseline will be measured by means of a CE marked oximeter capable of nightly recording and storage of data. The average numbers will be compared between treatment groups.
measure: Adverse Events (AE)
time frame: From screening/baseline to 4 weeks after last day of treatment.
description: All adverse events occurring to patients after recruitment in the study will be recorded. The total number of AEs, their severity and their seriousness will be compared between treatment groups.
arm group label: Treatment Group 1
arm group type: Experimental
description: AD128 for 7 days, then, after a wash-out period of 7-10 days, placebo for 7 days
arm group label: Treatment Group 2
arm group type: Experimental
description: Placebo for 7 days, then, after a wash-out period of 7-10 days, AD128 for 7 days
intervention type: Drug
intervention name: AD128
description: Oral administration of two capsules before sleep for 7 days.
arm group label: Treatment Group 1
arm group label: Treatment Group 2
intervention type: Drug
intervention name: Placebo
description: Oral administration of two capsules before sleep for 7 days.
arm group label: Treatment Group 1
arm group label: Treatment Group 2
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Elisa Perger, MD
role: Principal Investigator
affiliation: Istituto Auxologico Italiano
facility: 
country: Italy
responsible party type: Sponsor
mesh term: Apnea
mesh term: Sleep Apnea Syndromes
mesh term: Sleep Apnea, Obstructive
submitted: June 6, 2022
returned: March 17, 2023