<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/NCT04497519</url>
  </required_header>
  <id_info>
    <org_study_id>CARRIED-01</org_study_id>
    <nct_id>NCT04497519</nct_id>
  </id_info>
  <brief_title>Local Tolerability and Pharmacokinetic Evaluation of Cyclops Dry Powder Hydroxychloroquine Inhalation in Healthy Volunteers</brief_title>
  <official_title>Local Tolerability and Pharmacokinetic Evaluation of Cyclops Dry Powder Hydroxychloroquine Inhalation in Healthy Volunteers; a Pilot Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Medical Center Groningen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Medical Center Groningen</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      Rationale:&#xD;
&#xD;
      This protocol describes a study on the local tolerability of dry powder hydroxychloroquine&#xD;
      using the Cyclops in healthy volunteers.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
        -  Primary objective is to assess the local tolerability of dry powder hydroxychloroquine&#xD;
           sulphate via the Cyclops at different dosages.&#xD;
&#xD;
        -  Secondary objective is to investigate systemic pharmacokinetic parameters of dry powder&#xD;
           hydroxychloroquine sulphate via the Cyclops at different dosages.&#xD;
&#xD;
      Study design: single center, ascending dose study Study population: twelve healthy volunteers&#xD;
&#xD;
      Main study parameters/endpoints:&#xD;
&#xD;
      The local tolerability of the inhalation of dry powder hydroxychloroquine sulphate (5, 10 and&#xD;
      20 mg) defined by a lung function deterioration (a drop of forced expiratory volume in 1&#xD;
      second (FEV1) of &gt;15%), cough, or any other reported adverse event. Pharmacokinetic&#xD;
      parameters will be derived from calculated actual inhaled dose (dose minus remainder in&#xD;
      inhaler after inhalation) and in blood samples drawn pre-dose, at 0.5 and 2 and 3.5 hrs after&#xD;
      inhalation. The inspiratory parameters during the inhalation maneuver are critical to explore&#xD;
      predictors for drug exposure. The following parameters will be measured/calculated: dPmax&#xD;
      (maximum pressure drop), Vi (inhaled volume), Ti (total inhalation time), PIF (peak&#xD;
      inspiratory flow rate), MIF (mean inspiratory flow rate) and the FIR (average flow increase&#xD;
      rate between 20% and 80% of PIF).&#xD;
&#xD;
      Nature and extent of the burden and risks associated with participation, benefit and group&#xD;
      relatedness: The participants included are healthy volunteers. They will receive three&#xD;
      different doses of hydroxychloroquine sulphate using the dry powder inhaler (DPI) with (at&#xD;
      least) seven days in between doses. Before using the dry powder inhaler (DPI), they will&#xD;
      receive instructions and their inspiratory flow will be tested. To investigate local&#xD;
      tolerability, lung function tests will be performed, and the occurrence of adverse events&#xD;
      will be scored. Furthermore, before each test dose an indwelling cannula will be inserted and&#xD;
      blood samples will be taken before and after each test dose. Four blood samples will be&#xD;
      collected with each inhaled dose. Finally, five ECGs will be obtained to monitor for QT&#xD;
      prolongation, one at the screenings visit, one at base-line and one after each inhalation.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 15, 2020</start_date>
  <completion_date type="Actual">November 1, 2020</completion_date>
  <primary_completion_date type="Actual">October 15, 2020</primary_completion_date>
  <phase>Phase 1</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>
    <intervention_model_description>Healthy volunteers</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Local tolerability</measure>
    <time_frame>35 minutes after inhalation</time_frame>
    <description>Number of patients with a lung function deterioration (a drop of forced expiratory volume in 1 second (FEV1) of &gt;15%.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Local tolerability</measure>
    <time_frame>95 minutes after inhalation</time_frame>
    <description>Number of patients with a lung function deterioration (a drop of forced expiratory volume in 1 second (FEV1) of &gt;15%.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Local tolerability</measure>
    <time_frame>5 hours</time_frame>
    <description>Number of patients that report cough, or any other adverse event after inhalation.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic parameter</measure>
    <time_frame>0,5 hour</time_frame>
    <description>Calculated actual inhaled dose</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic parameter</measure>
    <time_frame>3,5 hours</time_frame>
    <description>Cmax</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic parameter</measure>
    <time_frame>3,5 hours</time_frame>
    <description>Tmax</description>
  </secondary_outcome>
  <enrollment type="Actual">12</enrollment>
  <condition>Covid19</condition>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>inhaled hydroxychloroquine</intervention_name>
    <description>ascending dose of iHCQ</description>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy volunteer&#xD;
&#xD;
          -  Age 18-65 years&#xD;
&#xD;
          -  Obtained written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Pregnancy or breastfeeding. Women in the fertility period and without using proper&#xD;
             contraceptives will undergo a urine pregnancy test.&#xD;
&#xD;
          2. Contra-indication to (hydroxy)chloroquine or quinine (allergic reaction, prolonged&#xD;
             QTc-interval (&gt; 450 msec), long-QT syndrome (LQTS), retinopathy, epilepsia, myasthenia&#xD;
             gravis, G6PD-deficiency).&#xD;
&#xD;
          3. Concurrent use of ciclosporin, digoxin, ritonavir, tamoxifen or tranylcypromine.&#xD;
&#xD;
          4. Concurrent use of high risk QTc prolongating drugs (amiodarone, erythromycin (daily&#xD;
             dose &gt; 1000 mg) or sotalol)16.&#xD;
&#xD;
          5. COVID-19 like symptoms, such as fever, couch, or sore throat; only by history taking.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>University Medical Center Groningen</name>
      <address>
        <city>Groningen</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>November 2020</verification_date>
  <study_first_submitted>July 27, 2020</study_first_submitted>
  <study_first_submitted_qc>July 31, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 4, 2020</study_first_posted>
  <last_update_submitted>November 9, 2020</last_update_submitted>
  <last_update_submitted_qc>November 9, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">November 10, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University Medical Center Groningen</investigator_affiliation>
    <investigator_full_name>Onno Akkerman</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Respiratory Aspiration</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hydroxychloroquine</mesh_term>
  </intervention_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/NCT04497519
org study id: CARRIED-01
nct id: NCT04497519
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Rationale:

      This protocol describes a study on the local tolerability of dry powder hydroxychloroquine
      using the Cyclops in healthy volunteers.

      Objective:

        -  Primary objective is to assess the local tolerability of dry powder hydroxychloroquine
           sulphate via the Cyclops at different dosages.

        -  Secondary objective is to investigate systemic pharmacokinetic parameters of dry powder
           hydroxychloroquine sulphate via the Cyclops at different dosages.

      Study design: single center, ascending dose study Study population: twelve healthy volunteers

      Main study parameters/endpoints:

      The local tolerability of the inhalation of dry powder hydroxychloroquine sulphate (5, 10 and
      20 mg) defined by a lung function deterioration (a drop of forced expiratory volume in 1
      second (FEV1) of >15%), cough, or any other reported adverse event. Pharmacokinetic
      parameters will be derived from calculated actual inhaled dose (dose minus remainder in
      inhaler after inhalation) and in blood samples drawn pre-dose, at 0.5 and 2 and 3.5 hrs after
      inhalation. The inspiratory parameters during the inhalation maneuver are critical to explore
      predictors for drug exposure. The following parameters will be measured/calculated: dPmax
      (maximum pressure drop), Vi (inhaled volume), Ti (total inhalation time), PIF (peak
      inspiratory flow rate), MIF (mean inspiratory flow rate) and the FIR (average flow increase
      rate between 20% and 80% of PIF).

      Nature and extent of the burden and risks associated with participation, benefit and group
      relatedness: The participants included are healthy volunteers. They will receive three
      different doses of hydroxychloroquine sulphate using the dry powder inhaler (DPI) with (at
      least) seven days in between doses. Before using the dry powder inhaler (DPI), they will
      receive instructions and their inspiratory flow will be tested. To investigate local
      tolerability, lung function tests will be performed, and the occurrence of adverse events
      will be scored. Furthermore, before each test dose an indwelling cannula will be inserted and
      blood samples will be taken before and after each test dose. Four blood samples will be
      collected with each inhaled dose. Finally, five ECGs will be obtained to monitor for QT
      prolongation, one at the screenings visit, one at base-line and one after each inhalation.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Healthy volunteers
primary purpose: Treatment
masking: None (Open Label)
measure: Local tolerability
time frame: 35 minutes after inhalation
description: Number of patients with a lung function deterioration (a drop of forced expiratory volume in 1 second (FEV1) of >15%.
measure: Local tolerability
time frame: 95 minutes after inhalation
description: Number of patients with a lung function deterioration (a drop of forced expiratory volume in 1 second (FEV1) of >15%.
measure: Local tolerability
time frame: 5 hours
description: Number of patients that report cough, or any other adverse event after inhalation.
measure: Pharmacokinetic parameter
time frame: 0,5 hour
description: Calculated actual inhaled dose
measure: Pharmacokinetic parameter
time frame: 3,5 hours
description: Cmax
measure: Pharmacokinetic parameter
time frame: 3,5 hours
description: Tmax
intervention type: Drug
intervention name: inhaled hydroxychloroquine
description: ascending dose of iHCQ
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: Netherlands
responsible party type: Principal Investigator
investigator affiliation: University Medical Center Groningen
investigator full name: Onno Akkerman
investigator title: Principal Investigator
mesh term: Respiratory Aspiration
mesh term: Hydroxychloroquine
sharing ipd: No