<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/NCT04475848</url>
  </required_header>
  <id_info>
    <org_study_id>BP41695</org_study_id>
    <secondary_id>2019-004486-41</secondary_id>
    <nct_id>NCT04475848</nct_id>
  </id_info>
  <brief_title>A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants</brief_title>
  <official_title>A Randomized, Investigator- /Subject-blind, Single- and Multiple-ascending Dose, Placebo-controlled Study to Investigate Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 (Including RO6953958 Effect on Midazolam) Following Oral Administration in Healthy Male Participants</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hoffmann-La Roche</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hoffmann-La Roche</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>
      This study will evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics&#xD;
      (PD) of single- and multiple-ascending doses (SAD (Part 1) and MAD (Part 2)) and food effect&#xD;
      (FE) of RO6953958 following oral administration in healthy male participants. Part 3&#xD;
      (Drug-drug interaction (DDI)) will assess the safety, tolerability, and effect of RO6953958&#xD;
      on the PK of the cytochrome P450 (CYP) 3A substrate midazolam.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 15, 2020</start_date>
  <completion_date type="Actual">February 6, 2022</completion_date>
  <primary_completion_date type="Actual">February 6, 2022</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Parts 1, 2 and 3: Percentage of Participants with Adverse Events</measure>
    <time_frame>Part 1: From randomization up to 7 weeks (or up to 14 weeks if the participant is part of the food effect cohort). Parts 2 and 3: From randomization up to 8 weeks</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 2: Change in suicide risk assessed using the Columbia Suicide Severity Rating Scale (C-SSRS)</measure>
    <time_frame>From randomization up to 8 weeks</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Parts 1, 2 and 3: Maximum Observed Plasma Concentration (Cmax) of RO6953958 and its Metabolites RO7021594 and RO7045755</measure>
    <time_frame>Day 1-14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Parts 2 and 3: Average Plasma Concentration (Cavg) of RO6953958 and its Metabolites RO7021594 and RO7045755</measure>
    <time_frame>Day 1-14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Parts 1, 2 and 3: Time to Reach Maximum Observed Plasma Concentration (Tmax) of RO6953958 and its Metabolites RO7021594 and RO7045755</measure>
    <time_frame>Day 1-14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1: Last Quantifiable Concentration (Clast) of RO6953958 and its Metabolites RO7021594 and RO7045755 in Fasted and Fed state</measure>
    <time_frame>Day 1-5</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1: Time To the Last Quantifiable Concentration (Tlast) of RO6953958 and its Metabolites RO7021594 and RO7045755</measure>
    <time_frame>Day 1-5</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Parts 1, 2 and 3: Terminal Elimination Phase Half-Life (t1/2) of RO6953958 and its Metabolites RO7021594 and RO7045755</measure>
    <time_frame>Day 1-14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Parts 2 and 3: Area Under the Concentration-Time Curve (AUC(0-t)) of RO6953958 and its Metabolites RO7021594 and RO7045755</measure>
    <time_frame>Day 1-14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1: Area Under the Plasma Concentration Versus Time Curve From Zero to 12h Postdose (AUC(0-12h)) of RO6953958 and its Metabolites RO7021594 and RO7045755</measure>
    <time_frame>Day 1-5</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1: Area Under the Plasma Concentration Versus Time Curve From Zero to the Last Measurable Concentration (AUC0-last) of RO6953958 and its Metabolites RO7021594 and RO7045755</measure>
    <time_frame>Day 1-5</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1: Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-inf) of RO6953958 and its Metabolites RO7021594 and RO7045755</measure>
    <time_frame>Day 1-5</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Parts 1, 2 and 3: Apparent Clearance (CL/F) of RO6953958</measure>
    <time_frame>Day 1-14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Parts 1, 2 and 3: Apparent Volume of Distribution (V/F) of RO6953958</measure>
    <time_frame>Day 1-14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Parts 1 and 2: Cumulative Amount of Unchanged Drug Excreted into the Urine (Ae) of RO6953958</measure>
    <time_frame>Day 1-14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Parts 1 and 2: Fraction of the Administered Drug Excreted into the Urine (Fe) of RO6953958</measure>
    <time_frame>Day 1-14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Parts 1 and 2: Renal Clearance of the Drug from Urine (CLR) of RO6953958</measure>
    <time_frame>Day 1-14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Parts 1, 2 and 3: Trough Plasma Concentration (Ctrough) of RO6953958 and its Metabolites RO7021594 and RO7045755</measure>
    <time_frame>Day 1-14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Parts 2 and 3: Accumulation Ratio based on AUC (RAUC) of RO6953958 and its Metabolites RO7021594 and RO7045755</measure>
    <time_frame>Day 1-14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Parts 2 and 3: Accumulation Ratio Based on Cmax (RCmax) of RO6953958 and its Metabolites RO7021594 and RO7045755</measure>
    <time_frame>Day 1-14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Parts 1, 2 and 3: Accumulation Ratio based on Ctrough (RCtrough) of RO6953958 and its Metabolites RO7021594 and RO7045755</measure>
    <time_frame>Day 1-14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Parts 1, 2 and 3: Molecular Weight Adjusted Metabolite-to-Parent Ratio for Cmax of RO6953958 and its Metabolites RO7021594 and RO7045755</measure>
    <time_frame>Day 1-14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Parts 1, 2 and 3: Molecular Weight Adjusted Metabolite-to-Parent Ratio for Area Under the Concentration-Time Curve (AUC(0-t)) of RO6953958 and its Metabolites RO7021594 and RO7045755</measure>
    <time_frame>Day 1-14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 3: Tmax of Midazolam</measure>
    <time_frame>Day 1-14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 3: Cmax of Midazolam</measure>
    <time_frame>Day 1-14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 3: T1/2 of Midazolam</measure>
    <time_frame>Day 1-14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 3: AUClast of Midazolam</measure>
    <time_frame>Day 1-14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 3: AUCinf of Midazolam</measure>
    <time_frame>Day 1-14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 3: VF of oral Midazolam</measure>
    <time_frame>Day 1-14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 3: RAUC of Midazolam</measure>
    <time_frame>Days 13 and 14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 3: RCmax of Midazolam</measure>
    <time_frame>Days 13 and 14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 3: CL: Total Plasma Clearance of IV Midazolam</measure>
    <time_frame>Days 1 and 13</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 3: Fraction Absorbed (F) of Midazolam</measure>
    <time_frame>Day 1-14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 3: Volume of Distribution under Steady-state Conditions (Vss) of Midazolam</measure>
    <time_frame>Days 1 and 13</time_frame>
  </secondary_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Actual">88</enrollment>
  <condition>Autistic Disorder</condition>
  <condition>Autism Spectrum Disorder</condition>
  <condition>Child Development Disorders, Pervasive</condition>
  <condition>Mental Disorders</condition>
  <condition>Neurodevelopmental Disorders</condition>
  <arm_group>
    <arm_group_label>Part 1: SAD/FE</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>There will be 7 cohorts in this study. In each cohort, participants will receive a single oral dose of RO6953958 while fasted. Participants in the fed (FE) cohort will return to receive the same single oral dose of RO6953958 repeated in the fed state.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 1: SAD placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>There will be 7 cohorts in this study. In each cohort, participants will receive a single oral dose of a placebo while fasted/fed.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 2: MAD</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>A maximum of 5 dose levels are anticipated. For each dose level, a minimum of 8 and a maximum of 16 participants will receive a multiple oral dose of RO6953958 once daily (QD) for 10 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 2: MAD placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>A maximum of 5 dose levels are anticipated. For each dose level, a minimum of 8 and a maximum of 16 participants will receive a multiple oral dose of RO6953958 QD for 10 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 3: DDI</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>RO6953958 will be administered at the maximum dose QD that was tested in the ongoing Part 2 (MAD).&#xD;
Participants will also be administered midazolam.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>RO6953958</intervention_name>
    <description>Part 1: RO6953958 will be administered in an adaptive manner. The starting dose is planned to be 5 milligrams (mg).&#xD;
Part 2: The starting dose is planned to be 45 mg.&#xD;
Part 3: RO6953958 will be administered QD following a standardized breakfast on Day 3 to Day 14 at the maximum dose QD that was tested in the ongoing Part 2 (MAD).</description>
    <arm_group_label>Part 1: SAD/FE</arm_group_label>
    <arm_group_label>Part 2: MAD</arm_group_label>
    <arm_group_label>Part 3: DDI</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Part 1: A placebo will be administered in an adaptive manner. The starting dose is planned to be 5 mg.&#xD;
Part 2: The starting dose is planned to be 45 mg.</description>
    <arm_group_label>Part 1: SAD placebo</arm_group_label>
    <arm_group_label>Part 2: MAD placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Midazolam</intervention_name>
    <description>Midazolam will be administered as single intervenous (IV) bolus injection of 100 micrograms (ug) on Day 1 and Day 13, and as single oral dose of 300 ug on Day 2 and Day 14.</description>
    <arm_group_label>Part 3: DDI</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Body mass index (BMI) within 18 to 31 kg/m2&#xD;
&#xD;
          -  During treatment and for at least 14 days after the last dose to remain abstinent&#xD;
&#xD;
          -  Refrain from donating sperm for at least 14 days after last dose&#xD;
&#xD;
          -  Part 2 (MAD) only - Participants must be prepared to collect a sleep log and wear an&#xD;
             actigraphy device the week before participation in the study. Participants must also&#xD;
             have scored 5 or less on the Pittsburgh Sleep Quality Index (PSQI), less than 13 on&#xD;
             the Epworth sleepiness scale (ESS), and not be considered an extreme morning or&#xD;
             evening type according to the morningness-eveningness questionnaire (MEQ) at screening&#xD;
             to be eligible.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History or evidence of any medical condition potentially altering the absorption,&#xD;
             metabolism, or elimination of drugs&#xD;
&#xD;
          -  History of any clinically significant gastrointestinal, renal, hepatic,&#xD;
             bronchopulmonary, neurological, psychiatric, cardiovascular, endocrinological,&#xD;
             hematological, or allergic disease, sleep disorders (Part 2 [MAD] only), unexplained&#xD;
             syncope (within 12 months prior to screening), metabolic disorder, cancer, or&#xD;
             cirrhosis&#xD;
&#xD;
          -  Use of any psychoactive medication, or medications known to have effects on central&#xD;
             nervous system (CNS), or blood flow&#xD;
&#xD;
          -  History of convulsions&#xD;
&#xD;
          -  History of clinically significant hypersensitivity (e.g., drugs, excipients) or&#xD;
             allergic reactions&#xD;
&#xD;
          -  Abnormal blood pressure (BP) and pulse rate&#xD;
&#xD;
          -  Presence of orthostatic hypotension&#xD;
&#xD;
          -  History or presence of clinically significant ECG abnormalities or cardiovascular&#xD;
             disease&#xD;
&#xD;
          -  Current or chronic history of liver disease or known hepatic or biliary abnormalities&#xD;
&#xD;
          -  Known active or any major episode of infection within 4 weeks prior to the start of&#xD;
             drug administration&#xD;
&#xD;
          -  Participants who test positive for acute respiratory syndrome coronavirus 2&#xD;
             (SARS-CoV-2)&#xD;
&#xD;
          -  Have used or intend to use over-the-counter (OTC) or prescription medication including&#xD;
             herbal medications within 30 days prior to dosing&#xD;
&#xD;
          -  Positive test for drugs, abuse of alcohol, human immunodeficiency virus (HIV),&#xD;
             hepatitis B or hepatitis C virus (HCV), presence of hepatitis B surface antigen&#xD;
             (HBsAg), or positive hepatitis C antibody test&#xD;
&#xD;
          -  Inability or unwillingness to fully consume standardized breakfast at Day 1&#xD;
&#xD;
          -  Part 2 (MAD) only - Participants who have issues sleeping or participants who have&#xD;
             travelled across 2 or more time zones in the past month.&#xD;
&#xD;
          -  Part 2 (MAD) only - Participants who cannot produce sufficient saliva for study&#xD;
             assessments&#xD;
&#xD;
          -  Participants who have donated more than 500 mL of blood or blood products or had&#xD;
             significant blood loss within 3 months prior to screening&#xD;
&#xD;
          -  Have a history of clinically significant back pain, back pathology, and/or back injury&#xD;
             that may predispose to complications from, or technical difficulty with, lumbar&#xD;
             puncture&#xD;
&#xD;
          -  Complications that would lead to difficulty in obtaining a lumbar puncture&#xD;
&#xD;
          -  Part 3 (DDI) only - History of hypersensitivity to benzodiazepines (including&#xD;
             midazolam) or its formulation ingredients&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <gender_based>Yes</gender_based>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Clinical Trials</last_name>
    <role>Study Director</role>
    <affiliation>Hoffmann-La Roche</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hammersmith Medicines Research; Central Middlesex Hospital</name>
      <address>
        <city>London</city>
        <zip>NW10 7EW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>February 2022</verification_date>
  <study_first_submitted>July 13, 2020</study_first_submitted>
  <study_first_submitted_qc>July 15, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 17, 2020</study_first_posted>
  <last_update_submitted>February 15, 2022</last_update_submitted>
  <last_update_submitted_qc>February 15, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">February 16, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Autism Spectrum Disorder</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Autism Spectrum Disorder</mesh_term>
    <mesh_term>Mental Disorders</mesh_term>
    <mesh_term>Autistic Disorder</mesh_term>
    <mesh_term>Neurodevelopmental Disorders</mesh_term>
    <mesh_term>Developmental Disabilities</mesh_term>
    <mesh_term>Child Development Disorders, Pervasive</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Midazolam</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).</ipd_description>
  </patient_data>
  <pending_results>
    <submitted>January 30, 2023</submitted>
  </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/NCT04475848
org study id: BP41695
secondary id: 2019-004486-41
nct id: NCT04475848
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This study will evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics
      (PD) of single- and multiple-ascending doses (SAD (Part 1) and MAD (Part 2)) and food effect
      (FE) of RO6953958 following oral administration in healthy male participants. Part 3
      (Drug-drug interaction (DDI)) will assess the safety, tolerability, and effect of RO6953958
      on the PK of the cytochrome P450 (CYP) 3A substrate midazolam.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Parts 1, 2 and 3: Percentage of Participants with Adverse Events
time frame: Part 1: From randomization up to 7 weeks (or up to 14 weeks if the participant is part of the food effect cohort). Parts 2 and 3: From randomization up to 8 weeks
measure: Part 2: Change in suicide risk assessed using the Columbia Suicide Severity Rating Scale (C-SSRS)
time frame: From randomization up to 8 weeks
measure: Parts 1, 2 and 3: Maximum Observed Plasma Concentration (Cmax) of RO6953958 and its Metabolites RO7021594 and RO7045755
time frame: Day 1-14
measure: Parts 2 and 3: Average Plasma Concentration (Cavg) of RO6953958 and its Metabolites RO7021594 and RO7045755
time frame: Day 1-14
measure: Parts 1, 2 and 3: Time to Reach Maximum Observed Plasma Concentration (Tmax) of RO6953958 and its Metabolites RO7021594 and RO7045755
time frame: Day 1-14
measure: Part 1: Last Quantifiable Concentration (Clast) of RO6953958 and its Metabolites RO7021594 and RO7045755 in Fasted and Fed state
time frame: Day 1-5
measure: Part 1: Time To the Last Quantifiable Concentration (Tlast) of RO6953958 and its Metabolites RO7021594 and RO7045755
time frame: Day 1-5
measure: Parts 1, 2 and 3: Terminal Elimination Phase Half-Life (t1/2) of RO6953958 and its Metabolites RO7021594 and RO7045755
time frame: Day 1-14
measure: Parts 2 and 3: Area Under the Concentration-Time Curve (AUC(0-t)) of RO6953958 and its Metabolites RO7021594 and RO7045755
time frame: Day 1-14
measure: Part 1: Area Under the Plasma Concentration Versus Time Curve From Zero to 12h Postdose (AUC(0-12h)) of RO6953958 and its Metabolites RO7021594 and RO7045755
time frame: Day 1-5
measure: Part 1: Area Under the Plasma Concentration Versus Time Curve From Zero to the Last Measurable Concentration (AUC0-last) of RO6953958 and its Metabolites RO7021594 and RO7045755
time frame: Day 1-5
measure: Part 1: Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-inf) of RO6953958 and its Metabolites RO7021594 and RO7045755
time frame: Day 1-5
measure: Parts 1, 2 and 3: Apparent Clearance (CL/F) of RO6953958
time frame: Day 1-14
measure: Parts 1, 2 and 3: Apparent Volume of Distribution (V/F) of RO6953958
time frame: Day 1-14
measure: Parts 1 and 2: Cumulative Amount of Unchanged Drug Excreted into the Urine (Ae) of RO6953958
time frame: Day 1-14
measure: Parts 1 and 2: Fraction of the Administered Drug Excreted into the Urine (Fe) of RO6953958
time frame: Day 1-14
measure: Parts 1 and 2: Renal Clearance of the Drug from Urine (CLR) of RO6953958
time frame: Day 1-14
measure: Parts 1, 2 and 3: Trough Plasma Concentration (Ctrough) of RO6953958 and its Metabolites RO7021594 and RO7045755
time frame: Day 1-14
measure: Parts 2 and 3: Accumulation Ratio based on AUC (RAUC) of RO6953958 and its Metabolites RO7021594 and RO7045755
time frame: Day 1-14
measure: Parts 2 and 3: Accumulation Ratio Based on Cmax (RCmax) of RO6953958 and its Metabolites RO7021594 and RO7045755
time frame: Day 1-14
measure: Parts 1, 2 and 3: Accumulation Ratio based on Ctrough (RCtrough) of RO6953958 and its Metabolites RO7021594 and RO7045755
time frame: Day 1-14
measure: Parts 1, 2 and 3: Molecular Weight Adjusted Metabolite-to-Parent Ratio for Cmax of RO6953958 and its Metabolites RO7021594 and RO7045755
time frame: Day 1-14
measure: Parts 1, 2 and 3: Molecular Weight Adjusted Metabolite-to-Parent Ratio for Area Under the Concentration-Time Curve (AUC(0-t)) of RO6953958 and its Metabolites RO7021594 and RO7045755
time frame: Day 1-14
measure: Part 3: Tmax of Midazolam
time frame: Day 1-14
measure: Part 3: Cmax of Midazolam
time frame: Day 1-14
measure: Part 3: T1/2 of Midazolam
time frame: Day 1-14
measure: Part 3: AUClast of Midazolam
time frame: Day 1-14
measure: Part 3: AUCinf of Midazolam
time frame: Day 1-14
measure: Part 3: VF of oral Midazolam
time frame: Day 1-14
measure: Part 3: RAUC of Midazolam
time frame: Days 13 and 14
measure: Part 3: RCmax of Midazolam
time frame: Days 13 and 14
measure: Part 3: CL: Total Plasma Clearance of IV Midazolam
time frame: Days 1 and 13
measure: Part 3: Fraction Absorbed (F) of Midazolam
time frame: Day 1-14
measure: Part 3: Volume of Distribution under Steady-state Conditions (Vss) of Midazolam
time frame: Days 1 and 13
arm group label: Part 1: SAD/FE
arm group type: Experimental
description: There will be 7 cohorts in this study. In each cohort, participants will receive a single oral dose of RO6953958 while fasted. Participants in the fed (FE) cohort will return to receive the same single oral dose of RO6953958 repeated in the fed state.
arm group label: Part 1: SAD placebo
arm group type: Placebo Comparator
description: There will be 7 cohorts in this study. In each cohort, participants will receive a single oral dose of a placebo while fasted/fed.
arm group label: Part 2: MAD
arm group type: Experimental
description: A maximum of 5 dose levels are anticipated. For each dose level, a minimum of 8 and a maximum of 16 participants will receive a multiple oral dose of RO6953958 once daily (QD) for 10 days.
arm group label: Part 2: MAD placebo
arm group type: Placebo Comparator
description: A maximum of 5 dose levels are anticipated. For each dose level, a minimum of 8 and a maximum of 16 participants will receive a multiple oral dose of RO6953958 QD for 10 days.
arm group label: Part 3: DDI
arm group type: Experimental
description: RO6953958 will be administered at the maximum dose QD that was tested in the ongoing Part 2 (MAD).
Participants will also be administered midazolam.
intervention type: Drug
intervention name: RO6953958
description: Part 1: RO6953958 will be administered in an adaptive manner. The starting dose is planned to be 5 milligrams (mg).
Part 2: The starting dose is planned to be 45 mg.
Part 3: RO6953958 will be administered QD following a standardized breakfast on Day 3 to Day 14 at the maximum dose QD that was tested in the ongoing Part 2 (MAD).
arm group label: Part 1: SAD/FE
arm group label: Part 2: MAD
arm group label: Part 3: DDI
intervention type: Drug
intervention name: Placebo
description: Part 1: A placebo will be administered in an adaptive manner. The starting dose is planned to be 5 mg.
Part 2: The starting dose is planned to be 45 mg.
arm group label: Part 1: SAD placebo
arm group label: Part 2: MAD placebo
intervention type: Drug
intervention name: Midazolam
description: Midazolam will be administered as single intervenous (IV) bolus injection of 100 micrograms (ug) on Day 1 and Day 13, and as single oral dose of 300 ug on Day 2 and Day 14.
arm group label: Part 3: DDI
criteria: 
gender: Male
gender based: Yes
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Clinical Trials
role: Study Director
affiliation: Hoffmann-La Roche
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Autism Spectrum Disorder
mesh term: Mental Disorders
mesh term: Autistic Disorder
mesh term: Neurodevelopmental Disorders
mesh term: Developmental Disabilities
mesh term: Child Development Disorders, Pervasive
mesh term: Midazolam
sharing ipd: No
ipd description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).
submitted: January 30, 2023