<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/NCT04443907</url>
  </required_header>
  <id_info>
    <org_study_id>CADPT03A12101</org_study_id>
    <secondary_id>2019-003489-41</secondary_id>
    <nct_id>NCT04443907</nct_id>
  </id_info>
  <brief_title>Study of Safety and Efficacy of Genome-edited Hematopoietic Stem and Progenitor Cells in Sickle Cell Disease (SCD)</brief_title>
  <official_title>A First-in-patient Phase I/II Clinical Study to Investigate the Safety, Tolerability and Efficacy of Genome-edited Hematopoietic Stem and Progenitor Cells in Subjects With Severe Complications of Sickle Cell Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Novartis Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Novartis</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is evaluating a genome-edited, autologous, hematopoietic stem and progenitor cell&#xD;
      (HSPC) product - OTQ923 to reduce the biologic activity of BCL11A, increasing fetal&#xD;
      hemoglobin (HbF) and reducing complications of sickle cell disease.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      CADPT03A12101 is a multicenter, multi-part, first-in-human, proof-of-concept, open label&#xD;
      non-randomized, clinical study in Sickle Cell Disease (SCD) subjects. This study includes&#xD;
      apheresis of mobilized hematopoietic stem and progenitor cells (HSPCs), ex vivo&#xD;
      CRISPR/Cas9-mediated genome editing and expansion, followed by myeloablative conditioning and&#xD;
      autologous hematopoietic stem cell transplant (HSCT) with follow-up for a minimum of one year&#xD;
      and up to two years.&#xD;
&#xD;
      The study is divided into the following parts:&#xD;
&#xD;
        -  Part A - Adult subjects dosed with OTQ923.&#xD;
&#xD;
        -  Part B - Assessment of OTQ923 in pediatric patients. Part B will not be opened.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">August 26, 2020</start_date>
  <completion_date type="Anticipated">September 18, 2026</completion_date>
  <primary_completion_date type="Anticipated">August 19, 2025</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>The is an open-label study.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Number of participants with adverse events and serious adverse events</measure>
    <time_frame>up to 24 months</time_frame>
    <description>Number of participants with adverse events (AEs) and serious adverse events (SAEs), including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Fetal hemoglobin (HbF) expression after hematopoietic stem cell transplant (HSCT)</measure>
    <time_frame>up to 24 months</time_frame>
    <description>Assessment of HbF expression will be done by measuring total fetal hemoglobin over time.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Time to reach absolute neutrophil count (ANC) ≥500/μL for 3 consecutive days</measure>
    <time_frame>up to 24 months</time_frame>
    <description>Time to engraftment is defined as first of 3 consecutive days when an absolute neutrophil count (ANC) ≥500/μL after receiving OTQ923 was reached.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Durability of hematologic engraftment</measure>
    <time_frame>up to 24 months</time_frame>
    <description>Engraftment durability/persistence by measuring the proportion of alleles with on-target CRISPR modification in peripheral blood (total white blood cells (WBC)) and bone marrow over time up to 24 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of subject to achieve 30% of total HbF at 12 months</measure>
    <time_frame>12 months</time_frame>
    <description>Assessment of HbF expression will be done by measuring total fetal hemoglobin over time.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to achieve 30% total HbF</measure>
    <time_frame>up to 24 months</time_frame>
    <description>Assessment of HbF expression will be done by measuring total fetal hemoglobin over time.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to peak total HbF</measure>
    <time_frame>up to 24 months</time_frame>
    <description>Assessment of HbF expression will be done by measuring total fetal hemoglobin over time.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of edited WBC and bone marrow cells by time points</measure>
    <time_frame>up to 24 months</time_frame>
    <description>Assessment of in vivo cellular kinetics</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with treatment induced anti-Cas9 humoral and cellular immunogenicity</measure>
    <time_frame>up to 24 months</time_frame>
    <description>To evaluate presence of pre-existing or treatment induced anti-Cas9 humoral and cellular immunogenicity</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>up to 24 months</time_frame>
    <description>To evaluate the overall survival which is defined as the time from date of start of treatment to date of death to any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Transplant-related mortality</measure>
    <time_frame>up to 24 months</time_frame>
    <description>Assessment of mortality</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures</measure>
    <time_frame>up to 24 months</time_frame>
    <description>Determine health status following instruments ASCQ-ME emotional impact</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with change from baseline of annualized VOC rate by 65%</measure>
    <time_frame>Baseline, 12 months</time_frame>
    <description>The annualized rate at baseline will be compared to that of vaso-occlusive crises (VOC) at 12 months.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with change from baseline of annualized SCD complications (aggregate of VOC, ACS, priapism and stroke) and if relevant, rate of transfusion by 65%</measure>
    <time_frame>Bseline, 12 months</time_frame>
    <description>The annualized rate at baseline will be compared to that of aggregate Sickle Cell Disease (SCD) complications (VOC, acute chest syndrome (ACS), priapism, and stroke) and transfusions at 12 months.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures</measure>
    <time_frame>up to 24 months</time_frame>
    <description>Determine health status following instruments PROMIS fatique</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures</measure>
    <time_frame>up to 24 months</time_frame>
    <description>Determine health status following instruments PROMIS physical functioning</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures</measure>
    <time_frame>up to 24 months</time_frame>
    <description>Determine health status following instruments ASCQ-ME sleep impact</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures</measure>
    <time_frame>up to 24 months</time_frame>
    <description>Determine health status following instruments ASCQ-ME pain impact</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">5</enrollment>
  <condition>Sickle Cell Disease</condition>
  <arm_group>
    <arm_group_label>OTQ923</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Single intravenous infusion of OTQ923 Part A - Adults treated with OTQ923; Part B - Children age 2-17 treated with OTQ923 based on review of data from Part A by Health agency after a formal interim analysis.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>OTQ923</intervention_name>
    <description>Single intravenous infusion of OTQ923 cell suspension</description>
    <arm_group_label>OTQ923</arm_group_label>
    <other_name>Adult Part A</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>OTQ923</intervention_name>
    <description>Single intravenous infusion of OTQ923, based on review of data from Part A by Health agencies after a formal interim analysis</description>
    <arm_group_label>OTQ923</arm_group_label>
    <other_name>Children 2-17 years old - Part B</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male or female subjects age 2-40 years inclusive&#xD;
&#xD;
          2. Confirmed diagnosis of sickle cell disease with globin typing (e.g. HbSS, HbSC,&#xD;
             HbS/β0-thalassemia or others)&#xD;
&#xD;
          3. Performance status &gt;70% (Karnofsky for subjects &gt;16 years of age and Lansky for&#xD;
             subjects &lt;16 years of age)&#xD;
&#xD;
          4. At least one of the following indicators of disease severity as defined in the&#xD;
             protocol - Vaso-occlusive pain crisis, Acute chest syndrome, Recurrent priapism, prior&#xD;
             stroke, receive chronic transfusions, Red cell alloimmunization&#xD;
&#xD;
          5. Subjects, who have failed, not tolerated or refused hydroxyurea therapy.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Available matched related donor for HSCT&#xD;
&#xD;
          2. Clinically significant active infection&#xD;
&#xD;
          3. Seropositive for HIV or HTLV&#xD;
&#xD;
          4. Active known malignancy, myelodysplasia, abnormal cytogenetics or immunodeficiency&#xD;
&#xD;
          5. Prior HSCT or gene therapy&#xD;
&#xD;
          6. Known hepatic cirrhosis, bridging hepatic fibrosis or active hepatitis&#xD;
&#xD;
          7. Protocol defined iron overload&#xD;
&#xD;
          8. Cerebrovascular procedure within one year, including pial synangiosis for Moyamoya&#xD;
&#xD;
          9. Severe or progressive arteriopathy or cerebrovascular disease, including Moyamoya&#xD;
&#xD;
        Other protocol defined inclusion/exclusion criteria may apply&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>2 Years</minimum_age>
    <maximum_age>40 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>University of Chicago SC - 2</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60637</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Cancer Ctr</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St Jude Children's Research Hospital</name>
      <address>
        <city>Memphis</city>
        <state>Tennessee</state>
        <zip>38105-3678</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Milano</city>
        <state>MI</state>
        <zip>20132</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>April 29, 2020</study_first_submitted>
  <study_first_submitted_qc>June 19, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 23, 2020</study_first_posted>
  <last_update_submitted>September 8, 2023</last_update_submitted>
  <last_update_submitted_qc>September 8, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 11, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Gene therapy</keyword>
  <keyword>genome-edited hematopoietic stem and progenitor cellular therapy</keyword>
  <keyword>sickle cell</keyword>
  <keyword>autologous transplant</keyword>
  <keyword>BCL11A</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anemia, Sickle Cell</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. Requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to protect the privacy of patients who have participated in the trial in line with applicable laws and regulations.&#xD;
This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com</ipd_description>
  </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/NCT04443907
org study id: CADPT03A12101
secondary id: 2019-003489-41
nct id: NCT04443907
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This study is evaluating a genome-edited, autologous, hematopoietic stem and progenitor cell
      (HSPC) product - OTQ923 to reduce the biologic activity of BCL11A, increasing fetal
      hemoglobin (HbF) and reducing complications of sickle cell disease.
CADPT03A12101 is a multicenter, multi-part, first-in-human, proof-of-concept, open label
      non-randomized, clinical study in Sickle Cell Disease (SCD) subjects. This study includes
      apheresis of mobilized hematopoietic stem and progenitor cells (HSPCs), ex vivo
      CRISPR/Cas9-mediated genome editing and expansion, followed by myeloablative conditioning and
      autologous hematopoietic stem cell transplant (HSCT) with follow-up for a minimum of one year
      and up to two years.

      The study is divided into the following parts:

        -  Part A - Adult subjects dosed with OTQ923.

        -  Part B - Assessment of OTQ923 in pediatric patients. Part B will not be opened.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
masking description: The is an open-label study.
measure: Number of participants with adverse events and serious adverse events
time frame: up to 24 months
description: Number of participants with adverse events (AEs) and serious adverse events (SAEs), including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs.
measure: Fetal hemoglobin (HbF) expression after hematopoietic stem cell transplant (HSCT)
time frame: up to 24 months
description: Assessment of HbF expression will be done by measuring total fetal hemoglobin over time.
measure: Time to reach absolute neutrophil count (ANC) ≥500/μL for 3 consecutive days
time frame: up to 24 months
description: Time to engraftment is defined as first of 3 consecutive days when an absolute neutrophil count (ANC) ≥500/μL after receiving OTQ923 was reached.
measure: Durability of hematologic engraftment
time frame: up to 24 months
description: Engraftment durability/persistence by measuring the proportion of alleles with on-target CRISPR modification in peripheral blood (total white blood cells (WBC)) and bone marrow over time up to 24 months
measure: Proportion of subject to achieve 30% of total HbF at 12 months
time frame: 12 months
description: Assessment of HbF expression will be done by measuring total fetal hemoglobin over time.
measure: Time to achieve 30% total HbF
time frame: up to 24 months
description: Assessment of HbF expression will be done by measuring total fetal hemoglobin over time.
measure: Time to peak total HbF
time frame: up to 24 months
description: Assessment of HbF expression will be done by measuring total fetal hemoglobin over time.
measure: Percentage of edited WBC and bone marrow cells by time points
time frame: up to 24 months
description: Assessment of in vivo cellular kinetics
measure: Number of participants with treatment induced anti-Cas9 humoral and cellular immunogenicity
time frame: up to 24 months
description: To evaluate presence of pre-existing or treatment induced anti-Cas9 humoral and cellular immunogenicity
measure: Overall Survival
time frame: up to 24 months
description: To evaluate the overall survival which is defined as the time from date of start of treatment to date of death to any cause.
measure: Transplant-related mortality
time frame: up to 24 months
description: Assessment of mortality
measure: Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures
time frame: up to 24 months
description: Determine health status following instruments ASCQ-ME emotional impact
measure: Number of participants with change from baseline of annualized VOC rate by 65%
time frame: Baseline, 12 months
description: The annualized rate at baseline will be compared to that of vaso-occlusive crises (VOC) at 12 months.
measure: Number of participants with change from baseline of annualized SCD complications (aggregate of VOC, ACS, priapism and stroke) and if relevant, rate of transfusion by 65%
time frame: Bseline, 12 months
description: The annualized rate at baseline will be compared to that of aggregate Sickle Cell Disease (SCD) complications (VOC, acute chest syndrome (ACS), priapism, and stroke) and transfusions at 12 months.
measure: Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures
time frame: up to 24 months
description: Determine health status following instruments PROMIS fatique
measure: Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures
time frame: up to 24 months
description: Determine health status following instruments PROMIS physical functioning
measure: Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures
time frame: up to 24 months
description: Determine health status following instruments ASCQ-ME sleep impact
measure: Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures
time frame: up to 24 months
description: Determine health status following instruments ASCQ-ME pain impact
arm group label: OTQ923
arm group type: Experimental
description: Single intravenous infusion of OTQ923 Part A - Adults treated with OTQ923; Part B - Children age 2-17 treated with OTQ923 based on review of data from Part A by Health agency after a formal interim analysis.
intervention type: Biological
intervention name: OTQ923
description: Single intravenous infusion of OTQ923 cell suspension
arm group label: OTQ923
other name: Adult Part A
intervention type: Biological
intervention name: OTQ923
description: Single intravenous infusion of OTQ923, based on review of data from Part A by Health agencies after a formal interim analysis
arm group label: OTQ923
other name: Children 2-17 years old - Part B
criteria: 
gender: All
minimum age: 2 Years
maximum age: 40 Years
healthy volunteers: No
facility: 
facility: 
facility: 
facility: 
country: Italy
country: United States
responsible party type: Sponsor
mesh term: Anemia, Sickle Cell
sharing ipd: No
ipd description: Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. Requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to protect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com