<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/NCT03765632</url>
  </required_header>
  <id_info>
    <org_study_id>OTL-101-5</org_study_id>
    <secondary_id>17IC04</secondary_id>
    <nct_id>NCT03765632</nct_id>
  </id_info>
  <brief_title>Efficacy and Safety of the Cryopreserved Formulation of OTL-101 in Subjects With ADA-SCID</brief_title>
  <official_title>Efficacy and Safety of a Cryopreserved Formulation of Autologous CD34+ Haematopoietic Stem Cells Transduced ex Vivo With Elongation Factor 1α Short Form (EFS) Lentiviral Vector Encoding for Human ADA Gene in Subjects With Severe Combined Immunodeficiency (SCID) Due to Adenosine Deaminase Deficiency</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Great Ormond Street Hospital for Children NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Orchard Therapeutics</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Great Ormond Street Hospital for Children NHS Foundation Trust</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>
      This is a prospective, non-randomized, single-cohort, longitudinal, single-center, clinical&#xD;
      study designed to assess the efficacy and safety of a cryopreserved formulation of OTL-101&#xD;
      (autologous CD34+ hematopoietic stem/progenitor cells transduced ex vivo with EFS (Elongation&#xD;
      Factor 1α Short form) Lentiviral Vector (LV) encoding for the human ADA gene) administered to&#xD;
      ADA-SCID subjects between the ages of &gt;/=30 days and &lt;18 years of age, who are not eligible&#xD;
      for an Human Leukocyte Antigen (HLA) matched sibling/family donor and meeting the&#xD;
      inclusion/exclusion criteria. The OTL-101 product is infused after a minimal interval of at&#xD;
      least 24 hours following the completion of reduced intensity conditioning. For subjects who&#xD;
      successfully receive the OTL-101 product, pegademase bovine (PEG-ADA) Enzyme Replacement&#xD;
      Therapy (ERT) is discontinued at Day+30 (-3/+15) after the transplant. After their discharge&#xD;
      from hospital, the subjects will be seen at regular intervals to review their history,&#xD;
      perform examinations and draw blood samples to assess immunity and safety.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 3, 2018</start_date>
  <completion_date type="Actual">September 28, 2022</completion_date>
  <primary_completion_date type="Actual">September 13, 2021</primary_completion_date>
  <phase>Phase 1/Phase 2</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>
  </study_design_info>
  <primary_outcome>
    <measure>Overall survival at 12 months post OTL-101 infusion</measure>
    <time_frame>12 Months</time_frame>
    <description>Overall survival is defined as the proportion of subjects alive</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Event free survival at 12 months post OTL-101 infusion</measure>
    <time_frame>12 Months</time_frame>
    <description>Event-free survival is defined as the proportion of subjects alive with no &quot;event&quot;, an &quot;event&quot; being the resumption of Peg-Ada ERT or the need for a rescue stem cell transplant (SCT), or death</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall survival at 24 months post OTL-101 infusion</measure>
    <time_frame>24 months</time_frame>
    <description>Overall survival is defined as the proportion of subjects alive</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Event free survival at 24 months post OTL-101 infusion</measure>
    <time_frame>24 Months</time_frame>
    <description>Event-free survival is defined as the proportion of subjects alive with no &quot;event&quot;, an &quot;event&quot; being the resumption of Peg-Ada ERT or the need for a rescue stem cell transplant (SCT), or death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety evaluation including infection rates</measure>
    <time_frame>12 and 24 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety evaluation including performance outcomes</measure>
    <time_frame>12 and 24 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety evaluation including immune reconstitution</measure>
    <time_frame>12 and 24 months</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">13</enrollment>
  <condition>Severe Combined Immunodeficiency Due to ADA Deficiency</condition>
  <arm_group>
    <arm_group_label>Gene Therapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Infusion of autologous cryopreserved EFS-ADA LV CD34+ cells</description>
  </arm_group>
  <intervention>
    <intervention_type>Genetic</intervention_type>
    <intervention_name>Infusion of autologous cryopreserved EFS-ADA LV CD34+ cells (OTL-101)</intervention_name>
    <description>Autologous cryopreserved EFS-ADA LV CD34+ cells (OTL-101) are infused intravenously</description>
    <arm_group_label>Gene Therapy</arm_group_label>
    <other_name>OTL-101</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Busulfan</intervention_name>
    <description>Busulfan is used for non-myeloablative conditioning</description>
    <arm_group_label>Gene Therapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Peg-Ada</intervention_name>
    <description>Peg-Ada Enzyme Replacement Therapy (ERT) is discontinued at Day +30 (-3/+15 days) after successful engraftment</description>
    <arm_group_label>Gene Therapy</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Provision of written informed consent prior to any study related procedures. In this&#xD;
             study consent must be provided by the parents/legal guardians and, where applicable&#xD;
             according to local laws, a signed assent from the child&#xD;
&#xD;
          2. Subjects ≥30 days and &lt;18 years of age,&#xD;
&#xD;
          3. With a diagnosis of ADA-SCID based on:&#xD;
&#xD;
               1. . Evidence of ADA deficiency, defined as: i. Decreased ADA enzymatic activity in&#xD;
                  erythrocytes, leukocytes, skin fibroblasts, or in cultured foetal cells to levels&#xD;
                  consistent with ADA-SCID as determined by the reference laboratory, or ii.&#xD;
                  Identified mutations in ADA alleles consistent with a severe reduction in ADA&#xD;
                  activity,&#xD;
&#xD;
               2. . Evidence of ADA-SCID based on either: i. Family history of a first order&#xD;
                  relative with ADA deficiency and clinical and laboratory evidence of severe&#xD;
                  immunologic deficiency, or ii. Evidence of severe immunologic deficiency in&#xD;
                  subjects prior to the institution of immune restorative therapy, based on&#xD;
&#xD;
             Lymphopenia (absolute lymphocyte count &lt;400 cells/mL) OR absence or low number of&#xD;
             T-cells (absolute CD3+ count &lt; 300 cells/mL), or&#xD;
&#xD;
             Severely decreased T lymphocyte blastogenic responses to phytohemagglutinin (either&#xD;
             &lt;10% of lower limit of normal controls for the diagnostic laboratory, or &lt;10% of the&#xD;
             response of the normal control of the day, or stimulation index &lt;10), or&#xD;
&#xD;
             Identification of SCID by neonatal screening revealing low T cell Receptor Excision&#xD;
             Circle (TREC) levels.&#xD;
&#xD;
          4. Ineligible for or with no available matched family donor for allogeneic Bone Marrow&#xD;
             (BM) transplantation, defined as the absence of a medically eligible HLA-identical&#xD;
             sibling or family donor, with normal immune function, who could serve as an allogeneic&#xD;
             bone marrow donor.&#xD;
&#xD;
          5. Females of child-bearing age will be required to provide a negative pregnancy test 30&#xD;
             days prior to Visit 2.&#xD;
&#xD;
          6. Subjects and their parents/legal guardians must be willing and able to comply with&#xD;
             study restrictions and to remain at the clinic for the required duration during the&#xD;
             study period and willing to return to the clinic for the follow up evaluation as&#xD;
             specified in the protocol.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Ineligible for autologous hematopoietic stem cell (HSC) procedure.&#xD;
&#xD;
          2. Other conditions which in the opinion of the Principal Investigator and/or&#xD;
             Co-Investigators, contraindicate the harvest of bone marrow, the administration of&#xD;
             Busulfan and the infusion of transduced cells, or which indicate an inability of the&#xD;
             subject or subject's parent/legal guardian to comply with the protocol.&#xD;
&#xD;
          3. Haematologic abnormality, defined as:&#xD;
&#xD;
             Anaemia (Hb &lt;8.0 g/dl). Evidence of bi/trilineage cytopaenia (haemoglobin &lt;8 g/dl,&#xD;
             neutrophils &lt;0.5 x 109/L, platelets 50 x 109/L). Thrombocytopaenia (platelet count&#xD;
             &lt;50,000/mm3). Prothrombin time or partial thromboplastin time (PTT) &gt;2 x upper limit&#xD;
             of normal (ULN) (subjects with a correctable deficiency controlled on medication will&#xD;
             not be excluded).&#xD;
&#xD;
               -  Cytogenetic abnormalities of Peripheral Blood (PB), BM or amniotic fluid (if&#xD;
                  available). If cytogenetic testing has not been performed on cells from&#xD;
                  amniocentesis, assessment should be by karyotype, Comparative genomic&#xD;
                  hybridization (CGH), and or whole exome sequencing (WES).&#xD;
&#xD;
               -  Prior allogeneic HSC transplant (HSCT) with cytoreductive conditioning.&#xD;
&#xD;
          4. Pulmonary abnormality, defined as:&#xD;
&#xD;
               -  Resting O2 saturation by pulse oximetry &lt;90% on room air.&#xD;
&#xD;
               -  Chest X-ray indicating active or progressive pulmonary disease. Note: Chest X-ray&#xD;
                  indicating residual signs of treated pneumonitis is acceptable for eligibility.&#xD;
&#xD;
          5. Cardiac abnormality, defined as:&#xD;
&#xD;
               -  Abnormal ECG indicating cardiac pathology.&#xD;
&#xD;
               -  Uncorrected congenital cardiac malformation with clinical symptoms.&#xD;
&#xD;
               -  Active cardiac disease, including clinical evidence of congestive heart failure,&#xD;
                  cyanosis, hypotension.&#xD;
&#xD;
               -  Poor cardiac function as evidenced by left ventricular ejection fraction &lt;40% on&#xD;
                  echocardiogram.&#xD;
&#xD;
          6. Neurologic abnormality, defined as:&#xD;
&#xD;
               -  Significant neurologic abnormality revealed by examination.&#xD;
&#xD;
               -  Uncontrolled seizure disorder.&#xD;
&#xD;
          7. Known history of significant renal abnormality.&#xD;
&#xD;
          8. Known history of significant hepatic or gastrointestinal abnormality.&#xD;
&#xD;
          9. Oncologic disease, defined as:&#xD;
&#xD;
               -  Evidence of active malignant disease other than Dermatofibrosarcoma Protuberans(&#xD;
                  DFSP) 2.&#xD;
&#xD;
               -  Evidence of DFSP expected to require anti-neoplastic therapy within the 5 years&#xD;
                  following the infusion of genetically corrected cells (if anti-neoplastic therapy&#xD;
                  has been completed, a subject with a history of DFSP can be included).&#xD;
&#xD;
               -  Evidence of DFSP expected to be life-limiting within the 5 years following the&#xD;
                  infusion of genetically corrected cells.&#xD;
&#xD;
         10. Known sensitivity to Busulfan.&#xD;
&#xD;
         11. Confirmation of an infectious disease by deoxyribonucleic acid (DNA) polymerase chain&#xD;
             reactions (PCR) positive at time of screening assessment according to local&#xD;
             protocols/procedures (including HIV-1 and hepatitis B).&#xD;
&#xD;
         12. The subject is pregnant or has a major congenital anomaly.&#xD;
&#xD;
         13. Is likely to require treatment during the study with drugs that are not permitted by&#xD;
             the study protocol.&#xD;
&#xD;
         14. The subject has previously received another form of gene therapy.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>30 Days</minimum_age>
    <maximum_age>17 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Claire Booth, Dr</last_name>
    <role>Principal Investigator</role>
    <affiliation>Great Ormond Street Hospital NHS Foundation Trust</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Great Ormond Street Hospital for Children NHS Foundation Trust</name>
      <address>
        <city>London</city>
        <zip>WC1N 3JH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>August 8, 2018</study_first_submitted>
  <study_first_submitted_qc>December 4, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 5, 2018</study_first_posted>
  <last_update_submitted>January 31, 2023</last_update_submitted>
  <last_update_submitted_qc>January 31, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 1, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Gene therapy</keyword>
  <keyword>Hematopoietic stem and progenitor cells</keyword>
  <keyword>Lentiviral vector</keyword>
  <keyword>ADA-SCID</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Severe Combined Immunodeficiency</mesh_term>
    <mesh_term>Immunologic Deficiency Syndromes</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Busulfan</mesh_term>
  </intervention_browse>
  <!-- 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/NCT03765632
org study id: OTL-101-5
secondary id: 17IC04
nct id: NCT03765632
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This is a prospective, non-randomized, single-cohort, longitudinal, single-center, clinical
      study designed to assess the efficacy and safety of a cryopreserved formulation of OTL-101
      (autologous CD34+ hematopoietic stem/progenitor cells transduced ex vivo with EFS (Elongation
      Factor 1α Short form) Lentiviral Vector (LV) encoding for the human ADA gene) administered to
      ADA-SCID subjects between the ages of >/=30 days and <18 years of age, who are not eligible
      for an Human Leukocyte Antigen (HLA) matched sibling/family donor and meeting the
      inclusion/exclusion criteria. The OTL-101 product is infused after a minimal interval of at
      least 24 hours following the completion of reduced intensity conditioning. For subjects who
      successfully receive the OTL-101 product, pegademase bovine (PEG-ADA) Enzyme Replacement
      Therapy (ERT) is discontinued at Day+30 (-3/+15) after the transplant. After their discharge
      from hospital, the subjects will be seen at regular intervals to review their history,
      perform examinations and draw blood samples to assess immunity and safety.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall survival at 12 months post OTL-101 infusion
time frame: 12 Months
description: Overall survival is defined as the proportion of subjects alive
measure: Event free survival at 12 months post OTL-101 infusion
time frame: 12 Months
description: Event-free survival is defined as the proportion of subjects alive with no "event", an "event" being the resumption of Peg-Ada ERT or the need for a rescue stem cell transplant (SCT), or death
measure: Overall survival at 24 months post OTL-101 infusion
time frame: 24 months
description: Overall survival is defined as the proportion of subjects alive
measure: Event free survival at 24 months post OTL-101 infusion
time frame: 24 Months
description: Event-free survival is defined as the proportion of subjects alive with no "event", an "event" being the resumption of Peg-Ada ERT or the need for a rescue stem cell transplant (SCT), or death
measure: Safety evaluation including infection rates
time frame: 12 and 24 months
measure: Safety evaluation including performance outcomes
time frame: 12 and 24 months
measure: Safety evaluation including immune reconstitution
time frame: 12 and 24 months
arm group label: Gene Therapy
arm group type: Experimental
description: Infusion of autologous cryopreserved EFS-ADA LV CD34+ cells
intervention type: Genetic
intervention name: Infusion of autologous cryopreserved EFS-ADA LV CD34+ cells (OTL-101)
description: Autologous cryopreserved EFS-ADA LV CD34+ cells (OTL-101) are infused intravenously
arm group label: Gene Therapy
other name: OTL-101
intervention type: Drug
intervention name: Busulfan
description: Busulfan is used for non-myeloablative conditioning
arm group label: Gene Therapy
intervention type: Drug
intervention name: Peg-Ada
description: Peg-Ada Enzyme Replacement Therapy (ERT) is discontinued at Day +30 (-3/+15 days) after successful engraftment
arm group label: Gene Therapy
criteria: 
gender: All
minimum age: 30 Days
maximum age: 17 Years
healthy volunteers: No
last name: Claire Booth, Dr
role: Principal Investigator
affiliation: Great Ormond Street Hospital NHS Foundation Trust
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Severe Combined Immunodeficiency
mesh term: Immunologic Deficiency Syndromes
mesh term: Busulfan