<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/NCT03001830</url>
  </required_header>
  <id_info>
    <org_study_id>UCL 13/0076</org_study_id>
    <secondary_id>2016-000925-38</secondary_id>
    <secondary_id>MR/L013185/1</secondary_id>
    <nct_id>NCT03001830</nct_id>
  </id_info>
  <brief_title>Gene Therapy for Haemophilia A.</brief_title>
  <acronym>GO-8</acronym>
  <official_title>GO-8: Gene Therapy for Haemophilia A Using a Novel Serotype 8 Capsid Pseudotyped Adeno-associated Viral Vector Encoding Factor VIII-V3</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University College, London</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Medical Research Council</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University College, London</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>
      The GO-8 study focuses on assessing safety and efficacy of gene therapy for patients with&#xD;
      severe haemophilia A&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Haemophilia A is an x-linked, life threatening bleeding disorder arising from defects in the&#xD;
      coagulation factor VIII (FVIII) gene. Current treatment for haemophilia A, the commonest&#xD;
      inherited bleeding disorder (prevalence of 1 in 5000 individuals) consists of life-long,&#xD;
      2-3X/week, intravenous injection of clotting factor concentrates, which is demanding,&#xD;
      exceedingly expensive not widely available nor curative. In contrast, gene therapy offers the&#xD;
      potential of a cure for haemophilia A as illustrated by our first unequivocal success in a&#xD;
      related condition, haemophilia B. In that study the investigators showed that a single&#xD;
      intravenous administration of a serotype 8 based adeno-associated virus, (AAV8) vector&#xD;
      encoding the factor IX (FIX) gene resulted in stable (&gt;6 years) therapeutic expression of FIX&#xD;
      without long-lasting toxicity. The investigators plan to use the same AAV8 platform to&#xD;
      evaluate a novel FVIII expression cassette, AAV2/8-HLP-FVIII-V3, in patient with haemophilia&#xD;
      A. Extensive preclinical studies demonstrate that AAV2/8-HLP-FVIII-V3 leads to long-term,&#xD;
      endogenous expression of FVIII in mouse and non-human primate models without toxicity even&#xD;
      when fifty-fold higher doses than the proposed starting clinical trial dose were used.&#xD;
      Therefore, an open label, Phase I/II dose escalation study entailing a single systemic&#xD;
      administration of AAV2/8-HLP-FVIII-V3 in adults (&gt;18 years of age) with severe haemophilia A&#xD;
      who have baseline factor FVIII levels of &lt;1% of normal has been designed to establish safety&#xD;
      and efficacy of our approach. Dosing will begin at 6x10^11 vector genome (vg)/kg progressing&#xD;
      sequentially to 2x10^12vg/kg and ultimately 6x10^12vg/kg in the absence of toxicity. A&#xD;
      minimum of 2 patients will be recruited at each dose with a possibility of expanding the dose&#xD;
      cohort to a maximum of 6 patients based on safety and efficacy. The study duration for each&#xD;
      patient will be 15 years after vector infusion.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">June 14, 2017</start_date>
  <completion_date type="Anticipated">June 2025</completion_date>
  <primary_completion_date type="Anticipated">December 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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety - Dose Limiting Toxicity possibly attributable to the ATIMP development</measure>
    <time_frame>Up to 15 years post-infusion</time_frame>
    <description>Toxicity will be assessed according to CTCAE, version 4.03 based on the monitoring schedule which comprises a number of clinical and laboratory evaluations</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety - Neutralising anti-hFVIII antibody development following gene therapy</measure>
    <time_frame>Up to 15 years post-infusion</time_frame>
    <description>The presence of neutralising hFVIII antibodies will be assessed by regular laboratory tests during patient follow up post infusion</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Plasma hFVIII activity</measure>
    <time_frame>Week 12 post-infusion</time_frame>
    <description>Assessments of plasma hFVIII activity using a validated chromogenic assay</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Bleeding frequency</measure>
    <time_frame>Annual review for 15 years</time_frame>
    <description>Assessment of bleeding frequency using participant diaries before and after gene transfer</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>hFVIII concentrate usage</measure>
    <time_frame>Annual review for 15 years</time_frame>
    <description>Assessment of hFVIII concentrate usage as per participant treatment records before and after gene transfer</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immune response to the AAV8 capsid.</measure>
    <time_frame>Weeks 3, 6, 9 &amp; 12 post-infusion &amp; Month 6 post-infusion</time_frame>
    <description>Immune response to the AAV8 capsid will be assessed by measurement of the AAV8 antibody titre (humoral response) in plasma samples collected at various time points after gene transfer. Cellular immune response to AAV capsid will be determined using gamma interferon (IFNγ) ELIspot assay to AAV8 capsid</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Viral shedding</measure>
    <time_frame>Weekly from 7 days post infusion until day 42.</time_frame>
    <description>Serum and bodily secretions will be collected to assess clearance of vector genomes</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">18</enrollment>
  <condition>Hemophilia A</condition>
  <arm_group>
    <arm_group_label>Treatment Arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Treatment with AAV2/8-HLP-FVIII-V3</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>AAV2/8-HLP-FVIII-V3</intervention_name>
    <description>Infusion of AAV2/8-HLP-FVIII-V3</description>
    <arm_group_label>Treatment Arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
        I. Adult males, ≥ 18 years of age; confirmed diagnosis of severe HA (baseline plasma hFVIII&#xD;
        levels of &lt;1% of normal; assessed by a one-stage clotting or chromogenic assay) resulting&#xD;
        from gene mutations that have a low risk for inhibitor development, such as intron 22&#xD;
        inversions, intron 1 inversions, splice-site mutations, small deletions/insertions,&#xD;
        duplications and missense mutations; II. A severe bleeding phenotype as defined by at least&#xD;
        one of the following: (a) On prophylaxis for a history of bleeding or (b) On demand therapy&#xD;
        with a current or past history of 4 or more bleeding episodes/year or (c) evidence of&#xD;
        chronic haemophilic arthropathy (pain, joint damage, and loss of range of motion) III.&#xD;
        Received treatment with hFVIII concentrates with at least &gt;50 exposure days; IV. Able to&#xD;
        give full informed consent and able to comply with all requirements of the trial including&#xD;
        5-year long-term follow-up; V. Willing to practice barrier contraception until at least&#xD;
        three consecutive semen samples after vector administration are below the sensitivity of&#xD;
        the assay for vector sequences;&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
        VI. Presence of neutralising anti-hFVIII antibodies (inhibitor, determined by the Bethesda&#xD;
        inhibitor assay) at the time of enrolment or a previous history of hFVIII inhibitor; VII.&#xD;
        Severe haemophilia A patients with large deletions (multiple exons) and nonsense mutations&#xD;
        of the F8 gene.&#xD;
&#xD;
        VIII. Use of investigational therapy for haemophilia within 30 days before enrolment; IX.&#xD;
        Subjects with active hepatitis B or C, and HBsAg or HCV RNA viral load positivity,&#xD;
        respectively or currently on antiviral therapy for hepatitis B or C. (Negative viral assays&#xD;
        in two samples, collected at least six months apart, will be required to be considered&#xD;
        negative. Both natural clearers and those who have cleared HCV on antiviral therapy are&#xD;
        eligible).&#xD;
&#xD;
        X. Serological evidence of HIV; XI. Evidence of liver dysfunction (persistently elevated&#xD;
        ALT &gt;1.5X upper limit of normal); XII. Uncontrolled glaucoma, diabetes mellitus, or&#xD;
        hypertension (systolic BP consistently ≥140 mmHg or diastolic BP consistently ≥90 mmHg);&#xD;
        XIII. Any disease or condition (including cancer) at the physician's discretion that would&#xD;
        prevent the patient from fully complying with the requirements of the study.; XIV.&#xD;
        Suspicious lung lesions on CT scan that raise the possibility of cancer or premalignant&#xD;
        pathology (based on chest CT scan done at screening or within 6 months prior to the&#xD;
        screening visit) XV. Presence of liver abnormality that is suspicious of malignancy on&#xD;
        screening liver ultrasound XVI. Patients with uncontrolled cardiac failure or unstable&#xD;
        angina; XVII. Detectable neutralising anti-AAV8 antibodies XVIII. Received an AAV vector,&#xD;
        or any other gene transfer agent in the previous 6 months XIX. History of active&#xD;
        tuberculosis, fungal disease or other chronic infection XX. Subjects who are unwilling to&#xD;
        provide the required semen samples XXI. Poor performance status (WHO score &gt;1) XXII.&#xD;
        Patients at high risk of thromboembolic events (high risk patients would include those with&#xD;
        a history of arterial or venous thromboembolism (e.g. deep vein thrombosis, pulmonary&#xD;
        embolism, non-haemorrhagic stroke, arterial embolus) and those with acquired thrombophilia&#xD;
        including conditions such as atrial fibrillation).&#xD;
&#xD;
        XXIII. Patients with a CHA2DS2-VASc score of 2 and above&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Pratima Chowdary, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Royal Free London NHS Foundation Trust</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Mark Phillips</last_name>
    <phone>+442078302068</phone>
    <phone_ext>38784</phone_ext>
    <email>mark.phillips@ucl.ac.uk</email>
  </overall_contact>
  <location>
    <facility>
      <name>University of Kentucky</name>
      <address>
        <city>Lexington</city>
        <state>Kentucky</state>
        <zip>40506</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Vlad Radulescu, MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>St Jude's Children's Research Hospital</name>
      <address>
        <city>Memphis</city>
        <state>Tennessee</state>
        <zip>38105-3678</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Ulrike Reiss, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Andrew Davidoff, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Royal Free Hospital</name>
      <address>
        <city>London</city>
        <zip>NW3 2QG</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Pratima Chowdary</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Amit Nathwani</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Edward Tuddenham</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2020</verification_date>
  <study_first_submitted>December 9, 2016</study_first_submitted>
  <study_first_submitted_qc>December 20, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 23, 2016</study_first_posted>
  <last_update_submitted>March 11, 2020</last_update_submitted>
  <last_update_submitted_qc>March 11, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">March 13, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hemophilia A</mesh_term>
  </condition_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/NCT03001830
org study id: UCL 13/0076
secondary id: 2016-000925-38
secondary id: MR/L013185/1
nct id: NCT03001830
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The GO-8 study focuses on assessing safety and efficacy of gene therapy for patients with
      severe haemophilia A
Haemophilia A is an x-linked, life threatening bleeding disorder arising from defects in the
      coagulation factor VIII (FVIII) gene. Current treatment for haemophilia A, the commonest
      inherited bleeding disorder (prevalence of 1 in 5000 individuals) consists of life-long,
      2-3X/week, intravenous injection of clotting factor concentrates, which is demanding,
      exceedingly expensive not widely available nor curative. In contrast, gene therapy offers the
      potential of a cure for haemophilia A as illustrated by our first unequivocal success in a
      related condition, haemophilia B. In that study the investigators showed that a single
      intravenous administration of a serotype 8 based adeno-associated virus, (AAV8) vector
      encoding the factor IX (FIX) gene resulted in stable (>6 years) therapeutic expression of FIX
      without long-lasting toxicity. The investigators plan to use the same AAV8 platform to
      evaluate a novel FVIII expression cassette, AAV2/8-HLP-FVIII-V3, in patient with haemophilia
      A. Extensive preclinical studies demonstrate that AAV2/8-HLP-FVIII-V3 leads to long-term,
      endogenous expression of FVIII in mouse and non-human primate models without toxicity even
      when fifty-fold higher doses than the proposed starting clinical trial dose were used.
      Therefore, an open label, Phase I/II dose escalation study entailing a single systemic
      administration of AAV2/8-HLP-FVIII-V3 in adults (>18 years of age) with severe haemophilia A
      who have baseline factor FVIII levels of <1% of normal has been designed to establish safety
      and efficacy of our approach. Dosing will begin at 6x10^11 vector genome (vg)/kg progressing
      sequentially to 2x10^12vg/kg and ultimately 6x10^12vg/kg in the absence of toxicity. A
      minimum of 2 patients will be recruited at each dose with a possibility of expanding the dose
      cohort to a maximum of 6 patients based on safety and efficacy. The study duration for each
      patient will be 15 years after vector infusion.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Safety - Dose Limiting Toxicity possibly attributable to the ATIMP development
time frame: Up to 15 years post-infusion
description: Toxicity will be assessed according to CTCAE, version 4.03 based on the monitoring schedule which comprises a number of clinical and laboratory evaluations
measure: Safety - Neutralising anti-hFVIII antibody development following gene therapy
time frame: Up to 15 years post-infusion
description: The presence of neutralising hFVIII antibodies will be assessed by regular laboratory tests during patient follow up post infusion
measure: Plasma hFVIII activity
time frame: Week 12 post-infusion
description: Assessments of plasma hFVIII activity using a validated chromogenic assay
measure: Bleeding frequency
time frame: Annual review for 15 years
description: Assessment of bleeding frequency using participant diaries before and after gene transfer
measure: hFVIII concentrate usage
time frame: Annual review for 15 years
description: Assessment of hFVIII concentrate usage as per participant treatment records before and after gene transfer
measure: Immune response to the AAV8 capsid.
time frame: Weeks 3, 6, 9 & 12 post-infusion & Month 6 post-infusion
description: Immune response to the AAV8 capsid will be assessed by measurement of the AAV8 antibody titre (humoral response) in plasma samples collected at various time points after gene transfer. Cellular immune response to AAV capsid will be determined using gamma interferon (IFNγ) ELIspot assay to AAV8 capsid
measure: Viral shedding
time frame: Weekly from 7 days post infusion until day 42.
description: Serum and bodily secretions will be collected to assess clearance of vector genomes
arm group label: Treatment Arm
arm group type: Experimental
description: Treatment with AAV2/8-HLP-FVIII-V3
intervention type: Biological
intervention name: AAV2/8-HLP-FVIII-V3
description: Infusion of AAV2/8-HLP-FVIII-V3
arm group label: Treatment Arm
criteria: 
gender: Male
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Pratima Chowdary, MD
role: Principal Investigator
affiliation: Royal Free London NHS Foundation Trust
last name: Mark Phillips
phone: +442078302068
phone ext: 38784
email: mark.phillips@ucl.ac.uk
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
investigator: 
investigator: 
facility: 
status: Recruiting
investigator: 
investigator: 
investigator: 
country: United Kingdom
country: United States
responsible party type: Sponsor
mesh term: Hemophilia A
sharing ipd: No