<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/NCT02240407</url>
  </required_header>
  <id_info>
    <org_study_id>IRB201400137</org_study_id>
    <secondary_id>20182574</secondary_id>
    <nct_id>NCT02240407</nct_id>
  </id_info>
  <brief_title>Re-administration of Intramuscular AAV9 in Patients With Late-Onset Pompe Disease</brief_title>
  <acronym>AAV9-GAA_IM</acronym>
  <official_title>Evaluation of Re-administration of Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase (rAAV9-DES-hGAA) in Patients With Late-Onset Pompe Disease (LOPD)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Florida</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Lacerta Therapeutics</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Florida</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>
      A recombinant AAV vector has been generated to carry the codon-optimized acid&#xD;
      alpha-glucosidase (coGAA) gene expressed from a human desmin enhancer/promoter (DES). The&#xD;
      proposed clinical trial is a within-participant, double-blind, randomized, phase I controlled&#xD;
      study evaluating the toxicology, biodistribution and potential activity of re-administration&#xD;
      of rAAV9-DES-hGAA injected intramuscularly into the TA. Nine participants (18 to 50-years&#xD;
      old) who reside within the United States with Late-Onset Pompe Disease (LOPD) will be&#xD;
      included. The goal of the immune modulation strategy is to ablate B-cells (Rituximab and&#xD;
      Sirolimus) prior to the initial exposure to the study agent in one leg and the subsequent&#xD;
      exposure of the same vector to the contralateral leg after four months. At each study agent&#xD;
      dosing, the contralateral leg will receive excipient. Patients will act as their own&#xD;
      controls. Repeated measures, at baseline and during the following 3 months after each&#xD;
      injection, will assess the safety, biochemical and functional impact of the vector.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Enrolling in this study will entail participating in 18 months of study-related visits.&#xD;
      Patients will be asked to come to the Clinical and Translational Research Building at the&#xD;
      University of Florida for a series of onsite study visits.&#xD;
&#xD;
      All the visits will be performed as outpatient procedures at the Clinical Research Center&#xD;
      (CRC) and at other facilities at the University of Florida. Overnight observation will not be&#xD;
      needed, however, patients will be asked to stay overnight in a hotel near the University of&#xD;
      Florida. During the first 4 months after each injection, patients will be asked to perform&#xD;
      outpatient laboratory work at a laboratory facility convenient for them.&#xD;
&#xD;
      In addition, during this study patients will be asked to take medications that will modulate&#xD;
      the ability of their immune system to react against foreign agents including the gene&#xD;
      transfer agent. The purpose of these medications is to improve the activity of the GAA within&#xD;
      the body. Patients will receive a Rituximab injection 21 days prior to the first injection of&#xD;
      the study agent and 7 days before each injection of the study agent and the day of the first&#xD;
      injection. Rituximab will be delivered by infusion that may last 2-6 hours. Patients will&#xD;
      need to take another medication (Sirolimus) every day starting 7 days before the first&#xD;
      injection of the study agent until four months after the second injection of the study agent.&#xD;
&#xD;
      The following discusses what will occur at each visit:&#xD;
&#xD;
      Baseline Baseline Evaluation and first Rituximab infusion - Day -22/-21/-20&#xD;
&#xD;
        -  Medical history: Patients will be asked to complete a questionnaire about his/her&#xD;
           medical history.&#xD;
&#xD;
        -  Physical exam: The study doctor will perform a general physical exam to evaluate&#xD;
           patients physical health.&#xD;
&#xD;
        -  Blood and urine tests: These tests will be used for evaluating the safety of the gene&#xD;
           transfer agent.&#xD;
&#xD;
        -  Electrocardiogram (ECG): This test will measure the electrical activity of patient's&#xD;
           heart to see if it is working properly.&#xD;
&#xD;
        -  Quantitative Muscle Testing (QMT): This test finds out how strong the patient's leg&#xD;
           muscles are.&#xD;
&#xD;
        -  10 Meter Walk Test: Patients will be instructed to walk a set distance (10 meters); time&#xD;
           will be measured while patient walks the set distance and the distance covered will be&#xD;
           divided by the time it took to walk that distance.&#xD;
&#xD;
        -  Gait analysis: Gait will be tested with Gait Mat II, which will record the spatial and&#xD;
           temporal parameters of his/her walk such as cadence, speed and distance between your&#xD;
           feet.&#xD;
&#xD;
        -  Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS): MRI and MRS testing will be&#xD;
           done inside a large magnet that lets the study doctors measure the size and health of&#xD;
           the patient's muscles. These tests are done at the same time. MRI and MRS testing will&#xD;
           require the patient to stay very still for up to an hour.&#xD;
&#xD;
        -  Magnetic stimulation of the common fibular nerve: The common fibular nerve, which is the&#xD;
           nerve that controls the injected muscle, will be stimulated with a magnetic field to&#xD;
           test the impact of the gene transfer agent to the nervous system.&#xD;
&#xD;
        -  The patient will receive the first Rituximab infusion. It might last between 2 and 6&#xD;
           hours.&#xD;
&#xD;
      Rituximab infusion - Day -6&#xD;
&#xD;
        -  The patient will receive the 2nd Rituximab infusion 7 days before the gene transfer&#xD;
           agent. It might last between 2 and 6 hours.&#xD;
&#xD;
        -  Patient will begin Rapamycin.&#xD;
&#xD;
           1st Injection - Day 0/1&#xD;
&#xD;
        -  The patient will receive the 3rd Rituximab infusion the day before the gene transfer&#xD;
           agent. It might last between 2 and 6 hours.&#xD;
&#xD;
        -  Patient will receive the gene transfer agent in 1 injection (a total of about 1&#xD;
           teaspoon) into the tibialis anterior (TA) muscle of one leg. The other leg will receive&#xD;
           a pharmacologically inactive solution. An ultrasound will be used to detect the proper&#xD;
           location of injection. A photograph of the injection at the injection site may be taken.&#xD;
           If the patient agrees to this, he/she will be asked to sign a consent form for this&#xD;
           procedure.&#xD;
&#xD;
      On day 1, blood tests will be done.&#xD;
&#xD;
      Outpatient lab work - Day 3/7/15/30/60&#xD;
&#xD;
        -  Blood and urine tests&#xD;
&#xD;
      Onsite visit - Day 89/90&#xD;
&#xD;
        -  Medical history&#xD;
&#xD;
        -  Physical Exam&#xD;
&#xD;
        -  Blood and urine tests&#xD;
&#xD;
        -  Quantitative Muscle Testing (QMT)&#xD;
&#xD;
        -  10 Meter Walk Test&#xD;
&#xD;
        -  Gait analysis&#xD;
&#xD;
        -  Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS)&#xD;
&#xD;
        -  Muscle Biopsy: Tissue samples obtained will be used for evaluation of muscle glycogen&#xD;
           and GAA activity in the injected muscle.&#xD;
&#xD;
        -  Magnetic stimulation of the common fibular nerve&#xD;
&#xD;
      Rituximab infusion - Day 114&#xD;
&#xD;
        -  The patient will receive the 4th Rituximab infusion, it might last between 2-6 hours.&#xD;
&#xD;
           2nd Injection - Day 121/122&#xD;
&#xD;
        -  The patient will receive the second gene transfer agent injection in the leg that&#xD;
           previously received the inactive solution. The leg that previously received the study&#xD;
           agent will receive the inactive solution. The injection procedure and the amount of&#xD;
           study agent injected will be the same as the first injection.&#xD;
&#xD;
      On day 122, blood tests will be done.&#xD;
&#xD;
      Outpatient lab work - Day 124/128/135/150/180&#xD;
&#xD;
        -  Blood and urine tests&#xD;
&#xD;
      Onsite visit - Day 209/210&#xD;
&#xD;
        -  Medical History&#xD;
&#xD;
        -  Physical Exam&#xD;
&#xD;
        -  Blood and urine tests&#xD;
&#xD;
        -  Quantitative Muscle Testing (QMT)&#xD;
&#xD;
        -  10 Meter Walk Test&#xD;
&#xD;
        -  Gait analysis&#xD;
&#xD;
        -  Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS)&#xD;
&#xD;
        -  Muscle Biopsy&#xD;
&#xD;
        -  Magnetic stimulation of the common fibular nerve&#xD;
&#xD;
      Onsite visit - Day 365&#xD;
&#xD;
        -  Medical history&#xD;
&#xD;
        -  Physical exam&#xD;
&#xD;
        -  Quantitative Muscle Testing (QMT)&#xD;
&#xD;
        -  10 Meter Walk Test&#xD;
&#xD;
        -  Blood and urine tests&#xD;
&#xD;
      Onsite visit - Day 520&#xD;
&#xD;
        -  Medical history&#xD;
&#xD;
        -  Physical exam&#xD;
&#xD;
        -  Quantitative Muscle Testing (QMT)&#xD;
&#xD;
        -  10 Meter Walk Test&#xD;
&#xD;
        -  Blood and urine tests&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 17, 2017</start_date>
  <completion_date type="Actual">August 26, 2021</completion_date>
  <primary_completion_date type="Actual">August 26, 2021</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>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety of rAAV9-DES-hGAA vector in LOPD by blood and urine test.</measure>
    <time_frame>520 days</time_frame>
    <description>Safety will be tested by clinical pathology tests, blood assay for vector genomes, antibodies against GAA and T-cell ELISPOT against GAA and AAV.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Neurophysiological tests will be performed for neuro function of rAAV9-DES-hGAA vector.</measure>
    <time_frame>520 days</time_frame>
    <description>Neurophysiological tests: Surface testing of the common fibular nerve and neuromuscular junction transmission.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Muscle biopsy will be performed for muscular function of rAAV9-DES-hGAA vector.</measure>
    <time_frame>520 days</time_frame>
    <description>Muscle biopsy for biochemistry and immunochemistry tests.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical tests will be performed for function of rAAV9-DES-hGAA vector.</measure>
    <time_frame>520 days</time_frame>
    <description>Clinical tests: 10 meter walk test and muscle strength test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Magnetic Resonance Imaging will be performed for visualization of muscle with rAAV9-DES-hGAA vector.</measure>
    <time_frame>520 days</time_frame>
    <description>MRI will provide a non-invasive means of evaluating maximum cross-sectional area (CSAmax) - an index of muscle mass - and the MR proton traverse relaxation time (T2) - an index of muscle damage and edema.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Spectroscopy will be performed for function of rAAV9-DES-hGAA vector.</measure>
    <time_frame>520 days</time_frame>
    <description>MRS will provide a non-invasive means of evaluating glycogen concentration in muscle.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">2</enrollment>
  <condition>Pompe Disease</condition>
  <arm_group>
    <arm_group_label>rAAV9-DES-hGAA vector</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Each subject will receive Rituxan and Rapamycin prior to the initial exposure to the study agent in one leg and the subsequent exposure of the same vector to the contralateral leg after four months. Diphenhydramine and acetaminophen will be provided before each Rituxan dose. Immune Globulin will be administered to each subject every other month after first exposure to Rituxan and as clinical necessary. Lidocaine will be administered through percutaneous infiltration before injection of the study agent. Side of administration will be randomized at first Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase injection.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Excipient</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>Each subject will receive Rituxan and Rapamycin prior to the initial exposure to the study agent in one leg and the subsequent exposure of the same vector to the contralateral leg after four months. Diphenhydramine and acetaminophen will be provided before each Rituxan dose. Immune Globulin will be administered to each subject every other month after first exposure to Rituxan and as clinical necessary. Lidocaine will be administered through percutaneous infiltration before injection of the study agent. Side of administration will be randomized at first saline injection.</description>
  </arm_group>
  <intervention>
    <intervention_type>Genetic</intervention_type>
    <intervention_name>Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase</intervention_name>
    <description>The dose selected for this study is a fixed dose of 4.6 x 10^13 vg per TA muscle (range of 7.64 x 10^11 vg/gm to 4.6 x 10^11 vg/gm based on TA weight).</description>
    <arm_group_label>rAAV9-DES-hGAA vector</arm_group_label>
    <other_name>rAAV9-DES-hGAA</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rapamycin</intervention_name>
    <description>Patients will receive Rapamycin (dose 0.6-2 mg/m^2/day, adjusted to maintain a trough serum sirolimus level of 2-4 ng/mL.) every day starting from 7 days before first injection of AAV9 until four months after second injection.</description>
    <arm_group_label>Excipient</arm_group_label>
    <arm_group_label>rAAV9-DES-hGAA vector</arm_group_label>
    <other_name>Sirolimus</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>saline</intervention_name>
    <description>Same volume as rAAV9-DES-hGAA injection will be used.</description>
    <arm_group_label>Excipient</arm_group_label>
    <other_name>Excipient</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rituxan</intervention_name>
    <description>Patients will receive Rituxan (dose: 750 mg/m^2 twice) 21 and 7 day prior first AAV9 injection, with a Rituxan dose 375 mg/m^2 on the day of the injection. Rituxan will be repeated 7 days prior to the 2nd injection of the vector. The maintenance dose of Rituxan will be 375 mg/m^2.</description>
    <arm_group_label>Excipient</arm_group_label>
    <arm_group_label>rAAV9-DES-hGAA vector</arm_group_label>
    <other_name>Rituximab</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Diphenhydramine</intervention_name>
    <description>25-50mg will be provided before each Rituximab dose.</description>
    <arm_group_label>Excipient</arm_group_label>
    <arm_group_label>rAAV9-DES-hGAA vector</arm_group_label>
    <other_name>Benadryl</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Acetaminophen</intervention_name>
    <description>We will provide 650 mg of tylenol before each dose of Rituximab.</description>
    <arm_group_label>Excipient</arm_group_label>
    <arm_group_label>rAAV9-DES-hGAA vector</arm_group_label>
    <other_name>Tylenol</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lidocaine</intervention_name>
    <description>Lidocaine will be used based on standard of care: Percutaneous infiltration, concentration 0.5-1%, 1-10 mL, 5-300mg total dose.</description>
    <arm_group_label>Excipient</arm_group_label>
    <arm_group_label>rAAV9-DES-hGAA vector</arm_group_label>
    <other_name>Xylocaine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>LMX 4 Topical Cream</intervention_name>
    <description>Topical anesthesia cream will be used prior to gene therapy/saline injection.</description>
    <arm_group_label>Excipient</arm_group_label>
    <arm_group_label>rAAV9-DES-hGAA vector</arm_group_label>
    <other_name>Lidocaine 4%</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or female subjects 18 to 50-years old&#xD;
&#xD;
          -  Have a diagnosis of Pompe disease, as defined by protein assay AND/OR DNA sequence of&#xD;
             the acid alpha-glucosidase gene, AND clinical symptoms of the disease&#xD;
&#xD;
          -  Have residual ability to complete the 10 meter walk test&#xD;
&#xD;
          -  Willing to discontinue aspirin, aspirin-containing products and other drugs that may&#xD;
             alter platelet function, 7 days prior to dosing, resuming 24 hours after the dose has&#xD;
             been administered&#xD;
&#xD;
          -  Consistently taking enzyme replacement therapy (ERT) or remain off ERT from baseline&#xD;
             until Day 520&#xD;
&#xD;
          -  United States residents only.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Be pregnant or nursing, and if the subject is of child bearing potential they should&#xD;
             use contraception until the end of the study&#xD;
&#xD;
          -  Have required oral or systemic corticosteroids within the last 15 days prior to&#xD;
             baseline screening&#xD;
&#xD;
          -  Have a platelet count less than 75,000/mm^3&#xD;
&#xD;
          -  Have an INR greater than 1.3&#xD;
&#xD;
          -  Have seronegative to AAV9 capsid protein (neutralizing Ab titers &lt;1:5 and total&#xD;
             binding Ab titer &lt;50 U/ml)&#xD;
&#xD;
          -  Have transaminases and alkaline phosphatase more than ten times the upper limit of&#xD;
             normal at screening or Day-1&#xD;
&#xD;
          -  Have bilirubin and gamma-glutamyl transpeptidase greater than 2 times the upper limit&#xD;
             of normal at screening or Day -1&#xD;
&#xD;
          -  Have any chronic liver disease (aside from hepatic dysfunction related to Pompe&#xD;
             disease) such as hepatitis B and C and cirrhosis&#xD;
&#xD;
          -  Be currently, or within the past 30 days, participating in any other research protocol&#xD;
             involving investigational agents or therapies&#xD;
&#xD;
          -  Have history of platelet dysfunction, evidence of abnormal platelet function at&#xD;
             screening, or history of recent use of drugs that may alter platelet function, which&#xD;
             the subject is unable/unwilling to discontinue for study agent administration&#xD;
&#xD;
          -  Have received gene transfer agents within the past 6 months&#xD;
&#xD;
          -  Have any medical condition or circumstance for which an MRI evaluation is&#xD;
             contraindicated&#xD;
&#xD;
          -  Have any other concurrent condition that, in the opinion of the investigator, would&#xD;
             make the subject unsuitable for the study&#xD;
&#xD;
          -  Inconsistent with use of ERT.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Manuela Corti, P.T., PhD.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Florida</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Clinical and Translational Research Building (CTRB), University of Florida</name>
      <address>
        <city>Gainesville</city>
        <state>Florida</state>
        <zip>32610</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
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    <citation>Corti M, Smith BK, Falk DJ, Lawson LA, Fuller DD, Subramony SH, Byrne BJ, Christou EA. Altered activation of the tibialis anterior in individuals with Pompe disease: Implications for motor unit dysfunction. Muscle Nerve. 2015 Jun;51(6):877-83. doi: 10.1002/mus.24444. Epub 2015 Apr 24.</citation>
    <PMID>25186912</PMID>
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    <citation>Mah C, Pacak CA, Cresawn KO, Deruisseau LR, Germain S, Lewis MA, Cloutier DA, Fuller DD, Byrne BJ. Physiological correction of Pompe disease by systemic delivery of adeno-associated virus serotype 1 vectors. Mol Ther. 2007 Mar;15(3):501-7. doi: 10.1038/sj.mt.6300100. Epub 2007 Jan 23.</citation>
    <PMID>17245350</PMID>
  </reference>
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    <citation>Pacak CA, Conlon T, Mah CS, Byrne BJ. Relative persistence of AAV serotype 1 vector genomes in dystrophic muscle. Genet Vaccines Ther. 2008 Oct 15;6:14. doi: 10.1186/1479-0556-6-14.</citation>
    <PMID>18854054</PMID>
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    <citation>Spencer CT, Bryant RM, Day J, Gonzalez IL, Colan SD, Thompson WR, Berthy J, Redfearn SP, Byrne BJ. Cardiac and clinical phenotype in Barth syndrome. Pediatrics. 2006 Aug;118(2):e337-46. doi: 10.1542/peds.2005-2667. Epub 2006 Jul 17.</citation>
    <PMID>16847078</PMID>
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    <citation>Smith BK, Collins SW, Conlon TJ, Mah CS, Lawson LA, Martin AD, Fuller DD, Cleaver BD, Clement N, Phillips D, Islam S, Dobjia N, Byrne BJ. Phase I/II trial of adeno-associated virus-mediated alpha-glucosidase gene therapy to the diaphragm for chronic respiratory failure in Pompe disease: initial safety and ventilatory outcomes. Hum Gene Ther. 2013 Jun;24(6):630-40. doi: 10.1089/hum.2012.250.</citation>
    <PMID>23570273</PMID>
  </reference>
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    <citation>Smith BK, Martin AD, Lawson LA, Vernot V, Marcus J, Islam S, Shafi N, Corti M, Collins SW, Byrne BJ. Inspiratory muscle conditioning exercise and diaphragm gene therapy in Pompe disease: Clinical evidence of respiratory plasticity. Exp Neurol. 2017 Jan;287(Pt 2):216-224. doi: 10.1016/j.expneurol.2016.07.013. Epub 2016 Jul 21.</citation>
    <PMID>27453480</PMID>
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    <citation>Corti M, Elder M, Falk D, Lawson L, Smith B, Nayak S, Conlon T, Clement N, Erger K, Lavassani E, Green M, Doerfler P, Herzog R, Byrne B. B-Cell Depletion is Protective Against Anti-AAV Capsid Immune Response: A Human Subject Case Study. Mol Ther Methods Clin Dev. 2014;1:14033-. doi: 10.1038/mtm.2014.33.</citation>
    <PMID>25541616</PMID>
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    <citation>Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, Linch DC, Chowdary P, Riddell A, Pie AJ, Harrington C, O'Beirne J, Smith K, Pasi J, Glader B, Rustagi P, Ng CY, Kay MA, Zhou J, Spence Y, Morton CL, Allay J, Coleman J, Sleep S, Cunningham JM, Srivastava D, Basner-Tschakarjan E, Mingozzi F, High KA, Gray JT, Reiss UM, Nienhuis AW, Davidoff AM. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med. 2011 Dec 22;365(25):2357-65. doi: 10.1056/NEJMoa1108046. Epub 2011 Dec 10.</citation>
    <PMID>22149959</PMID>
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    <PMID>26390092</PMID>
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    <PMID>16122966</PMID>
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    <citation>Barker SP, Freedman W, Hillstrom H. A novel method of producing a repetitive dynamic signal to examine reliability and validity of gait analysis systems. Gait Posture. 2006 Dec;24(4):448-52. doi: 10.1016/j.gaitpost.2005.09.008. Epub 2006 Jan 18.</citation>
    <PMID>16413189</PMID>
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    <citation>Wary C, Laforet P, Eymard B, Fardeau M, Leroy-Willig A, Bassez G, Leroy JP, Caillaud C, Poenaru L, Carlier PG. Evaluation of muscle glycogen content by 13C NMR spectroscopy in adult-onset acid maltase deficiency. Neuromuscul Disord. 2003 Sep;13(7-8):545-53. doi: 10.1016/s0960-8966(03)00069-5.</citation>
    <PMID>12921791</PMID>
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    <citation>Marden FA, Connolly AM, Siegel MJ, Rubin DA. Compositional analysis of muscle in boys with Duchenne muscular dystrophy using MR imaging. Skeletal Radiol. 2005 Mar;34(3):140-8. doi: 10.1007/s00256-004-0825-3. Epub 2004 Oct 22.</citation>
    <PMID>15538561</PMID>
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    <citation>Harris RC, Hultman E, Nordesjo LO. Glycogen, glycolytic intermediates and high-energy phosphates determined in biopsy samples of musculus quadriceps femoris of man at rest. Methods and variance of values. Scand J Clin Lab Invest. 1974 Apr;33(2):109-20. No abstract available.</citation>
    <PMID>4852173</PMID>
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    <citation>Clark BC, Cook SB, Ploutz-Snyder LL. Reliability of techniques to assess human neuromuscular function in vivo. J Electromyogr Kinesiol. 2007 Feb;17(1):90-101. doi: 10.1016/j.jelekin.2005.11.008. Epub 2006 Jan 19.</citation>
    <PMID>16427317</PMID>
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    <citation>Stalberg E, Trontelj JV. The study of normal and abnormal neuromuscular transmission with single fibre electromyography. J Neurosci Methods. 1997 Jun 27;74(2):145-54. doi: 10.1016/s0165-0270(97)02245-0.</citation>
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  <verification_date>March 2022</verification_date>
  <study_first_submitted>September 11, 2014</study_first_submitted>
  <study_first_submitted_qc>September 12, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 15, 2014</study_first_posted>
  <last_update_submitted>March 24, 2022</last_update_submitted>
  <last_update_submitted_qc>March 24, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 5, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Pompe Disease</keyword>
  <keyword>Gene Therapy</keyword>
  <keyword>Repeated dosing</keyword>
  <keyword>Immune modulation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glycogen Storage Disease Type II</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acetaminophen</mesh_term>
    <mesh_term>Diphenhydramine</mesh_term>
    <mesh_term>Promethazine</mesh_term>
    <mesh_term>Sirolimus</mesh_term>
    <mesh_term>Rituximab</mesh_term>
    <mesh_term>Lidocaine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT02240407
org study id: IRB201400137
secondary id: 20182574
nct id: NCT02240407
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
A recombinant AAV vector has been generated to carry the codon-optimized acid
      alpha-glucosidase (coGAA) gene expressed from a human desmin enhancer/promoter (DES). The
      proposed clinical trial is a within-participant, double-blind, randomized, phase I controlled
      study evaluating the toxicology, biodistribution and potential activity of re-administration
      of rAAV9-DES-hGAA injected intramuscularly into the TA. Nine participants (18 to 50-years
      old) who reside within the United States with Late-Onset Pompe Disease (LOPD) will be
      included. The goal of the immune modulation strategy is to ablate B-cells (Rituximab and
      Sirolimus) prior to the initial exposure to the study agent in one leg and the subsequent
      exposure of the same vector to the contralateral leg after four months. At each study agent
      dosing, the contralateral leg will receive excipient. Patients will act as their own
      controls. Repeated measures, at baseline and during the following 3 months after each
      injection, will assess the safety, biochemical and functional impact of the vector.
Enrolling in this study will entail participating in 18 months of study-related visits.
      Patients will be asked to come to the Clinical and Translational Research Building at the
      University of Florida for a series of onsite study visits.

      All the visits will be performed as outpatient procedures at the Clinical Research Center
      (CRC) and at other facilities at the University of Florida. Overnight observation will not be
      needed, however, patients will be asked to stay overnight in a hotel near the University of
      Florida. During the first 4 months after each injection, patients will be asked to perform
      outpatient laboratory work at a laboratory facility convenient for them.

      In addition, during this study patients will be asked to take medications that will modulate
      the ability of their immune system to react against foreign agents including the gene
      transfer agent. The purpose of these medications is to improve the activity of the GAA within
      the body. Patients will receive a Rituximab injection 21 days prior to the first injection of
      the study agent and 7 days before each injection of the study agent and the day of the first
      injection. Rituximab will be delivered by infusion that may last 2-6 hours. Patients will
      need to take another medication (Sirolimus) every day starting 7 days before the first
      injection of the study agent until four months after the second injection of the study agent.

      The following discusses what will occur at each visit:

      Baseline Baseline Evaluation and first Rituximab infusion - Day -22/-21/-20

        -  Medical history: Patients will be asked to complete a questionnaire about his/her
           medical history.

        -  Physical exam: The study doctor will perform a general physical exam to evaluate
           patients physical health.

        -  Blood and urine tests: These tests will be used for evaluating the safety of the gene
           transfer agent.

        -  Electrocardiogram (ECG): This test will measure the electrical activity of patient's
           heart to see if it is working properly.

        -  Quantitative Muscle Testing (QMT): This test finds out how strong the patient's leg
           muscles are.

        -  10 Meter Walk Test: Patients will be instructed to walk a set distance (10 meters); time
           will be measured while patient walks the set distance and the distance covered will be
           divided by the time it took to walk that distance.

        -  Gait analysis: Gait will be tested with Gait Mat II, which will record the spatial and
           temporal parameters of his/her walk such as cadence, speed and distance between your
           feet.

        -  Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS): MRI and MRS testing will be
           done inside a large magnet that lets the study doctors measure the size and health of
           the patient's muscles. These tests are done at the same time. MRI and MRS testing will
           require the patient to stay very still for up to an hour.

        -  Magnetic stimulation of the common fibular nerve: The common fibular nerve, which is the
           nerve that controls the injected muscle, will be stimulated with a magnetic field to
           test the impact of the gene transfer agent to the nervous system.

        -  The patient will receive the first Rituximab infusion. It might last between 2 and 6
           hours.

      Rituximab infusion - Day -6

        -  The patient will receive the 2nd Rituximab infusion 7 days before the gene transfer
           agent. It might last between 2 and 6 hours.

        -  Patient will begin Rapamycin.

           1st Injection - Day 0/1

        -  The patient will receive the 3rd Rituximab infusion the day before the gene transfer
           agent. It might last between 2 and 6 hours.

        -  Patient will receive the gene transfer agent in 1 injection (a total of about 1
           teaspoon) into the tibialis anterior (TA) muscle of one leg. The other leg will receive
           a pharmacologically inactive solution. An ultrasound will be used to detect the proper
           location of injection. A photograph of the injection at the injection site may be taken.
           If the patient agrees to this, he/she will be asked to sign a consent form for this
           procedure.

      On day 1, blood tests will be done.

      Outpatient lab work - Day 3/7/15/30/60

        -  Blood and urine tests

      Onsite visit - Day 89/90

        -  Medical history

        -  Physical Exam

        -  Blood and urine tests

        -  Quantitative Muscle Testing (QMT)

        -  10 Meter Walk Test

        -  Gait analysis

        -  Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS)

        -  Muscle Biopsy: Tissue samples obtained will be used for evaluation of muscle glycogen
           and GAA activity in the injected muscle.

        -  Magnetic stimulation of the common fibular nerve

      Rituximab infusion - Day 114

        -  The patient will receive the 4th Rituximab infusion, it might last between 2-6 hours.

           2nd Injection - Day 121/122

        -  The patient will receive the second gene transfer agent injection in the leg that
           previously received the inactive solution. The leg that previously received the study
           agent will receive the inactive solution. The injection procedure and the amount of
           study agent injected will be the same as the first injection.

      On day 122, blood tests will be done.

      Outpatient lab work - Day 124/128/135/150/180

        -  Blood and urine tests

      Onsite visit - Day 209/210

        -  Medical History

        -  Physical Exam

        -  Blood and urine tests

        -  Quantitative Muscle Testing (QMT)

        -  10 Meter Walk Test

        -  Gait analysis

        -  Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS)

        -  Muscle Biopsy

        -  Magnetic stimulation of the common fibular nerve

      Onsite visit - Day 365

        -  Medical history

        -  Physical exam

        -  Quantitative Muscle Testing (QMT)

        -  10 Meter Walk Test

        -  Blood and urine tests

      Onsite visit - Day 520

        -  Medical history

        -  Physical exam

        -  Quantitative Muscle Testing (QMT)

        -  10 Meter Walk Test

        -  Blood and urine tests
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Safety of rAAV9-DES-hGAA vector in LOPD by blood and urine test.
time frame: 520 days
description: Safety will be tested by clinical pathology tests, blood assay for vector genomes, antibodies against GAA and T-cell ELISPOT against GAA and AAV.
measure: Neurophysiological tests will be performed for neuro function of rAAV9-DES-hGAA vector.
time frame: 520 days
description: Neurophysiological tests: Surface testing of the common fibular nerve and neuromuscular junction transmission.
measure: Muscle biopsy will be performed for muscular function of rAAV9-DES-hGAA vector.
time frame: 520 days
description: Muscle biopsy for biochemistry and immunochemistry tests.
measure: Clinical tests will be performed for function of rAAV9-DES-hGAA vector.
time frame: 520 days
description: Clinical tests: 10 meter walk test and muscle strength test.
measure: Magnetic Resonance Imaging will be performed for visualization of muscle with rAAV9-DES-hGAA vector.
time frame: 520 days
description: MRI will provide a non-invasive means of evaluating maximum cross-sectional area (CSAmax) - an index of muscle mass - and the MR proton traverse relaxation time (T2) - an index of muscle damage and edema.
measure: Spectroscopy will be performed for function of rAAV9-DES-hGAA vector.
time frame: 520 days
description: MRS will provide a non-invasive means of evaluating glycogen concentration in muscle.
arm group label: rAAV9-DES-hGAA vector
arm group type: Experimental
description: Each subject will receive Rituxan and Rapamycin prior to the initial exposure to the study agent in one leg and the subsequent exposure of the same vector to the contralateral leg after four months. Diphenhydramine and acetaminophen will be provided before each Rituxan dose. Immune Globulin will be administered to each subject every other month after first exposure to Rituxan and as clinical necessary. Lidocaine will be administered through percutaneous infiltration before injection of the study agent. Side of administration will be randomized at first Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase injection.
arm group label: Excipient
arm group type: Sham Comparator
description: Each subject will receive Rituxan and Rapamycin prior to the initial exposure to the study agent in one leg and the subsequent exposure of the same vector to the contralateral leg after four months. Diphenhydramine and acetaminophen will be provided before each Rituxan dose. Immune Globulin will be administered to each subject every other month after first exposure to Rituxan and as clinical necessary. Lidocaine will be administered through percutaneous infiltration before injection of the study agent. Side of administration will be randomized at first saline injection.
intervention type: Genetic
intervention name: Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase
description: The dose selected for this study is a fixed dose of 4.6 x 10^13 vg per TA muscle (range of 7.64 x 10^11 vg/gm to 4.6 x 10^11 vg/gm based on TA weight).
arm group label: rAAV9-DES-hGAA vector
other name: rAAV9-DES-hGAA
intervention type: Drug
intervention name: Rapamycin
description: Patients will receive Rapamycin (dose 0.6-2 mg/m^2/day, adjusted to maintain a trough serum sirolimus level of 2-4 ng/mL.) every day starting from 7 days before first injection of AAV9 until four months after second injection.
arm group label: Excipient
arm group label: rAAV9-DES-hGAA vector
other name: Sirolimus
intervention type: Other
intervention name: saline
description: Same volume as rAAV9-DES-hGAA injection will be used.
arm group label: Excipient
other name: Excipient
intervention type: Drug
intervention name: Rituxan
description: Patients will receive Rituxan (dose: 750 mg/m^2 twice) 21 and 7 day prior first AAV9 injection, with a Rituxan dose 375 mg/m^2 on the day of the injection. Rituxan will be repeated 7 days prior to the 2nd injection of the vector. The maintenance dose of Rituxan will be 375 mg/m^2.
arm group label: Excipient
arm group label: rAAV9-DES-hGAA vector
other name: Rituximab
intervention type: Drug
intervention name: Diphenhydramine
description: 25-50mg will be provided before each Rituximab dose.
arm group label: Excipient
arm group label: rAAV9-DES-hGAA vector
other name: Benadryl
intervention type: Drug
intervention name: Acetaminophen
description: We will provide 650 mg of tylenol before each dose of Rituximab.
arm group label: Excipient
arm group label: rAAV9-DES-hGAA vector
other name: Tylenol
intervention type: Drug
intervention name: Lidocaine
description: Lidocaine will be used based on standard of care: Percutaneous infiltration, concentration 0.5-1%, 1-10 mL, 5-300mg total dose.
arm group label: Excipient
arm group label: rAAV9-DES-hGAA vector
other name: Xylocaine
intervention type: Drug
intervention name: LMX 4 Topical Cream
description: Topical anesthesia cream will be used prior to gene therapy/saline injection.
arm group label: Excipient
arm group label: rAAV9-DES-hGAA vector
other name: Lidocaine 4%
criteria: 
gender: All
minimum age: 18 Years
maximum age: 50 Years
healthy volunteers: No
last name: Manuela Corti, P.T., PhD.
role: Principal Investigator
affiliation: University of Florida
facility: 
country: United States
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responsible party type: Sponsor
mesh term: Glycogen Storage Disease Type II
mesh term: Acetaminophen
mesh term: Diphenhydramine
mesh term: Promethazine
mesh term: Sirolimus
mesh term: Rituximab
mesh term: Lidocaine
sharing ipd: Undecided