<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/NCT04432623</url>
  </required_header>
  <id_info>
    <org_study_id>PB04-001</org_study_id>
    <secondary_id>R33HL147845</secondary_id>
    <nct_id>NCT04432623</nct_id>
  </id_info>
  <brief_title>The BENeFiTS Trial in Beta Thalassemia Intermedia</brief_title>
  <acronym>PB04-001</acronym>
  <official_title>A Phase 1b Sequential Open Label Dose-Ranging Study of Safety, Pharmacokinetics, and Preliminary Activity of Benserazide in Subjects With Beta Thalassemia Intermedia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Phoenicia BioScience</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Heart, Lung, and Blood Institute (NHLBI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Phoenicia BioScience</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>
      Beta-thalassemias and hemoglobinopathies are serious inherited blood diseases caused by&#xD;
      abnormal or deficiency of beta A chains of hemoglobin, the protein in red blood cells which&#xD;
      delivers oxygen throughout the body.The diseases are characterized by hemolytic anemia, organ&#xD;
      damage, and early mortality without treatment. Increases in another type of (normal)&#xD;
      hemoglobin, fetal globin (HbF), which is normally silenced in infancy, reduces anemia and&#xD;
      morbidity. Even incremental augmentation of fetal globin is established to reduce red blood&#xD;
      cell pathology, anemia, certain complications, and to improve survival.&#xD;
&#xD;
      This trial will evaluate an oral drug discovered in a high throughput screen, which increases&#xD;
      fetal globin protein (HbF and red blood cells expressing HbF)and messenger ribonucleic acid&#xD;
      (mRNA) to high levels in anemic nonhuman primates and in transgenic mice. The study drug acts&#xD;
      by suppressing 4 repressors of the fetal globin gene promoter in progenitor cells from&#xD;
      patients. The drug has been used for 50 years in a combination product for different actions&#xD;
      - to enhance half-life and reduce side effects of a different active drug- and is considered&#xD;
      safe for long-term use.&#xD;
&#xD;
      This trial will first evaluate 3 dose levels in small cohorts of nontransfused patients with&#xD;
      beta thalassemia intermedia. The most active dose will then be evaluated in larger subject&#xD;
      groups with beta thalassemia and other hemoglobinopathies, such as sickle cell disease.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study will first evaluate 3 doses of the investigational drug which are considered safe&#xD;
      with chronic use in a combination therapeutic used widely for a different disease in Europe&#xD;
      and Canada. The doses to be studied are human equivalent doses of doses that are active in&#xD;
      nonhuman primates in inducing high level fetal globin messenger ribonucleic acid (mRNA),&#xD;
      protein, and proportions of red blood cells expressing fetal globin protein (F-cells).&#xD;
      Additive effects are observed with hydroxyurea in sickle cell patients' cells in vitro.&#xD;
&#xD;
      The study will first evaluate the study therapeutic in male and female patients who are 18&#xD;
      years and older. After a screening period to obtain baseline medical and laboratory data, the&#xD;
      study drug will be taken by mouth once per day, every other day. The first dose will be taken&#xD;
      in a clinical unit, and thereafter will be taken at home for 12 weeks. Laboratory tests,&#xD;
      physical exams, and tolerability will be assessed 6 times over 4 months, including for one&#xD;
      month after completion of dosing.&#xD;
&#xD;
      The cohorts will be enrolled sequentially. Each new cohort will begin after the prior lower&#xD;
      dose cohort has received 2 weeks of treatment without serious adverse events related to the&#xD;
      study drug. The dose that increases fetal globin assays to the highest degree will be&#xD;
      evaluated in a larger group of subjects.Other regimens or test doses may be added as needed&#xD;
      to identify an active dose and regimen. The study drug is expected to be safe when added to&#xD;
      most other medications used to treat thalassemia.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">October 5, 2020</start_date>
  <completion_date type="Anticipated">December 2023</completion_date>
  <primary_completion_date type="Anticipated">December 2023</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <intervention_model_description>Each higher dose level cohort will be enrolled after 2 weeks of treatment in the lower dose level. Additional doses or regimens may be added. Expansion cohorts at the most active dose will be evaluated.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety and Tolerability</measure>
    <time_frame>12 to 24 weeks</time_frame>
    <description>Number of participants with treatment-related adverse events as assessed by CTCAE v4.0</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum plasma concentration (Cmax)</measure>
    <time_frame>4 weeks</time_frame>
    <description>drug concentration (ng/ml)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Minimum plasma drug concentration (Cmin)</measure>
    <time_frame>4 weeks</time_frame>
    <description>Minimum drug plasma concentration, (ng/ml)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Plasma drug concentration over time</measure>
    <time_frame>4 weeks</time_frame>
    <description>area under the curve</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>F-cells</measure>
    <time_frame>12 to 24 weeks</time_frame>
    <description>% Red blood cells containing HbF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>HbF protein per cell</measure>
    <time_frame>12 to 24 weeks</time_frame>
    <description>Mean fluorescent intensity (MFI)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fetal hemoglobin (HbF)</measure>
    <time_frame>12 to 24 weeks</time_frame>
    <description>% and absolute (g/dl)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hemoglobin</measure>
    <time_frame>16 to 24 weeks</time_frame>
    <description>gram/dl</description>
  </secondary_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Anticipated">36</enrollment>
  <condition>Beta Thalassemia Intermedia</condition>
  <condition>Sickle Cell Disease</condition>
  <arm_group>
    <arm_group_label>Low dose</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>A low dose, by mouth, once per day, on Monday, Wednesday, and Friday for 12 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Middle dose</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>A middle dose, by mouth, once per day, on Monday, Wednesday, and Friday, for 12 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>High dose 3 days per week</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Highest dose, by mouth, once per day, on Monday, Wednesday, and Friday, for 12 to 24 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>High dose 5 days per week</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The highest dose, by mouth once per day on 5 days per week for 24 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sickle Cell Disease Arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The most active dose given once per day on the most active regimen for up 24 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Benserazide Only Product</intervention_name>
    <description>Investigational drug</description>
    <arm_group_label>High dose 3 days per week</arm_group_label>
    <arm_group_label>High dose 5 days per week</arm_group_label>
    <arm_group_label>Low dose</arm_group_label>
    <arm_group_label>Middle dose</arm_group_label>
    <arm_group_label>Sickle Cell Disease Arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Beta thalassemia intermedia (BTI) or (NTDT, Non-Transfusion Dependent Thalassemia)&#xD;
             with at least one documented beta thalassemia mutation, including HbE beta thalassemia&#xD;
&#xD;
          -  &gt;18 years of age at time of consent&#xD;
&#xD;
          -  Average of 2 total hemoglobin (Hgb) levels between 6.0 and 10.0 g/dL in the preceding&#xD;
             6 months&#xD;
&#xD;
          -  Able and willing to give consent and comply with all study procedures&#xD;
&#xD;
          -  If female and of childbearing potential, must have a documented negative pregnancy&#xD;
             test prior to entry and agree to use one or more locally medically accepted methods of&#xD;
             contraception&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Red blood cell (RBC) transfusion within 2 months prior to administration of study&#xD;
             medication&#xD;
&#xD;
          -  Participating in a chronic transfusion program&#xD;
&#xD;
          -  Pulmonary hypertension requiring oxygen therapy&#xD;
&#xD;
          -  Use of erythropoiesis stimulating agents within 90 days of first dose&#xD;
&#xD;
          -  Transaminases &gt; 3 times upper limit of institution normal (ULN)&#xD;
&#xD;
          -  Total and direct bilirubin &gt; 3 times institution ULN unless due solely to hemolysis&#xD;
&#xD;
          -  Known infection with HIV or hepatitis C (untreated)&#xD;
&#xD;
          -  Fever &gt; 38.5°C in the week prior to first administration of study medication&#xD;
&#xD;
          -  History of osteoporosis or osteomalacia with a fragility fracture&#xD;
&#xD;
          -  Received other investigational systemic therapy within 30 days prior to first dose&#xD;
&#xD;
          -  Narrow angle glaucoma&#xD;
&#xD;
          -  Currently pregnant or breast feeding a child&#xD;
&#xD;
          -  Known current drug or alcohol abuse&#xD;
&#xD;
          -  Taking monoamine oxidase inhibitors&#xD;
&#xD;
          -  Other co-morbidity that substantially increases subject risk for the study per&#xD;
             Investigator discretion&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Susan Perrine, MD</last_name>
    <role>Study Director</role>
    <affiliation>Phoenicia BioScience</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Kevin Kuo, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Health Network, Toronto General Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Sylvia Singer, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>UCSF Benioff Children's Hospital at Oakland</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Hanny D Al-Samkari, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Massachusetts General Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Sujit Sheth, MD MS</last_name>
    <role>Principal Investigator</role>
    <affiliation>Weill Medical College of Cornell University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Susan Perrine, MD</last_name>
    <phone>617 335-7002</phone>
    <email>sperrine@bu.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Melissa Askin, RN</last_name>
    <phone>410 231-1512</phone>
    <email>Melissa.Askin@acroclinical.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>UCSF Benioff Children's Hospital at Oakland</name>
      <address>
        <city>Oakland</city>
        <state>California</state>
        <zip>94609</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sylvia Singer, MD</last_name>
      <phone>510-428-3169</phone>
      <email>Sylvia.Singer@UCSF.edu</email>
    </contact>
    <contact_backup>
      <last_name>Diego Martinez Mendiola, BA</last_name>
      <phone>510- 428-3885</phone>
      <phone_ext>5361</phone_ext>
      <email>Diego.martinezmendiola@UCSF.edu</email>
    </contact_backup>
    <investigator>
      <last_name>Ashtosh Lal, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Elliott P Vichinsky, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Hanny Al-Samkari, MD</last_name>
      <phone>617-643-6214</phone>
      <email>hal-samkari@mgh.harvard.edu</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Susan Perrine</name>
      <address>
        <city>Weston</city>
        <state>Massachusetts</state>
        <zip>02493</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Susan Perrine, MD</last_name>
      <phone>617-335-7002</phone>
      <email>Sperrine@bu.edu</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Weil Cornell Medicine</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sujit Sheth, MD</last_name>
      <phone>212-746-3400</phone>
      <email>shethsu@med.cornell.edu</email>
    </contact>
    <investigator>
      <last_name>Sujit Sheth, MD,MS</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University Health Network and Toronto General Hospital</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G2C4</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kevin Kuo, MD</last_name>
      <phone>416 340-4800</phone>
      <phone_ext>6729</phone_ext>
      <email>Kevin.Kuo@uhn.ca</email>
    </contact>
    <contact_backup>
      <last_name>RBCD Trial Info Cellphone</last_name>
      <phone>437 929-5158</phone>
      <email>rbcd.clinicaltrials@uhn.ca</email>
    </contact_backup>
    <investigator>
      <last_name>Jacob Prendergast, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Canada</country>
    <country>United States</country>
  </location_countries>
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  </reference>
  <reference>
    <citation>Perrine SP, Pace BS, Faller DV. Targeted fetal hemoglobin induction for treatment of beta hemoglobinopathies. Hematol Oncol Clin North Am. 2014 Apr;28(2):233-48. doi: 10.1016/j.hoc.2013.11.009.</citation>
    <PMID>24589264</PMID>
  </reference>
  <reference>
    <citation>Steinberg MH, Rodgers GP. Pharmacologic modulation of fetal hemoglobin. Medicine (Baltimore). 2001 Sep;80(5):328-44. doi: 10.1097/00005792-200109000-00007. No abstract available.</citation>
    <PMID>11552087</PMID>
  </reference>
  <reference>
    <citation>Weatherall DJ. The inherited diseases of hemoglobin are an emerging global health burden. Blood. 2010 Jun 3;115(22):4331-6. doi: 10.1182/blood-2010-01-251348. Epub 2010 Mar 16.</citation>
    <PMID>20233970</PMID>
  </reference>
  <reference>
    <citation>Taher AT, Cappellini MD. How I manage medical complications of beta-thalassemia in adults. Blood. 2018 Oct 25;132(17):1781-1791. doi: 10.1182/blood-2018-06-818187. Epub 2018 Sep 11.</citation>
    <PMID>30206117</PMID>
  </reference>
  <reference>
    <citation>Borgna-Pignatti C. Modern treatment of thalassaemia intermedia. Br J Haematol. 2007 Aug;138(3):291-304. doi: 10.1111/j.1365-2141.2007.06654.x. Epub 2007 Jun 12.</citation>
    <PMID>17565568</PMID>
  </reference>
  <reference>
    <citation>Sripichai O, Makarasara W, Munkongdee T, Kumkhaek C, Nuchprayoon I, Chuansumrit A, Chuncharunee S, Chantrakoon N, Boonmongkol P, Winichagoon P, Fucharoen S. A scoring system for the classification of beta-thalassemia/Hb E disease severity. Am J Hematol. 2008 Jun;83(6):482-4. doi: 10.1002/ajh.21130.</citation>
    <PMID>18186524</PMID>
  </reference>
  <reference>
    <citation>Nuinoon M, Makarasara W, Mushiroda T, Setianingsih I, Wahidiyat PA, Sripichai O, Kumasaka N, Takahashi A, Svasti S, Munkongdee T, Mahasirimongkol S, Peerapittayamongkol C, Viprakasit V, Kamatani N, Winichagoon P, Kubo M, Nakamura Y, Fucharoen S. A genome-wide association identified the common genetic variants influence disease severity in beta0-thalassemia/hemoglobin E. Hum Genet. 2010 Mar;127(3):303-14. doi: 10.1007/s00439-009-0770-2.</citation>
    <PMID>20183929</PMID>
  </reference>
  <reference>
    <citation>Uda M, Galanello R, Sanna S, Lettre G, Sankaran VG, Chen W, Usala G, Busonero F, Maschio A, Albai G, Piras MG, Sestu N, Lai S, Dei M, Mulas A, Crisponi L, Naitza S, Asunis I, Deiana M, Nagaraja R, Perseu L, Satta S, Cipollina MD, Sollaino C, Moi P, Hirschhorn JN, Orkin SH, Abecasis GR, Schlessinger D, Cao A. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia. Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1620-5. doi: 10.1073/pnas.0711566105. Epub 2008 Feb 1.</citation>
    <PMID>18245381</PMID>
  </reference>
  <reference>
    <citation>Labie D, Pagnier J, Lapoumeroulie C, Rouabhi F, Dunda-Belkhodja O, Chardin P, Beldjord C, Wajcman H, Fabry ME, Nagel RL. Common haplotype dependency of high G gamma-globin gene expression and high Hb F levels in beta-thalassemia and sickle cell anemia patients. Proc Natl Acad Sci U S A. 1985 Apr;82(7):2111-4. doi: 10.1073/pnas.82.7.2111.</citation>
    <PMID>2580306</PMID>
  </reference>
  <reference>
    <citation>Silva M, Grillot D, Benito A, Richard C, Nunez G, Fernandez-Luna JL. Erythropoietin can promote erythroid progenitor survival by repressing apoptosis through Bcl-XL and Bcl-2. Blood. 1996 Sep 1;88(5):1576-82.</citation>
    <PMID>8781412</PMID>
  </reference>
  <reference>
    <citation>Pootrakul P, Sirankapracha P, Hemsorach S, Moungsub W, Kumbunlue R, Piangitjagum A, Wasi P, Ma L, Schrier SL. A correlation of erythrokinetics, ineffective erythropoiesis, and erythroid precursor apoptosis in thai patients with thalassemia. Blood. 2000 Oct 1;96(7):2606-12.</citation>
    <PMID>11001918</PMID>
  </reference>
  <reference>
    <citation>Singer ST, Vichinsky EP, Sweeters N, Rachmilewitz E. Darbepoetin alfa for the treatment of anaemia in alpha- or beta- thalassaemia intermedia syndromes. Br J Haematol. 2011 Jul;154(2):281-4. doi: 10.1111/j.1365-2141.2011.08617.x. Epub 2011 Apr 18. No abstract available.</citation>
    <PMID>21496003</PMID>
  </reference>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>June 9, 2020</study_first_submitted>
  <study_first_submitted_qc>June 11, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 16, 2020</study_first_posted>
  <last_update_submitted>April 9, 2022</last_update_submitted>
  <last_update_submitted_qc>April 9, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 15, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Non-transfusion dependent beta thalassemia</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anemia, Sickle Cell</mesh_term>
    <mesh_term>Thalassemia</mesh_term>
    <mesh_term>beta-Thalassemia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Benserazide</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Results will be provided in abstracts as the study is being conducted and in a publication after completion and analysis.</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/NCT04432623
org study id: PB04-001
secondary id: R33HL147845
nct id: NCT04432623
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Beta-thalassemias and hemoglobinopathies are serious inherited blood diseases caused by
      abnormal or deficiency of beta A chains of hemoglobin, the protein in red blood cells which
      delivers oxygen throughout the body.The diseases are characterized by hemolytic anemia, organ
      damage, and early mortality without treatment. Increases in another type of (normal)
      hemoglobin, fetal globin (HbF), which is normally silenced in infancy, reduces anemia and
      morbidity. Even incremental augmentation of fetal globin is established to reduce red blood
      cell pathology, anemia, certain complications, and to improve survival.

      This trial will evaluate an oral drug discovered in a high throughput screen, which increases
      fetal globin protein (HbF and red blood cells expressing HbF)and messenger ribonucleic acid
      (mRNA) to high levels in anemic nonhuman primates and in transgenic mice. The study drug acts
      by suppressing 4 repressors of the fetal globin gene promoter in progenitor cells from
      patients. The drug has been used for 50 years in a combination product for different actions
      - to enhance half-life and reduce side effects of a different active drug- and is considered
      safe for long-term use.

      This trial will first evaluate 3 dose levels in small cohorts of nontransfused patients with
      beta thalassemia intermedia. The most active dose will then be evaluated in larger subject
      groups with beta thalassemia and other hemoglobinopathies, such as sickle cell disease.
The study will first evaluate 3 doses of the investigational drug which are considered safe
      with chronic use in a combination therapeutic used widely for a different disease in Europe
      and Canada. The doses to be studied are human equivalent doses of doses that are active in
      nonhuman primates in inducing high level fetal globin messenger ribonucleic acid (mRNA),
      protein, and proportions of red blood cells expressing fetal globin protein (F-cells).
      Additive effects are observed with hydroxyurea in sickle cell patients' cells in vitro.

      The study will first evaluate the study therapeutic in male and female patients who are 18
      years and older. After a screening period to obtain baseline medical and laboratory data, the
      study drug will be taken by mouth once per day, every other day. The first dose will be taken
      in a clinical unit, and thereafter will be taken at home for 12 weeks. Laboratory tests,
      physical exams, and tolerability will be assessed 6 times over 4 months, including for one
      month after completion of dosing.

      The cohorts will be enrolled sequentially. Each new cohort will begin after the prior lower
      dose cohort has received 2 weeks of treatment without serious adverse events related to the
      study drug. The dose that increases fetal globin assays to the highest degree will be
      evaluated in a larger group of subjects.Other regimens or test doses may be added as needed
      to identify an active dose and regimen. The study drug is expected to be safe when added to
      most other medications used to treat thalassemia.
allocation: Non-Randomized
intervention model: Sequential Assignment
intervention model description: Each higher dose level cohort will be enrolled after 2 weeks of treatment in the lower dose level. Additional doses or regimens may be added. Expansion cohorts at the most active dose will be evaluated.
primary purpose: Treatment
masking: None (Open Label)
measure: Safety and Tolerability
time frame: 12 to 24 weeks
description: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
measure: Maximum plasma concentration (Cmax)
time frame: 4 weeks
description: drug concentration (ng/ml)
measure: Minimum plasma drug concentration (Cmin)
time frame: 4 weeks
description: Minimum drug plasma concentration, (ng/ml)
measure: Plasma drug concentration over time
time frame: 4 weeks
description: area under the curve
measure: F-cells
time frame: 12 to 24 weeks
description: % Red blood cells containing HbF
measure: HbF protein per cell
time frame: 12 to 24 weeks
description: Mean fluorescent intensity (MFI)
measure: Fetal hemoglobin (HbF)
time frame: 12 to 24 weeks
description: % and absolute (g/dl)
measure: Hemoglobin
time frame: 16 to 24 weeks
description: gram/dl
arm group label: Low dose
arm group type: Experimental
description: A low dose, by mouth, once per day, on Monday, Wednesday, and Friday for 12 weeks
arm group label: Middle dose
arm group type: Experimental
description: A middle dose, by mouth, once per day, on Monday, Wednesday, and Friday, for 12 weeks
arm group label: High dose 3 days per week
arm group type: Experimental
description: Highest dose, by mouth, once per day, on Monday, Wednesday, and Friday, for 12 to 24 weeks
arm group label: High dose 5 days per week
arm group type: Experimental
description: The highest dose, by mouth once per day on 5 days per week for 24 weeks
arm group label: Sickle Cell Disease Arm
arm group type: Experimental
description: The most active dose given once per day on the most active regimen for up 24 weeks
intervention type: Drug
intervention name: Benserazide Only Product
description: Investigational drug
arm group label: High dose 3 days per week
arm group label: High dose 5 days per week
arm group label: Low dose
arm group label: Middle dose
arm group label: Sickle Cell Disease Arm
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Susan Perrine, MD
role: Study Director
affiliation: Phoenicia BioScience
last name: Kevin Kuo, MD
role: Principal Investigator
affiliation: University Health Network, Toronto General Hospital
last name: Sylvia Singer, MD
role: Principal Investigator
affiliation: UCSF Benioff Children's Hospital at Oakland
last name: Hanny D Al-Samkari, MD
role: Principal Investigator
affiliation: Massachusetts General Hospital
last name: Sujit Sheth, MD MS
role: Principal Investigator
affiliation: Weill Medical College of Cornell University
last name: Susan Perrine, MD
phone: 617 335-7002
email: sperrine@bu.edu
last name: Melissa Askin, RN
phone: 410 231-1512
email: Melissa.Askin@acroclinical.com
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
investigator: 
facility: 
status: Recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
country: Canada
country: United States
citation: Boosalis MS, Sangerman JI, White GL, Wolf RF, Shen L, Dai Y, White E, Makala LH, Li B, Pace BS, Nouraie M, Faller DV, Perrine SP. Novel Inducers of Fetal Globin Identified through High Throughput Screening (HTS) Are Active In Vivo in Anemic Baboons and Transgenic Mice. PLoS One. 2015 Dec 29;10(12):e0144660. doi: 10.1371/journal.pone.0144660. eCollection 2015.
PMID: 26713848
citation: Dai Y, Sangerman J, Luo HY, Fucharoen S, Chui DH, Faller DV, Perrine SP. Therapeutic fetal-globin inducers reduce transcriptional repression in hemoglobinopathy erythroid progenitors through distinct mechanisms. Blood Cells Mol Dis. 2016 Jan;56(1):62-9. doi: 10.1016/j.bcmd.2015.10.004. Epub 2015 Oct 27.
PMID: 26603726
citation: Dai Y, Sangerman J, Nouraie M, Faller AD, Oneal P, Rock A, Owoyemi O, Niu X, Nekhai S, Maharaj D, Cui S, Taylor R, Steinberg M, Perrine S. Effects of hydroxyurea on F-cells in sickle cell disease and potential impact of a second fetal globin inducer. Am J Hematol. 2017 Jan;92(1):E10-E11. doi: 10.1002/ajh.24590. Epub 2016 Nov 18. No abstract available.
PMID: 27766663
citation: Chen Z, Luo HY, Steinberg MH, Chui DH. BCL11A represses HBG transcription in K562 cells. Blood Cells Mol Dis. 2009 Mar-Apr;42(2):144-9. doi: 10.1016/j.bcmd.2008.12.003. Epub 2009 Jan 18.
PMID: 19153051
citation: Sedgewick AE, Timofeev N, Sebastiani P, So JCC, Ma ESK, Chan LC, Fucharoen G, Fucharoen S, Barbosa CG, Vardarajan BN, Farrer LA, Baldwin CT, Steinberg MH, Chui DHK. BCL11A is a major HbF quantitative trait locus in three different populations with beta-hemoglobinopathies. Blood Cells Mol Dis. 2008 Nov-Dec;41(3):255-258. doi: 10.1016/j.bcmd.2008.06.007. Epub 2008 Aug 8.
PMID: 18691915
citation: Zhou D, Liu K, Sun CW, Pawlik KM, Townes TM. KLF1 regulates BCL11A expression and gamma- to beta-globin gene switching. Nat Genet. 2010 Sep;42(9):742-4. doi: 10.1038/ng.637. Epub 2010 Aug 1.
PMID: 20676097
citation: Cao H, Stamatoyannopoulos G, Jung M. Induction of human gamma globin gene expression by histone deacetylase inhibitors. Blood. 2004 Jan 15;103(2):701-9. doi: 10.1182/blood-2003-02-0478. Epub 2003 Aug 14.
PMID: 12920038
citation: Franco RS, Yasin Z, Palascak MB, Ciraolo P, Joiner CH, Rucknagel DL. The effect of fetal hemoglobin on the survival characteristics of sickle cells. Blood. 2006 Aug 1;108(3):1073-6. doi: 10.1182/blood-2005-09-008318.
PMID: 16861353
citation: Perrine RP, Brown MJ, Clegg JB, Weatherall DJ, May A. Benign sickle-cell anaemia. Lancet. 1972 Dec 2;2(7788):1163-7. doi: 10.1016/s0140-6736(72)92592-5. No abstract available.
PMID: 4117591
citation: Wang X, Thein SL. Switching from fetal to adult hemoglobin. Nat Genet. 2018 Apr;50(4):478-480. doi: 10.1038/s41588-018-0094-z.
PMID: 29610477
citation: Singer ST, Kuypers FA, Olivieri NF, Weatherall DJ, Mignacca R, Coates TD, Davies S, Sweeters N, Vichinsky EP; E/beta Thalassaemia Study Group. Fetal haemoglobin augmentation in E/beta(0) thalassaemia: clinical and haematological outcome. Br J Haematol. 2005 Nov;131(3):378-88. doi: 10.1111/j.1365-2141.2005.05768.x.
PMID: 16225658
citation: Perrine SP, Mankidy R, Boosalis MS, Bieker JJ, Faller DV. Erythroid Kruppel-like factor (EKLF) is recruited to the gamma-globin gene promoter as a co-activator and is required for gamma-globin gene induction by short-chain fatty acid derivatives. Eur J Haematol. 2009 Jun;82(6):466-76. doi: 10.1111/j.1600-0609.2009.01234.x. Epub 2009 Feb 5.
PMID: 19220418
citation: Tanabe O, McPhee D, Kobayashi S, Shen Y, Brandt W, Jiang X, Campbell AD, Chen YT, Chang Cs, Yamamoto M, Tanimoto K, Engel JD. Embryonic and fetal beta-globin gene repression by the orphan nuclear receptors, TR2 and TR4. EMBO J. 2007 May 2;26(9):2295-306. doi: 10.1038/sj.emboj.7601676. Epub 2007 Apr 12.
PMID: 17431400
citation: Borg J, Papadopoulos P, Georgitsi M, Gutierrez L, Grech G, Fanis P, Phylactides M, Verkerk AJ, van der Spek PJ, Scerri CA, Cassar W, Galdies R, van Ijcken W, Ozgur Z, Gillemans N, Hou J, Bugeja M, Grosveld FG, von Lindern M, Felice AE, Patrinos GP, Philipsen S. Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin. Nat Genet. 2010 Sep;42(9):801-5. doi: 10.1038/ng.630. Epub 2010 Aug 1.
PMID: 20676099
citation: Atweh GF, Sutton M, Nassif I, Boosalis V, Dover GJ, Wallenstein S, Wright E, McMahon L, Stamatoyannopoulos G, Faller DV, Perrine SP. Sustained induction of fetal hemoglobin by pulse butyrate therapy in sickle cell disease. Blood. 1999 Mar 15;93(6):1790-7.
PMID: 10068649
citation: Centis F, Tabellini L, Lucarelli G, Buffi O, Tonucci P, Persini B, Annibali M, Emiliani R, Iliescu A, Rapa S, Rossi R, Ma L, Angelucci E, Schrier SL. The importance of erythroid expansion in determining the extent of apoptosis in erythroid precursors in patients with beta-thalassemia major. Blood. 2000 Nov 15;96(10):3624-9.
PMID: 11071663
citation: Collins AF, Pearson HA, Giardina P, McDonagh KT, Brusilow SW, Dover GJ. Oral sodium phenylbutyrate therapy in homozygous beta thalassemia: a clinical trial. Blood. 1995 Jan 1;85(1):43-9.
PMID: 7528572
citation: Niihara Y, Miller ST, Kanter J, Lanzkron S, Smith WR, Hsu LL, Gordeuk VR, Viswanathan K, Sarnaik S, Osunkwo I, Guillaume E, Sadanandan S, Sieger L, Lasky JL, Panosyan EH, Blake OA, New TN, Bellevue R, Tran LT, Razon RL, Stark CW, Neumayr LD, Vichinsky EP; Investigators of the Phase 3 Trial of l-Glutamine in Sickle Cell Disease. A Phase 3 Trial of l-Glutamine in Sickle Cell Disease. N Engl J Med. 2018 Jul 19;379(3):226-235. doi: 10.1056/NEJMoa1715971.
PMID: 30021096
citation: Minniti CP. l-Glutamine and the Dawn of Combination Therapy for Sickle Cell Disease. N Engl J Med. 2018 Jul 19;379(3):292-294. doi: 10.1056/NEJMe1800976. No abstract available.
PMID: 30021091
citation: Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev. 2007 Jan;21(1):37-47. doi: 10.1016/j.blre.2006.07.001. Epub 2006 Nov 7.
PMID: 17084951
citation: Saraf S, Farooqui M, Infusino G, Oza B, Sidhwani S, Gowhari M, Vara S, Gao W, Krauz L, Lavelle D, DeSimone J, Molokie R, Saunthararajah Y. Standard clinical practice underestimates the role and significance of erythropoietin deficiency in sickle cell disease. Br J Haematol. 2011 May;153(3):386-92. doi: 10.1111/j.1365-2141.2010.08479.x. Epub 2011 Mar 21.
PMID: 21418176
citation: Perrine SP, Pace BS, Faller DV. Targeted fetal hemoglobin induction for treatment of beta hemoglobinopathies. Hematol Oncol Clin North Am. 2014 Apr;28(2):233-48. doi: 10.1016/j.hoc.2013.11.009.
PMID: 24589264
citation: Steinberg MH, Rodgers GP. Pharmacologic modulation of fetal hemoglobin. Medicine (Baltimore). 2001 Sep;80(5):328-44. doi: 10.1097/00005792-200109000-00007. No abstract available.
PMID: 11552087
citation: Weatherall DJ. The inherited diseases of hemoglobin are an emerging global health burden. Blood. 2010 Jun 3;115(22):4331-6. doi: 10.1182/blood-2010-01-251348. Epub 2010 Mar 16.
PMID: 20233970
citation: Taher AT, Cappellini MD. How I manage medical complications of beta-thalassemia in adults. Blood. 2018 Oct 25;132(17):1781-1791. doi: 10.1182/blood-2018-06-818187. Epub 2018 Sep 11.
PMID: 30206117
citation: Borgna-Pignatti C. Modern treatment of thalassaemia intermedia. Br J Haematol. 2007 Aug;138(3):291-304. doi: 10.1111/j.1365-2141.2007.06654.x. Epub 2007 Jun 12.
PMID: 17565568
citation: Sripichai O, Makarasara W, Munkongdee T, Kumkhaek C, Nuchprayoon I, Chuansumrit A, Chuncharunee S, Chantrakoon N, Boonmongkol P, Winichagoon P, Fucharoen S. A scoring system for the classification of beta-thalassemia/Hb E disease severity. Am J Hematol. 2008 Jun;83(6):482-4. doi: 10.1002/ajh.21130.
PMID: 18186524
citation: Nuinoon M, Makarasara W, Mushiroda T, Setianingsih I, Wahidiyat PA, Sripichai O, Kumasaka N, Takahashi A, Svasti S, Munkongdee T, Mahasirimongkol S, Peerapittayamongkol C, Viprakasit V, Kamatani N, Winichagoon P, Kubo M, Nakamura Y, Fucharoen S. A genome-wide association identified the common genetic variants influence disease severity in beta0-thalassemia/hemoglobin E. Hum Genet. 2010 Mar;127(3):303-14. doi: 10.1007/s00439-009-0770-2.
PMID: 20183929
citation: Uda M, Galanello R, Sanna S, Lettre G, Sankaran VG, Chen W, Usala G, Busonero F, Maschio A, Albai G, Piras MG, Sestu N, Lai S, Dei M, Mulas A, Crisponi L, Naitza S, Asunis I, Deiana M, Nagaraja R, Perseu L, Satta S, Cipollina MD, Sollaino C, Moi P, Hirschhorn JN, Orkin SH, Abecasis GR, Schlessinger D, Cao A. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia. Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1620-5. doi: 10.1073/pnas.0711566105. Epub 2008 Feb 1.
PMID: 18245381
citation: Labie D, Pagnier J, Lapoumeroulie C, Rouabhi F, Dunda-Belkhodja O, Chardin P, Beldjord C, Wajcman H, Fabry ME, Nagel RL. Common haplotype dependency of high G gamma-globin gene expression and high Hb F levels in beta-thalassemia and sickle cell anemia patients. Proc Natl Acad Sci U S A. 1985 Apr;82(7):2111-4. doi: 10.1073/pnas.82.7.2111.
PMID: 2580306
citation: Silva M, Grillot D, Benito A, Richard C, Nunez G, Fernandez-Luna JL. Erythropoietin can promote erythroid progenitor survival by repressing apoptosis through Bcl-XL and Bcl-2. Blood. 1996 Sep 1;88(5):1576-82.
PMID: 8781412
citation: Pootrakul P, Sirankapracha P, Hemsorach S, Moungsub W, Kumbunlue R, Piangitjagum A, Wasi P, Ma L, Schrier SL. A correlation of erythrokinetics, ineffective erythropoiesis, and erythroid precursor apoptosis in thai patients with thalassemia. Blood. 2000 Oct 1;96(7):2606-12.
PMID: 11001918
citation: Singer ST, Vichinsky EP, Sweeters N, Rachmilewitz E. Darbepoetin alfa for the treatment of anaemia in alpha- or beta- thalassaemia intermedia syndromes. Br J Haematol. 2011 Jul;154(2):281-4. doi: 10.1111/j.1365-2141.2011.08617.x. Epub 2011 Apr 18. No abstract available.
PMID: 21496003
responsible party type: Sponsor
mesh term: Anemia, Sickle Cell
mesh term: Thalassemia
mesh term: beta-Thalassemia
mesh term: Benserazide
sharing ipd: No
ipd description: Results will be provided in abstracts as the study is being conducted and in a publication after completion and analysis.