<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/NCT03029429</url>
  </required_header>
  <id_info>
    <org_study_id>IND 133103</org_study_id>
    <nct_id>NCT03029429</nct_id>
  </id_info>
  <brief_title>Theophylline Treatment for Pseudohypoparathyroidism</brief_title>
  <official_title>Phase 2 Study of Theophylline Treatment for Pseudohypoparathyroidism</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vanderbilt University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Harvard University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Vanderbilt University Medical Center</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>
      Pseudohypoparathyroidism is a genetic disorder with limited treatment options. Patients have&#xD;
      early-onset obesity, short stature and increased risk of type 2 diabetes. This phase 2&#xD;
      clinical trial will test the efficacy of theophylline, a phosphodiesterase inhibitor, in&#xD;
      pseudohypoparathyroidism. The investigators hypothesize that theophylline will cause weight&#xD;
      loss, improve glucose tolerance and slow growth plate closure in children and young adults.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Pseudohypoparathyroidism (PHP) is a rare, genetic disorder caused by impaired stimulatory G&#xD;
      protein (Gsα) signaling through downregulation of the gene, GNAS. The resultant hormone&#xD;
      abnormalities can be treated with hormone replacement therapy, but other aspects of the&#xD;
      disorder such as early-onset obesity and premature epiphyseal closure are without effective&#xD;
      treatment options. Gsα signaling is essential for the normal hormonal function of the&#xD;
      pituitary, thyroid, gonads, renal proximal tubules and hypothalamus. While many of the&#xD;
      resulting hormone deficiencies can be treated with hormone replacement therapy (HRT), HRT is&#xD;
      not an effective therapy for the severe early-onset obesity and short stature which are major&#xD;
      features of the PHP phenotype. Therefore, the goal of this proposal is to test the efficacy&#xD;
      of upstream therapy aimed at correcting the function of two Gsα-dependent receptors&#xD;
      responsible for the obesity (melanocortin-4 receptor, MC4R) and short stature (parathyroid&#xD;
      hormone, PTH, receptor) phenotype in children with PHP. Gsα-coupled receptor signaling&#xD;
      cascade begins with an increase in cyclic adenosine monophosphate (cAMP) which is rapidly&#xD;
      degraded by the enzyme phosphodiesterase (PDE). PDE inhibitors act by prolonging cAMP&#xD;
      signaling by decreasing the rate of degradation. Given that patients with PHP have reduced,&#xD;
      but not completely absent, cAMP production, the investigators seek to test the hypothesis&#xD;
      that the PDE inhibitor theophylline will reduce BMI, glucose intolerance, and hormone&#xD;
      resistance in children and young adults with PHP through improved Gsα-coupled receptor&#xD;
      signaling. The investigators will conduct a 52-week randomized, placebo controlled clinical&#xD;
      trial of theophylline in children and young adults with PHP. Theophylline is a non-selective&#xD;
      PDE inhibitor that is generically available and has a long history of use in pediatric&#xD;
      patients, making it an ideal drug for re-purposing in youth with PHP. Furthermore, the&#xD;
      pharmacokinetics of theophylline are well understood and serum drug levels are easily&#xD;
      measured. The investigators primary outcome is change in body mass index. Secondary outcome&#xD;
      measures include change in glucose tolerance and HRT dose. Anticipating a 10% dropout rate,&#xD;
      the investigators will enroll 34 patients and expect that 30 patients will complete the&#xD;
      study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">September 1, 2018</start_date>
  <completion_date type="Anticipated">November 1, 2025</completion_date>
  <primary_completion_date type="Anticipated">July 1, 2025</primary_completion_date>
  <phase>Phase 2</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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in body mass index</measure>
    <time_frame>baseline and 52 weeks</time_frame>
    <description>BMI will be expressed a percent of the 95th percentile</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in insulinogenic index</measure>
    <time_frame>baseline and 52 weeks</time_frame>
    <description>Insulinogenic index measured during a 75g oral glucose tolerance test</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>change in levothyroxine dose</measure>
    <time_frame>baseline and 52 weeks</time_frame>
    <description>levothyroxine dose (mcg/kg/day)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>change in calcitriol dose</measure>
    <time_frame>baseline and 52 weeks</time_frame>
    <description>calcitriol dose (mcg/kg/day)</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Change in body mass index z-score</measure>
    <time_frame>baseline and 52 weeks</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Change in BMI</measure>
    <time_frame>52 weeks</time_frame>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">34</enrollment>
  <condition>Pseudohypoparathyroidism</condition>
  <condition>Albright Hereditary Osteodystrophy</condition>
  <arm_group>
    <arm_group_label>Theophylline</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Theophylline capsules by mouth once daily or Theophylline elixir by mouth q6h (dose determined by serum drug levels)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebos</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Theophylline capsule by mouth once daily or Theophylline elixir by mouth q6h</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Theophylline</intervention_name>
    <description>oral theophylline</description>
    <arm_group_label>Theophylline</arm_group_label>
    <other_name>Theo-24, Elixophyllin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebos</intervention_name>
    <description>oral placebo</description>
    <arm_group_label>Placebos</arm_group_label>
    <other_name>placebo</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age 13 years and above&#xD;
&#xD;
          2. Clinical diagnosis of PHP (per the EuroPHP network classification guidelines1):&#xD;
             Presence of PTH resistance or ectopic classification OR brachydactyly type E plus 2&#xD;
             minor criteria (TSH resistance, other hormonal resistance, developmental delay,&#xD;
             intrauterine or post-natal growth retardation, obesity/overweight, specific facial&#xD;
             features)&#xD;
&#xD;
          3. Obesity (BMI &gt;95th percentile for age/gender and/or ≥30 kg/m2)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Use of a PDE inhibitor in the past 30 days&#xD;
&#xD;
          2. History of a seizure disorder unrelated to hypocalcemia&#xD;
&#xD;
          3. History of a cardiac arrhythmia (not including bradycardia)&#xD;
&#xD;
          4. Hepatic insufficiency including cirrhosis and acute hepatitis (AST or ALT &gt;3x upper&#xD;
             limit of normal)&#xD;
&#xD;
          5. Congestive heart failure&#xD;
&#xD;
          6. Current cigarette use or alcohol abuse&#xD;
&#xD;
          7. Pregnancy or intention to become pregnant during the next year&#xD;
&#xD;
          8. Untreated hypothyroidism (defined as free thyroxine below the lower limit of normal)&#xD;
&#xD;
          9. Active peptic ulcer disease&#xD;
&#xD;
         10. Current use of medications known to effect theophylline levels&#xD;
&#xD;
         11. History of hypersensitivity to theophylline or other medication components&#xD;
&#xD;
         12. History of Major Depressive Disorder in the past 2 years, lifetime history of suicide&#xD;
             attempt, history of any suicidal behavior in the past month, history of other sever&#xD;
             psychiatric disorders (e.g. schizophrenia, bipolar disorder)&#xD;
&#xD;
         13. PHQ-9 score is ≥15 or suicidal ideation of type 4 or 5 (C-SSR) in the past month&#xD;
&#xD;
         14. Unable to comply with study procedures in the opinion of the investigator&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>13 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ashley Shoemaker, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Vanderbilt University Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Sarah Wright, RN</last_name>
    <phone>6153438116</phone>
    <email>sarah.e.wright@vumc.org</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Ashley Shoemaker</last_name>
    <phone>6153438116</phone>
    <email>ashley.h.shoemaker@vumc.org</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Ashley Shoemaker</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37212</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ashley Shoemaker, MD</last_name>
      <phone>615-343-8116</phone>
      <email>ashley.h.shoemaker@vanderbilt.edu</email>
    </contact>
    <investigator>
      <last_name>Ashley Shoemaker, MD, MSCI</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.facebook.com/pseudohypoparathyroidism</url>
    <description>Vanderbilt PHP Research Page</description>
  </link>
  <reference>
    <citation>Shoemaker AH, Juppner H. Nonclassic features of pseudohypoparathyroidism type 1A. Curr Opin Endocrinol Diabetes Obes. 2017 Feb;24(1):33-38. doi: 10.1097/MED.0000000000000306.</citation>
    <PMID>27875418</PMID>
  </reference>
  <reference>
    <citation>Wang L, Shoemaker AH. Eating behaviors in obese children with pseudohypoparathyroidism type 1a: a cross-sectional study. Int J Pediatr Endocrinol. 2014;2014(1):21. doi: 10.1186/1687-9856-2014-21. Epub 2014 Oct 15.</citation>
    <PMID>25337124</PMID>
  </reference>
  <reference>
    <citation>Shoemaker AH, Lomenick JP, Saville BR, Wang W, Buchowski MS, Cone RD. Energy expenditure in obese children with pseudohypoparathyroidism type 1a. Int J Obes (Lond). 2013 Aug;37(8):1147-53. doi: 10.1038/ijo.2012.200. Epub 2012 Dec 11.</citation>
    <PMID>23229731</PMID>
  </reference>
  <reference>
    <citation>Mano T, Uchimura K, Hayashi R, Kobahashi T, Fujiwara K, Makino M, Kakizawa H, Nagata M, Nakai A, Wada M, Nagasaka A, Itoh M. Increased urinary phosphate excretion in pseudohypoparathyroidism type II with long-term treatment with phosphodiesterase inhibitor. Horm Metab Res. 1999 Nov;31(11):602-5. doi: 10.1055/s-2007-978804.</citation>
    <PMID>10598827</PMID>
  </reference>
  <reference>
    <citation>Landreth H, Malow BA, Shoemaker AH. Increased Prevalence of Sleep Apnea in Children with Pseudohypoparathyroidism Type 1a. Horm Res Paediatr. 2015;84(1):1-5. doi: 10.1159/000381452. Epub 2015 Apr 23.</citation>
    <PMID>25925491</PMID>
  </reference>
  <reference>
    <citation>Perez KM, Lee EB, Kahanda S, Duis J, Reyes M, Juppner H, Shoemaker AH. Cognitive and behavioral phenotype of children with pseudohypoparathyroidism type 1A. Am J Med Genet A. 2018 Feb;176(2):283-289. doi: 10.1002/ajmg.a.38534. Epub 2017 Nov 28.</citation>
    <PMID>29193623</PMID>
  </reference>
  <reference>
    <citation>Curley KL, Kahanda S, Perez KM, Malow BA, Shoemaker AH. Obstructive Sleep Apnea and Otolaryngologic Manifestations in Children with Pseudohypoparathyroidism. Horm Res Paediatr. 2018;89(3):178-183. doi: 10.1159/000486715. Epub 2018 Feb 16.</citation>
    <PMID>29455209</PMID>
  </reference>
  <reference>
    <citation>Hanna P, Grybek V, Perez de Nanclares G, Tran LC, de Sanctis L, Elli F, Errea J, Francou B, Kamenicky P, Linglart L, Pereda A, Rothenbuhler A, Tessaris D, Thiele S, Usardi A, Shoemaker AH, Kottler ML, Juppner H, Mantovani G, Linglart A. Genetic and Epigenetic Defects at the GNAS Locus Lead to Distinct Patterns of Skeletal Growth but Similar Early-Onset Obesity. J Bone Miner Res. 2018 Aug;33(8):1480-1488. doi: 10.1002/jbmr.3450. Epub 2018 Jun 7.</citation>
    <PMID>29693731</PMID>
  </reference>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>January 18, 2017</study_first_submitted>
  <study_first_submitted_qc>January 23, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 24, 2017</study_first_posted>
  <last_update_submitted>August 22, 2023</last_update_submitted>
  <last_update_submitted_qc>August 22, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 23, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Vanderbilt University Medical Center</investigator_affiliation>
    <investigator_full_name>Ashley Shoemaker</investigator_full_name>
    <investigator_title>Assistant Professor of Pediatrics</investigator_title>
  </responsible_party>
  <keyword>pseudohypoparathyroidism</keyword>
  <keyword>AHO</keyword>
  <keyword>Albright Hereditary Osteodystrophy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pseudohypoparathyroidism</mesh_term>
    <mesh_term>Pseudopseudohypoparathyroidism</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Theophylline</mesh_term>
  </intervention_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/NCT03029429
org study id: IND 133103
nct id: NCT03029429
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Pseudohypoparathyroidism is a genetic disorder with limited treatment options. Patients have
      early-onset obesity, short stature and increased risk of type 2 diabetes. This phase 2
      clinical trial will test the efficacy of theophylline, a phosphodiesterase inhibitor, in
      pseudohypoparathyroidism. The investigators hypothesize that theophylline will cause weight
      loss, improve glucose tolerance and slow growth plate closure in children and young adults.
Pseudohypoparathyroidism (PHP) is a rare, genetic disorder caused by impaired stimulatory G
      protein (Gsα) signaling through downregulation of the gene, GNAS. The resultant hormone
      abnormalities can be treated with hormone replacement therapy, but other aspects of the
      disorder such as early-onset obesity and premature epiphyseal closure are without effective
      treatment options. Gsα signaling is essential for the normal hormonal function of the
      pituitary, thyroid, gonads, renal proximal tubules and hypothalamus. While many of the
      resulting hormone deficiencies can be treated with hormone replacement therapy (HRT), HRT is
      not an effective therapy for the severe early-onset obesity and short stature which are major
      features of the PHP phenotype. Therefore, the goal of this proposal is to test the efficacy
      of upstream therapy aimed at correcting the function of two Gsα-dependent receptors
      responsible for the obesity (melanocortin-4 receptor, MC4R) and short stature (parathyroid
      hormone, PTH, receptor) phenotype in children with PHP. Gsα-coupled receptor signaling
      cascade begins with an increase in cyclic adenosine monophosphate (cAMP) which is rapidly
      degraded by the enzyme phosphodiesterase (PDE). PDE inhibitors act by prolonging cAMP
      signaling by decreasing the rate of degradation. Given that patients with PHP have reduced,
      but not completely absent, cAMP production, the investigators seek to test the hypothesis
      that the PDE inhibitor theophylline will reduce BMI, glucose intolerance, and hormone
      resistance in children and young adults with PHP through improved Gsα-coupled receptor
      signaling. The investigators will conduct a 52-week randomized, placebo controlled clinical
      trial of theophylline in children and young adults with PHP. Theophylline is a non-selective
      PDE inhibitor that is generically available and has a long history of use in pediatric
      patients, making it an ideal drug for re-purposing in youth with PHP. Furthermore, the
      pharmacokinetics of theophylline are well understood and serum drug levels are easily
      measured. The investigators primary outcome is change in body mass index. Secondary outcome
      measures include change in glucose tolerance and HRT dose. Anticipating a 10% dropout rate,
      the investigators will enroll 34 patients and expect that 30 patients will complete the
      study.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Change in body mass index
time frame: baseline and 52 weeks
description: BMI will be expressed a percent of the 95th percentile
measure: Change in insulinogenic index
time frame: baseline and 52 weeks
description: Insulinogenic index measured during a 75g oral glucose tolerance test
measure: change in levothyroxine dose
time frame: baseline and 52 weeks
description: levothyroxine dose (mcg/kg/day)
measure: change in calcitriol dose
time frame: baseline and 52 weeks
description: calcitriol dose (mcg/kg/day)
measure: Change in body mass index z-score
time frame: baseline and 52 weeks
measure: Change in BMI
time frame: 52 weeks
arm group label: Theophylline
arm group type: Experimental
description: Theophylline capsules by mouth once daily or Theophylline elixir by mouth q6h (dose determined by serum drug levels)
arm group label: Placebos
arm group type: Placebo Comparator
description: Theophylline capsule by mouth once daily or Theophylline elixir by mouth q6h
intervention type: Drug
intervention name: Theophylline
description: oral theophylline
arm group label: Theophylline
other name: Theo-24, Elixophyllin
intervention type: Drug
intervention name: Placebos
description: oral placebo
arm group label: Placebos
other name: placebo
criteria: 
gender: All
minimum age: 13 Years
maximum age: 99 Years
healthy volunteers: No
last name: Ashley Shoemaker, MD
role: Principal Investigator
affiliation: Vanderbilt University Medical Center
last name: Sarah Wright, RN
phone: 6153438116
email: sarah.e.wright@vumc.org
last name: Ashley Shoemaker
phone: 6153438116
email: ashley.h.shoemaker@vumc.org
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
url: http://www.facebook.com/pseudohypoparathyroidism
description: Vanderbilt PHP Research Page
citation: Shoemaker AH, Juppner H. Nonclassic features of pseudohypoparathyroidism type 1A. Curr Opin Endocrinol Diabetes Obes. 2017 Feb;24(1):33-38. doi: 10.1097/MED.0000000000000306.
PMID: 27875418
citation: Wang L, Shoemaker AH. Eating behaviors in obese children with pseudohypoparathyroidism type 1a: a cross-sectional study. Int J Pediatr Endocrinol. 2014;2014(1):21. doi: 10.1186/1687-9856-2014-21. Epub 2014 Oct 15.
PMID: 25337124
citation: Shoemaker AH, Lomenick JP, Saville BR, Wang W, Buchowski MS, Cone RD. Energy expenditure in obese children with pseudohypoparathyroidism type 1a. Int J Obes (Lond). 2013 Aug;37(8):1147-53. doi: 10.1038/ijo.2012.200. Epub 2012 Dec 11.
PMID: 23229731
citation: Mano T, Uchimura K, Hayashi R, Kobahashi T, Fujiwara K, Makino M, Kakizawa H, Nagata M, Nakai A, Wada M, Nagasaka A, Itoh M. Increased urinary phosphate excretion in pseudohypoparathyroidism type II with long-term treatment with phosphodiesterase inhibitor. Horm Metab Res. 1999 Nov;31(11):602-5. doi: 10.1055/s-2007-978804.
PMID: 10598827
citation: Landreth H, Malow BA, Shoemaker AH. Increased Prevalence of Sleep Apnea in Children with Pseudohypoparathyroidism Type 1a. Horm Res Paediatr. 2015;84(1):1-5. doi: 10.1159/000381452. Epub 2015 Apr 23.
PMID: 25925491
citation: Perez KM, Lee EB, Kahanda S, Duis J, Reyes M, Juppner H, Shoemaker AH. Cognitive and behavioral phenotype of children with pseudohypoparathyroidism type 1A. Am J Med Genet A. 2018 Feb;176(2):283-289. doi: 10.1002/ajmg.a.38534. Epub 2017 Nov 28.
PMID: 29193623
citation: Curley KL, Kahanda S, Perez KM, Malow BA, Shoemaker AH. Obstructive Sleep Apnea and Otolaryngologic Manifestations in Children with Pseudohypoparathyroidism. Horm Res Paediatr. 2018;89(3):178-183. doi: 10.1159/000486715. Epub 2018 Feb 16.
PMID: 29455209
citation: Hanna P, Grybek V, Perez de Nanclares G, Tran LC, de Sanctis L, Elli F, Errea J, Francou B, Kamenicky P, Linglart L, Pereda A, Rothenbuhler A, Tessaris D, Thiele S, Usardi A, Shoemaker AH, Kottler ML, Juppner H, Mantovani G, Linglart A. Genetic and Epigenetic Defects at the GNAS Locus Lead to Distinct Patterns of Skeletal Growth but Similar Early-Onset Obesity. J Bone Miner Res. 2018 Aug;33(8):1480-1488. doi: 10.1002/jbmr.3450. Epub 2018 Jun 7.
PMID: 29693731
responsible party type: Principal Investigator
investigator affiliation: Vanderbilt University Medical Center
investigator full name: Ashley Shoemaker
investigator title: Assistant Professor of Pediatrics
mesh term: Pseudohypoparathyroidism
mesh term: Pseudopseudohypoparathyroidism
mesh term: Theophylline
sharing ipd: No