<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/NCT04403698</url>
  </required_header>
  <id_info>
    <org_study_id>BC-6072</org_study_id>
    <nct_id>NCT04403698</nct_id>
  </id_info>
  <brief_title>The Use of Steovess/Binosto After Denosumab Discontinuation to Prevent Increase in Bone Turnover</brief_title>
  <official_title>The Use of Buffered Soluble Alendronate 70 mg (Steovess/Binosto) After Denosumab Discontinuation to Prevent Increase in Bone Turnover</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital, Ghent</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Amgen</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>EffRx Pharmaceuticals</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University Hospital, Ghent</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      It is hypothesized that effervescent alendronate will be able to maintain bone turnover&#xD;
      markers within the pre-menopausal reference range and thereby reducing the likelihood of bone&#xD;
      turnover associated changes (rebound effect), after discontinuation of denosumab treatment in&#xD;
      a non-osteoporotic population.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Denosumab discontinuation is associated with a rebound effect in bone turnover and loss in&#xD;
      bone mass density. These changes resulted in an increase of fracture incidence in patients&#xD;
      with postmenopausal osteoporosis back to background levels. However, no excess in fracture&#xD;
      incidence was observed. Amongst patients who presented with vertebral fractures after&#xD;
      treatment discontinuation, there was a slightly higher incidence of multiple vertebral&#xD;
      fractures in patients discontinuing Prolia versus those who discontinued the placebo&#xD;
      treatment.&#xD;
&#xD;
      A 2 year, randomized, crossover study demonstrated that alendronate intake after&#xD;
      discontinuing denosumab treatment, lead to remaining stable bone mass densitometry (BMD)&#xD;
      values in postmenopausal women.&#xD;
&#xD;
      In a study within a non-osteoporotic study population, ongoing at our department, increases&#xD;
      in bone turnover are to be expected as soon as patients end study participation (i.e. open&#xD;
      label treatment with denosumab, Prolia, anti-RANK ligand inhibition).&#xD;
&#xD;
      It is currently recommended that alternative anti-resorptive therapy may be warranted after&#xD;
      Prolia discontinuation. One study describes the use of oral alendronate after denosumab&#xD;
      therapy to maintain bone mineral density. However, gastro-intestinal upset and tolerability,&#xD;
      as well as difficulty in swallowing pills may limit oral alendronate compliance. To attenuate&#xD;
      this concern, buffered soluble (effervescent) alendronate 70 mg, developed with the aim to&#xD;
      improve the gastrointestinal tolerability through full dissolution of alendronate in buffered&#xD;
      palatable solution before ingestion, will be used.&#xD;
&#xD;
      This study wants to provide a follow up and study wether the use of effervescent alendronate&#xD;
      after previous denosumab treatment can prevent a rebound effect in bone turnover that is to&#xD;
      be expected when denosumab is discontinued. Subjects that completed our erosive hand OA study&#xD;
      and therefore discontinued denosumab 60 mg/every 3 months, will receive alendronate.&#xD;
      Moreover, the study wants to asses if there is difference between using alendronate for six&#xD;
      or twelve months, starting at the earliest three months but no later than four months after&#xD;
      the last injection of denosumab.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 13, 2019</start_date>
  <completion_date type="Actual">March 9, 2022</completion_date>
  <primary_completion_date type="Actual">March 9, 2022</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>
    <intervention_model_description>40 subjects randomized in 2 groups (n=20). 1 group will receive effervescent alendronate treatment for 24 weeks, the other group will receive the same treatment for 48 weeks.</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Bone turnover marker above the premenopausal reference range at week 48</measure>
    <time_frame>48 weeks</time_frame>
    <description>the number of patients that maintain C-terminal telopeptide of type I collagen (CTx-I) levels within the premenopausal reference range at week 48</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Bone turnover marker above the premenopausal reference range at week 12 and week 24</measure>
    <time_frame>12, 24 and 48 weeks</time_frame>
    <description>The number of patients that maintain CTx-I levels within the premenopausal reference range at week 12 and 24 as well as the changes in CTx-I and N-terminal propeptide of type I procollagen (P1NP) levels from baseline until 12, 24 and 48 weeks</description>
  </secondary_outcome>
  <other_outcome>
    <measure>BMD changes</measure>
    <time_frame>24 and 48 weeks</time_frame>
    <description>Other outcomes are changes in T-score at lumbar spine and hip at BMD from baseline to week 24 and week 48.</description>
  </other_outcome>
  <other_outcome>
    <measure>Hand radiographic changes</measure>
    <time_frame>24 and 48 weeks</time_frame>
    <description>The radiographic changes at the finger joints in terms of new erosive joints and changes according to the Ghent University scoring system (GUSS) between W24 and W48 and baseline.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">30</enrollment>
  <condition>Erosive Osteoarthritis</condition>
  <arm_group>
    <arm_group_label>24 weeks</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subject receiving alendronate treatment for 24 weeks (n = 20)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>48 weeks</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subject receiving alendronate treatment for 48 weeks (n = 20)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Alendronate Effervescent Oral Tablet</intervention_name>
    <description>At the earliest three months but no later than four months after the last denosumab injection, subjects will be randomized to effervescent alendronate administered for either 24 or 48 weeks</description>
    <arm_group_label>24 weeks</arm_group_label>
    <arm_group_label>48 weeks</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subjects must have completed the 48 weeks of the randomised placebo-controlled study&#xD;
             phase followed by the 96 weeks open label denosumab 60 mg SC every 3 months phase.&#xD;
             (EudraCT number: 2015-003223-53)&#xD;
&#xD;
          -  Last denosumab injection minimal 3 months or maximum 4 months before baseline&#xD;
&#xD;
          -  Able and willing to give written informed consent and to comply with the requirements&#xD;
             of the study protocol&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with clinically significant hypersensitivity to any of the components of&#xD;
             effervescent alendronate.&#xD;
&#xD;
          -  Patient who is pregnant or planning pregnancy&#xD;
&#xD;
          -  Female subjects who are breast-feeding.&#xD;
&#xD;
          -  History of osteonecrosis of the jaw, and/or recent (within 3 months) tooth extraction&#xD;
             or other unhealed dental surgery; or planned invasive dental work during the study&#xD;
&#xD;
          -  Subject has any kind of disorder that compromises the ability of the subject to give&#xD;
             written informed consent and/or to comply with study procedures&#xD;
&#xD;
          -  Hypocalcaemia.&#xD;
&#xD;
          -  Oesophageal disease, gastritis, duodenitis, ulcers, or with a recent history (within&#xD;
             the previous year) of major gastro-intestinal disease such as peptic ulcer, or active&#xD;
             gastro-intestinal bleeding, or surgery of the upper gastro-intestinal tract other than&#xD;
             pyloroplasty.&#xD;
&#xD;
          -  Abnormalities of the oesophagus and other factors which delay oesophageal emptying&#xD;
             such as stricture or achalasia.&#xD;
&#xD;
          -  Inability to stand or sit upright for at least 30 minutes.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>30 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ruth Wittoek, Prof. dr.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Ghent Universitary Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Ghent University Hospital</name>
      <address>
        <city>Ghent</city>
        <zip>9000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belgium</country>
  </location_countries>
  <reference>
    <citation>Miller PD, Bolognese MA, Lewiecki EM, McClung MR, Ding B, Austin M, Liu Y, San Martin J. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone. 2008 Aug;43(2):222-229. doi: 10.1016/j.bone.2008.04.007. Epub 2008 Apr 26.</citation>
    <PMID>18539106</PMID>
  </reference>
  <reference>
    <citation>Brown JP, Roux C, Torring O, Ho PR, Beck Jensen JE, Gilchrist N, Recknor C, Austin M, Wang A, Grauer A, Wagman RB. Discontinuation of denosumab and associated fracture incidence: analysis from the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. J Bone Miner Res. 2013 Apr;28(4):746-52. doi: 10.1002/jbmr.1808.</citation>
    <PMID>23109251</PMID>
  </reference>
  <reference>
    <citation>Cummings SR, Ferrari S, Eastell R, Gilchrist N, Jensen JB, McClung M, Roux C, Torring O, Valter I, Wang AT, Brown JP. Vertebral Fractures After Discontinuation of Denosumab: A Post Hoc Analysis of the Randomized Placebo-Controlled FREEDOM Trial and Its Extension. J Bone Miner Res. 2018 Feb;33(2):190-198. doi: 10.1002/jbmr.3337. Epub 2017 Nov 22.</citation>
    <PMID>29105841</PMID>
  </reference>
  <reference>
    <citation>Freemantle N, Satram-Hoang S, Tang ET, Kaur P, Macarios D, Siddhanti S, Borenstein J, Kendler DL; DAPS Investigators. Final results of the DAPS (Denosumab Adherence Preference Satisfaction) study: a 24-month, randomized, crossover comparison with alendronate in postmenopausal women. Osteoporos Int. 2012 Jan;23(1):317-26. doi: 10.1007/s00198-011-1780-1. Epub 2011 Sep 17.</citation>
    <PMID>21927922</PMID>
  </reference>
  <reference>
    <citation>Hodges LA, Connolly SM, Winter J, Schmidt T, Stevens HN, Hayward M, Wilson CG. Modulation of gastric pH by a buffered soluble effervescent formulation: A possible means of improving gastric tolerability of alendronate. Int J Pharm. 2012 Aug 1;432(1-2):57-62. doi: 10.1016/j.ijpharm.2012.04.073. Epub 2012 May 4.</citation>
    <PMID>22564778</PMID>
  </reference>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>May 19, 2020</study_first_submitted>
  <study_first_submitted_qc>May 25, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 27, 2020</study_first_posted>
  <last_update_submitted>April 20, 2022</last_update_submitted>
  <last_update_submitted_qc>April 20, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 22, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Osteoarthritis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alendronate</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>All collected IPD that underlie results in a publication will be shared</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>6 months after publication. Data will stay available for 3 years after publication</ipd_time_frame>
  </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/NCT04403698
org study id: BC-6072
nct id: NCT04403698
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
It is hypothesized that effervescent alendronate will be able to maintain bone turnover
      markers within the pre-menopausal reference range and thereby reducing the likelihood of bone
      turnover associated changes (rebound effect), after discontinuation of denosumab treatment in
      a non-osteoporotic population.
Denosumab discontinuation is associated with a rebound effect in bone turnover and loss in
      bone mass density. These changes resulted in an increase of fracture incidence in patients
      with postmenopausal osteoporosis back to background levels. However, no excess in fracture
      incidence was observed. Amongst patients who presented with vertebral fractures after
      treatment discontinuation, there was a slightly higher incidence of multiple vertebral
      fractures in patients discontinuing Prolia versus those who discontinued the placebo
      treatment.

      A 2 year, randomized, crossover study demonstrated that alendronate intake after
      discontinuing denosumab treatment, lead to remaining stable bone mass densitometry (BMD)
      values in postmenopausal women.

      In a study within a non-osteoporotic study population, ongoing at our department, increases
      in bone turnover are to be expected as soon as patients end study participation (i.e. open
      label treatment with denosumab, Prolia, anti-RANK ligand inhibition).

      It is currently recommended that alternative anti-resorptive therapy may be warranted after
      Prolia discontinuation. One study describes the use of oral alendronate after denosumab
      therapy to maintain bone mineral density. However, gastro-intestinal upset and tolerability,
      as well as difficulty in swallowing pills may limit oral alendronate compliance. To attenuate
      this concern, buffered soluble (effervescent) alendronate 70 mg, developed with the aim to
      improve the gastrointestinal tolerability through full dissolution of alendronate in buffered
      palatable solution before ingestion, will be used.

      This study wants to provide a follow up and study wether the use of effervescent alendronate
      after previous denosumab treatment can prevent a rebound effect in bone turnover that is to
      be expected when denosumab is discontinued. Subjects that completed our erosive hand OA study
      and therefore discontinued denosumab 60 mg/every 3 months, will receive alendronate.
      Moreover, the study wants to asses if there is difference between using alendronate for six
      or twelve months, starting at the earliest three months but no later than four months after
      the last injection of denosumab.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: 40 subjects randomized in 2 groups (n=20). 1 group will receive effervescent alendronate treatment for 24 weeks, the other group will receive the same treatment for 48 weeks.
primary purpose: Prevention
masking: None (Open Label)
measure: Bone turnover marker above the premenopausal reference range at week 48
time frame: 48 weeks
description: the number of patients that maintain C-terminal telopeptide of type I collagen (CTx-I) levels within the premenopausal reference range at week 48
measure: Bone turnover marker above the premenopausal reference range at week 12 and week 24
time frame: 12, 24 and 48 weeks
description: The number of patients that maintain CTx-I levels within the premenopausal reference range at week 12 and 24 as well as the changes in CTx-I and N-terminal propeptide of type I procollagen (P1NP) levels from baseline until 12, 24 and 48 weeks
measure: BMD changes
time frame: 24 and 48 weeks
description: Other outcomes are changes in T-score at lumbar spine and hip at BMD from baseline to week 24 and week 48.
measure: Hand radiographic changes
time frame: 24 and 48 weeks
description: The radiographic changes at the finger joints in terms of new erosive joints and changes according to the Ghent University scoring system (GUSS) between W24 and W48 and baseline.
arm group label: 24 weeks
arm group type: Experimental
description: Subject receiving alendronate treatment for 24 weeks (n = 20)
arm group label: 48 weeks
arm group type: Experimental
description: Subject receiving alendronate treatment for 48 weeks (n = 20)
intervention type: Drug
intervention name: Alendronate Effervescent Oral Tablet
description: At the earliest three months but no later than four months after the last denosumab injection, subjects will be randomized to effervescent alendronate administered for either 24 or 48 weeks
arm group label: 24 weeks
arm group label: 48 weeks
criteria: 
gender: All
minimum age: 30 Years
maximum age: N/A
healthy volunteers: No
last name: Ruth Wittoek, Prof. dr.
role: Principal Investigator
affiliation: Ghent Universitary Hospital
facility: 
country: Belgium
citation: Miller PD, Bolognese MA, Lewiecki EM, McClung MR, Ding B, Austin M, Liu Y, San Martin J. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone. 2008 Aug;43(2):222-229. doi: 10.1016/j.bone.2008.04.007. Epub 2008 Apr 26.
PMID: 18539106
citation: Brown JP, Roux C, Torring O, Ho PR, Beck Jensen JE, Gilchrist N, Recknor C, Austin M, Wang A, Grauer A, Wagman RB. Discontinuation of denosumab and associated fracture incidence: analysis from the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. J Bone Miner Res. 2013 Apr;28(4):746-52. doi: 10.1002/jbmr.1808.
PMID: 23109251
citation: Cummings SR, Ferrari S, Eastell R, Gilchrist N, Jensen JB, McClung M, Roux C, Torring O, Valter I, Wang AT, Brown JP. Vertebral Fractures After Discontinuation of Denosumab: A Post Hoc Analysis of the Randomized Placebo-Controlled FREEDOM Trial and Its Extension. J Bone Miner Res. 2018 Feb;33(2):190-198. doi: 10.1002/jbmr.3337. Epub 2017 Nov 22.
PMID: 29105841
citation: Freemantle N, Satram-Hoang S, Tang ET, Kaur P, Macarios D, Siddhanti S, Borenstein J, Kendler DL; DAPS Investigators. Final results of the DAPS (Denosumab Adherence Preference Satisfaction) study: a 24-month, randomized, crossover comparison with alendronate in postmenopausal women. Osteoporos Int. 2012 Jan;23(1):317-26. doi: 10.1007/s00198-011-1780-1. Epub 2011 Sep 17.
PMID: 21927922
citation: Hodges LA, Connolly SM, Winter J, Schmidt T, Stevens HN, Hayward M, Wilson CG. Modulation of gastric pH by a buffered soluble effervescent formulation: A possible means of improving gastric tolerability of alendronate. Int J Pharm. 2012 Aug 1;432(1-2):57-62. doi: 10.1016/j.ijpharm.2012.04.073. Epub 2012 May 4.
PMID: 22564778
responsible party type: Sponsor
mesh term: Osteoarthritis
mesh term: Alendronate
sharing ipd: Yes
ipd description: All collected IPD that underlie results in a publication will be shared
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd time frame: 6 months after publication. Data will stay available for 3 years after publication