<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/NCT03293108</url>
  </required_header>
  <id_info>
    <org_study_id>DEN.ARY.AJ.95 (III)</org_study_id>
    <nct_id>NCT03293108</nct_id>
  </id_info>
  <brief_title>Comparing Efficacy and Safety of AryoGen Pharmed Biosimilar Denosumab 60 mg (Arylia) Versus Prolia® in Improvement of Bone Mineral Densitometry (BMD) Among Osteoporotic Postmenopausal Women</brief_title>
  <official_title>A Phase III, Randomized, Two-armed, Parallel, Double-blind, Active-controlled, Non-inferiority Clinical Trial to Determine the Non-inferior Therapeutic Efficacy and Safety Between Arylia (60 mg, Denosumab, Produced by AryoGen Pharmed) Compared With Prolia® (60 mg, Denosumab, the Reference Drug, Produced by Amgen Company) in the Improvement of Bone Mineral Densitometry (BMD) Among Osteoporotic Postmenopausal Women</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>AryoGen Pharmed Co.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>AryoGen Pharmed Co.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to compare the efficacy and safety of Denosumab 60 mg produced&#xD;
      by AryoGen Pharmed and Amgen Denosumab 60 mg among osteoporotic postmenopausal women.&#xD;
      Postmenopausal women diagnosed with osteoporosis according to their Bone mineral density&#xD;
      result (BMD), aged between 45 to 75 are included in this trial. This is a Phase III,&#xD;
      randomized, two armed, double-blind, parallel, active-controlled,non-inferiority clinical&#xD;
      trial. The eligible patients are randomized in a 1:1 ratio to receive Arylia or Prolia®&#xD;
      subcutaneous injections, at the beginning of the trial and every 6 months at month 6 and 12,&#xD;
      in an 18-month study period. Along with, all women will receive daily supplements containing&#xD;
      at least 1000 mg of elemental calcium (divided into two doses) and at least 400 IU vitamin D&#xD;
      daily during 18 months of the study.&#xD;
&#xD;
      The primary objective of this study is to assess non-inferiority of test- Denosumab 60 mg&#xD;
      (Arylia) to the reference Denosumab 60 mg (Prolia®) in terms of efficacy among osteoporotic&#xD;
      postmenopausal women.&#xD;
&#xD;
      The secondary objectives of this study are:&#xD;
&#xD;
      To further compare efficacy of test- Denosumab 60 mg to reference Denosumab 60 mg; To assess&#xD;
      the safety of test- Denosumab 60 mg compared to reference Denosumab 60 mg.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The purpose of this study is to compare the efficacy and safety of Denosumab 60 mg produced&#xD;
      by AryoGen Pharmed and Amgen Denosumab 60 mg among osteoporotic postmenopausal women.&#xD;
      Postmenopausal women diagnosed with osteoporosis according to their Bone mineral density&#xD;
      result (BMD) and aged between 45 to 75 are included in this trial. This is a Phase III,&#xD;
      randomized, two armed, double-blind, parallel, active-controlled,non-inferiority clinical&#xD;
      trial. Visits are going to be conducted at screening, 0, 1, 3, 6, 9, 12, 15 and 18 months.&#xD;
&#xD;
      After signing the written informed consent, patients are randomized in a 1:1 ratio to receive&#xD;
      Arylia or Prolia® subcutaneous injections, at the beginning of the trial and every 6 months&#xD;
      at month 6 and 12, in an 18-month study period. Along with, all women will receive daily&#xD;
      supplements containing at least 1000 mg of elemental calcium (divided into two doses) and at&#xD;
      least 400 IU vitamin D daily during 18 months of the study.&#xD;
&#xD;
      The primary objective of this study is to assess percentage change from baseline in BMD at&#xD;
      the lumbar spine (L1-L4), femoral neck and total hip by dual-energy x-ray absorptiometry to&#xD;
      18 months of the study, and compare it between two treatment groups.&#xD;
&#xD;
      The second objectives of this study are to assess the followings between treatment groups:&#xD;
&#xD;
        -  The incidence of new vertebral fracture;&#xD;
&#xD;
        -  Evolution of biochemical markers of bone metabolism at baseline, first month and&#xD;
           afterward every 3 months from baseline.&#xD;
&#xD;
        -  Comparing adverse events;&#xD;
&#xD;
        -  Comparing immunogenicity of two products.&#xD;
&#xD;
      Before initiation, the trial is reviewed by food and drug administration of Iran. The&#xD;
      protocol, electronic case report form (eCRF), information for patients and informed consent&#xD;
      forms are submitted to the ethics committees responsible for review and approval purposes,&#xD;
      according to national regulatory guidelines.&#xD;
&#xD;
      Sample size:&#xD;
&#xD;
      172 patients will be equally (1:1) divided into intervention arms for achieving 80% power in&#xD;
      order to determine non-inferiority using a one-sided, independent sample t-test. Efficacy of&#xD;
      Prolia® in comparison with placebo for lumbar spine BMD improvement in previous studies is&#xD;
      reported 7.1%. The margin of non-inferiority is 1.78. The true difference between the means&#xD;
      is assumed to be 0.000. The significance level (alpha) of the test is 0.025. The data are&#xD;
      drawn from populations with standard deviations of 4.116 and 4.116. However, we have&#xD;
      calculated that 190 patients should enter the study, by considering that there might be 10%&#xD;
      drop-outs of participants during the trial.&#xD;
&#xD;
      Blinding:&#xD;
&#xD;
      To prevent the influence of knowing intervention group on study conclusion, the subjects and&#xD;
      those who assess the study outcomes will be unaware of the state of the patient with regard&#xD;
      to receiving the test drug or reference drug.&#xD;
&#xD;
      For this purpose, subjects and administrator of the drug will be blinded by using a similar&#xD;
      masked prefilled syringes. All drugs packages will be identified by unique numbers.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">April 29, 2017</start_date>
  <completion_date type="Anticipated">September 30, 2020</completion_date>
  <primary_completion_date type="Anticipated">September 30, 2020</primary_completion_date>
  <phase>Phase 3</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>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>BMD percentage change from baseline at lumbar spine (L1-L4), femoral neck and total hip.</measure>
    <time_frame>Baseline and at 18 months.</time_frame>
    <description>Percentage change from baseline in BMD at lumbar spine (L1-L4), femoral neck and total hip by dual-energy x-ray absorptiometry to 18 months of the study, and compare between two groups.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>The incidence of new vertebral fracture.</measure>
    <time_frame>Baseline and at 18 months</time_frame>
    <description>The incidence of new vertebral fracture assessed by Lateral spine X-ray radiography (T4-L4) at baseline then at 18 months, and compare between two groups.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evolution of biochemical markers of bone metabolism.</measure>
    <time_frame>Baseline,at month 1,at month 3,at month 6,at month 9, at month 12, at month 15 and at month 18.</time_frame>
    <description>Evolution of biochemical markers of bone metabolism at baseline, first month and afterwards every 3 months from baseline, and compare between two groups.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Comparing adverse events between two products.</measure>
    <time_frame>baseline,at month 1,at month 3,at month 6,at month 9,at month 12, at month 15 and at month 18.</time_frame>
    <description>Evaluation of the following parameters at each visit including 0, 1, 3, 6, 9, 12, 15 and 18 months, and compare between two groups.&#xD;
Adverse events (AEs), Adverse drug reactions (ADR)&#xD;
Changes in physical examination findings&#xD;
Changes in vital signs&#xD;
Clinical laboratory testing for systemic safety, including liver function, renal function, complete blood count, and clinical chemistries.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Comparing immunogenicity between two products.</measure>
    <time_frame>Baseline,at month 6,at month 12 and at month 18.</time_frame>
    <description>Evaluation of immunogenicity at visit 0, 6, 12 and 18 months for both arms, and compare between two groups.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">190</enrollment>
  <condition>Osteoporosis</condition>
  <arm_group>
    <arm_group_label>AryoGen Pharmed Denosumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Arylia (Denosumab Prefilled Syringe produced by AryoGen Pharmed) 60 mg/1 ml in a prefilled syringe.&#xD;
Denosumab 60 mg is subcutaneously administered to osteoporotic patients at baseline, month 6 and month 12. Along with, all women will receive daily supplements containing at least 1000 mg of elemental calcium (divided into two doses) and at least 400 IU vitamin D daily during 18 months of the study.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Amgen Denosumab</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Prolia® (Denosumab Prefilled Syringe produced by Amgen) 60 mg/1 ml in a prefilled syringe.&#xD;
Denosumab 60 mg is subcutaneously administered to osteoporotic patients at baseline, month 6 and month 12. Along with, all women will receive daily supplements containing at least 1000 mg of elemental calcium (divided into two doses) and at least 400 IU vitamin D daily during 18 months of the study.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Denosumab</intervention_name>
    <description>Denosumab 60 mg is subcutaneously administered to osteoporotic patients at baseline, month 6 and month 12.</description>
    <arm_group_label>Amgen Denosumab</arm_group_label>
    <arm_group_label>AryoGen Pharmed Denosumab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>calcium</intervention_name>
    <description>All women will receive daily supplements containing at least 1000 mg of elemental calcium (divided in two doses), during 18 month of the study.</description>
    <arm_group_label>Amgen Denosumab</arm_group_label>
    <arm_group_label>AryoGen Pharmed Denosumab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>vitamin D</intervention_name>
    <description>All women will receive daily supplements containing at least 400 IU vitamin D daily during 18 month of the study.</description>
    <arm_group_label>Amgen Denosumab</arm_group_label>
    <arm_group_label>AryoGen Pharmed Denosumab</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Postmenopausal women aged between 45 up to 75;&#xD;
&#xD;
          -  Bone mineral density T score at the lumbar spine (L1-L4), femoral neck or total hip&#xD;
             should be equal or less than -2.5 and equal or more than -4. (-4 ≤ T score ≤-2.5); or&#xD;
             patients with high risk of fracture on the basis of FRAX criteria which according to&#xD;
             osteoporosis treatment guidelines, need medicinal treatment.&#xD;
&#xD;
          -  Ability to comprehend and willingness to sign the Informed Consent Form for this&#xD;
             study;&#xD;
&#xD;
          -  Signed informed consent with full knowledge and mental health.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Lack of consent for being in the trial and not complying with an 18-months follow-up;&#xD;
&#xD;
          -  Having hypersensitivity to denosumab or any component in the formulation (excipients&#xD;
             include acetic acid, sorbitol, polysorbate 20, sodium hydroxide, water for&#xD;
             injections);&#xD;
&#xD;
          -  Malabsorption syndrome;&#xD;
&#xD;
          -  History of thyroid surgery, parathyroid surgery or intestinal resection which has been&#xD;
             caused malabsorption.&#xD;
&#xD;
          -  Patient with CKD stage 4 and 5 should be exclude (GFR &lt;30cc/min)&#xD;
&#xD;
          -  Level of serum 25-(OH) vitamin D less than 20 ng/ml; (If vitamin deficiency has been&#xD;
             corrected, and two tests show the level above 20 ng/ml within a month, the patient can&#xD;
             be enrolled.)&#xD;
&#xD;
          -  Pre-existing hypocalcemia (Albumin-adjusted serum calcium level less than 8 mg/dl in&#xD;
             fasting specimens) which is uncorrectable;&#xD;
&#xD;
          -  Untreated hypercalciuria (&gt;250 mg/24h) and hypocalciuria (&lt;100 mg/24h). If urine&#xD;
             calcium level of patient is less than 100 mg per 24 hours and by vitamin D treatment&#xD;
             the problem has been solved or if urine calcium level of patient is greater than 250&#xD;
             mg per 24 hours, but PTH is normal, the patient can be enrolled.&#xD;
&#xD;
          -  Presence of osteonecrosis of jaw (ONJ) risk factors including a diagnosis of cancer,&#xD;
             poor oral hygiene, periodontal and/or dental diseases, having dentures; and comorbid&#xD;
             disorders (anemia (hemoglobin level less than 11 g/dl, if it is corrected, patient can&#xD;
             enter the study), history of diseases with coagulopathy, oral and dental infection);&#xD;
&#xD;
          -  Malignancy;&#xD;
&#xD;
          -  Having severe and active infections; (Severe infection is a difficult treated&#xD;
             infection, like diabetic foot infection, but if the infection is treatable, after&#xD;
             treatment, the patient can be enrolled.)&#xD;
&#xD;
          -  Being bed rest (for 2 weeks during the past 3 months)&#xD;
&#xD;
          -  A case in which the patient cannot take 1000 mg oral elemental calcium per day; (as&#xD;
             supplement)&#xD;
&#xD;
          -  A case in which bone mineral density could not be accurately measured;&#xD;
&#xD;
          -  Conditions that influence bone metabolism, including hyperparathyroidism or&#xD;
             hypoparathyroidism, hyperthyroidism or hypothyroidism, hypocalcemia, inflammatory&#xD;
             rheumatologic diseases such as rheumatoid arthritis, Paget's disease of bone,&#xD;
             osteomalacia that is resistant to therapy (definition of resistant to therapy: not&#xD;
             being responder to 1-month administration of vitamin D).&#xD;
&#xD;
          -  Patients will be excluded if they have one severe or more than 2 moderate vertebral&#xD;
             fractures. (Severe fracture is defined as more than 50 percent vertebral height loss&#xD;
             and moderate fracture is defined as 25-50 percent vertebral height loss).&#xD;
&#xD;
          -  Use of injectable bisphosphonates within the previous 12 months;&#xD;
&#xD;
          -  Use of oral bisphosphonates within the previous 3 months;&#xD;
&#xD;
          -  History of severe skeletal pain with bisphosphonates;&#xD;
&#xD;
          -  Use of parathyroid hormone or its derivatives, systemic hormone-replacement therapy,&#xD;
             selective estrogen-receptor modulator, calcitonin, or calcitriol within 6 weeks before&#xD;
             study enrollment.&#xD;
&#xD;
          -  Use of corticosteroids (&gt;5 mg/prednisone daily or equivalent for ≥ 3months), in the&#xD;
             past 3 months and more.&#xD;
&#xD;
          -  Use of heparin (more than 20,000 international units/day for 6 months and longer), in&#xD;
             the past 6 months and more.&#xD;
&#xD;
          -  Patient that is possible to be administrated corticosteroids (&gt;5 mg/prednisone daily&#xD;
             or equivalent for ≥ 3months) or heparin (more than 20,000 international units/day for&#xD;
             6 months and longer) in the 18 month of the study, because of her chronic disease(s)&#xD;
             such as allergy, asthma, coagulation disorders, should be excluded.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>45 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Rheumatology Center of Iran</name>
      <address>
        <city>Tehran</city>
        <zip>021</zip>
        <country>Iran, Islamic Republic of</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Iran, Islamic Republic of</country>
  </location_countries>
  <reference>
    <citation>Lim SY, Bolster MB. Current approaches to osteoporosis treatment. Curr Opin Rheumatol. 2015 May;27(3):216-24. doi: 10.1097/BOR.0000000000000169.</citation>
    <PMID>25760281</PMID>
  </reference>
  <reference>
    <citation>Drake MT, Clarke BL, Lewiecki EM. The Pathophysiology and Treatment of Osteoporosis. Clin Ther. 2015 Aug;37(8):1837-50. doi: 10.1016/j.clinthera.2015.06.006. Epub 2015 Jul 7.</citation>
    <PMID>26163201</PMID>
  </reference>
  <reference>
    <citation>Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, Lindsay R; National Osteoporosis Foundation. Clinician's Guide to Prevention and Treatment of Osteoporosis. Osteoporos Int. 2014 Oct;25(10):2359-81. doi: 10.1007/s00198-014-2794-2. Epub 2014 Aug 15. Erratum In: Osteoporos Int. 2015 Jul;26(7):2045-7.</citation>
    <PMID>25182228</PMID>
  </reference>
  <reference>
    <citation>Cairoli E, Eller-Vainicher C, Chiodini I. Update on denosumab in the management of postmenopausal osteoporosis: patient preference and adherence. Int J Womens Health. 2015 Oct 13;7:833-9. doi: 10.2147/IJWH.S75681. eCollection 2015.</citation>
    <PMID>26508890</PMID>
  </reference>
  <reference>
    <citation>Diedhiou D, Cuny T, Sarr A, Norou Diop S, Klein M, Weryha G. Efficacy and safety of denosumab for the treatment of osteoporosis: A systematic review. Ann Endocrinol (Paris). 2015 Dec;76(6):650-7. doi: 10.1016/j.ando.2015.10.009. Epub 2015 Nov 27.</citation>
    <PMID>26639186</PMID>
  </reference>
  <reference>
    <citation>Herrero S, Pico Y. Treatments for post-menopausal osteoporotic women, what's new? How can we manage long-term treatment? Eur J Pharmacol. 2016 May 15;779:8-21. doi: 10.1016/j.ejphar.2016.02.053. Epub 2016 Feb 26.</citation>
    <PMID>26923729</PMID>
  </reference>
  <reference>
    <citation>Black DM, Rosen CJ. Clinical Practice. Postmenopausal Osteoporosis. N Engl J Med. 2016 Jan 21;374(3):254-62. doi: 10.1056/NEJMcp1513724. Erratum In: N Engl J Med. ;374(18):1797.</citation>
    <PMID>26789873</PMID>
  </reference>
  <reference>
    <citation>Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009 Aug 20;361(8):756-65. doi: 10.1056/NEJMoa0809493. Epub 2009 Aug 11. Erratum In: N Engl J Med. 2009 Nov 5;361(19):1914.</citation>
    <PMID>19671655</PMID>
  </reference>
  <reference>
    <citation>McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, Peacock M, Miller PD, Lederman SN, Chesnut CH, Lain D, Kivitz AJ, Holloway DL, Zhang C, Peterson MC, Bekker PJ; AMG 162 Bone Loss Study Group. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006 Feb 23;354(8):821-31. doi: 10.1056/NEJMoa044459.</citation>
    <PMID>16495394</PMID>
  </reference>
  <reference>
    <citation>Brown JP, Prince RL, Deal C, Recker RR, Kiel DP, de Gregorio LH, Hadji P, Hofbauer LC, Alvaro-Gracia JM, Wang H, Austin M, Wagman RB, Newmark R, Libanati C, San Martin J, Bone HG. Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J Bone Miner Res. 2009 Jan;24(1):153-61. doi: 10.1359/jbmr.0809010.</citation>
    <PMID>18767928</PMID>
  </reference>
  <reference>
    <citation>Gu HF, Gu LJ, Wu Y, Zhao XH, Zhang Q, Xu ZR, Yang YM. Efficacy and Safety of Denosumab in Postmenopausal Women With Osteoporosis: A Meta-Analysis. Medicine (Baltimore). 2015 Nov;94(44):e1674. doi: 10.1097/MD.0000000000001674.</citation>
    <PMID>26554766</PMID>
  </reference>
  <reference>
    <citation>Bone HG, Bolognese MA, Yuen CK, Kendler DL, Wang H, Liu Y, San Martin J. Effects of denosumab on bone mineral density and bone turnover in postmenopausal women. J Clin Endocrinol Metab. 2008 Jun;93(6):2149-57. doi: 10.1210/jc.2007-2814. Epub 2008 Apr 1.</citation>
    <PMID>18381571</PMID>
  </reference>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>September 19, 2017</study_first_submitted>
  <study_first_submitted_qc>September 23, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 26, 2017</study_first_posted>
  <last_update_submitted>July 8, 2020</last_update_submitted>
  <last_update_submitted_qc>July 8, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 10, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Osteoporosis</keyword>
  <keyword>Denosumab</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Osteoporosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vitamin D</mesh_term>
    <mesh_term>Denosumab</mesh_term>
    <mesh_term>Calcium</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>September 9, 2022</submitted>
    <returned>July 28, 2023</returned>
  </pending_results>
  <!-- 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/NCT03293108
org study id: DEN.ARY.AJ.95 (III)
nct id: NCT03293108
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The purpose of this study is to compare the efficacy and safety of Denosumab 60 mg produced
      by AryoGen Pharmed and Amgen Denosumab 60 mg among osteoporotic postmenopausal women.
      Postmenopausal women diagnosed with osteoporosis according to their Bone mineral density
      result (BMD), aged between 45 to 75 are included in this trial. This is a Phase III,
      randomized, two armed, double-blind, parallel, active-controlled,non-inferiority clinical
      trial. The eligible patients are randomized in a 1:1 ratio to receive Arylia or Prolia®
      subcutaneous injections, at the beginning of the trial and every 6 months at month 6 and 12,
      in an 18-month study period. Along with, all women will receive daily supplements containing
      at least 1000 mg of elemental calcium (divided into two doses) and at least 400 IU vitamin D
      daily during 18 months of the study.

      The primary objective of this study is to assess non-inferiority of test- Denosumab 60 mg
      (Arylia) to the reference Denosumab 60 mg (Prolia®) in terms of efficacy among osteoporotic
      postmenopausal women.

      The secondary objectives of this study are:

      To further compare efficacy of test- Denosumab 60 mg to reference Denosumab 60 mg; To assess
      the safety of test- Denosumab 60 mg compared to reference Denosumab 60 mg.
The purpose of this study is to compare the efficacy and safety of Denosumab 60 mg produced
      by AryoGen Pharmed and Amgen Denosumab 60 mg among osteoporotic postmenopausal women.
      Postmenopausal women diagnosed with osteoporosis according to their Bone mineral density
      result (BMD) and aged between 45 to 75 are included in this trial. This is a Phase III,
      randomized, two armed, double-blind, parallel, active-controlled,non-inferiority clinical
      trial. Visits are going to be conducted at screening, 0, 1, 3, 6, 9, 12, 15 and 18 months.

      After signing the written informed consent, patients are randomized in a 1:1 ratio to receive
      Arylia or Prolia® subcutaneous injections, at the beginning of the trial and every 6 months
      at month 6 and 12, in an 18-month study period. Along with, all women will receive daily
      supplements containing at least 1000 mg of elemental calcium (divided into two doses) and at
      least 400 IU vitamin D daily during 18 months of the study.

      The primary objective of this study is to assess percentage change from baseline in BMD at
      the lumbar spine (L1-L4), femoral neck and total hip by dual-energy x-ray absorptiometry to
      18 months of the study, and compare it between two treatment groups.

      The second objectives of this study are to assess the followings between treatment groups:

        -  The incidence of new vertebral fracture;

        -  Evolution of biochemical markers of bone metabolism at baseline, first month and
           afterward every 3 months from baseline.

        -  Comparing adverse events;

        -  Comparing immunogenicity of two products.

      Before initiation, the trial is reviewed by food and drug administration of Iran. The
      protocol, electronic case report form (eCRF), information for patients and informed consent
      forms are submitted to the ethics committees responsible for review and approval purposes,
      according to national regulatory guidelines.

      Sample size:

      172 patients will be equally (1:1) divided into intervention arms for achieving 80% power in
      order to determine non-inferiority using a one-sided, independent sample t-test. Efficacy of
      Prolia® in comparison with placebo for lumbar spine BMD improvement in previous studies is
      reported 7.1%. The margin of non-inferiority is 1.78. The true difference between the means
      is assumed to be 0.000. The significance level (alpha) of the test is 0.025. The data are
      drawn from populations with standard deviations of 4.116 and 4.116. However, we have
      calculated that 190 patients should enter the study, by considering that there might be 10%
      drop-outs of participants during the trial.

      Blinding:

      To prevent the influence of knowing intervention group on study conclusion, the subjects and
      those who assess the study outcomes will be unaware of the state of the patient with regard
      to receiving the test drug or reference drug.

      For this purpose, subjects and administrator of the drug will be blinded by using a similar
      masked prefilled syringes. All drugs packages will be identified by unique numbers.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: BMD percentage change from baseline at lumbar spine (L1-L4), femoral neck and total hip.
time frame: Baseline and at 18 months.
description: Percentage change from baseline in BMD at lumbar spine (L1-L4), femoral neck and total hip by dual-energy x-ray absorptiometry to 18 months of the study, and compare between two groups.
measure: The incidence of new vertebral fracture.
time frame: Baseline and at 18 months
description: The incidence of new vertebral fracture assessed by Lateral spine X-ray radiography (T4-L4) at baseline then at 18 months, and compare between two groups.
measure: Evolution of biochemical markers of bone metabolism.
time frame: Baseline,at month 1,at month 3,at month 6,at month 9, at month 12, at month 15 and at month 18.
description: Evolution of biochemical markers of bone metabolism at baseline, first month and afterwards every 3 months from baseline, and compare between two groups.
measure: Comparing adverse events between two products.
time frame: baseline,at month 1,at month 3,at month 6,at month 9,at month 12, at month 15 and at month 18.
description: Evaluation of the following parameters at each visit including 0, 1, 3, 6, 9, 12, 15 and 18 months, and compare between two groups.
Adverse events (AEs), Adverse drug reactions (ADR)
Changes in physical examination findings
Changes in vital signs
Clinical laboratory testing for systemic safety, including liver function, renal function, complete blood count, and clinical chemistries.
measure: Comparing immunogenicity between two products.
time frame: Baseline,at month 6,at month 12 and at month 18.
description: Evaluation of immunogenicity at visit 0, 6, 12 and 18 months for both arms, and compare between two groups.
arm group label: AryoGen Pharmed Denosumab
arm group type: Experimental
description: Arylia (Denosumab Prefilled Syringe produced by AryoGen Pharmed) 60 mg/1 ml in a prefilled syringe.
Denosumab 60 mg is subcutaneously administered to osteoporotic patients at baseline, month 6 and month 12. Along with, all women will receive daily supplements containing at least 1000 mg of elemental calcium (divided into two doses) and at least 400 IU vitamin D daily during 18 months of the study.
arm group label: Amgen Denosumab
arm group type: Active Comparator
description: Prolia® (Denosumab Prefilled Syringe produced by Amgen) 60 mg/1 ml in a prefilled syringe.
Denosumab 60 mg is subcutaneously administered to osteoporotic patients at baseline, month 6 and month 12. Along with, all women will receive daily supplements containing at least 1000 mg of elemental calcium (divided into two doses) and at least 400 IU vitamin D daily during 18 months of the study.
intervention type: Drug
intervention name: Denosumab
description: Denosumab 60 mg is subcutaneously administered to osteoporotic patients at baseline, month 6 and month 12.
arm group label: Amgen Denosumab
arm group label: AryoGen Pharmed Denosumab
intervention type: Dietary Supplement
intervention name: calcium
description: All women will receive daily supplements containing at least 1000 mg of elemental calcium (divided in two doses), during 18 month of the study.
arm group label: Amgen Denosumab
arm group label: AryoGen Pharmed Denosumab
intervention type: Dietary Supplement
intervention name: vitamin D
description: All women will receive daily supplements containing at least 400 IU vitamin D daily during 18 month of the study.
arm group label: Amgen Denosumab
arm group label: AryoGen Pharmed Denosumab
criteria: 
gender: Female
minimum age: 45 Years
maximum age: 75 Years
healthy volunteers: No
facility: 
country: Iran, Islamic Republic of
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PMID: 25182228
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PMID: 26508890
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PMID: 26789873
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responsible party type: Sponsor
mesh term: Osteoporosis
mesh term: Vitamin D
mesh term: Denosumab
mesh term: Calcium
sharing ipd: No
submitted: September 9, 2022
returned: July 28, 2023