<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/NCT04476511</url>
  </required_header>
  <id_info>
    <org_study_id>PAT17-LOADS</org_study_id>
    <secondary_id>2018-000508-40</secondary_id>
    <nct_id>NCT04476511</nct_id>
  </id_info>
  <brief_title>The Efficacy and the Safety of Vitamin D3 30,000 IU for Loading Dose Schedules</brief_title>
  <official_title>Controlled Randomized Open Label Clinical Study to Compare the Efficacy and the Safety of the Loading Dose Schedules of Vitamin D3 (Colecalciferol) 30,000 IU Product in Deficient Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Semmelweis University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Pharma Patent Kft.</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Semmelweis University</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>
      Treatment: A: Slower Loading Group (SLD): 30.000 IU cholecalciferol once weekly for ten&#xD;
      weeks, followed by 30.000 IU cholecalciferol every two weeks for four weeks.&#xD;
&#xD;
      B: Moderate Loading Dose group (MLD): 30.000 IU cholecalciferol twice weekly for five weeks,&#xD;
      followed by 30.000 IU cholecalciferol every two weeks for four weeks.&#xD;
&#xD;
      Every patients will receive calcium-citrate supplementation if average daily calcium intake&#xD;
      does not reach the recommended daily amount.&#xD;
&#xD;
      Setting: two-arms, controlled, randomised, comparative open-label, multicentric clinical&#xD;
      trial aimed to assess the comparative efficacy on 25(OH)D elevation and on safety of the two&#xD;
      loading dose schedules of 30.000 IU Vitamin D3 oral tablets (administered as &quot;Moderate&#xD;
      Loading Dose&quot;or &quot;Slower Loading Dose&quot;) combined with an follow-up maintenance period of&#xD;
      biweekly administration. The comparative assessment is based on the elevation of 25(OH)D&#xD;
      levels due to treatment efficacy from baseline and by the end of the maintenance (biweekly&#xD;
      30.000 IU) period for each treatment groups, and also the ratio of patients in target range&#xD;
      (30-50 ng/ml) in order to evaluate the most beneficial &quot;loading dose&quot; schedule. Upon the&#xD;
      serum 25(OH)D levels are exceeded the 55ng/ml limits by the end of the loading period the&#xD;
      trial subjects should continue with the standard maintenance dose of vitamin D3 for the&#xD;
      remaining four weeks of the study. The evaluation of the comparative safety will be done also&#xD;
      by controlling the serum and the urinary calcium levels and the registration of adverse drug&#xD;
      reaction.&#xD;
&#xD;
      The primary objective is to assess the efficacy of the orally administered loading dose&#xD;
      schedules of vitamin D3 in deficient patients. Efficacy is measured as the elevation of&#xD;
      25(OH)D levels compared to baseline.&#xD;
&#xD;
      Rationale: Oral vitamin D3 is the treatment of choice in vitamin D deficiency. The UK NOS&#xD;
      guideline recommended where rapid correction of vitamin D deficiency is required, such as in&#xD;
      patients with symptomatic disease or about to start treatment with a potent antiresorptive&#xD;
      agent, the recommended treatment regimen is based on fixed loading doses followed by regular&#xD;
      maintenance therapy. The loading dose regimen to provide a total of approximately 300,000 IU&#xD;
      vitamin D, given either as separate weekly or daily doses over 6 to 10 weeks followed by a&#xD;
      maintenance therapy comprising vitamin D in doses equivalent to 800-2000 IU daily in general&#xD;
      or up to 4,000 IU daily), given either daily or intermittently at higher doses. (NOS&#xD;
      guidelines 2014). Recent research on vitamin D and the widening range of therapeutic&#xD;
      applications available for cholecalciferol, which can be classified as both a vitamin and a&#xD;
      pro-hormone. Additionally, it was now realized that the Food and Nutrition Board's previously&#xD;
      defined Upper Limit (UL) for safe intake at 2,000 IU/day was set far too low and that the&#xD;
      physiologic requirement for vitamin D in adults may be as high as 5,000 IU/day, which is less&#xD;
      than half of the &gt;10,000 IU that can be produced endogenously with full-body sun exposure.&#xD;
&#xD;
      In a recent study showed that the safety of doses over 2000 IU/day-4000 IU/day for 3 months&#xD;
      resulting in a ~360,000 UI cumulative dose. According to the study results, for the majority&#xD;
      of the patients the 4000 IU/day (360,000 UI cumulative dose) was needed to achieve a 25(OH)D&#xD;
      serum concentration above 75nmol/L (30 ng/mL), which is otherwise set as the target value by&#xD;
      Endocrine Society Clinical Practice Guideline (Holick 2011b).&#xD;
&#xD;
      Another study (Verussio et al 2014) cited shows the safety and efficacy of 50.000 IU/week for&#xD;
      8 weeks (400,000 UI cumulative dose for 8 weeks), followed by 25,000 IU twice a month which&#xD;
      was more effective in raising the 25(OH)D level to the target range (of &gt;30 ng/L) than 25,000&#xD;
      IU twice a month (50,000 IU/ month). In the latter group only 40% of the patients reached the&#xD;
      target 25(OH)D levels at 6 months, compared to the 72% in the first group. The study supports&#xD;
      efficacy of dosing and safety of the treatment of vitamin D deficiency a 50,000 IU /week&#xD;
      loading dose scheme with a 8 weeks cumulative dose of &gt;400,000 UI.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 5, 2018</start_date>
  <completion_date type="Actual">December 15, 2021</completion_date>
  <primary_completion_date type="Actual">December 15, 2021</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>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Serum 25-hydroxyvitamin-D increase after loading period</measure>
    <time_frame>5/10 weeks</time_frame>
    <description>Serum 25OHD level will be measured at screening, after loading period and after maintenance period</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Proportion of subjects reaching target range of serum 25-hydroxyvitamin-D after loading dose</measure>
    <time_frame>5/10 weeks</time_frame>
    <description>Serum 25OHD level will be measured at screening, after loading period and after maintenance period. Target range: 30-50 ng/ml</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of subjects remaining in target range of serum 25-hydroxyvitamin-D after maintenance dose</measure>
    <time_frame>4 weeks</time_frame>
    <description>Serum 25OHD level will be measured at screening, after loading period and after maintenance period. Target range: 30-50 ng/ml</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Efficacy of maintenance dose</measure>
    <time_frame>4 weeks</time_frame>
    <description>Serum 25OHD level will be measured at screening, after loading period and after maintenance period. Target range: 30-50 ng/ml</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frequency of adverse events</measure>
    <time_frame>up to 20 weeks, continuously</time_frame>
    <description>Adverse event recording will be performed at every study visits and unscheduled visits if applicable.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum calcium level</measure>
    <time_frame>up to 20 weeks, continuously</time_frame>
    <description>Serum calcium level will be measured at screening, after loading period and after maintenance period and whenever clinically relevant.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Urinary calcium excretion</measure>
    <time_frame>whole study</time_frame>
    <description>Urinary calcium level will be measured at screening, after loading period and after maintenance period and whenever clinically relevant from 24 hours collected urine.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Bone turnover markers</measure>
    <time_frame>up to 20 weeks, continuously</time_frame>
    <description>osteocalcin; collagen-ß-crosslaps</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">75</enrollment>
  <condition>Vitamin D Deficiency</condition>
  <arm_group>
    <arm_group_label>Slower Loading Dose</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>30.000IU cholecalciferol once weekly for ten weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Moderate Loading Dose</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>30.000IU cholecalciferol twice weekly for five weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cholecalciferol</intervention_name>
    <description>tablet containing 30.000IU cholecalciferol</description>
    <arm_group_label>Moderate Loading Dose</arm_group_label>
    <arm_group_label>Slower Loading Dose</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age between 18 and 70 years&#xD;
&#xD;
          -  25OHD level is no more than 16 ng/ml&#xD;
&#xD;
          -  Postmenopausal state or adequate contraception in female patients&#xD;
&#xD;
          -  Willing and able to give legal informed consent for study entry&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Severe endocrine or metabolic disease, significant metabolic bone disease (except&#xD;
             primary age-related osteoporosis)&#xD;
&#xD;
          -  significant obesity (BMI &gt;36 kg/m2)&#xD;
&#xD;
          -  hypercalcemia at screening or within one year (seCa &gt; 2.60 mmol/l)&#xD;
&#xD;
          -  long standing hypercalciuria, kidney stones within 2 years&#xD;
&#xD;
          -  sever kidney injury (KDIGO CKD 3 or more)&#xD;
&#xD;
          -  chronic disease which significantly affects bone metabolism, vitamin D metabolism or&#xD;
             calcium absorption&#xD;
&#xD;
          -  significant malabsorption that affects calcium metabolism&#xD;
&#xD;
          -  heart failure or angina pectoris&#xD;
&#xD;
          -  alcohol or drug abuse&#xD;
&#xD;
          -  daily vitamin D intake is more than 1000 IU within 2 months&#xD;
&#xD;
          -  suspected or proved pregnancy&#xD;
&#xD;
          -  any other symptoms or findings which may interact with the safety of the study drug,&#xD;
             evaluated by investigator&#xD;
&#xD;
          -  participating in other clinical trial within 3 months of study entry&#xD;
&#xD;
          -  planned journey to geographic location with high natural UV-B exposition for mor than&#xD;
             4 days during the study or regular (more than 2 times per month) artificial UV-B&#xD;
             exposition (eg. sun parlor)&#xD;
&#xD;
          -  Taking prohibited medication:&#xD;
&#xD;
          -  glycosides&#xD;
&#xD;
          -  magnesium containing medications (eg. antacids)&#xD;
&#xD;
          -  cholestyramine and other ion exchange resins, orlistat&#xD;
&#xD;
          -  thiazide type diuretics&#xD;
&#xD;
          -  microsomal enzyme inductors (eg. anticonvulsants, sedatives)&#xD;
&#xD;
          -  corticosteroids&#xD;
&#xD;
          -  phosphates&#xD;
&#xD;
          -  laxatives&#xD;
&#xD;
          -  medications decreasing lipid absorption&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Istvan Takacs, MD, PhD, DSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>Semmelweis University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Semmelweis University - Dept. of Medicine and Oncology</name>
      <address>
        <city>Budapest</city>
        <zip>1083</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Uno Medical Trials Kft.</name>
      <address>
        <city>Budapest</city>
        <zip>1135</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Central Hospital of the Hungarian Homeland Defence Forces</name>
      <address>
        <city>Budapest</city>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Szalay János Outpatient Clinic</name>
      <address>
        <city>Hajdúnánás</city>
        <zip>4080</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Somogy County Kaposi Mór Teaching Hospital</name>
      <address>
        <city>Kaposvár</city>
        <zip>7400</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Jutrix Healthcare Ltd.</name>
      <address>
        <city>Kecskemét</city>
        <zip>6000</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rub-Int Health Center</name>
      <address>
        <city>Székesfehérvár</city>
        <zip>8000</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Hungary</country>
  </location_countries>
  <verification_date>March 2022</verification_date>
  <study_first_submitted>May 5, 2019</study_first_submitted>
  <study_first_submitted_qc>July 14, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 20, 2020</study_first_posted>
  <last_update_submitted>March 3, 2022</last_update_submitted>
  <last_update_submitted_qc>March 3, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 4, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Semmelweis University</investigator_affiliation>
    <investigator_full_name>Istvan Takacs</investigator_full_name>
    <investigator_title>M.D., DSc., Director of Department</investigator_title>
  </responsible_party>
  <keyword>vitamin D deficiency</keyword>
  <keyword>vitamin D loading dose</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vitamin D Deficiency</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cholecalciferol</mesh_term>
    <mesh_term>Vitamin D</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04476511
org study id: PAT17-LOADS
secondary id: 2018-000508-40
nct id: NCT04476511
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Treatment: A: Slower Loading Group (SLD): 30.000 IU cholecalciferol once weekly for ten
      weeks, followed by 30.000 IU cholecalciferol every two weeks for four weeks.

      B: Moderate Loading Dose group (MLD): 30.000 IU cholecalciferol twice weekly for five weeks,
      followed by 30.000 IU cholecalciferol every two weeks for four weeks.

      Every patients will receive calcium-citrate supplementation if average daily calcium intake
      does not reach the recommended daily amount.

      Setting: two-arms, controlled, randomised, comparative open-label, multicentric clinical
      trial aimed to assess the comparative efficacy on 25(OH)D elevation and on safety of the two
      loading dose schedules of 30.000 IU Vitamin D3 oral tablets (administered as "Moderate
      Loading Dose"or "Slower Loading Dose") combined with an follow-up maintenance period of
      biweekly administration. The comparative assessment is based on the elevation of 25(OH)D
      levels due to treatment efficacy from baseline and by the end of the maintenance (biweekly
      30.000 IU) period for each treatment groups, and also the ratio of patients in target range
      (30-50 ng/ml) in order to evaluate the most beneficial "loading dose" schedule. Upon the
      serum 25(OH)D levels are exceeded the 55ng/ml limits by the end of the loading period the
      trial subjects should continue with the standard maintenance dose of vitamin D3 for the
      remaining four weeks of the study. The evaluation of the comparative safety will be done also
      by controlling the serum and the urinary calcium levels and the registration of adverse drug
      reaction.

      The primary objective is to assess the efficacy of the orally administered loading dose
      schedules of vitamin D3 in deficient patients. Efficacy is measured as the elevation of
      25(OH)D levels compared to baseline.

      Rationale: Oral vitamin D3 is the treatment of choice in vitamin D deficiency. The UK NOS
      guideline recommended where rapid correction of vitamin D deficiency is required, such as in
      patients with symptomatic disease or about to start treatment with a potent antiresorptive
      agent, the recommended treatment regimen is based on fixed loading doses followed by regular
      maintenance therapy. The loading dose regimen to provide a total of approximately 300,000 IU
      vitamin D, given either as separate weekly or daily doses over 6 to 10 weeks followed by a
      maintenance therapy comprising vitamin D in doses equivalent to 800-2000 IU daily in general
      or up to 4,000 IU daily), given either daily or intermittently at higher doses. (NOS
      guidelines 2014). Recent research on vitamin D and the widening range of therapeutic
      applications available for cholecalciferol, which can be classified as both a vitamin and a
      pro-hormone. Additionally, it was now realized that the Food and Nutrition Board's previously
      defined Upper Limit (UL) for safe intake at 2,000 IU/day was set far too low and that the
      physiologic requirement for vitamin D in adults may be as high as 5,000 IU/day, which is less
      than half of the >10,000 IU that can be produced endogenously with full-body sun exposure.

      In a recent study showed that the safety of doses over 2000 IU/day-4000 IU/day for 3 months
      resulting in a ~360,000 UI cumulative dose. According to the study results, for the majority
      of the patients the 4000 IU/day (360,000 UI cumulative dose) was needed to achieve a 25(OH)D
      serum concentration above 75nmol/L (30 ng/mL), which is otherwise set as the target value by
      Endocrine Society Clinical Practice Guideline (Holick 2011b).

      Another study (Verussio et al 2014) cited shows the safety and efficacy of 50.000 IU/week for
      8 weeks (400,000 UI cumulative dose for 8 weeks), followed by 25,000 IU twice a month which
      was more effective in raising the 25(OH)D level to the target range (of >30 ng/L) than 25,000
      IU twice a month (50,000 IU/ month). In the latter group only 40% of the patients reached the
      target 25(OH)D levels at 6 months, compared to the 72% in the first group. The study supports
      efficacy of dosing and safety of the treatment of vitamin D deficiency a 50,000 IU /week
      loading dose scheme with a 8 weeks cumulative dose of >400,000 UI.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Serum 25-hydroxyvitamin-D increase after loading period
time frame: 5/10 weeks
description: Serum 25OHD level will be measured at screening, after loading period and after maintenance period
measure: Proportion of subjects reaching target range of serum 25-hydroxyvitamin-D after loading dose
time frame: 5/10 weeks
description: Serum 25OHD level will be measured at screening, after loading period and after maintenance period. Target range: 30-50 ng/ml
measure: Proportion of subjects remaining in target range of serum 25-hydroxyvitamin-D after maintenance dose
time frame: 4 weeks
description: Serum 25OHD level will be measured at screening, after loading period and after maintenance period. Target range: 30-50 ng/ml
measure: Efficacy of maintenance dose
time frame: 4 weeks
description: Serum 25OHD level will be measured at screening, after loading period and after maintenance period. Target range: 30-50 ng/ml
measure: Frequency of adverse events
time frame: up to 20 weeks, continuously
description: Adverse event recording will be performed at every study visits and unscheduled visits if applicable.
measure: Serum calcium level
time frame: up to 20 weeks, continuously
description: Serum calcium level will be measured at screening, after loading period and after maintenance period and whenever clinically relevant.
measure: Urinary calcium excretion
time frame: whole study
description: Urinary calcium level will be measured at screening, after loading period and after maintenance period and whenever clinically relevant from 24 hours collected urine.
measure: Bone turnover markers
time frame: up to 20 weeks, continuously
description: osteocalcin; collagen-ß-crosslaps
arm group label: Slower Loading Dose
arm group type: Active Comparator
description: 30.000IU cholecalciferol once weekly for ten weeks
arm group label: Moderate Loading Dose
arm group type: Active Comparator
description: 30.000IU cholecalciferol twice weekly for five weeks
intervention type: Drug
intervention name: Cholecalciferol
description: tablet containing 30.000IU cholecalciferol
arm group label: Moderate Loading Dose
arm group label: Slower Loading Dose
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Istvan Takacs, MD, PhD, DSc
role: Principal Investigator
affiliation: Semmelweis University
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Hungary
responsible party type: Principal Investigator
investigator affiliation: Semmelweis University
investigator full name: Istvan Takacs
investigator title: M.D., DSc., Director of Department
mesh term: Vitamin D Deficiency
mesh term: Cholecalciferol
mesh term: Vitamin D
sharing ipd: Undecided