<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/NCT03288324</url>
  </required_header>
  <id_info>
    <org_study_id>WI211648</org_study_id>
    <nct_id>NCT03288324</nct_id>
  </id_info>
  <brief_title>Open-label Study of Tofacitinib for Moderate to Severe Skin Involvement in Young Adults With Lupus</brief_title>
  <official_title>A 3-part Open-label Study Assessing Safety, Tolerability, Pharmacokinetic and -Dynamic Profiles, and Efficacy of Tofacitinib in Young Adults From Age 18 to 45 With Moderate to Severe Skin Involvement Due to Lupus</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Children's Hospital Medical Center, Cincinnati</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Pfizer</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Children's Hospital Medical Center, Cincinnati</source>
  <oversight_info>
    <has_dmc>No</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>
      This 76-week, 3-part Phase 1b/2 study is intended to evaluate the pharmacological properties&#xD;
      (pharmacokinetics and pharmacodynamics), safety, tolerability and preliminary effectiveness&#xD;
      of TOFA administrated to young adults (18-45 years) with moderately to severely active&#xD;
      SLE-CL. Subjects will be studied at the Cincinnati Children's Hospital Medical Center (CCHMC)&#xD;
      and in Cleveland at MetroHealth Medical Center.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Cohort 1 (n=10, weight &gt; 40kg and age &gt; 18 years and ≤ 45 years ) will undergo intense&#xD;
      PK-sampling to determine exposures following TOFA dosed at 5 mg BID. TOFA dose escalation&#xD;
      will not be considered for inadequate response of SLE-CL.&#xD;
&#xD;
      Cohort 2 (n=10, weight &gt; 40kg and age &gt; 18 years and ≤ 45 years) will be treated with the&#xD;
      same dose as Cohort 1. No PK sampling will occur for Cohort 2. Enrollment of Cohort 2 will&#xD;
      only start once Cohort 1 has completed 8 weeks of TOFA and results of PK analyses from Cohort&#xD;
      1 are available.&#xD;
&#xD;
        -  Part A (up to week 8) requires stable background medications;&#xD;
&#xD;
        -  Part B (up to week 24) allows for tapering of corticosteroids (CS) in the setting of&#xD;
           significant clinical improvement of SLE-CL as defined by a decrease in Cutaneous Lupus&#xD;
           Erythematosus Disease Area and Severity Index (CLASI) activity score by &gt;50% from&#xD;
           baseline , and&#xD;
&#xD;
        -  Part C (until week 76) permits tapering of other background medications in subjects with&#xD;
           clinical remission of SLE-CL (CLASI activity score=0). TOFA dosing is kept stable during&#xD;
           Part C.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 23, 2017</start_date>
  <completion_date type="Actual">December 1, 2022</completion_date>
  <primary_completion_date type="Actual">November 1, 2022</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Oral Clearance (CL/F) (Cohort 1 only)</measure>
    <time_frame>Day 5</time_frame>
    <description>Apparent total clearance of the drug from plasma after oral administration</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) score</measure>
    <time_frame>weeks 4, 8 and 24 compared to baseline.</time_frame>
    <description>Proportion of subjects who achieve a skin response per the validated CLASI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUCt (Cohort 1 only)</measure>
    <time_frame>Day 5</time_frame>
    <description>Area under the plasma concentration-time curve from time zero to time t</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cmax (Cohort 1 only)</measure>
    <time_frame>Day 5</time_frame>
    <description>Maximum (or peak) plasma concentration of Tofacitinib</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>tmax (Cohort 1 only)</measure>
    <time_frame>Day 5</time_frame>
    <description>Time to reach maximum (peak) plasma concentration following administration of Tofacitinib</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Vz/F (Cohort 1 only)</measure>
    <time_frame>Day 5</time_frame>
    <description>Apparent volume of distribution during terminal phase after non-intravenous administration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>half-life of Tofacitinib (Cohort 1 only)</measure>
    <time_frame>Day 5</time_frame>
    <description>half-life of Tofacitinib</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety of Tofacitinib: Nature, severity, and frequency of adverse events (Cohorts 1 and 2)</measure>
    <time_frame>76 weeks</time_frame>
    <description>Rate and severity of adverse events and lab abnormalities</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Steroid dose comparison</measure>
    <time_frame>76 weeks</time_frame>
    <description>Assess steroid sparing properties of Tofacitinib by comparing doses to baseline and rate of steroid discontinuation</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in SLE Disease Activity Index (SLEDAI) score</measure>
    <time_frame>76 weeks</time_frame>
    <description>Measure Tofacitinib impact on disease activity</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in British Isles Lupus Activity Group (BILAG) score</measure>
    <time_frame>76 weeks</time_frame>
    <description>Measure Tofacitinib impact on disease activity</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in SKINDEX score</measure>
    <time_frame>Baseline, week 24 and week 76</time_frame>
    <description>Quality-of-life measure for patients with skin disease</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in patients global assessment score</measure>
    <time_frame>Baseline, week 24 and week 76</time_frame>
    <description>Quality-of-life measure for patients</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">13</enrollment>
  <condition>Cutaneous Lupus</condition>
  <condition>Systemic Lupus Erythematosus</condition>
  <arm_group>
    <arm_group_label>Tofacitinib Arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>open-label study</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tofacitinib</intervention_name>
    <description>Tofacitinib 5 mg twice daily</description>
    <arm_group_label>Tofacitinib Arm</arm_group_label>
    <other_name>Xeljanz</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male or female &gt; 18 years of age and &lt; 45 years of age and &gt; 40 kg body weight.&#xD;
&#xD;
          2. Fulfilled at least 4 out of the 11 Classification Criteria for SLE by the time of&#xD;
             screening.&#xD;
&#xD;
          3. Willing to give written informed consent, must fully understand the requirements of&#xD;
             the trial, and must be willing to comply with all trial visits and assessments.&#xD;
&#xD;
          4. CLASI activity score of 8 or higher at screening and baseline despite standard of care&#xD;
             therapy.&#xD;
&#xD;
          5. Stable dose of prednisone of ≤ 20 mg/day within 2 weeks of enrollment.&#xD;
&#xD;
          6. Female subjects of childbearing potential must use a highly effective method of&#xD;
             contraception to prevent pregnancy (abstinence is considered highly effective) and&#xD;
             must agree to continue to practice adequate contraception for the duration of their&#xD;
             participation in the trial and for 28 days after their last dose of TOFA.&#xD;
&#xD;
          7. Female subjects of childbearing potential must have a negative serum pregnancy test at&#xD;
             screening and a negative urine pregnancy test at Trial Day 1 before dosing.&#xD;
&#xD;
          8. For subjects receiving leflunomide treatment, total daily dose does not exceed 20 mg.&#xD;
&#xD;
          9. A negative QuantiFERON-TB Gold In-Tube test performed within the 3 months prior to&#xD;
             screening, or within the screening period prior to baseline. A negative PPD test can&#xD;
             be substituted for the QuantiFERON-TB.&#xD;
&#xD;
         10. Subjects either have protective varicella titers or evidence of having been vaccinated&#xD;
             against varicella.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Mild SLE-CL defined as a CLASI activity score of 7 or lower at screening and baseline.&#xD;
&#xD;
          2. Increase in CS dosing within 2 weeks prior to Trial Day 1, or expected to require an&#xD;
             increase in CS dosing during the first 4 weeks of the study.&#xD;
&#xD;
          3. Use of i.v. corticosteroids within 4 weeks prior to Trial Day 1.&#xD;
&#xD;
          4. Increase in dosing of methotrexate, leflunomide, within 4 weeks before Trial Day 1 or&#xD;
             expected to require an increase during the first 8-weeks of the study.&#xD;
&#xD;
          5. Increase in dosing of hydroxychloroquine, or chloroquine within 4 weeks before Trial&#xD;
             Day 1 or expected to require an increase during the first 8-weeks of the study.&#xD;
&#xD;
          6. Rituximab within 1 year of Trial Day 1.&#xD;
&#xD;
          7. Increase in dosing of any medication or herbal treatment considered to have&#xD;
             immunosuppressive properties with 4 weeks before Trial Day 1.&#xD;
&#xD;
          8. Prior treatment with or known intolerability of TOFA.&#xD;
&#xD;
          9. Use of cyclophosphamide (i.v. or oral), cyclosporine, or tacrolimus within 12 weeks&#xD;
             prior to Trial Day 1.&#xD;
&#xD;
         10. Treatment with other investigational agents within the last 6 months or 5 half-lives,&#xD;
             or as per washout requirement from the previous protocol, whichever is longer.&#xD;
&#xD;
         11. Estimated glomerular filtration rate less than or equal to 60 mL/min /1.73 m2.&#xD;
&#xD;
         12. Known positive Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV), or&#xD;
             Hepatitis B surface antigen (HBsAg) serology.&#xD;
&#xD;
         13. Any condition, including findings in the laboratory tests, medical history, or other&#xD;
             screening assessments, that, in the opinion of the Investigator, constitutes an&#xD;
             inappropriate risk or a contraindication for participation in the trial or that could&#xD;
             interfere with the trial's objectives, conduct, or evaluation.&#xD;
&#xD;
         14. Active central nervous system SLE deemed to be severe or progressive and/or associated&#xD;
             with significant cognitive impairment leading to inability to provide informed consent&#xD;
             and/or comply with the protocol.&#xD;
&#xD;
         15. Significant renal disease due to a reason(s) other than Lupus Nephritis (e.g. diabetes&#xD;
             mellitus, renovascular disease, or antiphospholipid syndrome).&#xD;
&#xD;
         16. Severely active Lupus Nephritis defined as a renal BILAG A score.&#xD;
&#xD;
         17. History of dialysis within 3 months prior to Trial Day 1 or expected to need during&#xD;
             the trial.&#xD;
&#xD;
         18. History of or planned renal or other organ transplantation.&#xD;
&#xD;
         19. Known active clinically significant viral, bacterial or fungal infection, or any major&#xD;
             episode of infection requiring hospitalization or treatment with parenteral&#xD;
             anti-infectives within 8 weeks of screening, or completion of oral anti-infectives&#xD;
             within 2 weeks of Trial Day 1.&#xD;
&#xD;
         20. Breastfeeding or currently pregnant.&#xD;
&#xD;
         21. Legal incapacity or limited legal capacity to provide informed consent or assent.&#xD;
&#xD;
         22. Blood dyscrasias, including:&#xD;
&#xD;
               -  Hgb &lt;10 g/dL or Hct &lt;33%.&#xD;
&#xD;
               -  WBC &lt;3.0 x 109/L.&#xD;
&#xD;
               -  Neutrophil count &lt;1.2 x 109/L.&#xD;
&#xD;
               -  Platelet count &lt;100 x 109/L.&#xD;
&#xD;
               -  Lymphocyte count of &lt;0.5 x 109/L.&#xD;
&#xD;
         23. AST or ALT &gt; 1.5 times the upper limit of normal or any other clinically significant&#xD;
             laboratory abnormality.&#xD;
&#xD;
         24. History of any other rheumatic autoimmune disease.&#xD;
&#xD;
         25. Infections:&#xD;
&#xD;
               -  Latent or active TB or any history of previous TB.&#xD;
&#xD;
               -  Chronic infections.&#xD;
&#xD;
               -  Any infection requiring hospitalization, parenteral antimicrobial therapy or&#xD;
                  judged to be opportunistic by the investigator within the 6 months prior to the&#xD;
                  first dose of study drug.&#xD;
&#xD;
               -  Any treated infections within 2 weeks.&#xD;
&#xD;
               -  History of recurrent (more than one episode) herpes zoster or disseminated (a&#xD;
                  single episode) herpes zoster or disseminated (a single episode) herpes simplex.&#xD;
&#xD;
               -  History or current symptoms suggestive of any lymphoproliferative disorder,&#xD;
                  including Cytomegaly Virus (CMV) or Epstein Barr Virus (EBV) related&#xD;
                  lymphoproliferative disorder, history of lymphoma, leukemia, or signs and&#xD;
                  symptoms suggestive of current lymphatic disease.&#xD;
&#xD;
         26. Subjects taking potent and moderate cytochrome P450 3A4 (CYP3A4) inhibitors (see&#xD;
             Appendix 2).&#xD;
&#xD;
         27. Subjects taking potent and moderate CYP3A4 inducers (see Appendix 2).&#xD;
&#xD;
         28. Subjects who have been vaccinated with live or attenuated vaccines within the 6 weeks&#xD;
             prior to the first dose of study medication. All subjects should be up-to-date with&#xD;
             respect to standard of care vaccinations (as defined by their country health ministry)&#xD;
             as permitted by past immunosuppressive therapy for SLE.&#xD;
&#xD;
         29. Subjects with a malignancy or with a history of malignancy with the exception of&#xD;
             adequately treated or excised non-metastatic basal cell or squamous cell cancer of the&#xD;
             skin or cervical carcinoma in situ.&#xD;
&#xD;
         30. Subjects with a history or current diagnosis of diverticulitis.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Hermine Brunner, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Cincinnati Childrens Hospital Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cincinnati Childrens Hospital Medical Center</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MetroHealth Medical Center</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>August 29, 2017</study_first_submitted>
  <study_first_submitted_qc>September 18, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 20, 2017</study_first_posted>
  <last_update_submitted>August 29, 2023</last_update_submitted>
  <last_update_submitted_qc>August 29, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 30, 2023</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>Lupus Erythematosus, Systemic</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tofacitinib</mesh_term>
  </intervention_browse>
  <!-- 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/NCT03288324
org study id: WI211648
nct id: NCT03288324
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This 76-week, 3-part Phase 1b/2 study is intended to evaluate the pharmacological properties
      (pharmacokinetics and pharmacodynamics), safety, tolerability and preliminary effectiveness
      of TOFA administrated to young adults (18-45 years) with moderately to severely active
      SLE-CL. Subjects will be studied at the Cincinnati Children's Hospital Medical Center (CCHMC)
      and in Cleveland at MetroHealth Medical Center.
Cohort 1 (n=10, weight > 40kg and age > 18 years and ≤ 45 years ) will undergo intense
      PK-sampling to determine exposures following TOFA dosed at 5 mg BID. TOFA dose escalation
      will not be considered for inadequate response of SLE-CL.

      Cohort 2 (n=10, weight > 40kg and age > 18 years and ≤ 45 years) will be treated with the
      same dose as Cohort 1. No PK sampling will occur for Cohort 2. Enrollment of Cohort 2 will
      only start once Cohort 1 has completed 8 weeks of TOFA and results of PK analyses from Cohort
      1 are available.

        -  Part A (up to week 8) requires stable background medications;

        -  Part B (up to week 24) allows for tapering of corticosteroids (CS) in the setting of
           significant clinical improvement of SLE-CL as defined by a decrease in Cutaneous Lupus
           Erythematosus Disease Area and Severity Index (CLASI) activity score by >50% from
           baseline , and

        -  Part C (until week 76) permits tapering of other background medications in subjects with
           clinical remission of SLE-CL (CLASI activity score=0). TOFA dosing is kept stable during
           Part C.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Oral Clearance (CL/F) (Cohort 1 only)
time frame: Day 5
description: Apparent total clearance of the drug from plasma after oral administration
measure: Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) score
time frame: weeks 4, 8 and 24 compared to baseline.
description: Proportion of subjects who achieve a skin response per the validated CLASI
measure: AUCt (Cohort 1 only)
time frame: Day 5
description: Area under the plasma concentration-time curve from time zero to time t
measure: Cmax (Cohort 1 only)
time frame: Day 5
description: Maximum (or peak) plasma concentration of Tofacitinib
measure: tmax (Cohort 1 only)
time frame: Day 5
description: Time to reach maximum (peak) plasma concentration following administration of Tofacitinib
measure: Vz/F (Cohort 1 only)
time frame: Day 5
description: Apparent volume of distribution during terminal phase after non-intravenous administration
measure: half-life of Tofacitinib (Cohort 1 only)
time frame: Day 5
description: half-life of Tofacitinib
measure: Safety of Tofacitinib: Nature, severity, and frequency of adverse events (Cohorts 1 and 2)
time frame: 76 weeks
description: Rate and severity of adverse events and lab abnormalities
measure: Steroid dose comparison
time frame: 76 weeks
description: Assess steroid sparing properties of Tofacitinib by comparing doses to baseline and rate of steroid discontinuation
measure: Change in SLE Disease Activity Index (SLEDAI) score
time frame: 76 weeks
description: Measure Tofacitinib impact on disease activity
measure: Change in British Isles Lupus Activity Group (BILAG) score
time frame: 76 weeks
description: Measure Tofacitinib impact on disease activity
measure: Change in SKINDEX score
time frame: Baseline, week 24 and week 76
description: Quality-of-life measure for patients with skin disease
measure: Change in patients global assessment score
time frame: Baseline, week 24 and week 76
description: Quality-of-life measure for patients
arm group label: Tofacitinib Arm
arm group type: Experimental
description: open-label study
intervention type: Drug
intervention name: Tofacitinib
description: Tofacitinib 5 mg twice daily
arm group label: Tofacitinib Arm
other name: Xeljanz
criteria: 
gender: All
minimum age: 18 Years
maximum age: 45 Years
healthy volunteers: No
last name: Hermine Brunner, MD
role: Principal Investigator
affiliation: Cincinnati Childrens Hospital Medical Center
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Lupus Erythematosus, Systemic
mesh term: Tofacitinib