<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/NCT03781310</url>
  </required_header>
  <id_info>
    <org_study_id>0563-18-TLV</org_study_id>
    <nct_id>NCT03781310</nct_id>
  </id_info>
  <brief_title>Therapeutic Drug Monitoring of Tocilizumab in Rheumatoid Arthritis</brief_title>
  <official_title>Therapeutic Drug Monitoring of Tocilizumab in Rheumatoid Arthritis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Tel-Aviv Sourasky Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Amsterdam Rheumatology and Immunology Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Tel-Aviv Sourasky Medical Center</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>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Rationale: A wide range of serum trough concentrations is observed in tocilizumab-treated&#xD;
      rheumatoid arthritis (RA) patients, while 1 mg/L tocilizumab is sufficient to block systemic&#xD;
      interleukin-6 receptor. A substantial proportion of patients has higher serum tocilizumab&#xD;
      concentrations and is likely to be overexposed. We expect that patients can at least reduce&#xD;
      the dose aiming for a concentration of 5 mg/L without reducing efficacy.&#xD;
&#xD;
      Objective: To evaluate the feasibility of the study after 20 weeks of follow-up, this&#xD;
      includes the evaluation of the dose-reduction algorithm in tocilizumab-treated patients with&#xD;
      RA.&#xD;
&#xD;
      Study design: Double-blind randomized controlled pilot study with a follow up of 20 weeks.&#xD;
&#xD;
      Study population: Consecutive RA patients that are treated with tocilizumab intravenously&#xD;
      every four weeks for at least 24 weeks. Patients are screened for tocilizumab concentration&#xD;
      after signing informed consent.&#xD;
&#xD;
      Intervention: Patients with a concentration below 5 mg/L will continue the dose. Those&#xD;
      patients with a tocilizumab concentration above 5 mg/L are randomly assigned (2:1) to dose&#xD;
      reduction or to continuation of the standard care tocilizumab dose. In the intervention&#xD;
      group, the precise dose-reduction is calculated per patient in order to achieve a tocilizumab&#xD;
      concentration of 5 mg/L (range 4-6 mg/L).&#xD;
&#xD;
      Main study parameters/endpoints:&#xD;
&#xD;
      The feasibility of the study logistics is evaluated according to the dropout rate and&#xD;
      patients opinion about the study. Second, the proportion of patients achieving the targeted&#xD;
      tocilizumab concentration after dose reduction is evaluated.&#xD;
&#xD;
      Nature and extent of the burden and risks associated with participation, benefit and group&#xD;
      relatedness:&#xD;
&#xD;
      Dose-reduction will lead to lower drug costs and possibly to reduce the risk of adverse&#xD;
      events. Since we lower the tocilizumab concentration in a proportion of the patients, risk of&#xD;
      a exacerbation of the disease exists. In this case, patients will receive their original&#xD;
      dose. Previous studies showed that disease activity is controlled adequately after returning&#xD;
      to the standard dose. However, our algorithm is designed to reach concentrations of 5 mg/L&#xD;
      (range 4-6 mg/L) and studies showed that 1 mg/L of tocilizumab is sufficient to maintain&#xD;
      clinical effect. The expected burden of this study is low, since study visits are planned at&#xD;
      the time of infusion and therefore do not take extra time. The additional burden consists of&#xD;
      an extra blood sample taken every visit and the fingerprick that is performed once.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      INTRODUCTION AND RATIONALE Rheumatoid arthritis (RA) is a chronic inflammatory disease with a&#xD;
      symmetric polyarthritis. One of the cytokines playing a role in RA is interleukin-6&#xD;
      (IL-6)(1;2). Tocilizumab is a humanized monoclonal antibody targeting IL-6 receptor (IL-6R)&#xD;
      and is proved to be effective in reducing inflammation and symptoms in RA. Tocilizumab&#xD;
      intravenously (IV) is approved by the European Medical agency (EMA) in a standard dose of 8&#xD;
      mg/kg every 4 weeks for RA patients. The FDA approved a standard dose of 4 mg/kg every 4&#xD;
      weeks, with a possibility to increase the dose to 8 mg/kg. This raises the question whether a&#xD;
      proportion of patients treated with 8 mg/kg are overexposed.&#xD;
&#xD;
      Previously, it has been showed that 8 mg/kg results in a wide range of serum tocilizumab&#xD;
      concentrations, although serum concentrations above 1 mg/L are reported to be sufficient to&#xD;
      inhibit IL-6 signaling and to normalize CRP levels (CRP ≤ 10 mg/L), suggesting a systemic&#xD;
      IL-6R blockade (3;4). In a previous study, the median tocilizumab concentration was 10.6 mg/L&#xD;
      after 24 weeks of treatment, suggesting that a substantial proportion of patients is likely&#xD;
      to be overexposed to tocilizumab (4). A recent study showed that overexposure, defined by&#xD;
      high serum drug concentration, can be reduced in adalimumab-treated RA patients by prolonging&#xD;
      the dose-interval (5). The wide variation in tocilizumab concentrations and sufficient target&#xD;
      blockade at a fixed serum trough concentration suggests that a similar approach to reduce&#xD;
      overexposure is possible in tocilizumab treatment too. Moreover, Levi and colleagues showed&#xD;
      improvements in the disease activity score using 28 joints (DAS28) were associated with a C50&#xD;
      (concentration at which the 50% of the effect is achieved) between 2-5 µg/ml. (8) We,&#xD;
      therefore, expect that patients can reduce the dose aiming at a concentration of 5 mg/L&#xD;
      without reducing efficacy. Around 70% of the patients had a tocilizumab concentration above 5&#xD;
      mg/L in a previous study and can potentially reduce the dose (3).&#xD;
&#xD;
      Reducing overexposure is necessary in light of high drug costs and, possibly, the risk of&#xD;
      adverse events. Therefore, our aim is to study whether overexposure can be reduced without&#xD;
      affecting disease activity in tocilizumab-treated RA patients. We have developed an algorithm&#xD;
      to reduce the dose in order to achieve a tocilizumab concentration of 5 mg/L in each patient.&#xD;
&#xD;
      OBJECTIVES Primary objective: To evaluate the feasibility of reducing the dose of tocilizumab&#xD;
      according to serum trough levels at baseline, after 20 weeks follow-up.&#xD;
&#xD;
      Secondary objective: To evaluate the dose-reduction algorithm in tocilizumab-treated RA&#xD;
      patients with tocilizumab concentrations above 5 mg/L after 20 weeks of follow-up.&#xD;
&#xD;
      STUDY DESIGN Double-blind randomized controlled pilot study in RA patients treated with&#xD;
      tocilizumab IV every four weeks for at least 24 weeks. Patients will receive their&#xD;
      tocilizumab infusion at the outpatient clinic of the department of Rheumatology in Tel Aviv&#xD;
      Sourasky Medical center. The treatment will be at the discretion of treating rheumatologist;&#xD;
      patients can receive tocilizumab treatment as monotherapy or in combination with concomitant&#xD;
      DMARD therapy or prednisone. After given informed consent, tocilizumab trough concentration&#xD;
      will be determined and those patients with concentration above 5 mg/L will be randomly&#xD;
      assigned (2:1 ratio) to dose reduction or to continuation of their tocilizumab dose. Patients&#xD;
      with concentrations below 5 mg/L will continue the dose they received at the screening visit.&#xD;
      All included patients will have a follow up of 20 weeks independent of the tocilizumab&#xD;
      concentration, treatment arm or medication adjustments. Clinical data are collected at the&#xD;
      baseline visit and at 12, and 20 weeks thereafter. Blood samples are collected every&#xD;
      infusion, namely at baseline and at 4, 8, 12, 16 and 20 weeks thereafter.&#xD;
&#xD;
      The study visit will take place at the same day of the tocilizumab infusion. After performing&#xD;
      the clinical/ laboratory assessments and infusion at 20 weeks of follow up, the allocation&#xD;
      will be revealed. This allows the treating rheumatologist, in consultation with the patient,&#xD;
      to decide whether to continue with the dose given during the study phase or to change the&#xD;
      dose.&#xD;
&#xD;
      Intervention Those patients with tocilizumab concentration above 5 mg/L, that are assigned to&#xD;
      the intervention group, will reduce the tocilizumab dose at the baseline visit. A&#xD;
      dose-reduction algorithm is developed, using a population pharmacokinetic (PK) model, to&#xD;
      calculate the dose needed for each patient to achieve a tocilizumab concentration of 5 mg/L&#xD;
      (range 4-6 mg/L). As is shown in Table 1, the dose-reduction is dependent of the tocilizumab&#xD;
      concentration measured at the screenings visit. Patients are followed for 20 weeks to&#xD;
      evaluate the serum concentration after several infusions.&#xD;
&#xD;
      Table 1. Dose-reduction algorithm Tocilizumab concentration*, mg/L &gt;30 ≥20 &lt;30 ≥ 15 &lt;20 ≥10&#xD;
      &lt;15 ≥5 &lt;10 Dose reduction‡, % 60 50 40 30 15&#xD;
&#xD;
      *Serum trough concentration measured at the screening visit. ‡Percentage of dose-reduction&#xD;
      compared to prescribed dose at screening visit.&#xD;
&#xD;
      5. TREATMENT OF SUBJECTS 5.1 Investigational treatment Those patients that are allocated to&#xD;
      the intervention group will reduce the dose at the baseline visit (week 0) and maintain that&#xD;
      dose till 20 weeks of follow-up. The reduced dose is dependent of the tocilizumab serum&#xD;
      concentration, measured at the screening visit, and is calculated according to the&#xD;
      dose-reduction algorithm (as described in the &quot;study design&quot;).&#xD;
&#xD;
      5.2 Escape medication Treatment can be changed in case of flare (defined in subheading &quot;flare&#xD;
      criteria&quot; in study procedures). In this case, the original dose is given to the patient,&#xD;
      without unblinding the patients and treating rheumatologist. If the flare persists after 4&#xD;
      weeks, treatment will be adjusted in consultation with the treating rheumatologist. This&#xD;
      includes; increasing DMARDs or NSAIDs dosage, adding glucocorticoids or switching to another&#xD;
      biologic/anti-rheumatic drug. If the patient or physician wants to reinstate the original&#xD;
      dose, but the flare criteria are not met, this will be logged as protocol violation.&#xD;
&#xD;
      6. METHODS 6.1 Randomisation, blinding and treatment allocation Randomization allocation&#xD;
      ratio will be 2:1 (therapeutic drug monitoring versus standard care). Randomization&#xD;
      procedure: block randomization with variable block sizes (2 to 4 per block) generated by an&#xD;
      online program. Variable blocks are used to ensure that the allocation of participants will&#xD;
      not be predictable when the treating rheumatologist and participant are unblinded after the&#xD;
      study. During the study, patients, physicians, nurses and researchers are blinded for drug&#xD;
      concentrations and treatment allocation. The infusions for the study will be prepared by the,&#xD;
      designated departmental nurse based on the randomization number. The physical appearance of&#xD;
      the medication will be the same to enable blinding of participating patients and study staff.&#xD;
      Allocation concealment: randomization list is an excel document managed by an independent&#xD;
      co-worker of Reade and a backup independent co-worker.&#xD;
&#xD;
      Study procedures At screening patients will be checked for eligibility, informed consent will&#xD;
      be signed and, afterwards, tocilizumab concentration will be determined. The assessments&#xD;
      listed below will be performed at baseline (week 0), and 12 and 20 weeks thereafter. Blood&#xD;
      samples are collected every infusion, namely at baseline and at 4, 8, 12, 16 and 20 weeks&#xD;
      thereafter. In case of a (suspected) flare, an extra visit will be planned to perform the&#xD;
      same assessments as during the regular visits Disease activity and functioning Swollen and&#xD;
      tender joint count of 66/68 joints, patient pain visual analogue score(VAS) (0-100 scale),&#xD;
      physician global VAS (0-100 scale), patient global disease activity VAS (0-100 scale).&#xD;
      Functional status will be assessed with the simplified Health Assessment Questionnaire&#xD;
      (sHAQ), which is included in the routine assessment of patient index data 3 (RAPID-3).&#xD;
      DAS28-ESR, SDAI and CDAI will be calculated every visit.&#xD;
&#xD;
      Safety Patients will be asked for (serious) adverse events (AEs) during the past 3 months.&#xD;
      This will be recorded by the examiner on an already designated questionnaire form. Nature,&#xD;
      seriousness, duration, localization and consequences of the events will be recorded.&#xD;
&#xD;
      Laboratory investigations Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP),&#xD;
      complete blood count (Hb, Ht, white cell count, platelets), creatinine, alanine&#xD;
      aminotransferase (ALT) will be measured. Blood samples for serum (5 ml) are collected prior&#xD;
      to each infusion and 15 minutes afterwards, in order to measure the tocilizumab concentration&#xD;
      at trough and at peak moment, respectively. Tocilizumab concentrations (except screening&#xD;
      samples) are measured in one batch at the end of the study.&#xD;
&#xD;
      Other variables Other variables recorded at baseline are: age, gender, duration of disease,&#xD;
      immunoglobulin M (IgM) rheumatoid factor and anti-cyclic citrullinated peptide status,&#xD;
      presence of erosive disease, length and weight, current medication, medication history&#xD;
      regarding DMARD and NSAID therapy, prednisone and biological use. Patients perspective&#xD;
      towards therapeutic drug monitoring (TDM) and current study procedures will be asked and&#xD;
      noted during the first and final visit.&#xD;
&#xD;
      Flare criteria A flare is defined as an increase in DAS28 between visits of &gt;1.2 (or &gt;0.6 if&#xD;
      current DAS28≥3.2) and/or DMARDs is increased, or a DMARD and/or triamcinolone treatment is&#xD;
      added (both intramuscular or intra-articular). Clinical and laboratory assessment will be&#xD;
      performed at the moment a patient is examined for a flare.&#xD;
&#xD;
      Medication:&#xD;
&#xD;
      Current medication use will be asked for each visit, with special attention to changes in&#xD;
      DMARD or NSAID therapy and the use of glucocorticoids. It is aimed to leave all rheumatic&#xD;
      co-medication unaltered during the study period. However, changes in use of paracetamol&#xD;
      (acetaminophen), tramadol, NSAIDs, oral glucocorticoids, methylprednisone (Depo-medrol),&#xD;
      triamcinolone (kenacort) and DMARDs are allowed during this study if a recent DAS28-score is&#xD;
      reported. During each visit, patients are asked about the use of these medications. Changes&#xD;
      in co-medication are left to the discretion of the treating rheumatologist, but treatment&#xD;
      alterations without recent DAS28 score will be logged as protocol violations.&#xD;
&#xD;
      6.2 Follow-up of subjects withdrawn from treatment Follow up of patients withdrawn from&#xD;
      treatment will be part of the study. Patients will be asked to complete 20 weeks follow-up.&#xD;
&#xD;
      6.3 Premature termination of the study The study will be prematurely terminated if safety of&#xD;
      patients can no longer be guaranteed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Anticipated">December 2018</start_date>
  <completion_date type="Anticipated">December 2019</completion_date>
  <primary_completion_date type="Anticipated">June 30, 2019</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Disease flare rate</measure>
    <time_frame>20 weeks</time_frame>
    <description>Percent of patients experiencing a flare in RA disease activity according to DAS28-ESR score from week 0 until week 20.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Drop-out rate</measure>
    <time_frame>20 weeks</time_frame>
    <description>Percentage of patients completing 20-weeks on assigned treatment arm without withdrawing from the trial.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>DAS28 score</measure>
    <time_frame>20 weeks</time_frame>
    <description>The DAS28 (Disease Activity Score 28) is a system developed and validated by the EULAR (European League Against Rheumatism) to measure the progress and improvement of Rheumatoid Arthritis. DAS28 is often used in clinical trials for the development of RA. DAS28 values range from 2.0 to 10.0 while higher values mean a higher disease activity. A DAS 28 below the value of 2.6 is interpreted as Remission.&#xD;
&quot;28&quot; describes the number of different joints including in the measurement: proximal interphalangeal joints (10 joints), metacarpophalangeal joints (10), wrists (2), elbows (2), shoulders (2), knees (2).&#xD;
When looking at these joints, both the number of joints with tenderness upon touching and swelling are counted. In addition, the erythrocyte sedimentation rate is measured. Also, the patient makes a subjective assessment of disease activity during the preceding 7 days on a scale between 0 and 100, where 0 is &quot;no activity&quot; and 100 is &quot;highest activity possible&quot;.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>SDAI score</measure>
    <time_frame>20 weeks</time_frame>
    <description>Disease activity according to Simplified Disease Activity Index (SDAI) score. The simplified disease activity index (SDAI) is an established instruments to measure disease activity in rheumatoid arthritis (RA).&#xD;
The SDAI is the sum of five outcome parameters&#xD;
tender joint count based on a 28-joint assessment&#xD;
swollen joint count based on a 28-joint assessment&#xD;
patient global assessment of disease activity on a visual analogue scale (VAS)&#xD;
investigator global assessment of disease activity on a visual analogue scale (VAS)&#xD;
CRP:level of CRP (C-reactive protein) measured in mg/dl</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CDAI score</measure>
    <time_frame>20 weeks</time_frame>
    <description>Disease activity according to Clinical Disease Activity Index (CDAI) score. The clinical disease activity index (CDAI) is an established instrument to measure disease activity in rheumatoid arthritis (RA).&#xD;
The CDAI is composite index calculated as the sum of four outcome parameters&#xD;
tender joint count based on a 28-joint assessment&#xD;
swollen joint count based on a 28-joint assessment&#xD;
patient global assessment of disease activity on a visual analogue scale (VAS)&#xD;
investigator global assessment of disease activity on a visual analogue scale (VAS)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Swollen joint count</measure>
    <time_frame>20 weeks</time_frame>
    <description>Number of swollen joints out of a total of 66 joints.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tender joint count</measure>
    <time_frame>20 weeks</time_frame>
    <description>Number of swollen joints out of a total of 68 joints.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>patient pain VAS</measure>
    <time_frame>20 weeks</time_frame>
    <description>Quantification of joint pain in the past week by the patient according to the patient pain visual analogue score (VAS).&#xD;
The VAS is self-completed by the patient. The respondent is asked to place a 10 cm line perpendicular to the VAS line at the point that represents their pain intensity. Using a ruler, the score is determined by measuring the distance (mm) on the 10-cm line between the &quot;no pain&quot; anchor and the patient's mark, providing a range of scores from 0-100. A higher score indicates greater pain intensity.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>physician global VAS</measure>
    <time_frame>20 weeks</time_frame>
    <description>Quantification of general state of the patient in the past week, by the physician, according to the physician global visual analogue score (VAS).&#xD;
The VAS is completed by the physician. The respondent is asked to place a 10 cm line perpendicular to the VAS line at the point that represents all the ways arthritis affects the patient.&#xD;
Using a ruler, the score is determined by measuring the distance (mm) on the 10-cm line between the &quot;no affect&quot; anchor and the physician's mark, providing a range of scores from 0-100. A higher score indicates a worse disase state.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>patient disease activity VAS</measure>
    <time_frame>20 weeks</time_frame>
    <description>Quantification of overall disease activity in the past week by the patient according to the patient disease activity visual analogue score (VAS).&#xD;
Quantification of diseasse activity in the past week by the patient according to the patient disease activity visual analogue score (VAS).&#xD;
The VAS is self-completed by the patient. The respondent is asked to place a 10 cm line perpendicular to the VAS line at the point that represents t all the ways arthritis affects the patient. Using a ruler, the score is determined by measuring the distance (mm) on the 10-cm line between the &quot;no affect&quot; anchor and the patient's mark, providing a range of scores from 0-100. A higher score indicates worse disease activity.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>sHAQ</measure>
    <time_frame>20 weeks</time_frame>
    <description>Functional status assessed with the simplified Health Assessment Questionnaire (sHAQ). The sHAQ is a general index. In the context of Rheumatoid arthritis, this index considers how arthritis has an impact on everyday life. The questionnaire is designed to be completed by the patient himself, without the help of a doctor.&#xD;
The value of the sHAQ index can be interpreted in terms of three categories:&#xD;
from 0 to 1: mild difficulties to moderate disability, from 1 to 2: disability moderate to severe, from 2 to 3: severe to very severe disability.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>RAPID-3</measure>
    <time_frame>20 weeks</time_frame>
    <description>Disease activity according to the RAPID-3 questionnaire completed by the patient.&#xD;
RAPID3 or Routine Assessment of Patient Index Data 3 is a disease activity index that is computed from a short and simple questionnaire. It assesses the effect of arthritis on daily life. RAPID3 is designed to be quick and easy to fill by a patient, without requiring the help of a practitioner. Although it is quite simple, this index accurately captures the disease activity and is sensitive to change.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">80</enrollment>
  <condition>Rheumatoid Arthritis</condition>
  <condition>Tocilizumab</condition>
  <arm_group>
    <arm_group_label>Dose reduction</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Reduce the Tocilizumab dose at the baseline visit (week 0) and maintain that dose until 20 weeks of follow-up. The reduced dose is dependent of the tocilizumab serum concentration, measured at the screening visit, and is calculated according to the pre-defined dose-reduction algorithm.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Maintain dose</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Maintain the original dose at baseline visit (week 0) until 20 weeks of follow-up.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tocilizumab</intervention_name>
    <description>IV Tocilizumab once every 4 weeks at reduced dose according to algorithm.</description>
    <arm_group_label>Dose reduction</arm_group_label>
    <arm_group_label>Maintain dose</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  RA according to the ACR 1987 or 2010 criteria;&#xD;
&#xD;
          -  Current use of tocilizumab IV, with a consistent interval of 4 weeks for at least 24&#xD;
             weeks.&#xD;
&#xD;
          -  18 years of age and older.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  A potential subject will be excluded from participation in case of a scheduled surgery&#xD;
             in the next 20 weeks or other preplanned reasons for treatment discontinuation.&#xD;
&#xD;
          -  Children, pregnant women and individuals with a lack of judgement.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Uri Arad</last_name>
    <role>Principal Investigator</role>
    <affiliation>Tel-Aviv Sourasky Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Uri Arad</last_name>
    <phone>+972524262446</phone>
    <email>uria@tlvmc.gov.il</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Sara Pel</last_name>
    <phone>+972524266605</phone>
    <email>sarap@tlvmc.gov.il</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Department of Rheumatology, Tel Aviv Medical Center</name>
      <address>
        <city>Tel Aviv</city>
        <zip>64239</zip>
        <country>Israel</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ori Elkayam, M.D</last_name>
      <phone>97236973668</phone>
      <email>orie@tasmc.health.gov.il</email>
    </contact>
  </location>
  <location_countries>
    <country>Israel</country>
  </location_countries>
  <verification_date>December 2018</verification_date>
  <study_first_submitted>December 17, 2018</study_first_submitted>
  <study_first_submitted_qc>December 18, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 19, 2018</study_first_posted>
  <last_update_submitted>December 23, 2018</last_update_submitted>
  <last_update_submitted_qc>December 23, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">December 26, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Tel-Aviv Sourasky Medical Center</investigator_affiliation>
    <investigator_full_name>michal roll</investigator_full_name>
    <investigator_title>Research and Developemnt, Head</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Arthritis</mesh_term>
    <mesh_term>Arthritis, Rheumatoid</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03781310
org study id: 0563-18-TLV
nct id: NCT03781310
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
Rationale: A wide range of serum trough concentrations is observed in tocilizumab-treated
      rheumatoid arthritis (RA) patients, while 1 mg/L tocilizumab is sufficient to block systemic
      interleukin-6 receptor. A substantial proportion of patients has higher serum tocilizumab
      concentrations and is likely to be overexposed. We expect that patients can at least reduce
      the dose aiming for a concentration of 5 mg/L without reducing efficacy.

      Objective: To evaluate the feasibility of the study after 20 weeks of follow-up, this
      includes the evaluation of the dose-reduction algorithm in tocilizumab-treated patients with
      RA.

      Study design: Double-blind randomized controlled pilot study with a follow up of 20 weeks.

      Study population: Consecutive RA patients that are treated with tocilizumab intravenously
      every four weeks for at least 24 weeks. Patients are screened for tocilizumab concentration
      after signing informed consent.

      Intervention: Patients with a concentration below 5 mg/L will continue the dose. Those
      patients with a tocilizumab concentration above 5 mg/L are randomly assigned (2:1) to dose
      reduction or to continuation of the standard care tocilizumab dose. In the intervention
      group, the precise dose-reduction is calculated per patient in order to achieve a tocilizumab
      concentration of 5 mg/L (range 4-6 mg/L).

      Main study parameters/endpoints:

      The feasibility of the study logistics is evaluated according to the dropout rate and
      patients opinion about the study. Second, the proportion of patients achieving the targeted
      tocilizumab concentration after dose reduction is evaluated.

      Nature and extent of the burden and risks associated with participation, benefit and group
      relatedness:

      Dose-reduction will lead to lower drug costs and possibly to reduce the risk of adverse
      events. Since we lower the tocilizumab concentration in a proportion of the patients, risk of
      a exacerbation of the disease exists. In this case, patients will receive their original
      dose. Previous studies showed that disease activity is controlled adequately after returning
      to the standard dose. However, our algorithm is designed to reach concentrations of 5 mg/L
      (range 4-6 mg/L) and studies showed that 1 mg/L of tocilizumab is sufficient to maintain
      clinical effect. The expected burden of this study is low, since study visits are planned at
      the time of infusion and therefore do not take extra time. The additional burden consists of
      an extra blood sample taken every visit and the fingerprick that is performed once.
INTRODUCTION AND RATIONALE Rheumatoid arthritis (RA) is a chronic inflammatory disease with a
      symmetric polyarthritis. One of the cytokines playing a role in RA is interleukin-6
      (IL-6)(1;2). Tocilizumab is a humanized monoclonal antibody targeting IL-6 receptor (IL-6R)
      and is proved to be effective in reducing inflammation and symptoms in RA. Tocilizumab
      intravenously (IV) is approved by the European Medical agency (EMA) in a standard dose of 8
      mg/kg every 4 weeks for RA patients. The FDA approved a standard dose of 4 mg/kg every 4
      weeks, with a possibility to increase the dose to 8 mg/kg. This raises the question whether a
      proportion of patients treated with 8 mg/kg are overexposed.

      Previously, it has been showed that 8 mg/kg results in a wide range of serum tocilizumab
      concentrations, although serum concentrations above 1 mg/L are reported to be sufficient to
      inhibit IL-6 signaling and to normalize CRP levels (CRP ≤ 10 mg/L), suggesting a systemic
      IL-6R blockade (3;4). In a previous study, the median tocilizumab concentration was 10.6 mg/L
      after 24 weeks of treatment, suggesting that a substantial proportion of patients is likely
      to be overexposed to tocilizumab (4). A recent study showed that overexposure, defined by
      high serum drug concentration, can be reduced in adalimumab-treated RA patients by prolonging
      the dose-interval (5). The wide variation in tocilizumab concentrations and sufficient target
      blockade at a fixed serum trough concentration suggests that a similar approach to reduce
      overexposure is possible in tocilizumab treatment too. Moreover, Levi and colleagues showed
      improvements in the disease activity score using 28 joints (DAS28) were associated with a C50
      (concentration at which the 50% of the effect is achieved) between 2-5 µg/ml. (8) We,
      therefore, expect that patients can reduce the dose aiming at a concentration of 5 mg/L
      without reducing efficacy. Around 70% of the patients had a tocilizumab concentration above 5
      mg/L in a previous study and can potentially reduce the dose (3).

      Reducing overexposure is necessary in light of high drug costs and, possibly, the risk of
      adverse events. Therefore, our aim is to study whether overexposure can be reduced without
      affecting disease activity in tocilizumab-treated RA patients. We have developed an algorithm
      to reduce the dose in order to achieve a tocilizumab concentration of 5 mg/L in each patient.

      OBJECTIVES Primary objective: To evaluate the feasibility of reducing the dose of tocilizumab
      according to serum trough levels at baseline, after 20 weeks follow-up.

      Secondary objective: To evaluate the dose-reduction algorithm in tocilizumab-treated RA
      patients with tocilizumab concentrations above 5 mg/L after 20 weeks of follow-up.

      STUDY DESIGN Double-blind randomized controlled pilot study in RA patients treated with
      tocilizumab IV every four weeks for at least 24 weeks. Patients will receive their
      tocilizumab infusion at the outpatient clinic of the department of Rheumatology in Tel Aviv
      Sourasky Medical center. The treatment will be at the discretion of treating rheumatologist;
      patients can receive tocilizumab treatment as monotherapy or in combination with concomitant
      DMARD therapy or prednisone. After given informed consent, tocilizumab trough concentration
      will be determined and those patients with concentration above 5 mg/L will be randomly
      assigned (2:1 ratio) to dose reduction or to continuation of their tocilizumab dose. Patients
      with concentrations below 5 mg/L will continue the dose they received at the screening visit.
      All included patients will have a follow up of 20 weeks independent of the tocilizumab
      concentration, treatment arm or medication adjustments. Clinical data are collected at the
      baseline visit and at 12, and 20 weeks thereafter. Blood samples are collected every
      infusion, namely at baseline and at 4, 8, 12, 16 and 20 weeks thereafter.

      The study visit will take place at the same day of the tocilizumab infusion. After performing
      the clinical/ laboratory assessments and infusion at 20 weeks of follow up, the allocation
      will be revealed. This allows the treating rheumatologist, in consultation with the patient,
      to decide whether to continue with the dose given during the study phase or to change the
      dose.

      Intervention Those patients with tocilizumab concentration above 5 mg/L, that are assigned to
      the intervention group, will reduce the tocilizumab dose at the baseline visit. A
      dose-reduction algorithm is developed, using a population pharmacokinetic (PK) model, to
      calculate the dose needed for each patient to achieve a tocilizumab concentration of 5 mg/L
      (range 4-6 mg/L). As is shown in Table 1, the dose-reduction is dependent of the tocilizumab
      concentration measured at the screenings visit. Patients are followed for 20 weeks to
      evaluate the serum concentration after several infusions.

      Table 1. Dose-reduction algorithm Tocilizumab concentration*, mg/L >30 ≥20 <30 ≥ 15 <20 ≥10
      <15 ≥5 <10 Dose reduction‡, % 60 50 40 30 15

      *Serum trough concentration measured at the screening visit. ‡Percentage of dose-reduction
      compared to prescribed dose at screening visit.

      5. TREATMENT OF SUBJECTS 5.1 Investigational treatment Those patients that are allocated to
      the intervention group will reduce the dose at the baseline visit (week 0) and maintain that
      dose till 20 weeks of follow-up. The reduced dose is dependent of the tocilizumab serum
      concentration, measured at the screening visit, and is calculated according to the
      dose-reduction algorithm (as described in the "study design").

      5.2 Escape medication Treatment can be changed in case of flare (defined in subheading "flare
      criteria" in study procedures). In this case, the original dose is given to the patient,
      without unblinding the patients and treating rheumatologist. If the flare persists after 4
      weeks, treatment will be adjusted in consultation with the treating rheumatologist. This
      includes; increasing DMARDs or NSAIDs dosage, adding glucocorticoids or switching to another
      biologic/anti-rheumatic drug. If the patient or physician wants to reinstate the original
      dose, but the flare criteria are not met, this will be logged as protocol violation.

      6. METHODS 6.1 Randomisation, blinding and treatment allocation Randomization allocation
      ratio will be 2:1 (therapeutic drug monitoring versus standard care). Randomization
      procedure: block randomization with variable block sizes (2 to 4 per block) generated by an
      online program. Variable blocks are used to ensure that the allocation of participants will
      not be predictable when the treating rheumatologist and participant are unblinded after the
      study. During the study, patients, physicians, nurses and researchers are blinded for drug
      concentrations and treatment allocation. The infusions for the study will be prepared by the,
      designated departmental nurse based on the randomization number. The physical appearance of
      the medication will be the same to enable blinding of participating patients and study staff.
      Allocation concealment: randomization list is an excel document managed by an independent
      co-worker of Reade and a backup independent co-worker.

      Study procedures At screening patients will be checked for eligibility, informed consent will
      be signed and, afterwards, tocilizumab concentration will be determined. The assessments
      listed below will be performed at baseline (week 0), and 12 and 20 weeks thereafter. Blood
      samples are collected every infusion, namely at baseline and at 4, 8, 12, 16 and 20 weeks
      thereafter. In case of a (suspected) flare, an extra visit will be planned to perform the
      same assessments as during the regular visits Disease activity and functioning Swollen and
      tender joint count of 66/68 joints, patient pain visual analogue score(VAS) (0-100 scale),
      physician global VAS (0-100 scale), patient global disease activity VAS (0-100 scale).
      Functional status will be assessed with the simplified Health Assessment Questionnaire
      (sHAQ), which is included in the routine assessment of patient index data 3 (RAPID-3).
      DAS28-ESR, SDAI and CDAI will be calculated every visit.

      Safety Patients will be asked for (serious) adverse events (AEs) during the past 3 months.
      This will be recorded by the examiner on an already designated questionnaire form. Nature,
      seriousness, duration, localization and consequences of the events will be recorded.

      Laboratory investigations Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP),
      complete blood count (Hb, Ht, white cell count, platelets), creatinine, alanine
      aminotransferase (ALT) will be measured. Blood samples for serum (5 ml) are collected prior
      to each infusion and 15 minutes afterwards, in order to measure the tocilizumab concentration
      at trough and at peak moment, respectively. Tocilizumab concentrations (except screening
      samples) are measured in one batch at the end of the study.

      Other variables Other variables recorded at baseline are: age, gender, duration of disease,
      immunoglobulin M (IgM) rheumatoid factor and anti-cyclic citrullinated peptide status,
      presence of erosive disease, length and weight, current medication, medication history
      regarding DMARD and NSAID therapy, prednisone and biological use. Patients perspective
      towards therapeutic drug monitoring (TDM) and current study procedures will be asked and
      noted during the first and final visit.

      Flare criteria A flare is defined as an increase in DAS28 between visits of >1.2 (or >0.6 if
      current DAS28≥3.2) and/or DMARDs is increased, or a DMARD and/or triamcinolone treatment is
      added (both intramuscular or intra-articular). Clinical and laboratory assessment will be
      performed at the moment a patient is examined for a flare.

      Medication:

      Current medication use will be asked for each visit, with special attention to changes in
      DMARD or NSAID therapy and the use of glucocorticoids. It is aimed to leave all rheumatic
      co-medication unaltered during the study period. However, changes in use of paracetamol
      (acetaminophen), tramadol, NSAIDs, oral glucocorticoids, methylprednisone (Depo-medrol),
      triamcinolone (kenacort) and DMARDs are allowed during this study if a recent DAS28-score is
      reported. During each visit, patients are asked about the use of these medications. Changes
      in co-medication are left to the discretion of the treating rheumatologist, but treatment
      alterations without recent DAS28 score will be logged as protocol violations.

      6.2 Follow-up of subjects withdrawn from treatment Follow up of patients withdrawn from
      treatment will be part of the study. Patients will be asked to complete 20 weeks follow-up.

      6.3 Premature termination of the study The study will be prematurely terminated if safety of
      patients can no longer be guaranteed.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Disease flare rate
time frame: 20 weeks
description: Percent of patients experiencing a flare in RA disease activity according to DAS28-ESR score from week 0 until week 20.
measure: Drop-out rate
time frame: 20 weeks
description: Percentage of patients completing 20-weeks on assigned treatment arm without withdrawing from the trial.
measure: DAS28 score
time frame: 20 weeks
description: The DAS28 (Disease Activity Score 28) is a system developed and validated by the EULAR (European League Against Rheumatism) to measure the progress and improvement of Rheumatoid Arthritis. DAS28 is often used in clinical trials for the development of RA. DAS28 values range from 2.0 to 10.0 while higher values mean a higher disease activity. A DAS 28 below the value of 2.6 is interpreted as Remission.
"28" describes the number of different joints including in the measurement: proximal interphalangeal joints (10 joints), metacarpophalangeal joints (10), wrists (2), elbows (2), shoulders (2), knees (2).
When looking at these joints, both the number of joints with tenderness upon touching and swelling are counted. In addition, the erythrocyte sedimentation rate is measured. Also, the patient makes a subjective assessment of disease activity during the preceding 7 days on a scale between 0 and 100, where 0 is "no activity" and 100 is "highest activity possible".
measure: SDAI score
time frame: 20 weeks
description: Disease activity according to Simplified Disease Activity Index (SDAI) score. The simplified disease activity index (SDAI) is an established instruments to measure disease activity in rheumatoid arthritis (RA).
The SDAI is the sum of five outcome parameters
tender joint count based on a 28-joint assessment
swollen joint count based on a 28-joint assessment
patient global assessment of disease activity on a visual analogue scale (VAS)
investigator global assessment of disease activity on a visual analogue scale (VAS)
CRP:level of CRP (C-reactive protein) measured in mg/dl
measure: CDAI score
time frame: 20 weeks
description: Disease activity according to Clinical Disease Activity Index (CDAI) score. The clinical disease activity index (CDAI) is an established instrument to measure disease activity in rheumatoid arthritis (RA).
The CDAI is composite index calculated as the sum of four outcome parameters
tender joint count based on a 28-joint assessment
swollen joint count based on a 28-joint assessment
patient global assessment of disease activity on a visual analogue scale (VAS)
investigator global assessment of disease activity on a visual analogue scale (VAS)
measure: Swollen joint count
time frame: 20 weeks
description: Number of swollen joints out of a total of 66 joints.
measure: Tender joint count
time frame: 20 weeks
description: Number of swollen joints out of a total of 68 joints.
measure: patient pain VAS
time frame: 20 weeks
description: Quantification of joint pain in the past week by the patient according to the patient pain visual analogue score (VAS).
The VAS is self-completed by the patient. The respondent is asked to place a 10 cm line perpendicular to the VAS line at the point that represents their pain intensity. Using a ruler, the score is determined by measuring the distance (mm) on the 10-cm line between the "no pain" anchor and the patient's mark, providing a range of scores from 0-100. A higher score indicates greater pain intensity.
measure: physician global VAS
time frame: 20 weeks
description: Quantification of general state of the patient in the past week, by the physician, according to the physician global visual analogue score (VAS).
The VAS is completed by the physician. The respondent is asked to place a 10 cm line perpendicular to the VAS line at the point that represents all the ways arthritis affects the patient.
Using a ruler, the score is determined by measuring the distance (mm) on the 10-cm line between the "no affect" anchor and the physician's mark, providing a range of scores from 0-100. A higher score indicates a worse disase state.
measure: patient disease activity VAS
time frame: 20 weeks
description: Quantification of overall disease activity in the past week by the patient according to the patient disease activity visual analogue score (VAS).
Quantification of diseasse activity in the past week by the patient according to the patient disease activity visual analogue score (VAS).
The VAS is self-completed by the patient. The respondent is asked to place a 10 cm line perpendicular to the VAS line at the point that represents t all the ways arthritis affects the patient. Using a ruler, the score is determined by measuring the distance (mm) on the 10-cm line between the "no affect" anchor and the patient's mark, providing a range of scores from 0-100. A higher score indicates worse disease activity.
measure: sHAQ
time frame: 20 weeks
description: Functional status assessed with the simplified Health Assessment Questionnaire (sHAQ). The sHAQ is a general index. In the context of Rheumatoid arthritis, this index considers how arthritis has an impact on everyday life. The questionnaire is designed to be completed by the patient himself, without the help of a doctor.
The value of the sHAQ index can be interpreted in terms of three categories:
from 0 to 1: mild difficulties to moderate disability, from 1 to 2: disability moderate to severe, from 2 to 3: severe to very severe disability.
measure: RAPID-3
time frame: 20 weeks
description: Disease activity according to the RAPID-3 questionnaire completed by the patient.
RAPID3 or Routine Assessment of Patient Index Data 3 is a disease activity index that is computed from a short and simple questionnaire. It assesses the effect of arthritis on daily life. RAPID3 is designed to be quick and easy to fill by a patient, without requiring the help of a practitioner. Although it is quite simple, this index accurately captures the disease activity and is sensitive to change.
arm group label: Dose reduction
arm group type: Experimental
description: Reduce the Tocilizumab dose at the baseline visit (week 0) and maintain that dose until 20 weeks of follow-up. The reduced dose is dependent of the tocilizumab serum concentration, measured at the screening visit, and is calculated according to the pre-defined dose-reduction algorithm.
arm group label: Maintain dose
arm group type: Active Comparator
description: Maintain the original dose at baseline visit (week 0) until 20 weeks of follow-up.
intervention type: Drug
intervention name: Tocilizumab
description: IV Tocilizumab once every 4 weeks at reduced dose according to algorithm.
arm group label: Dose reduction
arm group label: Maintain dose
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Uri Arad
role: Principal Investigator
affiliation: Tel-Aviv Sourasky Medical Center
last name: Uri Arad
phone: +972524262446
email: uria@tlvmc.gov.il
last name: Sara Pel
phone: +972524266605
email: sarap@tlvmc.gov.il
facility: 
status: Recruiting
contact: 
country: Israel
responsible party type: Principal Investigator
investigator affiliation: Tel-Aviv Sourasky Medical Center
investigator full name: michal roll
investigator title: Research and Developemnt, Head
mesh term: Arthritis
mesh term: Arthritis, Rheumatoid
sharing ipd: No