Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Therapeutic Drug Monitoring of Tocilizumab in Rheumatoid Arthritis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03781310
Recruitment Status : Recruiting
First Posted : December 19, 2018
Last Update Posted : December 25, 2018
Sponsor:
Collaborator:
Amsterdam Rheumatology and Immunology Center
Information provided by (Responsible Party):
michal roll, Tel-Aviv Sourasky Medical Center

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Rheumatoid Arthritis Tocilizumab Drug: Tocilizumab Phase 4

  Show Detailed Description

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Therapeutic Drug Monitoring of Tocilizumab in Rheumatoid Arthritis
Estimated Study Start Date : December 2018
Estimated Primary Completion Date : June 30, 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Tocilizumab

Arm Intervention/treatment
Experimental: Dose reduction
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.
Drug: Tocilizumab
IV Tocilizumab once every 4 weeks at reduced dose according to algorithm.

Active Comparator: Maintain dose
Maintain the original dose at baseline visit (week 0) until 20 weeks of follow-up.
Drug: Tocilizumab
IV Tocilizumab once every 4 weeks at reduced dose according to algorithm.




Primary Outcome Measures :
  1. Disease flare rate [ Time Frame: 20 weeks ]
    Percent of patients experiencing a flare in RA disease activity according to DAS28-ESR score from week 0 until week 20.

  2. Drop-out rate [ Time Frame: 20 weeks ]
    Percentage of patients completing 20-weeks on assigned treatment arm without withdrawing from the trial.


Secondary Outcome Measures :
  1. DAS28 score [ Time Frame: 20 weeks ]

    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".


  2. SDAI score [ Time Frame: 20 weeks ]

    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

    1. tender joint count based on a 28‐joint assessment
    2. swollen joint count based on a 28‐joint assessment
    3. patient global assessment of disease activity on a visual analogue scale (VAS)
    4. investigator global assessment of disease activity on a visual analogue scale (VAS)
    5. CRP:level of CRP (C‐reactive protein) measured in mg/dl

  3. CDAI score [ Time Frame: 20 weeks ]

    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

    1. tender joint count based on a 28‐joint assessment
    2. swollen joint count based on a 28‐joint assessment
    3. patient global assessment of disease activity on a visual analogue scale (VAS)
    4. investigator global assessment of disease activity on a visual analogue scale (VAS)

  4. Swollen joint count [ Time Frame: 20 weeks ]
    Number of swollen joints out of a total of 66 joints.

  5. Tender joint count [ Time Frame: 20 weeks ]
    Number of swollen joints out of a total of 68 joints.

  6. patient pain VAS [ Time Frame: 20 weeks ]

    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.


  7. physician global VAS [ Time Frame: 20 weeks ]

    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.


  8. patient disease activity VAS [ Time Frame: 20 weeks ]

    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.


  9. sHAQ [ Time Frame: 20 weeks ]

    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.


  10. RAPID-3 [ Time Frame: 20 weeks ]

    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.




Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • RA according to the ACR 1987 or 2010 criteria;
  • Current use of tocilizumab IV, with a consistent interval of 4 weeks for at least 24 weeks.
  • 18 years of age and older.

Exclusion Criteria:

  • A potential subject will be excluded from participation in case of a scheduled surgery in the next 20 weeks or other preplanned reasons for treatment discontinuation.
  • Children, pregnant women and individuals with a lack of judgement.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03781310


Contacts
Layout table for location contacts
Contact: Uri Arad +972524262446 uria@tlvmc.gov.il
Contact: Sara Pel +972524266605 sarap@tlvmc.gov.il

Locations
Layout table for location information
Israel
Department of Rheumatology, Tel Aviv Medical Center Recruiting
Tel Aviv, Israel, 64239
Contact: Ori Elkayam, M.D    97236973668    orie@tasmc.health.gov.il   
Sponsors and Collaborators
Tel-Aviv Sourasky Medical Center
Amsterdam Rheumatology and Immunology Center
Investigators
Layout table for investigator information
Principal Investigator: Uri Arad Tel-Aviv Sourasky Medical Center

Layout table for additonal information
Responsible Party: michal roll, Research and Developemnt, Head, Tel-Aviv Sourasky Medical Center
ClinicalTrials.gov Identifier: NCT03781310     History of Changes
Other Study ID Numbers: 0563-18-TLV
First Posted: December 19, 2018    Key Record Dates
Last Update Posted: December 25, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
Layout table for MeSH terms
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Benzocaine
Anesthetics, Local
Anesthetics
Central Nervous System Depressants
Physiological Effects of Drugs
Sensory System Agents
Peripheral Nervous System Agents