Rheumatoid Arthritis Clinical Trial
Official title:
Therapeutic Drug Monitoring of Tocilizumab in Rheumatoid Arthritis
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.
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