Clinical trial NCT04485325: Capability of Tofacitinib or Etanercept to Accelerate Tapering of NSAID and Treat-to-target Guided De-escalation of Corticosteroids in RA Patients
Official title: Capability of Tofacitinib or Etanercept to Accelerate Clinical Relevant Tapering of Non-steroidal Anti-inflammatory Drugs (NSAID) and Treat-to-target Guided De-escalation of Corticosteroids in Patients With Active Rheumatoid Arthritis (RA) and an Inadequate Response to Previous csDMARD Therapy (AcceleRAte)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Rheumatic Arthritis
Keywords: treat-to-target
pain
Lead sponsor: Fraunhofer Institute for Translational Medicine and Pharmacology ITMP
Sponsor class: OTHER
Collaborators: name: Pfizer
First posted: 2020-07-24
Enrollment: 92
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: two arm, randomized, open-label, parallel group
Primary purpose: TREATMENT

Brief summary: Patients with active rheumatic arthritis (RA) and lack of efficacy of at least one csDMARD (Disease-modifying anti-rheumatic drug) treatment will be randomized to receive either Tofacitinib (TOFA) or etanercept (ETA). The study will be separated into two parts: The capability to decrease and discontinue pain-reducing treatment with a NSAID (non-steroidal anti-inflammatory drug) over the first 12 weeks of treatment will be measured for primary outcome measured using a visual analogue scale (VAS) at week 12 compared to baseline between the two treatment groups.

Starting at week 12, the capability to taper corticosteroid (CS) treatment using a treat-to-target strategy, i.e. when at least low disease activity (LDA-DAS28) is achieved, will be measured in both groups.

Detailed description: In this clinical study, a design was chosen to reflect European standards recommended by EULAR for treatment of active RA by comparison of a Treat-to- target (T2T) approach in two treatment groups: Patients with active RA and lack of efficacy of at least one csDMARD treatment will be randomized to receive either TOFA or ETA. The study will be separated into two parts: The capability to decrease and discontinue pain-reducing treatment with a NSAID (Celecoxib, two times 200 mg as maximum standard dosage for RA) over the first 12 weeks of treatment will be measured for primary outcome. The proportion of patients with successful discontinuation of Celecoxib and significant and clinical relevant decrease of pain-levels measured using a visual analogue scale (VAS) with a reduction of at least 30% at week 12 compared to baseline will be compared between the two treatment groups.

Starting at week 12, the capability to taper CS treatment using a treat-to-target strategy, i.e. when at least low disease activity (LDA-DAS28) is achieved, will be measured in both groups. In addition to efficacy assessments (DAS28, ACR-response, SJC, TJC), patient reported outcomes, Quality of Life (QoL) measurements and patient satisfaction will be evaluated. Safety (severity and frequency of adverse events) will be evaluated over the 24-week treatment period.

Eligibility criteria: Inclusion Criteria:

* Patients with active RA and an inadequate response to up to two previous conventional synthetic Disease modifying anti-rheumatic drug (csDMARD) treatments (methotrexate (MTX), leflunomide (LEF),sulfasalazine (SSZ)) with or without ongoing csDMARD therapy
* RA according to ACR classification criteria
* Age 18 - 65 years
* Active RA is defined as

  * DAS28 \> 3.2 and
  * TJC ≥ 3 and SJC ≥ 3
* VAS-pain ≥ 60 mm (0-100 mm)
* Accompanying CS treatment for RA with a stable dosage of ≥ 2mg/d and ≤ 10 mg/d 2 weeks prior to BL (not more than 30% of patients without CS)
* Accompanying need of NSAID or analgesic treatment due to arthritis and in dosages not exceeding the maximum dose according to Summary of Product characteristics (SmPC)
* If ongoing csDMARD treatment, stable treatment will be defined as either

  * MTX treatment with a dosage of ≥ 10 mg/week and ≤ 25 mg/week, continuously for at least 12 weeks prior to Screening (SCR) with a stable dose of MTX for at least 2 weeks prior to BL or
  * LEF treatment with a dosage between 10 to 20 mg/day, continuously for at least 12 weeks prior to SCR with a stable dose of LEF for at least 2 weeks prior to BL or
  * SSZ treatment with dosage between 1 to 3 g/day, continuously for at least 12 weeks prior to SCR with a stable dose of SSZ for at least 2 weeks prior to BL
* Presence of documented negative results for testing of Hepatitis B and C
* Completed SARS-CoV-2-immunisation as currently recommended by the Standing Committee of Vaccination
* Written informed consent obtained prior to the initiation of any protocol-required procedures
* Willingness to comply to study procedures and study protocol

Exclusion Criteria:

* Previous use of Tofacitinib or other Janus-Kinase (JAK)-inhibitors
* Previous use of Etanercept
* Previous use of any biological agent for RA

  * which was stopped due to lack of efficacy
  * one previous use of biological stopped due to intolerance will be allowed
* CS treatment with dosages \>10 mg at BL
* Known hypersensitivity to any component of the study medication (TOFA, ETA, Celecoxib)
* Previous use of Celecoxib as analgesic therapy which was stopped due to lack of efficacy or intolerance
* Concomitant diseases with chronic pain syndrome or need of extended dosages or long-term treatment with the maximum dosages of NSAID/analgesics (according to SmPC) due to other concomitant diseases/pain symptoms in discretion of the treating physician Exclusion criteria related to general health
* Patients with other chronic inflammatory articular disease or systemic autoimmune disease
* Patients with active Tuberculosis (Tb) (evaluation of Tb according to local standards in clinical care)
* Patients with latent Tb, that are not pre-treated for at least 1 month and planned to be treated 9 months in total with Isozid once a day
* Any active infection, a history of recurrent clinically significant infections (e.g. human immune deficiency virus (HIV)), or a history of recurrent bacterial infections with encapsulated organisms
* Primary or secondary immunodeficiency
* Current malignancy or history of malignancies except adequately treated or excised basal cell or squamous cell carcinoma or cervical carcinoma in situ.
* Patients of 50 years and older, if they have one or more cardiovascular risk factors (CVRF) defined as:

  * Current cigarette smoking,
  * Known diagnosis of hypertension,
  * HDL \<40 mg/dl,
  * Diabetes mellitus,
  * History of coronary artery disease: history of revascularization procedure, coronary artery bypass grafting, myocardial infarction, cardiac arrest, unstable angina, acute coronary syndrome or
  * History of premature coronary heart disease or sudden death documented in first degree relatives (male relative before 55 years, female relative before 65 years)
* Evidence of significant uncontrolled concomitant diseases or serious and/or uncontrolled diseases that are likely to interfere with the evaluation of the patient's safety and with the study outcome
* History of a severe psychological illness or condition
* Known hypersensitivity to sulfonamides
* Active peptic ulceration or gastrointestinal (GI) bleeding
* Patients who have experienced asthma, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other allergic-type reactions after taking acetylsalicylic acid (aspirin) or other NSAIDs including Cyclooxigenase (COX)-2 inhibitors
* Risk for or history of thrombotic events (e.g. pulmonary embolism or thrombosis) Severe hepatic dysfunction (serum albumin \< 25 g/L or Child-Pugh score ≥ 10)
* Patients with estimated creatinine clearance \< 30 mL/min
* Inflammatory bowel disease
* Congestive heart failure (New York Heart Association (NYHA) II-IV)
* Established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease
* Women lactating, pregnant, nursing or of childbearing potential with a positive pregnancy test
* Males or females of reproductive potential not willing to use effective contraception (e.g. contraceptive pill, intrauterine device (IUD), physical barrier)
* Alcohol, drug or chemical abuse Exclusion criteria related to prior treatments
* Current participation in another interventional clinical trial or participation within the last 90 days Exclusion criteria related to formal aspects
* Underage or incapable patients

Primary outcomes:
measure: Discontinuation of Celecoxib treatment and clinically relevant improvement in pain
timeFrame: Baseline to week 12
Secondary outcomes:
measure: Mean dosage of Celecoxib in patients
timeFrame: at 12 weeks
measure: discontinuation of CS-treatment
timeFrame: at week 24
measure: rescue treatment
timeFrame: at week 12
measure: Mean dosage of Corticosteroids (CS) in the patients who achieve Low Disease activity (LDA) in the two treatment groups
timeFrame: at week 24
measure: Mean dosage of Corticosteroids (CS)
timeFrame: at week 24
measure: NSAID treatment
timeFrame: at week 24
measure: re-started NSAID treatment
timeFrame: week 12 to week 24
measure: Absolute pain levels
timeFrame: at week 2
measure: Absolute pain levels
timeFrame: at week 4
measure: Absolute pain levels
timeFrame: at week 8
measure: Absolute pain levels
timeFrame: at week 12
measure: Absolute pain levels
timeFrame: at week 16
measure: Absolute pain levels
timeFrame: at week 20
measure: Absolute pain levels
timeFrame: at week 24
measure: relative (percent) pain levels
timeFrame: at week 2
measure: relative (percent) pain levels
timeFrame: at week 4
measure: relative (percent) pain levels
timeFrame: at week 8
measure: relative (percent) pain levels
timeFrame: at week 12
measure: relative (percent) pain levels
timeFrame: at week 16
measure: relative (percent) pain levels
timeFrame: at week 20
measure: relative (percent) pain levels
timeFrame: at week 24
measure: Change in pain levels
timeFrame: at week 2
measure: Change in pain levels
timeFrame: at week 4
measure: Change in pain levels
timeFrame: at week 8
measure: Change in pain levels
timeFrame: at week 12
measure: Change in pain levels
timeFrame: at week 16
measure: Change in pain levels
timeFrame: at week 20
measure: Change in pain levels
timeFrame: at week 24
measure: Determination of flares
timeFrame: between week 12 and week 24
measure: Proportion of LDA
timeFrame: at week 4
measure: Proportion of LDA
timeFrame: at week 12
measure: Proportion of LDA
timeFrame: at week 16
measure: Proportion of LDA
timeFrame: at week 20
measure: Proportion of LDA
timeFrame: at week 24
measure: Proportion of DAS remission
timeFrame: at week 4
measure: Proportion of DAS remission
timeFrame: at week 12
measure: Proportion of DAS remission
timeFrame: at week 16
measure: Proportion of DAS remission
timeFrame: at week 20
measure: Proportion of DAS remission
timeFrame: at week 24
measure: Proportion of ACR20 response
timeFrame: at week 4
measure: Proportion of ACR20 response
timeFrame: at week 12
measure: Proportion of ACR20 response
timeFrame: at week 16
measure: Proportion of ACR20 response
timeFrame: at week 20
measure: Proportion of ACR20 response
timeFrame: at week 24
measure: Proportion of ACR 50 response
timeFrame: at week 4
measure: Proportion of ACR 50 response
timeFrame: at week 12
measure: Proportion of ACR 50 response
timeFrame: at week 16
measure: Proportion of ACR 50 response
timeFrame: at week 20
measure: Proportion of ACR 50 response
timeFrame: at week 24
measure: Proportion of ACR 70 response
timeFrame: at week 4
measure: Proportion of ACR 70 response
timeFrame: at week 12
measure: Proportion of ACR 70 response
timeFrame: at week 16
measure: Proportion of ACR 70 response
timeFrame: at week 20
measure: Proportion of ACR 70 response
timeFrame: at week 24
measure: Changes in ACR core set
timeFrame: at baseline
measure: Changes in ACR core set
timeFrame: at week 4
measure: Changes in ACR core set
timeFrame: at week 12
measure: Changes in ACR core set
timeFrame: at week 16
measure: Changes in ACR core set
timeFrame: at week 20
measure: Changes in ACR core set
timeFrame: at week 24
measure: DAS28 (ESR)
timeFrame: at baseline
measure: DAS28 (ESR)
timeFrame: at week 4
measure: DAS28 (ESR)
timeFrame: at week 12
measure: DAS28 (ESR)
timeFrame: at week 16
measure: DAS28 (ESR)
timeFrame: at week 20
measure: DAS28 (ESR)
timeFrame: at week 24
measure: SJC (66),
timeFrame: at baseline
measure: SJC (66),
timeFrame: at week 4
measure: SJC (66),
timeFrame: at week 12
measure: SJC (66),
timeFrame: at week 16
measure: SJC (66),
timeFrame: at week 20
measure: SJC (66),
timeFrame: at week 24
measure: TJC (68)
timeFrame: at baseline
measure: TJC (68)
timeFrame: at week 4
measure: TJC (68)
timeFrame: at week 12
measure: TJC (68)
timeFrame: at week 16
measure: TJC (68)
timeFrame: at week 20
measure: TJC (68)
timeFrame: at week 24
measure: Quality of Life: SF36 (36 items short form health survey)
timeFrame: at baseline
measure: Quality of Life: SF36 (36 items short form health survey)
timeFrame: at week 4
measure: Change in Quality of Life: SF36 (36 items short form health survey)
timeFrame: at week 4
measure: Quality of Life: SF36 (36 items short form health survey)
timeFrame: at week 12
measure: Change in Quality of Life: SF36 (36 items short form health survey)
timeFrame: at week 12
measure: Quality of Life: SF36 (36 items short form health survey)
timeFrame: at week 16
measure: Change in Quality of Life: SF36 (36 items short form health survey)
timeFrame: at week 16
measure: Quality of Life: SF36 (36 items short form health survey)
timeFrame: at week 20
measure: Change in Quality of Life: SF36 (36 items short form health survey)
timeFrame: at week 20
measure: Quality of Life: SF36 (36 items short form health survey)
timeFrame: at week 24
measure: Change in Quality of Life: SF36 (36 items short form health survey)
timeFrame: at week 24
measure: Quality of Life HAQ-DI (health assessment questionnaire - disability index)
timeFrame: at baseline
measure: Quality of Life HAQ-DI (health assessment questionnaire - disability index)
timeFrame: at week 4
measure: Change in Quality of Life HAQ-DI (health assessment questionnaire - disability index)
timeFrame: at week 4
measure: Quality of Life HAQ-DI (health assessment questionnaire - disability index)
timeFrame: at week 12
measure: Change of Quality of Life HAQ-DI (health assessment questionnaire - disability index)
timeFrame: at week 12
measure: Quality of Life HAQ-DI (health assessment questionnaire - disability index)
timeFrame: at week 16
measure: Change of Quality of Life HAQ-DI (health assessment questionnaire - disability index)
timeFrame: at week 16
measure: Quality of Life HAQ-DI (health assessment questionnaire - disability index)
timeFrame: at week 20
measure: Change of Quality of Life HAQ-DI (health assessment questionnaire - disability index)
timeFrame: at week 20
measure: Quality of Life HAQ-DI (health assessment questionnaire - disability index)
timeFrame: at week 24
measure: Change of Quality of Life HAQ-DI (health assessment questionnaire - disability index)
timeFrame: at week 24
measure: Correlation of SF36 and HAQ-DI results
timeFrame: through study completion, an average of 24 weeks
measure: Treatment satisfaction: TSQM-14 scores
timeFrame: at week 4
measure: Treatment satisfaction: TSQM-14 scores
timeFrame: at week 12
measure: Treatment satisfaction: TSQM-14 scores
timeFrame: at week 16
measure: Treatment satisfaction: TSQM-14 scores
timeFrame: at week 24
measure: Patient's expectation on treatment
timeFrame: at baseline
measure: Patient's expectation on treatment
timeFrame: at week 12
measure: Patient's expectation on treatment
timeFrame: at week 24
measure: Correlation of TSQM-14 results and patient's expectation on treatment
timeFrame: through study completion, an average of 24 weeks
measure: drug accountability
timeFrame: at week 4
measure: drug accountability
timeFrame: at week 12
measure: drug accountability
timeFrame: at week 16
measure: drug accountability
timeFrame: at week 20
measure: drug accountability
timeFrame: at week 24
measure: eGFR (estimated glomerular filtration rate)
timeFrame: at baseline
measure: eGFR (estimated glomerular filtration rate)
timeFrame: at week 4
measure: change in eGFR (estimated glomerular filtration rate)
timeFrame: at week 4
measure: eGFR (estimated glomerular filtration rate)
timeFrame: at week 12
measure: change in eGFR (estimated glomerular filtration rate)
timeFrame: at week 12
measure: change in eGFR (estimated glomerular filtration rate)
timeFrame: at week 16
measure: eGFR (estimated glomerular filtration rate)
timeFrame: at week 16
measure: change in eGFR (estimated glomerular filtration rate)
timeFrame: at week 20
measure: eGFR (estimated glomerular filtration rate)
timeFrame: at week 24
measure: change in eGFR (estimated glomerular filtration rate)
timeFrame: at week 24
measure: blood pressure (mmHg)
timeFrame: at baseline
measure: blood pressure (mmHg)
timeFrame: at week 4
measure: change in blood pressure (mmHg)
timeFrame: at week 4
measure: blood pressure (mmHg)
timeFrame: at week 12
measure: change in blood pressure (mmHg)
timeFrame: at week 12
measure: blood pressure (mmHg)
timeFrame: at week 16
measure: change in blood pressure (mmHg)
timeFrame: at week 16
measure: blood pressure (mmHg)
timeFrame: at week 20
measure: change in blood pressure (mmHg)
timeFrame: at week 20
measure: blood pressure (mmHg)
timeFrame: at week 24
measure: change in blood pressure (mmHg)
timeFrame: at week 24
measure: pain characteristics measured by QST (quantitative sensory testing)
timeFrame: at Baseline
measure: pain characteristics measured by QST (quantitative sensory testing)
timeFrame: at week 4
measure: pain characteristics measured by QST (quantitative sensory testing)
timeFrame: at week 8
measure: pain characteristics measured by QST (quantitative sensory testing)
timeFrame: at week 12
measure: pain characteristics measured by QST (quantitative sensory testing)
timeFrame: at week 24
measure: adverse events (AEs)
timeFrame: through study completion, an average of 24 weeks
measure: Infections
timeFrame: through study completion, an average of 24 weeks
measure: Documentation of all lab abnormalities
timeFrame: through study completion, an average of 24 weeks
measure: Cardiovascular events
timeFrame: through study completion, an average of 24 weeks
measure: Malignencies
timeFrame: through study completion, an average of 24 weeks
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin, Med. Klinik mit Schwerpunkt Rheumatologie und klinische Immunologie
city: Berlin
country: Germany
facility: Rheumatologische Schwerpunktpraxis im Ärztehaus am Walter-Schreiber-Platz
city: Frankfurt
country: Germany
facility: CIRI - Centrum für innovative Diagnostik & Therapie, Rheumatologie/ Immunologie GmbH
city: Herne
country: Germany
facility: Katholische Kliniken Rhein-Ruhr, St. Elisabeth Gruppe GmbH, Rheumazentrum Ruhrgebiet
city: München
country: Germany
facility: Praxis Prof. Dr. Kellner
city: Ratingen
country: Germany
facility: Rheumazentrum Ratingen
Study officials:
affiliation: Fraunhofer IME
name: Harald Burkhardt, MD
role: PRINCIPAL_INVESTIGATOR
References: