Rheumatic Arthritis
Conditions
Keywords
treat-to-target, pain
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.
Interventions
DRUGTofacitinib
5 mg twice daily, p.o.
BIOLOGICALEtanercept
50 mg once per week, s.c.
Sponsors
Pfizer
Dr. Frank Behrens
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
two arm, randomized, open-label, parallel group
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Discontinuation of Celecoxib treatment and clinically relevant improvement in pain | Baseline to week 12 | Proportion of patients who can discontinue Celecoxib treatment and in whom clinically relevant improvement in pain levels are measured, defined as reduction in VAS pain of ≥ 30% |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Documentation of all lab abnormalities | through study completion, an average of 24 weeks | incidence rates of lab abnormalities |
| Cardiovascular events | through study completion, an average of 24 weeks | incidence rates of cardio vascular events |
| Mean dosage of Celecoxib in patients | at 12 weeks | Mean dosage of Celecoxib in patients |
| discontinuation of CS-treatment | at week 24 | Proportion of patients with discontinuation of CS-treatment at week 24 |
| rescue treatment | at week 12 | Proportion of patients who require rescue treatment at week 12 |
| Mean dosage of Corticosteroids (CS) in the patients who achieve Low Disease activity (LDA) in the two treatment groups | at week 24 | Mean dosage of CS in the patients who achieve LDA at week 24 in the two treatment groups |
| Mean dosage of Corticosteroids (CS) | at week 24 | Mean dosage of CS at week 24 (W24) |
| NSAID treatment | at week 24 | Number of patients with NSAID treatment at W24 |
| re-started NSAID treatment | week 12 to week 24 | Proportion of patients who re-started NSAID treatment after week 12 (W12) until W24 |
| Absolute pain levels | at week 2 | Absolute pain levels measured by visual analogue scale (VAS). minimum is 0 mm, maximum is 100 mm whereas 0 is no pain and 100 is worst |
| relative (percent) pain levels | at week 2 | relative (percent) pain levels measured by visual analogue scale (VAS). minimum is 0 mm, maximum is 100 mm whereas 0 is no pain and 100 is worst |
| Change in pain levels | at week 2 | Change in pain levels measured by visual analogue scale (VAS) compared to BL. minimum is 0 mm, maximum is 100 mm whereas 0 is no pain and 100 is worst |
| Determination of flares | between week 12 and week 24 | Determination of flares (measured by FLARE questionnaire) between week 12 and week 24 |
| Proportion of LDA | at week 4 | Proportion of patients who achieve LDA (Disease Activity Score 28 (DAS28) calculated by Erythrocyte sediment rate (ESR) (DAS28 (ESR) ≤ 3.2) |
| Proportion of DAS remission | at week 4 | Proportion of patients who achieve DASremission (Disease Activity Score 28 (DAS28) calculated by Erythrocyte sediment rate (ESR) DAS28 (ESR) ≤ 2.6) |
| Proportion of ACR20 response | at week 4 | Proportion of patients who achieve ACR20 response - measure based on American College of Rheumatology (ACR) criteria improvement of at least 20% |
| Proportion of ACR 50 response | at week 4 | Proportion of patients who achieve ACR50 response - measure based on American College of Rheumatology (ACR) criteria improvement of at least 50% |
| Infections | through study completion, an average of 24 weeks | Incidence rates of serious infection events (SIEs), |
| Proportion of ACR 70 response | at week 4 | Proportion of patients who achieve ACR70 response - measure based on American College of Rheumatology (ACR) criteria improvement of at least 70% |
| Changes in ACR core set | at baseline | Changes in ACR core set |
| DAS28 (ESR) | at baseline | DAS28 (ESR) change compared to BL |
| SJC (66), | at baseline | Swollen joint count (66 joints) change compared to BL |
| TJC (68) | at baseline | tender joint count (TJC) - 68 joints change compared to BL |
| Quality of Life: SF36 (36 items short form health survey) | at baseline | Quality of Life: SF36 scores |
| Change in Quality of Life: SF36 (36 items short form health survey) | at week 4 | Quality of Life: SF36 change to BL. SF36 is a 36 items short form health survey and consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability. |
| Quality of Life HAQ-DI (health assessment questionnaire - disability index) | at baseline | Quality of Life HAQ-DI scores The HAQ-DI is a health assessment questionnaire - disability index that consists of 8 subcategories. For each the single scales range from 0 (no difficulty) to 3 (unable to do). |
| Change in Quality of Life HAQ-DI (health assessment questionnaire - disability index) | at week 4 | Quality of Life HAQ-DI change to BL. The HAQ-DI is a health assessment questionnaire - disability index that consists of 8 subcategories. For each the single scales range from 0 (no difficulty) to 3 (unable to do). |
| Change of Quality of Life HAQ-DI (health assessment questionnaire - disability index) | at week 12 | Quality of Life HAQ-DI change to BL. The HAQ-DI is a health assessment questionnaire - disability index that consists of 8 subcategories. For each the single scales range from 0 (no difficulty) to 3 (unable to do). |
| Correlation of SF36 and HAQ-DI results | through study completion, an average of 24 weeks | Correlation of SF36 and HAQ-DI results. The HAQ-DI is a health assessment questionnaire - disability index that consists of 8 subcategories. For each the single scales range from 0 (no difficulty) to 3 (unable to do). SF36 is a 36 items short form health survey and consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability. |
| Treatment satisfaction: TSQM-14 scores | at week 4 | Treatment Satisfaction Questionnaire for Medication (TSQM-14) scores. The TSQM items are answered on 5- or 7-point Likert type scale and cover four domains: effectiveness; side effects; convenience and global satisfaction. A score can be obtained for each domain by summing of the corresponding items transformed on a 0-100 scale; higher values indicate higher satisfaction, better perceived effectiveness, lower burden associated to side-effects, better convenience. |
| Patient's expectation on treatment | at baseline | Patient's expectation on treatment asked and documented as free text |
| Correlation of TSQM-14 results and patient's expectation on treatment | through study completion, an average of 24 weeks | Correlation of TSQM-14 results and patient's expectation on treatment |
| drug accountability | at week 4 | Evaluation of results of treatment adherence (drug accountability) using patient diary |
| eGFR (estimated glomerular filtration rate) | at baseline | eGFR value |
| Malignencies | through study completion, an average of 24 weeks | incidence rates of malignancies |
| blood pressure (mmHg) | at baseline | blood pressure (mmHg) Systolic or Diastolic Blood Pressure |
| change in blood pressure (mmHg) | at week 4 | blood pressure (mmHg) Systolic or Diastolic Blood Pressure change to BL |
| pain characteristics measured by QST (quantitative sensory testing) | at Baseline | Correlation of pain characteristics measured by QST, VAS pain and pain relief |
| adverse events (AEs) | through study completion, an average of 24 weeks | Documentation of type, frequency and seriousness of adverse events (AEs) |
| change in eGFR (estimated glomerular filtration rate) | at week 4 | eGFR change to BL |
Countries
Germany
Outcome results
None listed