Capability of Tofacitinib or Etanercept to Accelerate Tapering of NSAID and Treat-to-target Guided De-escalation of Corticosteroids in RA Patients

Rheumatic Arthritis Clinical Trial

— AcceleRAte  

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04485325
• Other study ID #: TMP-0731-2018
• Status: Recruiting
• Phase: Phase 4
• Start date: November 4, 2019
• Est. completion date: June 2022

Study information

• Verified date: March 2022
• Source: Fraunhofer Institute for Molecular Biology and Applied Ecology
• Contact: Anja Kuehne
• Phone: 00 49 69 6301
• Email: anja.kuehne[@]ime.fraunhofer.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 192
• Est. completion date: June 2022
• Est. primary completion date: June 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Arthritis
• Rheumatic Arthritis
• Rheumatic Fever

Intervention

Drug:
• Tofacitinib
5 mg twice daily, p.o.

Biological:
• Etanercept
50 mg once per week, s.c.

Locations

Country	Name	City	State
Germany	Charité Universitätsmedizin Berlin, Med. Klinik mit Schwerpunkt Rheumatologie und klinische Immunologie	Berlin
Germany	Rheumatologische Schwerpunktpraxis im Ärztehaus am Walter-Schreiber-Platz	Berlin
Germany	CIRI - Centrum für innovative Diagnostik & Therapie, Rheumatologie/ Immunologie GmbH	Frankfurt
Germany	Katholische Kliniken Rhein-Ruhr, St. Elisabeth Gruppe GmbH, Rheumazentrum Ruhrgebiet	Herne
Germany	Praxis Prof. Dr. Kellner	München
Germany	Rheumazentrum Ratingen	Ratingen

Sponsors (2)

Lead Sponsor	Collaborator
Dr. Frank Behrens	Pfizer

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Discontinuation of Celecoxib treatment and clinically relevant improvement in pain	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%	Baseline to week 12
Secondary	Mean dosage of Celecoxib in patients	Mean dosage of Celecoxib in patients	at 12 weeks
Secondary	discontinuation of CS-treatment	Proportion of patients with discontinuation of CS-treatment at week 24	at week 24
Secondary	rescue treatment	Proportion of patients who require rescue treatment at week 12	at week 12
Secondary	Mean dosage of Corticosteroids (CS) in the patients who achieve Low Disease activity (LDA) in the two treatment groups	Mean dosage of CS in the patients who achieve LDA at week 24 in the two treatment groups	at week 24
Secondary	Mean dosage of Corticosteroids (CS)	Mean dosage of CS at week 24 (W24)	at week 24
Secondary	NSAID treatment	Number of patients with NSAID treatment at W24	at week 24
Secondary	re-started NSAID treatment	Proportion of patients who re-started NSAID treatment after week 12 (W12) until W24	week 12 to week 24
Secondary	Absolute pain levels	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	at week 2
Secondary	Absolute pain levels	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	at week 4
Secondary	Absolute pain levels	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	at week 8
Secondary	Absolute pain levels	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	at week 12
Secondary	Absolute pain levels	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	at week 16
Secondary	Absolute pain levels	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	at week 20
Secondary	Absolute pain levels	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	at week 24
Secondary	relative (percent) pain levels	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	at week 2
Secondary	relative (percent) pain levels	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	at week 4
Secondary	relative (percent) pain levels	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	at week 8
Secondary	relative (percent) pain levels	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	at week 12
Secondary	relative (percent) pain levels	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	at week 16
Secondary	relative (percent) pain levels	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	at week 20
Secondary	relative (percent) pain levels	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	at week 24
Secondary	Change in pain levels	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	at week 2
Secondary	Change in pain levels	Change in pain levels visual analogue scale (VAS) compared to BL. minimum is 0 mm, maximum is 100 mm whereas 0 is no pain and 100 is worst	at week 4
Secondary	Change in pain levels	Change in pain levels visual analogue scale (VAS) compared to BL. minimum is 0 mm, maximum is 100 mm whereas 0 is no pain and 100 is worst	at week 8
Secondary	Change in pain levels	Change in pain levels visual analogue scale (VAS) compared to BL. minimum is 0 mm, maximum is 100 mm whereas 0 is no pain and 100 is worst	at week 12
Secondary	Change in pain levels	Change in pain levels visual analogue scale (VAS) compared to BL. minimum is 0 mm, maximum is 100 mm whereas 0 is no pain and 100 is worst	at week 16
Secondary	Change in pain levels	Change in pain levels visual analogue scale (VAS) compared to BL. minimum is 0 mm, maximum is 100 mm whereas 0 is no pain and 100 is worst	at week 20
Secondary	Change in pain levels	Change in pain levels visual analogue scale (VAS) compared to BL. minimum is 0 mm, maximum is 100 mm whereas 0 is no pain and 100 is worst	at week 24
Secondary	Determination of flares	Determination of flares (measured by FLARE questionnaire) between week 12 and week 24	between week 12 and week 24
Secondary	Proportion of LDA	Proportion of patients who achieve LDA (Disease Activity Score 28 (DAS28) calculated by Erythrocyte sediment rate (ESR) (DAS28 (ESR) = 3.2)	at week 4
Secondary	Proportion of LDA	Proportion of patients who achieve LDA (Disease Activity Score 28 (DAS28) calculated by Erythrocyte sediment rate (ESR) (DAS28 (ESR) = 3.2)	at week 12
Secondary	Proportion of LDA	Proportion of patients who achieve LDA (Disease Activity Score 28 (DAS28) calculated by Erythrocyte sediment rate (ESR) (DAS28 (ESR) = 3.2)	at week 16
Secondary	Proportion of LDA	Proportion of patients who achieve LDA (Disease Activity Score 28 (DAS28) calculated by Erythrocyte sediment rate (ESR) (DAS28 (ESR) = 3.2)	at week 20
Secondary	Proportion of LDA	Proportion of patients who achieve LDA (Disease Activity Score 28 (DAS28) calculated by Erythrocyte sediment rate (ESR) (DAS28 (ESR) = 3.2)	at week 24
Secondary	Proportion of DAS remission	Proportion of patients who achieve DASremission (Disease Activity Score 28 (DAS28) calculated by Erythrocyte sediment rate (ESR) DAS28 (ESR) = 2.6)	at week 4
Secondary	Proportion of DAS remission	Proportion of patients who achieve DASremission (Disease Activity Score 28 (DAS28) calculated by Erythrocyte sediment rate (ESR) DAS28 (ESR) = 2.6)	at week 12
Secondary	Proportion of DAS remission	Proportion of patients who achieve DASremission (Disease Activity Score 28 (DAS28) calculated by Erythrocyte sediment rate (ESR) DAS28 (ESR) = 2.6)	at week 16
Secondary	Proportion of DAS remission	Proportion of patients who achieve DASremission (Disease Activity Score 28 (DAS28) calculated by Erythrocyte sediment rate (ESR) DAS28 (ESR) = 2.6)	at week 20
Secondary	Proportion of DAS remission	Proportion of patients who achieve DASremission (Disease Activity Score 28 (DAS28) calculated by Erythrocyte sediment rate (ESR) DAS28 (ESR) = 2.6)	at week 24
Secondary	Proportion of ACR20 response	Proportion of patients who achieve ACR20 response - measure based on American College of Rheumatology (ACR) criteria improvement of at least 20%	at week 4
Secondary	Proportion of ACR20 response	Proportion of patients who achieve ACR20 response - measure based on American College of Rheumatology (ACR) criteria improvement of at least 20%	at week 12
Secondary	Proportion of ACR20 response	Proportion of patients who achieve ACR20 response - measure based on American College of Rheumatology (ACR) criteria improvement of at least 20%	at week 16
Secondary	Proportion of ACR20 response	Proportion of patients who achieve ACR20 response - measure based on American College of Rheumatology (ACR) criteria improvement of at least 20%	at week 20
Secondary	Proportion of ACR20 response	Proportion of patients who achieve ACR20 response - measure based on American College of Rheumatology (ACR) criteria improvement of at least 20%	at week 24
Secondary	Proportion of ACR 50 response	Proportion of patients who achieve ACR50 response - measure based on American College of Rheumatology (ACR) criteria improvement of at least 50%	at week 4
Secondary	Proportion of ACR 50 response	Proportion of patients who achieve ACR50 response - measure based on American College of Rheumatology (ACR) criteria improvement of at least 50%	at week 12
Secondary	Proportion of ACR 50 response	Proportion of patients who achieve ACR50 response - measure based on American College of Rheumatology (ACR) criteria improvement of at least 50%	at week 16
Secondary	Proportion of ACR 50 response	Proportion of patients who achieve ACR50 response - measure based on American College of Rheumatology (ACR) criteria improvement of at least 50%	at week 20
Secondary	Proportion of ACR 50 response	Proportion of patients who achieve ACR50 response - measure based on American College of Rheumatology (ACR) criteria improvement of at least 50%	at week 24
Secondary	Proportion of ACR 70 response	Proportion of patients who achieve ACR70 response - measure based on American College of Rheumatology (ACR) criteria improvement of at least 70%	at week 4
Secondary	Proportion of ACR 70 response	Proportion of patients who achieve ACR70 response - measure based on American College of Rheumatology (ACR) criteria improvement of at least 70%	at week 12
Secondary	Proportion of ACR 70 response	Proportion of patients who achieve ACR70 response - measure based on American College of Rheumatology (ACR) criteria improvement of at least 70%	at week 16
Secondary	Proportion of ACR 70 response	Proportion of patients who achieve ACR70 response - measure based on American College of Rheumatology (ACR) criteria improvement of at least 70%	at week 20
Secondary	Proportion of ACR 70 response	Proportion of patients who achieve ACR70 response - measure based on American College of Rheumatology (ACR) criteria improvement of at least 70%	at week 24
Secondary	Changes in ACR core set	Changes in ACR core set	at baseline
Secondary	Changes in ACR core set	Changes in ACR core set	at week 4
Secondary	Changes in ACR core set	Changes in ACR core set	at week 12
Secondary	Changes in ACR core set	Changes in ACR core set	at week 16
Secondary	Changes in ACR core set	Changes in ACR core set	at week 20
Secondary	Changes in ACR core set	Changes in ACR core set change	at week 24
Secondary	DAS28 (ESR)	DAS28 (ESR) change compared to BL	at baseline
Secondary	DAS28 (ESR)	DAS28 (ESR) change compared to BL	at week 4
Secondary	DAS28 (ESR)	DAS28 (ESR) change compared to BL	at week 12
Secondary	DAS28 (ESR)	DAS28 (ESR) change compared to BL	at week 16
Secondary	DAS28 (ESR)	DAS28 (ESR) change compared to BL	at week 20
Secondary	DAS28 (ESR)	DAS28 (ESR) change compared to BL	at week 24
Secondary	SJC (66),	Swollen joint count (66 joints) change compared to BL	at baseline
Secondary	SJC (66),	Swollen joint count (66 joints) change compared to BL	at week 4
Secondary	SJC (66),	Swollen joint count (66 joints) change compared to BL	at week 12
Secondary	SJC (66),	Swollen joint count (66 joints) change compared to BL	at week 16
Secondary	SJC (66),	Swollen joint count (66 joints) change compared to BL	at week 20
Secondary	SJC (66),	Swollen joint count (SJC) (66 joints) change compared to BL	at week 24
Secondary	TJC (68)	tender joint count (TJC) - 68 joints change compared to BL	at baseline
Secondary	TJC (68)	tender joint count (TJC) - 68 joints change compared to BL	at week 4
Secondary	TJC (68)	tender joint count (TJC) - 68 joints change compared to BL	at week 12
Secondary	TJC (68)	tender joint count (TJC) - 68 joints change compared to BL	at week 16
Secondary	TJC (68)	tender joint count (TJC) - 68 joints change compared to BL	at week 20
Secondary	TJC (68)	tender joint count (TJC) - 68 joints change compared to BL	at week 24
Secondary	Quality of Life: SF36 (36 items short form health survey)	Quality of Life: SF36 scores	at baseline
Secondary	Quality of Life: SF36 (36 items short form health survey)	Quality of Life: SF36 scores.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.	at week 4
Secondary	Change in Quality of Life: SF36 (36 items short form health survey)	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.	at week 4
Secondary	Quality of Life: SF36 (36 items short form health survey)	Quality of Life: SF36 scores. 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.	at week 12
Secondary	Change in Quality of Life: SF36 (36 items short form health survey)	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.	at week 12
Secondary	Quality of Life: SF36 (36 items short form health survey)	Quality of Life: SF36 scores. 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.	at week 16
Secondary	Change in Quality of Life: SF36 (36 items short form health survey)	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.	at week 16
Secondary	Quality of Life: SF36 (36 items short form health survey)	Quality of Life: SF36 scores. 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.	at week 20
Secondary	Change in Quality of Life: SF36 (36 items short form health survey)	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.	at week 20
Secondary	Quality of Life: SF36 (36 items short form health survey)	Quality of Life: SF36 scores. 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.	at week 24
Secondary	Change in Quality of Life: SF36 (36 items short form health survey)	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.	at week 24
Secondary	Quality of Life HAQ-DI (health assessment questionnaire - disability index)	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).	at baseline
Secondary	Quality of Life HAQ-DI (health assessment questionnaire - disability index)	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).	at week 4
Secondary	Change in Quality of Life HAQ-DI (health assessment questionnaire - disability index)	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).	at week 4
Secondary	Quality of Life HAQ-DI (health assessment questionnaire - disability index)	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).	at week 12
Secondary	Change of Quality of Life HAQ-DI (health assessment questionnaire - disability index)	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).	at week 12
Secondary	Quality of Life HAQ-DI (health assessment questionnaire - disability index)	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).	at week 16
Secondary	Change of Quality of Life HAQ-DI (health assessment questionnaire - disability index)	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).	at week 16
Secondary	Quality of Life HAQ-DI (health assessment questionnaire - disability index)	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).	at week 20
Secondary	Change of Quality of Life HAQ-DI (health assessment questionnaire - disability index)	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).	at week 20
Secondary	Quality of Life HAQ-DI (health assessment questionnaire - disability index)	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).	at week 24
Secondary	Change of Quality of Life HAQ-DI (health assessment questionnaire - disability index)	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).	at week 24
Secondary	Correlation of SF36 and HAQ-DI results	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.	through study completion, an average of 24 weeks
Secondary	Treatment satisfaction: TSQM-14 scores	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.	at week 4
Secondary	Treatment satisfaction: TSQM-14 scores	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.	at week 12
Secondary	Treatment satisfaction: TSQM-14 scores	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.	at week 16
Secondary	Treatment satisfaction: TSQM-14 scores	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.	at week 24
Secondary	Patient's expectation on treatment	Patient's expectation on treatment asked and documented as free text	at baseline
Secondary	Patient's expectation on treatment	Patient's expectation on treatment asked and documented as free text	at week 12
Secondary	Patient's expectation on treatment	Patient's expectation on treatment asked and documented as free text	at week 24
Secondary	Correlation of TSQM-14 results and patient's expectation on treatment	Correlation of TSQM-14 results and patient's expectation on treatment	through study completion, an average of 24 weeks
Secondary	drug accountability	Evaluation of results of treatment adherence (drug accountability) using patient diary	at week 4
Secondary	drug accountability	Evaluation of results of treatment adherence (drug accountability) using patient diary	at week 12
Secondary	drug accountability	Evaluation of results of treatment adherence (drug accountability) using patient diary	at week 16
Secondary	drug accountability	Evaluation of results of treatment adherence (drug accountability) using patient diary	at week 20
Secondary	drug accountability	Evaluation of results of treatment adherence (drug accountability) using patient diary	at week 24
Secondary	eGFR (estimated glomerular filtration rate)	eGFR value	at baseline
Secondary	eGFR (estimated glomerular filtration rate)	eGFR value	at week 4
Secondary	change in eGFR (estimated glomerular filtration rate)	eGFR change to BL	at week 4
Secondary	eGFR (estimated glomerular filtration rate)	eGFR value	at week 12
Secondary	change in eGFR (estimated glomerular filtration rate)	eGFR change to BL	at week 12
Secondary	change in eGFR (estimated glomerular filtration rate)	eGFR change to BL	at week 16
Secondary	eGFR (estimated glomerular filtration rate)	eGFR value	at week 16
Secondary	change in eGFR (estimated glomerular filtration rate)	eGFR change to BL	at week 20
Secondary	eGFR (estimated glomerular filtration rate)	eGFR value	at week 24
Secondary	change in eGFR (estimated glomerular filtration rate)	eGFR change to BL	at week 24
Secondary	blood pressure (mmHg)	blood pressure (mmHg) Systolic or Diastolic Blood Pressure	at baseline
Secondary	blood pressure (mmHg)	blood pressure (mmHg) Systolic or Diastolic Blood Pressure	at week 4
Secondary	change in blood pressure (mmHg)	blood pressure (mmHg) Systolic or Diastolic Blood Pressure change to BL	at week 4
Secondary	blood pressure (mmHg)	blood pressure (mmHg) Systolic or Diastolic Blood Pressure	at week 12
Secondary	change in blood pressure (mmHg)	blood pressure (mmHg) Systolic or Diastolic Blood Pressure change to BL	at week 12
Secondary	blood pressure (mmHg)	blood pressure (mmHg) Systolic or Diastolic Blood Pressure	at week 16
Secondary	change in blood pressure (mmHg)	blood pressure (mmHg) Systolic or Diastolic Blood Pressure change to BL	at week 16
Secondary	blood pressure (mmHg)	blood pressure (mmHg) Systolic or Diastolic Blood Pressure	at week 20
Secondary	change in blood pressure (mmHg)	blood pressure (mmHg) Systolic or Diastolic Blood Pressure change to BL	at week 20
Secondary	blood pressure (mmHg)	blood pressure (mmHg) Systolic or Diastolic Blood Pressure	at week 24
Secondary	change in blood pressure (mmHg)	blood pressure (mmHg) Systolic or Diastolic Blood Pressure change to BL	at week 24
Secondary	pain characteristics measured by QST (quantitative sensory testing)	Correlation of pain characteristics measured by QST, VAS pain and pain relief	at Baseline
Secondary	pain characteristics measured by QST (quantitative sensory testing)	Correlation of pain characteristics measured by QST, VAS pain and pain relief	at week 4
Secondary	pain characteristics measured by QST (quantitative sensory testing)	Correlation of pain characteristics measured by QST, VAS pain and pain relief	at week 8
Secondary	pain characteristics measured by QST (quantitative sensory testing)	Correlation of pain characteristics measured by QST, VAS pain and pain relief	at week 12
Secondary	pain characteristics measured by QST (quantitative sensory testing)	Correlation of pain characteristics measured by QST, VAS pain and pain relief	at week 24
Secondary	adverse events (AEs)	Documentation of type, frequency and seriousness of adverse events (AEs)	through study completion, an average of 24 weeks
Secondary	Infections	Incidence rates of serious infection events (SIEs),	through study completion, an average of 24 weeks
Secondary	Documentation of all lab abnormalities	incidence rates of lab abnormalities	through study completion, an average of 24 weeks
Secondary	Cardiovascular events	incidence rates of cardio vascular events	through study completion, an average of 24 weeks
Secondary	Malignencies	incidence rates of malignancies	through study completion, an average of 24 weeks