Clinical trial NCT02779114: RETRO (REduction of Therapy in RA Patients in Ongoing Remission)
Official title: A Phase 3, Multicenter, Randomized, Open, Prospective, Controlled, Parallel Group Study of Reduction of Therapy in Patients With Rheumatoid Arthritis in Ongoing Remission.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Rheumatoid Arthritis
Keywords: Rheumatoid Arthritis
Remission
Dose reduction
Lead sponsor: University of Erlangen-Nürnberg Medical School
Sponsor class: OTHER
First posted: 2016-05-20
Enrollment: 318
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a phase 3, multicenter, randomized, open, prospective, controlled, parallel-group intervention study in 318 patients with Rheumatoid Arthritis. The study is composed of 3 phases: a pre-randomization phase for up to 10 days followed by a 1-year randomized, open three arm treatment phase for each patient, followed by a 5-year observational phase for all patients still in remission.

Detailed description: Rheumatoid Arthritis (RA) is characterized by progressive synovitis leading to degradation of articular cartilage leading to erosions in juxtaarticular bones driven by auto antibodies. Few clinical studies could show that quick and thorough control of inflammatory processes could stop degradation processes \[17, 18, 19, 20, 21\] and had presumably better prognosis of remission than untreated and/or uncontrolled RA disease \[20\]. These studies aimed at low disease activity \[20\], often focused on early RA \[18, 19\], evaluating different therapy strategies, mostly escalating instead of deescalating medications \[20, 21\]. Real "RA- in - remission" or therapy reduction studies are missing up to now, even if first small trials focusing on one preparation showed promising results \[16, 17\].

In this study all conventional medications in usual combinations are being evaluated for the treatment of Rheumatoid Arthritis in different stages of disease duration. The study is scheduled as a 365-day (12-months), phase 3 multicenter, randomized, open, prospective, controlled, parallel-group intervention study in 318 patients with Rheumatoid Arthritis.

Based on the results of the clinical studies mentioned above, and the need for a guideline with therapy proposals for RA- patients in remission all current preparations will be evaluated in subjects under the controlled setting of a clinical study. The information obtained from this study will assess the formulation of new guidelines regarding patients with Rheumatoid Arthritis in remission.

Eligibility criteria: Inclusion Criteria:

* Must understand and voluntarily sign an informed consent form including written consentfor data protection
* Must be able to adhere to the study visit schedule and other protocol requirements
* Must be male or female and aged ≥ 18 years at time of consent
* Must have a diagnosis of RA according to ACR criteria \[26\] for at least 12 months
* Must have a DAS 28 score of less than 2.6 (means: remission) at randomization (documented in at least three subsequent controls for six months; compare figure three in the appendix for details)
* At screening-visit patients should have been treated without alterations of therapy for at least six months with one of the following therapies: (i) one or more of the following conventional DMARDS (with or without concomitant use of glucocorticoids): Methotrexate, Leflunomide, Ciclosporine A, Sulfasalazine, Azathioprine or Hydroxychloroquine, (ii) a combination of a conventional DMARD (Methotrexate, Leflunomide, Ciclosporine A, Sulfasalazine, Azathioprine or Hydroxychloroquine) with one of the following biologicals (with or without concomitant use of glucocorticoids): Infliximab, Adalimumab, Etanercept, Tocilizumab, Golimumab, Certolizumab, Abatacept, (iii) or one of the biologicals mentioned above without combination with a conventional DMARD. All of the aforementioned biologicals are also allowed in combination with glucocorticoids, (iv) monotherapy treatment with glucocorticoids (without any DMARD or biological treatment).

Exclusion Criteria:

* Treatment with Rituximab during the last 12 months before screening
* Intake of a daily dosage of more than 5mg Prednisolone - equivalent during the last 6 months before randomization; intraarticular injections of glucocorticoids do not represent an exclusion criteria
* Current treatment with other DMARDS (for example MMF or preparations still in development) than mentioned above
* Any anti-inflammatory or immunosuppressive therapy for other reasons than RA during the last 3 months before screening
* Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study
* Any other rheumatological/immunological disease such as Psoriasis, Psoriatic Arthritis, SLE, PSS, MCTD, M. Bechterew, M. Behcet or M. Wegener. Should the respective diagnosis be confirmed after inclusion into the study the patient will leave the study and data is recorded via "unscheduled visit"- and follow-up form
* Florid autoimmune conditions such as autoimmune hepatitis or Hashimoto's disease while still under treatment
* Patients with a florid malignancy
* Participation in another phase 1-4 treatment study for RA
* Patients who are younger than 18 years or are incapable to understand the aim, importance and consequences of the study and to give legal informed consent (according to § 40 Abs. 4 and § 41 Abs. 2 und Abs. 3 AMG)
* Pregnant or lactating female
* Females of childbearing potential (FCBP is a sexually mature female who 1. has not undergone a hysterectomy or bilateral oophorectomy, or 2. has not been postmenopausal for at least 24 consecutive months) have to use adequate forms of contraception with respect to standard treatment recommendations. However if there is suspicion of a pregnancy in spite of standard treatment recommendations a urine pregnancy test is to be carried out by the Investigator
* Also males must also use adequate forms of contraception
* Patients who possibly are dependent on the Principal Investigator or investigator

Primary outcomes:
measure: Proportion of subjects in each treatment group who are still in remission after 12 months (remission defined as DAS 28 < 2.6) reduction or even discontinuation in RA-patients after achievement of long lasting remission.
timeFrame: 12 months
Secondary outcomes:
measure: Proportion of subjects in each treatment group who are still in remission after 3, 6, 9 months (remission defined as DAS 28 < 2.6).
timeFrame: 12 months
measure: Proportion of subjects in each treatment group who are still in remission after 3, 6, 9 months (remission defined according to Pinals - criteria)
timeFrame: 12months
measure: Proportion of subjects in each treatment group with increased disease activity
timeFrame: 12 months
measure: Proportion of adverse events (to be documented via "unscheduled visit"-sheet)
timeFrame: 12 months
measure: DAS 28 after 3, 6, 9 and 12 months
timeFrame: 12 months
measure: CRP after 3, 6, 9 and 12 months
timeFrame: 12 months
measure: ESR after 3, 6, 9 and 12 months
timeFrame: 12 months
measure: Swollen joint counts after 3, 6, 9 and 12 months
timeFrame: 12 months
measure: Tender joint counts after 3, 6, 9 and 12 months
timeFrame: 12 months
measure: Patient self assessment of pain (VAS) after 3, 6, 9 and 12 months
timeFrame: 12 months
measure: Physician's and patient's assessment of global disease activity (VAS) after 3, 6, 9 and 12 months
timeFrame: 12 months
measure: Duration of joint stiffness after 3, 6, 9 and 12 months
timeFrame: 12 months
measure: HAQ (Health Assessment Questionnaire) after 3, 6, 9 and 12 months
timeFrame: 12 months
measure: SF-36 (Short Form) Score after 3, 6, 9 and 12 months
timeFrame: 12 months
measure: Coping-Questionnaire after 3, 6, 9 and 12 months
timeFrame: 12 months
measure: PASS (patient acceptable symptom state) after 3, 6, 9 and 12 months
timeFrame: 12 months
measure: WPAI:RA (Work Productivity and Activity Impairment Questionnaire) after 3, 6, 9, 12 months
timeFrame: 12 months
measure: BDI - II (Beck-Depression Inventory) after 3, 6, 9 and 12 months
timeFrame: 12 months
measure: Flare Questionnaire RA (German version): At time of potential flare
timeFrame: 12 months
Other outcomes:
Locations:
city: Bad Abbach
country: Germany
facility: Asklepios Klinikum Bad Abbach
city: Bamberg
country: Germany
facility: Rheumapraxis Manger
city: Bayreuth
country: Germany
facility: Rheumapraxis Bayreuth
city: Berlin
country: Germany
facility: Schlosspark-Klinik
city: Burghausen
country: Germany
facility: Schwerpunktpraxis für Rheumatologie Burghausen
city: Erlangen
country: Germany
facility: PGRN.de Praxisgemeinschaft Rheumatologie Nephrologie
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg; Medizinische Klinik V
city: Hildesheim
country: Germany
facility: Gemeinschaftspraxis Dres. Demary und von Hinüber
city: München
country: Germany
facility: Praxiszentrum St. Bonifatius
city: Nürnberg
country: Germany
facility: Praxis Professor Nüsslein
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen; Zentrum für Interdisziplinäre Klinische Immunologie, Rheumatologie und Autoimmunerkrankungen - INDIRA
city: Würzburg
country: Germany
facility: Medizinische Klinik 2 und Poliklinik, Universitätsklinikum Würzburg
Study officials:
affiliation: University Clinic Erlangen, Clinical Trial Unit, Department of Internal Medicine 3, Rheumatology & Immunology
name: Georg Schett, Prof. Dr. univ.
role: STUDY_DIRECTOR
References: