A Multicenter, Randomized, Open-label, Blinded-assessor, Phase 4 Study in Patients With Early Rheumatoid Arthritis to Compare Active Conventional Therapy Versus Three Biologic Treatments, and Two De-escalation Strategies in Patients Who Respond to Treatment
试验速览
- 阶段
- 4 期
- 入组人数
- 812
- 试验地点
- 28
- 主要终点
- The proportion of patients in remission at week 24 after dose-reduction according to CDAI
研究概览
简要总结
This is an international (Sweden, Finland, Norway, Denmark, Iceland and the Netherlands) trial designed to compare the safety and efficacy of active conventional therapy (ACT) and three biologic treatments in subjects with early rheumatoid arthritis (RA). The global aim of this study is to assess and compare
- the proportion of subjects who achieve remission with ACT versus three different biologic therapies (Certolizumab-pegol, Abatacept or Tocilizumab)
- two alternative de-escalation strategies in patients who respond to first-line therapy.
详细描述
After completed enrollment a total of 812 patients were included in the study.
371 of the included patients have entered treatment part 2, 256 patients have exited the study after treatment part 1, 207 patients have had early termination and 322 patients have completed the full study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subject is ≥18 years of age.
- •Subject has a diagnosis of RA as defined by the newly established ACR/EULAR criteria,
- •(Patients should also be classified according to the 1987-revised ACR-classification criteria, without this being an inclusion criteria).
- •<24 months from arthritis symptom debut (symptom duration will be registered).
- •Subject must have DAS28 (CRP) > 3.
- •≥ 2 swollen joints AND ≥ 2 tender joints.
- •Subject must fulfill one of the following three criteria: RF positive OR ACPA positive OR CRP >10 mg/L.
- •Female subject is either not of childbearing potential (postmenopausal, surgically sterile etc.), or is of childbearing potential and practicing one of the following methods of birth control throughout the study and for 150 days after study completion:
- •Intrauterine device (IUD)
- •Contraceptives (oral, parenteral, patch) for three months prior to study drug administration)
- •A vasectomized partner
- •Female subjects of childbearing potential must have a negative serum pregnancy test at the Screening visit.
- •Subject is judged to be in good general health as determined by the principal investigator based upon the results of medical history, laboratory profile, physical examination, chest X-ray (CXR), and 12-lead electrocardiogram (ECG) performed at Screening.
- •Subjects must be able and willing to provide written informed consent and comply with the requirements of this study protocol.
- •Subjects must be able and willing to self-administer s.c. injections or have a qualified person available to administer s.c. injections.
排除标准
- •Subject has been previously treated with disease modifying antirheumatic drugs (DMARDs) for rheumatic diseases.
- •Current active inflammatory joint disease other than RA.
- •Subjects has had a dose of prednisone (or equivalent) >7.5 mg/day or has had a dose change within the preceding 4 weeks.
- •Subject has been treated with intra-articular or parenteral administration of corticosteroids in the preceding 4 weeks. Inhaled corticosteroids for stable medical conditions are allowed.
- •Subject has undergone joint surgery within the preceding two months (at joints to be assessed within the study).
- •Subject has chronic arthritis diagnosed before age 17 years.
- •Subject has a history of an allergic reaction or significant sensitivity to constituents of study drugs.
- •Subject has been treated with any investigational drug within one month prior to screening visit.
- •Active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization within 4 weeks of screening.
- •Subject has a poorly controlled medical condition, such as uncontrolled diabetes, unstable heart disease, congestive heart failure, recent cerebrovascular accidents and any other condition which, in the opinion of the investigator, would put the subject at risk by participation in the study.
- •Subject has a history of clinically significant hematologic (e.g., severe anemia, leukopenia, thrombocytopenia), renal or liver disease (e.g., fibrosis, cirrhosis, hepatitis).
- •Subject has history of neurologic symptoms suggestive of central nervous system (CNS) demyelinating disease and/or diagnosis of central demyelinating disease.
- •Subject has history of cancer or lymphoproliferative disease. Allowable exceptions:
- •Successfully treated cutaneous squamous cell or basal cell carcinoma
- •Localized carcinoma in situ of the cervix
- •Curatively treated malignancy (treatment terminated) > 5 years prior to screening
- •Subject has a history of listeriosis, histoplasmosis, untreated TB, persistent chronic infections, or recent active infections requiring hospitalization or treatment with intravenous (iv) anti-infectives within 30 days or oral anti-infectives within 14 days prior to the BL visit.
- •Subjects will be evaluated for latent TB infection with a PPD or QuantiFERON test and X-ray. Subjects with evidence for latent TB will not be enrolled but first assessed according to local guidelines.
- •Subject is known to have immune deficiency, history of Human Immunodeficiency Virus (HIV) or is otherwise severely immunocompromised.
- •Female subject who is pregnant or breast-feeding or considering becoming pregnant during the study or within 150 days after the last dose of study medication.
- •Men who are planning to father a child during the time they are included in the study
- •Subject has a history of clinically significant drug or alcohol usage in the last year.
- •Subject has a chronic widespread pain syndrome.
- •Subject is considered by the investigator, for any reason, to be an unsuitable candidate for the study.
- •Subject is unwilling to comply with the study protocol.
- •Screening clinical laboratory analyses show any of the following abnormal laboratory results:
- •Aspartate transaminase (AST) or alanine transaminase (ALT) > 1.75 times upper limit of normal (ULN).
- •Positive serum human chorionic gonadotropin (hCG).
- •Positive tests for hepatitis B surface antigen (HBsAg) or hepatitis C serology indicative of current infection.
- •Creatinine levels > 2x the ULN. If creatinine 1-2 times ULN, check GFR.
- •Hemoglobin < 90 g/L.
- •Absolute neutrophil count (ANC) < 1.5 x 10^3/microL.
- •Serum total bilirubin > 1.5 mg/dL (>26 micromol/L).
研究组 & 干预措施
Active conventional therapy (ACT)
Non-biological DMARD's: Methotrexate plus steroids or Methotrexate plus Sulphasalazine and Hydroxychloroquine and steroids
干预措施: Non-biological DMARD's (Drug)
Biologic agent 1
Cimzia: Certolizumab-pegol plus Methotrexate and steroids
干预措施: Cimzia (Biological)
Biologic agent 2
Orencia: Abatacept plus Methotrexate and steroids
干预措施: Orencia (Biological)
Biologic agent 3
RoActemra: Tocilizumab plus Methotrexate and steroids
干预措施: RoActemra (Biological)
结局指标
主要结局
The proportion of patients in remission at week 24 after dose-reduction according to CDAI
时间窗: 24 weeks after dose-reduction
Treatment Part 2: The primary efficacy outcome is the proportion of patients in remission according to CDAI, at the time point 24 weeks after the dose was first reduced
The radiographic progression of total Sharp van der Heijde score after 48 weeks from baseline
时间窗: 48 weeks from BL
The primary efficacy outcome is the progression of total Sharp van der Heijde score after 48 weeks from BL
The proportion of patients in remission at week 24 from baseline according to CDAI
时间窗: 24 weeks from BL
Treatment Part 1: The primary efficacy outcome is the proportion of patients in remission at week 24 from BL according to CDAI
次要结局
未报告次要终点
研究者
Ronald van Vollenhoven, prof.
Principal Investigator
Karolinska Institutet