Impact of Concomitant Methotrexate on Efficacy, Safety and Adherence of Ustekinumab-treatment in Patients With Active Psoriasis Arthritis
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 186
- 试验地点
- 1
- 主要终点
- Assessment of mean values of DAS28 at week 24
研究概览
简要总结
Methotrexate (MTX) co-medication can improve the therapeutic effect of biological therapies (e.g. Tumor necrosis factor (TNF) -inhibitors) in rheumatoid arthritis (RA), but its role in Psoriatic Arthritis (PsA) remains unclear.
No data from Randomized Clinical Trials (RCTs) are available to address the questions whether add-on of MTX to UST monotherapy, or a withdrawal of continuous MTX therapy in patients with newly initiated Ustekinumab (UST) treatment or simultaneously induction of MTX with UST in naive active PsA-patients will influence outcome measurements.
So, the purpose of the study is to analyse the effects of blinded MTX-co-medication on outcome in patients treated with UST: Non-inferiority at week 24 of UST monotherapy compared to add-on to MTX in patients with active PsA and at least 12 weeks of MTX treatment prior to screening or who are actually not treated with MTX and do not have prior inadequate response to MTX-treatment for PsA will be demonstrated.
详细描述
Methotrexate (MTX) co-medication can improve the therapeutic effect of biological therapies (e.g. TNF-inhibitors) in rheumatoid arthritis (RA), but its role in Psoriatic Arthritis (PsA) remains unclear. Differences in phenotypical manifestations between PsA and RA might influence the impact of co-medication, treatment response and treatment adherence differently.
Independent from this data, the impact of use of MTX in Ustekinumab (UST) treated patients with active PsA remains unclear: No data from Randomized Clinical Trials (RCTs) are available to address the questions whether add-on of MTX to UST monotherapy, or the other way around, a withdrawal of continuous MTX therapy in patients with newly initiated UST treatment or simultaneously induction of MTX with UST in patients will influence outcome.
There is some evidence that MTX may contribute to improved treatment persistence with anti-TNF therapy, particularly when used in combination with infliximab, but there is very little data to support a benefit in effectiveness in patients receiving concomitant MTX.
Additionally, MTX may play a role in immunogenicity: In the PSUMMIT program the patients with concomitant MTX had lower anti-drug-antibody (ADA) rates than those on UST-monotherapy, although there was no effect on efficacy and safety.
Furthermore, methotrexate treatment manifestations such as dactylitis or enthesitis seems to be ineffective.
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
- Triple (Participant, Care Provider, Investigator)
盲法说明
Methotrexate tablets will be encapsulated equal to Placebo to ensure blinding. Ustekinumab will be open-label
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
- •Patients with active psoriatic arthritis who are naïve to UST will be stratified to either without MTX-therapy or on MTX-treatment (dosage 15mg once weekly) for at least 12 weeks prior to screening.
- •Active PsA is defined as TJC ≥4 and SJC ≥4 (68/66 joint count) and DAS28 ≥ 3,2 at screening
- •PsA according to CASPAR criteria
- •At least age of 18 years
- •Presence of chest x-ray without signs of active or latent infection (esp. for tuberculosis) within the last 3 months
- •Permitted pre-treatment with up to three biologic-agents, whereupon only one biologic agent must be withdrawn due to inadequate response.
- •For MTX-naive patients: Previous use of NSAID
- •Written informed consent obtained prior to the initiation of any protocol-required procedures
- •Compliance to study procedures and study protocol Inclusion criteria related to MTX
- •For the group on MTX: Patients must have stable MTX dosages of at least 15mg once weekly for at least 12 weeks prior to screening and stable MTX dosages of at 15mg once weekly for at least 4 weeks prior to screening
- •Compliance of intake of MTX must be documented by treating physician
- •For the group without MTX therapy: patients must be eligible for MTX treatment (according to SmPC) and have not failed prior MTX treatment for the treatment of PsA
排除标准
- •Exclusion criteria related to Investigational medicinal product (IMP):
- •Previous use of UST or any other anti-IL23 agent
- •according to SmPC
- •Exclusion criteria for the group without MTX:
- •Inadequate Response to prior MTX-treatment for Psoriatic Arthritis
- •Exclusion criteria related to general health:
- •previous B-cell depleting therapy
- •Patients with other chronic inflammatory articular disease or systemic autoimmune disease with musculoskeletal symptoms
- •Patients with active Tb
- •Patients with latent Tb, measured by Interferon gamma release assay, that are not pre-treated for at least 1 months and planned to be treated 9 months in total with INH once a day according to local guidelines
- •Any active infection, a history of recurrent clinically significant infection, a history of recurrent bacterial infections with encapsulated organisms
- •Primary or secondary immunodeficiency
- •History of cancer with curative treatment not longer than 5 years ago except basal-cell carcinoma of the skin that had been excised
- •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 of the study outcome
- •History of a severe psychological illness or condition
- •Known hypersensitivity to any component of the product
- •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, IUD, physical barrier)
- •Alcohol, drug or chemical abuse Exclusion criteria related to prior treatments
- •Previous DMARD therapy other than MTX at least for the last 28 days prior screening due to washout time of different DMARD therapies (including Leflunomide etc.)
- •Previous immunosuppressive biologic therapy at least for the last
- •4 weeks prior to screening for Enbrel® (etanercept) - with a terminal half-life of 102 ± 30 hours (s.c. route)
- •10 weeks prior to screening for Humira® (adalimumab) - with a terminal half-life of 10-20 days (average 2 weeks) (s.c. route)
- •10 weeks prior to screening for Simponi® (golimumab) - with a terminal half-life of 11-14 days
- •10 weeks prior to screening for Cimzia® (certolizumab) - with a terminal half-life of approx. 14 days
- •8 weeks prior to screening for Remicade® (infliximab) - with a terminal half-life of 8.0-9.5 days (i.v. infusion)
- •60 days prior to screening due to washout time of other immunosuppressive biologic therapies
- •current participation in another interventional clinical trial
- •Exclusion criteria related to laboratory:
- •Haemoglobin < 8.5 g / dl
- •Neutrophil counts < 1.500 / μl
- •Platelet count < 75.000 / μl
- •Lower than 1 x 1000 / μl lymphopenia for more than three months prior to inclusion.
- •Serum creatinine > 1.4 mg / dl for women or 1.6 mg / dl for men
- •AST or ALT > 2.5 time upper limit of norm
- •Exclusion criteria related to formal aspects:
- •Underage or incapable patients
研究组 & 干预措施
Methotrexate pre-treated subjects-Ustekinumab and Methotrexate
subjects pretreated with Methotrexate will be randomised to receive Methotrexate or Placebo, Ustekinumab will be given open-label
干预措施: Methotrexate (Drug)
Methotrexate naive - Ustekinumab and Methotrexate
Methotrexate naive subjects will be randomised to receive Methotrexate or Placebo, Ustekinumab will be given open-label
干预措施: Methotrexate (Drug)
Methotrexate naive - Ustekinumab and Methotrexate
Methotrexate naive subjects will be randomised to receive Methotrexate or Placebo, Ustekinumab will be given open-label
干预措施: Ustekinumab (Drug)
Methotrexate naive - Ustekinumab and Placebo to Methotrexate
Methotrexate naive subjects will be randomised to receive Methotrexate or Placebo, Ustekinumab will be given open-label
干预措施: Ustekinumab (Drug)
Methotrexate naive - Ustekinumab and Placebo to Methotrexate
Methotrexate naive subjects will be randomised to receive Methotrexate or Placebo, Ustekinumab will be given open-label
干预措施: Placebo (Other)
Methotrexate pre-treated subjects-Ustekinumab and Methotrexate
subjects pretreated with Methotrexate will be randomised to receive Methotrexate or Placebo, Ustekinumab will be given open-label
干预措施: Ustekinumab (Drug)
Methotrexate pre-treated subjects-Ustekinumab and PLC
subjects pretreated with Methotrexate will be randomised to receive Methotrexate or Placebo, Ustekinumab will be given open-label
干预措施: Ustekinumab (Drug)
Methotrexate pre-treated subjects-Ustekinumab and PLC
subjects pretreated with Methotrexate will be randomised to receive Methotrexate or Placebo, Ustekinumab will be given open-label
干预措施: Placebo (Other)
结局指标
主要结局
Assessment of mean values of DAS28 at week 24
时间窗: week 24
To demonstrate non-inferiority of mean values of DAS28 at week 24 of UST monotherapy compared to add-on to MTX with stratification according to patients on or without MTX before randomization.
次要结局
- Assessment of BSA(week 52)
- Treatment adherence measured by patient diary(through treatment period; normally 52 weeks)
- Compliance measured by questionnaire CQR5(through treatment period; normally 52 weeks)
- Quality of life measured by HAQ(week 52)
- Assessment of mean DAS28 at week 52(week 52)
- Assessment of DAS28(week 52)
- change in DAS28(baseline to week 52)
- DAS28-ESR remission(week 52)
- Assessment of Tender joint count/Swollen joint count (TJC/SJC) (68/66)(week 4)
- Assessment of TJC/SJC (68/66)(week 52)
- ACR (20/50/70) response(week 52)
- Change in ACR core set(baseline to week 52)
- Quality of life measured by DLQI(week 52)
- Assessment of PASI(week 52)
- Quality of life measured by HAQ,(week 24)
- Assessment of BASDAI(week 52)
- Quality of life measured by EQ5D(week 52)
- Assessment of Change in Dactylitis(week 4, 16, 24, 40 and week 52)
- Assessment of Change in Enthesitis (LEI)(week 4, 16, 24, 40 and week 52)
- Assessment of mtNAPSI(week 4, 16, 24, 40 and week 52)
- Ultrasound (US) assessment of joints and enthesis according to PASON22(Week 4, 24 and week 52)
- Frequency and seriousness of adverse events as reported and documented in Case report form(each study visit (week 0 to week 52))
研究者
Dr. Frank Behrens
Coordinating Investigator and representative of sponsor
Fraunhofer Institute for Molecular Biology and Applied Ecology