Impact of Concomitant MTX on Efficacy, Safety and Adherence of Ustekinumab-treatment in Patients With Active PsA

Study Overview
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Brief Summary
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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.

Detailed Description
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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. In this study, the effect of blinded MTX-co-medication on outcome in patients treated with UST will be analysed. Differences on efficacy, safety and treatment adherence will be calculated related to MTX use in four arms of the stratified, randomized placebo-controlled clinical trial which contains a study treatment period of 52 weeks. The primary endpoint, differences in DAS28 in the treatment groups, will be measured at week 24.

Official Title
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Impact of Concomitant Methotrexate on Efficacy, Safety and Adherence of Ustekinumab-treatment in Patients With Active Psoriasis Arthritis

Conditions
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Psoriatic Arthritis

Intervention / Treatment
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* Drug: Methotrexate
* Drug: Ustekinumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: randomised, placebo-controlled, double-blind, multicenter study
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Methotrexate naive - Ustekinumab and Methotrexate<br>Methotrexate naive subjects will be randomised to receive Methotrexate or Placebo, Ustekinumab will be given open-label | Drug: Methotrexate<br>* subjects will receive once weekly 15 mg (3 capsules) MTX<br>Drug: Ustekinumab<br>* subject will receive Ustekinumab open-label over a treatment period of 52 weeks<br>* Other names: Stelara;|
| Placebo Comparator: Methotrexate naive - Ustekinumab and Placebo to Methotrexate<br>Methotrexate naive subjects will be randomised to receive Methotrexate or Placebo, Ustekinumab will be given open-label | Drug: Ustekinumab<br>* subject will receive Ustekinumab open-label over a treatment period of 52 weeks<br>* Other names: Stelara;Other: Placebo<br>* subjects will receive once weekly 3 capsules PLC to MTX<br>|
| Active Comparator: Methotrexate pre-treated subjects-Ustekinumab and Methotrexate<br>subjects pretreated with Methotrexate will be randomised to receive Methotrexate or Placebo, Ustekinumab will be given open-label | Drug: Methotrexate<br>* subjects will receive once weekly 15 mg (3 capsules) MTX<br>Drug: Ustekinumab<br>* subject will receive Ustekinumab open-label over a treatment period of 52 weeks<br>* Other names: Stelara;|
| Placebo Comparator: Methotrexate pre-treated subjects-Ustekinumab and PLC<br>subjects pretreated with Methotrexate will be randomised to receive Methotrexate or Placebo, Ustekinumab will be given open-label | Drug: Ustekinumab<br>* subject will receive Ustekinumab open-label over a treatment period of 52 weeks<br>* Other names: Stelara;Other: Placebo<br>* subjects will receive once weekly 3 capsules PLC to MTX<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of mean values of DAS28 at 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. | week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of mean DAS28 at week 52 | The Disease Activity Score (DAS) consists of SJC and TJC measurements, the erythrocyte sedimentation rate (or CRP) and the subject's global assessment of disease activity. | week 52 | 
| Assessment of DAS28 | The Disease Activity Score (DAS) consists of SJC and TJC measurements, the erythrocyte sedimentation rate (or CRP) and the subject's global assessment of disease activity. | week 4 | 
| Assessment of DAS28 | The Disease Activity Score (DAS) consists of SJC and TJC measurements, the erythrocyte sedimentation rate (or CRP) and the subject's global assessment of disease activity. | week 16 | 
| Assessment of DAS28 | The Disease Activity Score (DAS) consists of SJC and TJC measurements, the erythrocyte sedimentation rate (or CRP) and the subject's global assessment of disease activity. | week 24 | 
| Assessment of DAS28 | The Disease Activity Score (DAS) consists of SJC and TJC measurements, the erythrocyte sedimentation rate (or CRP) and the subject's global assessment of disease activity. | week 40 | 
| Assessment of DAS28 | The Disease Activity Score (DAS) consists of SJC and TJC measurements, the erythrocyte sedimentation rate (or CRP) and the subject's global assessment of disease activity. | week 52 | 
| change in DAS28 | The Disease Activity Score (DAS) consists of SJC and TJC measurements, the erythrocyte sedimentation rate (or CRP) and the subject's global assessment of disease activity. | baseline to week 4 | 
| change in DAS28 | The Disease Activity Score (DAS) consists of SJC and TJC measurements, the erythrocyte sedimentation rate (or CRP) and the subject's global assessment of disease activity. | baseline to week 16 | 
| change in DAS28 | The Disease Activity Score (DAS) consists of SJC and TJC measurements, the erythrocyte sedimentation rate (or CRP) and the subject's global assessment of disease activity. | baseline to week 24 | 
| change in DAS28 | The Disease Activity Score (DAS) consists of SJC and TJC measurements, the erythrocyte sedimentation rate (or CRP) and the subject's global assessment of disease activity. | baseline to week 40 | 
| change in DAS28 | The Disease Activity Score (DAS) consists of SJC and TJC measurements, the erythrocyte sedimentation rate (or CRP) and the subject's global assessment of disease activity. | baseline to week 52 | 
| DAS28-ESR remission |  | week 4 | 
| DAS28-ESR remission |  | week 16 | 
| DAS28-ESR remission |  | week 24 | 
| DAS28-ESR remission |  | week 40 | 
| DAS28-ESR remission |  | week 52 | 
| Assessment of Tender joint count/Swollen joint count (TJC/SJC) (68/66) | Tender and swollen joint will be assessed and counted by trained personel | week 4 | 
| Assessment of TJC/SJC (68/66) | Tender and swollen joint will be assessed and counted by trained personel | week 16 | 
| Assessment of TJC/SJC (68/66) | Tender and swollen joint will be assessed and counted by trained personel | week 24 | 
| Assessment of TJC/SJC (68/66) | Tender and swollen joint will be assessed and counted by trained personel | week 40 | 
| Assessment of TJC/SJC (68/66) | Tender and swollen joint will be assessed and counted by trained personel | week 52 | 
| ACR (20/50/70) response | Portion of Patient that reach 20%, 50% or 70% improvement in ACR score consisting of SJC and TJC measurements, subject's assessment of pain, subject's global assessment of disease activity, physician's global assessment of disease activity, HAQ and measurements of erythrocyte sedimentation rate and CRP | week 4 | 
| ACR (20/50/70) response | Portion of Patient that reach 20%, 50% or 70% improvement in ACR score consisting of SJC and TJC measurements, subject's assessment of pain, subject's global assessment of disease activity, physician's global assessment of disease activity, HAQ and measurements of erythrocyte sedimentation rate and CRP | week 16 | 
| ACR (20/50/70) response | Portion of Patient that reach 20%, 50% or 70% improvement in ACR score consisting of SJC and TJC measurements, subject's assessment of pain, subject's global assessment of disease activity, physician's global assessment of disease activity, HAQ and measurements of erythrocyte sedimentation rate and CRP | week 24 | 
| ACR (20/50/70) response | Portion of Patient that reach 20%, 50% or 70% improvement in ACR score consisting of SJC and TJC measurements, subject's assessment of pain, subject's global assessment of disease activity, physician's global assessment of disease activity, HAQ and measurements of erythrocyte sedimentation rate and CRP | week 40 | 
| ACR (20/50/70) response | Portion of Patient that reach 20%, 50% or 70% improvement in ACR score consisting of SJC and TJC measurements, subject's assessment of pain, subject's global assessment of disease activity, physician's global assessment of disease activity, HAQ and measurements of erythrocyte sedimentation rate and CRP | week 52 | 
| Change in ACR core set | Changes in SJC, TJC, HAQ, patient's and physician's global assessment, pain, CRP and ESR will be described | baseline to week 4 | 
| Change in ACR core set | Changes in SJC, TJC, HAQ, patient's and physician's global assessment, pain, CRP and ESR will be described | baseline to week 16 | 
| Change in ACR core set | Changes in SJC, TJC, HAQ, patient's and physician's global assessment, pain, CRP and ESR will be described | baseline to week 24 | 
| Change in ACR core set | Changes in SJC, TJC, HAQ, patient's and physician's global assessment, pain, CRP and ESR will be described | baseline to week 40 | 
| Change in ACR core set | Changes in SJC, TJC, HAQ, patient's and physician's global assessment, pain, CRP and ESR will be described | baseline to week 52 | 
| Assessment of PASI | The Psoriasis Area and Severity Index (PASI) is used for evaluation of severity and extend of skin involvement of the included patients | week 4 | 
| Assessment of BASDAI | The Bath ankylosing spondylitis disease activity index will be performed for those patients who have radiological findings suspect for axial involvement | week 4 | 
| Assessment of BSA | The body surface area will be evaluated to measure the extend of Psoriasis in the included PsA patients. | week 4 | 
| Assessment of BASDAI | The Bath ankylosing spondylitis disease activity index will be performed for those patients who have radiological findings suspect for axial involvement | week 16 | 
| Assessment of PASI | The Psoriasis Area and Severity Index (PASI) is used for evaluation of severity and extend of skin involvement of the included patients | week 16 | 
| Assessment of BSA | The body surface area will be evaluated to measure the extend of Psoriasis in the included PsA patients. | week 16 | 
| Assessment of BASDAI | The Bath ankylosing spondylitis disease activity index will be performed for those patients who have radiological findings suspect for axial involvement | week 24 | 
| Assessment of PASI | The Psoriasis Area and Severity Index (PASI) is used for evaluation of severity and extend of skin involvement of the included patients | week 24 | 
| Assessment of BSA | The body surface area will be evaluated to measure the extend of Psoriasis in the included PsA patients. | week 24 | 
| Assessment of PASI | The Psoriasis Area and Severity Index (PASI) is used for evaluation of severity and extend of skin involvement of the included patients | week 40 | 
| Assessment of BSA | The body surface area will be evaluated to measure the extend of Psoriasis in the included PsA patients. | week 40 | 
| Assessment of BASDAI | The Bath ankylosing spondylitis disease activity index will be performed for those patients who have radiological findings suspect for axial involvement | week 40 | 
| Assessment of PASI | The Psoriasis Area and Severity Index (PASI) is used for evaluation of severity and extend of skin involvement of the included patients | week 52 | 
| Assessment of BSA | The body surface area will be evaluated to measure the extend of Psoriasis in the included PsA patients. | week 52 | 
| Assessment of BASDAI | The Bath ankylosing spondylitis disease activity index will be performed for those patients who have radiological findings suspect for axial involvement | week 52 | 
| Treatment adherence measured by patient diary | Compliance with treatment will be determined by patient diary | through treatment period; normally 52 weeks | 
| Compliance measured by questionnaire CQR5 | The CQR5 consists of 5 questions addressing information on treatment compliance of the patient. | through treatment period; normally 52 weeks | 
| Quality of life measured by HAQ | Stanford Health Assessment Questionnaire disability index is a patient reported questionnaire specific for RA | week 4 | 
| Quality of life measured by EQ5D | EQ5D is a standardised instrument for use as a measure of health outcome | week 4 | 
| Quality of life measured by DLQI | The Dermatology Life Quality Index is a 10-question validated questionnaire. | week 4 | 
| Quality of life measured by EQ5D | EQ5D is a standardised instrument for use as a measure of health outcome | week 16 | 
| Quality of life measured by HAQ | Stanford Health Assessment Questionnaire disability index is a patient reported questionnaire specific for RA | week 16 | 
| Quality of life measured by DLQI | The Dermatology Life Quality Index is a 10-question validated questionnaire. | week 16 | 
| Quality of life measured by DLQI | The Dermatology Life Quality Index is a 10-question validated questionnaire. | week 24 | 
| Quality of life measured by EQ5D | EQ5D is a standardised instrument for use as a measure of health outcome | week 24 | 
| Quality of life measured by HAQ, | Stanford Health Assessment Questionnaire disability index is a patient reported questionnaire specific for RA | week 24 | 
| Quality of life measured by HAQ | Stanford Health Assessment Questionnaire disability index is a patient reported questionnaire specific for RA | week 40 | 
| Quality of life measured by EQ5D | EQ5D is a standardised instrument for use as a measure of health outcome | week 40 | 
| Quality of life measured by DLQI | The Dermatology Life Quality Index is a 10-question validated questionnaire. | week 40 | 
| Quality of life measured by HAQ | Stanford Health Assessment Questionnaire disability index is a patient reported questionnaire specific for RA | week 52 | 
| Quality of life measured by EQ5D | EQ5D is a standardised instrument for use as a measure of health outcome | week 52 | 
| Quality of life measured by DLQI | The Dermatology Life Quality Index is a 10-question validated questionnaire. | week 52 | 
| Assessment of Change in Dactylitis | Functional assessment: Change in number and severity of digits involved) involved | week 4, 16, 24, 40 and week 52 | 
| Assessment of Change in Enthesitis (LEI) | functional outcome | week 4, 16, 24, 40 and week 52 | 
| Assessment of mtNAPSI | The modified target Nail Psoriasis Severity Index is used for evaluation of nail involvement in patients | week 4, 16, 24, 40 and week 52 | 
| Ultrasound (US) assessment of joints and enthesis according to PASON22 | selected sites only | Week 4, 24 and week 52 | 
| Frequency and seriousness of adverse events as reported and documented in Case report form | Documentation of the occurence, frequency and seriousness of adverse events as reported and documented in Case report form | each study visit (week 0 to week 52) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DAS28, Psoriatic Arthritis, Ustekinumab, Methotrexate