MUST: Impact of Concomitant MTX on Efficacy, Safety and Adherence of Ustekinumab-treatment in Patients With Active PsA
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Methotrexate naive - Ustekinumab and Methotrexate Methotrexate naive subjects will be randomised to receive Methotrexate or Placebo, Ustekinumab will be given open-label |
Drug: Methotrexate
subjects will receive once weekly 15 mg (3 capsules) MTX
Drug: Ustekinumab
subject will receive Ustekinumab open-label over a treatment period of 52 weeks
Other Names:
|
| Placebo Comparator: Methotrexate naive - Ustekinumab and Placebo to Methotrexate Methotrexate naive subjects will be randomised to receive Methotrexate or Placebo, Ustekinumab will be given open-label |
Drug: Ustekinumab
subject will receive Ustekinumab open-label over a treatment period of 52 weeks
Other Names:
Other: Placebo
subjects will receive once weekly 3 capsules PLC to MTX
|
| Active Comparator: 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 |
Drug: Methotrexate
subjects will receive once weekly 15 mg (3 capsules) MTX
Drug: Ustekinumab
subject will receive Ustekinumab open-label over a treatment period of 52 weeks
Other Names:
|
| Placebo Comparator: 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 |
Drug: Ustekinumab
subject will receive Ustekinumab open-label over a treatment period of 52 weeks
Other Names:
Other: Placebo
subjects will receive once weekly 3 capsules PLC to MTX
|
Outcome Measures
Primary Outcome Measures
- Assessment of mean values of DAS28 at week 24 [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.
Secondary Outcome Measures
- Assessment of mean DAS28 at week 52 [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.
- Assessment of DAS28 [week 4]
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.
- Assessment of DAS28 [week 16]
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.
- Assessment of DAS28 [week 24]
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.
- Assessment of DAS28 [week 40]
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.
- Assessment of DAS28 [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.
- change in DAS28 [baseline to week 4]
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.
- change in DAS28 [baseline to week 16]
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.
- change in DAS28 [baseline to week 24]
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.
- change in DAS28 [baseline to week 40]
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.
- change in DAS28 [baseline to 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.
- 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) [week 4]
Tender and swollen joint will be assessed and counted by trained personel
- Assessment of TJC/SJC (68/66) [week 16]
Tender and swollen joint will be assessed and counted by trained personel
- Assessment of TJC/SJC (68/66) [week 24]
Tender and swollen joint will be assessed and counted by trained personel
- Assessment of TJC/SJC (68/66) [week 40]
Tender and swollen joint will be assessed and counted by trained personel
- Assessment of TJC/SJC (68/66) [week 52]
Tender and swollen joint will be assessed and counted by trained personel
- ACR (20/50/70) response [week 4]
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
- ACR (20/50/70) response [week 16]
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
- ACR (20/50/70) response [week 24]
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
- ACR (20/50/70) response [week 40]
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
- ACR (20/50/70) response [week 52]
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
- Change in ACR core set [baseline to week 4]
Changes in SJC, TJC, HAQ, patient's and physician's global assessment, pain, CRP and ESR will be described
- Change in ACR core set [baseline to week 16]
Changes in SJC, TJC, HAQ, patient's and physician's global assessment, pain, CRP and ESR will be described
- Change in ACR core set [baseline to week 24]
Changes in SJC, TJC, HAQ, patient's and physician's global assessment, pain, CRP and ESR will be described
- Change in ACR core set [baseline to week 40]
Changes in SJC, TJC, HAQ, patient's and physician's global assessment, pain, CRP and ESR will be described
- Change in ACR core set [baseline to week 52]
Changes in SJC, TJC, HAQ, patient's and physician's global assessment, pain, CRP and ESR will be described
- Assessment of PASI [week 4]
The Psoriasis Area and Severity Index (PASI) is used for evaluation of severity and extend of skin involvement of the included patients
- Assessment of BASDAI [week 4]
The Bath ankylosing spondylitis disease activity index will be performed for those patients who have radiological findings suspect for axial involvement
- Assessment of BSA [week 4]
The body surface area will be evaluated to measure the extend of Psoriasis in the included PsA patients.
- Assessment of BASDAI [week 16]
The Bath ankylosing spondylitis disease activity index will be performed for those patients who have radiological findings suspect for axial involvement
- Assessment of PASI [week 16]
The Psoriasis Area and Severity Index (PASI) is used for evaluation of severity and extend of skin involvement of the included patients
- Assessment of BSA [week 16]
The body surface area will be evaluated to measure the extend of Psoriasis in the included PsA patients.
- Assessment of BASDAI [week 24]
The Bath ankylosing spondylitis disease activity index will be performed for those patients who have radiological findings suspect for axial involvement
- Assessment of PASI [week 24]
The Psoriasis Area and Severity Index (PASI) is used for evaluation of severity and extend of skin involvement of the included patients
- Assessment of BSA [week 24]
The body surface area will be evaluated to measure the extend of Psoriasis in the included PsA patients.
- Assessment of PASI [week 40]
The Psoriasis Area and Severity Index (PASI) is used for evaluation of severity and extend of skin involvement of the included patients
- Assessment of BSA [week 40]
The body surface area will be evaluated to measure the extend of Psoriasis in the included PsA patients.
- Assessment of BASDAI [week 40]
The Bath ankylosing spondylitis disease activity index will be performed for those patients who have radiological findings suspect for axial involvement
- Assessment of PASI [week 52]
The Psoriasis Area and Severity Index (PASI) is used for evaluation of severity and extend of skin involvement of the included patients
- Assessment of BSA [week 52]
The body surface area will be evaluated to measure the extend of Psoriasis in the included PsA patients.
- Assessment of BASDAI [week 52]
The Bath ankylosing spondylitis disease activity index will be performed for those patients who have radiological findings suspect for axial involvement
- Treatment adherence measured by patient diary [through treatment period; normally 52 weeks]
Compliance with treatment will be determined by patient diary
- Compliance measured by questionnaire CQR5 [through treatment period; normally 52 weeks]
The CQR5 consists of 5 questions addressing information on treatment compliance of the patient.
- Quality of life measured by HAQ [week 4]
Stanford Health Assessment Questionnaire disability index is a patient reported questionnaire specific for RA
- Quality of life measured by EQ5D [week 4]
EQ5D is a standardised instrument for use as a measure of health outcome
- Quality of life measured by DLQI [week 4]
The Dermatology Life Quality Index is a 10-question validated questionnaire.
- Quality of life measured by EQ5D [week 16]
EQ5D is a standardised instrument for use as a measure of health outcome
- Quality of life measured by HAQ [week 16]
Stanford Health Assessment Questionnaire disability index is a patient reported questionnaire specific for RA
- Quality of life measured by DLQI [week 16]
The Dermatology Life Quality Index is a 10-question validated questionnaire.
- Quality of life measured by DLQI [week 24]
The Dermatology Life Quality Index is a 10-question validated questionnaire.
- Quality of life measured by EQ5D [week 24]
EQ5D is a standardised instrument for use as a measure of health outcome
- Quality of life measured by HAQ, [week 24]
Stanford Health Assessment Questionnaire disability index is a patient reported questionnaire specific for RA
- Quality of life measured by HAQ [week 40]
Stanford Health Assessment Questionnaire disability index is a patient reported questionnaire specific for RA
- Quality of life measured by EQ5D [week 40]
EQ5D is a standardised instrument for use as a measure of health outcome
- Quality of life measured by DLQI [week 40]
The Dermatology Life Quality Index is a 10-question validated questionnaire.
- Quality of life measured by HAQ [week 52]
Stanford Health Assessment Questionnaire disability index is a patient reported questionnaire specific for RA
- Quality of life measured by EQ5D [week 52]
EQ5D is a standardised instrument for use as a measure of health outcome
- Quality of life measured by DLQI [week 52]
The Dermatology Life Quality Index is a 10-question validated questionnaire.
- Assessment of Change in Dactylitis [week 4, 16, 24, 40 and week 52]
Functional assessment: Change in number and severity of digits involved) involved
- Assessment of Change in Enthesitis (LEI) [week 4, 16, 24, 40 and week 52]
functional outcome
- Assessment of mtNAPSI [week 4, 16, 24, 40 and week 52]
The modified target Nail Psoriasis Severity Index is used for evaluation of nail involvement in patients
- Ultrasound (US) assessment of joints and enthesis according to PASON22 [Week 4, 24 and week 52]
selected sites only
- Frequency and seriousness of adverse events as reported and documented in Case report form [each study visit (week 0 to week 52)]
Documentation of the occurence, frequency and seriousness of adverse events as reported and documented in Case report form
Eligibility Criteria
Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | CIRI | Frankfurt am Main | Hessia | Germany | 60526 |
Sponsors and Collaborators
- Dr. Frank Behrens
- Janssen-Cilag Ltd.
Investigators
- Principal Investigator: Frank Behrens, MD, Fraunhofer IME
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- TMP-1115_01