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| Name | Class |
|---|---|
| Janssen-Cilag Ltd. | INDUSTRY |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Methotrexate naive - Ustekinumab and Methotrexate | Active Comparator | Methotrexate naive subjects will be randomised to receive Methotrexate or Placebo, Ustekinumab will be given open-label |
|
| Methotrexate naive - Ustekinumab and Placebo to Methotrexate | Placebo Comparator | Methotrexate naive subjects will be randomised to receive Methotrexate or Placebo, Ustekinumab will be given open-label |
|
| Methotrexate pre-treated subjects-Ustekinumab and Methotrexate | Active Comparator | subjects pretreated with Methotrexate will be randomised to receive Methotrexate or Placebo, Ustekinumab will be given open-label |
|
| Methotrexate pre-treated subjects-Ustekinumab and PLC | Placebo Comparator | subjects pretreated with Methotrexate will be randomised to receive Methotrexate or Placebo, Ustekinumab will be given open-label |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Methotrexate | Drug | subjects will receive once weekly 15 mg (3 capsules) MTX |
|
| 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 |
| 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 |
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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.
Exclusion Criteria:
Exclusion criteria related to Investigational medicinal product (IMP):
Exclusion criteria for the group without MTX:
- Inadequate Response to prior MTX-treatment for Psoriatic Arthritis
Exclusion criteria related to general health:
Exclusion criteria related to laboratory:
Exclusion criteria related to formal aspects:
- Underage or incapable patients
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| Name | Affiliation | Role |
|---|---|---|
| Frank Behrens, MD | Fraunhofer IME | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| CIRI | Frankfurt am Main | Hessia | 60526 | Germany |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38251504 | Derived | Koehm M, Rossmanith T, Foldenauer AC, Herrmann E, Brandt-Jurgens J, Burmester GR, Kellner H, Kiltz U, Kofler DM, Rech J, Mojtahed-Poor S, Jonetzko C, Burkhardt H, Behrens F; MUST Investigator Group. Methotrexate plus ustekinumab versus ustekinumab monotherapy in patients with active psoriatic arthritis (MUST): a randomised, multicentre, placebo-controlled, phase 3b, non-inferiority trial. Lancet Rheumatol. 2023 Jan;5(1):e14-e23. doi: 10.1016/S2665-9913(22)00329-0. | |
| 37079726 |
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| ID | Term |
|---|---|
| D015535 | Arthritis, Psoriatic |
| ID | Term |
|---|---|
| D025242 | Spondylarthropathies |
| D025241 | Spondylarthritis |
| D013166 | Spondylitis |
| D013122 | Spinal Diseases |
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| ID | Term |
|---|---|
| D008727 | Methotrexate |
| D000069549 | Ustekinumab |
| ID | Term |
|---|---|
| D000630 | Aminopterin |
| D011622 | Pterins |
| D011621 | Pteridines |
| D006574 | Heterocyclic Compounds, 2-Ring |
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randomised, placebo-controlled, double-blind, multicenter study
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Methotrexate tablets will be encapsulated equal to Placebo to ensure blinding. Ustekinumab will be open-label
| Ustekinumab | Drug | subject will receive Ustekinumab open-label over a treatment period of 52 weeks |
|
|
| Placebo | Other | subjects will receive once weekly 3 capsules PLC to MTX |
|
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) |
| Derived |
| Mojtahed Poor S, Henke M, Ulshofer T, Kohm M, Behrens F, Burkhardt H, Schiffmann S. The role of antidrug antibodies in ustekinumab therapy and the impact of methotrexate. Rheumatology (Oxford). 2023 Dec 1;62(12):3993-3999. doi: 10.1093/rheumatology/kead177. |
| D001847 |
| Bone Diseases |
| D009140 | Musculoskeletal Diseases |
| D001168 | Arthritis |
| D007592 | Joint Diseases |
| D011565 | Psoriasis |
| D017444 | Skin Diseases, Papulosquamous |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D000072471 |
| Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |