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

NCT ID: NCT03148860

Last Updated: 2022-03-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 186 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-12-15
• Study Completion Date: 2021-10-21

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.

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.

Conditions

Psoriatic Arthritis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Methotrexate naive - Ustekinumab and Methotrexate

Methotrexate naive subjects will be randomised to receive Methotrexate or Placebo, Ustekinumab will be given open-label

Group Type: ACTIVE_COMPARATOR

Methotrexate

Intervention Type: DRUG

subjects will receive once weekly 15 mg (3 capsules) MTX

Ustekinumab

Intervention Type: DRUG

subject will receive Ustekinumab open-label over a treatment period of 52 weeks

Methotrexate naive - Ustekinumab and Placebo to Methotrexate

Methotrexate naive subjects will be randomised to receive Methotrexate or Placebo, Ustekinumab will be given open-label

Group Type: PLACEBO_COMPARATOR

Ustekinumab

Intervention Type: DRUG

subject will receive Ustekinumab open-label over a treatment period of 52 weeks

Placebo

Intervention Type: OTHER

subjects will receive once weekly 3 capsules PLC to MTX

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

Group Type: ACTIVE_COMPARATOR

Methotrexate

Intervention Type: DRUG

subjects will receive once weekly 15 mg (3 capsules) MTX

Ustekinumab

Intervention Type: DRUG

subject will receive Ustekinumab open-label over a treatment period of 52 weeks

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

Group Type: PLACEBO_COMPARATOR

Ustekinumab

Intervention Type: DRUG

subject will receive Ustekinumab open-label over a treatment period of 52 weeks

Placebo

Intervention Type: OTHER

subjects will receive once weekly 3 capsules PLC to MTX

Interventions

Methotrexate

subjects will receive once weekly 15 mg (3 capsules) MTX

Intervention Type: DRUG

Ustekinumab

subject will receive Ustekinumab open-label over a treatment period of 52 weeks

Intervention Type: DRUG

Placebo

subjects will receive once weekly 3 capsules PLC to MTX

Intervention Type: OTHER

Other Intervention Names

Stelara

Eligibility 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
• 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

• Previous use of UST or any other anti-IL23 agent
• according to SmPC

• Inadequate Response to prior MTX-treatment for Psoriatic Arthritis

• 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)
• 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

• 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

• Underage or incapable patients

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Janssen-Cilag Ltd.

INDUSTRY

Sponsor Role: collaborator

Dr. Frank Behrens

OTHER

Sponsor Role: lead

Responsible Party

Dr. Frank Behrens

Coordinating Investigator and representative of sponsor

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Frank Behrens, MD

Role: PRINCIPAL_INVESTIGATOR

Fraunhofer IME

Locations

CIRI

Frankfurt am Main, Hessia, Germany

Countries

Germany

References

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.

Reference Type: DERIVED

PMID: 38251504 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 37079726 (View on PubMed)

Other Identifiers

TMP-1115_01

Identifier Type: -

Identifier Source: org_study_id