Severe Psoriatic Arthritis - Early intervEntion to Control Disease: the SPEED Trial

Study Overview
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Brief Summary
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SPEED is a three arm interventional trial nested within a cohort (Trials Within Cohorts or TWiCs design). This tests more aggressive early therapy in patients newly diagnosed with moderate to severe PsA. Arm 1 will receive standard step up therapy in the cohort and act as the control group. Arm 2 will receive early combination conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs). Arm 3 will receive early tumour necrosis factor (TNF) inhibitor therapy.

Detailed Description
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Arm 1: Control 'step-up' therapy in the cohort (MONITOR-PsA study). Therapy for the cohort is defined by standard practice in these PsA clinics following current international recommendations[11] and National requirements for the prescription of biologic therapy[19-22]. Whilst physician discretion is used, most commonly Initial therapy will be with methotrexate alone (15mg/week rising to 25mg/week as tolerated by week 8 of therapy) unless this is contraindicated. In cases of non-response or intolerance to methotrexate, participants will have an alternative DMARD (most commonly sulfasalazine or leflunomide) added or switched to at the discretion of the rheumatologist. In cases of failure of two DMARDs, treatment can be escalated to biologic therapy as per National Institute for Health and Clinical Excellence (NICE) recommendations[19-22] usually with a TNF inhibitor as first line. If the requisite disease activity is not met or if there are contraindications to biologics, alternative DMARD combinations will be used. Further details are available in the PsA clinic treatment protocol which is Appendix D in the MONITOR-PsA protocol. ARM 2: Combination DMARD arm. All participants will be prescribed methotrexate with an additional DMARD (either sulfasalazine or leflunomide) at baseline, staggering the start of these additional therapies by one week to allow more accurate attribution of adverse events. Either sulfasalazine or leflumonide will be used in combination depending on physician preference (taking into account disease presentation, arthritis, enthesitis, skin disease, risk of hypertension and liver disease).Response will be assessed after 12 weeks of therapy using the Minimal Disease Activity (MDA) criteria. These assess 7 different outcomes and patients should meet at least 5 of the 7 items to be classified as being in MDA. Participants who achieve the MDA criteria by week 12 on this combination therapy will continue on this therapy. Participants who show a significant response by in week 12 (a reduction in tender and swollen joint counts of at least 20%) but do not yet meet the MDA criteria should continue on this therapy for an additional 12 weeks before review. Participants failing to show significant response (reduction in joint counts by less than 20%) by week 12 on this combination therapy or those failing to meet MDA criteria by week 24 will be eligible for rescue therapy following the standard PsA clinic treatment protocol (as per arm 1 above and as detailed in the PsA clinic treatment protocol which is found in appendix D of the MONITOR-PsA protocol). Participants may be eligible at this time point for biologic therapy most commonly using TNF inhibitors under NICE guidelines. These state that patients should have failed adequate trials of at least 2 standard DMARDs and that they should have active disease defined as at least 3 tender and 3 swollen joints. If they do not fulfil these NICE criteria (≥3 tender and ≥3 swollen joints) they will be prescribed alternative DMARDs. ARM 3: Early biologic arm. All participants will be prescribed methotrexate (given weekly) with a TNF inhibitor (adalimumab given every two weeks) at baseline staggering the start of these therapies by one week to allow more accurate attribution of adverse events (TNF inhibitor from week 0, methotrexate from week 1). Treatment with TNF inhibitor will be continued until week 24 at which time the TNF inhibitor will be tapered by spacing out doses which will be received at week 28 and week 32. The TNF inhibitor will be stopped completely after week 32 and participants will continue on methotrexate. In case of flare of disease, participants will be eligible for rescue therapy following the standard PsA clinic treatment protocol (as per arm 1 above and as detailed in the PsA clinic treatment protocol which is found in appendix D of the MONITOR-PsA protocol). According to this protocol they will be started on combination DMARD therapy (sulfasalazine or leflunomide) and may subsequently be eligible for further TNF inhibitor treatment at a later point if they fulfil NICE criteria (as above). The Investigational Medicinal Products (IMPs) used in this trial are methotrexate, sulfasalazine, leflunomide and adalimumab. All of these medications are used routinely in PsA patients in standard care.

Official Title
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Clinical Effectiveness of Standard Step up Care (Methotrexate) Compared to Early Combination DMARD Therapy With Standard Step up Care Compared to Early Use of TNF Inhibitors With Standard Step up Care for the Treatment of Moderate to Severe Psoriatic Arthritis: a 3-arm Parallel Group Randomised Controlled Trial.

Conditions
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Psoriatic Arthritis

Intervention / Treatment
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* Drug: Methotrexate
* Drug: Sulfasalazine
* Drug: Leflunomide
* Drug: Adalimumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant is willing and able to give informed consent for participation in the trial. Male or Female, aged 18 years or above. Participants consented to the PsA inception cohort (MONITOR-PsA) and to be approached for alternate interventional therapies. Poor prognostic factors at baseline. Either Polyarticular disease with ≥5 active joints at baseline assessment OR Oligoarticular disease with <5 active joints at baseline but with one or more of the following poor prognostic factors: raised C reactive protein, radiographic damage, health assessment questionnaire>1 Female participants of child bearing potential and male participants whose partner is of child bearing potential must be willing to ensure that they or their partner use effective contraception during the trial and for 3 months thereafter (or 2 years if received leflunomide unless treated with washout therapy) as in standard practice. Participant has clinically acceptable laboratory results within 28 days of baseline: Haemoglobin count > 8.5 g/dL White blood count (WBC) > 3.5 x 109/L Absolute neutrophil count (ANC) > 1.5 x 109/L Platelet count > 100 x 109/L Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) and alkaline phosphatase levels <3 x upper limit of normal In the Investigator's opinion, is able and willing to comply with all trial requirements. Willing to allow his or her general practitioner and consultant, if appropriate, to be notified of participation in the trial. Exclusion Criteria: Previous treatment for articular disease with DMARDs including, but not limited to, methotrexate, sulfasalazine, leflunomide and ciclosporin Female patient who is pregnant, breast-feeding or planning pregnancy during the course of the trial. Significant renal (estimated glomerular filtration rate <30ml/min) or hepatic impairment. Patients who test positive for Hepatitis B, C or HIV. Contraindication to any of the investigative drugs. Patients who currently abuse drugs or alcohol Scheduled elective surgery or other procedures requiring general anaesthesia during the trial. Patient with life expectancy of less than 6 months. Any other significant disease or disorder which, in the opinion of the Investigator, may either put patients at risk because of participation in the trial, or may influence the result of the trial, or their ability to participate in the trial. Participation in another research trial involving an investigational product in the past 12 weeks. Additional exclusion criteria apply to patients randomised to arm 3 and receiving adalimumab therapy: Active tuberculosis (TB), chronic viral infections, recent serious bacterial infections, those receiving live vaccinations within 3 months of the anticipated first dose of study medication, or those with chronic illnesses that would, in the opinion of the investigator, put the participant at risk. Latent TB unless they have received appropriate anti-tuberculous treatment as per local guidelines History of cancer in the last 5 years, other than non-melanoma skin cell cancers cured by local resection or carcinoma in situ.

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: Single Group Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard care<br>Control 'step-up' therapy in the cohort (MONITOR-PsA study). Therapy for the cohort is defined by standard NHS practice following international recommendations and National requirements for the prescription of biologic therapy[19-22]. Commonly Initial therapy will be with methotrexate alone (15mg/week rising to 25mg/week as tolerated by week 8 of therapy) unless this is contraindicated. In cases of non-response or intolerance to methotrexate, participants will have an alternative DMARD (most commonly sulfasalazine or leflunomide) added or switched to. In cases of failure of two DMARDs, treatment can be escalated to biologic therapy as per National Institute for Health and Clinical Excellence (NICE) recommendations. If the requisite disease activity is not met or if there are contraindications to biologics, alternative DMARD combinations will be used. | Drug: Methotrexate<br>* Used in all three arms of study<br>Drug: Sulfasalazine<br>* Used in arm 2 of study<br>Drug: Leflunomide<br>* Used in arm 2 of study<br>|
| Experimental: Combination csDMARD<br>Arm 2 - Combination DMARD arm. All participants will be prescribed methotrexate with an additional DMARD (either sulfasalazine or leflunomide) at baseline. Response will be assessed after 12 weeks of therapy using the Minimal Disease Activity (MDA) criteria. Participants who achieve the MDA criteria by week 12 on this combination therapy will continue . Participants who show a significant response by in week 12 (a reduction in tender and swollen joint counts of at least 20%) but do not yet meet the MDA criteria should continue on this therapy for an additional 12 weeks before review. Participants failing to show significant response (reduction in joint counts by less than 20%) by week 12 on this combination therapy or those failing to meet MDA criteria by week 24 will be eligible for rescue therapy | Drug: Methotrexate<br>* Used in all three arms of study<br>Drug: Sulfasalazine<br>* Used in arm 2 of study<br>Drug: Leflunomide<br>* Used in arm 2 of study<br>|
| Experimental: Early TNF inhibition<br>Early biologic arm. All participants will be prescribed methotrexate (given weekly) with a TNF inhibitor (adalimumab given every two weeks) at baseline. Treatment with TNF inhibitor will be continued until week 24 at which time the TNF inhibitor will be tapered to week 32. The TNF inhibitor will be stopped completely after week 32 and participants will continue on methotrexate. In case of flare of disease, participants will be eligible for rescue therapy | Drug: Methotrexate<br>* Used in all three arms of study<br>Drug: Adalimumab<br>* Used in arm 3 of the study only<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Psoriatic arthritis disease activity score (PASDAS) | A composite measure of PsA disease activity. This score is a composite measure of disease activity in PsA. There is only one total score which ranges from 0-10 with higher numbers indicating more active disease. Low disease activity is defined as <3.2. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Psoriatic arthritis disease activity score (PASDAS) | A composite measure of PsA disease activity. This score is a composite measure of disease activity in PsA. There is only one total score which ranges from 0-10 with higher numbers indicating more active disease. Low disease activity is defined as <3.2. | 48 weeks | 
| Minimal Disease Activity (MDA) | Response will be assessed after 12 weeks of therapy using the Minimal Disease Activity (MDA) criteria. These assess 7 different outcomes and patients should meet at least 5 of the 7 items to be classified as being in MDA. The MDA criteria are shown in the box below: Outcome Measure (see Section 8) Score +1 for each outcome measure which is below the value below. Total score of ≥5 indicates MDA achieved Tender joint count (TJC) (using 68 joint count) ≤1 Swollen joint count (SJC) (using 66 joint count) ≤1 Enthesitis count (using LEI or SPARCC) ≤1 Skin assessment PASI≤1 or BSA≤3% Patient global VAS (mm) ≤20 Patient pain VAS (mm) ≤15 HAQ ≤0.5 | 12, 24, 36, 48 weeks | 
| Psoriatic Arthritis Impact of Disease (PsAID) | A questionnaire assessing the overall impact of disease on a patient. This is a scale of 12 questions (scored 0-10) which are combined with published weighting scales to one final 0-10 score where 0 is no impact and 10 is maximal impact. There are no subscales. Patient acceptable symptom state is <=4. | 12, 24, 36, 48 weeks |