Primary Objective: To compare the effectiveness of the administration of secukinumab to standard care in newly diagnosed Psoriatic Arthritis patients on the ACR50 response at 6 months. Secondary Objectives: To compare effectiveness at 6 and 12…
ID
Source
Brief title
Condition
- Autoimmune disorders
- Synovial and bursal disorders
- Epidermal and dermal conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The ACR50 response will be used to determine efficacy at 6 months. A subject is
defined as an ACR50 responder if, and only if, the following three conditions
are met:
1. they have a >= 50% improvement in the number of tender joints (based on 68
joints)
2. they have a >= 50% improvement in the number of swollen joints (based on 66
joints)
3. they have a >= 50% improvement in three of the following five domains:
- Patient*s global assessment of disease activity (measured on a VAS scale,
0-100)
- Physician*s global assessment of disease activity (measured on a VAS scale,
0-100)
- Patient*s assessment of PsA pain (measured on a VAS scale, 0-100)
- Health Assessment Questionnaire - Disability Index (HAQ-DI©) score
- Acute phase reactant (hsCRP or ESR)
Secondary outcome
- ACR20 and ACR70 at 6 months;
- ACR20/50/70 at 12 months;
- MDA (The proportion of subjects achieving minimal disease activity,
which is defined as 5 of the following 7 domains: <= 1 tender joint count, <= 1
swollen joint count, PASI <= 1 or BSA<=3%, patient pain VAS <= 15, patient global
assessment of disease activity VAS <= 20, HAQ-DI© <= 0.5, tender entheseal points
<= 1) at 12 months
- VLDA (Very Low Disease Activity), DAPSA (Disease Activity in PSoriatic
Arthritis) and PASDAS (Psoriatic Arthritis Disease Activity Score) at 6 and 12
months;
- SF-36 (36-item, patient-reported survey of patient health), BRAF (Bristol
Rheumatoid Arthritis Fatigue Multi-Dimensional Questionnaire) and PSAID
(Psoriatic Arthritis Impact of Disease Questionnaire) at 12 months;
- PCQ (Psychological Capital Questionnaire) at 12 months;
- The PsA-modified Sharp/van der Heijde score (SHS) at 12 months.
Background summary
Psoriatic Arthritis (PsA) is a chronic inflammatory joint disease with an
estimated prevalence of 0.5% in the general population. It manifests in skin,
joints, enthesis and spine and when left untreated results in joint damage,
structural changes in the enthesis and spine. Moreover, it can have a dramatic
impact on the quality of life. Over recent years treatment options are vastly
expanding.
With more emergent effective treatments for inflammatory arthritis, the concept
of treat-to-target is growing to its full potential. In rheumatoid arthritis
(RA), this treatment approach has been proven to be effective, leading to less
erosive progression, more drug free remission and better quality of life. Treat
to target is a treatment strategy in which treatment is optimized to reach and
maintain explicitly specified goals, such as remission or low disease activity.
In PsA, the treat to target principle is less often applied and has only been
studied by Coates et al. The TICOPA study used a step-up approach in the tight
control arm. Patients were started on methotrexate, sulfasalazine and
subsequently a TNF blocker was added if patients did not meet the pre-specified
target of Minimal Disease Activity (MDA). Patients in the tight control group
had a higher chance (odds) of achieving an ACR-20 response than the standard
care group (odds ratio 1·91, 95% CI 1·03-3·55; p=0·04). ACR50, ACR70, and
PASI75 responses were also achieved more frequently in the tight control group
than in the standard care group. However, there was little difference for
resolvement of dactylitis and enthesitis in the tight control group as compared
to the standard care group, and there was no difference in damage progression.
This indicates that a treat to target approach is feasible in the treatment of
PsA, but not all disease features responded well on the TICOPA regime
suggesting that better treatment strategies are needed.
Studies in patients with RA established that early aggressive treatment in a
treat to target strategy improves outcome. For instance, in the BEST study and
the TREACH study combination therapy arms outperformed the mono therapy arms on
joint damage and drug free remission. However, up to date there is ample to no
data on early aggressive treat to target treatment in PsA.
The initial drug used in the TICOPA trial was methotrexate. Methotrexate is a
controversial drug in the treatment of PsA. The effect on skin psoriasis has
been proven extensively, however there is little to no evidence for the
efficacy of methotrexate in PsA treatment. Despite this drug being generally
regarded and reflected in guidelines as first line treatment for the arthritis
component of PsA, this is not the case for its effect on inflammatory backpain,
enthesitis or dactylitis. This implicates that early strategies using treatment
covering all PsA disease features could improve outcome.
Over the past couple of years, therapeutic targets for treatment of PsA are
rapidly evolving. Interleukine-17a blockade (e.g. secukinumab) is one of the
evolving treatments and plays an important role in the pathophysiology of PsA.
In contrast to methotrexate, in clinical setting it is beneficial on all the
effected sites in patients with PsA. It also significantly improves patient
reported outcome measures. We hypothesize that treatments covering all features
of PsA by early aggressive therapeutic intervention, using secukinumab as an
initial treatment strategy will improve treat to target in PsA.
Study objective
Primary Objective:
To compare the effectiveness of the administration of secukinumab to standard
care in newly diagnosed Psoriatic Arthritis patients on the ACR50 response at 6
months.
Secondary Objectives:
To compare effectiveness at 6 and 12 months between two treatment arms,
mimicking standard care (arm 1) and early secukinumab arm (arm 2) using:
- Patients achieving ACR 20 and 70 at 6 months
- Patients achieving ACR 20, 50, 70 at 12 months
- Patients achieving MDA and VLDA at 6 and 12 months
- DAPSA and PASDAS scores at 6 and 12 months
To compare Quality of life at 12 months between two treatment arms, mimicking
standard care (arm 1) and early secukinumab arm (arm 2) using:
- SF36
- PSAID
- BRAF
To compare work performance (presenteeism and absenteeism) at 12 months between
between two treatment arms, mimicking standard care (arm 1) and early
secukinumab arm (arm 2)
To compare progression of radiological damage at 12 months between two
treatment arms, mimicking standard care (arm 1) and early secukinumab arm (arm
2) using:
- PsA modified Sharp vd Heijde (SHS) at 12 months
To assess the cost-effectiveness between two treatment arms, mimicking standard
care (arm 1) and early secukinumab arm (arm 2).
Study design
The DEPAR-t2t trial is designed as a randomized, controlled, parallel group,
open label, multi-center comparing two treat-to-target strategies within a
cohort.
Arm 1: Mimicking standard care. The standard care is based on data from the
DEPAR cohort and interviews with Dutch rheumatologists.
Arm 2: Secukinumab 300 mg
Therapy in each arm will be escalated using a 3 monthly scheme in patients not
achieving the treatment target (MDA).
For this research we will use a Trials Within Cohorts (TWiCs) design. This
method recruits a central cohort having *treatment as usual* with regular
observations and then adds pragmatic trials of alternative therapies in which a
random group of eligible patients are selected. This allows robust
generalizability from studies to routine health care, avoids attrition and
disappointment bias from controls in open label studies as patients receive
only information relevant to their care, aids recruitment to trials, allows
routine collection of long term outcomes and increases efficiency with multiple
trials within one cohort. The currently running DEPAR cohort will function as
the central cohort. Patients fulfilling the inclusion criteria for the treat to
target trial will be offered to participate in the study. Patients refusing
aforementioned will remain in the central cohort.
Patients diagnosed by the rheumatologist and fulfilling the CASPAR criteria for
Psoriatic Arthritis will be eligible if they present with oligo-arthritis (2 to
5 involved joints) or with poly-arthritis (5 or more joints).
Participants in this study will attend for study visits at baseline and months
3, 6, 9 and 12. After 6 weeks patients will be asked to fill out 5
questionnaires. At the 3-monthly visits, participants will be assessed
clinically for disease activity and will be asked to complete patient reported
outcomes via questionnaires. Visits in between these will be performed based on
clinical need when adjustment to therapy is required.
Based on the evaluations, MDA will be calculated and therapy will be escalated
or continued
Intervention
This is a 2-arm strategy study.
ARM 1: Mimicking standard care.
Therapy for the cohort is defined by the usual treatment strategy applied by
rheumatologists for the treatment of oligo-and polyarticular PsA. The initial
therapy (step 1) in this arm is methotrexate mono-therapy (starting 15mg/week
rising escalated to 25mg/week in 6 weeks). In addition, all patients will be
administered triamcinolone 80mg or depomedrol 120mg intramuscular (IM). In
cases of non-response, sulfasalazine twice daily 1000mg will be added to the
methotrexate (step 2). In case of failure of these two DMARDs, treatment will
be escalated by adding a biological DMARD. In this study is opted for a TNF
blocker (step 3). When the combination of conventional DMARD and a first TNF
blocker fails, the TNF blocker will be switched to a second TNF blocker (step
4). The choice of which TNF blocker to use is at the discretion of the treating
rheumatologist. The dosing of TNF blockers will be the standard dose for PsA
according to current guidelines in line with National reimbursement guidelines.
In addition, folic acid 10mg/week will be subscribed in every step of the
escalation scheme.
ARM 2: Secukinumab
All participants will be prescribed secukinumab 300 mg every 4 weeks, with a
loading scheme of the first 4 300 mg injections weekly, in combination with
methotrexate 15mg/week. In addition, all patients will be administered
triamcinolone 80 mg or depomedrol 120mg intramuscular (IM). (step 1).
Secukinumab is not registered for the first line treatment of PsA patients and
is not in accordance with national reimbursement guidelines and therefore
provided by Novartis. In case the first step fails (secukinumab 300mg +
methotrexate 15mg/week) treatment will be switched to a TNF blocker (step 2)
and to a second TNF blocker if the first TNF blocker fails (step 3). The choice
of which TNF blocker to use is at the discretion of the treating
rheumatologist. The dosing of TNF blockers will be the standard dose for PsA
according to current guidelines in line with national reimbursement guidelines.
When a second TNF blocker fails, this drug will be switched to apremilast 30mg
twice daily (step 4). Apremilast therapy is in line with national reimbursement
guidelines. In addition, folic acid 10mg/week will be subscribed in every step
of the escalation scheme.
Study burden and risks
In our opinion, the implementation of this study is justified when we take into
account the number of study visits for the patient/burden of filling out the
questionnaires in relation to the knowlegde we are expecting to gain from this
study.
's Gravendijkwal 230
Rotterdam 3015 CE
NL
's Gravendijkwal 230
Rotterdam 3015 CE
NL
Listed location countries
Age
Inclusion criteria
1. A new diagnosis of PsA as per CASPAR criteria at least 3 months.
2. A minimum of two swollen joints.
3. Patients must be able to understand and communicate with the Investigator
and comply with the requirements of the study and must give a written, signed
and dated informed consent before any study assessment is performed.
4. Male or female patients between 18 and 80 years of age.
5. 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 as in standard practice.
Exclusion criteria
1. Evidence of ongoing infectious or malignant process obtained within 3 months
prior to screening and evaluated by a qualified health care professional.
2. Current or previous treatment of arthritis with DMARDs (including
methotrexate, leflunomide or sulfasalazine) or biologics (including TNF,
IL12/23 or IL17 inhibitor therapies)
3. Pregnant or nursing (lactating) women, in which pregnancy is defined as the
state of a female after conception and until the termination of gestation,
confirmed by a positive human chorionic gonadotropin (hCG) laboratory test.
4. Women of child-bearing potential, defined as all women physiologically
capable of becoming pregnant, unless they are using effective methods of
contraception during dosing of study drug.
5. Underlying metabolic, hematologic, renal, hepatic, pulmonary, neurologic,
endocrine, cardiac, infectious or gastrointestinal conditions which in the
opinion of the Investigator immunocompromises the patient and/or places the
patient at unacceptable risk for participation in an immunomodulatory therapy.
6. Significant medical problems or diseases, including but not limited to the
following: uncontrolled hypertension (>= 160/95 mmHg), congestive heart failure
(New York Heart Association status of class III or IV), and uncontrolled
diabetes.
7. History of clinically significant liver disease or liver injury as indicated
by abnormal liver function tests (LFT) such as aspartate aminotransferase/serum
glutamic oxaloacetic transaminase (AST/SGOT), alanine aminotransferase/ serum
glutamic pyruvic transaminase (ALT/SGPT), alkaline phosphatase, or serum
bilirubin. The Investigator should be guided by the following criteria: Any
single parameter may not exceed 2 x upper limit of normal (ULN). A single
parameter elevated up to and including 2 x ULN should be re-checked once more
as soon as possible, and in all cases, at least prior to
enrollment/randomization, to rule out laboratory error.
8. History of renal trauma, glomerulonephritis, or subjects with one kidney
only, or a glomerular filtration rate (GFR) < 30 ml/min.
9. Active systemic infections during the last two weeks (exception: common
cold) prior to randomization.
10. History of ongoing, chronic or recurrent infectious disease or evidence of
tuberculosis infection as defined by either a positive PPD skin test or a
positive QuantiFERON TB-Gold test untreated or insufficiently treated according
to the national guideline.
11. Known infection with human immunodeficiency virus, hepatitis B or hepatitis
C at screening or randomization.
12. History of lymphoproliferative disease or any known malignancy or history
of malignancy of any organ system within the past 5 years (except for basal
cell carcinoma or actinic keratoses that have been treated with no evidence of
recurrence in the past 3 months, carcinoma in situ of the cervix or
non-invasive malignant colon polyps that have been removed).
13. Current severe progressive or uncontrolled disease, which in the judgment
of the clinical Investigator renders the patient unsuitable for the trial.
14. Inability or unwillingness to undergo repeated venipuncture (e.g. because
of poor tolerability or lack of access to veins).
15. Any medical or psychiatric condition which, in the Investigator*s opinion,
would preclude the participant from adhering to the protocol or completing the
study per protocol.
16. History or evidence of ongoing alcohol or drug abuse, within the last 6
months before randomization
17. Corticosteroid use within 8 weeks prior to randomization if used
intra-muscular or oral and within 4 weeks prior if used intra-articular.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-004724-11-NL |
| CCMO | NL68512.078.18 |