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About
The investigators propose an open label pragmatic clinical and laboratory study designed to investigate, in detail, the clinical and molecular effects of Interleukin 17 (IL-17) and inhibition of IL-17 with secukinumab, on neutrophil function in vitro and ex vivo.
As secondary, exploratory objectives, the investigators will utilise the fact that secukinumab is to be administering to 20 patients with Psoriatic Arthritis (PsA) and investigate whether there is any relationship between vitamin D status and response to secukinumab, with respect to efficacy and adverse events. The results of this secondary exploratory analysis will inform the design of a larger, definitive study.
Full description
Phase: Phase 2 Clinical Trial of an Investigational Medicinal Product (CTIMP)
Sample Size: 20 patients plus 10 healthy controls are to be enrolled in total.
Study Population:
Patient treatment group: 20 patients with active psoriatic arthritis (fulfilling Classification Criteria for Psoriatic Arthritis [CASPAR] criteria) affecting ≥2 peripheral joints (swollen and tender) that have not responded to at least one standard Disease-modifying antirheumatic drugs (DMARDs).
Healthy control group: 10 healthy control blood samples (matched for gender to the patients and within 5 years of mean age within each gender subgroup).
Number of Sites: 1 - Rheumatology clinic at Aintree University Hospital, Liverpool
Study Duration: 24 months in total with 12 months of therapy, and 12 months for staggered enrolment and laboratory investigations
Description of Agent/Intervention
Secukinumab 150mg/300mg subcutaneous injection once weekly for the first 4 weeks then 150mg subcutaneous injection 4 weekly for up to 11 months.
Primary Aim:
The primary aim is to determine the molecular effects of IL-17 and inhibition of IL-17 with secukinumab on neutrophil phenotype, lifespan, function and production of IL-17.
Secondary Aims:
Exploratory Aims:
Study Design:
Screening for eligibility
Patient group: Patients attending routine rheumatology assessments will be screened for suitability for the study. Eligible patients, based on diagnosis of PsA (meeting CASPAR criteria and with peripheral joint involvement), will be approached to determine if they are willing to participate.
Eligible patients will be registered into the study and will receive secukinumab treatment in addition to their standard DMARD treatment.
Healthy Control Group: Healthy controls matched by gender and within 5 years of mean patient age (assessed in patient group) will be recruited from National health Service (NHS) and university staff.
Baseline assessment:
Baseline assessment of Vitamin D, VDR, Neutrophil function ACR20, Body Surface Area (BSA), PASI 75 and 90, Nail Psoriasis Severity Index (NAPSI), Psoriatic Arthritis Response Criteria (PSARC), EuroQol five dimensions questionnaire (EQ5D) & Health Assessment Questionnaire (HAQ).
Secukinumab group
3 months - assessment of Vitamin D, VDR, Neutrophil function, ACR20, PASI 75 AND 90, NAPSI, PSARC, EQ5D, HAQ
6 months - assessment of Vitamin D, VDR, Neutrophil function, ACR20, PASI 75 AND 90, NAPSI, PSARC, EQ5D, HAQ
9 months - assessment of Vitamin D, VDR , ACR20, PASI 75 AND 90, NAPSI, PSARC, EQ5D HAQ
12 months - assessment of Vitamin D, VDR, Neutrophil function, ACR20, PASI 75 AND 90, NAPSI, PSARC, EQ5D, HAQ
13 months (final follow up visit) - pregnancy test, Full Blood Count (FBC), LFTs, serum creatinine and body temperature measurement.
Then exit study
Healthy Control Group: Blood sample obtained at baseline for assessment of Vitamin D, VDR and neutrophil function.
Analysis Plan:
Phase 1:
Phase 2:
Enrollment
Sex
Ages
Volunteers
Inclusion and exclusion criteria
Patients Inclusion Criteria:
Patients Exclusion Criteria:
Active or chronic infection including mycobacterium tuberculosis, HIV, hepatitis B or C
Absence of active psoriatic arthritis
Patients who are starting anti-TNF therapy for treating PsA
Pregnancy and planning pregnancy
Malignancy
Chest X-ray or chest MRI with evidence of ongoing infectious or malignant process obtained within 3 months prior to Screening and evaluated by a qualified physician.
Patients with hyponatraemia and nephrotic syndrome
Previous exposure to secukinumab or other biologic drug directly targeting IL-17 or IL-17 receptor.
Use of any investigational drug and/or devices within 4 weeks before registration or a period of 5 half-lives of the investigational drug, whichever is longer.
Significant comorbidity that, in the opinion of the investigator, would impact on ability to participate
Any change in the dose of oral glucocorticosteroids or DMARDS in the prior 6 weeks prior to the Baseline visit or use of i.v. intramuscular or intra-articular glucocorticosteroid during the last 6 weeks prior to the enrolment visit.
Patients who have previously been treated with TNFα inhibitors (investigational or approved).
History of hypersensitivity to the study drug or its excipients or to drugs of similar classes.
Previous treatment with any cell-depleting therapies including but not limited to anti-CD20 investigational agents (e.g. CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19).
Active ongoing inflammatory diseases other than PsA that might confound the evaluation of the benefit of secukinumab therapy.
Underlying metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine,cardiac, infectious or gastrointestinal conditions which in the opinion of the Investigator immunocompromise the patient and/or place the patient at unacceptable risk for participation in an immunomodulatory therapy.
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), uncontrolled diabetes.
History of clinically significant liver disease or liver injury as indicated by abnormal liver function tests (LFT) such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, or serum bilirubin. The Investigator should be guided by the following criteria:
History of renal trauma, glomerulonephritis, or patients with 1 kidney only, or a serum creatinine level exceeding 1.5 mg/dL (132.6 μmol/L).
Screening total white blood cell (WBC) count < 3 000/μL, or platelets < 100 000/μL or neutrophils < 1 500/μL or hemoglobin < 8.5 g/dL (85 g/L).
Active systemic infections during the last 2 weeks (exception: common cold) prior to registration.
History of ongoing, chronic or recurrent infectious disease or evidence of tuberculosis according to local practice/guidelines) or a positive QuantiFERON TB-Gold test or TB-Spot Test (as indicated in Section 4.1 and Table 6-1). Patients with a positive test may participate in the study if further work up (according to local practice/guidelines) establishes conclusively that the patient has no evidence of active tuberculosis. If presence of latent tuberculosis is established then treatment according to local country guidelines must have been initiated.
Known infection with human immunodeficiency virus, hepatitis B or hepatitis C at Screening or registration.
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).
Use of Vitamin D containing supplements.
Inability or unwillingness to undergo repeated venepuncture (e.g. because of poor tolerability or lack of access to veins).
Patients who have received a live vaccine within 4 weeks prior to planned registration must be excluded.
Healthy Controls Inclusion Criteria:
Primary purpose
Allocation
Interventional model
Masking
30 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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