Clinical trial NCT04537689: Outcomes With Treatment and Withdraw of Ixekizumab in Patients With Plaque Psoriasis
Official title: Outcomes With Treatment and Withdraw of Ixekizumab in Patients With Plaque Psoriasis Compared to Standard Care --- a Pragmatic Observational Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Plaque Psoriasis
Lead sponsor: Singapore General Hospital
Sponsor class: OTHER
Collaborators: name: Translational Immunology Institute
First posted: 2020-09-03
Enrollment: 40
Sex: ALL
Minimum age (years): 22
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: To evaluate the real-life effectiveness of ixekizumab as first-line systemic treatment in participants with moderate to severe PsO, the investigators would recruit a pragmatic control arm.

⦁ Intervention arm: Eligible participants will be offered ixekizumab as first-line systemic treatment for PsO. Standard dose of subcutaneous ixekizumab for moderate to severe PsO will be given at 160 mg at week 0, followed by ixekizumab 80mg at weeks 2, 4, 6, 8, 10 and 12, then 4 weekly thereafter, for a total duration of 6 months.

Ixekizumab will be withdrawn after 6 months. For some participants, there may be relapse of PsO. Relapses will be managed as per standard care.

⦁ Pragmatic control arm

Eligible participants will be recruited to pragmatic control arm in these circumstances:

* Patient disagree to ixekizumab for personal reasons.
* The quota for ixekizumab is exhausted.
* The management of PsO in this pragmatic control arm will be the same as that in the standard care.
Primary purpose: OTHER

Brief summary: Psoriasis (PsO) is a systemic immune disease that affect 2-4% of the population worldwide. PsO causes tremendous burden in terms of quality of life, psychological impact, disability and work productivity of affected individuals. PsO is associated with an increased risk of cardiovascular morbidities and mortality in the long term. Up to 30% of PsO patients develop psoriatic arthritis (PsA) over time causing joint deformities and further disabilities. Majority of patients with PsA developed PsO first, and arthritis develop 5-10 years afterwards. PsA and PsO are increasingly recognized as two entities under the umbrella of psoriatic diseases.

Advances in biological treatments have greatly improved the prognosis of patients with PsO. Remarkable efficacies have been demonstrated for patients with moderate to severe PsO in randomized controlled trials (RCTs). However, the high cost of biological treatment is one of the major barriers to prescription of biological treatment and many patients may have limited access to these treatments.

The best strategy of treatment for PsO that takes into account efficacy and cost effectiveness is unknown. For instance, whether some PsO patients can stop biological treatment and be retreated with non-biologic medications upon relapse, which may enhance cost effectiveness of treatment. Preliminary studies have shown that some PsO patients were able to maintain good control of disease without medications after biologics withdrawal. The patho-immunological mechanisms behind long term remission after drug withdrawal is poorly understood. Better understanding on patho-immunological mechanisms on maintenance of remission and relapses will advance the development of biomarkers that eventually guide development of best treatment strategies for PsO.

Ixekizumab is a humanized immunoglobulin G4 (IgG4 kappa) monoclonal antibody targeting interleukin (IL)-17A. It is highly efficacious in the treatment of plague PsO with and favorable safety profile as shown in randomized controlled trials, and is an approved treatment for moderate-to-severe PsO by the U.S. Food and Drug Administration and Health Sciences Authority. With the proven efficacies, ixekizumab could be a choice of first-line treatment for patients with moderate to severe PsO. The 2013 American Academy of Dermatology position statement have stated that the old paradigm of stepwise-therapy starting first with phototherapy and oral systemic therapies before biologic treatment is not required for patients with moderate to severe PsO. In the recent 2017 update of the European S3 guidelines also recommend the use of IL-17 inhibitors as either a first- or second-line agent. In a RCT that evaluated relapses after withdrawal of ixekizumab among patients who achieved a clearance of PsO, loss of PsO clearance were seen after a median of 20 weeks. Response can be successfully recaptured in over 80% of patients with retreatment with ixekizumab, suggesting that the treatment regimen could be interrupted in some patients. However, real-life data on biologic treatment or withdrawal for moderate to severe PsO is scatty.

Detailed description: First, the investigators hypothesize that a proportion of patients with moderate to severe PsO may sustain reasonable good outcomes when a short course of ixekizumab is withdrawn.

Second, the investigators hypothesize that the investigators can identify the perturbations in the architecture of the immunome which are pathogenic, and to discriminate such perturbations based on treatment and clinical responses, thus distilling theragnostic signatures.

Therefore, the objectives of the study are as follow:

Specific aim 1: To describe the clinical course, sustained good outcomes, relapse rate, time to relapse and quality of life in PsO patients who stopped a 6-month short course treatment of ixekizumab, till the end of 2-years.

Specific aim 2: To identify the genomic and immunomic signatures in skin biopsies and blood in PsO patients who has good outcomes (PASI 75) at 6 months, comparing treatment vs pragmatic control.

Specific aim 3: To identify the genomic and immunomic signatures in skin biopsies and blood in PsO patients who sustained good outcomes at 1 year after stopping ixekizumab, compared to those relapsed.

Eligibility criteria: Inclusion Criteria:

* Adults (\>21-year-old).
* Diagnosed by dermatologist as plague-type PsO.
* Having moderate to severe plague-type PsO as defined by the following:
* Psoriasis Area and Severity Index (PASI) ≥12/72,
* And, investigator Global Assessment Score (IGA) ≥3,
* And, PsO involving body surface area involvement (BSA) ≥10%
* And Candidate for phototherapy and/or systemic therapy
* Topical corticosteroid up to moderate potencies are allowed
* Able to provide informed consent.

Exclusion Criteria:

* Forms of PsO other than plaque-type.
* Evidence of skin conditions at the time of the screening visit (e.g. eczema) that would interfere with evaluation of the effect of the investigational product on PsO.
* Evidence of active tuberculosis or other active infections (like Hepatitis C/B), malignancy; active or known use of other immunosuppressive drugs (eg. AIDS, rheumatoid arthritis, organ rejection etc) at the screening visit.
* Previous exposure to any systemic immunosuppressants (eg. methotrexate) or phototherapy
* History or current signs of a severe, progressive, or uncontrolled renal, cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, psychiatric, or metabolic disturbances.
* Having current or history of malignancy, except non-melanoma skin cancer, within the previous 5 years that have been adequately treated.
* History of inflammatory bowel disease.
* Pregnancy or lactating mothers.
* As treatment regimen is different, participants with evidence of PsA will be excluded

Primary outcomes:
measure: Proportion of ixekizumab treated PsO participants free of relapse after ixekizumab withdrawal
timeFrame: 12 months from ixekizumab withdrawal or 18 months from baseline.
Secondary outcomes:
measure: Proportion of ixekizumab treated PsO participants free of relapse after ixekizumab withdrawal
timeFrame: 15, 18, and 24 months from ixekizumab withdrawal or 21, 24, and 30 months from baseline.
measure: Proportion of participants achieving PASI 50
timeFrame: 3 months and 6 months
measure: Proportion of participants achieving PASI 75
timeFrame: 3 months and 6 months
measure: Proportion of participants achieving PASI 90
timeFrame: 3 months and 6 months
measure: Proportion of participants achieving clearance
timeFrame: 3 months and 6 months
measure: Quality of life 1 (EuroQoL-5D-5L)
timeFrame: 3, 6, 9, 12, 15, 18, 24 and 30 months
measure: Quality of life 2 (Dermatology Life Quality Index - DLQI)
timeFrame: 3, 6, 9, 12, 15, 18, 24 and 30 months
measure: Quality of life 3 (Hospital Anxiety and Depression Scale - HADS)
timeFrame: 3, 6, 9, 12, 15, 18, 24 and 30 months
measure: Patient Global Assessment
timeFrame: 3, 6, 9, 12, 15, 18, 24 and 30 months
measure: Patient Acceptable Symptom State (PASS)
timeFrame: 3, 6, 9, 12, 15, 18, 24 and 30 months
measure: Proportion of participants in ixekizumab treatment arm maintaining PASI 50 after ixekizumab withdrawal
timeFrame: 9, 12, 18, 24 and 30 months from baseline
measure: Proportion of participants in ixekizumab treatment arm maintaining PASI 75 after ixekizumab withdrawal
timeFrame: 9, 12, 18, 24 and 30 months from baseline
measure: Proportion of participants in ixekizumab treatment arm maintaining PASI 90 after ixekizumab withdrawal
timeFrame: 9, 12, 18, 24 and 30 months from baseline
measure: Proportion of participants in ixekizumab treatment arm maintaining clearance after ixekizumab withdrawal
timeFrame: 9, 12, 18, 24 and 30 months from baseline
measure: Proportion of participants in ixekizumab treatment arm flaring after ixekizumab withdrawal
timeFrame: 9, 12, 18, 24 and 30 months from baseline
measure: Histological changes in the skin biopsies of participants in ixekizumab treatment arm who relapsed after ixekizumab withdrawal (or at 18 months if no relapse)
timeFrame: Baseline, 6 months, at relapse (or 18 months if no relapse)
measure: Skin genomic profiles in the skin biopsies of participants in ixekizumab treatment arm who relapsed after ixekizumab withdrawal (or at 18 months if no relapse)
timeFrame: Baseline, 6 months, at relapse (or 18 months if no relapse)
measure: Peripheral blood immunome profiles of participants in ixekizumab treatment arm who relapsed after ixekizumab withdrawal (or at 18 months if no relapse)
timeFrame: Baseline, 6 months, at relapse (or 18 months if no relapse)
measure: Histological changes in the skin biopsies
timeFrame: Baseline and 6 months
measure: Skin genomic profiles
timeFrame: Baseline and 6 months
measure: Peripheral blood immunome profiles
timeFrame: Baseline and 6 months
Other outcomes:
Locations:
city: Outram Park
country: Singapore
facility: Singapore General Hospital
Study officials:
affiliation: Singapore General Hospital
name: Ying Ying Leung, MD
role: PRINCIPAL_INVESTIGATOR
References: