Outcomes With Treatment and Withdraw of Ixekizumab in Patients With Plaque Psoriasis

Outcomes With Treatment and Withdraw of Ixekizumab in Patients With Plaque Psoriasis Compared to Standard Care --- a Pragmatic Observational Study

Sponsors

Lead Sponsor: Singapore General Hospital

Collaborator: Translational Immunology Institute

Source Singapore General Hospital
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) Ixekizumab 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 (RCT), 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 initial (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, we 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, we hypothesize that we 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 our 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.

Overall Status Not yet recruiting
Start Date October 1, 2020
Completion Date December 31, 2027
Primary Completion Date December 31, 2027
Phase Phase 4
Study Type Interventional
Primary Outcome
Measure Time Frame
Proportion of ixekizumab treated PsO participants free of relapse after ixekizumab withdrawal 12 months from ixekizumab withdrawal or 18 months from baseline.
Secondary Outcome
Measure Time Frame
Proportion of ixekizumab treated PsO participants free of relapse after ixekizumab withdrawal 15, 18, and 24 months from ixekizumab withdrawal or 21, 24, and 30 months from baseline.
Proportion of participants achieving PASI 50 3 months and 6 months
Proportion of participants achieving PASI 75 3 months and 6 months
Proportion of participants achieving PASI 90 3 months and 6 months
Proportion of participants achieving clearance 3 months and 6 months
Quality of life 1 (EuroQoL-5D-5L) 3, 6, 9, 12, 15, 18, 24 and 30 months
Quality of life 2 (Dermatology Life Quality Index - DLQI) 3, 6, 9, 12, 15, 18, 24 and 30 months
Quality of life 3 (Hospital Anxiety and Depression Scale - HADS) 3, 6, 9, 12, 15, 18, 24 and 30 months
Patient Global Assessment 3, 6, 9, 12, 15, 18, 24 and 30 months
Patient Acceptable Symptom State (PASS) 3, 6, 9, 12, 15, 18, 24 and 30 months
Proportion of participants in ixekizumab treatment arm maintaining PASI 50 after ixekizumab withdrawal 9, 12, 18, 24 and 30 months from baseline
Proportion of participants in ixekizumab treatment arm maintaining PASI 75 after ixekizumab withdrawal 9, 12, 18, 24 and 30 months from baseline
Proportion of participants in ixekizumab treatment arm maintaining PASI 90 after ixekizumab withdrawal 9, 12, 18, 24 and 30 months from baseline
Proportion of participants in ixekizumab treatment arm maintaining clearance after ixekizumab withdrawal 9, 12, 18, 24 and 30 months from baseline
Proportion of participants in ixekizumab treatment arm flaring after ixekizumab withdrawal 9, 12, 18, 24 and 30 months from baseline
Histological changes in the skin biopsies of participants in ixekizumab treatment arm who relapsed after ixekizumab withdrawal (or at 18 months if no relapse) Baseline, 6 months, at relapse (or 18 months if no relapse)
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) Baseline, 6 months, at relapse (or 18 months if no relapse)
Peripheral blood immunome profiles of participants in ixekizumab treatment arm who relapsed after ixekizumab withdrawal (or at 18 months if no relapse) Baseline, 6 months, at relapse (or 18 months if no relapse)
Histological changes in the skin biopsies Baseline and 6 months
Skin genomic profiles Baseline and 6 months
Peripheral blood immunome profiles Baseline and 6 months
Enrollment 40
Condition
Intervention

Intervention Type: Biological

Intervention Name: Ixekizumab

Description: Ixekizumab for 6 months, given 160mg at weeks 0, followed by 80mg at 2, 4, 6, 8, 10 and 12, then 4 weekly till 6 months. Given subcutaneously.

Arm Group Label: Ixekizumab

Intervention Type: Drug

Intervention Name: Methotrexate

Description: Oral tablet up to 15mg per week

Arm Group Label: Standard Care

Intervention Type: Drug

Intervention Name: Cyclosporin A

Description: Oral capsule up to 200mg per day

Arm Group Label: Standard Care

Intervention Type: Drug

Intervention Name: Acitretin

Description: Oral capsule up to 25mg per day

Arm Group Label: Standard Care

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

Gender: All

Minimum Age: 22 Years

Maximum Age: 90 Years

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Ying Ying Leung, MD Principal Investigator Singapore General Hospital
Overall Contact

Last Name: Ying Ying Leung, MD

Phone: +65 63265276

Email: [email protected]

Location
Facility: Contact: Investigator: Singapore General Hospital Ying Ying Leung, MD +65 63265276 [email protected] Ying Ying Leung, MD Principal Investigator
Location Countries

Singapore

Verification Date

August 2020

Responsible Party

Type: Sponsor

Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Ixekizumab

Type: Experimental

Description: Participants will be offered ixekizumab as first-line systemic treatment for moderate to severe PsO. The indication for ixekizumab will be equivalent to current registered indications. 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.

Label: Standard Care

Type: Active Comparator

Description: The management of PsO in the control arm will be the same as that in the standard care. The standard care for moderate to severe PsO in Singapore is to start either phototherapy, methotrexate, acitretin or cyclosporin A.

Patient Data No
Study Design Info

Allocation: Non-Randomized

Intervention Model: Parallel Assignment

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

Masking: None (Open Label)

Source: ClinicalTrials.gov