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

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Биопрепарат Ixekizumab
  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.
• Препарат Methotrexate
  Oral tablet up to 15mg per week
• Препарат Cyclosporin A
  Oral capsule up to 200mg per day
• Препарат Acitretin
  Oral capsule up to 25mg per day

Первичные конечные точки

• Proportion of ixekizumab treated PsO participants free of relapse after ixekizumab withdrawal [Срок оценки: 12 months from ixekizumab withdrawal or 18 months from baseline.]

Вторичные конечные точки (12)

• Proportion of ixekizumab treated PsO participants free of relapse after ixekizumab withdrawal [Срок оценки: 15, 18, and 24 months from ixekizumab withdrawal or 21, 24, and 30 months from baseline.]
• Proportion of participants achieving PASI 50 [Срок оценки: 3 months and 6 months]
• Proportion of participants achieving PASI 75 [Срок оценки: 3 months and 6 months]
• Proportion of participants achieving PASI 90 [Срок оценки: 3 months and 6 months]
• Proportion of participants achieving clearance [Срок оценки: 3 months and 6 months]
• Quality of life 1 (EuroQoL-5D-5L) [Срок оценки: 3, 6, 9, 12, 15, 18, 24 and 30 months]
• Quality of life 2 (Dermatology Life Quality Index - DLQI) [Срок оценки: 3, 6, 9, 12, 15, 18, 24 and 30 months]
• Quality of life 3 (Hospital Anxiety and Depression Scale - HADS) [Срок оценки: 3, 6, 9, 12, 15, 18, 24 and 30 months]
• Patient Global Assessment [Срок оценки: 3, 6, 9, 12, 15, 18, 24 and 30 months]
• Patient Acceptable Symptom State (PASS) [Срок оценки: 3, 6, 9, 12, 15, 18, 24 and 30 months]
• Proportion of participants in ixekizumab treatment arm maintaining PASI 50 after ixekizumab withdrawal [Срок оценки: 9, 12, 18, 24 and 30 months from baseline]
• Proportion of participants in ixekizumab treatment arm maintaining PASI 75 after ixekizumab withdrawal [Срок оценки: 9, 12, 18, 24 and 30 months from baseline]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Другое

Центры проведения

Сингапур · 1 центр

• Singapore General Hospital — Outram Park

Идентификаторы

NCT: NCT04537689 · PsO_IXE

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗