Comparing Anakinra versus placebo in the treatment of pustular psoriasis

• Register: EUCTR
• Last refreshed on: 19 October 2020
• Main ID: EUCTR2015-003600-23-GB
• Date of registration: 28/01/2016
• Prospective Registration: Yes
• Primary sponsor: Guy's and St Thomas NHS Foundation Trust
• Public title: Comparing Anakinra versus placebo in the treatment of pustular psoriasis
• Scientific title: Treatment of Pustular Psoriasis with the IL-1 receptor antagonist anakinra: a randomised, placebo controlled trial and associated mechanistic studies
• Date of first enrolment: 01/04/2016
• Target sample size: 64
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-003600-23
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: no; Cross over: no; Other: yes; Other trial design description: Double blind, randomised, placebo controlled, 2 stage adaptive design, with an open label extension; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes

Countries of recruitment

United Kingdom

Contacts

• Name: Prof. Catherine Smith
• Affiliation: Guy's and St Thomas Foundation Trust

• Name: Prof. Catherine Smith
• Affiliation: Guy's and St Thomas Foundation Trust

Key inclusion & exclusion criteria

Inclusion criteria:
Inclusion criteria for the for the double-blind treatment stage, placebo controlled study.
i. Adults (18 years and over) with diagnosis of Palmo-Plantar Pustulosis (PPP) made by a trained dermatologist with disease of sufficient impact and severity to require systemic therapy
ii. Disease duration of >6 months, not responding to an adequate trial of topical therapy including very potent corticosteroids
iii. Evidence of active pustulation on palms and /or soles to ensure sufficient baseline disease activity to detect efficacy
iv. At least moderate disease on the PPP Investigator’s Global Assessment (PPP-IGA)
v. Women of child bearing potential who are on adequate contraception (see Appendix A , contraception guidelines), who are not pregnant or not breast feeding
vi. Who have given written, informed consent to participate

Inclusion Criteria for the Open Label Extension
i. Participation in the double-blind placebo controlled study.
ii. Completion past Visit 4 (Week 8) of the double-blind placebo controlled study.
iii. Women of child bearing potential who are on adequate contraception (see Appendix A), contraception guidelines), who are not pregnant or not breast feeding
iv. Who have given written, informed consent to participate



Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 64
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 64

Exclusion criteria:
Double-blind stage
i. Previous treatment with anakinra or other IL-1 antagonists
ii. A history of recurrent bacterial, fungal or viral infections which, in the opinion of the principal investigator, present a risk to the patient
iii. Evidence of active infection or latent TB or who are HIV, Hepatitis B or C sero-positive
iv. A history of malignancy of any organ system (other than treated, localised non melanoma skin cancer), treated or untreated, within the past 5 years
v. Use of therapies with potential or known efficacy in psoriasis during or within the following specified timeframe before treatment initiation (week 0, visit 2):
a. very potent topical corticosteroids within 2 weeks b. topical treatment that is likely to impact signs and symptoms of psoriasis (e.g. corticosteroids, vitamin D analogues, calcineurin inhibitors, retinoids, keratolytics, tar, urea) within 2 weeks c. methotrexate, ciclosporin, acitretin, alitretinoin within 4 weeks d. phototherapy or PUVA within 4 weeks e. etanercept or adalimumab within 4 weeks f. infliximab or ustekinumab or secukinumab within 3 months g. other TNF antagonists within 3 months h. other immunosuppressive or immunomodulatory therapy within 30 days or 5 half lives prior to treatment initiation, whichever is longer
i. any other investigational drugs within 30 days(or 3 months for investigational monoclonal antibodies)or 5 half-lives prior to treatment initiation, whichever is longer
vi. With moderate renal impairment[CrCl<50ml/min]
vii. With neutropenia(<1.5x109/L)
viii. With thrombocytopenia(<150x109/L)
ix. With known moderate hepatic disease &/or raised hepatic transaminases (ALT/AST) >2xULN at baseline. Patients who fail this criterion may still be considered following review by a hepatologist&confirmed expert opinion that study entry is clinically appropriate.
x. Live vaccinations within 3 months prior to the start of study medication, during the trial, & up to 3 months following the last dose
xi. Women who are pregnant, breastfeeding or of child bearing age not on adequate contraception or men planning conception
xii. Poorly controlled diabetes mellitus, cardiovascular disease, asthma, concomitant therapy that may interact with anakinra(eg phenytoin or warfarin)or any condition where, in the opinion of the investigator, anakinra would present risk to the patient.
xiii. Unable to given written, informed consent.
xiv. Unable to comply with the study visit schedule
xv.Diagnosis(or historic diagnosis)of either childhood or adult onset Still’s disease.
Open Label Extension
i. A history of recurrent bacterial, fungal or viral infections which, in the opinion of the principal investigator, present a risk to the patient
ii.Evidence of active infection or latent TB or who are HIV, Hepatitis B or C sero-positive(only required for patients who are beyond Visit 5 the double-blind treatment stage, placebo controlled study).
iii.A history of malignancy of any organ system(other than treated, localised non-melanoma skin cancer),treated or untreated, within the past 5 years
iv.Use of therapies with potential or known efficacy in psoriasis during or within the following specified timeframe before treatment initiation (Visit OLE 1):
a. methotrexate, ciclosporin, acitretin, alitretinoin within 4 weeks b. phototherapy or PUVA within 4 weeks c. etanercept or adalimumab within 4 weeks d. infliximab or ustekinumab or secukinumab within 3 months e. other TNF antagonists within 3 months f. other immunosuppres

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Skin and Connective Tissue Diseases [C17]

Acral Pustular Psoriasis, specifically but not limited to Palmo-Plantar Pustulosis will be the target population for therapeutic intervention with Anakinra in this study.
MedDRA version: 20.0 Level: PT Classification code 10037575 Term: Pustular psoriasis System Organ Class: 10040785 - Skin and subcutaneous tissue disorders

Intervention(s)

Trade Name: Anakinra
Product Name: Anakinra
Pharmaceutical Form: Solution for injection
INN or Proposed INN: ANAKINRA
CAS Number: 143090-92-0
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: At the end of treatment at 8 weeks and end of follow up at 12 weeks.

Main Objective: To determine the efficacy of anakinra in treatment of adults with PPP compared to placebo. The primary endpoint is change in disease activity over 8 weeks, adjusted for baseline (visit 1), measured using fresh pustule count, the default primary outcome, unless PPPASI is more discriminating (to be reviewed at the end of stage one).

The Stage 1 review occurred on 22nd January 2018. As a result of this review the DMC recommended the primary outcome to be PPPASI and this was passed by the TSC. Fresh pustule count will be a secondary outcome.

Primary end point(s): The determination of the efficacy of anakinra in treatment of adults with PPP compared to placebo, measured by an independent blinded assessor using:

1. Fresh pustule count on palms and soles across 1, 4 and 8 weeks, OR
2. Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) across 1, 4 and 8 weeks
The default primary endpoint will be fresh pustule count unless PPPASI is more discriminating (to be reviewed at the end of stage one).
The Stage 1 review occurred on 22nd January 2018. As a result of this review the DMC recommended the primary outcome to be PPPASI and this was passed by the TSC. Fresh pustule count will be a secondary outcome.

Secondary Objective: - describe any treatment effect of anakinra, indicated by change in disease activity over 8 weeks using the Palmoplantar Pustulosis Psoriasis Area Severity Index (PPPASI)
- determine the following:
- time to response of PPP and relapse rate with anakinra
- proportion of randomised patients achieving clearance of PPP with anakinra by 8 weeks
- any treatment effect of anakinra in pustular psoriasis at non acral sites as measured by change in percentage area of involvement at 8 weeks
- any treatment effect of anakinra in plaque type psoriasis (using Psoriasis Area and Severity Index (PASI) at 8 weeks)
- collect data on the adverse event profile and adverse reactions induced by anakinra to evaluate the safety and tolerability of anakinra
- the impact of anakinra on patients' symptoms and quality of life
- the proportion of randomised patients who find the treatment acceptable or worthwhile
- the proportion of randomised patients adhering to treatment

Secondary Outcome(s)

Secondary end point(s): Investigator Assessed
1. Total pustule count on palms and soles across 1, 4, 8 weeks adjusted for baseline (visit 1)
2. Investigator's Global Assessment (PPP-IGA) at 1, 4 and 8 compared to baseline (visit 1)
3. Time to response of PPP (defined as a 75% reduction in fresh pustule count [default primary outcome] compared to baseline), and relapse rate (defined as return to baseline fresh pustule count)
4. Achievement of ‘clear ‘ on PPP-IGA by 8 weeks
5. Development of a disease flare (ie: >50% deterioration in PPPASI compared to baseline, visit 1)
6. Pustular psoriasis at non acral sites as measured by change in percentage area of involvement at 8 weeks compared to baseline (visit 1)
7. Plaque type psoriasis (if present) measured using Psoriasis Area and Severity Index (PASI) at 8 weeks compared to baseline (visit 1)
8. Serious infection as defined by any infection leading to death, hospital admission or requiring IV antibiotics
9. Neutropenia (ie: neutrophil count of 1.0x10-9/l on at least one occasion)
Patient Reported Outcomes
1. Patient's Global Assessment (clear, nearly clear, mild, moderate, severe, very severe) across 1, 4, 8 weeks compared to baseline (visit 1)
2. Palmoplantar Quality of Life Instrument score in randomised patients at 8 weeks compared to baseline (visit 0)
3. Dermatology Life Quality Index at 8 weeks compared to baseline (visit 0)
4. EQ5D-3L score at 8 weeks compared to baseline (visit 0)
5. Treatment acceptability (ie: whether the treatment is 'worthwhile') evaluated using a brief questionnaire with a response scale of 1-5 at study end
6. Adherence to treatment measured by responses to daily text message over 8 weeks of treatment

Timepoint(s) of evaluation of this end point: At the end of treatment at 8 weeks and end of follow up at 12 weeks.

Secondary ID(s)

APRICOT

Source(s) of Monetary Support

MRC NIHR EME programme

Ethics review

Status: Approved
Approval date: 01/04/2016
Contact: