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A Phase 2 Study of Anakinra in Inflammatory Pustular Dermatoses: Evaluation of Therapeutic Efficacy and Validation of PathogenicMechanisms

Phase 2
18 Years
Open (Enrolling)
Pustular Dermatosis

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Trial Information

A Phase 2 Study of Anakinra in Inflammatory Pustular Dermatoses: Evaluation of Therapeutic Efficacy and Validation of PathogenicMechanisms


Inflammatory disorders that present with neutrophilic pustular skin lesions, including
generalized pustular psoriasis, are characterized by severe cutaneous manifestations,
generalized inflammation and significant morbidity. Recent studies in patients with
phenotypically similar pustular diseases have identified two monogenic forms of neutrophilic
pustular psoriasis implicating interleukin (IL)-1 in disease pathogenesis. Deficiency of
the IL-1 receptor antagonist (IL1RN, DIRA) is an autosomal recessive condition characterized
by severe generalized pustular eruptions in the neonatal period, osteopenia, lytic bone
lesions, joint pain, respiratory insufficiency, thrombosis, elevated acute phase reactants
and significant mortality. Patients with this condition have responded rapidly to IL-1
receptor antagonist, anakinra. Deficiency of IL-36 receptor antagonist (IL-36RN/IL1F5,
DITRA) is an autosomal recessive condition with episodic widespread pustular skin lesions,
fevers and systemic inflammation defined by marked leukocytosis and elevated creactive
protein. Both IL1RN and IL36RN/IL1F5 are highly expressed in epidermal keratinocytes,
suggesting a role for keratinocytes in initiating innate immunity-mediated inflammatory skin
diseases, and ultimately manifesting in a pustular phenotype. Patients with inflammatory
pustular diseases often respond poorly to conventional treatment with methotrexate,
cyclosporine and anti-TNF agents. Two recent case reports describe patients with pustular
psoriasis unresponsive to TNF inhibition who responded to anti-IL-1 receptor therapy with
anakinra. We hypothesize that monogenic and polygenic inflammatory pustular skin diseases
share common pathogenic mechanisms mediated by IL-1. We propose a phase 2 study that will
utilize a collaborative bench-to-bedside approach, applying targeted anti-IL-1 therapy,
novel imaging modalities, and laboratory techniques including immunohistochemistry, gene
expression and cytokine studies, and in vitro manipulations of skin to dissect and validate
pathways in these complex diseases.


To characterize the clinical efficacy, optimal dosing and safety of anakinra in patients

with pustular dermatoses.


Age >= 18 years.

Active macroscopic noninfectious pustular skin lesions involving >= 5% of the total body

surface area, or palmoplantar involvement.

Histopathologic confirmation of epidermal neutrophilic pustulosis.

Patients must have maintained a stable dose of immunosuppressant therapy, retinoids or

anti-neutrophil therapy for 2 weeks prior to study initiation with resultant stable or

worsening skin disease.

Use of biologic agents requires a washout period of at least 3 half-lives prior to study


Patients must have organ and marrow function as defined below:

leukocytes > 3,000/mcL

absolute neutrophil count > 1,500/mcL

platelets > 100,000/mcL

creatinine within normal institutional limits OR creatinine clearance > 60 mL/min/1.73 m2
for patients with creatinine levels above institutional normal.


A 16-week, open-label phase 2 study. Patients will initially receive treatment with
anakinra 100 mg/day by self-administered subcutaneous injection. Disease response will be
assessed every 4 weeks, and determination of dose escalation will be made based on clinical
assessment. Dose escalation can increase up to 200 mg/day, and for patients > 75 kg up to
300 mg/day at the end of week 8. If a response is achieved with anakinra, other
immunosuppressants administered for the purpose of treatment of pustular skin disease may be
tapered per physician discretion. Clinical assessment, and laboratory and subjective data
will be collected in-person every 4 weeks to determine disease response. Telephone
assessments will be performed weekly. Twenty-five evaluable patients will be enrolled onto
this trial. The accrual ceiling for this study will be set to 30.

Inclusion Criteria


Females and males, aged greater than or equal to 18.

Patients must demonstrate active noninfectious inflammatory pustular skin lesions
resembling pustular psoriasis and involving >= 5% total body surface area, or palmoplantar
involvement. Conditions may include, but are not be limited to, pustular psoriasis,
Sneddon-Wilkinson disease, subcorneal pustular dermatosis, reactive arthritis,
palmoplantar pustulosis, acrodermatitis continua of Hallopeau and palmoplantar pustular

Patients must have histopathologic confirmation of epidermal neutrophilic pustular skin

If taking immunosuppressants, retinoids or anti-neutrophil therapy, participants must
maintain stable doses of these medications during the 2 weeks prior to study initiation.

Patients must have stable topical medication regimen for 2 weeks prior to study initiation

Patients must have normal organ and marrow function as defined below:

leukocytes > 3,000/mcL

absolute neutrophil count > 1,500/mcL

platelets > 100,000/mcL

creatinine within normal institutional limits OR creatinine clearance > 60 mL/min/1.73 m2
for patients with creatinine levels above institutional normal.

Patients must have either (1) a negative PPD test per CDC guidelines and no evidence of
active TB on chest radiograph at the time of enrollment, or (2) a positive PPD with no
evidence of active TB by history or on chest radiograph at the time of enrollment AND
either past or present treatment with adequate therapy for at least one month prior to
first dose of study medication.

Patients must be able to understand and sign a written informed consent document and
complete study-related procedures and questionnaires.


Enrollment in any other investigational treatment study or use of an investigational
agent, or has not yet completed at least 3 half-lives since ending another investigational
device or drug trial.

History of treatment with canakinumab within the 12 months prior to study initiation.

History of anakinra use.

History of phototherapy within 2 weeks prior to study initiation.

Patients may NOT concurrently be on biologic therapy such as etanercept, adalimumab,
alefacept, infliximab, rituximab or rilonacept (Appendix A). If there is a history of use
of biologic agents, there must be a washout period of at least 3 half-lives prior to study

Subjects who experience a significant flare after discontinuation of a TNF inhibitor as
part of this study that requires urgent medical management or hospitalization, or in the
estimation of the principal investigator poses excessive risk to the patient to enter the

Other defined dermatologic conditions which may include pustules as part of the clinical
presentation, but which clinically and/or histologically do not resemble pustular
psoriasis. Examples include, but are not limited to acute generalized exanthematous
pustulosis (AGEP, a drug-induced pustular dermatosis typically caused by beta-lactam
antibiotics, tetracyclines, oral antifungals and other drugs), bacterial or fungal
folliculitis, cutaneous candidiasis, tinea pedis, tinea corporis, neutrophilic eccrine
hidradenitis or eosinophilic pustular folliculitis (Ofuji syndrome).

Known diagnosis of DIRA.

History of allergic reactions attributed to compounds of similar chemical or biologic
composition to anakinra or other agents used in study. Known hypersensitivity to CHO-cell
derived biologics or any components of anakinra.

Treatment with a live virus vaccine during the 3 months prior to baseline visit. No live
vaccines will be allowed throughout the course of this study.

Pregnant or lactating females.

Patients with active or untreated malignancy-- with the exception of cutaneous basal or
squamous cell carcinomas, or in situ cervical carcinoma-- are ineligible because of the
immunomodulating effects of anakinra. The risk of recurrent malignancy secondary to this
drug is unknown.

Presence of active infection. History of exposure to TB (positive PPD) who have not been
treated with a TB prophylaxis regimen for at least one month.

Chest x-ray demonstrating pleural scarring and/or calcified granuloma consistent with
prior or current untreated TB.

History of chronic or recurrent infection including but not limited to HIV, hepatitis B or
hepatitis C.

Individuals with severe or uncontrolled recurrent cutaneous infections who are considered
at elevated risk for serious infection on anakinra therapy will be excluded per physician

Presence of other known significant autoimmune or inflammatory disease. Examples include
major chronic infectious/inflammatory/immunologic diseases such as systemic lupus
erythematosus, rheumatoid arthritis, Sjogren?s syndrome and periodic fever syndromes.

Other immunoregulatory or immunodeficiency diseases, such as multiple sclerosis.

Individuals with life-threatening or disabling inflammation of the eyes, gut or joints
requiring urgent or immediate medical attention, or at the physician?s discretion.

Subjects for whom there is concern about compliance with the protocol procedures.

Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, uncontrolled or unmonitored psychiatric illness/social situations, or history
of congestive heart failure, unstable angina pectoris or medically significant cardiac
arrhythmia that would limit compliance with study requirements.

Presence of other severe acute or chronic medical or psychiatric condition, or significant
laboratory abnormality requiring further investigation that may cause undue risk for the
subject?s safety, inhibit protocol participation, or interfere with interpretation of
study results, and in the judgment of the investigator would make the subject enrollment

The effects of anakinra on the developing human fetus are unknown. Women of childbearing
potential and men must agree to use adequate contraception (hormonal or barrier method of
birth control or abstinence) prior to study entry and for the duration of study
participation. Should a woman become pregnant or suspect she is pregnant while she or her
partner is participating in this study, she should inform her treating physician
immediately. Females of childbearing potential must have a negative urine pregnancy test
at screening. Females must also have a negative serum pregnancy test at baseline and prior
to performance of any radiologic procedure or administration of study medication and
during each NIH visit. Lactating mothers will discontinue breastfeeding prior to study

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Obtain an estimate of the response rate to treatment

Outcome Time Frame:

3 months

Safety Issue:


Principal Investigator

Edward W Cowen, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Federal Government

Study ID:




Start Date:

January 2013

Completion Date:

January 2016

Related Keywords:

  • Pustular Dermatosis
  • Efficacy
  • Optimal Dosing
  • Safety
  • Pustular Skin Lesion
  • Neutrophilic Pustulosis
  • Skin Diseases



National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892