Apremilast in Patients With Moderate to Severe Palmoplantar Pustulosis (PPP) (APLANTUS)
Condition: Palmoplantar Pustulosis
MeSH terms: Psoriasis
Intervention: Apremilast
Intervention description: Apremilast was taken orally twice daily (except Day 1). Patients received tablets in blister/bottles sufficient for one month. To mitigate potential gastrointestinal side effects (primarily mild-to-moderate nausea and diarrhoea), dose titration was implemented in this study in accordance with the Summary of Product Characteristics (SmPC). A titration pack included tablets of 10, 20 and 30 mg for a period of one month. During the first 5 days, the dosage was up-titrated. The initial dose on day 1 was 10 mg in the morning; this was increased to 10 mg in the morning and evening on day 2. The evening dose was further increased by 10 mg (to 20 mg) on day 3. On day 4, the morning dose was increased to 20 mg, so that 20 mg was taken twice daily, and on day 5 the evening dose was increased to 30 mg. From Day 6 onwards, patients received the 30 mg dose twice a day. Subsequent packs included only tablets of 30 mg strength.
Intervention MeSH terms: Apremilast
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Intervention model description: This was an open-label, single-arm, pilot study to evaluate the efficacy and safety of apremilast.
Masking: None (Open Label)
Enrollment: 21.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: PPP; Palmoplantar Pustulosis; Apremilast; Otezla

Summary:

      Multicenter, open-label, single-arm, phase II, pilot study. The screening period was up to 4
      weeks and treatment took place over 20 weeks per patient. Five visits per patient were
      performed including: Visit 1 at week -4 to -1 (screening), Visit 2 at week 0 (baseline),
      Visit 3 at week 4, Visit 4 at week 12, and Visit 5 at week 20 (end of study). There was no
      follow-up period.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male and female patients aged 18 years or more at screening visit.

          -  Patients with chronic PPP (disease history of at least 6 months of diagnosis), who
             were eligible for treatment with systemic therapy defined as having PPP inadequately
             controlled by topical treatment and/or phototherapy and/or previous systemic therapy

          -  Patients with chronic moderate to severe PPP defined as patients with a PPPASI ≥12
             with or without concomitant plaque-type psoriasis

          -  Negative result of a urine pregnancy test taken at screening and at baseline for all
             women, except those who were surgically sterile or at least 1 year postmenopausal
             (i.e. at least 12 consecutive months with amenorrhea without other known or suspected
             medical cause)

          -  Willingness and capability of using a highly effective contraceptive measures from
             Screening visit until the end of at least one menstrual cycle (but not less than 28
             days) following discontinuation of apremilast as defined below:

               -  Female patient of childbearing potential (fertile, following menarche and until
                  becoming post- menopausal unless permanently sterile) using a highly effective
                  method of contraception OR female patients of non-childbearing potential
                  (surgically sterilized [e.g. hysterectomy, bilateral salpingectomy and bilateral
                  oophorectomy] or postmenopausal)

               -  Male patient, and their female partner of childbearing potential, using a highly
                  effective method of contraception

               -  Adequate contraceptive method defined as:

                    -  A method with less than 1% failure rate (e.g. permanent sterilization,
                       hormone implants, hormone injections, some intrauterine devices, or
                       vasectomized partner) OR

                    -  The use of two methods of contraception (e.g. one barrier method [condom,
                       diaphragm or cervical/vault caps] with spermicide and one hormonal
                       contraceptive [e.g. combined oral contraceptives, patch, vaginal ring,
                       injectables and implants])

          -  Patient was capable of understanding and giving written, voluntary informed consent
             before study screening.

          -  Willingness and capability of complying with all study procedure requirements, as per
             the Investigator's judgment (e.g. patient able to swallow the apremilast tablets,
             blood sampling).

        Exclusion Criteria:

          -  General:

               -  Pregnant or breast-feeding women

               -  Current or history of psychiatric disease that would interfere with the ability
                  to comply with the study protocol or give informed consent

               -  Patients known to have had a substance abuse (drug or alcohol) problem within the
                  previous 12 month

               -  Individuals who were involved in the organization of the study

               -  Patients who were in any way dependent on the investigator

               -  Patients who were participating in a clinical study

               -  Relatives, partner or staff of any clinical site personnel

          -  Disease-related:

               -  Evidence of skin conditions (e.g. eczema) other than PPP/psoriasis that would
                  interfere with evaluations of the effect of study medication on PPP or psoriasis.

               -  Laboratory values from routine blood test taken within the 8 weeks prior to
                  screening with any of the following:

                    -  Serum creatinine >1.4 x upper limit of normal (ULN) for age and gender

                    -  Estimated Glomerular Filtration Rate (eGFR) <30 mL/min/1.73m2 according to
                       the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation

               -  Pustular psoriasis lesions on the part of body other than hands or feet

               -  Significant concurrent medical conditions at the time of screening, including:

                    -  Risk factors for renal toxicity (renal inflammation)

                    -  Severe hepatic dysfunction

                    -  Unstable angina pectoris

                    -  Uncompensated congestive heart failure

                    -  Severe pulmonary disease requiring hospitalization or supplemental oxygen
                       therapy

                    -  Immunodeficiency disorders: primary or secondary

                    -  Known positive human immunodeficiency virus (HIV) test result, hepatitis B
                       surface (HBS) antigen or hepatitis C virus (HCV) test result

                    -  Uncontrolled insulin-dependent diabetes mellitus

                    -  Cancer or history of cancer (except for resected cutaneous basal cell or
                       squamous cell carcinoma) in the last 5 years

                    -  Open cutaneous ulcers

               -  Any condition that, in the judgment of the investigator, might cause this study
                  to be detrimental to the patient.

          -  Medication-related:

               -  Ultraviolet B (UVB) therapy, topical steroids, topical calcineurin inhibitors,
                  topical Vitamin A or D analog preparations, or anthralin within 14 days of
                  baseline. Exceptions: low potency topical corticosteroids (class I and II,
                  according to European classification for potency of topical corticosteroids) were
                  allowed as therapy for the face, groin, axillae in accordance with the
                  manufacturer's suggested usage dose

               -  Psoralen plus ultraviolet A radiation (PUVA), ciclosporin, acitretin,
                  alitretinoin, alefacept (Amevive®), anakinra (Kineret®), systemic
                  corticosteroids, methotrexate, fumaric acids or any other systemic anti-
                  psoriasis therapy within 28 days of baseline

               -  Prior (within the last 2 years) or concomitant use of antipsoriatic biologic
                  therapy with TNF-alpha blocker and/or ustekinumab and/or ixekizumab and/or
                  secukinumab and/or brodalumab and/or guselkumab

               -  Concomitant use of strong cytochrome P450 3A4 (CYP3A4) enzyme inductors (e.g.
                  rifampicin, phenobarbital, carbamazepin, phenytoin and St. John's wort)

               -  Use of an investigational drug within 4 weeks prior to baseline or 5
                  pharmacokinetic/pharmacodynamics half-lives (whichever is longer)

               -  Prior treatment with apremilast/Otezla®

               -  Receipt of any live (attenuated) vaccine within 28 days prior to baseline

               -  Concomitant use of any other PDE4 inhibitor

               -  Patients with hereditary problems of galactose intolerance, lapp lactase
                  deficiency or glucose-galactose malabsorption

               -  For patients with skin biopsy samples taken: patients with clinically relevant
                  coagulation disorders or medication or known hypersensitivity against local
                  anesthetics.