Apremilast in Patients With Moderate to Severe Palmoplantar Pustulosis (PPP) (APLANTUS)

Palmoplantar Pustulosis Clinical Trial

— APLANTUS  

Official title:

A Multicenter, Open Label, Single-arm Pilot Study to Evaluate the Efficacy and Safety of Oral Apremilast in Patients With Moderate to Severe Palmoplantar Pustulosis (PPP) (APLANTUS)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04572997
• Other study ID #: 069-008.
• Secondary ID: 2016-005122-11
• Status: Completed
• Phase: Phase 2
• Start date: November 29, 2018
• Est. completion date: August 29, 2019

Study information

• Verified date: September 2021
• Source: Universitätsklinikum Hamburg-Eppendorf
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

This was a multicenter, open-label, single-arm, phase II, pilot study to evaluate the efficacy and safety of apremilast involving 21 patients with PPP. The screening period was up to 4 weeks and treatment took place over 20 weeks per patient. No follow up period took place. No extension was done.

Recruitment period was 4 months; hence study duration from first patient in to last patient out was approximately 9 months. About 4-6 patients per center were recruited, assuming enrolment of both genders with distribution according to prevalence of condition.

Patient recruitment took place at 5 centers in Germany. The investigators had relevant expertise in diagnosing and treating PPP or were specialized in dermatology. Patients were enrolled until approximately 20 patients were included into the study. One drop-out was replaced during the recruitment phase.

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

• Visit 5 at week 20 (end of study)

After the end of study participation the investigator ensured that the patient received a suitable therapy appropriate to patient's condition.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 21
• Est. completion date: August 29, 2019
• Est. primary completion date: August 29, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Palmoplantar Pustulosis
• Psoriasis

Intervention

Drug:
• Apremilast
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.

Locations

Country	Name	City	State
Germany	University Hospital Bonn	Bonn
Germany	Universitätsmedizin Göttingen / Georg-August-Universität Department for Dermatology, Venereology and Allergology	Göttingen
Germany	SCIderm GmbH	Hamburg-Harburg
Germany	Universitätsklinik Schleswig-Holstein, Campus Kiel, PSORIASIS-ZENTRUM KIEL, Klinik für Dermatologie, Venerologie und Allergologie	Kiel
Germany	Universitätsklinikum Münster Klinik für Hautkrankheiten	Münster

Sponsors (1)

Lead Sponsor	Collaborator
Kristian Reich

Country where clinical trial is conducted

Germany, 

References & Publications (1)

Wilsmann-Theis D, Kromer C, Gerdes S, Linker C, Magnolo N, Sabat R, Reich K, Mössner R. A multicentre open-label study of apremilast in palmoplantar pustulosis (APLANTUS). J Eur Acad Dermatol Venereol. 2021 Jun 2. doi: 10.1111/jdv.17441. [Epub ahead of pr — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Hand and Feet Physician Global Assessment (H&F PGA)	The H&F PGA describes the severity of psoriasis on the hands and/or feet using five categories ranging from 0 (clear) to 4 (severe).	At Visit 2 (Baseline), Visit 3 (Week 4) , Visit 4 (Week 12) and Visit 5 (Week 20).
Other	Pustules Count Percent Change From Baseline	Percentage change from baseline in Pustules count after 20 weeks of treatment with Apremilast	At Visit 2 (Baseline) and Visit 5 (End of Study - Week 20)
Other	Number of Participants With Pustules Count 50 and 75 Response	Patients experiencing a 50% and 75% decrease in Pustules count from baseline	At Visit 3 (Week 4), Visit 4 (Week 12) and Visit 5 (End of Study-Week 20).
Other	Visual Analogue Scale (VAS) Discomfort/Pain	VAS was used to assess discomfort/pain. The patient was asked to place a vertical stroke on a 100 mm VAS on which the left-hand boundary represented no discomfort/pain (at 0 mm), and the right-hand boundary (at 100 mm) represented discomfort/pain as severe as can be imagined. The distance from the mark to the left-hand boundary was recorded, with higher values indicating more discomfort/pain (worse conditions).	At Visit 2 (Baseline), Visit 3 (Week 4), Visit 4 (Week 12) and Visit 5 (End of Study - Week 20).
Other	Visual Analogue Scale (VAS) Pruritus/Itch	VAS was used to assess pruritus/itch. The patient was asked to place a vertical stroke on a 100 mm VAS on which the left-hand boundary (at 0 mm) represented no pruritus/itch, and the right-hand boundary (at 100 mm) represented pruritus/itch as severe as can be imagined. The distance from the mark to the left-hand boundary was recorded, with higher values indicating more pruritus/itch (worse outcomes).	At Visit 2 (Baseline), Visit 3 (Week 4), Visit 4 (Week 12) and Visit 5 (End of Study - Week 20).
Other	Psoriasis Area and Severity Index (PASI)	The PASI is a measure of psoriatic disease severity taking into account qualitative lesion characteristics (erythema, thickness, and scaling) and degree of skin surface area involvement on defined anatomical regions. PASI scores range from 0 to 72, with higher scores reflecting greater disease severity. Erythema, thickness, and scaling are scored on a scale of 0 (none) to 4 (very severe) on 4 anatomic regions of the body: head, trunk, upper limbs, and lower limbs. Degree of involvement on each of the 4 anatomic regions is scored on a scale of 0 (no involvement) to 6 (90% to 100% involvement). The total qualitative score (sum of erythema, thickness, and scaling scores) is multiplied by the degree of involvement for each anatomic region and then multiplied by a constant. These values for each anatomic region are summed to yield the PASI score.	At Visit 2 (Baseline), Visit 3 (Week 4), Visit 4 (Week 12) and Visit 5 (End of Study - Week 20).
Other	Dynamic H&F PGA	The dynamic H&F PGA describes the global improvement compared with baseline. It relies on the physician's memory of the baseline severity to evaluate the level of alteration. The categories vary between 0 (cleared) and 6 (worse).	At Visit 3 (Week 4), Visit 4 (Week 12) and Visit 5 (End of Study - Week 20).
Primary	Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) at Week 20 Compared With Baseline	The PPPASI assess palms of hands and soles of feet for psoriasis involvement. The PPPASI score range from 0-72, with higher scores indicating more severe disease.	PPPASI Score at baseline and Week 20.
Secondary	Number of Participants With PPPASI 50 Response	PPPASI 50 response defined as a 50% decrease in PPPASI from baseline.	At Visit 3 (Week 4), Visit 4 (Week 12) and Visit 5 (Week 20).
Secondary	Number of Participants With PPPASI 75 Response	PPPASI 75 response defined as a 75% decrease in PPPASI from baseline.	At Visit 3 (Week 4), Visit 4 (Week 12) and Visit 5 (Week 20).
Secondary	Dermatology Life Quality Index (DLQI)	The DLQI is a dermatology-specific quality of life instrument designed to assess the impact of a disease on the patient's daily life which is also validated for PPP. It is a 10-item questionnaire and can be used to assess 6 different aspects: symptoms and feelings, leisure, daily activities, work or school performance, personal relationship and treatment. The DLQI was calculated by summing the score of each question resulting in a maximum of 30 and a minimum of 0. The higher the score, the more quality of life was impaired.; Meaning of DLQI scores: 0 to 1 = No effect at all on patient's life; 2 to 5 = Small effect on patient's life; 6 to 10 = Moderate effect on patient's life; 11 to 20 = Very large effect on patient's life; 21 to 30 = Extremely large effect on patient's life	At Visit 2 (Baseline), Visit 4 (Week 12) and Visit 5 (Week 20).