Efficacy of Alitretinoin Treatment in Patients With Pustular Form of Psoriasis

Study Overview
=================
Brief Summary
-----------------
The main purpose of this study is to demonstrate the improvement in the skin condition rate of patients receiving alitretinoin compared to patients receiving placebo.

Detailed Description
-----------------
Palmo-plantar pustulosis (PPP) is an inflammatory skin disease affecting palms and soles. The disease is considered as a sub-form of psoriasis and presents with sterile pustules of the palms and the soles. This study investigates the efficacy of alitretinoin in patients who have not responded to topical drugs (e.g., steroid creams), who are suffering for at least 6 month from the condition and whose disease severity is confirmed by a score.

Official Title
-----------------
Efficacy of Oral Alitretinoin Treatment in Patients With Palmo-plantar Pustulosis (PPP) Inadequately Responding to Standard Topical Treatment

Conditions
-----------------
Psoriasis

Intervention / Treatment
-----------------
* Drug: alitretinoin
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea and a follicle stimulating hormone concentration of ≥40 international units (IU)/L. Child-bearing potential with negative pregnancy test as determined by human chorionic gonadotropin (hCG) test at screening or prior to dosing and either 1) agrees to use a medically acceptable contraception method for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point and continue contraception until the end of the study, or 2) has only same-sex partners, when this is her preferred and usual lifestyle. Capable of understanding and willing to provide signed and dated written voluntary informed consent (and any local or national authorization requirements) before any protocol specific procedures are performed. Male or female aged at least 18 years at time of consent and at time of first dose. Have PPP for at least 6 months, with or without psoriasis lesions on other areas of the skin A PPPASI score of at least 8 with involvement of at least 10% of the palms and/or the soles Refractory to standard topical corticosteroid therapy Exclusion Criteria: Unable to comply with the requirement of the study Female subjects who are pregnant or who plan to become pregnant or who are breast feeding Subjects whose disease is adequately controlled by standard non-medicated therapy (skin moisturizing and protection) Known hypersensitivity to other retinoids or vitamin A derivatives, or to any study medication component, especially soybean oil and partly hydrogenated soybean oil Treated with any of the following treatments 4 weeks before the start of study treatment: systemic drugs: corticosteroids, immunosuppressants, methotrexate phototherapy: ultraviolet B light therapy [UVB], psoralen with ultraviolet A combination therapy [PUVA], Grenz rays, X-rays Treated with biologic treatments within 6 weeks prior to start of study treatment. Abnormal hematology Treated with any systemic or topical retinoids within 3 months or 1 month, respectively, before start of study treatment Treated with high-potency topical corticosteroids within 2 weeks before the start of study treatment Severe generalized pustular psoriasis A skin condition of palms and/or soles that interferes with the diagnosis of PPP by the investigator Any condition that, in the judgment of the investigator, would put the subject at unacceptable risk for participation in the study. Hepatic insufficiency, severe renal failure, uncontrolled hypercholesterolemia as characterized by: AST/ ALT >2.5 x upper limit of normal (ULN) Creatinine clearance <60 mL/min (calculated, Cockcroft-Gault) Fasting triglyceridemia >1.5 x upper limit of normal (ULN) Fasting cholesterol >1.5 x ULN Fasting low-density lipoprotein (LDL) cholesterol >1.5x ULN Subjects with hypothyroidism as indicated by thyroid stimulating hormone (TSH) above ULN and thyroxine (T4) test below LLN or hypervitaminosis A Subjects with unstable cardiac disease or poorly controlled cardiovascular risk factors, for example: Acute coronary syndrome or coronary revascularization (percutaneous coronary intervention [PCI], coronary artery bypass graft [CABG]) within 3 months before start of study treatment Poorly controlled diabetes mellitus (HbA1c >8.5%) Systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥100 mm Hg at the screening examination Subjects receiving drugs with a potential for drug-drug interaction, such as systemic tetracyclines, ketoconazole, or St. John's Wort within 1 week, or receiving systemic itraconazole within 2 weeks, before start of study treatment Subjects included in the study of an investigational drug within 2 months before start of study treatment (3 months for biologics) Subjects with a score of 20 or more on the Center for Epidemiologic Studies Depression scale (CES-D), or with active major psychiatric disorder (eg, Major Depressive Disorder, Generalized Anxiety Disorder, Bipolar Disorder [I or II], or schizophrenia) Subjects who score a 4 or 5 for the previous 30 days on the Columbia Suicide Severity Rating Scale (CSSRS) at Screening or Baseline Subjects who have made a suicide attempt within the 6 months preceding the Screening or Baseline visits

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active<br>to receive study drug (alitretinoin, 20 patients) | Drug: alitretinoin<br>* to receive verum (20 patients)<br>* Other names: Toctino;|
| Placebo Comparator: Placebo<br>to receive placebo (dummy drug, 10 patients) | Drug: Placebo<br>* to receive placebo (10 patients)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Palmo-plantar Pustulosis Psoriasis Area and Severity Index (PPPASI) Score at the End of Treatment (EOT) (Week 24) or at the Last Assessment | The investigator evaluated the PPPASI score on a 5-point scale. The parameters of erythema, total number of pustules, and desquamation were scored for the right/left palm and the right/left sole. After correcting the scores for area (based on a 7-point scale) and the site involved (palm or sole), the PPPASI score per palm/sole was produced. The final PPPASI score was calculated as the sum of the PPPASI score for the right sole + the PPPASI score for the left sole + the PPPASI score for the right palm + the PPPASI score for the left palm and ranges from 0 (no palmo-plantar pustulosis psoriasis [PPP]) to 72 (most severe PPP). Change from Baseline is defined as value at the EOT minus the Baseline value. | Baseline and EOT (Week 24) or the last assessment | 
| Number of Participants With PPPASI 50 Response and PPPASI 75 Response | The investigator evaluated the PPPASI score on a 5-point scale. The parameters of erythema, total number of pustules, and desquamation were scored for the right/left palm and the right/left sole. After correcting the scores for area (based on a 7-point scale) and the site involved (palm or sole), the PPPASI score per palm/sole was produced. The final PPPASI score was calculated as the sum of the PPPASI score for the right sole + the PPPASI score for the left sole + the PPPASI score for the right palm + the PPPASI score for the left palm and ranges from 0 (no palmo-plantar pustulosis psoriasis [PPP]) to 72 (most severe PPP). Change from Baseline is defined as value at the EOT minus the Baseline value. PPPASI 50 response and PPPASI 75 response are defined as a 50% and 75% decrease, respectively, in the PPPASI score from Baseline. | From Baseline until EOT (Week 24) or the last assessment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Pustule Count at Baseline; Weeks 4, 8, 12, 16, and 20; and at EOT (Week 24) | The overall number of fresh and older pustules on the left and right palms and soles was assessed at Baseline, at each visit during the treatment period (Weeks 4, 8, 12, 16, and 20), and at the EOT visit. The total pustule count was calculated as the sum of the pustule count for the left/right palm and left/right sole. | Baseline; Weeks 4, 8, 12, 16, and 20; and EOT (Week 24) | 
| Absolute Change From Baseline (BL) in Total Pustule Count at Weeks 4, 8, 12, 16, and 20 and at EOT (Week 24) | The overall number of fresh and older pustules on the left and right palms and soles was assessed at Baseline, at each visit during the treatment period (Weeks 4, 8, 12, 16, and 20), and at the End of Treatment visit. The total pustule count was calculated as the sum of the pustule count for the left/right palm and left/right sole. Change from Baseline is defined as the value at the post-Baseline visit minus the Baseline value. | Baseline; Weeks 4, 8, 12, 16, and 20; and EOT (Week 24) | 
| Mean Modified Psoriasis Area Severity Index (mPASI) Score at Baseline; Weeks 4, 8, 12, 16, and 20; and EOT (Week 24) | Psoriatic plaques were graded based on three criteria: redness (R), thickness (T), and scaliness (S). Severity was rated for each criterion on a 5-point scale (0=no involvement, up to 4=severe involvement). Fraction of the total surface area affected on the head, upper extremities, trunk, and lower extremities was graded on a 7-point scale (0=no involvement, up to 6=greater than 90% involvement). The four body regions were weighted to reflect their respective proportion of body surface area, and the composite mPASI score for all body regions was calculated based on the redness, thickness, and scaliness scores of plaques (0-4 each) for the head, upper extremities, trunk, and lower extremities and the area of psoriatic involvement score (0-6). The lowest possible mPASI score was zero and highest up to 72; Higher score values represents greater severity of psoriasis. mPASI scores were continuous, with 0.1 increments within these values. | Baseline; Weeks 4, 8, 12, 16, and 20; and EOT (Week 24) | 
| Change From Baseline in the mPASI Score at EOT (Week 24) or at the Last Assessment | Psoriatic plaques were graded based on three criteria: redness (R), thickness (T), and scaliness (S). Severity was rated for each criterion on a 5-point scale (0=no involvement, up to 4=severe involvement). Fraction of the total surface area affected on the head, upper extremities, trunk, and lower extremities was graded on a 7-point scale (0=no involvement, up to 6=greater than 90% involvement). The four body regions were weighted to reflect their respective proportion of body surface area, and the composite mPASI score for all body regions was calculated based on redness, thickness, and scaliness scores of plaques (0-4 each) for head, upper extremities, trunk, lower extremities and area of psoriatic involvement score (0-6). Lowest possible mPASI score was 0 and highest up to 72; Higher score values represents greater severity of psoriasis. mPASI scores were continuous, with 0.1 increments within these values. Change from Baseline is defined as the value at EOT minus baseline value. | Baseline and EOT (Week 24) or the last assessment | 
| Number of Participants With mPASI 50 Response and mPASI 75 Response | Psoriatic plaques were graded based on three criteria: redness (R), thickness (T), and scaliness (S). Severity was rated for each criterion on a 5-point scale (0=no involvement, up to 4=severe involvement). The fraction of the total surface area affected on the head, upper extremities, trunk, and lower extremities was graded on a 7-point scale (0=no involvement, up to 6=greater than 90% involvement). The four body regions were weighted to reflect their respective proportion of body surface area, and the composite mPASI score for all body regions was calculated. mPASI 50 response and mPASI 75 response is defined as a 50% and 75% decrease, respectively, in the mPASI score from Baseline. | From Baseline until EOT (Week 24) | 
| Mean Nail Psoriasis Severity Index (NAPSI) Score for Nail Bed Psoriasis and Nail Matrix Psoriasis at Baseline, Week 12, and EOT (Week 24) | The severity of nail lesions was assessed for all participants with psoriatic nail involvement by obtaining the NAPSI score. Scores were taken for fingernails only. No scores were taken for participants with traumatic or fungal changes in nails. The nail was divided into four quadrants, each of which was rated with a 0 or 1, based on the absence (0) or presence (1) of pathological signs resulting from involvement of both the nail matrix and the nail bed. Each nail was given a score for nail bed psoriasis (0-4) and nail matrix psoriasis (0-4) depending on the presence of nail psoriasis in that quadrant. Possible scores for matrix and nail bed psoriasis: 0=none, 1=present in 1/4 nail, 2=present in 2/4 nail, 3=present in 3/4 nail, 4=present in 4/4 nail. NAPSI score for nail matrix (0-4) and nail bed (0-4) were reported at Baseline, Week 12, and at the EOT visit (Week 24). | Baseline, Week 12, and EOT (Week 24) | 
| Absolute Change From Baseline in NAPSI Score for Nail Bed Psoriasis and Nail Matrix Psoriasis at Week 12, and EOT (Week 24) | The severity of nail lesions was assessed for all participants with psoriatic nail involvement by obtaining the NAPSI score. Scores were taken for fingernails only. No scores were taken for participants with traumatic or fungal changes in nails. The nail was divided into four quadrants, each of which was rated with a 0 or 1, based on the absence (0) or presence (1) of pathological signs resulting from involvement of both the nail matrix and the nail bed. Each nail was given a score for nail bed psoriasis (0-4) and nail matrix psoriasis (0-4) depending on the presence of nail psoriasis in that quadrant. Possible scores for matrix and nail bed psoriasis: 0=none, 1=present in 1/4 nail, 2=present in 2/4 nail, 3=present in 3/4 nail, 4=present in 4/4 nail. NAPSI score for nail matrix (0-4) and nail bed (0-4) were reported at Baseline, Week 12, and at the EOT visit (Week 24). Change from Baseline is defined as the value at the post-Baseline visit minus the Baseline value. | Baseline, Week 12, and EOT (Week 24) | 
| Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) and an AE/SAE Related to Study Treatment | An AE was any adverse change from the participant's Baseline (pre-treatment) clinical condition, including intercurrent illness, which occurred during the course of a clinical study after written informed consent had been given, whether considered related to treatment or not. The relationship of AEs to the study treatment was assessed as unrelated, remotely related, possibly related, and probably related. For an AE to be considered serious, it fell into one or more of the following categories: results in death, is life threatening, results in persistent or significant disability/incapacity, results in or prolongs inpatient hospitalization, and is a congenital abnormality or birth defect. | From Baseline until safety follow up (Week 29) | 
| Absolute Change From Baseline in Fasted Lipid Laboratory Test Values at Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and at Safety Follow-up (Week 29) | Fasted lipid laboratory parameters included triglycerides, total cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. Change from Baseline is defined as the value at the post-Baseline visit minus the Baseline value. | Baseline; Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and safety follow-up (Week 29) | 
| Absolute Change From Baseline in Fasted LDL/HDL Ratio at Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and at Safety Follow-up (Week 29) | Change from Baseline is defined as the value at the safety follow up visit minus baseline value. | Baseline; Weeks 4, 8, 12, 16, and 20; EOT (Week 24) and safety follow-up (Week 29) | 
| Number of Participants With the Indicated Shift in the Indicated Laboratory Values From Baseline (BL) to EOT (Week 24) | Laboratory parameters included triglycerides, total cholesterol, HDL cholesterol, LDL cholesterol, LDL/HDL ratio, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and amylase and lipase. The central laboratory classified a finding as either abnormal or normal. | From Baseline until EOT (Week 24) | 
| Mean Center for Epidemiological Studies Depression Scale (CES-D) Scores at Screening; Baseline; Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and Safety Follow-up (Week 29) | The CES-D scale is a short, self-report scale designed to measure depressive symptomatology in the general population. The CES-D consists of 20 questions. Participants were instructed to circle the number for each statement that best described how often they felt or behaved a particular way during the past week. The score was the sum of the weights of the 20 items. Responses range from 0 to 3 for each item (0=rarely or none of the time, 1=some or little of the time, 2=moderately or much of the time, 3=most or almost all the time). The CES-D score ranges from 0 to 60, with higher scores indicating greater depression. Participants with a CES-D score of 20 or higher were re-evaluated within 2 weeks. If a CES-D score of 20 or higher was confirmed on the second occasion, and if the score represents an increase over Baseline of 4 points or more, study treatment was interrupted and the participants were referred for psychiatric evaluation. | Screening; Baseline; Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and safety follow-up (Week 29) | 
| Absolute Change From Baseline (BL) in CES-D Scores at Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and Safety Follow-up (Week 29) | The CES-D scale is a short, self-report scale designed to measure depressive symptomatology in the general population. The CES-D consists of 20 questions. Participants were instructed to circle the number for each statement that best described how often they felt or behaved a particular way during the past week. The score was the sum of the weights of the 20 items. Responses range from 0 to 3 for each item (0=rarely or none of the time, 1=some or little of the time, 2=moderately or much of the time, 3=most or almost all the time). The CES-D score ranges from 0 to 60, with higher scores indicating greater depression. Participants with a CES-D score of >=20 were re-evaluated within 2 weeks. If a CES-D score of >=20 was confirmed on the second occasion, and if the score represents an increase over BL of 4 points or more, study treatment was interrupted and the participants were referred for psychiatric evaluation. Change from BL is defined as the post-BL value minus the BL value. | Baseline; Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and safety follow-up (Week 29) | 
| Mean Columbia Suicide Severity Rating Scale (CSSRS) Scores at Screening; Baseline; Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and Safety Follow-up (Week 29) | The assessment of suicidality was conducted using the CSSRS, a brief questionnaire designed to assess severity and change in suicidality using a semi-structured interview to probe participant responses. The suicidal ideation intensity total score was the sum of suicidal ideation severity rating scores for frequency, duration, controllability, deterrents, and reasons for ideation. For each item, each participant got an intensity score from 0(none) to 5(worst). Therefore, the suicidal ideation intensity total score range from 0 to 25, with a score of 0 given for no suicidal ideation. CSSRS scores were reported at Screening; Baseline; Week 4, 8, 12, 16, 20; EOT (Week 24);and safety follow-up (Week 29). | Screening; Baseline; Weeks 4, 8, 12, 16, and 20; EOT (Week 24), and safety follow-up (Week 29) | 
| Absolute Change From Baseline in the CSSRS Score at Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and Safety Follow-up (Week 29) | The assessment of suicidality was conducted using the CSSRS, a brief questionnaire designed to assess severity and change in suicidality using a semi-structured interview to probe participant responses. The suicidal ideation intensity total score was the sum of suicidal ideation severity rating scores for frequency, duration, controllability, deterrents, and reasons for ideation. For each item, each participant got an intensity score from 0(none) to 5(worst). Therefore, the suicidal ideation intensity total score range from 0 to 25, with a score of 0 given for no suicidal ideation. CSSRS scores were reported at Baseline; Week 4, 8, 12, 16, 20; EOT (Week 24); and safety follow-up (Week 29). Change from Baseline is defined as the value at the post-Baseline visit minus the Baseline value. | Baseline; Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and safety follow-up (Week 29) | 
| Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Screening, Baseline, and EOT (Week 24) | SBP and DBP were assessed at Screening, Baseline, and EOT. | Screening, Baseline, and EOT (Week 24) | 
| Mean Heart Rate (HR) at Baseline, Screening, and EOT (Week 24) | HR is defined as the rate at which the heart beats. | Screening, Baseline, and EOT (Week 24) | 
| Mean Body Weight at Screening, Baseline ,and EOT (Week 24) | Body weight was measured at Screening, Baseline, and EOT. | Screening, Baseline, and EOT (Week 24) | 
| Change From Baseline in SBP and DBP at EOT (Week 24) | Change from Baseline is defined as the value at EOT minus the Baseline value. | Baseline and EOT (Week 24) | 
| Change From Baseline in Heart Rate at EOT (Week 24) | HR is defined as the rate at which the heart beats. Change from Baseline is defined as the value at EOT minus the Baseline value. | Baseline and EOT (Week 24) | 
| Change From Baseline in Weight at EOT (Week 24) | Change from Baseline is defined as the value at EOT minus the value at Baseline. | Baseline and EOT (Week 24) | 
| Number of Participants With Normal/Abnormal Physical Status at Baseline With a Worst Post-Baseline Finding of Normal/Abnormal | A physical examination for each participant was performed at Baseline and at EOT (Week 24). The primary investigator classified physical status as either normal or abnormal. | Baseline and EOT (Week 24) | 
| Number of Participants With a Negative Serum Pregnancy Test at Screening; Baseline; Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and Safety Follow-up (Week 29) | Serum pregnancy tests were performed at each visit for females of childbearing potential. | Screening; Baseline; Weeks 4, 8, 12, 16, and 20; EOT (Week 24); safety follow-up (Week 29) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Palmo-Plantar Pustolosis