Study To Assess Efficacy, Safety, Tolerability And Pharmacokinetics Of PF-07038124 Ointment In Participants With Atopic Dermatitis Or Plaque Psoriasis (EMPORIA)

• ClinicalTrials.gov Identifier: NCT04664153
• Recruitment Status: Completed
• First Posted: December 11, 2020
• Results First Posted: August 26, 2022
• Last Update Posted: August 26, 2022
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Study Description

Brief Summary:

This study is being conducted to provide data on efficacy, safety, tolerability and PK of PF-07038124 ointment versus vehicle control in the treatment of mild to moderate AD and mild to moderate plaque psoriasis.

Condition or disease	Intervention/treatment	Phase
Atopic Dermatitis; Plaque Psoriasis	Drug: PF-07038124 ointment; Drug: Vehicle ointment	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 104 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A PHASE 2A, RANDOMIZED, DOUBLE BLIND, VEHICLE CONTROLLED, PARALLEL GROUP STUDY TO ASSESS THE EFFICACY, SAFETY, TOLERABILITY AND PHARMACOKINETICS OF PF-07038124 OINTMENT FOR 6 WEEKS IN PARTICIPANTS WITH MILD TO MODERATE ATOPIC DERMATITIS OR PLAQUE PSORIASIS
• Actual Study Start Date: December 21, 2020
• Actual Primary Completion Date: August 18, 2021
• Actual Study Completion Date: August 18, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: atopic dermatitis - PF-07038124 ointment	Drug: PF-07038124 ointment; PF-07038124 ointment at 0.01% with QD dosing for 6 weeks
Placebo Comparator: atopic dermatitis - vehicle ointment	Drug: Vehicle ointment; Vehicle ointment with QD dosing for 6 weeks
Experimental: plaque psoriasis - PF-07038124 ointment	Drug: PF-07038124 ointment; PF-07038124 ointment at 0.01% with QD dosing for 6 weeks
Experimental: plaque psoriasis - vehicle ointment	Drug: Vehicle ointment; Vehicle ointment with QD dosing for 6 weeks

Outcome Measures

Primary Outcome Measures :

1. Percent Change From Baseline in Eczema Area and Severity Index (EASI) Total Score at Week 6 for AD Participants [ Time Frame: Baseline, Week 6 ]
   EASI evaluated severity of participants' AD (excluded scalp, palms, soles) based on severity of AD clinical signs and % of body surface area (BSA) affected. Severity of clinical signs of AD (erythema, induration/papulation, excoriation and lichenification) scored separately for each of 4 body regions (head and neck, upper limbs, trunk [including axillae and groin] and lower limbs [including buttocks]) on 4-point scale: 0= absent; 1= mild; 2= moderate; 3= severe. EASI area score was based upon % BSA with AD in body region: 0 (0%), 1 (>0 to <10%), 2 (10 to <30%), 3 (30 to <50%), 4 (50 to <70%), 5 (70 to <90%) and 6 (90 to 100%). Total EASI score =0.1*Ah*(Eh+Ih+Exh+Lh) + 0.2*Au*(Eu+Iu+ExU+Lu) + 0.3*At*(Et+It+Ext+Lt) + 0.4*Al*(El+Il+Exl+Ll); A = EASI area score; E = erythema; I = induration/papulation; Ex = excoriation; L = lichenification; h = head and neck; u = upper limbs; t = trunk; l = lower limbs. Total EASI score ranged from 0.0 to 72.0, higher scores = greater severity of AD.
2. Change From Baseline in Psoriasis Area and Severity Index (PASI) Score at Week 6 for Plaque Psoriasis Participants [ Time Frame: Baseline, Week 6 ]
   Combined assessment of lesion severity and area affected into single score. Body was divided into 4 sections: head, arms, trunk, legs. For each section, percent area of skin involved was estimated: 0= 0% to 6= 90-100%. Severity was estimated by clinical signs: erythema, induration, desquamation; scale: 0= none to 4= maximum. Final PASI = sum of severity parameters for each section*area score*weight of section (head: 0.1, arms: 0.2, body: 0.3, legs: 0.4); total possible score range: 0= no disease to 72= maximal disease, where higher scores = greater severity of psoriasis.

Secondary Outcome Measures :

1. Percentage of AD Participants Achieving Investigator's Global Assessment (IGA) Score of Clear (0) or Almost Clear (1) (on a 5-Point Scale) and a Reduction From Baseline of >=2 Points at Week 6 [ Time Frame: Baseline, Week 6 ]
   IGA assessed severity of AD on a 5 point scale (0 to 4, higher scores indicate more severity). Scores: 0= clear, no inflammatory signs of AD; 1= almost clear, AD not fully cleared-light pink residual lesions (except post-inflammatory hyperpigmentation), just perceptible erythema, papulation/induration lichenification, excoriation, and no oozing/crusting; 2= mild AD with light red lesions, slight but definite erythema, papulation/induration, lichenification, excoriation and no oozing/crusting; 3= moderate AD with red lesions, moderate erythema, papulation/induration, lichenification, excoriation and slight oozing/crusting; 4= severe AD with deep dark red lesions, severe erythema, papulation/induration, lichenification, excoriation and moderate to severe oozing/crusting. In this OM, percentages of participants with an IGA score of 0 or 1 and a reduction of >=2 from Baseline in IGA score are reported.
2. Percentage of AD Participants Achieving EASI 75 (75% Improvement From Baseline) at Weeks 1, 2, 4, 6 and Follow-up (FUP)/End of Study (EOS) [ Time Frame: Baseline, Weeks 1, 2, 4, 6 and FUP/EOS (28-35 days post-last dose) ]
   EASI evaluated severity of participants' AD based on severity of AD clinical signs and % of BSA affected. Severity of clinical signs of AD (erythema, induration/papulation, excoriation and lichenification) scored separately for each of 4 body regions (head and neck, upper limbs, trunk and lower limbs) on 4-point scale: 0= absent; 1= mild; 2= moderate; 3= severe. EASI area score was based upon % BSA with AD in body region: 0 (0%), 1 (>0 to <10%), 2 (10 to <30%), 3 (30 to <50%), 4 (50 to <70%), 5 (70 to <90%) and 6 (90 to 100%). Total EASI score =0.1*Ah*(Eh+Ih+Exh+Lh) + 0.2*Au*(Eu+Iu+ExU+Lu) + 0.3*At*(Et+It+Ext+Lt) + 0.4*Al*(El+Il+Exl+Ll); A = EASI area score; E = erythema; I = induration/papulation; Ex = excoriation; L = lichenification; h = head and neck; u = upper limbs; t = trunk; l = lower limbs. Total EASI score ranged from 0.0 to 72.0, higher scores = greater severity of AD. EASI 75 response was defined as at least a 75 percent (%) reduction in EASI relative to Baseline.
3. Percentage of AD Participants Having >=4 Points of Reduction in Weekly Averages of Peak Pruritus Numerical Rating Scale (PP-NRS) From Baseline at Weeks 1, 2, 4 and 6 [ Time Frame: Baseline, Weeks 1, 2, 4 and 6 ]
   The PP-NRS was a daily patient-reported assessment of intensity of pruritus on an 11-point numerical rating scale, ranging from 0 ('No Itch) to 10 ('Worst Itch Imaginable') with a 24 hour recall period. For the PP-NRS score, baseline was defined as the average of all values recorded between Day -7 and Day -1. In this OM, percentages of AD participants with >=4 points of reduction in weekly averages of PP-NRS from baseline are reported (percentage based on number of participants with baseline >=4).
4. Change From Baseline in EASI Total Score at Weeks 1, 2, 4, 6 and FUP/EOS for AD Participants [ Time Frame: Baseline, Weeks 1, 2, 4, 6 and FUP/EOS (28-35 days post-last dose) ]
   EASI evaluated severity of participants' AD (excluded scalp, palms, soles) based on severity of AD clinical signs and % of BSA affected. Severity of clinical signs of AD (erythema, induration/papulation, excoriation and lichenification) scored separately for each of 4 body regions (head and neck, upper limbs, trunk [including axillae and groin] and lower limbs [including buttocks]) on 4-point scale: 0= absent; 1= mild; 2= moderate; 3= severe. EASI area score was based upon % BSA with AD in body region: 0 (0%), 1 (>0 to <10%), 2 (10 to <30%), 3 (30 to <50%), 4 (50 to <70%), 5 (70 to <90%) and 6 (90 to 100%). Total EASI score =0.1*Ah*(Eh+Ih+Exh+Lh) + 0.2*Au*(Eu+Iu+ExU+Lu) + 0.3*At*(Et+It+Ext+Lt) + 0.4*Al*(El+Il+Exl+Ll); A = EASI area score; E = erythema; I = induration/papulation; Ex = excoriation; L = lichenification; h = head and neck; u = upper limbs; t = trunk; l = lower limbs. Total EASI score ranged from 0.0 to 72.0, higher scores = greater severity of AD.
5. Percentage of AD Participants Achieving IGA Score of Clear (0) or Almost Clear (1) at Weeks 1, 2, 4, 6 and FUP/EOS [ Time Frame: Weeks 1, 2, 4, 6 and FUP/EOS (28-35 days post-last dose) ]
   IGA assessed severity of AD on a 5 point scale (0 to 4, higher scores indicate more severity). Scores: 0= clear, no inflammatory signs of AD; 1= almost clear, AD not fully cleared- light pink residual lesions (except post-inflammatory hyperpigmentation), just perceptible erythema, papulation/induration lichenification, excoriation, and no oozing/crusting; 2= mild AD with light red lesions, slight but definite erythema, papulation/induration, lichenification, excoriation and no oozing/crusting; 3= moderate AD with red lesions, moderate erythema, papulation/induration, lichenification, excoriation and slight oozing/crusting; 4= severe AD with deep dark red lesions, severe erythema, papulation/induration, lichenification, excoriation and moderate to severe oozing/crusting. In this OM, percentages of participants with an IGA score of 0 or 1 are reported.
6. Percentage of Psoriasis Participants With Physician Global Assessment (PGA) Score Clear (0) or Almost Clear (1) (on a 5-Point Scale) and >=2 Points Improvement From Baseline at Week 6 [ Time Frame: Baseline, Week 6 ]
   The PGA of psoriasis was scored on a 5-point scale, reflecting a global consideration of the erythema, induration, and scaling across all psoriatic lesions. Average erythema, induration, and scaling were scored separately over the whole body according to a 5-point severity scale (0 [no symptom] to 4 [severe symptom]). The total score was calculated as average of the 3 severity scores and rounded to the nearest whole number score to determine the PGA score and category (0=clear; 1=almost clear; 2=mild; 3=moderate; and 4=severe). PGA response was defined as 0 (clear) or 1 (almost clear). In this OM, percentages of participants with a PGA score of 0 or 1 and an improvement of >=2 from Baseline in PGA score are reported.
7. Percentage of Psoriasis Participants Achieving PASI 75 (75% or Greater Improvement From Baseline) at Weeks 1, 2, 4, 6 and FUP/EOS [ Time Frame: Baseline, Weeks 1, 2, 4, 6 and FUP/EOS (28-35 days post-last dose) ]
   The PASI quantified the severity of a participant's psoriasis based on both, "lesion severity" and the "percent of BSA" affected. PASI was a composite scoring by the investigator of degree of erythema, induration, and scaling (each scored separately) for each of 4 body regions (head and neck, upper limbs, trunk [including axillae and groin], and lower limbs [including buttocks]), with adjustment for the percent of BSA involved for each body region and for the proportion of the body region to the whole body. The PASI score could vary in increments of 0.1 and range from 0.0 to 72.0, with higher scores representing greater severity of psoriasis. PASI 75 response was defined as at least a 75 percent (%) reduction in PASI relative to Baseline.
8. Percentage of Psoriasis Participants Who Achieved a Psoriasis Symptoms Inventory (PSI) Score of 0 (Not at All) or 1 (Mild) on Every Item at Weeks 1, 2, 4, 6 and FUP/EOS [ Time Frame: Weeks 1, 2, 4, 6 and FUP/EOS (28-35 days post-last dose) ]
   PSI was a self-administered 8 item questionnaire that measured the severity of psoriasis symptoms over the past 24 hours and the past 7 days. The measure included concepts of itch, pain, burning, stinging, cracking, scaling, flaking, and redness. Participants were asked to respond to each item using a 5 point Likert response scale: 0: not all severe, 1: mild, 2: moderate, 3: severe and 4: very severe. In this OM, percentages of participants with a PSI score of 0 or 1 on every item at weeks 1, 2, 4, 6 and FUP/EOS are reported.
9. Change From Baseline in PASI Scores at Weeks 1, 2, 4 and FUP/EOS [ Time Frame: Baseline, Weeks 1, 2, 4 and FUP/EOS (28-35 days post-last dose) ]
   Combined assessment of lesion severity and area affected into single score. Body was divided into 4 sections: head, arms, trunk, legs. For each section, percent area of skin involved was estimated: 0= 0% to 6= 90-100%. Severity was estimated by clinical signs: erythema, induration, desquamation; scale: 0= none to 4= maximum. Final PASI = sum of severity parameters for each section*area score*weight of section (head: 0.1, arms: 0.2, body: 0.3, legs: 0.4); total possible score range: 0= no disease to 72= maximal disease, where higher scores = greater severity of psoriasis.
10. Percent Change From Baseline in PASI Scores at Weeks 1, 2, 4, 6 and FUP/EOS [ Time Frame: Baseline, Weeks 1, 2, 4, 6 and FUP/EOS (28-35 days post-last dose) ]
    Combined assessment of lesion severity and area affected into single score. Body was divided into 4 sections: head, arms, trunk, legs. For each section, percent area of skin involved was estimated: 0= 0% to 6= 90-100%. Severity was estimated by clinical signs: erythema, induration, desquamation; scale: 0= none to 4= maximum. Final PASI = sum of severity parameters for each section*area score*weight of section (head: 0.1, arms: 0.2, body: 0.3, legs: 0.4); total possible score range: 0= no disease to 72= maximal disease, where higher scores = greater severity of psoriasis.
11. Percentage of Psoriasis Participants With PGA Score Clear (0) or Almost Clear (1) at Weeks 1, 2, 4, 6 and FUP/EOS [ Time Frame: Weeks 1, 2, 4, 6 and FUP/EOS (28-35 days post-last dose) ]
    The PGA of psoriasis was scored on a 5-point scale, reflecting a global consideration of the erythema, induration, and scaling across all psoriatic lesions. Average erythema, induration, and scaling were scored separately over the whole body according to a 5-point severity scale (0 [no symptom] to 4 [severe symptom]). The total score was calculated as average of the 3 severity scores and rounded to the nearest whole number score to determine the PGA score and category (0=clear; 1=almost clear; 2=mild; 3=moderate; and 4=severe). PGA response was defined as 0 (clear) or 1 (almost clear). In this OM, percentages of participants with a PGA score of 0 or 1 are reported.
12. Percent Change From Baseline in Affected Body Surface Area (BSA) at Weeks 1, 2, 4, 6 and FUP/EOS [ Time Frame: Baseline, Weeks 1, 2, 4, 6 and FUP/EOS (28-35 days post-last dose) ]
    Four body regions were evaluated: head and neck, upper limbs, trunk (including axillae and groin) and lower limbs (including buttocks). Scalp, palms and soles were excluded. BSA was calculated using handprint method. Number of handprints (size of participant's hand with fingers in a closed position) fitting in the affected area of a body region was estimated. Maximum number of handprints were 10 for head and neck, 20 for upper limbs, 30 for trunk and 40 for lower limbs. Surface area of body region equivalent to 1 handprint: 1 handprint was equal to 10% for head and neck, 5% for upper limbs, 3.33% for trunk and 2.5% for lower limbs. Percent BSA for a body region was calculated as = total number of handprints in a body region * % surface area equivalent to 1 handprint. Overall % BSA for an individual: arithmetic mean of % BSA of all 4 body regions, ranges from 0 to 100%, with higher values representing greater severity of AD.
13. Number of Participants With All-Causality Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Day 1 through Week 6 ]
    An adverse event (AE) was any untoward medical occurrence in a clinical investigation where participants administered a product or medical device; the event needed not necessarily have a causal relationship with the treatment or usage. TEAEs were events between first dose of study drug and up to discharge from study that were absent before treatment or that worsened relative to pretreatment state. An SAE was any untoward medical occurrence at any dose that: resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or resulted in congenital anomaly/birth defect.
14. Number of Participants With Vital Signs Data Meeting Pre-defined Criteria [ Time Frame: Day 1 through Week 6 ]
    Abnormality in vital signs: increase and decrease of change of supine diastolic blood pressure from baseline >=20 mmHg, supine systolic blood pressure <90 mmHg, and increase in change of supine systolic blood pressure from baseline >=30 mmHg.
15. Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-defined Criteria [ Time Frame: Day 1 through Week 6 ]
    ECG abnormalities criteria included: value of PR interval >=300 msec, percent change of PR interval >=25/50% and change of corrected QT interval using Fridericia's Formula (QTcF) >=30 msec and <60 msec.
16. Number of Participants With Laboratory Test Abnormalities [ Time Frame: Day 1 through Week 6 ]
    Laboratory parameters included: hematology (hemoglobin, hematocrit, red blood cell, platelet and white blood cell count, neutrophils, eosinophils, monocytes, basophils and lymphocytes), chemistry (blood urea nitrogen, creatinine, sodium, potassium, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, albumin, total protein and serum pregnancy test [for all female participants]) and urine (urine pregnancy test [for all female participants]).
17. Number of Participants With Different Severity Grades in Skin Tolerability at Day 1, Weeks 1, 2, 4, 6, Early Termination (ET) and FUP [ Time Frame: Day 1, Weeks 1, 2, 4, 6, ET and FUP (28-35 days post-last dose) ]
    The investigator or designee assessed tolerability at the site of investigational product application (pre-dose and immediately post-dose). This assessment focused on the treated non-lesional skin using the scale: none = no evidence of local intolerance; mild = minimal erythema and/or oedema, slight glazed appearance; moderate = definite erythema and/or oedema with peeling and/or cracking but needs no adaptation of posology; severe (to be reported as an AE) = erythema, oedema glazing with fissures, few vesicles or papules: consider removing topical agent (if still in place); very severe (to be reported as an AE) = strong reaction spreading beyond the treated area, bullous reaction, erosions: removal of topical agent (if still in place).

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Atopic Dermatitis (AD): Have been diagnosed with AD for at least 3 months; Have an Investigator's Global Assessment (IGA) score of 2 (mild), or 3 (moderate); Have AD covering 5% to 20% (inclusive) of BSA.
• Plaque psoriasis: Have been diagnosed with plaque psoriasis (psoriasis vulgaris) for at least 6 months; Have a Physician Global Assessment (PGA) score of 2 (mild), or 3 (moderate); Having plaque psoriasis covering 5% to 15% (inclusive) of BSA.

Exclusion Criteria:

• Presence of skin comorbidities that would interfere with study assessment or response to treatment.
• Current or recent history of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, metabolic, endocrine, pulmonary, cardiovascular, or neurological disease.
• Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study.

Contacts and Locations

Locations

United States, California

First OC Dermatology

Fountain Valley, California, United States, 92708

United States, Florida

Renaissance Research and Medical Group

Cape Coral, Florida, United States, 33991

Olympian Clinical Research

Clearwater, Florida, United States, 33756

Moonshine Research Center, Inc.

Doral, Florida, United States, 33166

Clinical Neuroscience Solutions

Orlando, Florida, United States, 32801

Center for Clinical Studies

Tampa, Florida, United States, 33613

United States, Indiana

Dawes Fretzin Clinical Research Group, LLC

Indianapolis, Indiana, United States, 46250

The Indiana Clinical Trials Center, PC

Plainfield, Indiana, United States, 46168

United States, Michigan

Henry Ford Medical Center, New Center One

Detroit, Michigan, United States, 48202

United States, North Carolina

M3 Wake Research, Inc.

Raleigh, North Carolina, United States, 27612

United States, Oregon

Oregon Dermatology and Research Center

Portland, Oregon, United States, 97210

United States, Tennessee

Clinical Neuroscience Solutions, Inc. dba CNS Healthcare

Memphis, Tennessee, United States, 38119

United States, Texas

studies in Dermatology, LLC

Cypress, Texas, United States, 77433

Center for Clinical Studies

Houston, Texas, United States, 77004

Center for Clinical Studies, LTD. LLP

Webster, Texas, United States, 77598

Australia, New South Wales

Australian Clinical Research Network

Maroubra, New South Wales, Australia, 2035

Australia, Victoria

Emeritus Research

Camberwell, Victoria, Australia, 3124

Canada, Ontario

Dermatrials Research Inc.

Hamilton, Ontario, Canada, L8N 1Y2

Lynderm Research Inc.

Markham, Ontario, Canada, L3P 1X3

DermEdge Research

Mississauga, Ontario, Canada, L5H 1G9

Canada, Quebec

Innovaderm Research Inc.

Montréal, Quebec, Canada, H2X 2V1

Canada

Centre de Recherche Dermatologique du Quebec metropolitain

Quebec, Canada, G1V 4X7

Poland

NZOZ Specjalistyczny Osrodek Dermatologiczny DERMAL

Bialystok, Poland, 15-453

Mazowieckie Centrum Badań Klinicznych

Grodzisk Mazowiecki, Poland, 05-825

Centrum Medyczne Angelius Provita

Katowice, Poland, 40-611

Centrum Terapii Wspolczesnej J. M. Jasnorzewska Spolka Komandytowo-Akcyjna

Lodz, Poland, 90-242

Dermedic Jacek Zdybski

Ostrowiec Swietokrzyski, Poland, 27-400

Kliniczny Szpital Wojewódzki nr 1 im. F. Chopina w Rzeszowie

Rzeszow, Poland, 35-055

ETG Warszawa

Warszawa, Poland, 02-793

Sponsors and Collaborators

Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

  Study Documents (Full-Text)

Documents provided by Pfizer:

Study Protocol  [PDF] August 19, 2020

Statistical Analysis Plan  [PDF] June 16, 2021

More Information

Additional Information:

To obtain contact information for a study center near you, click here. 

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT04664153
• Other Study ID Numbers: C3941002; 2020-003977-23 ( EudraCT Number )
• First Posted: December 11, 2020
• Results First Posted: August 26, 2022
• Last Update Posted: August 26, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
• URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Pfizer:

atopic dermatitis, plaque psoriasis

Additional relevant MeSH terms:

Dermatitis, Atopic; Psoriasis; Dermatitis; Eczema; Skin Diseases, Papulosquamous; Skin Diseases; Skin Diseases, Genetic; Genetic Diseases, Inborn; Skin Diseases, Eczematous; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases