A Study of the Impact of Apremilast (CC-10004) on Quality of Life, Efficacy, and Safety in Adults With Manifestations of Plaque Psoriasis and Impaired Quality of Life

Phase 4

Completed

Conditions: Psoriasis

Interventions: Drug: Apremilast
Drug: Placebo

Registration Number: NCT03774875

Lead Sponsor: Amgen

Brief Summary: The primary objective of the study is to assess the impact of treatment with apremilast 30 mg twice daily for 16 weeks, compared to placebo, on health-related quality of life (QOL) in adults with manifestations of plaque psoriasis and impaired quality of life.

Detailed Description: Participants will be randomized 2 (apremilast):1 (placebo) in approximately 10 countries in Western Europe. Participants will be block-randomized to each of the manifestations of psoriasis (scalp psoriasis, nail psoriasis, palmoplantar psoriasis, genital psoriasis, and psoriasis in visible locations). Participants presenting with multiple manifestations will be allocated to the manifestation which is most severe, as determined by the participant. All manifestations will be assessed for efficacy at each study visit.

The study will consist of 4 phases:

* Screening Phase - up to 5 weeks (35 days)

* Double-blind Placebo-controlled Phase - Weeks 0 to 16 Participants will receive treatment with either apremilast or matched placebo.

* Apremilast Extension Phase - Weeks 16 through 52 All participants will be switched to (or continue with) apremilast at week 16 and will maintain this dosing through week 52.

* Post-treatment Observational Follow-up Phase 4-week post-treatment observational follow-up phase for all participants who complete the study on treatment or discontinue from the study treatment early.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 277

Inclusion Criteria

Subjects must satisfy the following criteria to be enrolled in the study:

Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).
Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
Subject has diagnosis of chronic plaque psoriasis for at least 6 months prior to baseline, that cannot be controlled by topical therapy.
Subject has a PASI score ranging from ≥ 3 to ≤ 10 at baseline.
Subject has a DLQI score > 10 at baseline.
Subject has presence of ≥ 1 clinical manifestations of plaque psoriasis, defined as at least one of the following:
1. Moderate to severe scalp psoriasis, defined as Scalp Physician Global Assessment (ScPGA) ≥ 3
2. Nail psoriasis, defined as onycholysis and onychodystrophy in at least 2 fingernails
3. Moderate to severe genital plaque psoriasis, defined as modified static Physicians Global Assessment of Genitalia (sPGA-G) ≥ 3
4. Moderate to severe palmoplantar psoriasis, defined as Palmoplantar Psoriasis Physicians Global Assessment (PPPGA) ≥ 3
5. Moderate to severe plaque psoriasis in visible locations (dorsal hand, face, neck, and hairline) with static Physicians Global Assessment (sPGA) ≥ 3
Subject must be in general good health (except for psoriasis) as judged by the Investigator, based on medical history, physical examination, and clinical laboratories.

(NOTE: The definition of good health means a subject does not have uncontrolled significant co-morbid conditions.)
Subject must have failed to respond to, or be contraindicated to, or intolerant to other systemic therapy, including, but not limited to, cyclosporine, methotrexate, acitretin, psoralen and ultraviolet-A-light (PUVA) fumaric acid esters or biologic therapies.
Subjects (in Italy only) must be non-responder to, contraindicated to, or intolerant to other systemic therapy (including cyclosporine, methotrexate, or PUVA) AND also be contraindicated to, or intolerant to biologics.
Females of childbearing potential (FCBP) must have a negative pregnancy test at Screening and Baseline. While on investigational product and for at least 28 days after taking the last dose of investigational product, FCBP who engage in activity in which conception is possible must use one of the approved contraceptive options described below:

Option 1: Any one of the following highly effective methods: hormonal contraception (oral, injection, implant, transdermal patch, vaginal ring); intrauterine device (IUD); tubal ligation; or partner's vasectomy; OR Option 2: Male or female condom (latex condom or nonlatex condom NOT made out of natural [animal] membrane [for example, polyurethane]) PLUS one additional barrier method: (a) diaphragm with spermicide; (b) cervical cap with spermicide; or (c) contraceptive sponge with spermicide.

NOTE: Option 2 may not be acceptable as a highly effective contraception option in all countries per local guidelines/regulations.

Exclusion Criteria

The presence of any of the following will exclude a subject from enrollment:

Subject has any condition, including other inflammatory diseases or dermatologic conditions, which confounds the ability to interpret data from the study, including other types of psoriasis (ie, erythrodermic, or guttate), other than plaque psoriasis or inverse psoriasis.
Subject has history of drug-induced psoriasis.
Subject has arthritis that requires systemic treatment.
Subject unable to avoid use of tanning booths for at least 4 weeks prior to baseline and during study.
Subject is currently enrolled in any other clinical trial involving an investigational product.
Other than psoriasis, subject has history of clinically significant or uncontrolled disease (as determined by the Investigator), including the presence of laboratory abnormalities, cardiac, endocrinologic, pulmonary, neurologic, psychiatric, hepatic, renal, hematologic, immunologic disease, or other major disease, which places the subject at unacceptable risk if he/she were to participate in the study
Prior history of suicide attempt at any time in the subject's lifetime prior to signing the informed consent, or major psychiatric illness requiring hospitalization within the last 3 years prior to signing the informed consent.
Subjects with severe renal impairment, defined by estimated glomerular filtration rate (eGFR) or creatinine clearance (CLcr) less than 30 mL/min, are also categorized as having Stage 4 chronic kidney disease (CKD), and are excluded from the study.
Malignancy or history of malignancy or myeloproliferative or lymphoproliferative disease within the past 3 years, except for treated (ie, cured) basal cell or squamous cell in situ skin carcinomas.
Bacterial infections requiring treatment with oral or injectable antibiotics, or significant viral or fungal infections, within 4 weeks of Screening. Any treatment for such infections must have been completed and the infection cured, at least 4 weeks prior to Screening and no new or recurrent infections prior to the Baseline Visit.
Subject has received a live vaccine within 3 months of baseline or plans to do so during study.
Subject is a pregnant or breastfeeding (lactating) woman.
Subject has used topical therapy within 2 weeks of randomization (including, but not limited to, topical corticosteroids, retinoids or vitamin D analog preparations, tacrolimus, pimecrolimus, anthralin/dithranol, or moisturizers which contain urea or salicylic acid). Use of phototherapy within 4 weeks prior to randomization. Use of conventional systemic therapy or systemic corticosteroids within 4 weeks prior to randomization, except for conditions other than psoriasis or psoriatic arthritis. Use of biologic therapy within 5 pharmacokinetic half-lives.
Prior treatment with apremilast, or participation in a clinical study, involving apremilast.
Subject has any condition that confounds the ability to interpret data from the study.
Subject has history of allergy or hypersensitivity to any components of the IP (including placebo).
Subject has rare hereditary problem of galactose intolerance, lapp lactase deficiency or glucose-galactose malabsorption.
Subject's most severe manifestation corresponds to a manifestation whose randomization block has already been fully enrolled.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo / Apremilast 30 mg	Placebo	Participants will take placebo tablets orally twice a day for 16 weeks. After week 16, participants will be switched to receive apremilast 30 mg twice daily until Week 52.
Apremilast 30 mg	Apremilast	Participants will take apremilast 30 mg tablets orally twice a day for up to 52 weeks.
Placebo / Apremilast 30 mg	Apremilast	Participants will take placebo tablets orally twice a day for 16 weeks. After week 16, participants will be switched to receive apremilast 30 mg twice daily until Week 52.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Who Achieved a ≥ 4-point Reduction From Baseline in Dermatology Life Quality Index (DLQI) at Week 16	Baseline and week 16	The DLQI is a 10-item skin disease-specific questionnaire used to evaluate the impact of skin disease on health-related quality of life (QOL). The items address symptoms and feelings, daily activities, leisure, work/school, personal relationships, and issues with treatment. Questions are answered on a 4-point scale from 0 (not at all/not applicable) to 3 (very much). Item scores are added to provide a total score from 0 to 30, with higher scores indicating greater impairment of QOL.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in DLQI at Week 16	Baseline and week 16	The DLQI is a 10-item skin disease-specific questionnaire used to evaluate the impact of skin disease on health-related quality of life. The items address symptoms and feelings, daily activities, leisure, work/school, personal relationships, and issues with treatment. Questions are answered on a 4-point scale from 0 (not at all/not applicable) to 3 (very much). Item scores are added to provide a total score from 0 to 30, with higher scores indicating greater impairment of QOL. A negative change from baseline indicates improvement in quality of life.
Change From Baseline in WPAI: PSO at Week 16: Percentage Activity Impairment	Baseline and week 16	The WPAI: PSO is a self-administered questionnaire designed to address impairment to the work productivity and activity of participants due to psoriasis in the past 7 days. Percent activity impairment is derived from the patient's assessment of the degree to which psoriasis affected their regular daily unpaid activities, measured on a VAS from 1 (no effect on daily activities) to 10 (psoriasis completely prevented daily activities). A higher percentage indicates greater impairment and less productivity, and a negative change from baseline indicates improvement.
Percent Change From Baseline in European Quality of Life 5-Dimension (EQ-5D) VAS Score at Week 16	Baseline and week 16	EQ-5D measures the participant's general health state on a vertical VAS and five quality of life domains. The EQ-5D VAS score ranges from 0 to 100, where a score of 0 indicates the worst imaginable health states and a score of 100 indicates the best imaginable health state. A positive change from baseline indicates improvement.
Change From Baseline in Blood Pressure During the Placebo-controlled Period	Baseline, week 2, week 4, and week 16
Change From Baseline in Body Weight During the Placebo-controlled Period	Baseline and week 2, week 4, and week 16
Percent Change From Baseline in EQ-5D Index Score at Week 16	Baseline and week 16	EQ-5D measures the participants general health state as a vertical VAS and 5 quality of life domains: mobility, self-care, main activity (work, study, housework, family/leisure activities), pain/discomfort, and anxiety/depression. Each dimension is rated on three levels (no problems, some/moderate problems, extreme problems). An EQ-5D summary index is derived by applying a formula that attaches values (weights) to each of the levels in each dimension. EQ-5D index values were derived using the UK scoring algorithm, where a higher score indicates a better health state. The range of the score is from -0.224 to 1, with 0 corresponding to death, 1 corresponding to full health, and negative numbers indicate health states worse than death. A positive change from baseline indicates improvement.
Change From Baseline in WPAI: PSO at Week 16: Percentage Work Impairment	Baseline and week 16	The WPAI: PSO is a self-administered questionnaire designed to address impairment to the work productivity and activity of participants due to psoriasis in the past 7 days. Percent impairment while working was derived from the participant's assessment of the degree to which psoriasis affected their productivity while working. A higher percentage indicates greater impairment and less productivity, and a negative change from baseline indicates improvement.
Number of Participants With Marked Laboratory Abnormalities During the Placebo-controlled Period	16 weeks	Marked laboratory abnormalities are defined for each parameter below. ULN = upper limit of normal
Change From Baseline in Waist Circumference During the Placebo-controlled Period	Baseline and week 2, week 4, and week 16
Percent Change From Baseline in Body Surface Area (BSA) Affected by Psoriasis at Week 16	Baseline and week 16	Body surface area is a measurement of involved skin. The overall BSA affected by psoriasis was estimated based on the palm area of the participant's hand (entire palmar surface or "handprint"), which equates to approximately 1% of total BSA.
Change From Baseline in Skin Discomfort/Pain Visual Analog Scale (VAS) at Week 16	Baseline and week 16	Participants were asked to indicate their level of skin discomfort/pain in the past week by placing a vertical stroke on a 100 mm horizontal line on which the left-hand boundary (0) represents no skin discomfort/pain, and the right-hand boundary (100) represents worst possible skin discomfort/pain. The distance from the mark to the left-hand boundary was recorded. A negative change from baseline indicates improvement in skin discomfort/pain.
Change From Baseline in WPAI: PSO at Week 16: Percentage Overall Work Impairment	Baseline and week 16	The WPAI: PSO is a self-administered questionnaire designed to address impairment to the work productivity and activity of participants due to psoriasis in the past 7 days. Percent overall work impairment takes into account both hours missed due to psoriasis symptoms and the participant's assessment of the degree to which psoriasis affected their productivity while working. A higher percentage indicates greater impairment and less productivity, and a negative change from baseline indicates improvement.
Percentage of Participants Who Achieved a ≥ 4-point Reduction From Baseline in DLQI at Weeks 32 and 52	Baseline, week 32 and week 52	The DLQI is a 10-item skin disease-specific questionnaire used to evaluate the impact of skin disease on health-related quality of life (QOL). The items address symptoms and feelings, daily activities, leisure, work/school, personal relationships, and issues with treatment. Questions are answered on a 4-point scale from 0 (not at all/not applicable) to 3 (very much). Item scores are added to provide a total score from 0 to 30, with higher scores indicating greater impairment of QOL.
Change From Baseline in Skin Discomfort/Pain VAS at Weeks 32 and 52	Baseline, week 32 and week 52	Participants were asked to indicate their level of skin discomfort/pain in the past week by placing a vertical stroke on a 100 mm horizontal line on which the left-hand boundary (0) represents no skin discomfort/pain, and the right-hand boundary (100) represents worst possible skin discomfort/pain. The distance from the mark to the left-hand boundary was recorded. A negative change from baseline indicates improvement in skin discomfort/pain.
Percent Change From Baseline in EQ-5D Index Score at Week 52	Baseline and week 52	EQ-5D measures the participants general health state as a vertical VAS and 5 quality of life domains: mobility, self-care, main activity (work, study, housework, family/leisure activities), pain/discomfort, and anxiety/depression. Each dimension is rated on three levels (no problems, some/moderate problems, extreme problems). An EQ-5D summary index is derived by applying a formula that attaches values (weights) to each of the levels in each dimension. EQ-5D index values were derived using the UK scoring algorithm, where a higher score indicates a better health state. The range of the score is from -0.224 to 1, with 0 corresponding to death, 1 corresponding to full health, and negative numbers indicate health states worse than death. A positive change from baseline indicates improvement.
Change From Baseline in Itch Numeric Rating Scale (NRS) Score at Week 16	Baseline and week 16	The Itch Numeric Rating Scale (NRS) asked participants to assess the worst severity of itch experienced over the past 24 hours on an 11-point scale anchored from 0, representing 'no itching' to 10, representing 'worst itch imaginable'. A negative change from baseline indicates improvement in itch severity.
Percentage of Participants Who Achieved a Psoriasis Area Severity Index (PASI) Score < 3 at Week 16	Week 16	The PASI score 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. 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 and the values for each anatomic region are summed to yield the PASI score. PASI scores range from 0 to 72, with higher scores reflecting greater disease severity.
Percentage of Participants Who Achieved a Patient Benefit Index (PBI) Global Score of ≥ 1 at Week 16	Week 16	The PBI is a validated patient-reported instrument to assess patient-relevant benefits of psoriasis treatment. Prior to starting study treatment, participants were asked to assess the importance of a series of treatment goals (from not important to very important) by completing the Patient Needs Questionnaire (PNQ). After a period of treatment (16 weeks), participants were then asked to assess the extent to which these goals were achieved (from not at all to very) by completing the Patient Benefit Questionnaire (PBQ). The Patient Benefit Index represents the benefits realized as a function of most important needs. The PBI score ranges from 0 (no benefit) to 4 (maximum benefit).
Change From Baseline in Work Productivity and Activity Impairment Questionnaire: Psoriasis (WPAI: PSO) at Week 16: Percentage Work Time Missed	Baseline and week 16	The WPAI: PSO is a self-administered questionnaire designed to address impairment to the work productivity and activity of participants due to psoriasis in the past 7 days. Percent of work time missed is derived from the number of hours of work missed due to psoriasis symptoms as a percentage of total hours that should have been worked. A higher percentage indicates more hours missed, and a negative change from baseline indicates improvement.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) During the Placebo-controlled Period	From first dose of study drug to week 16 or up to 28 days after last dose for participants who didn't enter the apremilast extension period.	An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. Any worsening of a preexisting condition was considered an AE. A serious adverse event (SAE) is any AE occurring 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; * Was a congenital anomaly/birth defect; * Constituted an important medical event. The Investigator assessed the severity/intensity of each event as mild, moderate, or severe based on level of symptoms.
Change From Baseline in Pulse Rate During the Placebo-controlled Period	Baseline and week 2, week 4, and week 16
Change From Baseline in DLQI at Weeks 32 and 52	Baseline, week 32 and week 52	The DLQI is a 10-item skin disease-specific questionnaire used to evaluate the impact of skin disease on health-related quality of life. The items address symptoms and feelings, daily activities, leisure, work/school, personal relationships, and issues with treatment. Questions are answered on a 4-point scale from 0 (not at all/not applicable) to 3 (very much). Item scores are added to provide a total score from 0 to 30, with higher scores indicating greater impairment of QOL. A negative change from baseline indicates improvement in quality of life.
Change From Baseline in Itch NRS Score at Weeks 32 and 52	Baseline, week 32 and week 52	The Itch Numeric Rating Scale (NRS) asked participants to assess the worst severity of itch experienced over the past 24 hours on an 11-point scale anchored from 0, representing 'no itching' to 10, representing 'worst itch imaginable'. A negative change from baseline indicates improvement in itch severity.
Percent Change From Baseline in BSA Affected by Psoriasis at Weeks 32 and 52	Baseline, week 32 and week 52	Body surface area is a measurement of involved skin. The overall BSA affected by psoriasis was estimated based on the palm area of the participant's hand (entire palmar surface or "handprint"), which equates to approximately 1% of total BSA.
Percentage of Participants Who Achieved a PBI Score of ≥ 1 at Weeks 32 and 52	Week 32 and week 52	The PBI is a validated patient-reported instrument to assess patient-relevant benefits of psoriasis treatment. Prior to starting study treatment, participants were asked to assess the importance of a series of treatment goals (from not important to very important) by completing the Patient Needs Questionnaire (PNQ). After a period of treatment (32 weeks and 52 weeks), participants were then asked to assess the extent to which these goals were achieved (from not at all to very) by completing the Patient Benefit Questionnaire (PBQ). The Patient Benefit Index represents the benefits realized as a function of most important needs. The PBI score ranges from 0 (no benefit) to 4 (maximum benefit).
Change From Baseline in Blood Pressure at End of Apremilast Extension Period	Baseline (defined as the last value measured on or before the day of the first apremilast dose) and end of apremilast extension period; week 52, or earlier for participants who discontinued prior to week 52
Change From Baseline in Waist Circumference at End of Apremilast Extension Period	Baseline (defined as the last value measured on or before the day of the first apremilast dose) and end of apremilast extension period; week 52, or earlier for participants who discontinued prior to week 52
Percentage of Participants Who Achieved a PASI Score < 3 at Weeks 32 and 52	Week 32 and week 52	The PASI score 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. 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 and the values for each anatomic region are summed to yield the PASI score. PASI scores range from 0 to 72, with higher scores reflecting greater disease severity.
Percent Change From Baseline in EQ-5D VAS Score at Week 52	Baseline and week 52	EQ-5D measures the participant's general health state on a vertical VAS and five quality of life domains. The EQ-5D VAS score ranges from 0 to 100, where a score of 0 indicates the worst imaginable health states and a score of 100 indicates the best imaginable health state. A positive change from baseline indicates improvement.
Change From Baseline in Body Weight at End of Apremilast Extension Period	Baseline (defined as the last value measured on or before the day of the first apremilast dose) and end of apremilast extension period; week 52, or earlier for participants who discontinued prior to week 52
Change From Baseline in WPAI: PSO at Week 52: Percentage Work Time Missed	Baseline and week 52	The WPAI: PSO is a self-administered questionnaire designed to address impairment to the work productivity and activity of participants due to psoriasis in the past 7 days. Percent of work time missed is derived from the number of hours of work missed due to psoriasis symptoms as a percentage of total hours that should have been worked. A higher percentage indicates more hours missed, and a negative change from baseline indicates improvement.
Change From Baseline in WPAI: PSO at Week 52: Percentage Work Impairment	Baseline and week 52	The WPAI: PSO is a self-administered questionnaire designed to address impairment to the work productivity and activity of participants due to psoriasis in the past 7 days. Percent impairment while working was derived from the participant's assessment of the degree to which psoriasis affected their productivity while working. A higher percentage indicates greater impairment and less productivity, and a negative change from baseline indicates improvement.
Change From Baseline in WPAI: PSO at Week 52: Percentage Overall Work Impairment	Baseline and week 52	The WPAI: PSO is a self-administered questionnaire designed to address impairment to the work productivity and activity of participants due to psoriasis in the past 7 days. Percent overall work impairment takes into account both hours missed due to psoriasis symptoms and the participant's assessment of the degree to which psoriasis affected their productivity while working. A higher percentage indicates greater impairment and less productivity, and a negative change from baseline indicates improvement.
Number of Participants With Marked Laboratory Abnormalities During Apremilast Treatment	From first dose of apremilast up to 28 days after last dose; up to 40 weeks for participants initially randomized to placebo and 56 weeks for participants initially randomized to apremilast.
Change From Baseline in Pulse Rate at End of Apremilast Extension Period	Baseline (defined as the last value measured on or before the day of the first apremilast dose) and end of apremilast extension period; week 52, or earlier for participants who discontinued prior to week 52
Change From Baseline in WPAI: PSO at Week 52: Percentage Activity Impairment	Baseline and week 52	The WPAI: PSO is a self-administered questionnaire designed to address impairment to the work productivity and activity of participants due to psoriasis in the past 7 days. Percent activity impairment is derived from the patient's assessment of the degree to which psoriasis affected their regular daily unpaid activities, measured on a VAS from 1 (no effect on daily activities) to 10 (psoriasis completely prevented daily activities). A higher percentage indicates greater impairment and less productivity, and a negative change from baseline indicates improvement.
Number of Participants With TEAEs During Apremilast Treatment	From first dose of apremilast up to 28 days after last dose; up to 40 weeks for participants initially randomized to placebo and 56 weeks for participants initially randomized to apremilast.	An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. Any worsening of a preexisting condition was considered an AE. A serious adverse event (SAE) is any AE occurring 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; * Was a congenital anomaly/birth defect; * Constituted an important medical event. The Investigator assessed the severity/intensity of each event as mild, moderate, or severe based on level of symptoms.