Efficacy and Safety Study of Apremilast (CC-10004) in Pediatric Subjects From 6 Through 17 Years of Age With Moderate to Severe Plaque Psoriasis

Study Overview
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Brief Summary
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This is a Phase 3, multicenter, randomized, placebo-controlled, double-blind study of the efficacy and safety of apremilast (CC-10004) in pediatric subjects with moderate to severe plaque psoriasis. At least 230 pediatric subjects (ages 6 through 17 years) will be randomized 2:1 to receive either apremilast or placebo for the first 16 weeks and then all subjects will receive apremilast during the 36 week Extension Phase for a total of 52 weeks. Randomization to apremilast arm or placebo arm will be stratified by age group (6 to 11 years or 12 to 17 years). Subjects will receive apremilast treatment of either 20 mg twice daily (BID) or 30 mg BID, depending on weight. This Phase 3 study is being conducted to evaluate the safety and efficacy of apremilast in the treatment of pediatric subjects.

Detailed Description
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Treatment will be assigned by weight with subjects 20 kg to < 50 kg receiving apremilast 20 mg BID or placebo BID and subjects ≥ 50 kg receiving apremilast 30 mg BID or placebo BID. Total study duration is up to 71 weeks. Subjects completing all 52 weeks of the treatment and extension phase will be able to enter the Long-term study. Subjects not entering the Long-term study will return for 3 observational follow-up visits, 4, 8 and 14 weeks after last dose of study drug.

Official Title
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A PHASE 3, MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO ASSESS THE EFFICACY AND SAFETY OF APREMILAST (CC-10004) IN PEDIATRIC SUBJECTS FROM 6 THROUGH 17 YEARS WITH MODERATE TO SEVERE PLAQUE PSORIASIS

Conditions
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Psoriasis

Intervention / Treatment
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* Drug: Apremilast (CC-10004)
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or female subjects 6 to 17 years of age, inclusive, at the time the informed consent form is signed by the legal guardian Subjects must have a weight of ≥ 20 kg Diagnosis of chronic plaque psoriasis for at least 6 months prior to Screening. Has moderate to severe plaque psoriasis at Screening and Baseline as defined by: PASI score ≥ 12; and Body surface area (BSA) ≥ 10%; and sPGA ≥ 3 (moderate to severe) Disease inadequately controlled by or inappropriate for topical therapy for psoriasis Candidate for systemic therapy or phototherapy Exclusion Criteria: Guttate, erythrodermic, or pustular psoriasis at Screening and Baseline Psoriasis flare or rebound within 4 weeks prior to Screening Prior history of suicide attempt at any time in the subject's lifetime prior to Screening or randomization in the study, or major psychiatric illness requiring hospitalization within 3 years prior to signing the assent and informed consent Answer Yes to any question on the Columbia-Suicide Severity Rating Scale during Screening or at Baseline Current or planned concurrent use of the following therapies that may have a possible effect on psoriasis a. Topical therapy within 2 weeks prior to randomization (including but not limited to topical corticosteroids, topical retinoid or vitamin D analog preparations, tacrolimus, pimecrolimus, or anthralin/dithranol) Exceptions*: i. Low potency or weak corticosteroids (please refer to the Investigators' Manual) will be allowed as background therapy for treatment of the face, axillae and groin in accordance with manufacturer's suggested usage ii. Unmedicated skin moisturizer (eg, Eucerin®) will also be permitted for body lesions *Subjects should not use these topical treatments within 24 hours prior to the clinic visit. b. Conventional systemic therapy for psoriasis within 4 weeks prior to randomization c. Phototherapy treatment (ie, ultraviolet B [UVB], PUVA) within 4 weeks prior to randomization d. Biologic therapy within 4 weeks prior to randomization or 5 PK/PD half-lives (whichever is longer).

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Administration of Apremilast (CC-10004) - 20mg<br>Apremilast 20mg Twice Daily (BID) | Drug: Apremilast (CC-10004)<br>* Apremilast (CC-10004)<br>|
| Experimental: Administration of Apremilast (CC-10004) - 30mg<br>Apremilast 30mg Twice Daily (BID) | Drug: Apremilast (CC-10004)<br>* Apremilast (CC-10004)<br>|
| Placebo Comparator: Administration of Placebo<br>Placebo tablet Twice Daily (BID) | Other: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Static Physician Global Assessment (sPGA) Response at Week 16 | The sPGA is the assessment by the Investigator of the overall disease severity of plaque psoriasis at the time of evaluation. The sPGA is a 5-point scale ranging from 0 (clear) to 4 (severe), incorporating an assessment of the severity of the three primary signs of the disease: erythema, scaling and plaque elevation. The results presented are for the percentage of participants with a sPGA response. An sPGA response was defined as a score of clear (0) or almost clear (1) with at least a 2-point reduction from baseline at Week 16. | Baseline to Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved At Least 75% Reduction in Psoriasis Area Severity Index (PASI-75) From Baseline at Week 16 | The Psoriasis Area Severity Index (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. The PASI scores range from 0 to 72, with higher scores reflecting greater disease severity. The results presented are for the percentage of participants with PASI-75. PASI-75 was defined as at least a 75% reduction in PASI score from baseline. | Baseline and Week 16 | 
| Percentage of Participants Who Achieved At Least 50% Reduction in Psoriasis Area Severity Index (PASI-50) From Baseline at Week 16 | 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. The PASI scores range from 0 to 72, with higher scores reflecting greater disease severity. The results presented are for the percentage of participants with PASI-50. PASI-50 was defined as at least a 50% reduction in PASI score from baseline. | Baseline and Week 16 | 
| Percentage Change From Baseline in Total PASI Score at Week 16 | 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. The PASI scores range from 0 to 72, with higher scores reflecting greater disease severity. Positive percentage change from baseline scores indicate a worsening of disease severity, and negative percentage change from baseline scores indicate an improvement in disease severity. | Baseline and Week 16 | 
| Percentage Change From Baseline in Body Surface Area (BSA) Affected by Psoriasis at Week 16 | BSA is a measurement of involved skin of the whole body affected by psoriasis, which ranges from 0% to 100%. Positive percentage change from baseline indicates that a greater BSA was affected by psoriasis. A negative percentage change from baseline indicates that a lesser BSA was affected by psoriasis. | Baseline and Week 16 | 
| Percentage of Participants Who Achieved a Children's Dermatology Life Quality Index (CDLQI) Score of 0 or 1 at Week 16 | The CDLQI is designed to measure the impact of skin disease on children's quality of life. The CDLQI measures how much the participant's psoriasis has affected them over the last week, and includes 10 questions with possible answers ranging from not at all (score of 0) to very much (score of 3). The CDLQI total score ranged from 0 (no effect on the participant's life) to 30 (extremely large effect on the participant's life). The results presented are for the percentage of participants who achieved a total CDLQI score of 0 or 1 at Week 16. | Week 16 | 
| Change From Baseline in CDLQI Score at Week 16 | The CDLQI is designed to measure the impact of skin disease on children's quality of life. The CDLQI measures how much the participant's psoriasis has affected them over the last week, and includes 10 questions with possible answers ranging from not at all (score of 0) to very much (score of 3). The CDLQI total score ranged from 0 (no effect on the participant's life) to 30 (extremely large effect on the participant's life). A positive change from baseline score indicates that a participant's quality of life has worsened. A negative change from baseline score indicates that a participant's quality of life has improved. | Baseline and Week 16 | 
| Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) During the Placebo-controlled Phase | An adverse event (AE) was defined as any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of the study. A TEAE is any AE that occurred after first dose of the investigational product. | 16 weeks | 
| Number of Participants Who Experienced a TEAE During the Apremilast Exposure Period | An AE was defined as any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of the study. A TEAE is any AE that occurred after first dose of the investigational product. | 52 weeks | 
| Number of Participants Who Experienced a Treatment-emergent Serious Adverse Event (TESAE) During the Placebo-controlled Phase | A TESAE is any AE occurring at any dose after first dose that results in death, is life-threatening (ie, in the opinion of the Investigator, the participant is at immediate risk of death from the AE), requires inpatient hospitalization or prolongation of existing hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay), results in persistent or significant disability/incapacity (a substantial disruption of the participant's ability to conduct normal life functions), is a congenital anomaly/birth defect, or constitutes an important medical event. | 16 weeks | 
| Number of Participants Who Experienced a TESAE During the Apremilast Exposure Period | A TESAE is any AE occurring at any dose after first dose that results in death, is life-threatening (ie, in the opinion of the Investigator, the participant is at immediate risk of death from the AE), requires inpatient hospitalization or prolongation of existing hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay), results in persistent or significant disability/incapacity (a substantial disruption of the participant's ability to conduct normal life functions), is a congenital anomaly/birth defect, or constitutes an important medical event. | 52 weeks | 
| Number of Participants Who Experienced a Treatment-related Adverse Event (TRAE) During the Placebo-controlled Phase | A TREAE is any AE that is determined by the Investigator to have a possibly causal relationship to the investigational product. | 16 weeks | 
| Number of Participants Who Experienced a TRAE During the Apremilast Exposure Period | A TREAE is any AE that is determined by the Investigator to have a possibly causal relationship to the investigational product. | 52 weeks | 
| Number of Participants With Diarrhea During the Placebo-controlled Phase | Diarrhea was defined as having 3 or more liquid or watery stools in a day. Participants and their parent/guardian were supplied with diaries (either paper or electronic) that were filled out daily to record and describe any diarrhea and associated symptoms. | Up to approximately 113 days | 
| Number of Participants With Diarrhea During the Apremilast Exposure Period | Diarrhea was defined as having 3 or more liquid or watery stools in a day. Participants and their parent/guardian were supplied with diaries (either paper or electronic) that were filled out daily to record and describe any diarrhea and associated symptoms. | Day 1 up to approximately 365 days | 
| Number of Participants With Diarrhea Symptoms During the Placebo-controlled Phase | Diarrhea symptoms were nausea, vomiting, abdominal cramps, abdominal pain, fever, bloating, and other symptoms. Participants and their parent/guardian were supplied with diaries (either paper or electronic) that were filled out daily to record and describe any diarrhea and associated symptoms. | Up to approximately 113 days | 
| Number of Participants With Diarrhea Symptoms During the Apremilast Exposure Period | Diarrhea symptoms were nausea, vomiting, abdominal cramps, abdominal pain, fever, bloating, and other symptoms. Participants and their parent/guardian were supplied with diaries (either paper or electronic) that were filled out daily to record and describe any diarrhea and associated symptoms. | Day 1 up to approximately 365 days | 
| Number of Participants With Suicidal Ideation or Behavior Per the Columbia-Suicide Severity Rating Scale (C-SSRS) During the Placebo-controlled Phase | The C-SSRS is a questionnaire that is used to assess suicidal ideation and behavior. The C-SSRS questionnaire measures suicidal ideation, intensity of ideation, and suicidal behaviors. Results presented are for the number of participants who recorded suicidal ideation or behavior on the C-SSRS. | 16 weeks | 
| Number of Participants With Suicidal Ideation or Behavior Per the C-SSRS During the Apremilast-extension Phase | The C-SSRS is a questionnaire that is used to assess suicidal ideation and behavior. The C-SSRS questionnaire measures suicidal ideation, intensity of ideation, and suicidal behaviors. Results presented are for the number of participants who recorded suicidal ideation or behavior on the C-SSRS. | Week 16 to Week 52 | 
| Number of Female Participants at Stage I-V of Sexual Development Per Tanner Staging of Sexual Development | The Tanner Staging of sexual development is a scale of physical development as children transition into adolescence and then adulthood. The scale defines physical measurements of development based on characteristics, such as the size of the breasts, genitals, testicular volume, and growth of pubic hair. The scale ranges from stage I (pre-adolescent) to stage V (adult development). The results presented are for the number of participants at stage I-V of development. | Week 52 | 
| Number of Male Participants at Stage I-V of Sexual Development Per Tanner Staging of Sexual Development | The Tanner Staging of sexual development is a scale of physical development as children transition into adolescence and then adulthood. The scale defines physical measurements of development based on characteristics, such as the size of the breasts, genitals, testicular volume, and growth of pubic hair. The scale ranges from stage I (pre-adolescent) to stage V (adult development). The results presented are for the number of participants at stage I-V of development. | Week 52 | 
| Mean Body Weight of Participants During the Placebo-controlled Phase | The participants' body weight in kilograms (kg) was recorded. | Baseline and Week 16 | 
| Mean Body Weight of Participants During the Apremilast Exposure Period | The participants' body weight in kilograms (kg) was recorded. | Baseline and Week 52 | 
| Mean Height of Participants During the Placebo-controlled Phase | The participants' height in centimeters (cm) was recorded. | Baseline and Week 16 | 
| Mean Height of Participants During the Apremilast Exposure Period | The participants' height in centimeters (cm) was recorded. | Baseline and Week 52 | 
| Mean Body Mass Index (BMI) of Participants During the Placebo-controlled Phase | The participants' BMI was calculated as body weight (kg)/height (m^2). | Baseline and Week 16 | 
| Mean BMI of Participants During the Apremilast Exposure Period | The participants' BMI was calculated as body weight (kg)/height (m^2). | Baseline and Week 52 | 
| Number of Participants Who Experienced a Psoriasis Flare During the Placebo-controlled Phase | A psoriasis flare was defined as a sudden intensification of psoriasis (new generalized erythrodermic, inflammatory or pustular psoriasis) requiring medical intervention beyond allowable medications. | 16 weeks | 
| Number of Participants Who Experienced a Psoriasis Flare During the Apremilast Exposure Period | A psoriasis flare was defined as a sudden intensification of psoriasis (new generalized erythrodermic, inflammatory or pustular psoriasis) requiring medical intervention beyond allowable medications. | 52 weeks | 
| Number of Participants Who Experienced a Psoriasis Rebound | A psoriasis rebound was defined as an adverse event of psoriasis that started after the last dose date for participants who received treatment in the study. | 14 weeks post last dose (max mean treatment duration in placebo-controlled phase was 15.3 weeks, and 41.9 weeks in the apremilast-exposure period) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Apremilast, Otezla, 6 through 17 years, Plaque Psoriasis, Psoriasis, CC-10004, Children, Adolescents, Pediatric, SPROUT