Study to Evaluate Safety and Effectiveness of Oral Apremilast (CC-10004) in Patients With Moderate to Severe Plaque Psoriasis (ESTEEM 1)

• ClinicalTrials.gov Identifier: NCT01194219
• Recruitment Status: Completed
• First Posted: September 2, 2010
• Results First Posted: November 5, 2014
• Last Update Posted: March 15, 2022
• Sponsor: Amgen
• Information provided by (Responsible Party): Amgen

Study Description

Brief Summary:

This study evaluated the effects of an called apremilast. Apremilast works by lowering some of the chemicals that affect psoriasis and therefore improves the symptoms of psoriasis. The purpose of this study was to test apremilast and compare its effects to placebo (an inactive substance which contains no medicine but is in the same form as the drug). This study was able to test for efficacy (improvement of signs and symptoms) and safety of apremilast in patients with moderate to severe psoriasis.

Condition or disease	Intervention/treatment	Phase
Plaque Psoriasis	Drug: Apremilast; Drug: Placebo; Drug: Topical treatments or phototherapy	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 844 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of Apremilast (CC-10004) in Subjects With Moderate to Severe Plaque Psoriasis
• Actual Study Start Date: September 9, 2010
• Actual Primary Completion Date: February 23, 2012
• Actual Study Completion Date: November 22, 2016

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Apremilast; Subjects initially randomized to apremilast 30 mg twice a day, and who demonstrate a PASI 75 response at Week 32 will be randomized (1 to 1) to either continue to receive apremilast 30 mg ) BID or to receive placebo (until effect is lost). At the time effect is lost, subjects will be treated with apremilast 30 mg twice a day for the duration of their participation in the study.	Drug: Apremilast; Other Names: CC-10004; Otezla; Drug: Placebo; Identical matching placebo
Placebo Comparator: Placebo; Subjects initially randomized to placebo, are assigned to apremilast 30 mg twice a day beginning at Week 16 for the duration of the subject's participation in the study.	Drug: Apremilast; Other Names: CC-10004; Otezla; Drug: Placebo; Identical matching placebo
Active Comparator: Apremilast 30 mg; Apremilast 30 mg by mouth (PO) twice a day (BID). Participants initially randomized to apremilast 30 mg BID, and who were able to demonstrate a Psoriasis Area Severity Index (PASI) -75 response at week 32 were randomized (1 to 1) to either apremilast 30 mg BID or oral placebo (until effect is lost). At relapse/loss of response to therapy prior to Week 52 (the time at which 75% improvement in PASI score compared to baseline was lost) or at Week 52, participants were re-treated with apremilast 30 mg BID for the duration of their participation in the study. Non-responders or partial responders (PASI response <75) received additional topical therapies or phototherapy beginning at Week 32.	Drug: Apremilast; Other Names: CC-10004; Otezla; Drug: Placebo; Identical matching placebo; Drug: Topical treatments or phototherapy; At week 32, participants considered partial responders or non-responders had the option of adding topical therapies and/or phototherapy to their treatment regimen.; Other Names: Corticosteroid creams; Light Therapy

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants Who Achieved a 75% Improvement (Response) in the Psoriasis Area Severity Index (PASI-75) at Week 16 From Baseline [ Time Frame: Baseline to Week 16 ]
   PASI-75 response is the percentage of participants who achieved at least a 75% reduction (improvement) from baseline in PASI score at Week 16. The improvement in PASI score was used as a measure of efficacy. The PASI was a measure of psoriatic disease severity taking into account qualitative lesion characteristics (erythema, thickness, and scaling) and degree of skin surface area involvement on defined anatomical regions. PASI scores range from 0 to 72, with higher scores reflecting greater disease severity. Erythema, thickness, and scaling are scored on a scale of 0 (none) to 4 (very severe) on 4 anatomic regions of the body: head, trunk, upper limbs, and lower limbs. Degree of involvement on each of the 4 anatomic regions is scored on a scale of 0 (no involvement) to 6 (90% to 100% involvement). The PASI score was set to missing if any severity score or degree of involvement is missing.

Secondary Outcome Measures :

1. Percentage of Participants Who Achieved a Static Physician Global Assessment (sPGA) Score of Clear (0) or Almost Clear (1) With At Least 2 Points Reduction From Baseline [ Time Frame: Baseline to Week 16 ]
   The sPGA was a 5-point scale ranging from 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), to 4 (severe), incorporating an assessment of the severity of the three primary signs of the disease: erythema, scaling and plaque elevation. When making the assessment of overall severity, the Investigator factored in areas that have already been cleared (ie, have scores of 0) and did not just evaluate remaining lesions for severity, ie, the severity of each sign was averaged across all areas of involvement, including cleared lesions. In the event of different severities across disease signs, the sign that is the predominant feature of the disease should be used to help determine the sPGA score.
2. Percent Change From Baseline in Percent of Affected Body Surface Area (BSA) at Week 16 [ Time Frame: Baseline and Week 16 ]
   BSA was 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" including the fingers), which equates to approximately 1% of total body surface area. BSA percent change from baseline (Visit 2 Week 0) was determined at each visit of the study, which is calculated as 100*(visit BSA - baseline BSA) / baseline BSA (%).
3. Percent Change From Baseline in the Psoriasis Area Severity Index (PASI) Score at Week 16 [ Time Frame: Baseline to Week 16 ]
   Psoriasis Area Severity Index (PASI) scores range from 0 to 72, with higher scores reflecting greater disease severity. Erythema, thickness, and scaling are scored on a scale of 0 (none) to 4 (very severe) on 4 anatomic regions of the body: head, trunk, upper limbs, and lower limbs. Degree of involvement on each of the 4 anatomic regions is scored on a scale of 0 (no involvement) to 6 (90% to 100% involvement). The total qualitative score (sum of erythema, thickness, and scaling scores) is multiplied by the degree of involvement for each anatomic region and then multiplied by a constant. These values for each anatomic region are summed to yield the PASI score. The PASI score was set to missing if any severity score or degree of involvement is missing. PASI score percent change from baseline was calculated as 100* (visit score - baseline score)/baseline score (%).
4. Percentage of Participants Who Achieved a 50% Improvement (Response) in the PASI Score (PASI-50) at Week 16 From Baseline [ Time Frame: Baseline to Week 16 ]
   A participant was classified as having at least a 50% improvement in PASI score from baseline, which was equivalent to a percent change from baseline ranging from -100% to -50%. PASI score is based on an assessment of erythema (reddening), induration (plaque thickness), desquamation (scaling), and the percent area affected as observed on the day of examination.
5. Change From Baseline in Pruritus Visual Analog Scale (VAS) Score at Week 16 [ Time Frame: Baseline and Week 16 ]
   The Pruritus Visual Analog Scores (VAS) were used to measure the amount of itching and discomfort a participant experiences. Participant's Assessment of Pruritus (Itch) asked: On average, how much itch have you had because of your condition in the past week? All VAS values range from 0 to 100. Higher scores correspond to more severe symptom or disease. Change from baseline was calculated for the VAS scale, where change = visit value - baseline value.
6. Change From Baseline in the Dermatology Life Quality Index (DLQI) Total Score at Week 16 [ Time Frame: Baseline to Week 16 ]
   DLQI is a simple, compact, and practical questionnaire for use in a dermatology clinical setting to assess limitations related to the impact of skin disease. The instrument contains ten items dealing with the participant's skin. With the exception of Item Number 7, the participant responds on a four-point scale, ranging from "Very Much" (score 3) to "Not at All" or "Not relevant" (score 0). Item Number 7 is a multi-part item, the first part of which ascertains whether the participant's skin prevented them from working or studying (Yes or No, scores 3 or 0 respectively), and if "No," then the participant is asked how much of a problem the skin has been at work or study over the past week, with response alternatives being "A lot," "A little," or "Not at all" (scores 2, 1, or 0 respectively). The DLQI total score is derived by summing all item scores, which has a possible range of 0 to 30, with 30 corresponding to the worst quality of life, and 0 corresponding to the best.
7. Change From Baseline in the Mental Component Summary (MSC) Score of the Medical Outcome Study Short Form 36-item (SF-36) Health Survey Version 2.0 at Week 16 [ Time Frame: Baseline to Week 16 ]
   The SF-36 was a 36-item general health status instrument and consists of 8 scales: physical function (PF), role limitations-physical (RP), vitality (VT), general health perceptions (GH), bodily pain (BP), social function (SF), role limitations-emotional (RE), and mental health (MH). Scale scores range from 0 to 100, with higher scores indicating better health. Two overall summary scores were obtained - a Physical Component Summary score (PCS) and a Mental Component Summary score (MCS). Scores from the 8 scales, PCS and MCS were transformed to the norm-based scores using weights from U.S. general population, with 50 as the average and 10 as the standard deviation, higher scores indicating better health. For norm based scores, change from baseline were calculated for the 8 scales and the two summary scales, where change = visit value - baseline value.
8. Percentage of Participants Who Achieved Both a 75% Improvement (Response) in the PASI and sPGA Score of Clear (0) or Almost Clear (1) With at Least 2 Points Reduction at Week 16 From Baseline [ Time Frame: Baseline to Week 16 ]
   PASI-75 response was the percentage of participants who achieved at least a 75% reduction (improvement) from baseline in PASI score at Week 16. The improvement in PASI score was used as a measure of efficacy. See Outcome Measure #1 for further description. sPGA is a 5-point scale ranging from 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), to 4 (severe), incorporating an assessment of the severity of the three primary signs of the disease: erythema, scaling and plaque elevation. See OCM #2 for further description.
9. Kaplan Meier Estimate of Time to Loss of PASI-75 Response (Loss of Effect) at Week 32 During the Re-Randomized Treatment Withdrawal Phase [ Time Frame: Week 32 to Week 52 ]
   Time to loss was the time between the re-randomization date and the date of the first assessment where loss of PASI-75 was observed (event); or the time between the re-randomization date and the date of the last PASI assessment in the Weeks 32-52 interval prior to addition of protocol-prohibited medication/therapy, or resumption of APR 30 BID, or discontinuation, or Week 52 if no loss (censored).
10. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) During the Placebo-Controlled Phase [ Time Frame: Week 0 to Week 16; mean duration of exposure was 14.8 weeks and 15.0 weeks for subjects randomized to placebo and apremilast respectively. ]
    An AE was any noxious, unintended, or untoward medical occurrence, that may appear or worsen in a participant during the course of 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 (ie, any clinically significant adverse change in the frequency or intensity of a preexisting condition) was considered an AE. A serious AE (SAE) is any untoward adverse event that is fatal, life-threatening, results in persistent or significant disability or incapacity, requires or prolongs existing in-patient hospitalization, is a congenital anomaly or birth defect, or a condition that may jeopardize the patient or may require intervention to prevent one of the outcomes listed above. An AE is a treatment emergent AE if the AE start date is on or after the date of the first dose of study drug and no later than 28 days after the last dose.
11. Number of Participants With TEAEs During the Apremilast-Exposure Period Through Week 260 [ Time Frame: Week 0 to Week 260; mean exposure to apremilast 30 mg BID during the Apremilast-exposure Period up to Week 260 was 97.83 weeks ]
    The Apremilast-exposure Period started on the date of the first dose of apremilast (Week 0 for participants originally randomized to apremilast or Week 16 for participants originally randomized to placebo) to the last dose of apremilast. Adverse events that started after 28 days of initiating placebo and before resuming apremilast treatment in the Randomized Treatment Withdrawal Phase (Weeks 32 to 52) were excluded in the Apremilast-exposure Period. A serious AE (SAE) is any untoward adverse event that is fatal, life-threatening, results in persistent or significant disability or incapacity, requires or prolongs existing in-patient hospitalization, is a congenital anomaly or birth defect, or a condition that may jeopardize the patient or may require intervention to prevent one of the outcomes listed above. An AE is a treatment emergent AE if the AE start date is on or after the date of the first dose of study drug and no later than 28 days after the last dose.
12. Number of Participants With a Psoriasis Flare or Rebound During the Placebo-Controlled Phase [ Time Frame: Weeks 0 to Week 16 ]
    Psoriasis flare was defined as a sudden intensification of psoriasis requiring medical intervention, or a diagnosis of new generalized erythrodermic, inflammatory, or pustular psoriasis. Rebound is defined as a severe and sudden worsening of disease that occurs after treatment has been discontinued. Note categories below. [1] Psoriasis adverse events (ie, preferred term as Guttate psoriasis, Psoriasis, Pustular psoriasis) started on or after the first dose date and on or before the last dose date within the phase. [2] Psoriasis adverse events (ie, preferred term as Guttate psoriasis, Psoriasis, Pustular psoriasis, Rebound psoriasis) started after the last dose date for participants who discontinued within the phase. [3] PASI >= 125% of baseline score at any visit after the last dose date for participants who discontinued within the phase and were not included in [1] and/or [2].
13. Number of Participants With a Psoriasis Flare or Rebound During the During the Apremilast-exposure Period Through Week 260 [ Time Frame: Week 0 to Week 260 ]
    Psoriasis flare was defined as a sudden intensification of psoriasis requiring medical intervention, or a diagnosis of new generalized erythrodermic, inflammatory, or pustular psoriasis. Rebound is defined as a severe and sudden worsening of disease that occurs after treatment has been discontinued. Note categories below. [1] Psoriasis adverse events (ie, preferred term as Guttate psoriasis, Psoriasis, Pustular psoriasis) started on or after the first dose date and on or before the last dose date within the phase. [2] Psoriasis adverse events (ie, preferred term as Guttate psoriasis, Psoriasis, Pustular psoriasis, Rebound psoriasis) started after the last dose date for participants who discontinued within the phase. [3] PASI >= 125% of baseline score at any visit after the last dose date for participants who discontinued within the phase and were not included in [1] and/or [2].

Eligibility Criteria

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

Criteria

Inclusion Criteria:

1. Males or females, ≥ 18 years of age at the time of signing the informed consent document

2. Diagnosis of chronic plaque psoriasis for at least 12 months prior to Screening

   a. Have moderate to severe plaque psoriasis at Screening and Baseline

3. Must meet all laboratory criteria
4. Females of childbearing potential (FCBP) must have a negative pregnancy test at Screening and Baseline. FCBP who engage in activity in which conception is possible must use 2 forms of contraception as described by the Study Doctor while on study medication and for at least 28 days after taking the last dose of study medication
5. Male subjects (including those who have had a vasectomy) who engage in activity in which conception is possible must use barrier contraception (latex condom or any nonlatex condom NOT made out of natural [animal] membrane [eg, polyurethane]) while on study medication and for a least 28 days after the last dose of study medication.

Exclusion Criteria:

1. Other than psoriasis, history of any clinically significant (as determined by the Investigator) or other major uncontrolled disease.

   .

2. Pregnant or breast feeding
3. History of allergy to any component of the study drug
4. Hepatitis B surface antigen positive at Screening
5. Anti-hepatitis C antibody positive at Screening
6. Active tuberculosis (TB) or a history of incompletely treated TB
7. Clinically significant abnormality on 12-Lead Electrocardiogram (ECG) at Screening
8. Clinically significant abnormal chest x-ray
9. History of positive human immunodeficiency virus (HIV), or have congenital or acquired immunodeficiency
10. Active substance abuse or a history of substance abuse within 6 months prior to Screening
11. Bacterial infections requiring treatment with oral or injectable antibiotics, or significant viral or fungal infections, within 4 weeks of Screening
12. Malignancy or history of malignancy (except for treated [ie, cured] basal cell or squamous cell in situ skin carcinomas and treated [ie, cured] cervical intraepithelial neoplasia [CIN] or carcinoma in situ of the cervix with no evidence of recurrence within the previous 5 years)
13. Psoriasis flare or rebound within 4 weeks prior to Screening
14. Evidence of skin conditions that would interfere with clinical assessments
15. Topical therapy within 2 weeks of randomization
16. Systemic therapy for psoriasis within 4 weeks prior to randomization
17. Use of phototherapy within 4 weeks prior to randomization (ie, Ultraviolet B (UVB), psoralen and ultraviolet A (PUVA)
18. Adalimumab, etanercept, infliximab, or certolizumab pegol within 12 weeks prior to randomization
19. Alefacept, briakinumab, or ustekinumab within 24 weeks prior to randomization
20. Use of any investigational drug within 4 weeks prior to randomization
21. Prolonged sun exposure or use of tanning booths or other ultraviolet (UV) light sources
22. Prior treatment with apremilast

Contacts and Locations

Sponsors and Collaborators

Amgen

Investigators

• Study Director: MD; Amgen

More Information

Publications of Results:

Reich K, Mrowietz U, Menter A, Griffiths CEM, Bagel J, Strober B, Nunez Gomez N, Shi R, Guerette B, Lebwohl M. Effect of baseline disease severity on achievement of treatment target with apremilast: results from a pooled analysis. J Eur Acad Dermatol Venereol. 2021 Dec;35(12):2409-2414. doi: 10.1111/jdv.17520. Epub 2021 Aug 23.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT01194219
• Other Study ID Numbers: CC-10004-PSOR-008
• First Posted: September 2, 2010
• Results First Posted: November 5, 2014
• Last Update Posted: March 15, 2022
• Last Verified: April 2020

Keywords provided by Amgen:

Plaque Psoriasis

Additional relevant MeSH terms:

Psoriasis; Skin Diseases, Papulosquamous; Skin Diseases; Apremilast; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action