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Apremilast Safety and PK Study in Recalcitrant Plaque Psoriasis

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Celgene Corporation
ClinicalTrials.gov Identifier:
NCT00521339
First received: August 24, 2007
Last updated: November 11, 2014
Last verified: November 2014
  Purpose

The study will test the safety and tolerability of Apremilast twice a day in participants with recalcitrant plaque type psoriasis.


Condition Intervention Phase
Plaque-Type Psoriasis
Drug: Apremilast
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 2, Open-label Multi-center Study to Evaluate the Safety, Pharmacodynamics, Pharmacokinetics, and Efficacy of Apremilast in Subjects With Recalcitrant Plaque-type Psoriasis

Resource links provided by NLM:


Further study details as provided by Celgene Corporation:

Primary Outcome Measures:
  • Treatment Emergent Adverse Events (TEAEs) During the Treatment Phase [ Time Frame: Week 0 to Week 12 ] [ Designated as safety issue: Yes ]

    TEAE = any AE occurring or worsening on or after the first treatment with any study drug. Related = suspected by investigator to be related to study treatment. National Cancer Institute [NCI] Common Toxicity Criteria for Adverse Events [CTCAE], Version 3.0, grades: 1 = mild, 2 = moderate, 3 = severe, 4 = life threatening, 5 = death.

    Adverse event (AE) = any noxious, unintended, or untoward medical occurrence occurring at any dose that may appear or worsen in a participant during the course of a study, including new intercurrent illness, worsening concomitant illness, injury, or any concomitant impairment of participant's health, including laboratory test values, regardless of etiology. Serious adverse event (SAE) = any AE which results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect; constitutes an important medical event.


  • Treatment Emergent Adverse Events (TEAEs) During the Extension Phase [ Time Frame: Week 12 to Week 24 ] [ Designated as safety issue: Yes ]

    TEAE = any AE occurring or worsening on or after the first treatment with any study drug. Related = suspected by investigator to be related to study treatment. National Cancer Institute [NCI] Common Toxicity Criteria for Adverse Events [CTCAE], Version 3.0, grades: 1 = mild, 2 = moderate, 3 = severe, 4 = life threatening, 5 = death.

    Adverse event (AE) = any noxious, unintended, or untoward medical occurrence occurring at any dose that may appear or worsen in a participant during the course of a study, including new intercurrent illness, worsening concomitant illness, injury, or any concomitant impairment of participant's health, including laboratory test values, regardless of etiology. Serious adverse event (SAE) = any AE which: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event.



Secondary Outcome Measures:
  • Percentage of Participants With at Least a 1 Point Reduction on 0 to 5 Point Scale From Baseline in Static Physician Global Assessment (sPGA) at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    The static Physician's Global Assessment (sPGA) rated the investigator's overall clinical assessment of a participants plaque thickness, erythema, and scaling on a 6-point scale ranging from 0 (clear, except for residual discoloration) to 5 (majority of plaques have severe thickness, erythema, and scale). To assign a sPGA score, the investigator examined all psoriatic lesions and assigned a severity score ranging from 0 to 5 for thickness, erythema, and scaling. Scores for thickness, erythema, and scaling are summed and the mean of these 3 scores equals the overall sPGA score. Decreases in sPGA correspond to clinical improvement.

  • Percent Change From Baseline in Psoriasis Area Severity Index (PASI) Score at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    The PASI score 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 total qualitative score (sum of erythema, thickness, and scaling scores) was 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.

  • Percentage of Participants Who Achieved a PASI-75 Score at Week 12 [ Time Frame: Baseline to Week 12 ] [ Designated as safety issue: No ]
    PASI-75 response is the percentage of participants who achieved at least a 75% reduction (improvement) from baseline in PASI score at Week 12. 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 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 the4 anatomic regions was 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) was multiplied by the degree of involvement for each anatomic region and then multiplied by a constant.

  • Percentage of Participants Who Achieved a PASI-50 Score at Week 12 [ Time Frame: Baseline to Week 12 ] [ Designated as safety issue: No ]
    PASI -50 response is the percentage of participants who achieved at least a 50% reduction (improvement) from baseline in PASI score at Week 12. 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 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 the4 anatomic regions was 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) was multiplied by the degree of involvement for each anatomic region and then multiplied by a constant.

  • Maximal PASI Response Documented for Each Participant During Treatment Phase [ Time Frame: Baseline to Week 12 ] [ Designated as safety issue: No ]
    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 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.

  • Percent Change From Baseline in the Psoriasis Affected Body Surface Area (BSA) Involvement at Week 12 [ Time Frame: Baseline to Week 12 ] [ Designated as safety issue: No ]
    The BSA estimate was based on the palm area of the hand of the participant which equates to 1% of the total body surface area.

  • Time to Clinically Relevant Response (Time to Achieve PASI-50) During Treatment Phase [ Designated as safety issue: No ]
    Time to clinically relevant response (time to achieve PASI-50) during treatment phase was not analyzed. 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 the4 anatomic regions was 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) was 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.

  • Time to Achieve PASI-75 During Treatment Phase [ Designated as safety issue: No ]
    Time to achieve PASI-75 during treatment phase was not analyzed. 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 the4 anatomic regions was 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) was 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.

  • Time to Relapse of Psoriasis (50% Loss of Maximal PASI Score Improvement in Participants Who Achieved at Least PASI-50 During the Treatment Phase) During the Observational Follow up Phase [ Time Frame: 28-day Observational Follow-up Phase; Days 168 to Day 196. ] [ Designated as safety issue: No ]
    Time to relapse of psoriasis (50% loss of maximal PASI score improvement in participants who achieved at least PASI-50 during the treatment phase) during the observational follow up phase was not analyzed. Time to relapse of psoriasis was defined as a 50% loss of maximal PASI score improvement in participants who achieved at least PASI-50 during the treatment or extension phase. The lesion on each area of the body was assessed for redness, thickness, and scaling.

  • Percent of Participants With Psoriatic Arthritis Who Achieved an American College of Rheumatology 20% Improvement (ACR-20) Response at Week 12 [ Time Frame: Baseline to Week 12 ] [ Designated as safety issue: No ]

    A participant was a responder if the following 3 criteria for improvement from baseline were met:

    • ≥ 20% improvement in 78 tender joint count;
    • ≥ 20% improvement in 76 swollen joint count; and
    • ≥ 20% improvement in at least 3 of the 5 following parameters: Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); Patient's global assessment of disease activity (measured on a 100 mm VAS); Physician's global assessment of disease activity (measured on a 100 mm VAS); Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index (HAQ-DI)); C-Reactive Protein.

  • Time to Relapse of Psoriatic Arthritis During the Observational Follow-up Phase [ Time Frame: Observational follow up phase; Days 168 to Day 196 ] [ Designated as safety issue: No ]

    A relapse was defined as a 50% loss of maximal American College of Rheumatoid (ACR) Score improvement in participants with psoriatic arthritis who achieved at least an ACR 20 score during the treatment phase.

    Relapses were only captured prior to the prescription of concomitant psoriatic treatment.


  • Area Under the Plasma Concentration Time-curve From 0 to 12 Hours Post Dose (AUC 0-12) [ Time Frame: Day 85 Pre-dose, 0.5, 1, 2, 4, 8, and 12 hours after the AM dose ] [ Designated as safety issue: No ]

    Plasma concentrations of apremilast were determined using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). For Day 1, AUC0-12 was calculated, using linear trapezoidal area method in WinNonlin (linear-linear trapezoidal). For Days 85 and 169/170, the AUC during a dosing interval (12 hours) (AUC0-12), was calculated at steady-state using the partial area function within WinNonlin.

    .


  • Peak (Maximum) Plasma Concentration of Medication (Cmax) [ Time Frame: Day 85 Pre-dose, 0.5, 1, 2, 4, 8, and 12 hours after the AM dose ] [ Designated as safety issue: No ]
    The maximum observed plasma concentration of apremilast (Cmax); the maximum plasma concentration (Cmax) was obtained directly from the observed concentration-time data on Days 1, 85, and 169/170, respectively.

  • Trough Plasma Concentration (Cmin) [ Time Frame: Day 85 Pre-dose ] [ Designated as safety issue: No ]
    The trough observed plasma concentration of apremilast (Cmin) was determined directly from the observed pre-AM dose concentration on Day 85.

  • Time to Maximum Plasma Concentration (Tmax) During the Treatment Phase [ Time Frame: Day 85 Pre-dose, 0.5, 1, 2, 4, 8, and 12 hours after the AM dose ] [ Designated as safety issue: No ]
    The time to reach Cmax (Tmax) was obtained directly from the observed concentration-time data on Day 85. Actual times utilized were used for reporting Tmax values.

  • Terminal Phase Elimination Half Life of Apremilast (t½) [ Time Frame: Day 85 Pre-dose, 0.5, 1, 2, 4, 8, and 12 hours after the AM dose ] [ Designated as safety issue: No ]
    Terminal phase elimination half-life (t1/2) was calculated as follows: t1/2 = 0.693/λz. The terminal elimination rate constant (λZ) was estimated by linear regression of the log-transformed concentration-time data.

  • Apparent Total Clearance of Apremilast From Plasma After Extravascular Administration (CLz/F) During the Treatment Phase [ Time Frame: Day 85 Pre-dose, 0.5, 1, 2, 4, 8, and 12 hours after the AM dose ] [ Designated as safety issue: No ]

    The apparent total clearance of apremilast from plasma after extravascular administration (CLz/F); for Day 1, apparent clearance of drug from plasma (CL/F) was not calculated.

    For Day 85, Apparent clearance of drug from plasma after extravascular administration (CL/F) was calculated as follows: CL/F= Dose/AUC^12 where τ=12.


  • Apparent Total Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F) During the Treatment Phase [ Time Frame: Day 85 ] [ Designated as safety issue: No ]

    Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F) (for Days 1, 85, and 169/170)

    1. For Day 1, Vz/F was not calculated.
    2. For Days 85 and 169/170, apparent volume of distribution of drug (V/z) based on the terminal phase was calculated as follows: Vz/F=Dose/(λ*AUC^12)

  • Accumulation Index (R) [ Time Frame: Day 85 Pre-dose, 0.5, 1, 2, 4, 8, and 12 hours after the AM dose ] [ Designated as safety issue: No ]
    Accumulation represents the relationship between the dosing interval and the rate of elimination for the drug.

  • Mean Residence Time (MRT) During the Treatment Phase [ Time Frame: Day 85 Pre-dose, 0.5, 1, 2, 4, 8, and 12 hours after the AM dose ] [ Designated as safety issue: No ]
    Mean Residence Time (MRT) is defined as the mean duration of time the drug spends in the body. The average concentration at steady state (Cavg) (for Day 85 was calculated as follows: Cavg = (Day 85 AUC0-12)/(12).

  • Change From Baseline in Peripheral Blood T Cell, B Cell, and NK Cell Subsets at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    T cells or T lymphocytes, a type of white blood cell, play a role in cell-mediated immunity. T cells are distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on the cell surface and mature in the thymus. B cells, a type of lymphocyte in the humoral immunity of the adaptive immune system can be distinguished by the presence of a protein on the B cells outer surface called a B cell receptor (BCR). This receptor protein allows a B cell to bind to a specific antigen and make antibodies against antigens [(antigen-presenting cells APCs)], and to develop into memory B cells after activation by antigen interaction. Natural Killer Cells (NK) are a type of cytotoxic lymphocyte critical to the innate immune system. Their role is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. They constitute the third kind of cells differentiated from the common lymphoid progenitor generating B and T lymphocytes and mature in the bone marrow.

  • Percent Change From Baseline of CD3 in the Dermis of the Psoriatic Skin Biopsy at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    The aim of the study was to measure the pharmacodynamic effects of apremilast in participants with plaque psoriasis in skin affected by psoriasis, immune cells enter the skin through blood vessels and cause the epidermis to grow very rapidly and to stop shedding properly. This causes thickening of the skin as well as the scaly build up composed of dead skin cells seen on areas affected by psoriasis.

  • Percent Change From Baseline of CD3 in the Epidermis of the Psoriatic Skin Biopsy at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    The aim of the study was to measure the pharmacodynamic effects of apremilast in participants with plaque psoriasis in skin affected by psoriasis, immune cells enter the skin through blood vessels and cause the epidermis to grow very rapidly and to stop shedding properly. This causes thickening of the skin as well as the scaly build up composed of dead skin cells seen on areas affected by psoriasis.

  • Percent Change From Baseline of CD 11c in the Dermis of the Psoriatic Skin Biopsy at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    The aim of the study was to measure the pharmacodynamic effects of apremilast in participants with plaque psoriasis in skin affected by psoriasis, immune cells enter the skin through blood vessels and cause the epidermis to grow very rapidly and to stop shedding properly. This causes thickening of the skin as well as the scaly build up composed of dead skin cells seen on areas affected by psoriasis.

  • Percent Change From Baseline of CD11c in the Epidermis of the Psoriatic Skin Biopsy at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    The aim of the study was to measure the pharmacodynamic effects of apremilast in participants with plaque psoriasis in skin affected by psoriasis, immune cells enter the skin through blood vessels and cause the epidermis to grow very rapidly and to stop shedding properly. This causes thickening of the skin as well as the scaly build up composed of dead skin cells seen on areas affected by psoriasis.

  • Percent Change From Baseline of CD56 in the Dermis of the Psoriatic Skin Biopsy at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    The aim of the study was to measure the pharmacodynamic effects of apremilast in participants with plaque psoriasis in skin affected by psoriasis, immune cells enter the skin through blood vessels and cause the epidermis to grow very rapidly and to stop shedding properly. This causes thickening of the skin as well as the scaly build up composed of dead skin cells seen on areas affected by psoriasis.

  • Percent Change From Baseline of CD56 in the Epidermis of the Psoriatic Skin Biopsy at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    The aim of the study was to measure the pharmacodynamic effects of apremilast in participants with plaque psoriasis in skin affected by psoriasis, immune cells enter the skin through blood vessels and cause the epidermis to grow very rapidly and to stop shedding properly. This causes thickening of the skin as well as the scaly build up composed of dead skin cells seen on areas affected by psoriasis.

  • Percent Change From Baseline of Langerin in the Dermis of Psoriatic Skin Biopsy at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    The aim of the study was to measure the pharmacodynamic effects of apremilast in participants with plaque psoriasis in skin affected by psoriasis, immune cells enter the skin through blood vessels and cause the epidermis to grow very rapidly and to stop shedding properly. This causes thickening of the skin as well as the scaly build up composed of dead skin cells seen on areas affected by psoriasis.

  • Percent Change From Baseline of Langerin in the Epidermis of the Psoriatic Skin Biopsy at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    The aim of the study was to measure the pharmacodynamic effects of apremilast in participants with plaque psoriasis in skin affected by psoriasis, immune cells enter the skin through blood vessels and cause the epidermis to grow very rapidly and to stop shedding properly. This causes thickening of the skin as well as the scaly build up composed of dead skin cells seen on areas affected by psoriasis.

  • Percent Change From Baseline of Epidermal Thickness in the Psoriatic Skin Biopsy at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    The aim of the study was to measure the pharmacodynamic effects of apremilast in participants with plaque psoriasis in skin affected by psoriasis, immune cells enter the skin through blood vessels and cause the epidermis to grow very rapidly and to stop shedding properly. This causes thickening of the skin as well as the scaly build up composed of dead skin cells seen on areas affected by psoriasis.

  • Percent Change From Baseline in the Inducible Nitric Oxide (iNOS) Inflammatory Marker in Psoriatic Skin Biopsies [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    Inflammatory markers associated with psoriasis (using skin biopsies) were used to detect acute inflammation and as markers of treatment response. The inflammatory markers were measured using Reverse transcriptase polymerase chain reaction (RT-PCR) and the messenger Ribonucleic acid (mRNA) is being measured.

  • Percent Change From Baseline in the Interleukin (IL) IL-22 Inflammatory Marker in Psoriatic Skin Biopsies [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    Inflammatory markers associated with psoriasis (using skin biopsies) were used to detect acute inflammation and as markers of treatment response. The inflammatory markers were measured using Reverse transcriptase polymerase chain reaction (RT-PCR) and the messenger Ribonucleic acid (mRNA) is being measured.

  • Percent Change From Baseline in the p40 Inflammatory Marker in Psoriatic Skin Biopsies [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    Inflammatory markers associated with psoriasis (using skin biopsies) were used to detect acute inflammation and as markers of treatment response. The inflammatory markers were measured using Reverse transcriptase polymerase chain reaction (RT-PCR) and the messenger Ribonucleic acid (mRNA) is being measured.

  • Percent Change From Baseline in the Defensin Beta 4 (DEFB4) Inflammatory Marker in Psoriatic Skin Biopsies [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    Inflammatory markers associated with psoriasis (using skin biopsies) were used to detect acute inflammation and as markers of treatment response. The inflammatory markers were measured using Reverse transcriptase polymerase chain reaction (RT-PCR) and the messenger Ribonucleic acid (mRNA) i being measured.

  • Percent Change From Baseline in the keratin16 (K16) Inflammatory Marker in Psoriatic Skin Biopsies [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    Inflammatory markers associated with psoriasis (using skin biopsies) were used to detect acute inflammation and as markers of treatment response. The inflammatory markers were measured using Reverse transcriptase polymerase chain reaction (RT-PCR) and the messenger Ribonucleic acid (mRNA) is being measured.

  • Percent Change From Baseline in the pluripotent19 (P19) Inflammatory Marker in Psoriatic Skin Biopsies [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    Inflammatory markers associated with psoriasis (using skin biopsies) were used to detect acute inflammation and as markers of treatment response. The inflammatory markers were measured using Reverse transcriptase polymerase chain reaction (RT-PCR) and the messenger Ribonucleic acid (mRNA) is being measured.

  • Percent Change From Baseline in the IL8 Inflammatory Marker in Psoriatic Skin Biopsies [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    Inflammatory markers associated with psoriasis (using skin biopsies) were used to detect acute inflammation and as markers of treatment response. The inflammatory markers were measured using Reverse transcriptase polymerase chain reaction (RT-PCR) and the messenger Ribonucleic acid (mRNA) is being measured.

  • Percent Change From Baseline in the MX1 (Gene That Encodes the Interferon-induced p78 Protein) Inflammatory Marker in Psoriatic Skin Biopsies [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    Inflammatory markers associated with psoriasis (using skin biopsies) were used to detect acute inflammation and as markers of treatment response. The inflammatory markers were measured using Reverse transcriptase polymerase chain reaction (RT-PCR) and the messenger Ribonucleic acid (mRNA) is being measured.

  • Percent Change From Baseline in the IL17A Inflammatory Marker in Psoriatic Skin Biopsies [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    Inflammatory markers associated with psoriasis (using skin biopsies) were used to detect acute inflammation and as markers of treatment response. The inflammatory markers were measured using Reverse transcriptase polymerase chain reaction (RT-PCR) and the messenger Ribonucleic acid (mRNA) is being measured.

  • Percent Change From Baseline in the Tumor Necrosing Factor (TNF) Alpha Inflammatory Marker in Psoriatic Skin Biopsies [ Time Frame: Week 0 to Week 12 ] [ Designated as safety issue: No ]
    Inflammatory markers associated with psoriasis (using skin biopsies) were used to detect acute inflammation and as markers of treatment response. The inflammatory markers were measured using Reverse transcriptase polymerase chain reaction (RT-PCR) and the messenger Ribonucleic acid (mRNA) is being measured.

  • Percent Change From Baseline in the Interferon (INF) Gamma Inflammatory Marker in Psoriatic Skin Biopsies [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    Inflammatory markers associated with psoriasis (using skin biopsies) were used to detect acute inflammation and as markers of treatment response. The inflammatory markers were measured using Reverse transcriptase polymerase chain reaction (RT-PCR) and the messenger Ribonucleic acid (mRNA) is being measured.

  • Percent Change From Baseline in the IL10 Inflammatory Marker in Psoriatic Skin Biopsies [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    Inflammatory markers associated with psoriasis (using skin biopsies) were used to detect acute inflammation and as markers of treatment response. The inflammatory markers were measured using Reverse transcriptase polymerase chain reaction (RT-PCR) and the messenger Ribonucleic acid (mRNA) is being measured.

  • Percent Change From Baseline in the Chemokine Ligand (CXCL9) Inflammatory Marker in Psoriatic Skin Biopsies [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    Inflammatory markers associated with psoriasis (using skin biopsies) were used to detect acute inflammation and as markers of treatment response. The inflammatory markers were measured using Reverse transcriptase polymerase chain reaction (RT-PCR) and the messenger Ribonucleic acid (mRNA) is being measured.

  • Percent Change From Baseline in the IL2 Inflammatory Marker in Psoriatic Skin Biopsies [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    Inflammatory markers associated with psoriasis (using skin biopsies) were used to detect acute inflammation and as markers of treatment response. The inflammatory markers were measured using Reverse transcriptase polymerase chain reaction (RT-PCR) and the messenger Ribonucleic acid (mRNA) is being measured.

  • Percent Change From Baseline in the Dendritic Cell (CD83) Inflammatory Marker in Psoriatic Skin Biopsies [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    Inflammatory markers associated with psoriasis (using skin biopsies) were used to detect acute inflammation and as markers of treatment response. The inflammatory markers were measured using Reverse transcriptase polymerase chain reaction (RT-PCR) and the messenger Ribonucleic acid (mRNA) is being measured.

  • Change From Baseline in the Dermatology Life Quality Index (DLQI) at Week 12 [ Time Frame: Baseline to Week 12 ] [ Designated as safety issue: No ]
    DLQI was the dermatology-specific quality of life (QOL) measure used for the psoriatic population. The DLQI was a validated, self-administered, 10-item questionnaire that measures the impact of skin disease on a participants QoL, based on recall over the past week. Domains include symptoms, feelings, daily activities, leisure, work, personal relationships, and treatment. Possible responses for each of the 10 items are: not at all, a little, a lot, and very much. Each question is rated on a scale of 0 to 3 with a total range of 0 to 30. Higher scores indicate greater impact of disease on QOL

  • Change From Baseline in the Medical Outcome Study Short Form 36-item Health Survey (SF-36) Scores, Mental and Physical Components to Week 12 [ Time Frame: Baseline to Week 12 ] [ Designated as safety issue: No ]
    The SF-36 was a self-administered instrument consisting of 8 multi-item scales that assess 8 health domains: 1) limitations in physical activities because of health problems; 2) limitations in social activities because of physical or emotional problems; 3) limitations in usual role activities because of physical health problems; 4) bodily pain; 5) general mental health (psychological distress and well-being); 6) limitations in usual role activities because of emotional problems; 7) vitality (energy and fatigue); and 8) general health perceptions. A higher score post-baseline is indicative of improvement in the disease state. The summary physical health score included physical functioning, role-physical, bodily pain and general health. The summary mental health score included: vitality, social functioning, role-emotional and mental health. The resulting score for each subscale is then standardized, to obtain values ranging from 0 to 100, with higher values indicating a better QOL.

  • Area Under the Plasma Concentration Time-curve From 0 to 12 Hours Post Dose (AUC 0-12) During the Extension Phase [ Time Frame: Day 169 pre-dose, 0.5, 1, 2, 4, 8 12, 24 and 36 hours after AM dose ] [ Designated as safety issue: No ]
    Plasma concentrations of apremilast were determined using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS).

  • Peak (Maximum) Plasma Concentration of Apremilast (Cmax) During the Extension Phase [ Time Frame: Day 169 pre-dose, 0.5, 1, 2, 4, 8 12, 24 and 36 hours after AM dose ] [ Designated as safety issue: No ]
    The maximum observed plasma concentration of CC-10004 (Cmax); the maximum plasma concentration (Cmax) was obtained directly from the observed concentration-time data on Days 169/170.

  • Time to Maximum Plasma Concentration (Tmax) During the Extension Phase [ Time Frame: Day 169 pre-dose, 0.5, 1, 2, 4, 8 12, 24 and 36 hours after AM dose ] [ Designated as safety issue: No ]
    The time to reach Cmax (Tmax) was obtained directly from the observed concentration-time data on Day 169/170. Actual times utilized were used for reporting Tmax values.

  • Terminal Phase Elimination Half Life of Apremilast (t½) During the Extension Phase [ Time Frame: Day 169 pre-dose, 0.5, 1, 2, 4, 8 12, 24 and 36 hours after AM dose ] [ Designated as safety issue: No ]
    Terminal phase elimination half-life (t1/2) was calculated as follows: t1/2 = 0.693/λz. The terminal elimination rate constant (λZ) was estimated by linear regression of the log-transformed concentration-time data.

  • Apparent Total Clearance of Apremilast From Plasma After Extravascular Administration (CL/F) During the Extension Phase [ Time Frame: Day 169 pre-dose, 0.5, 1, 2, 4, 8 12, 24 and 36 hours after AM dose ] [ Designated as safety issue: No ]
    For 169/170, apparent clearance of drug from plasma after extravascular administration (CL/F) was calculated as follows: CL/F= Dose/AUC12

  • Apparent Total Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F) During the Extension Phase [ Time Frame: Day 169 pre-dose, 0.5, 1, 2, 4, 8 12, 24 and 36 hours after AM dose ] [ Designated as safety issue: No ]
    For Days 169/170, apparent volume of distribution of drug (V/z) based on the terminal phase was calculated as follows: Vz/F=Dose/(λ*AUC12) where λ = the terminal elimination rate constant

  • Accumulation Index During the Extension Phase [ Time Frame: Day 169 pre-dose, 0.5, 1, 2, 4, 8 12, 24 and 36 hours after AM dose ] [ Designated as safety issue: No ]
    Accumulation represents the relationship between the dosing interval and the rate of elimination for the drug.

  • Mean Residence Time (MRT) During the Extension Phase [ Time Frame: Day 169 pre-dose, 0.5, 1, 2, 4, 8 12, 24 and 36 hours after AM dose ] [ Designated as safety issue: No ]
    Mean Residence Time (MRT) is defined as the mean duration of time the drug spends in the body. The average concentration at steady state (Cavg) (for Days169/170) was calculated as follows: Cavg = (Day 169/170)/(12)


Enrollment: 31
Study Start Date: August 2007
Study Completion Date: May 2009
Primary Completion Date: April 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Apremilast 20 mg twice a day (BID)
Apremilast 20 mg orally BID
Drug: Apremilast
20 mg PO (by mouth) twice a day (BID) for 84 days and then an additional 84 days during the optional treatment extension period. For participants meeting the dose escalation criteria, dosage during the optional treatment extension period can be increased to 30 mg BID.
Other Names:
  • CC-10004
  • Otezla

Detailed Description:

This is a phase 2, multicenter, open-label, study to evaluate the safety, tolerability, pharmacodynamics, pharmacokinetics and efficacy of Apremilast in participants with recalcitrant plaque-type psoriasis.

Approximately 31 participants were enrolled and received 20 mg apremilast orally BID and, in participants who are non-responders after 84 days of apremilast, 30 mg Apremilast over the course of the two study treatment phases. The study consisted of four phases: Screening Phase - up to 35 days, Treatment Phase of 84 days, Extension Phase of 84 days and a Observational Follow-up Phase of 28 days.

During the Treatment Phase, participants received two 20 mg Apremilast capsules each day. Following the Treatment Phase, participants had the option to continue on treatment during the Extension Phase. During the Extension Phase, participants either continued to take two 20 mg or dose escalated to two 30 mg of Apremilast each day. Participants who were considered responders (achieved a Psoriasis Area and Severity Index (PASI-75) at the beginning of the Extension Phase continued on 20 mg twice per day (BID) while the remaining participants received 30 mg capsules BID. The Extension Phase was introduced after some participants had already completed the study; therefore, there were several participants who never had the opportunity to continue into the Extension Phase. All participants were asked to participate in a 4-week post-treatment observational follow-up phase either upon completion of the study or upon discontinuation of study drug for those participants who terminated the study early.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Must understand and voluntarily sign an informed consent form

  • Must be male or female subject of any ethnic origin or race that is >18 years at time of consent
  • Must have a documented history of plaque-type psoriasis for at least 6 months prior to screening visit
  • Subjects must fulfill criteria outlined in at least one of the following clinical categories:

    • Unresponsive to standard systemic therapy, as defined by clinical history, in the investigator's opinion, i.e. inadequate response to one or more adequate treatment course (s) of standard systemic therapy
    • Intolerant to or cannot receive (e.g., contraindication to prescribe) standard systemic therapy or biological interventions for psoriasis
  • Must have a Static Physician Global Assessment (sPGA) score of at least 3 and a Body surface area (BSA) ≥ 10% at screening
  • Must meet the specified laboratory criteria:

    o Must be able to adhere to the study visit schedule and study protocol requirements

  • Females of childbearing potential (FCBP) must have a negative urine pregnancy test at screening (Visit 1). In addition, FCBP must agree to use two of the following adequate forms of contraception methods such as oral, injectable, or implantable hormonal contraception; tubal ligation; intrauterine device; barrier contraceptive with spermicide or vasectomized partner while on study. A FCBP must agree to have pregnancy tests every 4 weeks while on study medication.
  • Males (including those who have had a vasectomy) must agree to use barrier contraception (latex condoms) when engaging in sexual activity with FCBP

Exclusion Criteria:

  • History of clinically significant (as determined by the investigator) cardiac, endocrinologic, pulmonary, neurologic, psychiatric, hepatic, renal, hematologic, immunologic, or other major disease
  • Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study
  • Pregnant or lactating females
  • History of active tuberculosis (TB) infection within 3 years prior to the screening visit. Infections which occurred > 3 years prior to entry must have been effectively treated
  • History of incompletely treated latent (as indicated by a positive PPD [purified protein derivative] skin results) TB infection
  • Clinically significant abnormality on the chest x-ray (CXR) at screening
  • Psoriasis flare within 30 days of screening, as defined by protocol
  • Use of systemic therapy for psoriasis within 28 days of Visit 2 (Baseline).
  • Topical therapy as defined in the protocol Adalimumab, etanercept, efalizumab or infliximab use within 56 days of Visit 2 (Baseline)
  • Alefacept use within 180 days of Visit 2 (Baseline)
  • Phototherapy Ultraviolet light A (UVA), Ultraviolet light B (UVB), Psoralens and long-wave ultraviolet radiation (PUVA) within 28 days of Visit 2 (Baseline)
  • Use of any investigational drug within 28 days of Visit 2 (Baseline), or 5 half lives if known (whichever is longer) Clinically significant abnormality on 12-lead Electrocardiogram (ECG) at screening
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00521339

Locations
United States, Massachusetts
Tufts-New England Medical Center Hospitals
Boston, Massachusetts, United States, 02111
United States, Missouri
Central Dermatology
St. Louis, Missouri, United States, 63117
United States, Oregon
Oregon Medical Research Center, P.C.
Portland, Oregon, United States, 97223
United States, Texas
Baylor Research Institute
Dallas, Texas, United States, 75246-1613
Sponsors and Collaborators
Celgene Corporation
Investigators
Study Director: Robert Day, PhD Celgene Corporation
  More Information

No publications provided by Celgene Corporation

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Celgene Corporation
ClinicalTrials.gov Identifier: NCT00521339     History of Changes
Other Study ID Numbers: CC-10004-PSOR-004
Study First Received: August 24, 2007
Results First Received: October 14, 2014
Last Updated: November 11, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Celgene Corporation:
Apremilast,
Psoriasis,
PASI-75,
sPGA

Additional relevant MeSH terms:
Psoriasis
Skin Diseases
Skin Diseases, Papulosquamous
Apremilast
Analgesics
Analgesics, Non-Narcotic
Anti-Inflammatory Agents
Anti-Inflammatory Agents, Non-Steroidal
Antirheumatic Agents
Central Nervous System Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Peripheral Nervous System Agents
Pharmacologic Actions
Phosphodiesterase Inhibitors
Physiological Effects of Drugs
Sensory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on November 25, 2014