Psoriasis
Conditions
Keywords
Psoriasis, Moderate to Severe Plaque Psoriasis, Plaque Psoriasis, CC-10004, Apremilast, Pharmacokinetics, Open-label, Safety, Pediatric
Brief summary
This is a Phase 2, multicenter, open-label study in subjects with moderate to severe plaque psoriasis aged 6 to 17 years, inclusive, intended to assess the safety, tolerability, and PK of apremilast with 2 weeks of oral apremilast treatment followed by a 48-week extension of apremilast treatment. Moderate to severe plaque psoriasis is defined as Psoriasis Area Severity Index (PASI) ≥ 12, Body Surface Area (BSA) ≥ 10%, and static Physician Global Assessment (sPGA) of ≥ 3. The total study duration for each subject will last for up to a total of 107 weeks which includes screening, treatment (including the PK portion of the study and the extension treatment period), two short-term follow-up periods and a long-term follow-up period.
Detailed description
Each subject will undergo a screening period of up to 5 weeks, a treatment period of 2 weeks with PK sample collection, and an extension treatment period of 48 weeks, to allow subjects access to apremilast treatment if medically appropriate (following the completion of the 2 week PK portion). Regardless of when they stop treatment, subjects should complete two post treatment follow-up visits at approximately 4 and 8 weeks after the last dose. All subjects should complete the final follow-up visit at Week 102 or at a timepoint 52 weeks after the last dose of apremilast was taken in subjects who have withdrawn at any time prior to Week 50. At least 32 subjects will be enrolled into this study to provide an adequate PK profile and safety assessment in subjects of different ages and body weight ranges. Subjects will be divided into 2 age groups (adolescents \[ages 12 to 17 years, inclusive\] and children \[ages 6 to 11 years, inclusive\]), with at least 16 subjects in each group. Apremilast treatment will start in older and heavier subjects. Group 1 (ages 12 to 17 years, inclusive; weight ≥ 35 kg) * The data collected from the first 8 subjects will be reviewed by an independent data monitoring committee (DMC) to determine if it is appropriate to proceed with dosing the balance of Group 1 subjects and to proceed with dosing in the Group 2 subjects. and an evaluation of these data by the DMC has been completed. Group 2 (ages 6 to 11 years, inclusive; weight ≥ 15 kg) * The dose regimens (dose strength and/or dose frequency) for these first 8 subjects will be based upon the PK and safety assessments from the first 8 subjects in Group 1. * For the remaining subjects in Group 2, the dose (dose strength and/or dose frequency) will be based upon the subject weight as determined by the PK and safety assessments. The dose strength and/or dose frequency will be adjusted for any safety concerns or for unexpected changes in exposure. In the event of a dose regimen adjustment after the second PK and safety assessment, the first 8 subjects in Group 2 will return to the site for the appropriate dosing adjustment.
Interventions
DRUGApremilast
Sponsors
Amgen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
\- Subjects must satisfy all of the following criteria to be enrolled in the study: 1. Male or female subjects 6 to 17 years of age, inclusive, at the time the informed consent document is signed by the legal guardian 2. Group 1 Only: ages 12 to 17 years, inclusive, and weighs ≥ 35 kg 3. Group 2 Only: ages 6 to 11 years, inclusive, and weighs ≥ 15 kg 4. Subject is able to swallow the apremilast tablet 5. Able to sign an assent with a legal guardian who can understand and voluntarily sign an informed consent 6. Able to adhere to the study visit schedule and other protocol requirements 7. Must agree to withhold vaccinations during the first 2 weeks of dosing. Inactivated vaccines will be allowed during the extension treatment period 8. Diagnosis of chronic plaque psoriasis for at least 6 months prior to Screening 9. Have moderate to severe plaque psoriasis at Screening and Baseline as defined by: * Psoriasis Area and Severity Index (PASI) score ≥ 12; and * Body surface area (BSA) ≥ 10%; and * Static Physician Global Assessment (sPGA) ≥ 3 (moderate to severe) 10. Disease inadequately controlled by or inappropriate for topical therapy for psoriasis 11. Candidate for systemic or phototherapy 12. Have not been exposed to any or have been exposed to no more than one systemic agent for psoriasis 13. At Screening, laboratory values must be within the following ranges: * White blood cell (WBC) count Age (yrs) Males (x 103 /µL) Females (x 103 /µL) 6-11 3.5 - 13.65 3.5 - 13.65 12-18 3.5 - 13.15 3.5 - 13.15 * Platelet count Age (yrs) Males (x 103 /µL) Females (x 103 /µL) 6-11 117 - 394 117 - 394 12-18 126 - 400 126 - 400 * Hemoglobin (Hb) Age (yrs) Males (g/dL) Females (g/dL) 6-11 10.0 - 15.5 10.0 - 15.5 12-18 11.0 - 18.1 10.0 - 16.4 14. Male subjects who engage in activity in which conception is possible must use barrier contraception (male latex condom or nonlatex condom NOT made out of natural \[animal\] membrane \[for example, polyurethane\]) while on apremilast and for at least 28 days after the last dose of apremilast 15. All females of childbearing potential (FCBP) must either practice abstinence\* from heterosexual contact or use one of the approved contraceptive options as described below while on apremilast and for at least 28 days after dministration of the last dose of apremilast. For the purposes of this study, a female subject is considered of childbearing potential if she is ≥ 12 years old or has reached menarche, whichever occurred first At the time of study entry, and at any time during the study when a female subject of childbearing potential's contraceptive measures or ability to become pregnant changes, the Investigator will educate the subject regarding abstinence or contraception options and the correct and consistent use of effective contraceptive methods in order to successfully prevent pregnancy Females of childbearing potential must have a negative pregnancy test at Screening and Baseline. All 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 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 \* Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
Exclusion criteria
* The presence of any of the following will exclude a subject from enrollment: 1. History of or currently active inflammatory bowel disease 2. Major concurrent medical conditions, pregnancy or lactation 3. Any condition that confounds the ability to interpret data from the study 4. Guttate, erythrodermic, or pustular psoriasis 5. Psoriasis flare or rebound within 4 weeks prior to Screening 6. Evidence of skin conditions that would interfere with clinical assessments 7. History of human immunodeficiency virus infection, or positive result to hepatitis B surface antigen or hepatitis C antibodies at Screening 8. Clinically significant abnormality on 12-Lead ECG at Screening 9. History of active mycobacterial infection with any species (including Mycobacterium tuberculosis) within 3 years of the Screening Visit and without documentation of successful treatment 10. Congenital and acquired immunodeficiencies (eg, Common Variable Immunodeficiency),immunoglobulin A deficiency 11. History of recurrent significant infections 12. Active infection or infection treated with antibiotic treatment within 2 weeks of first dose 13. Any history of or active malignancy 14. History of allergy/intolerance to any component of the investigational product, ie, apremilast, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, hypromellose 15 cP, titanium dioxide, polydextrose FCC, talc, maltodextrin, medium chain triglycerides, iron oxide red, iron oxide yellow, and iron oxide black. 15. Deficiencies in lactose metabolism, ie, galactose-1-phosphate uridylyltransferase, UDPglactose 4-epimerase, galactokinase or Fanconi Bickel syndrome, including congenital lactase deficiencies, and glucose-galactose malabsorption. 16. Any other significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study or which places the subject at unacceptable risk if he/she were to participate in the study 17. Prior history of suicide attempt at any time in the subject's lifetime prior to screening or enrollment in the study or major psychiatric illness requiring hospitalization within 3 years 18. Answering 'Yes' to any question on the Columbia-Suicide Severity Rating Scale during screening or at baseline 19. Having received biologic therapy within 5 terminal half-lives, including but not limited to the following time periods: * Four weeks prior to baseline for etanercept * Ten weeks prior to baseline for adalimumab * Twenty-four weeks prior to baseline for ustekinumab 20. Topical therapy within 2 weeks of baseline (including but not limited to topical corticosteroids, topical retinoid or vitamin D analog preparations, tacrolimus, pimecrolimus, or anthralin/dithranol) * Exceptions: low-potency corticosteroids (please refer to the Investigators' Manual) will be allowed as background therapy for treatment of the face, axillae, and groin in accordance with the manufacturers' suggested usage during the course of the study * Subjects with scalp psoriasis will be permitted to use coal tar shampoo and/or salicylic acid scalp preparations on scalp lesions * An unmedicated skin moisturizer (eg, Eucerin®) will be also permitted for body lesions only. Subjects should not use these topical treatments within 24 hours prior to the clinic visit 21. Systemic therapy for psoriasis within 4 weeks prior to baseline (including but not limited to cyclosporine, corticosteroids, methotrexate, oral retinoids, mycophenolate, thioguanine, hydroxyurea, sirolimus, sulfasalazine, azathioprine, and fumaric acid esters) 22. Use of phototherapy (ie, UVB, PUVA)within 4 weeks prior to baseline 23. Use of any investigational drug within 4 weeks prior to baseline, or 5 pharmacokinetic/pharmacodynamic half-lives, if known (whichever is longer) 24. Children in Care: a child who has been placed under the control or protection of an agency, organization, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation 25. Prior treatment with apremilast
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Terminal Phase Elimination Half-Life | For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose. | Terminal-phase elimination half-life (t ½). PK parameters were calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | From first dose of apremilast until 28 days after the last dose; up to 29 July 2019; median treatment duration for adolescents apremilast 20 mg and 30 mg was 50.00 and 50.57 weeks respectively and for children was 50.00 weeks. | A TEAE is an adverse event with a start date on or after the date of the first dose of apremilast and no later than 28 days after the last dose of apremilast. An adverse event is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the subject's health, including laboratory test values, regardless of etiology. A serious AE is any untoward AE that results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization or in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect or constitutes an important medical event. The investigator assessment of severity/intensity of an event was defined as mild, moderate or severe. |
| Maximum Observed Plasma Concentration (Cmax) of Apremilast | For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose. | Maximum observed plasma concentration (Cmax) of apremilast. PK parameters were calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule. |
| Time to Maximum Plasma Concentration (Tmax) of Apremilast | For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose. | Time to maximum observed plasma concentration obtained directly from the observed concentration versus time data. PK parameters were calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule. |
| Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours Post Dose of Apremilast (AUC0-12) | For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose. | Area under the plasma concentration-time curve from time zero to the 12 hours post dose was calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule. |
| Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration of Apremilast (AUC0-t) | For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose. | Area under the plasma concentration-time curve from time zero to the last quantifiable time point and was calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule. |
| Apparent Total Plasma Clearance When Dosed Orally (CL/F) for Apremilast | For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose. | Apparent total plasma clearance (CL/F) of apremilast was calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule. |
| Apparent Total Volume of Distribution When Dosed Orally, Based on Study-State (Vss/F) or in the Terminal Phase (Vz/F) | For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose. | Apparent total volume of distribution when dosed orally, based on study-state (Vss/F) or in the terminal phase (Vz/F). Pharmacokinetic parameters were calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Taste and Acceptability of Apremilast Tablets Using the Faces Likert Scale | Day 1 | Taste and acceptability of the apremilast tablet was assessed using a faces Likert Scale on Day 1, initial dosing. The scale consists of options from 1 (dislike very much, illustrated by a frowning face) to 5 (like very much, illustrated by a smiling face). |
Countries
Canada, Germany, Spain, United States
Participant flow
Recruitment details
The study was conducted at 11 study centers in 4 countries, including the United States, Canada, Germany and Spain.
Pre-assignment details
Participants were enrolled according to a staggered, stepwise approach by age range and weight starting with older and heavier participants. Dosing within and between groups was staggered based on PK data collected and a minimum of 2 weeks of safety data.
Participants by arm
| Arm | Count |
|---|---|
| Group 1 Adolescents: Apremilast 20 mg Participants ages 12 to 17 years old, with a weight of ≥ 35 kg to \< 70 kg received apremilast tablets 20 mg twice a day (BID) for 2 weeks followed by a 48-week extension of apremilast treatment. | 13 |
| Group 1 Adolescents: Apremilast 30 mg Participants ages 12 to 17 years old, with a weight of ≥ 70 kg received apremilast 30 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment. | 8 |
| Group 2 Children: Apremilast 20 mg Participants ages 6 to 11 years old, with a weight of ≥ 15 kg received apremilast 20 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment. | 21 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 2 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Miscellaneous | 2 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 1 | 2 |
Baseline characteristics
| Characteristic | Total | Group 2 Children: Apremilast 20 mg | Group 1 Adolescents: Apremilast 30 mg | Group 1 Adolescents: Apremilast 20 mg |
|---|---|---|---|---|
| Age, Continuous | 11.8 Years STANDARD_DEVIATION 2.95 | 9.3 Years STANDARD_DEVIATION 1.35 | 14.8 Years STANDARD_DEVIATION 2.05 | 13.8 Years STANDARD_DEVIATION 1.77 |
| Age, Customized 12 to 17 years | 21 Participants | 0 Participants | 8 Participants | 13 Participants |
| Age, Customized 6 to 11 years | 21 Participants | 21 Participants | 0 Participants | 0 Participants |
| Baseline Body Mass Index (BMI) category Healthy Weight | 23 Participants | 15 Participants | 1 Participants | 7 Participants |
| Baseline Body Mass Index (BMI) category Obesity | 15 Participants | 5 Participants | 6 Participants | 4 Participants |
| Baseline Body Mass Index (BMI) category Overweight | 4 Participants | 1 Participants | 1 Participants | 2 Participants |
| Baseline Weight Category (kg) ≥ 15 - < 35 kg | 13 Participants | 13 Participants | 0 Participants | 0 Participants |
| Baseline Weight Category (kg) < 15 kg | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Baseline Weight Category (kg) ≥ 35 - < 50 kg | 7 Participants | 4 Participants | 0 Participants | 3 Participants |
| Baseline Weight Category (kg) ≥ 50 - < 70 kg | 14 Participants | 4 Participants | 0 Participants | 10 Participants |
| Baseline Weight Category (kg) ≥ 70 kg | 8 Participants | 0 Participants | 8 Participants | 0 Participants |
| Duration of Plaque Psoriasis | 4.99 Years STANDARD_DEVIATION 3.611 | 2.75 Years STANDARD_DEVIATION 2.057 | 6.96 Years STANDARD_DEVIATION 4.057 | 7.41 Years STANDARD_DEVIATION 3.19 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 5 Participants | 3 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 33 Participants | 16 Participants | 5 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Psoriasis Area Severity Index (PASI) | 17.84 Units on a scale STANDARD_DEVIATION 7.854 | 18.09 Units on a scale STANDARD_DEVIATION 6.144 | 15.65 Units on a scale STANDARD_DEVIATION 3.43 | 18.78 Units on a scale STANDARD_DEVIATION 11.693 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 4 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 3 Participants | 1 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White or Caucasian | 32 Participants | 16 Participants | 6 Participants | 10 Participants |
| Sex: Female, Male Female | 23 Participants | 13 Participants | 1 Participants | 9 Participants |
| Sex: Female, Male Male | 19 Participants | 8 Participants | 7 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 8 | 0 / 21 |
| other Total, other adverse events | 13 / 13 | 7 / 8 | 19 / 21 |
| serious Total, serious adverse events | 0 / 13 | 0 / 8 | 1 / 21 |
Outcome results
Primary
Apparent Total Plasma Clearance When Dosed Orally (CL/F) for Apremilast
Apparent total plasma clearance (CL/F) of apremilast was calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule.
Time frame: For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose.
Population: The PK population included all enrolled participants who received one dose of apremilast and had evaluable PK data. PK data was considered evaluable if there were measurable drug levels of apremilast in plasma from at least 3 time points that extended over a minimal 5-hour period within 12 hours post a dose, eg, predose, 2 and 8 hours post a dose.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1 Adolescents: Apremilast 20 mg | Apparent Total Plasma Clearance When Dosed Orally (CL/F) for Apremilast | 11.113 Liters/hour | Geometric Coefficient of Variation 36 |
| Group 1 Adolescents: Apremilast 30 mg | Apparent Total Plasma Clearance When Dosed Orally (CL/F) for Apremilast | 10.338 Liters/hour | Geometric Coefficient of Variation 41.2 |
| Group 2 Children: Apremilast 20 mg | Apparent Total Plasma Clearance When Dosed Orally (CL/F) for Apremilast | 7.859 Liters/hour | Geometric Coefficient of Variation 40.8 |
Primary
Apparent Total Volume of Distribution When Dosed Orally, Based on Study-State (Vss/F) or in the Terminal Phase (Vz/F)
Apparent total volume of distribution when dosed orally, based on study-state (Vss/F) or in the terminal phase (Vz/F). Pharmacokinetic parameters were calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule.
Time frame: For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose.
Population: The PK population included all enrolled participants who received one dose of apremilast and had evaluable PK data. PK data was considered evaluable if there were measurable drug levels of apremilast in plasma from at least 3 time points that extended over a minimal 5-hour period within 12 hours post a dose, eg, predose, 2 and 8 hours post a dose.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1 Adolescents: Apremilast 20 mg | Apparent Total Volume of Distribution When Dosed Orally, Based on Study-State (Vss/F) or in the Terminal Phase (Vz/F) | 86.870 Liters | Geometric Coefficient of Variation 56.1 |
| Group 1 Adolescents: Apremilast 30 mg | Apparent Total Volume of Distribution When Dosed Orally, Based on Study-State (Vss/F) or in the Terminal Phase (Vz/F) | 101.049 Liters | Geometric Coefficient of Variation 31.6 |
| Group 2 Children: Apremilast 20 mg | Apparent Total Volume of Distribution When Dosed Orally, Based on Study-State (Vss/F) or in the Terminal Phase (Vz/F) | 55.126 Liters | Geometric Coefficient of Variation 51.2 |
Primary
Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours Post Dose of Apremilast (AUC0-12)
Area under the plasma concentration-time curve from time zero to the 12 hours post dose was calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule.
Time frame: For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose.
Population: The PK population included all enrolled participants who received one dose of apremilast and had evaluable PK data. PK data was considered evaluable if there were measurable drug levels of apremilast in plasma from at least 3 time points that extended over a minimal 5-hour period within 12 hours post a dose, eg, predose, 2 and 8 hours post a dose.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1 Adolescents: Apremilast 20 mg | Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours Post Dose of Apremilast (AUC0-12) | 1799.717 ng*h/mL | Geometric Coefficient of Variation 36 |
| Group 1 Adolescents: Apremilast 30 mg | Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours Post Dose of Apremilast (AUC0-12) | 2901.795 ng*h/mL | Geometric Coefficient of Variation 41.2 |
| Group 2 Children: Apremilast 20 mg | Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours Post Dose of Apremilast (AUC0-12) | 2544.874 ng*h/mL | Geometric Coefficient of Variation 40.8 |
Primary
Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration of Apremilast (AUC0-t)
Area under the plasma concentration-time curve from time zero to the last quantifiable time point and was calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule.
Time frame: For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose.
Population: The PK population included all enrolled participants who received one dose of apremilast and had evaluable PK data. PK data was considered evaluable if there were measurable drug levels of apremilast in plasma from at least 3 time points that extended over a minimal 5-hour period within 12 hours post a dose, eg, predose, 2 and 8 hours post a dose.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1 Adolescents: Apremilast 20 mg | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration of Apremilast (AUC0-t) | 1794.815 ng*h/mL | Geometric Coefficient of Variation 35.9 |
| Group 1 Adolescents: Apremilast 30 mg | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration of Apremilast (AUC0-t) | 2900.472 ng*h/mL | Geometric Coefficient of Variation 41.4 |
| Group 2 Children: Apremilast 20 mg | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration of Apremilast (AUC0-t) | 2367.641 ng*h/mL | Geometric Coefficient of Variation 50.2 |
Primary
Maximum Observed Plasma Concentration (Cmax) of Apremilast
Maximum observed plasma concentration (Cmax) of apremilast. PK parameters were calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule.
Time frame: For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose.
Population: The PK population included all enrolled participants who received one dose of apremilast and had evaluable PK data. PK data was considered evaluable if there were measurable drug levels of apremilast in plasma from at least 3 time points that extended over a minimal 5-hour period within 12 hours post a dose, eg, predose, 2 and 8 hours post a dose.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1 Adolescents: Apremilast 20 mg | Maximum Observed Plasma Concentration (Cmax) of Apremilast | 274.272 ng/mL | Geometric Coefficient of Variation 34.3 |
| Group 1 Adolescents: Apremilast 30 mg | Maximum Observed Plasma Concentration (Cmax) of Apremilast | 410.929 ng/mL | Geometric Coefficient of Variation 39.7 |
| Group 2 Children: Apremilast 20 mg | Maximum Observed Plasma Concentration (Cmax) of Apremilast | 348.146 ng/mL | Geometric Coefficient of Variation 47.4 |
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
A TEAE is an adverse event with a start date on or after the date of the first dose of apremilast and no later than 28 days after the last dose of apremilast. An adverse event is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the subject's health, including laboratory test values, regardless of etiology. A serious AE is any untoward AE that results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization or in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect or constitutes an important medical event. The investigator assessment of severity/intensity of an event was defined as mild, moderate or severe.
Time frame: From first dose of apremilast until 28 days after the last dose; up to 29 July 2019; median treatment duration for adolescents apremilast 20 mg and 30 mg was 50.00 and 50.57 weeks respectively and for children was 50.00 weeks.
Population: The safety population consisted of all participants who received at least 1 dose of apremilast
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1 Adolescents: Apremilast 20 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 13 Participants |
| Group 1 Adolescents: Apremilast 20 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any Drug Related TEAE | 11 Participants |
| Group 1 Adolescents: Apremilast 20 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any Severe TEAE | 1 Participants |
| Group 1 Adolescents: Apremilast 20 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any Serious TEAE | 0 Participants |
| Group 1 Adolescents: Apremilast 20 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any Serious Drug-Related TEAE | 0 Participants |
| Group 1 Adolescents: Apremilast 20 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE Leading to Drug Interruption | 1 Participants |
| Group 1 Adolescents: Apremilast 20 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE Leading to Drug Withdrawal | 0 Participants |
| Group 1 Adolescents: Apremilast 20 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE Leading to Death | 0 Participants |
| Group 1 Adolescents: Apremilast 30 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any Severe TEAE | 0 Participants |
| Group 1 Adolescents: Apremilast 30 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE Leading to Drug Withdrawal | 0 Participants |
| Group 1 Adolescents: Apremilast 30 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any Serious TEAE | 0 Participants |
| Group 1 Adolescents: Apremilast 30 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any Serious Drug-Related TEAE | 0 Participants |
| Group 1 Adolescents: Apremilast 30 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE Leading to Drug Interruption | 0 Participants |
| Group 1 Adolescents: Apremilast 30 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 7 Participants |
| Group 1 Adolescents: Apremilast 30 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any Drug Related TEAE | 6 Participants |
| Group 1 Adolescents: Apremilast 30 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE Leading to Death | 0 Participants |
| Group 2 Children: Apremilast 20 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any Severe TEAE | 1 Participants |
| Group 2 Children: Apremilast 20 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any Drug Related TEAE | 17 Participants |
| Group 2 Children: Apremilast 20 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 20 Participants |
| Group 2 Children: Apremilast 20 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any Serious TEAE | 1 Participants |
| Group 2 Children: Apremilast 20 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE Leading to Drug Withdrawal | 2 Participants |
| Group 2 Children: Apremilast 20 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE Leading to Drug Interruption | 4 Participants |
| Group 2 Children: Apremilast 20 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any Serious Drug-Related TEAE | 0 Participants |
| Group 2 Children: Apremilast 20 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE Leading to Death | 0 Participants |
Primary
Terminal Phase Elimination Half-Life
Terminal-phase elimination half-life (t ½). PK parameters were calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule.
Time frame: For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose.
Population: The PK population included all enrolled participants who received one dose of apremilast and had evaluable PK data. PK data was considered evaluable if there were measurable drug levels of apremilast in plasma from at least 3 time points that extended over a minimal 5-hour period within 12 hours post a dose, eg, predose, 2 and 8 hours post a dose.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1 Adolescents: Apremilast 20 mg | Terminal Phase Elimination Half-Life | 5.418 hours | Geometric Coefficient of Variation 43.1 |
| Group 1 Adolescents: Apremilast 30 mg | Terminal Phase Elimination Half-Life | 6.775 hours | Geometric Coefficient of Variation 50.3 |
| Group 2 Children: Apremilast 20 mg | Terminal Phase Elimination Half-Life | 4.862 hours | Geometric Coefficient of Variation 30.2 |
Primary
Time to Maximum Plasma Concentration (Tmax) of Apremilast
Time to maximum observed plasma concentration obtained directly from the observed concentration versus time data. PK parameters were calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule.
Time frame: For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose.
Population: The PK population included all enrolled participants who received one dose of apremilast and had evaluable PK data. PK data was considered evaluable if there were measurable drug levels of apremilast in plasma from at least 3 time points that extended over a minimal 5-hour period within 12 hours post a dose, eg, predose, 2 and 8 hours post a dose.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 1 Adolescents: Apremilast 20 mg | Time to Maximum Plasma Concentration (Tmax) of Apremilast | 2.467 hours |
| Group 1 Adolescents: Apremilast 30 mg | Time to Maximum Plasma Concentration (Tmax) of Apremilast | 3.000 hours |
| Group 2 Children: Apremilast 20 mg | Time to Maximum Plasma Concentration (Tmax) of Apremilast | 2.000 hours |
Secondary
Taste and Acceptability of Apremilast Tablets Using the Faces Likert Scale
Taste and acceptability of the apremilast tablet was assessed using a faces Likert Scale on Day 1, initial dosing. The scale consists of options from 1 (dislike very much, illustrated by a frowning face) to 5 (like very much, illustrated by a smiling face).
Time frame: Day 1
Population: The Safety Population consisted of all participants who received at least 1 dose of apremilast.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1 Adolescents: Apremilast 20 mg | Taste and Acceptability of Apremilast Tablets Using the Faces Likert Scale | 5 (Like Very Much) | 6 Participants |
| Group 1 Adolescents: Apremilast 20 mg | Taste and Acceptability of Apremilast Tablets Using the Faces Likert Scale | 3 (Not Sure) | 5 Participants |
| Group 1 Adolescents: Apremilast 20 mg | Taste and Acceptability of Apremilast Tablets Using the Faces Likert Scale | 1 (Dislike Very Much) | 0 Participants |
| Group 1 Adolescents: Apremilast 20 mg | Taste and Acceptability of Apremilast Tablets Using the Faces Likert Scale | 2 (Dislike a Little) | 1 Participants |
| Group 1 Adolescents: Apremilast 20 mg | Taste and Acceptability of Apremilast Tablets Using the Faces Likert Scale | 4 (Like a Little) | 1 Participants |
| Group 1 Adolescents: Apremilast 30 mg | Taste and Acceptability of Apremilast Tablets Using the Faces Likert Scale | 2 (Dislike a Little) | 0 Participants |
| Group 1 Adolescents: Apremilast 30 mg | Taste and Acceptability of Apremilast Tablets Using the Faces Likert Scale | 5 (Like Very Much) | 3 Participants |
| Group 1 Adolescents: Apremilast 30 mg | Taste and Acceptability of Apremilast Tablets Using the Faces Likert Scale | 4 (Like a Little) | 1 Participants |
| Group 1 Adolescents: Apremilast 30 mg | Taste and Acceptability of Apremilast Tablets Using the Faces Likert Scale | 3 (Not Sure) | 4 Participants |
| Group 1 Adolescents: Apremilast 30 mg | Taste and Acceptability of Apremilast Tablets Using the Faces Likert Scale | 1 (Dislike Very Much) | 0 Participants |
| Group 2 Children: Apremilast 20 mg | Taste and Acceptability of Apremilast Tablets Using the Faces Likert Scale | 5 (Like Very Much) | 10 Participants |
| Group 2 Children: Apremilast 20 mg | Taste and Acceptability of Apremilast Tablets Using the Faces Likert Scale | 1 (Dislike Very Much) | 3 Participants |
| Group 2 Children: Apremilast 20 mg | Taste and Acceptability of Apremilast Tablets Using the Faces Likert Scale | 3 (Not Sure) | 3 Participants |
| Group 2 Children: Apremilast 20 mg | Taste and Acceptability of Apremilast Tablets Using the Faces Likert Scale | 4 (Like a Little) | 4 Participants |
| Group 2 Children: Apremilast 20 mg | Taste and Acceptability of Apremilast Tablets Using the Faces Likert Scale | 2 (Dislike a Little) | 1 Participants |