| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10071117 |
| E.1.2 | Term | Plaque psoriasis |
| E.1.2 | System Organ Class | 100000004858 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of the study is to evaluate the clinical efficacy of apremilast compared with placebo in children and adolescents (ages 6
through 17 years) with moderate to severe plaque psoriasis. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
•To evaluate the safety and tolerability of apremilast compared with placebo, in children and adolescents (ages 6 through 17 years) with
moderate to severe plaque psoriasis
•To evaluate the effect of apremilast compared with placebo on health-related quality of life (HRQoL) |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacodynamic Peripheral Blood RNA Gene Expression Analysis Sub-Study:
Type: pharmacodynamics.
Objective of this sub-study is analysis of specific RNAs to define the mechanism of action of apremilast in patient study population. Data may also inform on the subset of patients who are responding well to
apremilast treatment.
version and date of protocol final 15 August 2018
Pharmacogenetic DNA Analysis Sub-Study:
Type: pharmacogenetics.
The objective of this sub-study is to analyze the genetic polymorphisms that are associated with clinical and pharmacodynamic interaction with apremilast.
version and date of protocol final 15 August 2018
Skin Microbiome Analysis Sub-Study:
Type: other - Skin Microbiome Analysis
The objective of this sub-study is to assess the microbial species (bacterial and fungal) present on the patients' skin by swabbing the affected and unaffected skin and subjected the swabbed material to 16S
and ITS ribosomal RNA gene amplification and sequencing.
version and date of protocol final 15 August 2018 |
|
| E.3 | Principal inclusion criteria |
Subject must satisfy the following criteria to be enrolled in the study:
1. Males or female subjects 6 to 17 years of age, inclusive, at the time the informed consent form is signed by the legal guardian
2. Subjects must have a weight of ≥ 20 kg
3. Subject must have age and sex-specific BMI value no lower in range than the 5th percentile on the Centers for Disease Control (CDC) growth chart for children and adolescents.
4. Subject is able to swallow the study medication tablet
5. Able to sign an age-appropriate assent with a legal guardian(s) who understand(s) and voluntarily sign(s) an informed consent prior to any study-related assessments/procedures being conducted.
6. Be willing and able to adhere to the study visit schedule and other protocol requirements.
7. Diagnosis of chronic plaque psoriasis for at least 6 months prior to screening.
8. Has moderate to severe plaque psoriasis at screening and baseline as defined by:
• PASI score ≥ 12; and
• Body surface area (BSA) ≥ 10%; and
• sPGA ≥ 3 (moderate to severe)
9. Disease inadequately controlled by or inappropriate for topical therapy for psoriasis.
10. Candidate for systemic therapy or phototherapy.
11. At screening, laboratory values must be within the following ranges
•White blood cell (WBC) count
Age (years) Males (x 103 /µL) Females (x 103 /µL)
6-11 3.5 – 13.5 3.5 – 13.5
12-18 3.5 – 13.5 3.5 – 13.5
•Platelet count
Age (years) Males (x 103 /µL) Females (x 103 /µL)
6-11 125 – 500 125 – 500
12-18 125 – 500 125 – 500
•Serum creatinine ≤ 1.2 x upper-limit of normal (ULN) for age and gender. Please see reference ranges of the central laboratory
•Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 1.5 x ULN for age and gender. If initial test of ALT or AST is > 1.5 x ULN, one repeat test is allowed during Screening. Please see the reference ranges of the central laboratory
•Total bilirubin ≤ 2 mg/dL (≤ 34 µmol/L). If initial test result is > 2 mg/dL, one repeat test is allowed during the Screening period
•Hemoglobin (Hb)
Age (years) Males (g/dL) Females (g/dL)
6-11 10.0 – 15.0 10.0 – 15.0
12-18 11.0 – 16.5 10.5 – 15.5
12. 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
during any dose interruption, and for at least 28 days after administration of the last dose of apremilast. For the purpose of thisstudy, 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 highly effective methods: hormonal contraception (for example, birth control pills, intravaginal ring, transdermal patch, injection, implant); intrauterine device (IUD); tubal ligation; or partner's vasectomy.
OR
Option 2: Male or female latex condom or nonlatex condom NOT made out of natural (animal) membrane (for example, polyurethane); PLUS one additional barrier method: (a) diaphragm with spermicide; (b) cervical cap with spermicide; or (c) contraceptive sponge with spermicide.
NOTE: Option 2 may not be acceptable as a highly effective contraception option in all countries per local guidelines/regulations.
* True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
+ If a female subject is a FCBP when entering the study, the chosen form of contraception must be effective by the time the female subject is randomized into the study (for example, hormonal contraception should be initiated at least 28 days before randomization). |
|
| E.4 | Principal exclusion criteria |
The presence of any of the following will exclude a subject from
enrollment:
1. Other than psoriasis, history of any clinically significant (as
determined by the Investigator) cardiac, endocrinologic, pulmonary,
neurologic, psychiatric, hepatic, renal, hematologic, immunologic
disease, or other major uncontrolled disease.
2. Any condition, including the presence of laboratory abnormalities,
or psychiatric illness, that would place the subject at unacceptable risk
if he/she were to participate in the study
3. Any condition that confounds the ability to interpret data from the
study.
4. Evidence of skin conditions, other than psoriasis, that would
interfere with clinical assessments
5. Pregnant or breastfeeding
6. Guttate, erythrodermic, or pustular psoriasis at Screening and Baseline
7. Psoriasis flare or rebound within 4 weeks prior to Screening
8. Positive Hepatitis B surface antigen, or anti-hepatitis C antibody, at Screening
9. History of positive human immunodeficiency virus infection (HIV),
congenital and acquired immunodeficiencies (eg, common variable
immunodeficiency, immunoglobulin A deficiency)
10. Active tuberculosis (TB) or a history of incompletely treated TB
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 15cP, titanium dioxide, polydextrose food chemical color,
talc, maltodextrine, medium chain triglycerides, iron oxide red, iron
oxide yellow, and iron oxide black.
15. Deficiencies in lactose metabolism, ie, galactose-1-phosphate
uridylyltransferase, UDP-galactose 4-epimerase, galactokinase or
Fanconi Bickel syndrome, including congenital lactase deficiencies, and
glucose-galactose malabsorption.
16. Prior history of suicide attempt at any time in the subject's
lifetime prior to Screening or randomization in the study, or major
psychiatric illness requiring hospitalization within 3 years prior to
signing the assent and informed consent
17. Answer "Yes" to any question on the Columbia-Suicide Severity
Rating Scale during Screening or at Baseline
18. Current or planned concurrent use of the following therapies that
may have a possible effect on psoriasis
a. Topical therapy within 2 weeks prior to randomization (including
but not limited to topical corticosteroids, topical retinoid or vitamin D
analog preparations, tacrolimus, pimecrolimus, or anthralin/dithranol)
Exceptions*:
i. Low potency or weak corticosteroids (please refer to the
Investigators' Manual) will be allowed as background therapy for
treatment of the face, axillae and groin in accordance with
manufacturer's suggested usage
ii. Unmedicated skin moisturizer (eg, Eucerin®) will also be permitted
for body lesions
*Subjects should not use these topical treatments within 24 hours prior
to the clinic visit.
b. Conventional systemic therapy for psoriasis within 4 weeks prior to
randomization (including but not limited to cyclosporine,
corticosteroids, methotrexate, oral retinoids, mycophenolate,
thioguanine, hydroxyurea, sirolimus, sulfasalazine, azathioprine, and fumaric acid esters)
c. Phototherapy treatment (ie, ultraviolet B [UVB], PUVA) within 4
weeks prior to randomization
d. Biologic therapy:
i. Etanercept (or biosimilar) treatment four weeks prior to randomization
ii. Adalimumab (or biosimilar) treatment ten weeks prior to randomization
iii. Other TNF or IL-17 blockers (such as infliximab, certolizumab
pegol, secukinumab, ixekizumab, brodalumab, or their biosimilars) within 12 weeks prior to randomization
iv. Anti-IL-12 or anti-IL-23 treatment (such as ustekinumab,
guselkumab, or tildrakizumab) within 24 weeks prior to randomization
e. Use of any investigational drug within 4 weeks prior to
randomization, or 5 pharmacokinetic/pharmacodynamic half-lives, if
known (whichever is longer)
19. Prolonged sun exposure or use of tanning booths or other
ultraviolet (UV) light sources
20. 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
21. Prior treatment with apremilast |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Static Physician Global Assessment (sPGA) - Proportion of subjects
with an sPGA score of clear (0) or almost clear (1) with at least a 2-
point reduction from baseline. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Primary endpoint will be evaluated at the end of Week 16. |
|
| E.5.2 | Secondary end point(s) |
1. Psoriasis Area Severity Index-75 (PASI-75) - Proportion of subjects
who achieve at least a 75% reduction in PASI (PASI-75) from baseline
2. PASI-50 - Proportion of subjects who achieve at least a 75% reduction
in PASI (PASI-75) from baseline
3. PASI - Percent change from baseline in total PASI score
4. Children's Dermatological Life Quality Index (CDLQI) - Change from
baseline in CDLQI score
5. CDLQI (0/1) - Proportion of subjects who achieve CDLQI (0/1)
6. Body Surface Area (BSA) - Percent change from baseline in affected BSA |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| All secondary endpoints will be evaluated at the end of Week 16. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Israel |
| Russian Federation |
| United States |
| Austria |
| Belgium |
| Czechia |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
| Switzerland |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The End of Trial is defined as either the date of the last visit of the last subject to complete the post-treatment follow-up, or the date of receipt of the last data point from the last subject that is required for efficacy and/or safety assessments, as pre-specified in the protocol, whichever is the later date. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 14 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
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