| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to Severe Plaque-type Psoriasis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Moderate to Severe Psoriasis |
|
| 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 | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10037153 |
| E.1.2 | Term | Psoriasis |
| E.1.2 | System Organ Class | 10040785 - Skin and subcutaneous tissue disorders |
|
| 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 objectives of this study are to evaluate the efficacy and safety of 2 SC dosing tiers of ustekinumab in the treatment of adolescent subjects ≥ 12 to < 18 years of age with moderate to severe chronic plaque psoriasis. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to:
1. Evaluate the impact of ustekinumab on physical, social, emotional, and academic functioning as well as dermatologic symptom impact on health-related quality of life in adolescent subjects with moderate to severe chronic plaque psoriasis.
2. Evaluate the pharmacokinetics and immunogenicity of ustekinumab in adolescent subjects with moderate to severe chronic plaque psoriasis. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Potential subjects must satisfy all of the following criteria to be enrolled in the study:
• Boys or girls ≥ 12 and < 18 years of age.
• Have a diagnosis of plaque-type psoriasis with or without PsA for at least 6 months
prior to first administration of study agent, with widespread lesions defined by
PASI ≥ 12, PGA ≥ 3, and involved BSA ≥ 10%.
• Are candidates for phototherapy or systemic treatment of psoriasis (either naive or
history of previous treatment) or have psoriasis considered by the investigator as
poorly controlled with topical therapy after an adequate dose and duration of
therapy
• Girls must be either:
− Premenarchal or,
− surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal
ligation, or otherwise be incapable of pregnancy) or,
− abstinent (at the discretion of the investigator/per local regulations), or
− if sexually active, be practicing a highly effective method of birth control
(eg, prescription oral contraceptives, contraceptive injections, contraceptive
patch, intrauterine device, double-barrier method [eg, condoms, diaphragm,
or cervical cap, with spermicidal foam, cream, or gel], male partner
sterilization) as local regulations permit, before entry, and must agree to
continue to use the same method of contraception throughout the study and
for 15 weeks after receiving the last dose of study drug.
• All girls must have a negative urine pregnancy test at screening; and a negative
urine pregnancy test at Week 0.
• Boys must agree to use a double barrier method of birth control and to not donate
sperm during the study and for 15 weeks after receiving the last dose of study drug.
• Are considered eligible according to the following TB screening criteria:
− Have no history of latent or active TB prior to screening.
− Have no signs or symptoms suggestive of active TB upon medical history
and/or physical examination.
− Have had no recent close contact with a person with active TB or, if there has
been such contact, will be referred to a physician specializing in TB to
undergo additional evaluation and, if warranted, receive appropriate
treatment for latent TB prior to or simultaneously with the first administration
of study agent.
− Within 6 weeks prior to the first administration of study agent, have a
negative QuantiFERON-TB Gold test result (see Attachment 5), or have a
newly identified positive QuantiFERON-TB Gold test result in which active
TB has been ruled out and for which appropriate treatment for latent TB (see
Section 9.1.2) has been initiated either prior to or simultaneously with the
first administration of study agent. Indeterminate results should be handled
as outlined in Section 9.1.2. A negative tuberculin skin test (see
Attachment 6) or a newly identified positive tuberculin skin test result in
which active TB has been ruled out and for which appropriate treatment for
latent TB has been initiated either prior to or simultaneously with the first
administration of study agent is additionally required if the QuantiFERONTB
Gold test is not approved/registered in that country.
• Must have positive antibody titers to varicella and measles prior to the first
administration of study agent.
• Must agree not to receive a live virus or live bacterial vaccination at least 6 weeks
(or longer as indicated in the package insert of the relevant vaccine) prior to the
first administration of study agent, during the study, or within 15 weeks after the
last administration of study agent.
• Must agree not to receive a bacille Calmette-Guérin (BCG) vaccination within 12
months of screening, during the study, or within 12 months after the last
administration of study agent.
• Must avoid prolonged sun exposure and avoid use of tanning booths or other
ultraviolet light sources during study.
• Have screening laboratory test results within the following parameters:
− Hemoglobin ≥ 12 g/dL
− White blood cells ≥ 4.5 x 109/L
− Neutrophils ≥ 1.5 x 109/L
− Platelets ≥ 150 x 109/L
− Serum creatinine < 1.5 mg/dL (or < 133 μmol/L)
− AST, ALT, and alkaline phosphatase levels must be within the 1.5 x ULN for
the laboratory conducting the test.
• Subjects (or their legally-acceptable representatives) must have signed an informed
consent document indicating that they understand the purpose of and procedures
required for the study and are willing to participate in the study. (Assent is also
required of children capable of understanding the nature of the study [typically
7 years of age and older] as described in Section 16.2.3, Informed Consent). |
|
| E.4 | Principal exclusion criteria |
Potential subjects who meet any of the following criteria will be excluded from
participating in the study:
• Currently have nonplaque forms of psoriasis (eg, erythrodermic, guttate, or
pustular).
• Have current drug-induced psoriasis (eg, a new onset of psoriasis or an
exacerbation of psoriasis from beta blockers, calcium channel blockers, or lithium).
• Are pregnant, nursing, or planning a pregnancy or fathering a child while enrolled
in the study or within 15 weeks after receiving the last administration of study
agent.
• Have used any therapeutic agent targeted at reducing IL-12 or IL-23, including but
not limited to ustekinumab and briakinumab.
• Have used topical medications/treatments that could affect psoriasis or PASI
evaluation (including, but not limited to, corticosteroids, anthralin, calcipotriene,
topical vitamin D derivatives, retinoids, tazarotene, methoxsalen,
trimethylpsoralens) within 2 weeks of the first administration of study agent.
• Have received phototherapy or any systemic medications/treatments that could
affect psoriasis or PASI evaluation (including, but not limited to, oral or injectable
corticosteroids, retinoids, 1,25 dihydroxy vitamin D3 and analogues, psoralens,
sulfasalazine, hydroxyurea, or fumaric acid derivatives) within 4 weeks of the first
administration of study agent.
• Have received any systemic immunosuppressants (eg, MTX, azathioprine,
cyclosporine, 6-thioguanine, mercaptopurine, mycophenolate mofetil, hydroxyurea,
and tacrolimus) within 4 weeks of the first administration of study agent.
• Have received any biologic agent within the previous 3 months or 5 times the t1/2
of the agent, whichever is longer.
• Have received natalizumab, efalizumab, or agents that deplete B or T cells (eg,
rituximab, alemtuzumab, abatacept, or visilizumab) within 12 months of screening,
or, if after receiving these agents, evidence is available at screening of persistent
depletion of the targeted lymphocyte population.
• Are currently receiving lithium, antimalarials, or IM gold, or have received lithium,
antimalarials, or IM gold within 4 weeks of the first administration of study agent.
• Have used a topical investigational agent within 4 weeks or 5 times the t1/2 of the
investigational agent, whichever is longer, before the planned start of treatment or
are currently enrolled in a study of a topical agent.
• Have used a non-topical investigational drug within 3 months or 5 times the t1/2 of
the investigational agent, whichever is longer, before the planned start of treatment
or are currently enrolled in a study of a non-topical investigational agent.
• Have received, or are expected to receive, any live virus or bacterial vaccination at
least 6 weeks (or longer as indicated in the package insert of the relevant vaccine)
prior to the first administration of study agent, during the study, or within 15 weeks
after the last administration of study agent.
• Have had a BCG vaccination within 12 months of screening.
• Have a history of chronic or recurrent infectious disease, including but not limited
to chronic renal infection, chronic chest infection (eg, bronchiectasis), recurrent
urinary tract infection (recurrent pyelonephritis or chronic nonremitting cystitis), or
open, draining, or infected skin wounds or ulcers.
• Have or have had a serious infection (eg, sepsis, pneumonia or pyelonephritis), or
have been hospitalized or received IV antibiotics for an infection during the
2 months prior to screening.
• Have a history of latent or active granulomatous infection, including histoplasmosis
or coccidioidomycosis, prior to screening.
• Have had a nontuberculous mycobacterial infection within 6 months prior to
screening.
• Have ever had an opportunistic infection (eg, cytomegalovirus, pneumocystosis,
aspergillosis).
• Are known to be infected with HIV, hepatitis B, or hepatitis C.
• Have a documented history of immune deficiency syndrome (eg, severe combined
immuno deficiency syndrome, T cell deficiency syndromes, B cell deficiency
syndromes and chronic granulomatous disease).
• Have a known history of lymphoproliferative disease, including lymphoma, or
signs and symptoms suggestive of possible lymphoproliferative disease, such as
lymphadenopathy and/or splenomegaly.
• Have a history of or current signs or symptoms of severe, progressive, or
uncontrolled renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary,
cardiac, neurologic, cerebral, or psychiatric disease.
• Have any known malignancy or have a history of malignancy.
• Have a transplanted organ (with exception of a corneal transplant > 3 months prior
to the first administration of study agent).
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint in this study is the proportion of subjects who achieve a PGA score of cleared or minimal at Week 12. In the primary efficacy analysis, data from all randomized subjects will be analyzed according to their assigned treatment group.
Subjects who discontinue study treatment due to unsatisfactory therapeutic response or an AE of worsening psoriasis, or who started protocol-prohibited medications/therapies that could improve psoriasis after the baseline visit but prior to Week 12, or who enter early escape will be considered as nonresponders at Week 12. In addition, subjects who have a missing PGA score at Week 12 will be considered as not achieving the primary endpoint at Week 12.
In the primary analysis, the proportion of subjects with a PGA score of cleared or
minimal at Week 12 will be compared between the ustekinumab LD group and the
placebo group and between the ustekinumab HD group and the placebo group using
CMH chi-square test stratified by weight (≤ 60 kg or > 60 kg). The p-values will be
ordered. To maintain an overall Type I error rate of 0.05, the Holm’s procedure will be
used (Holm, 1979). The smaller p-value will be compared to 0.025 (2-sided). If this test is significant, then the other p-value will be compared to 0.05 (2 sided). Otherwise, both tests are considered not significant. To establish the efficacy of ustekinumab compared with placebo, at least 1 of the comparisons must be statistically significant (ie, at least the smaller p-value must be ≤ 0.025). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Proportion of patients that achieve Psoriasis Area and Severity Index(PASI) 75 response
Change from baseline in Children's Dermatology Life Quality Index
(CDLQI)
The proportion of patients who achieve a Psoriasis Area and SeverityIndex (PASI) 90 response |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | Yes |
| E.8.1.6 | Cross over | Yes |
| 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 | 4 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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 |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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