| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| moderate to severe chronic plaque psoriasis |
|
| E.1.1.1 | Medical condition in easily understood language |
| chronic inflammatory skin disease |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| MedDRA Classification |
| 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 |
Part A: Pharmacokinetics (PK) Component
To characterize PK and safety of tildrakizumab in pediatric subjects during a 16-week treatment period in support of final pediatric dose selection.
Part B: Randomized Trial Component
To evaluate the efficacy of tildrakizumab in pediatric subjects from 6 to <18 years of age with moderate to severe chronic plaque psoriasis as measured by the proportion of subjects with at least 75% improvement in the Psoriasis Area & Severity Index (PASI 75) response from baseline, and the proportion of subjects with Physician’s Global Assessment (PGA) score of “clear” or “almost clear” with at least a 2 grade reduction from baseline at Week 12 compared to placebo. |
|
| E.2.2 | Secondary objectives of the trial |
Assess efficacy of tildrakizumab compared to placebo as measured by the
proportion of subjects achieving PASI 75 & PGA score of “clear” or “almost
clear” with at least a 2 grade reduction.
Assess efficacy of tildrakizumab compared to placebo as measured by the
proportion of subjects achieving PASI 50, PASI 90, & PASI 100.
Assess changes in quality of life with the use of tildrakizumab for the
treatment of moderate-to-severe chronic plaque psoriasis as measured by
Children’s Dermatology Life Quality Index.
Assess long-term safety & tolerability.
Evaluate immunogenicity.
Assess percent of subjects with severe infections or any infection requiring IV antibiotics whether or not reported as a serious event as per the regulatory definition.
Assess percent of subjects with malignancies.
Assess percent of subjects with confirmed MACE.
Assess percent of subjects with drug-related hypersensitivity reactions. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A subject must have met all the criteria listed below to participate in the study.
- Subject must be 6 to < 18 years of age, of either sex, of any race/ ethnicity, must weigh > 15 Kg.
- Diagnosis of predominantly plaque psoriasis for ≥6 months (as determined by subject interview and confirmation of diagnosis through physical examination by investigator).
- Moderate to severe psoriasis at baseline defined as :
- At least 10% Body Surface Area (BSA) involvement
- PGA score ≥ 3
- PASI score ≥ 12
- Subject must be considered a candidate for systemic therapy, meaning psoriasis inadequately controlled by topical treatments (corticosteroids), and/or phototherapy, and/or previous systemic therapy
- Subject is considered to be eligible according to the following tuberculosis (TB) screening criteria:
a.Has no history of untreated latent or active TB prior to screening. Prophylactic treatment for latent TB (as per local guidelines) must be initiated at least 4 weeks prior to first administration of study medication.
b. Has no signs or symptoms suggestive of active TB upon
medical history and/or physical examination.
c. Has 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 at least 4 weeks prior to the first administration of study medication.
d. Within 4 weeks prior to first administration of study
medication, either has negative diagnostic TB test results (defined as a negative tuberculin skin test ) or a negative QuantiFERON-TB Gold test.
e. A subject who has a positive intradermal skin test or
positive QuantiFERON-TB Gold test, or who has had recent close contact with a person with active TB, or has signs or symptoms suggestive of active TB upon medical history and/or physical examination, or if required by local guidelines or regulations as part of routine TB screening, must have a negative chest radiograph (both posterior-anterior and lateral views) or chest computed tomography (CT) scan taken within 4 weeks prior to first administration of study medication. The radiograph or scan must be read by a qualified radiologist, and must have no evidence of current active TB or old inactive TB. (Note: If either the tuberculin skin or QuantiFERON-TB Gold test is positive, and the chest radiograph or chest CT scan is negative, the subject is considered to have latent TB infection [LTBI]. Subjects with LTBI may be included if they receive prophylactic treatment for latent TB or have previously completed an adequate course of prophylactic treatment according to local guidelines or regulations without subsequent new exposure to active TB. The investigator is strongly encouraged to consider referral to a TB specialist to assess the need for repeat of prophylactic therapy if there is a history of new exposure to active TB subsequent to completion of prior treatment for LTBI or if prior treatment of LTBI was completed more than 3 months prior to screening.)
-A maximum of 2 QuantiFERON tests will be allowed. A re-test is only permitted if the first is indeterminate; the result of the second test will then be used.
- Subject is unlikely to conceive, as indicated by at least one yes answer to the following questions:
- Subject is a male.
- Subject is a female of child-bearing potential and agrees to abstain from heterosexual activity OR use a medically accepted method of contraception OR use appropriate effective contraception as per local regulations or guidelines. Medically accepted methods of contraception include, but are not limited to, condoms (male or female) with or without a spermicidal agent, diaphragm or cervical cap with spermicide, medically prescribed Intra uterine Device (IUD), inert or copper-containing IUD, hormone-releasing IUD, systemic hormonal contraceptive, and surgical sterilization (e.g., hysterectomy or tubal ligation). Male subjects with female partners of childbearing potential who are not using birth control as described above must use a barrier method of contraception (eg, condom) if not surgically sterile (ie, vasectomy).
- Subject is a surgically sterilized female or is documented to be pre-menarchal
- For a female with childbearing potential, a negative serum pregnancy test at Screening and a negative urine pregnancy test within 24 hours prior to the first dose of study medication and on subsequent visits at which IMP doses are scheduled
- Subject must have results of a physical examination within normal limits or clinically acceptable limits to the investigator prior to the first dose of study medication. The investigator is encouraged to consult with the medical monitor (or appropriate designee) if there are questions regarding the significance of any out of range values. |
|
| E.4 | Principal exclusion criteria |
A subject meeting any of the exclusion criteria listed below must be excluded from participating in the trial:
- Subject has predominantly non-plaque forms of psoriasis specifically erythrodermic psoriasis, predominantly pustular psoriasis, medication-induced or medication-exacerbated psoriasis, or new-onset guttate psoriasis.
- Subject has laboratory abnormalities at screening including any of the following:
a) Alanine transaminase (ALT) or aspartate transaminase (AST) ≥2X the upper limit of normal
b) Creatinine ≥1.5X the upper limit of normal
c) serum direct bilirubin ≥ 1.5 mg/dL
d) white blood cell count < 3.0 x 103/μL
e) any other laboratory abnormality, which, in the opinion of the Investigator, will prevent the subject from completing the study or will interfere with the interpretation of the study results.
- Subject who is expected to require topical therapy, phototherapy, or additional systemic therapy for psoriasis during the trial.
- Female subjects of childbearing potential who are pregnant, intend to become pregnant (within 6 months of completing the trial), or are lactating. (Sexually active adolescent girls will be required to use contraception)
- Subject with presence of any infection or history of recurrent infection requiring treatment with systemic antibiotics within 2 weeks prior to Screening, or severe infection (e.g. pneumonia, cellulitis, bone or joint infections) requiring hospitalization or treatment with IV antibiotics within 8 weeks prior to Screening
- Subject with any previous use of tildrakizumab or other IL-23/Th-17 pathway inhibitors, including p40, p19 and IL-17 antagonists for psoriasis. (Prior use of TNF-alpha inhibitors will be allowed. However, the number of subjects with prior use of TNF-alpha inhibitors will be capped at 40% and the analysis will be stratified based on prior use of these biologics)
- Positive human immunodeficiency virus (HIV) test result, hepatitis B surface (HBS) antigen, or hepatitis C virus (HCV) test result.
- Prior malignancy or concurrent malignancy (excluding successfully treated basal cell carcinoma, squamous cell carcinoma of the skin in situ, squamous cell carcinoma with no evidence of recurrence within 5 years or carcinoma in situ of the cervix that has been adequately treated).
- Subject who has received live viral or bacterial vaccination within 4 weeks prior to baseline or who intends to receive live viral or bacterial vaccination during the trial.
- Subject who is currently participating in another interventional clinical trial or has participated in an interventional clinical trial within 5 half-lives (of the drug) to wash out prior to randomization. (Subjects participating in observational studies or non-interventional registry studies may be included in the study)
- Subject has sustained, uncontrolled hypertension (systolic blood pressure of ≥160 mmHg and/or diastolic blood pressure of ≥100 mmHg at Screening), or has uncontrolled diabetes.
- Within 6 months prior to screening, any significant organ dysfunction or clinically significant laboratory abnormalities that place the subject at unacceptable risk for participation in a trial of an immunomodulatory therapy in the judgment of the investigator.
- The subject or a family member is among the personnel of the investigational site or sponsor/designee staff directly involved with this trial.
- Any concomitant medical condition which in the opinion of the investigator could affect the trial outcome or present an unacceptable risk
- Subject who, in the opinion of the investigator, will not be a reliable participant in the trial.
- Subject who, has a history of alcohol and drug abuse in the previous year |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The co-primary endpoints of PASI 75 response rate and the proportion of subjects with PGA of "clear" or "minimal" with at least a 2 grade reduction from baseline at Week 12 will be analyzed using Fisher’s exact test for comparison between treatment groups. Subjects with missing data will be treated as non-responders. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The key secondary efficacy endpoints of PASI50, PASI90, PASI100 response rates, BSA, and CDLQI will be summarized across all time points with descriptive statistics. For all PASI responses, comparison between treatment groups will be analyzed using Fisher’s exact test.
BSA and DLQI will be analyzed between treatment groups using continuous methods. More detailed descriptions of these analyses will be presented in the Statistical Analysis Plan.
If at least one of the tests on the primary efficacy endpoints is significant, the subsequent tests on these five key secondary endpoints will be done in a stepdown manner to preserve the experimentwise error rate. The order of testing will be PASI90, PASI100, PASI50, CDLQI, and BSA. |
|
| 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 | 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) | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| 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 |
| France |
| Hungary |
| Poland |
| Spain |
|
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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