| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| moderate to severe chronic plaque psoriasis |
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| E.1.1.1 | Medical condition in easily understood language |
| chronic inflammatory skin disease |
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| 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: Dose finding 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 “minimal” with at least a 2 grade reduction from baseline at Week 12 compared to placebo. |
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| E.2.2 | Secondary objectives of the trial |
| 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 "minimal" with at least a 2 grade reduction from baseline at Week 12 compared to placebo. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Part A and Part B
A subject must have met all the criteria listed below to participate in the base study.
1. Subject must be 6 to ≤17years of age at screening, of either sex, of any race/ethnicity, and must weigh > 15kg.
2. Diagnosis of predominantly plaque psoriasis for ≥6 months (as determined by subject interview and confirmation of diagnosis through physical examination by the Investigator).
3. Moderate to severe psoriasis at baseline defined as:
a. At least 10% BSA involvement
b. PGA score ≥ 3
c. PASI score ≥ 12
4. Subject must be considered a candidate for systemic therapy and/or phototherapy.
5. Subject has a negative evaluation for tuberculosis (TB) within 4 weeks before initiating IMP, defined as a negative QuantiFERON test. Subjects with a positive or 2 successive indeterminate QuantiFERON tests are allowed if they have all of the following:
− No history of active TB or symptoms of TB,
− A posterior-anterior (PA) chest radiogram (with associated report available at the site) was performed within 3 months of screening with no evidence of active TB (or of any other pulmonary infectious diseases),
− If prior latent TB infection must have a history of adequate prophylaxis (per local standard of care),
− If the presence of latent TB is established, then treatment according to local country guidelines must have been followed for 4 weeks prior to inclusion in the study.
A maximum of 2 QuantiFERON tests are allowed. A re-test is only permitted if the first is indeterminate; the result of the second test will then be used.
6. Subject should have documentation of adequate, up-to-date, age-appropriate vaccination status at screening. If required, antibody titers may be checked at screening based on the Investigator’s discretion.
7. Subject is unlikely to conceive, as indicated by at least one yes answer to the following questions:
a. Subject is a male.
b. 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 for continued use during the study and for 6 months following the administration of the last dose of the investigational and medicinal product. 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 Intrauterine 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 (e.g., condom) if not surgically sterile (i.e., vasectomy).
c. Subject is a surgically sterilized female or is documented to be pre-menarchal.
8. For female subjects 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 at all subsequent visits as per the Schedule of Assessments
9. 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. Lab abnormalities deemed not clinically significant should be clarified with the CRO or Sponsor MM before proceeding with the trial
10. To participate in whole-body photography at designated sites, the subject must be willing to give assent or written informed consent and be able to adhere to dose and
visit schedules. Photography will be an optional procedure for subjects to participate in.
Inclusion criteria for Part C (LTE)
1. Willingness and ability to comply with the protocol.
2. Subject has completed at least 64 weeks of Part B of the study. Subjects rolled over from Part A to Part B to receive open-label Tildrakizumab and subjects initially randomized to Etanercept and receiving open label Tildrakizumab in Part B, can enter LTE from week 52 onwards.
3. Subject has a PGA score of ≤ 2 at the baseline visit of Part C.
See protocol for a complete list of Inclusion criteria
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|
| E.4 | Principal exclusion criteria |
Part A and Part B
1. 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.
2. 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.
3. Subject who is expected to require topical therapy, phototherapy, or additional systemic therapy for psoriasis during the trial.
4. Female subject of childbearing potential who are pregnant or intends to become pregnant (within 6 months following administration of the last dose of the investigational medicinal product) or are lactating (Sexually active adolescent girls will be required to use contraception).
5. Subject with the presence of any infection or history of recurrent infection requiring treatment with systemic antibiotics within 2 weeks prior to Screening or severe infection
6. 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 would be allowed. However, the number of subjects with prior use of TNF-alpha inhibitors would be capped at 40%, and the analysis will be stratified based on prior use of these biologics. When the number of subjects with prior use of TNF-alpha inhibitors reaches 40% of the sample size, the study population will be re-evaluated with respect to the general psoriasis population, and the % cap may be revised, if found necessary.
7. Positive human immunodeficiency virus (HIV) test result, hepatitis B surface (HBS) antigen, or hepatitis C virus (HCV) test result.
8. 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).
9. 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. Note: If needed, an entry into the study could be deferred until such vaccination is completed and adequate time (4 weeks) has elapsed until baseline.
10. 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).
11. Subject has sustained uncontrolled hypertension (defined as average SBP and/or DBP that is greater than or equal to the 95th percentile for sex, age, and height on three or more occasions), or has uncontrolled diabetes.
12. Subject has been hospitalized due to an acute cardiovascular event, illness, or surgery within 6 months prior to screening.
13. 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 immunomodulatory therapy in the judgment of the investigator.
Please see protocol for a full list of exclusion criteria.
Exclusion Criteria for Part C (LTE):
1. Females of childbearing potential, who are pregnant or intend to become pregnant (within 6 months following administration of the last dose of the investigational medicinal product) or are lactating (Sexually active adolescent girls will be required to use contraception).
2. Subject who intends to receive live viral or bacterial vaccination during the trial.
3. Subject has any active or uncontrolled significant organ dysfunction or clinically significant laboratory abnormalities that place the subject at unacceptable risk for participation in a long-term trial of an immunomodulatory therapy in the judgment of the investigator.
4. Subject who, in the opinion of the investigator, will not be able to participate optimally in the trial.
5. Subject is receiving or is anticipated to receive any of the prohibited medications, supplements and other substances listed in Table 6 during the course of the trial
6. Subject is receiving any investigational agent (details are listed in Table 6) prior to randomization and throughout the duration of the trial (including Part C).
7. History of hypersensitivity to tildrakizumab or any excipients. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Part A
Pharmacokinetic parameters of tildrakizumab like observed maximum plasma concentration (Cmax), time to observed maximum plasma concentration in plasma (Tmax), area under the plasma concentration-time curve (AUC), half-life (T1/2), apparent volume of distribution (Vd/F) and clearance (CL).
Part B
1. The proportion of subjects with at least 75% improvement in the PASI score (PASI 75 response) from baseline at Week 16.
2. The proportion of subjects with PGA score of “clear” or “minimal” with at least a 2-grade reduction from baseline at Week 16.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Key secondary endpoints
1. The proportion of subjects with at least 75% improvement in the PASI score (PASI 75 response) from baseline at Week 12.
2. The proportion of subjects with PGA score of “clear” or “minimal” with at least a 2-grade reduction from baseline at Week 12.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 |
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| 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 |
| India |
| United States |
| Hungary |
| Poland |
| Slovakia |
| 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
|
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| 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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