| 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 |
| Arthritis associated with 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10037160 |
| E.1.2 | Term | Psoriatic arthritis |
| E.1.2 | System Organ Class | 100000004859 |
|
| 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 |
Parts 1 and 2
Primary Efficacy Objective
- To evaluate the optimal dose regimen of tildrakizumab in subjects with psoriatic arthritis (PsA) as measured by the proportion of subjects achieving a 20% reduction from Baseline in American College of Rheumatology response criteria [ACR20]) at Week 24.
Primary safety Objective (Parts 1 and 2):
- To assess the safety/tolerability and immunogenicity of multiple-dose administration of tildrakizumab in subjects with PsA. |
|
| E.2.2 | Secondary objectives of the trial |
Parts 1 and 2
Secondary Objectives:
- To evaluate the effect of tildrakizumab on ACR20 at Week 52; and ACR50, ACR70, the components of ACR; the proportion of subjects who require adjustment of background therapy, Disease Activity Score (DAS)28(joints)-C-reactive protein (DAS28-CRP), minimal disease activity (MDA), dactylitis and enthesitis, and the Health Assessment Questionnaire Disability Index (HAQ-DI) at Weeks 24 and 52.
- To characterize the pharmacokinetics (PK) of tildrakizumab in subjects with PsA. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject has provided written informed consent.
2. Subject is ≥ 18 years of age at time of Screening.
3. Subject has a diagnosis of PsA (by the Classification of PsA criteria) with symptoms present for at least 6 months (see Appendix 1 of protocol).
4. Subject has ≥ 3 tender and ≥ 3 swollen joints at Screening and Baseline.
5. For subjects receiving non-steroidal anti-inflammatory drugs (NSAIDs) or low-potency opioids (e.g., tramadol), including as needed [PRN] use): subject must be on stable dose for ≥ 4 weeks prior to initiation of IMP and be expected to maintain a stable dose for the first 24 weeks of the study, unless change in dosage is required due to toxicity. Stable dose (including PRN use) is defined as subjects taking an NSAID or low-potency opioids on average 4 days per week for the 4-week period prior to Screening.
6. For subjects receiving non-drug therapy (including but not limited to physical therapy, massage, diet, exercise, emollients, and joint taping), this must be stable for the 4-week period prior to IMP initiation through to the end of Part 1.
7. For subjects receiving methotrexate (MTX) or leflunomide: subject has received treatment for at least 3 months, with a stable dose and method of dosing (not to exceed 25 mg MTX per week or 20 mg leflunomide per day) for at least 8 weeks prior to initiation of IMP, and be expected to maintain a stable dose for the first 24 weeks of the study, unless change in dosage is required due to toxicity. Subjects may not be receiving both leflunomide and MTX concomitantly.
8. For subjects receiving oral corticosteroids: the subject must be on a stable dose (not to exceed the equivalent of 10 mg of prednisone per day) for ≥ 4 weeks prior to initiation of IMP, and be expected to maintain a stable dose for the first 24 weeks of the study.
9. 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 site) performed within 3 months of Screening with no evidence of active TB (or of any other pulmonary infectious diseases),
− if prior latent TB infection (LTBI), must have history of adequate prophylaxis (per local standard of care),
− if presence of LTBI 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. |
|
| E.4 | Principal exclusion criteria |
1. Subject has a planned surgical intervention between Baseline and the Week 24 evaluation for a pretreatment condition.
2. Subject has an active infection or history of infections as follows:
- any active infection for which systemic anti-infectives were used within 28 days prior to first IMP dose, with the last dose having been received within 7 days of Screening,
- a serious infection, defined as requiring hospitalization or intravenous anti-infectives within 8 weeks prior to the first IMP dose, with the last dose having been received within 7 days of Screening,
- recurrent or chronic infections, e.g., chronic pyelonephritis, chronic osteomyelitis, bronchiectasis, or other active infection that might cause this study to be detrimental to the subject.
3. Major chronic inflammatory or connective tissue disease other than PsA (e.g., rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, Lyme disease, gout); PsA with spondylitis and/or sacroiliitis is permitted.
4. Subject has any concurrent medical condition or uncontrolled, clinically significant systemic disease, that, in the opinion of the Investigator, could cause this study to be detrimental to the subject.
5. Subject has a known history of infection with hepatitis B, hepatitis C, or human immunodeficiency virus.
6. Subject had myocardial infarction, unstable angina pectoris, or ischemic stroke within the past 6 months prior to the first IMP dose.
7. Subject has any active malignancy, including evidence of cutaneous basal or squamous cell carcinoma or melanoma.
8. Subject has a history of malignancy within 5 years EXCEPT treated and considered cured cutaneous basal or squamous cell carcinoma, in situ cervical carcinoma, OR in situ breast ductal carcinoma.
9. Subjects with a history of alcohol or drug abuse in the previous 2 years.
10. Significant risk of suicidality at the Screening assessment based on the Investigator’s judgment or, if appropriate, as indicated by a response of “yes” within the last 12 months to question 4 or 5 in the suicidal section, or any response in the behavioral section of the C-SSRS.
11. Subject has laboratory abnormalities at Screening, including any of the following:
- aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 2 times the upper limit of normal (ULN),
- creatinine ≥ 1.5 times the ULN,
- serum direct bilirubin ≥ 1.5 mg/dL,
- white blood cell count < 3.0 x 103/µL,
- positive test result for rheumatoid factor,
- 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.
12. Subject has used any of the following within 28 days of IMP initiation:
- high potency opioid analgesics
- sulfasalazine,
- hydroxychloroquine,
- systemically administered calcineurin inhibitors
- azathioprine,
- topical and parenteral corticosteroids including intramuscular or intra-articular administration (ophthalmic, intra-nasal and inhaled corticosteroids are permitted),
- live vaccines,
- has a need for use of a live vaccine within 10 weeks of final anticipated dose of IMP.
13. Use of commercially available or investigational biologic therapies for psoriasis and/or PsA as follows:
- prior use of more than 1 biologic treatment,
- use of etanercept within 4 weeks, infliximab within 8 weeks, and all other anti-TNF therapy within 3 months prior to IMP initiation,
- prior use of B-cell and T-cell depleting agents within 12 months of Screening,
- use of any other investigational or commercially available biologic therapies for psoriasis and/or PsA within 3 months or 5 half-lives (whichever is longer) prior to IMP initiation,
- use of apremilast or other approved or investigational medications for the treatment of PsA which are not identified as permitted therapies within 5 half-lives or 30 days (whichever is longer) prior to IMP initiation,
- any prior use of secukinumab , ustekinumab, ixekizumab, brodalumab, or any drug including MK3222 targeting interleukin (IL)-17, IL-23, or the IL-12/IL-23-shared p40 molecule.
14. Subject has known sensitivity to any of the products or any excipients to be administered during dosing.
15. Female subjects of childbearing potential who do not agree to abstain from heterosexual activity or practice a dual method of contraception. Male subjects with female partners of childbearing potential who are not using birth control must use a barrier method of contraception if not surgically sterile. Contraceptive methods must be practiced upon entering the study and through 16 weeks after the last dose of IMP. If a subject discontinues prematurely, the contraceptive method must be practiced for 16 weeks following final administration of IMP.
Further exclusion criteria is included in the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The proportion of subjects who achieve ACR20 at Week 24 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• The proportion of subjects who achieve ACR20 at Week 52.
• The proportion of subjects who achieve ACR50 at Weeks 24 and 52.
• The proportion of subjects who achieve ACR70 at Weeks 24 and 52.
• Change from Baseline in the individual components of ACR response at Weeks 24 and 52.
− Tender joint counts (68)
− Swollen joint counts (66)
− Physician Global Assessment (PGA) of disease activity Visual Analog Scale (VAS)
− Patient Global Assessment (PtGA) of disease activity (VAS)
− Patient's pain assessment (VAS)
− Patient's self-assessed disability
− Acute-phase CRP
− Erythrocyte sedimentation rate (ESR)
• The proportion of subjects who require adjustment of background therapy
• Change from Baseline in HAQ-DI at Weeks 24 and 52.
• The proportion of subjects who achieve a DAS28-CRP < 3.2 at Weeks 24 and 52.
• The proportion of subjects who achieve MDA criteria at Weeks 24 and 52.
− A subject is classified as achieving MDA when meeting 5 of the 7 following criteria: tender joint count ≤ 1; swollen joint count ≤ 1; PASI ≤ 1 or BSA ≤ 3; patient VAS ≤ 15; patient global disease activity VAS ≤ 20; HAQ-DI ≤ 0.5; tender entheseal points ≤ 1
• Change from Baseline in LDI and LEI at Weeks 24 and 52. |
|
| 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 | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Evaluate immunogenicity following IMP discontinuation |
|
| 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) | No |
| 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 | 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 | 18 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 49 |
| 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 |
| Argentina |
| Chile |
| Germany |
| Hungary |
| Mexico |
| Poland |
| Russian Federation |
| Spain |
| Ukraine |
| United Kingdom |
| United States |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 29 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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