| 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 |
| Active Psoriatic Arthritis |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| 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 |
Primary Efficacy Objective:
To evaluate the efficacy of tildrakizumab compared to placebo in anti-TNF naïve subjects with active 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:
To assess the safety and tolerability of tildrakizumab in anti-TNF naïve subjects with active PsA at Week 24. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of tildrakizumab compared to placebo in anti-TNF naïve subjects with active PsA at W24 as measured by the proportion of subjects achieving: - ACR50; - ACR70
- To evaluate the efficacy of tildrakizumab compared to placebo in anti-TNF naïve subjects with active psoriasis and body surface area ≥3% as measured by the proportion of subjects achieving a 75% reduction from Baseline in Psoriasis Area and Severity Index 75 Response at W24.
-To evaluate the efficacy of tildrakizumab compared to placebo in anti-TNF naïve subjects with active PsA as measured by the change from baseline in health assessment questionnaire – disability index (HAQ-DI) score at Week 24.
- To evaluate the efficacy of tildrakizumab compared to placebo in anti-TNF naïve subjects with active PsA in improving structural damage as measured by the change from Baseline in the van der Heijde modified total Sharp score of X-ray of hands, wrists & feet at W24.
|
|
| 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 active PsA (by the Classification of PsA criteria, APPENDIX 1) for at least 6 months before the first administration of the study agent and has active PsA confirmed at Screening and Baseline.
4. Subject has ≥ 3 tender and ≥ 3 swollen joints at Screening and Baseline)
Note: Dactylitis of a digit counts as one joint for the purpose of eligibility assessment. However, the individual joints will be counted for the efficacy assessments of Tender joint count (TJC) or Swollen joint count (SJC).
5. Rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (anti-CCP Ab) negative.
6. Diagnosis of active plaque PsO, with at least one psoriatic plaque of ≥2 cm diameter at Screening or a documented history of plaque PsO.
7. Subjects must have no prior exposure to anti-tumor necrosis factor (anti-TNF) agent(s) for the treatment of PsO or PsA.
8. For subjects receiving non-steroidal anti-inflammatory drugs (NSAIDs) or low potency opioids (e.g. only tramadol, meperidine, and codeine allowed), including as needed (PRN) use: the subject must be on a 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 a change in dosage is required due to toxicity. Stable dose and PRN use are defined as subjects taking an NSAID or low potency opioids on average 4 days per week over the 4-week period prior to Screening.
9. For subjects receiving non-drug therapy (including but not limited to physical therapy, massage, diet, exercise, emollients, and joint taping), must be stable for the 4week period prior to IMP initiation through to the end of double blinded study period (Week 24).
10. For subjects receiving methotrexate (MTX) or leflunomide: subject has received treatment for at least 3 months, with a stable dose and method of dosing (methotrexate: oral or subcutaneous injection; leflunomide: oral) (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 a change in dosage is required due to toxicity. Subjects may not be receiving both leflunomide and MTX concomitantly.
11. 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.
12. 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 radiograph (with associated report available at the 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, must have history of adequate prophylaxis (per local standard of care),
if presence of latent TB is established, then treatment according to local country guidelines must have been followed for at least 4 weeks, prior to dosing in the study at visit 2-week 0.
A maximum of 2 QuantiFERON tests of no more than 3 weeks apart 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 5224 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 (IV) anti-infectives within 8 weeks prior to the first IMP dose, with the last dose having been received within 7 days of Screening, Any recurrent or chronic infections, e.g.chronic pyelonephritis, chronic osteomyelitis, bronchiectasis, or other active infection that, in the opinion of the Investigator, might cause participation in this study to be detrimental to the subject
3. Major chronic inflammatory or connective tissue disease other than PsA; 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 participation in 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
5a Following algorithm shall be followed for all subjects for Hepatitis B or Hepatitis C to evaluate this exclusion criteria. Subjects having Hepatitis B surface antigen positive will be excluded from the study. Subjects having HBsAg negative test shall be tested for Hepatitis B core antibody (Anti-HBc). Subjects with negative Anti-HBc can be included in the study. Subjects with positive Anti-HBc shall further be tested for Hepatitis B virus deoxyribonucleic acid (HBV-DNA).Subjects tested negative for HBV-DNA shall be included in the study. Subjects tested positive for HBV-DNA shall be excluded from the study. In
the event the HBV DNA test cannot be performed, the subject shall NOT be considered eligible for this study. Subjects with Hepatitis C viral (HCV) antibody non-reactive will be included in the study. Subjects with Hepatitis C viral antibody reactive, shall be tested for Hepatitis C virus ribonucleic acid. If tested negative, subject can be included in the study. Subjects with HCV-RNA positive shall be excluded from the study
6.Subject had a 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 from the time of Screening 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 ideation section, or any response in the behavioral section of the Columbia-Suicide Severity Rating Scale
11.Subject has laboratory abnormalities at Screening, including any of the following
aspartate aminotransferase or alanine aminotransferase (ALT) ≥ 2 times the upper limit of normal (ULN)
creatinine ≥ 1.5 times ULN
serum direct bilirubin ≥ 1.5 mg/dL
white blood cell count < 3.0 x 103/μL
positive test result for RF and/or anti-CCP Ab, 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. Washouts and non-permitted drugs
12. Subject has used any of the following within 28 days of IMP initiation
high potency opioid analgesics, recreational marijuana, medical marijuana, and CBD
sulfasalazine
hydroxychloroquine
systemically administered calcineurin inhibitors
azathioprine
topical (within 14 days of IMP initiation) and parenteral corticosteroids and topical Vitamin D-derivatives (within 14 days of IMP initiation) including intramuscular or intra-articular administration (ophthalmic, intra-nasal, inhaled corticosteroids, and low potency topical corticosteroid and topical Vitamin D-derivatives applied to psoriatic lesions in the face and groins are permitted),
topical coal tar
live vaccines |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Key Secondary Efficacy Endpoints:
- The proportion of subjects achieving ACR50 at Week 24
- The proportion of subjects achieving ACR70 at Week 24
- The proportion of subjects achieving PASI75 response at Weeks 24 among subjects with BSA ≥3% at baseline
- The change from Baseline in the van der Heijde modified total Sharp score at Week 24
- The change from Baseline in the van der Heijde modified total Sharp score at Week 16
Secondary Efficacy Endpoints:
-The Change from Baseline in ACR Response Criteria Components Score at Week 24:
- Tender Joint Count (68)
- Swollen Joint Count (66)
- Physician's Global Assessment of Arthritis (VAS, 1-100)
- Patient's Global Assessment of Arthritis (VAS, 1-100)
- Patient's Assessment of Arthritis Pain (VAS, 1-100)
- CRP levels
- ESR levels
- The change from Baseline in BASDAI at Week 24
- The change from Baseline in LEI at Week 24
- The change from Baseline in LDI at Week 24
- The proportion of subjects who achieve a DAS-CRP < 3.2 at Week 24
- The change from Baseline in van der Heijde modified Sharp sub-scores (erosion score and joint space narrowing score) at Week 24
- The proportion of subjects with the Change in van der Heijde modified total Sharp score <0 at Week 24.
- The change from baseline in HAQ-DI at Week 24. The proportion of subjects with active PsO and BSA ≥3% at Week 24 with:
- PASI90
- PASI100
- The change from Baseline in anti-TNF naïve subjects with active PsO and BSA ≥ 3% at Week 24 in:
- PGA-PSO
- NAPSI
- The proportion of subjects achieving at Week 52 of:
- ACR20
- ACR50
- ACR70
- The change from Baseline in American College of Rheumatology Response Criteria Components Score at Week 52:
- Tender Joint Count (68)
- Swollen Joint Count (66)
- Physician's Global Assessment of Arthritis (VAS, 1-100)
- Patient's Global Assessment of Arthritis (VAS, 1-100)
- Patient's Assessment of Arthritis Pain (VAS, 1-100)
- CRP levels
- ESR levels
- The change from Baseline in BASDAI at Week 52.
- The change from Baseline at Week 52 in:
- LEI
- LDI
- HAQ-DI Score
- The proportion of subjects who achieve a DAS28–CRP < 3.2 at Week 52.
The change from Baseline in van der Heijde modified total Sharp score at Week 52.
The change from Baseline in van der Heijde modified Sharp sub-scores (erosion score and joint space
narrowing score) at Week 52.
- The proportion of subjects with the change in van der Heijde modified total Sharp score <0 at Week 52.
- In anti-TNF naïve subjects with active PsO and BSA ≥3%, the proportion of subjects at Week 52 with:
- PASI75
- PASI90
- PASI100
- In anti-TNF naïve subjects with active PsO and BSA ≥3% PsA, the change from Baseline in NAPSI at
Week 52.
- In anti-TNF naïve subjects with active PsO and BSA ≥3%, the change from Baseline in PGA-PsO at Week
52.
- The relationship of tildrakizumab exposure and ACR response in anti-TNF naïve subjects with PsA.
- The immunogenicity of tildrakizumab and its impact on serum level of tildrakizumab in anti-TNF naïve subjects with PsA |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At prespecified time points throughout the trial. |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Double-blind period is followed by an open-label period |
|
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| 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 |
| Ukraine |
| Australia |
| Japan |
| Korea, Republic of |
| United States |
| Czechia |
| Germany |
| Poland |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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