Efficacy and Safety of Tildrakizumab in Anti-TNF Naive Patients with Active Psoriatic Arthritis: A Phase III Randomized, Double-Blind, Placebo-Controlled Study
- Trial ID
- 2024-512142-42-00
- Protocol
- TILD-19-19
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of tildrakizumab compared to placebo in anti-Tumour Necrosis Factor (TNF) naïve subjects with active **psoriatic arthritis** (PsA). This is measured by the proportion of subjects achieving a 20% reduction from baseline in American College of Rheumatology response criteria (ACR20) at Week 24. Additionally, the study aims to assess the safety and tolerability of tildrakizumab in this patient population at the same time point. The primary objective is clinically relevant as it addresses the potential of tildrakizumab to improve clinical outcomes in patients with active PsA who have not previously received anti-TNF therapy, offering an alternative treatment option.
Secondary objectives include:
- Evaluating the efficacy of tildrakizumab compared to placebo in anti-TNF naïve subjects with active PsA at Week 24, as measured by the proportion of subjects achieving ACR50 and ACR70.
- Assessing the efficacy in subjects with active psoriasis (PsO) and body surface area (BSA) ≥3%, as measured by the proportion of subjects achieving a 75% reduction from baseline in Psoriasis Area and Severity Index 75 (PASI75 Response) at Week 24.
- Evaluating the change from baseline in health assessment questionnaire – disability index (HAQ-DI) score at Week 24.
- Assessing improvement in structural damage as measured by the change from baseline in the van der Heijde modified total Sharp score of X-ray of hands, wrists, and feet at Weeks 24 and 16.
Participants
The clinical trial involves a total of **126 participants** diagnosed with **Psoriatic Arthritis**. The study population includes both male and female subjects who are **18 years of age or older**. Participants were selected based on specific inclusion criteria, including a confirmed diagnosis of active Psoriatic Arthritis for at least six months, and the presence of at least three tender and three swollen joints at screening and baseline. Subjects must not have had prior exposure to anti-tumor necrosis factor agents for the treatment of Psoriatic Arthritis or Psoriasis. The trial population is not considered vulnerable, and participants are required to maintain stable doses of any ongoing treatments, such as methotrexate, leflunomide, oral corticosteroids, NSAIDs, or low potency opioids, for at least four weeks prior to the initiation of the investigational medicinal product and throughout the study period. Additionally, any non-drug therapies, including physical therapy, diet, and exercise, must also remain stable during the trial. The sponsor has not provided information regarding specific lifestyle considerations such as diet or physical activity beyond the stability requirements for non-drug therapies.
Plans and Procedures
The clinical trial is a **Phase III, randomized, double-blind, placebo-controlled** study designed to evaluate the efficacy and safety of **tildrakizumab** in subjects with active **psoriatic arthritis** who are naive to anti-Tumor Necrosis Factor (TNF) treatments. The trial aims to assess the proportion of subjects achieving a 20% reduction from baseline in the American College of Rheumatology response criteria (ACR20) at Week 24. The study is expected to last until August 2025, with participant recruitment having commenced in December 2020.
Participants will be randomly assigned to receive either tildrakizumab or a placebo, administered as a **subcutaneous injection**. The trial will include several key visits: an initial screening visit to confirm eligibility, followed by regular follow-up visits to monitor efficacy and safety, and a final end-of-study visit. The primary endpoint is the proportion of subjects achieving ACR20 at Week 24, with secondary endpoints including ACR50, ACR70, changes in the Health Assessment Questionnaire-Disability Index (HAQ-DI), and the Psoriasis Area and Severity Index (PASI75) response among subjects with a baseline Body Surface Area (BSA) of ≥3%.
Participants are expected to be involved in the study for a maximum of 108 weeks. Conditions that may lead to early termination from the study include non-compliance with the study protocol, adverse events, or withdrawal of consent. The trial is conducted under strict adherence to ethical guidelines, ensuring that all participants provide written informed consent prior to participation. The study is not categorized as low intervention, reflecting its comprehensive design and rigorous assessment of the investigational product's efficacy and safety.
Treatment
The clinical trial involves the administration of **Ilumetri**, a 100 mg solution for injection in a pre-filled syringe, containing the active substance **tildrakizumab**. Tildrakizumab is a protein-based therapeutic agent classified under the ATC code L04AC17. The pharmaceutical form is a solution for injection, specifically designed for subcutaneous administration. The dosage regimen involves a maximum daily dose of 100 mg, with a total maximum dose of 1000 mg over the treatment period. The treatment duration is set for a maximum of 108 weeks. The administration of Ilumetri is conducted under controlled conditions to ensure participant compliance and safety monitoring throughout the trial.
The study also includes a **placebo** comparator, which is a solution for injection in a pre-filled syringe, designed to match the appearance and administration route of the active treatment. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. This placebo control is essential for accurately assessing the efficacy and safety of tildrakizumab in subjects with active psoriatic arthritis who are naive to anti-TNF therapies. Compliance with the dosing schedule and administration is monitored closely to ensure the integrity of the trial results.
Efficacy
The efficacy of tildrakizumab in the clinical trial will be assessed by evaluating the proportion of subjects achieving a 20% reduction from baseline in the American College of Rheumatology response criteria (**ACR20**) at Week 24. This primary endpoint will provide a measure of the drug's effectiveness in treating active psoriatic arthritis in anti-TNF naive subjects. Secondary endpoints include the proportion of subjects achieving ACR50 and ACR70 at Week 24, the change from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 24, and the proportion of subjects achieving a 75% improvement in the Psoriasis Area and Severity Index (PASI75) response at Week 24 among subjects with a baseline Body Surface Area (BSA) of ≥3%. Additionally, changes from baseline in the van der Heijde modified total Sharp score will be assessed at Weeks 16 and 24.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Subject has provided written informed consent.
- Subject is ≥ 18 years of age at time of Screening.
- 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.
- 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).
- Rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (anti-CCP Ab) negative.
- Diagnosis of active plaque PsO, with at least one psoriatic plaque of ≥2 cm diameter at Screening or a documented history of plaque PsO.
- Subjects must have no prior exposure to anti-tumor necrosis factor (anti-TNF) agent(s) for the treatment of PsO or PsA.
- 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.
- 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).
- 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.
- 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.
- 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.
Exclusion Criteria
- Subject has a planned surgical intervention between Baseline and the Week 24 evaluation for a pretreatment condition.
- 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.
- Major chronic inflammatory or connective tissue disease other than PsA (e.g., rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ankylosing spondylitis, Lyme disease, Sjogren’s disease, mixed connective tissue disease, scleroderma, or gout and other conditions that might confound the evaluation of the benefit of tildrakizumab therapy as judged by the investigator); PsA with spondylitis and/or sacroiliitis is permitted.
- Subject has any concurrent medical condition or uncontrolled, clinically significant systemic disease (e.g., renal failure, heart failure, hypertension, liver disease, diabetes, or anemia) that, in the opinion of the Investigator, could cause participation in this study to be detrimental to the subject.
- Subject has a known history of infection with hepatitis B, hepatitis C, or human immunodeficiency virus. 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 (HBsAg) 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 (HCV) antibody reactive, shall be tested for Hepatitis C virus ribonucleic acid (HCV-RNA). If tested negative, subject can be included in the study. Subjects with HCV-RNA positive shall be excluded from the study.
- Subject had a myocardial infarction, unstable angina pectoris, or ischemic stroke within the past 6 months prior to the first IMP dose.
- Subject has any active malignancy, including evidence of cutaneous basal or squamous cell carcinoma or melanoma.
- 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.
- Subjects with a history of alcohol or drug abuse in the previous 2 years.
- 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 (C-SSRS).
- Subject has laboratory abnormalities at Screening, including any of the following (Subjects are allowed to have 1 re-testing should the Principal Investigator find the result incongruent with the subject’s medical history or highly suspicious of laboratory error): aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 2 times the upper limit of normal (ULN), IND NO. 128807 Tildrakizumab Protocol TILD-19-19 Amendment 2 EuDRA CT Number: 2020-000956-37 Sun Pharmaceutical Industries Limited [SPIL] Confidential Page 17 of 129 Name of Sponsor/Company: Sun Pharmaceutical Industries Limited [SPIL] Individual Study Table Referring to Part of the Dossier: Volume: Page: (For National Authority Use Only) Name of Product: Tildrakizumab Name of Active Ingredient: Tildrakizumab 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.
- Subject has used any of the following within 28 days of IMP initiation: high potency opioid analgesics (e.g., hydrocodone, methadone, hydromorphone, oxycodone, morphine, or fentanyl), recreational marijuana, medical marijuana, and CBD; sulfasalazine, hydroxychloroquine, systemically administered calcineurin inhibitors (e.g., cyclosporine, tacrolimus), 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 (inactivated flu vaccine injection allowed, but not live flu nasal spray vaccine), has a need for use of a live vaccine within 10 weeks of final anticipated dose of IMP. Vaccination for COVID-19: Vaccination with a non-live vaccine is allowed. This vaccination should preferably be completed at least 2 weeks before the first dose of the study drug administration. Administration of a COVID-19 vaccine during blinded part of the study should preferably be avoided. The CRO/sponsor MM should be consulted before administration of COVID-19 vaccine to the subject. The prescribing information of the vaccine and local requirements on use of the vaccine should be followed. Phototherapy
- Use of commercially available or investigational biologic therapies for PsO and/or PsA as follows: any use of anti-TNF therapy prior to IMP initiation, prior use of B-cell depleting agent or T-cell inhibitor within 12 months of Screening, use of any other investigational or commercially available biologic therapies for PsO and/or PsA within 3 months or 5 half-lives (whichever is longer) prior to IMP therapy initiation, any prior use of secukinumab, ustekinumab, ixekizumab, brodalumab, or any drugs targeting interleukin (IL)-17, IL-23, or the IL-12/IL-23-shared p40 molecule.
- Subject use of Apremilast or other approved or investigational medications for the treatment of PsA and/or PsO which are not identified as permitted therapies within 5 half-lives or 15 days (whichever is longer) prior to IMP initiation.
- Subject has known sensitivity to any of the products or any excipients to be administered during dosing (histidine, polysorbate 80, and sucrose).
- Female subjects of childbearing potential who do not agree to abstain from heterosexual activity or practice a dual method of contraception, for example, a combination of the following: (1) oral contraceptive, depo progesterone, or intrauterine device; and (2) a barrier method (condom or diaphragm). 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). Contraceptive methods must be practiced upon signing the Informed Consent and through 17 weeks after the last dose of IMP. If a subject discontinues prematurely, the contraceptive method must be practiced for 17 weeks following final administration of IMP. A follicle stimulating hormone (FSH) test should be performed to confirm menopause (per reference values of the laboratory) for those women with no menses for less than 1 year.
- Female is pregnant or breast feeding, or planning to become pregnant or initiate breastfeeding while enrolled in the study or up to 17 weeks after the last dose of IMP.
- Subject will not be available for protocol-required study visits, to the best of the subject’s and Investigator’s knowledge.
- Subject currently enrolled in another investigational device/procedure or drug study, or Baseline of this study is less than 30 days or 5 half-lives (whichever is longer) since ending another investigational device/procedure or drug study(s), or receiving other investigational agent(s).
- Subject previously has been enrolled (randomized) in this study.
- Subject has any kind of disorder that, in the opinion of the Investigator, may compromise the ability of the subject to give written informed consent and/or to comply with all required study procedures.
- Donation or loss of 400 milliliter (mL) or more of blood within 8 weeks before first dose of IMP.
- Subjects who have been placed in an institution on official or judicial orders.
- Subjects who are related to or dependent on the Investigator, Sponsor, or study site such that a conflict of interest could arise.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Recruiting | 22 Dec 2020 | 30 |
 Germany | Not Recruiting | 22 Dec 2020 | 8 |
 Poland | Not Recruiting | 22 Dec 2020 | 45 |
 Spain | Not Recruiting | 22 Dec 2020 | 25 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Ilumetri 100 mg solution for injection in pre-filled syringe | Test | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | SUBCUTANEOUS INJECTION | 100 | 108 | PRD6676422 |
Tildrakizumab placebo solution for injection in pre-filled syringe | Placebo | N/A | — | — | — | N/A |