A Phase III, Randomized, Double-Blind, Placebo-Controlled Study to Demonstrate the Efficacy and Safety of Tildrakizumab in Anti-TNF Experienced Subjects with Active Psoriatic Arthritis I (INSPIRE 1)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Sun Pharmaceutical Industries Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

Trial duration

15 Jan 2021 → 22 Dec 2025

Decision date (initial)

2024-06-04

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-507415-35-00

EudraCT number

2020-000955-11

ClinicalTrials.gov

NCT04314544

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

• To evaluate the efficacy of tildrakizumab compared to placebo in anti-TNF experienced 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.
• To assess the safety and tolerability of tildrakizumab in subjects with active PsA at Week 24.

Secondary objectives 4

1. To evaluate the efficacy of tildrakizumab compared to placebo in subjects with active PsA at Week 24 as measured by the proportion of subjects achieving: ACR50 / ACR70
2. To evaluate the efficacy of tildrakizumab compared to placebo 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.
3. To evaluate the efficacy of tildrakizumab compared to placebo in subjects with active PsA as measured by the change from baseline in health assessment questionnaire – disability index (HAQ-DI) score at Week 24.
4. To evaluate the efficacy of tildrakizumab compared to placebo in 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, and feet at Week 24.

Conditions and MedDRA coding

Psoriatic Arthritis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

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.
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 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. 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 blind 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.

Exclusion criteria 24

1. 1. Subject has a planned surgical intervention between Baseline and the Week 24 evaluation for a pretreatment condition.
2. 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 IV 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, in the opinion of the Investigator, might cause participation in this study to be detrimental to the subject.
3. 3. Major chronic inflammatory or connective tissue disease other than PsA (e.g., rheumatoid arthritis (RA), systemic lupus erythematosus, ankylosing spondylitis, Lyme disease, Sjogren’s disease, mixed connective tissue disease, scleroderma, or gout that might confound the evaluation of the benefit of tildrakizumab therapy as judged by the investigator); PsA with spondylitis and/or sacroiliitis is permitted.
4. 4. 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.
5. 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 (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.
6. 6. Subject had myocardial infarction, unstable angina pectoris, or ischemic stroke within the past 6 months prior to the first IMP dose.
7. 7. Subject has any active malignancy, including evidence of cutaneous basal or squamous cell carcinoma or melanoma.
8. 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. 9. Subjects with a history of alcohol or drug abuse in the previous 2 years.
10. 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 C-SSRS.
11. 11. Subject has laboratory abnormalities at Screening, including any of the following: - AST or ALT ≥ 2 times the 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 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. For subjects enrolled from Italy, - AST or ALT ≥ 2 times the ULN, - eGFR calculated using modification of diet in renal disease (MDRD) study equation ≤ 90 mL/min/1.73 m2 Note: MDRD study equation eGFR = 175 x (SCr)-1.154 x (age)-0.203 x 0.742 [if female] x 1.212 [if Black] where eGFR (estimated glomerular filtration rate) units are: mL/min/1.73 m2, Scr (serum creatinine) units are: mg/dL, and age is reported in years, - 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.
12. 12. 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), - sulfasalazine, - hydroxychloroquine, - systemically administered calcineurin inhibitors (e.g., cyclosporine, tacrolimus), - azathioprine, - topical and parenteral corticosteroids including intramuscular or intra-articular administration (ophthalmic, intra-nasal, inhaled corticosteroids, and low potency topical corticosteroid applied to psoriatic lesions in the face and groins are permitted), - topical coal tar, - live vaccines, 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
13. 13. Use of commercially available or investigational biologic therapies for PsO and/or PsA as follows: - 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 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 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.
14. 14. 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 15 days (whichever is longer) prior to IMP initiation
15. 15. Subject has known sensitivity to any of the products or any excipients to be administered during dosing (histidine, polysorbate 80, and sucrose).
16. 16. 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 entering the study 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 FSH test should be performed to confirm menopause for those women with no menses for less than 1 year.
17. 17. 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.
18. 18. Subject will not be available for protocol-required study visits, to the best of the subject’s and Investigator’s knowledge.
19. 19. 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).
20. 20. Subject previously has been enrolled (randomized) in this study.
21. 21. 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.
22. 22. Donation or loss of 400 mL or more of blood within 8 weeks before first dose of IMP.
23. 23. Subjects who have been placed in an institution on official or judicial orders.
24. 24. Subjects who are related to or dependent on the Investigator, Sponsor, or study site such that a conflict of interest could arise.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The proportion of subjects who achieve ACR20 at Week 24

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Sun Pharmaceutical Industries Limited

Sponsor organisation

Sun Pharmaceutical Industries Limited

Address

1 Plot No 201 B, Western Express Highway, Goregaon East Western Express Highway Goregaon East

City

Mumbai

Postcode

400063

Country

India

Scientific contact point

Organisation

Sun Pharmaceutical Industries Limited

Contact name

Richard Chou

Public contact point

Organisation

Sun Pharmaceutical Industries Limited

Contact name

Richard Chou

Third parties 6

Locations

7 EU/EEA countries · 35 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 69 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

10 submissions — initial application plus substantial / non-substantial modifications