| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Ankylosing spondylitis (AS) and Non-Radiographic Axial Spondyloarthritis (nr-axSpA) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Type of chronic inflammatory arthritis involving the spine and/or sacroiliac joints. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| 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 |
Primary Efficacy Objective (Part 1)
- To evaluate the efficacy of tildrakizumab in subjects with AS or nr-axSpA, as measured by the proportion of subjects achieving Assessment of SpondyloArthritis international Society (ASAS) criteria defined as ≥ 40% improvement in 3 of 4 assessment domains (ASAS40) response criteria 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 AS or nr-axSpA. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives (Parts 1 and 2):
- To evaluate the efficacy of tildrakizumab in subjects with AS or nr-axSpA, as measured by the proportion of subjects achieving ASAS40 response criteria at Week 52, and ASAS20 response criteria at Weeks 24 and 52.
- To characterize the PK of tildrakizumab in subjects with AS or nr-axSpA. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject has provided informed consent.
2. Subject is ≥ 18 years of age at time of Screening.
3. Definite AS based on the modified New York criteria (1984) with symptom duration of at least 3 months at Screening as defined by modified New York criteria (1984), or for nr-axSpA, a documented diagnosis of adult onset axial spondyloarthritis as defined by the specific ASAS criteria with at least 3 months symptom duration before Screening.
4. Subjects with nr-axSpA must have active inflammation (MRI) on Screening and no radiographic sacroiliitis that fulfils the 1984 modified New York criteria.
5. Active disease at Screening, defined as:
− BASDAI score (0-10) of at least 4, and
− Response to the BASDAI question of ‘How would you describe the overall level of AS neck, back or hip pain you have had?’ of 40 or more on the VAS (0-100 mm), despite maximum tolerated doses of nonsteroidal anti-inflammatory drugs (NSAIDs).
6. Have either an inadequate response for axial symptoms to 30 days of optimal daily doses of at least 1 NSAID or intolerance to at least 2 NSAIDs as defined to include indigestion, heartburn, dizziness, headache, nausea, vomiting, constipation, diarrhea, decreased appetite, and/or rash.
7. The following concomitant medications are allowed if the dosage remained stable for at least 4 weeks before the Baseline visit and during the study:
− sulfasalazine (up to 3 g a day), in subjects who have been treated for at least 3 months prior to Baseline,
− methotrexate (MTX) (up to 25 mg per week) with no change in route of administration and only in subjects who have been treated for at least 3 months prior to Baseline,
− prednisone or prednisone equivalent (up to 10 mg per day).
Tapering of any of these concomitant medications during the study is allowed only if there is toxicity (accompanied by recording of an AE on the electronic case report form [eCRF]); otherwise the dosage must remain the same throughout Part 1 of the study. Adjustment of concomitant medication is permitted throughout Part 2 (Week 25 to 52) as needed (PRN) per Investigator discretion and therapeutic needs of the subject.
8. For subjects receiving NSAIDs (including PRN use): the subject must be on a stable dose for ≥ 2 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.
9. Subject has a negative test for tuberculosis (TB) within 4 weeks before initiating IMP, defined as:
− a negative QuantiFERON® test,
− AND a posterior-anterior and lateral chest radiogram performed within 3 months of Screening with no evidence of active TB (or of any other pulmonary infectious diseases).
10. 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,
− if prior latent TB infection, the subject must have a 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 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. Radiographic evidence of total ankylosis of the spine (defined by syndesmophytes present on the lateral views of spinal radiographs at all intervertebral levels from T6 through S1; films will be read centrally).
2. Subjects with known diagnosis of fibromyalgia or complex regional pain syndromes.
3. Active uveitis or symptomatic inflammatory bowel disease requiring therapy at Screening.
4. Subject has a planned surgical intervention between Baseline and the Week 24 evaluation for a pre-treatment condition.
5. 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,
− any serious infection, defined as requiring hospitalization or intravenous anti-infectives within 8 weeks prior to the first investigational product 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 this study to be detrimental to the subject.
6. Major chronic inflammatory or connective tissue disease other than AS (e.g., psoriatic arthritis [PsA], rheumatoid arthritis, systemic lupus erythematosus, Lyme disease, and gout).
7. 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 this study to be detrimental to the subject.
8. Subject has known history of infection with hepatitis B, hepatitis C, or human immunodeficiency virus.
9. Subject had myocardial infarction, unstable angina pectoris, or ischemic stroke within the past 6 months prior to the first IMP dose.
10. Subject has any active malignancy, including evidence of cutaneous basal or squamous cell carcinoma or melanoma.
11. Subject has 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.
12. Subjects with a history of alcohol or drug abuse in the previous 2 years.
Laboratory abnormalities
13. 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 ULN,
− serum direct bilirubin ≥ 1.5 mg/dL,
− white blood cell (WBC) count < 3.0 x 103/μL,
− any other laboratory abnormality that, 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
14. Disease modifying anti-rheumatic drugs (DMARD) other than NSAIDs, MTX or sulfasalazine must be discontinued 4 weeks prior to randomization, except for leflunomide, which has to be discontinued for 8 weeks prior to randomization (in the absence of a washout with cholestyramine).
15. Subject has used any of the following within 28 days of IMP initiation:
− high potency opioid analgesics (e.g., methadone, hydromorphone, or morphine),
− parenteral corticosteroids including intramuscular or intraarticular administration,
− live vaccines,
− has a need for use of a live vaccine within 10 weeks of final dose of IMP.
16. Use of commercially available or investigational biologic therapies for AS as follows:
− use of more than 1 biologic treatment,
− use of entanercept 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 AS or nr-axSpA within 3 months or 5 half-lives (whichever is longer) prior to IMP initiation,
− any prior use of secukimumab, ustekinumab, ixekizumab, brodalumab, or any drug including MK-3222 targeting interleukin (IL)-17, IL-23, or the IL-12/IL-23-shared p40 molecule.
General
17. Subject has known sensitivity to any of the products or any excipients to be administered during dosing.
18. Female subjects of childbearing potential must agree to 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 (eg, condom) if not surgically sterile (ie, vasectomy).
See protocol for further exclusion criteria |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint for efficacy will be the proportion of subjects who achieve ASAS40 at Week 24. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints will be
- The proportion of subjects who achieve ASAS40 at Week 52
- The proportion of subject who achieve ASAS20 at Weeks 24 and 52
- Evaluation of PK parameters: area under the concentration-time curve (AUC), maximum concentration (Cmax), minimum concentration (Cmin), time of maximal concentration (tmax) and half-life (T1/2). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
ASAS40 at Week 52
ASAS20 at Weeks 24 and 52
PK samples for evaluation will be collected at timepoints detailed in the Schedule of Assessments in the protocol. |
|
| 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 | 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 | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| 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 | 32 |
| 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 |
| Germany |
| Hungary |
| Mexico |
| Poland |
| Spain |
| 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 | 4 |
| 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 | 4 |
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