| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate-to-severe active axial spondyloarthritis |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10058338 |
| E.1.2 | Term | Spondylarthritis |
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| 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 |
| The primary efficacy endpoint is the proportion of subjects meeting the Assessment in Ankylosing Spondylitis (ASAS) partial remission criteria at Week 28. The primary objective is to assess the proportion of subjects in the infliximab plus naproxen arm versus the placebo plus naproxen arm, in a population of subjects with moderate-to-severe active axial spondyloarthritis and disease duration of ≤3 years, who achieve the ASAS partial remission criteria. |
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| E.2.2 | Secondary objectives of the trial |
| Compare the proportion of subjects in ASAS partial remission at Wk 52/ET who are on naproxen (NPX) vs those without therapy (tx) between Wks 28-52; Assess the proportion of subjects in the naproxen (NPX)+NPX arm vs the placebo (PBO)+NPX arm who achieve ASAS partial remission at Wk 52/ET; Assess the effect of IFX+NPX vs pbo+NPX on the change of or absence of active inflammatory lesions on MRI of the spine and sacroiliac joints (SIJ); Assess the effect of NPX vs no tx between Wks 28-52/ET on the change of or absence of active inflammatory lesions on MRI of the spine and SIJ; Compare the duration of remission between NPX treatment with stopping all AS-tx’s between Wks 28 and 52/ET; To compare the % of subjects in ASAS partial remission who flare with NPX maintenance tx vs no maintenance; Compare the % of subjects achieving ASAS-40 and ASAS-20 in the INF+NPX arm with the PBO+NPX arm. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject must be willing to give written informed consent & be able to adhere to the dose & visit schedules
2. Subject must be 18 to 48 yrs of age, of either sex, & of any race
3. Subject must have a diagnosis of active axial spondyloarthritis, w/disease duration of ≤3 yrs, based on ALL of the following findings: chronic low back pain (for a duration of >3 months to ≤3 yrs, with onset before the age of 45), active inflammatory lesions of the sacroiliac joints shown on MRI. Active inflammatory lesions are defined as bone edema within or adjacent the sacroiliac joints, compatible w/active lesions seen in AS or axial spondyloarthritis as observed w/short inversion recovery (STIR). One or more of the following spondyloarthritis manifestations: Inflammatory back pain according to Calin Criteria or Rudwaleit et al, Uveitis, Arthritis, Dactylitis, Psoriasis, ď€ History of CD/ulcerative colitis, HLA-B27 positive, good response to NSAIDs, CRP levels elevated above upper limit of normal (local lab), positive family history for Spondyloarthritis, Enthesitis
4. Subject must have active disease at Screening & Baseline defined by both a total back pain evaluation of ≥40 mm on a VAS of 0 to 100 mm AND a BASDAI score of ≥40 mm
5. Subject must meet 1 of the following criteria: be NSAID-naïve, OR if subject has been treated with an NSAID before Screening, average dose during the last 2 wks must not have escalated to more than two-thirds of the maximal recommended dose, AND in addition a washout period of ≥3 days has occurred before Baseline
6. Subject who is on an NSAID at Screening (& goes through a ≥3-day washout period before Baseline) must have an increase in total back pain of ≥30% at Baseline visit compared to Screening visit as measured by the Total Back Pain VAS
7. Women of childbearing potential & all men must agree to use a medically accepted method of contraception prior to entering the study while receiving protocol-specified medication, & for 6 months after stopping the medication. Acceptable methods of contraception include condoms (male or female) with or without spermicide, diaphragm or cervical cap with spermicide, medically prescribed intrauterine device (IUD), oral or injectable hormonal contraceptive, & surgical sterilization (eg, hysterectomy, tubal ligation for women, and vasectomy for men).Women of non-childbearing potential do not have to use any contraceptive methods
8. Women of childbearing potential & men who are not currently sexually active must agree to use a medically acceptable method of contraception should they become sexually active while participating in the study & receiving protocol-specified medication or within 6 months after stopping the medication
9. Subject is considered eligible according to the following tuberculosis (TB) criteria:
has no history of latent or active TB within 3 months prior to Screening (according to local standards and laws), has no signs or symptoms suggestive of active TB upon medical history &/or physical examination during Screening, has had no recent close contact with a person with active TB OR, if there has been such contact, will be referred to a physician specializing in TB to undergo additional evaluation, & have active and latent TB ruled out (according to local standards and laws) prior to first administration of study medication. In the case of a positive TB-test (as per local standards and laws), a subject can participate in this trial only if the subject agrees to & is able to receive TB prophylaxis with isoniazid 300mg once daily starting from 4 wks prior to Baseline and until Wk 28 of the trial. In the case of isoniazid intolerance, rifampin can be an alternative. Subject must have a chest x-ray available from within the previous 3 months prior to Screening visit showing a negative outcome (no clinically significant findings). But if such a negative chest x-ray is not available, then subject must have a chest x-ray performed during the Screening visit showing a negative outcome
10. Subject must have Screening laboratory tests within the following parameters:
Hemoglobin (hgb) ≥10 g/dL (≥100 g/L), White blood cells (WBC) ≥3.5 x 109 cells/L, Neutrophils ≥1.5 x 109 cells/L, Platelets ≥100 x 109 cells/L, Lymphocytes >1.0 x 109 cells/L, Serum creatinine <1.5 mg/dL (<133 micromol/L), Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, & gamma-glutamyltransferase (GGT) all ≤2 times upper limit of normal, Total bilirubin ≤1.5 times upper limit of normal
11. Subject must have an x-ray of the sacroiliac joints available from within the previous 12 months prior to Screening visit. But if such an x-ray is not available, then the subject must have an x-ray of the sacroiliac joints performed during the Screening visit. Subjects will not be excluded based on the results of this x-ray
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| E.4 | Principal exclusion criteria |
1. Subject has history of esophageal, gastric, pyloric channel, duodenal ulceration or clinically relevant gastrointestinal bleeding w/in 5yrs prior to Screening or history of gastrointestinal bleeding/perforation, related to previous NSAIDs therapy
2. Subject has evidence of active inflammatory bowel disease (CD or UC)
3. Subject has clinical gastrointestinal malabsorption, regardless of etiology
4. Subject has uncontrolled hypertension as per the discretion of treating physician
5. Subject has history of coronary heart disease, myocardial infarction, stroke, transient ischemic attack, or diagnosis of congestive heart failure, even if the subject is medically controlled &/or asymptomatic
6. Subject has another chronic inflammatory articular disease or systemic autoimmune disease such as Systemic Lupus Erythematosus, Sjogren’s syndrome, active rheumatoid vasculitis, or chronic fatigue syndrome
7. Subject w/a history of chronic or recurrent infectious disease including but not limited to chronic renal infection, chronic chest infection (eg, bronchiectasis), recurrent urinary tract infection (recurrent pyelonephritis or chronic non-remitting cystitis), open, draining, infected skin wounds or ulcers, or a history of recurrent bacterial infections w/encapsulated organisms
8. Subject has/had an opportunistic infection (infection caused by an organism such as cytomegalovirus, Pneumocystis carinii, aspergillus, histoplasmosis, or mycobacteria other than TB, in a host whose resistance is lowered by another disease or drug[s]) w/in 6mnths prior to Screening
9. Subject has/had herpes zoster infection w/in 2mnths prior to Screening.
10. Subject is known to be infected w/human immunodeficiency virus (HIV), hepatitis B or C
11. Subject has primary or secondary immunodeficiency
12. Subject has known history of lymphoproliferative disease, including lymphoma, signs & symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy of unusual size/location
13. Subject has any known malignancy or history of malignancy w/in the previous 5yrs (w/the exception of basal cell carcinoma of the skin that has been treated w/no evidence of recurrence for 1yr prior to Screening)
14. Subject has had previous treatment w/a TNF-alpha targeted therapy or another biological agent
15. Subject has been on leflunomide during the previous 8wks prior to Screening (or during the previous 4wks prior to Screening if subject has undergone standard cholestyramine or activated charcoal washout)
16. Subject has been on DMARDs, sulfasalazine, methotrexate, corticosteroid (oral, intra-articular, parenteral) during previous 4wks prior to Screening
17. Subject has history of or current signs &/or symptoms of severe, progressive, uncontrolled renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary (eg, pulmonary insufficiency), cardiac, neurological, cerebral, or psychiatric disease
18. Subject has history of demyelinating disease, symptoms suggestive of multiple sclerosis or optic neuritis
19. Subject has a transplanted organ (w/the exception of a corneal transplant >3mnths prior to Baseline)
20. Subject has neuropathy that can interfere w/quality of life &/or pain assessment
21. Subject has known intolerance (including allergic reactions) to murine, chimeric proteins or human/murine recombinant products
22. Subject for whom a known intolerance to or contraindication for infliximab exists, or for whom infliximab is not recommended
23. Subject is not responsive to naproxen, subject for whom a known intolerance to or contraindication for naproxen exists, or for whom naproxen is not recommended
24. Subject has used an immunosuppressant at any time w/in the previous 4wks prior to Screening
25. Subject has used any systemic medication (other than NSAIDs) that could affect active axial spondyloarthritis or study evaluations w/in the previous 4wks prior to Screening
26. Subject has received a live virus or bacterial vaccination w/in the previous 3mnths prior to Screening or is expected to receive such a vaccination
27. Subject is a woman who is breastfeeding, pregnant, or intending to become pregnant
28. Subject is known to have had a substance abuse problem w/in the previous 3yrs prior to Screening
29. Subject has used an investigational drug at any time within the previous 4wks prior to Screening
30. Subject is unable or unwilling to undergo multiple venipunctures because of poor tolerability or lack of easy access to veins
31. Subject is participating in any other clinical study
32. Subject is part of staff personnel directly involved w/this study
33. Subject is a family member of the investigational study staff
34. Subject has any clinically significant laboratory result, medical condition, or situation, other than the condition being studied that, in the opinion of the investigator, would interfere w/the study evaluations or optimal participation in the study |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The Primary Efficacy Endpoint is related to the Primary Trial Objective.
The Primary Efficacy Endpoint for the current trial is the proportion of subjects in each study arm (Arm A and Arm B) meeting the ASAS partial remission criteria at Week 28.
The Primary Safety Endpoints for the current study are treatment-emergent serious adverse events (SAEs).
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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 | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 | Information not present in EudraCT |
| 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 |
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| 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
|
| The overall study ends when the last subject has completed or has been discontinued and the last protocol-specific contact (vistit or telefone contact) took place. |
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| 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 | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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