| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with active rheumatoid arthritis who are on a stable dose of methotrexate |
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| 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 |
| To evaluate the efficacy of tranilast at two different dosages compared to placebo in subjects with active RA when added to continuing methotrexate therapy. |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of tranilast at two different dosages compared to placebo in patients with RA receiving concomitant treatment with MTX.
To identify any significant differences in the safety or efficacy profile of the two doses of tranilast in subjects with RA when added to continuing MTX therapy.
Pharmacokinetic objectives
To determine the plasma concentrations of tranilast in subjects with RA receiving concomitant oral MTX therapy.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Sub-study 1
The study includes a intensive Pharmacokinetics sub-study, version: original, date: 20 Oct 2008 (N.B. this is included within the main protocol)
Objectives:
1.To determine the plasma concentrations and pharmacokinetics of tranilast in subjects with active RA receving concomitant oral MTX therapy;
2. To evaluate the potential for tranilast to affect the PK of orally administered MTX (intensive PK sub-study subjects only)
Sub-study 2
A Phase II, Randomized Multi-Center, Double-Blind Study of Tranilast with Concomitant Methotrexate (MTX) Compared to MTX Alone in Patients with Active Rheumatoid Arthritis (RA). An Exploratory Sub-study of Effect of Tranilast on Synovial Vascularity - Original: 16 Feb 2009, Amendment 1 16 Nov 2009
Synovial Vascularity sub-study objective
1. To examine the effect of tranilast on synovial vascularity and peripheral blood biomarkers when administered to active RA patients being co-administered a stable dose of oral methotrexate (MTX).
Sub-study 3
A Phase II, Randomized Multi-Center, Double-Blind Study of Tranilast with Concomitant Methotrexate (MTX) Compared to MTX Alone in Patients with Active Rheumatoid Arthritis (RA). An Exploratory Sub-study of Genotype on Susceptibility to Tranilast-induced Liver Injury - Original: 15 April 2010
Pharmacogenomic sub-study objective
To examine the potential association of genotype variants on susceptibility to tranilast-induced liver injury. |
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| E.3 | Principal inclusion criteria |
1. Signed and dated written Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved informed consent obtained from the subject in accordance with the local regulations;
2. Male or female subjects, ≥18 to ≤75 years of age, who have a diagnosis of RA (using the American Rheumatism Association 1987 Revised Criteria) for at least 6 months prior to screening, and are Functional Class 1-3 (as defined by the 1991 Revised Criteria for the Classification of Global Functional Status in Rheumatoid Arthritis) at baseline;
3. Subjects must be receiving MTX (oral or parenteral) at a dose of at least 10 mg/week for ≥6 months and at a stable dose and route of administration for ≥8 weeks prior to randomization (Day 0);
4. Subjects must receive at least 5 mg of folic acid or folinic acid per week at a stable dose for at least 4 weeks prior to randomization (Day 0);
5. Subjects must have at least 8 painful/tender and 6 swollen joints (based upon 68/66 joint counts) at screening and baseline (Day 0);
6. Subjects must have an elevated CRP level (defined as > the upper limit of normal [ULN] for the central lab) or an elevated ESR (defined as > the upper limit of normal [ULN] for the local lab) at screening;
7. Availability of normal chest X-ray within the last 6 months (i.e., no evidence of TB or chest infection). Patients who are clinically asymptomatic with minor changes consistent with rheumatoid lung are acceptable.
8. Subjects may be receiving:
• Oral steroids at a stable dose of <=10 mg/day of prednisone (or equivalent corticosteroid dose) if previously taken for at least one month prior to randomization (Day 0);
• Chronic NSAIDs if taken at a stable dose for at least one month prior to randomization (occasional use of NSAIDs for relief of headaches menstrual cramps, and minor pain unrelated to RA is allowed);
• Hydroxychloroquine if taken at a stable dose of 200-400 mg PO daily or chloroquine if taken at a stable dose of up to 250 mg PO daily for at least 3 months prior to randomization, with no evidence of ocular toxicity as documented by ophthalmologic exam within the previous 12 months;
• Sulfasalazine if taken at a stable daily dose of up to 3000 mg for at least 3 months prior to randomization;
9. Females of childbearing potential must agree to continue to use adequate contraception (i.e., hormonal [oral, depot, patch], IUD, or barrier and spermicide) throughout the study and for at least 1 month following their last study visit;
10. In the opinion of the investigator, the subject will be compliant and have a high probability of completing the study and all required procedures.
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| E.4 | Principal exclusion criteria |
1. Use of intra-articular corticosteroid injections within one month prior to randomization (Day 0);
2. Use of other anti-arthritic treatments not mentioned in the above inclusion criteria, including approved or experimental oral, topical, or injectable biologics or drugs, or devices within 3 months or 5 half-lives (whichever is longer)prior to randomization (Day 0);
3. Pregnant or nursing females;
4. Subjects who have received prior treatment with tranilast;
5. Subjects who have any known hypersensitivity to any of the excipients contained in the study drug formulation;
6. Use of any of the following other medications: (a) oral hypoglycemic agents: tolbutamide, glipizide, glimepiride, glyburide, repaglinide, nateglinide, or a thiazolidenedione (“glitazones”, e.g. rosiglitazone); (b) warfarin or coumarol; (c) phenytoin, paclitaxel, fluconazole, amiodarone, or isoniazid; (d) a uricosuric agent for gout; or (e) an investigational medication or participation in an investigational study within 3 months of Day 0
7. Subjects with any laboratory test at screening considered significantly abnormal. The following will be considered significantly abnormal:
• alanine transaminase (ALT), aspartate transaminase (AST), or alkaline phosphatase >=1.25 times the upper limit of normal (ULN) or
• cytopenia (to include any of the following: WBC <3.5x10cubed/μL; Hgb <10 g/dL; platelets <100x10cubed/μL; neutrophils absolute <1.5x10cubed/μL; lymphocytes absolute <0.8x10cubed/μL) or
• Creatinine >=1.25 times the upper limit of normal (ULN)
8. Has an elevated total bilirubin (e.g., outside the upper limit of normal), which persists upon repeat or a history of Gilbert’s syndrome;
9. History of clinically significant renal or hepatic dysfunction or disease;
10. Has a history of or has a current, clinically significant major psychiatric disorder
(e.g., major depressive disorder, psychosis, schizophrenia) according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM IV TR) [Exception; subjects with depression that has been adequately controlled for at least 6 months may enroll in the study];
11. Has a history of alcohol or drug dependence or abuse as defined by DSM IV TR criteria within the last 2 years;
12. Has a history of uric acid urolithiasis or gout;
13. Has a clinically significant systemic infection (e.g., chronic or acute infection, UTI, URI) within 30 days of Day 0, or a history or presence of recurrent or chronic infection
(e.g., viral infections, including hepatitis B or C, HIV), bacterial infections, systemic fungal infections, or syphilis);
14. Has evidence of tuberculosis as indicated by subjects with a positive tuberculin (TB) skin test at screening or within the 30 days prior to screening (defined as >=10 mm induration);
15. Has any other significant medical disease, mental impairment or other clinically significant abnormality on physical, neurological, laboratory, vital signs or ECG examination that the investigator or Sponsor believes would be detrimental to the subject or compromise the study;
16. Subject with any other condition, clinical finding, or reason that, in the opinion of the investigator and/or Sponsor, is determined to be unsuitable for enrollment into the study (e.g., subject with known compliance issues, geographical constraints for attending required clinic visits);
17. Presence of, or history of cancer with the exception of completely excised, non-metastatic squamous cell and basal cell carcinomas of the skin
18. Subjects planning or likely to require any surgical procedure during the study treatment period;
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy analysis will utilize the Efficacy Population and compare the proportions (%) of subjects achieving an ACR20 response in the tranilast 300 mg/day group and the placebo group at Week 12. This analysis will utilize an LOCF approach and results will be utilized by the Sponsor to determine the efficacy potential for tranilast in RA.
In addition, the primary endpoint will also be analyzed for the MITT population, but this will not be considered the primary efficacy analysis for this study. Non-responder imputation (all-cause dropouts and subjects with missing efficacy data at Week 12 are considered non-responders) will be utilized for this MITT population analysis
These analyses will be performed using the Cochran-Mantel-Haenszel chi-square test with participation in the PK sub-study as a stratification factors. However, if any of the resultant cells for prior exposure to biologic treatments has <2 placebo patients, the Cochran-Mantel-Haenszel chi-square test will adjust only for geographic region. The null hypothesis of equality of ACR20 response rates will be assessed using a two-sided test at the 5% level of significance. |
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| 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 | Yes |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | 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 | 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) | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| 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 | 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
|
| End of trial has been defined by the sponsor as being completion of study report |
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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