| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Rheumatoid Arthritis (RA) |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10039073 |
| E.1.2 | Term | <Manually entered code. Term in E.1.1> |
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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 objectives of this study are:
• To evaluate the safety and tolerability of three dose levels of LX3305 over 12 weeks in subjects with active RA who are also receiving stable doses of MTX;
• To evaluate the efficacy of three dose levels of LX3305 by utilizing the American College of Rheumatology 20% response criteria (ACR20) at 12 weeks in subjects with active RA who are also receiving stable doses of MTX.
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are:
• To evaluate the efficacy of three dose levels of LX3305 over time by utilizing the ACR 20%, 50%, and 70% response criteria (ACR20, ACR50, and ACR70, respectively) in subjects with active RA who are also receiving stable doses of MTX;
• To evaluate the efficacy of three dose levels of LX3305 over time by utilizing the Hybrid ACR response measure in subjects with active RA who are also receiving stable doses of MTX;
• To evaluate the efficacy of three dose levels of LX3305 by Disease Activity Score in 28 joints (DAS28) at 12 weeks in subjects with active RA who are also receiving stable doses of MTX;
• To evaluate the efficacy of three dose levels of LX3305 by change from baseline over time in Disease Activity Score in 28 joints (DAS28) in subjects with active RA who are also receiving stable doses of MTX.
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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 |
DNA Sub-Study
“A Phase 2, Multi-center, Randomized, Double-blind, Placebo-controlled, Multiple dose Study to Determine the Safety and Efficacy of Daily Orally Administered LX3305 in Subjects with Active Rheumatoid Arthritis (RA) on Stable Methotrexate (MTX) Therapy”
Version 2.0 dated 30 Jun 2009 |
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| E.3 | Principal inclusion criteria |
Subjects must meet all of the following criteria at screening to be considered eligible for participation in the study:
1. Adult subjects, aged >18 years and <75 years
2. Both males and females of childbearing potential must agree to practice two adequate methods of contraception from the screening visit through the end of the follow-up period. Childbearing potential is defined as those who have not undergone surgical sterilization, or those who are not considered post-menopausal (absence of menstruation for at least 2 years). Adequate methods of contraception for subjects and their partners include condoms with spermicidal gel, diaphragm with spermicidal gel, coil (intrauterine device), surgical sterilization, vasectomy, oral contraceptive pill or depoprogesterone injections, and abstinence. If a subject is not usually sexually active but becomes active, the subject and his or her partner should use medically accepted forms of contraception.
3. Active RA diagnosed at least 6 months prior to screening, functional class I to III RA (as defined by the 1987 ACR criteria)
4. Continued active disease as determined by the presence of:
a. A minimum of 6 swollen joints (at screening and Day 1) AND
b. A minimum of 6 tender joints (at screening and Day 1) AND
c. Serum C-reactive protein (CRP) level > ULN
5. Treated with MTX for at least 6 months (7.5 to 25 mg/week) prior to screening, and currently receiving a stable dose of MTX (>10 mg/week) and with a stable route of administration, as well as folate supplementation. Both MTX and folate supplementation must be stable for at least 8 weeks prior to Day 1, and they should remain stable throughout study participation.
6. If taking NSAIDs, steroids, minocycline, or doxycycline, must be on stable regimen for 6 weeks prior to Day 1 (oral steroid dose must be ≤10 mg prednisone per day, or equivalent)
7. If taking hydroxychloroquine or sulfasalazine, must be on a stable regimen for 12 weeks prior to Day 1
8. Ability to give written informed consent. |
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| E.4 | Principal exclusion criteria |
Subjects who meet any of the following criteria at screening will be excluded from participation in the study:
1. Women who are pregnant or nursing
2. RA diagnosis prior to 16 years of age (Juvenile RA)
3. Subjects who have demonstrated lack of response to >3 DMARDs, or subjects who have been exposed to >1 biologic DMARD
4. Use of DMARDs, other than MTX and those defined in the Inclusion Criteria, within 12 weeks prior to Day 1
5. Use of leflunomide within 4 weeks, or use of biologic DMARDs within 12 weeks, prior to Day 1, with the exception of rituximab or other B-cell depleting therapies, which cannot be used within 12 months prior to Day 1
6. Intra-articular and/or parenteral corticosteroids within 4 weeks prior to Day 1
7. Receipt of live vaccine within 4 weeks prior to Day 1
8. Major surgical procedure within 8 weeks prior to Day 1
9. Blood donation within 4 weeks prior to Day 1
10. Any systemic inflammatory condition that may interfere with the interpretation of outcome data
11. Recurrent infections, or presence of current infection within 2 weeks prior to Day 1, other than onychomycosis
12. History of bleeding diathesis
13. History of medically significant opportunistic infection
14. History of drug or alcohol abuse within 3 years prior to Day 1
15. History of cancer within 5 years prior to Day 1, other than resected basal cell carcinoma
16. Presence of hepatic or biliary disease, including symptomatic cholelithiasis
17. History of tuberculosis
18.Positive result for purified protein derivative (PPD) skin test, defined as >5 mm of induration. If a subject exhibits a positive PPD test, but prior immunization with Bacille Calmette Guerin (BCG) vaccine can be ascertained, a repeat test withQuantiferon-TB, in conjunction with a normal chest X-ray taken within 6 months prior to screening, may be used to establish eligibility
19. History of human immunodeficiency virus (HIV)
20. Abnormal laboratory results meeting the following criteria:
a. Hemoglobin <10.0 gm/dL
b. Absolute lymphocyte count <750/mm3
c. Platelet count <100,000/μL
d. Aspartate transaminase (AST) or alanine transaminase (ALT) >1.5 x ULN
e. Alkaline phosphatase (ALP) >1.5 x ULN
f. Presence of hepatitis B surface antigen (HBsAg) or hepatitis C antibody (HCVAb)
g. Microscopic hematuria
21. Any other clinically significant laboratory test results, ECG, X-ray, medical condition, or unspecified reason that, in the opinion of the investigator, make the subject unsuitable for enrollment
22. Previous exposure to LX3305
23. Use of any other investigational agent or participation in an investigational trial within 30 days prior to Day 1, or use of an investigational biologic agent within 90 days, or less than five half-lives, prior to Day 1
24. Inability to communicate or cooperate with the investigator for any reason, or inability to attend visits as outlined in the protocol. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Efficacy Endpoints
The primary efficacy endpoint is the proportion of subjects achieving an ACR20 response at Week 12.
The secondary efficacy endpoints are:
• Proportion of subjects achieving ACR20/50/70 responses at Weeks 4, 8, 12, and 14
• Mean Hybrid ACR response measure at Weeks 4, 8, 12, and 14
• Proportion of subjects determined to be European League Against Rheumatism (EULAR) responders with good and moderate responses to treatment as measured by DAS28 score, and change from baseline in DAS28 score, at Weeks 4, 8, 12, and 14
• Proportion of subjects determined to have low disease activity as measured by DAS28 score at Weeks 4, 8, 12, and 14
• Proportion of subjects determined to achieve remission as measured by DAS28 score at Weeks 4, 8, 12, and 14
2. Ancillary efficacy endpoints are:
• Mean change from baseline in DAS28 score at Weeks 4, 8, 12, and 14
• Mean change from baseline in Swollen Joint Count (SJC) in 28 joints
• Mean change from baseline in Tender Joint Count (TJC) in 28 joints
• Mean change from baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) score
• Mean change from baseline in C-reactive protein (CRP)
• Mean change from baseline in Erythrocyte Sedimentation Rate (ESR)
• Mean change from baseline in subject assessment of pain by VAS
• Mean change from baseline in subject global assessment of health by VAS
• Mean change from baseline in physician global assessment of disease activity by VAS
• Mean change from baseline in lymphocyte counts (absolute and individual subpopulations)
•Mean change from baseline in biochemical markers of bone and cartilage turnover.
3. Pharmacokinetic Endpoints
Pharmacokinetic endpoints include LX3305 concentrations in plasma and urine.
4. Pharmacodynamic and Biomarker Endpoints
Pharmacodynamic endpoints include the mean change from baseline at each time point in lymphocyte counts (absolute and individual T-cell, B-cell, and NK cell subpopulations), and biomarker endpoints include mean change from baseline at each time point in biochemical markers of bone and cartilage turnover.
5. Safety Endpoints
Subject safety will be assessed using the following endpoints:
• Incidence of treatment-emergent AEs, treatment-emergent AEs by severity, treatment-emergent AEs by relationship to study drug, SAEs, on-study deaths, and AEs leading to discontinuation from the study
• Change from baseline to each post-baseline visit in clinical laboratory tests
• Shifts from baseline to each post-baseline visit in abnormal clinical laboratory
• Change from baseline to each post-baseline visit in vital signs
• Shifts from baseline to each post-baseline visit in abnormal vital signs
• Clinically significant changes from baseline in ECG findings. |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| 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 | 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.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| 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 | 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
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| 30 day follow up period to Monitor for potential adverse events |
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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 | 0 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 84 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 84 |
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