| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| 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 clinical efficacy of two dosing regimens of TRU-015 in active seropositive RA subjects compared with placebo at 24 weeks |
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| E.2.2 | Secondary objectives of the trial |
| To evaluate safety, patient reported outcomes, PK, PD, MRI, additional efficacy data up to 52 weeks, and asessment the effect of additional pre-dose oral corticosteroids at 12 weeks on 24-week efficacy. |
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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 |
There are 3 substudies included in the main protocol (there is no separate protocol):
1) An MRI sub-study will be performed at select sites to evaluate MRIs of the wrist and MCP joints of the dominant hand.
2) A B cell and cytokines sub-study will be performed at select sites to study certain RA related cytokines and B cell populations response and correlation to clinical activity.
3) A pharmacogenomics sub study will be performed at selected sites to assess if changes in RNA and expression of gene have a role in response and correlation to clinical activity. |
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| E.3 | Principal inclusion criteria |
1. Age ≥ 18 years at time of signing the ICF
2. Meets the American Rheumatism Association 1987 revised criteria for classification of RA.
3. ACR functional class I-III.
4. At screening, active RA consisting of ≥ 5 swollen and ≥ 5 tender joints (28-joint count: see Attachment 3) and one or both of the following CRP or ESR criteria:
a. Erythrocyte sedimentation rate (ESR)(Westergren) ≥ 28 mm/hr
b. CRP ≥ 15 mg /L
5. Must be seropositive: Defined as a documented history of one or both of the following RF or anti-CCP criteria.
If a documented history of one or both of the following RF or anti-CCP criteria is not available, RF and anti-CCP will be tested with screening labs:
a. Positive RF
b.Positive anti-CCP
6. Currently receiving MTX regimen of 7.5 to 25mg of MTX weekly for at least 12 weeks prior to study day 1.
The dose and route of administration of MTX must be stable for at least 4 weeks prior to study day 1.
7. Women of childbearing potential must have a negative urine pregnancy test at screening and baseline. Women of childbearing potential are defined as women who are biologically capable of becoming pregnant, including women who are using contraceptives or whose sexual partners are either sterile or using contraceptives. Women of non-childbearing potential are defined as either postmenopausal (history of amenorrhea for ≥ 52 weeks) or who are surgically sterile, such as after hysterectomy, bilateral oophorectomy, or tubal ligation (procedure
performed ≥ 1 year before screening). This information must be documented in the subject’s source documents.
8. Women of childbearing potential must agree and commit to the use of hormonal contraception, double-barrier contraception, or an intrauterine device throughout the entire study (defined as the signing of the ICF to the
completion of the Conclusion of Subject Participation). Double-barrier contraception is defined as the use of a diaphragm, condom, or cervical cap plus a spermicidal vaginal foam, cream, jelly, suppository, or sponge.
WOCBP who have a vasectomized partner are also eligible for participation. Vasectomized partners must have had their vasectomy more than 6 months before study day 1.
9. Men must agree and commit to use a medically acceptable form of contraception for the entire study (defined as the signing of the ICF to the completion of the Conclusion of Subject Participation) unless surgically sterile.
Medically acceptable forms of contraception include properly used barrier forms of contraception. |
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| E.4 | Principal exclusion criteria |
1. Pregnant women, nursing mothers or women planning to become pregnant during the study. 2. Any cardiovascular, neurological, metabolic, immunological, infectious, hepatic, or renal condition that, in the opinion of the investigator, could be detrimental to subjects participating in this study, including any clinically important deviations from normal clinical laboratory values or important concurrent medical events. 3. Any active, severe infections
4. Severe heart failure (NYHA Class IV) or severe, uncontrolled cardiac disease 5. Subjects with active tuberculosis as per country specific guidelines or history of tuberculosis. The following applies to subjects in Germany only: History of tuberculosis or positive PPD skin test at screening. The following are PPD skin test guidelines: (a)The PPD skin test should be read between 48 & 72 hours after application (b)Only indurations should be taken into account when interpreting results. (c)No induration is considered a negative result. (d)Any result with an induration of >5 mm in diameter is considered positive. (e)If induration is ≤5 mm in diameter, a 2nd PPD skin test is to be performed on contralateral arm on the day of reading of first PPD skin test. If the induration of the 2nd PPD skin test is >5 mm in diameter, this is considered a positive result. (f)Prior BCG should not be taken into account when interpreting a PPD result. 6. Subjects with other objectively confirmed or suspected rheumatic diseases including but not limited to, Lyme disease, psoriatic arthritis, spondyloarthropathy, systemic lupus erythematosus, systemic vasculitis, polymyositis, infectious arthritis, reactive arthritis or overlap syndrome. 7. Cancer, or a history of cancer (other than adequately resected cutaneous basal cell & squamous cell carcinomas or in situ cervical cancer). 8. History of alcohol or drug abuse that, in the opinion of the investigator, would interfere with the ability to comply with the study protocol. 9. Documented immunodeficiency disease including subjects with known human immuno deficiency virus (HIV) at time of screening. The following applies to subjects in Germany only: Known history of HIV, or positive HIV screening test, at the time of screening. 10 Subjects positive forhepatitis B surface antigen (HBsAg), or hepatitis B core antibody (HBcAb), or hepatitis C antibody (HepCAb) with confirmation by RIBA, or history of drug-induced liver injury, or documented liver cirrhosis or documented fibrosis at any time before the Baseline visit. 11. Any clinically significant laboratory abnormality, including: Hemoglobin <8.5 g/dL (SI units: <85 g/L); White blood cell (WBC) count <3.50 x 103/mm3 (SI units: <3.50 x 10 to the power of 9/L); Platelets <125,000/mm3 or ≥ 1,000,000/mm3 (SI units: <125 x 10 to the power of 9/L or ≥1,000 x 10 to the power of 9/L); Aspartate minotransaminase (AST) or alanine aminotransaminase (ALT) >1.5 x upper limit of normal (ULN); Serum creatinine >2 mg/dL (SI units: >177 mol/L)
12. Clinically significant finding on chest radiograph.Chest x-ray must be performed during screening period unless radiograph was performed within the 24 weeks prior to Baseline. 13. For subjects who consent to the MRI sub-study:(a) Any permanent reactive metal implants contained in or on the body.(b) Contra indications to Gadolinium contrast agents including, but not limited to, glomerular filtration rate (GFR) <30 ml/min. 14. Lack of peripheral venous access. 15. Any prior use of rituximab, or other B cell depleting agents. 16. Receipt of live vaccine ≤ 8 weeks prior to the screening visit. 17. Known hypersensitivity to mouse immunoglobulin, mouse/human chimeric immunoglobulin, or other biopharmaceutical proteins. 18. Contraindications for treatment with MTX. 19. Known documented hypersensitivity to corticosteroids, acetaminophen/ paracetamol, or antihistamine that will be used prior to administration of the IV TA (TRU-015 or placebo). 20. Within 24 weeks before baseline; received yclophosphamide, chlorambucil, IV immunoglobulin (IG), Prosorba column (extracorporeal immunoadsorption protein A column), or leflunomide 21. Within 12 weeks before baseline: received hydroxychloroquine, any investigational drug or procedure 22. Within 8 weeks before baseline, received abatacept, adalimumab, or infliximab
23. Within 4 weeks before baseline: (a) received any other Disease-Modifying Antirheumatic Drug (DMARD) (b) received etanercept 24. Within 2 weeks before baseline: (a) Use of more than 10 mg/day of prednisone or equivalent, or change in the dose of prednisone or its equivalent, or having intra-articular (IA) corticosteroid injection or bolus intramuscular (IM) or
IV treatment with corticosteroids (≥ 20 mg prednisone or equivalent). (b) Current use of >1 nonsteroidal anti-inflammatory drug (NSAID), or change of dose of the NSAID, or NSAID use greater than the maximum recommended dose (Aspirin at doses up to 325 mg for cardiac protection daily is permitted). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the ACR 50 response rate at 24 weeks as assessed in Part A of this trial for the modified intent to treat (mITT) population. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint is the ACR 50 response rate at 24 weeks as assessed in Part A of this trial for the modified
intent to treat (mITT) population. |
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| E.5.2 | Secondary end point(s) |
| ACR Secondary efficacy evaluations included the ACR20, ACR50 (except week 24), and ACR70 at all time points, a standardized joint assessment, duration of morning stiffness, pain VAS, Physician and Patient Global Assessments of disease activity, General Health VAS, Health Assessment Questionnaire-Disability Index (HAQ-DI), Disease Activity Score (DAS)28, Short Form-36 (SF-36), European Quality of Life (EuroQol) 5 Dimension Scale (EQ-5D), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Productivity and Disease Burden Questionnaire, and European League Against Rheumatism (EULAR) response as derived from DAS28. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| To evaluate safety, patient reported outcomes, PK, PD, MRI, additional efficacy data up to 52 weeks, and asessment the effect of additional pre-dose oral corticosteroids at 12 weeks on 24-week efficacy. |
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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 | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Immunogenicity; health outcomes |
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| 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.8.2.4 | Number of treatment arms in the trial | 6 |
| 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 | 5 |
| 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 | 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 |
| Romania |
| Serbia |
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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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| 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 | 9 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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