| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Rheumatoid Arthritis (RA) |
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| E.1.1.1 | Medical condition in easily understood language |
| Rheumatoid Arthritis (RA) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10040107 |
| E.1.2 | Term | Seropositive rheumatoid arthritis |
| E.1.2 | System Organ Class | 100000004859 |
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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 |
• To evaluate the clinical efficacy of JTE-051 in subjects with active rheumatoid arthritis receiving background non-biologic disease-modifying anti-rheumatic drug therapy
• To evaluate the safety and tolerability of JTE-051 administered for 12 weeks to subjects with active rheumatoid arthritis receiving background non-biologic disease-modifying anti-rheumatic drug therapy
• To evaluate the pharmacokinetics of JTE-051 in plasma of subjects with active rheumatoid arthritis
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Males and females, 18 to 75 years of age (inclusive) at the Screening Visit (Visit 1);
2. A diagnosis of Rheumatoid Arthritis prior to the Screening Visit, based on the ACR/EULAR 2010 Classification Criteria (ACR: American College of Rheumatology, EULAR: European League Against Rheumatism). Refer to Appendix 1 of the protocol for further reference;
3. Active disease despite ongoing therapy with up to 2 non-biologic Disease Modifying Anti-Rheumatic Drugs (DMARDs), including methotrexate (MTX) at both the Screening and Baseline Visits (Visit 1 and Visit 2), as defined by both: ≥6 out of 68 tender joints AND ≥6 out of 66 swollen joints;
4. Screening hs-CRP ≥1.2 x ULN, based on the central laboratory values (hs-CRP: high-sensitivity C-reactive protein, ULN: Upper limit of normal);
5. Background treatment with up to 2 non-biologic DMARDs (Disease-modifying anti-rheumatic drugs), including MTX (mandatory) and one of the following medications (optional): sulfasalazine ≤3 g/day, hydroxychloroquine ≤400 mg/day or chloroquine: ≤250 mg/day, at the time of the Screening Visit (Visit 1). The MTX dose must be 15-25 mg/week (or the maximum documented tolerated dose for the subject, not <10 mg/week) and all background therapy must be stable, defined as no change in dose or route of administration for ≥12 weeks prior to the Randomization Visit (Day 1). See Section 3.5.4.1 for all concomitant medication-related restrictions.
6. Body Mass Index (BMI): 18 to 40 kg/m^2 (inclusive) at the Screening Visit (Visit 1);
7. Females may participate if they meet one of the following criteria: Surgically sterile (e.g., hysterectomy or bilateral oophorectomy); or: Post-menopausal (i.e., history compatible with menopause [i.e., reported lack of menses for ≥12 months prior to Visit 1] and no other biological/surgical cause AND a serum follicle-stimulating hormone (FSH) measurement of ≥40 mIU/mL at Visit 1); or: Of childbearing potential and are compliant with at least 2 acceptable forms of birth control (in conjunction with their partner) for the duration of the study and for at least 12 weeks after the last dose of study drug. Acceptable contraceptive methods include the following: intrauterine devices; partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate); condom with a spermicide; diaphragm, cervical cap, vaginal sponge, or “female condom”, all with spermicide;
**Notes: Females with sterilization history limited to tubal ligation will be considered of childbearing potential and must comply with the contraception regimen as described above. Females with a history compatible with menopause and have a serum FSH <40 mIU/mL (FSH: Follicle-stimulating hormone)at Visit 1 will be considered of childbearing potential and must agree to comply with a contraceptive regimen as described above. Concomitant use of a female condom and a male condom is not considered an acceptable method of contraception for the study.
8. Males with female partners of childbearing potential must agree to practice total abstinence or to utilize a barrier contraceptive method with spermicide for the duration of the study and for at least 12 weeks after the last dose of study drug; additionally, male subjects must not donate sperm for the duration of the study and within 12 weeks of the last dose of study drug; Female partners of male subjects randomized in this study must be surgically sterile, postmenopausal, or use an acceptable form of birth control (see description listed in inclusion criterion # 7; additionally, oral and implantable hormonal contraceptives are considered acceptable in female partners of male subjects) for the duration of the study and for at least 12 weeks after completing the study;
9. Able and willing to give written informed consent.
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| E.4 | Principal exclusion criteria |
1.Prior/current exposure to biologic and/or kinase inhibitor therapy
2.Does not meet all study restrictions described in Section 3.5.4 of the protocol
3.White blood cell count of <3.0x10^9/L, absolute neutrophil count of <1.5x10^9/L or absolute lymphocyte count <0.8x10^9/L at Screening Visit
4.Hemoglobin <9g/dL or platelet count <100,000/mm^3 at Screening Visit
5.Alanine aminotransferase ALT>1.2 x the ULN (Upper Limit of Normal); aspartate aminotransferase AST>1.2 x the ULN or total bilirubin >1.5 x the ULN at Screening Visit
6.Clinical evidence of renal impairment or an estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73m^2 at the Screening Visit, using the abbreviated Modification of Diet in Renal Disease equation
7.Serum triglycerides >400 mg/dL at Screening Visit
8.Positive viral serology at Screening: Human immunodeficiency virus; Hepatitis B virus; or Hepatitis C virus
9.History or presence of substance abuse, drug addiction or alcoholism within 1 year prior to Screening
10.Positive Purified Protein Derivative (PPD) or quantiFERON®-TB Gold-In-Tube test, positive chest radiography findings for tuberculosis; For subjects with Bacille Calmette-Guérin vaccination the quantiFERON®-TB Gold-In-Tube test should be performed; PPD test is considered positive if at 48 to 72 hrs of administration the induration obtained is ≥5mm; If the quantiFERON®B Gold-In-Tube test is indeterminate, a retest is allowed if results can be obtained prior to Visit 2, if the retest results are also indeterminate, the PPD test may be performed and if negative the subject may be randomized in the study; the quantiFERON®-TB Gold-In-Tube test should not be performed within ≤4weeks from the date of a live vaccination; Who have had contact with a person with active tuberculosis, unless documentation of appropriate completion of tuberculosis prophylaxis is provided
11.History of live attenuated vaccination within 6 weeks prior to Day 1, or have a live attenuated vaccination planned during the study or within 6 weeks after the last dose of study drug
12.Have donated or received any blood or blood products within 8 weeks prior to the Screening
13.History of a clinically-significant infection within 8 weeks prior to Day 1, except for treated urinary tract infections, which will be permitted if resolved >1 week prior to Day 1
14.History of opportunistic infections or requiring hospitalization or parenteral antibiotic, antiviral, antifungal, or antiparasitic therapy within 6 months prior to Day 1 or any history of recurrent infections or conditions predisposing to chronic infections
15.History of shingles within 12 months prior to the Screening Visit or any known history of disseminated/complicated herpes zoster
16.History of acute inflammatory joint disease of an origin other than RA (Rheumatoid Arthritis) or subject has any other rheumatic disease other than RA or fibromyalgia; Note: Subjects with Sjögren's syndrome secondary to RA are permitted
17.History or presence of any lymphoproliferative disorder, or signs and symptoms suggestive of current lymphatic disease, such as Hodgkin's or Non-Hodgkin's lymphoma
18.History of or current malignancies with the exception of adequately treated or excised non-metastatic basal cell or squamous cell carcinoma of the skin or cervical carcinoma in situ >6 months prior to the Screening
19.History of organ transplantation
20.Acute coronary syndrome, percutaneous coronary intervention, coronary artery bypass graft surgery, cerebrovascular accident or transient ischemic attack within 6 months prior to the Screening
21.History or presence of Class III or IV heart failure or known Rutherford category 4 or higher peripheral arterial disease
22.History or presence of clinically significant arrhythmia or ECG abnormalities
23.Uncontrolled arterial hypertension: repeated systolic blood pressure ≥160mmHg or diastolic blood pressure ≥100mmHg at Screening Visit
24.History or suspected presence of osteonecrosis, RPOA (Rapidly progressing osteoarthritis), spontaneous osteonecrosis of the knee (SPONK), subchondral insufficiency fractures, Kellgren grade 4 osteoarthritis or pathologic fractures
25.Osteoporosis - density T-score of -2.5 or below, or any other metabolic bone disorder (treatment for osteoporosis is permitted as long as the latest known bone mineral density T-score is >-2.5)
26.History or presence of clinically active autonomic neuropathy and polyneuropathy of any cause
27.Current symptoms or signs consistent with compression neuropathy, radioculopathy and plexopathy (cervicobrachial plexopathy pain and/or sensory symptoms lateral side upper arm and ulnar side hand/digits IV and V (thoracic outlet syndrome)
28.Pregnant or nursing females at Screening or Day 1 or subjects who plan to become pregnant or initiate breastfeeding during the study and within 12 weeks after the last dose of study drug
29.Significant history of drug or other hypersensitivities |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy: Percentage of subjects achieving at least 20% improvement from baseline in tender and swollen joint counts and at least 20% improvement from baseline in the 3 of the 5 remaining American College of Rheumatology
(ACR) core set measures (ACR20 response rate) at end of treatment (EOT).
Safety Parameters: Number of subjects with adverse events (AEs), type and severity of AEs, change from baseline in the safety laboratory, vital sign and electrocardiogram (ECG) parameters.
Pharmacokinetic (PK) Parameters: Trough plasma levels of JTE-051
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy: Tender and Swollen Joint Counts will be performed in all visits until the end of treatment (EOT). The measure of the improvement percentage will be performed at the end of treatment.
Safety: Safety information will be collected through the study.
Pharmacokinetic: Trough concentrations of JTE-051 will be measured at each visit during the Treatment Period; |
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| E.5.2 | Secondary end point(s) |
Secondary Efficacy:
• Percentage of subjects achieving at least 20, 50 and 70% improvement from baseline in tender and swollen joint counts and at least 20, 50 and 70% improvement from baseline in 3 of the 5 remaining ACR-core set measures, respectively (i.e., ACR20/50/70 response rate)
• Change from baseline in Simplified Disease Activity Index (SDAI)
• Percentage of subjects who achieved remission based on SDAI (≤3.3)
• Percentage of subjects who achieved low disease activity based on SDAI (≤11)
• Change from baseline in Clinical Disease Activity Index (CDAI)
• Percentage of subjects who achieved remission based on CDAI (≤2.8)
• Percentage of subjects who achieved low disease activity based on CDAI (≤10)
• Percentage of subjects in Boolean Remission
• Change from baseline in Disease Activity Score (DAS) based on hs-CRP (DAS28-CRP)
• Percentage of subjects with DAS28-CRP of <2.6
• Percentage of subjects with DAS28-CRP of <3.2
• Percentage of subjects with good EULAR response at Week 12
• Percentage of subjects with moderate EULAR response at Week 12
• The lowest percentage change from baseline of 3 measures: tender joint count, swollen joint count and median change of the remaining 5 core measures (numeric ACR [ACR-N] index)
• Change from baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI)
• Change from baseline in the number of tender and swollen joint counts (68/66 joints will be counted)
• Change from baseline in subject pain score by numeric rating scale (NRS)
• Change from baseline in subject global assessment (SGA) of disease activity by NRS
• Change from baseline in physician global assessment (PGA) of disease activity by NRS
• Change from baseline in hs-CRP
Supportive Efficacy: Non-hs CRP will be evaluated at Weeks 2 and 12 for the following secondary efficacy counterparts: ACR20/50/70, SDAI, Boolean remission, DAS28-CRP, EULAR response, ACR-N and CRP.
Exploratory Efficacy: Change from baseline in Vectra® DA score.
Pharmacokinetic (PK) - Exploratory: Relationship between the JTE-051 dose (exposure) and response. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Secondary Efficacy: To be evaluated at weeks 2, 4, 8, 12 and 16;
• Exploratory Efficacy Parameters: To be evaluated at weeks 2, 4, 8, 12 and 16;
• Exploratory Pharmacokinetic (PK) Parameters: To be evaluated at weeks 2, 4, 18 and 12 |
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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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| 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 | 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 | 5 |
| 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 | 13 |
| 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 |
| Argentina |
| Bulgaria |
| Colombia |
| Mexico |
| Peru |
| Poland |
| Romania |
| Russian Federation |
| Ukraine |
| United States |
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 11 |
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