| 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] - 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 | PT |
| E.1.2 | Classification code | 10039073 |
| E.1.2 | Term | Rheumatoid arthritis |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
|
| 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 |
| Cumulative response on ACR50 (ie. response from week 8 to week 24) |
|
| E.2.2 | Secondary objectives of the trial |
Response assessment:
- Cumulative response on ACR20 (ie. response from W8 to W24),
- Cumulative response on ACR70 (ie. response from W8 to W24),
- Cumulative response on ACR90 (ie. response from W8 to W24)
- ACRn from W8 to W24
- Time to first response according to ACR20 and ACR50
- DAS28 from week 8 to week 24:
DAS28 (disease activity score)
DAS28 < 2.6 (complete remission),
DAS28 ≤ 3.2 (low disease activity),
- CRP and ESR level from week 8 to week 24
CRP and ESR values
Percentage of patients with an improvement of CRP and ESR >50%, between 25 and 50%, between 0 and 25% or no improvement
Quality of life assessment:
- Visual assessment scale from week 8 to week 24: pain, asthenia, general health
- Quality of life assessed of SF36 from W8 to W24
- Health assessment questionnaire (HAQ) score and from W8 to W24
- Hamilton score from W8 to W24
- Fatigue Impact scale from W8 to W24
Safety assessments: Adverse events, vital signs, laboratory data. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient with rheumatoid arthritis diagnosed according to ACR criteria for at least 6 months.
2. Patient with ACR functional class I-III
3. Patient who have active RA consisting of
- ≥ 6 swollen joints (over 66 swollen joints);- ≥ 6 tender joints (over 68 tender joints);- and at least 2 out of 3 of the following:ESR/first hour ≥ 20 mm; CRP ≥ 10 mg/L;morning stiffness ≥ 45 minutes at both screening and baseline.
4. Patient who failed (defined as active RA with stable dose during 3 months) methotrexate at a dose ≥ 15 mg/week or any DMARD including biologics drugs if patients previously failed methotrexate at a dose ≥ 15 mg/week or methotrexate at a dose ≥ 15 mg/week in combination with any DMARD including biologics drugs (Biologic drugs being defined as any of the following therapies: anti-TNFα,Anti-CD20,Anti-IL1,Anti-IL6,CTLA4)
5. Patient with a disease onset at > 16 years of age
6. Patient with an adequate organ function:ACN ≥ 2 x 109/L;White blood cells count ≥ 4 x 109/L;Haemoglobin ≥ 10 g/dL;PLT ≥ 100 x 109/L;AST/ALT ≤ 3 x ULN;Bilirubin ≤ 1.5 x ULN;Creatinine clearance >60 mL/min;Albuminemia > 1 x LLN;Proteinuria < 30 mg/dL (1+) on the dipstick; in case of proteinuria ≥ 1+ on the dipstick, 24 hours proteinuria < 1.5g/24 hours
7. Male or female patient aged 18 to 75 years,weight>50 kg,BMI between 18 and 35 kg/m²
8. No active infection (tuberculosis,HIV,hepatitis, ...)
9. Female patient of childbearing potential (entering the study after a menstrual period and who have a negative pregnancy test),who agrees to use two highly effective methods (one for the patient and one for the partner) of medically acceptable forms of contraception during the study and for 3 months after the last treatment intake.Acceptable forms of contraception include:A documented placement of an intrauterine device (IUD) or intrauterine system (IUS) and the use of a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository);Documented tubal ligation (female sterilization). In addition, a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository) should also be used;Double barrier method:Condom and occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository;Any other contraceptive method with a documented failure rate of <1% per year;Abstinence
10. Male patients must use medically acceptable methods of contraception if your female partner is pregnant from the time of the first administration of the study drug until three months following administration of the last dose of study drug.Acceptable methods include:Condom;If you have undergone surgical sterilization (vasectomy with documentation of azoospermia) a condom should also be used. Male patients must use two highly effective methods (one for the patient and one for the partner) of medically acceptable forms of contraception during the study and for 3 months after the last treatment intake. The acceptable methods of contraception are as follows: Condom and occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository; Surgical sterilization (vasectomy with documentation of azoospermia) and a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository);Your female partner uses oral contraceptives (combination oestrogen/progesterone pills), injectable progesterone or subdermal implants and a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal; foam/gel/film/cream/suppository);Medically prescribed topically-applied transdermal contraceptive patch and a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository);Your female partner has undergone documented tubal ligation (female sterilization). In addition, a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository) should also be used; Your female partner has undergone documented placement of an intrauterine device (IUD) or intrauterine system (IUS) and the use of a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository); Abstinence.
11. Female patient of childbearing potential must have a negative pregnant test at screening and baseline
12. Patient able and willing to comply with study visits and procedures per protocol
13. Patient able to understand, sign, and date the written informed consent form at the screening visit prior to any protocol-specific procedures being performed.
14. Patient able to understand the patient card and to follow the patient card procedures in case of signs or symptoms of severe neutropenia or severe cutaneous toxicity, during the first 2 months of treatment |
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| E.4 | Principal exclusion criteria |
1. Patient from whom the use of methotrexate is contraindicated as per its SPC (i.e. patient with severe renal or liver failure, patient with pre-existing blood dyscrasia, patient with alcohol abuse, patient with acute or chronic infection, patient with methotrexate intolerance, patient being treated with live attenuated vaccine)
2. Patient with documented fibromyalgia
3. Patient who have had a major surgery within 2 weeks prior to study entry
4. Patient with lactose intolerance
5. Patient presenting with cardiac disorders defined by at least one of the following conditions:
Patient with recent cardiac history (within 6 months) of:
- Acute coronary syndrome
- Acute heart failure (class III or IV of the NYHA classification)
- Significant ventricular arrhythmia (persistent ventricular tachycardia, ventricular fibrillation, resuscitated sudden death)
Patient with cardiac failure class III or IV of the NYHA classification
Patient with severe conduction disorders which are not prevented by permanent pacing (atrio-ventricular block 2 and 3, sino-atrial block)
Syncope without known aetiology within 3 months
Uncontrolled severe hypertension, according to judgment of the investigator, or symptomatic hypertension
6. Patient with history of primary malignancy < 5 years; except treated basal cell skin cancer or cervical carcinoma in situ
7. Patient with a severe and/or uncontrolled medical condition
8. Pregnant or lactating woman
9. Patient with history of poor compliance or history of drug/alcohol abuse, or excessive alcohol beverage consumption that would interfere with the ability to comply with the study protocol, or current or past psychiatric disease that might interfere with the ability to comply with the study protocol or give informed consent.
10. Patient who were treated with methotrexate >20 mg cannot be included in the study
Previous treatments:
11. Administration of a DMARD (except methotrexate) within 4 weeks (or 5 half-lives, whichever is longer) prior to baseline except for leflunomide which requires a specific wash-out period of 12 weeks before baseline and infliximab which requires a wash-out period of 8 weeks.
12. Administration of more than one Non Steroidal Anti-Inflammatory Drug (NSAID) or change of dose of NSAID within 4 weeks of screening or NSAID use greater than the maximum recommended dose.
13. Administration of more than 10 mg/day of prednisone or equivalent or change in the dose of prednisone or equivalent, or having intra-articular corticosteroid injection or bolus intramuscular or intravenous treatment with corticosteroids (>20 mg prednisone or equivalent) within 4 weeks of screening.
14. Treatment with any investigational agent within 4 weeks of screening. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Cumulative response on ACR50 (ie. response from week 8 to week 24) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Cumulative response on ACR20 (ie. response from week 8 to week 24) |
|
| E.5.2 | Secondary end point(s) |
Response assessment:
- Cumulative response on ACR20 (ie. response from week 8 to week 24),
- Cumulative response on ACR70 (ie. response from week 8 to week 24),
- Cumulative response on ACR90 (ie. response from week 8 to week 24)
- ACRn from week 8 to week 24
- Time to first response according to ACR20 and ACR50
- DAS28 from week 8 to week 24:
DAS28 (disease activity score)
DAS28 < 2.6 (complete remission),
DAS28 ≤ 3.2 (low disease activity),
- CRP and ESR level from week 8 to week 24
CRP and ESR values
Percentage of patients with an improvement of CRP and ESR >50%, between 25 and 50%, between 0 and 25% or no improvement
Quality of life assessment:
- Visual assessment scale from week 8 to week 24:
pain
asthenia
general health
- Quality of life assessed of SF36 from week 8 to week 24
- Health Assessment Questionnaire (HAQ) score and from week 8 to week 24
- Hamilton score from week 8 to week 24
- Fatigue Impact scale from week 8 to week 24
Safety assessments: Adverse events, vital signs, laboratory data. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| response from week 8 to week 24 |
|
| 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 | No |
| 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) | 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 | 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) | Yes |
| 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 | 25 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| 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 |
| France |
| Greece |
| India |
| Poland |
| Romania |
| Slovakia |
| Spain |
| Thailand |
| Tunisia |
| Turkey |
| United States |
|
| 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
|
At week 24, in case of clinical benefit/response, defined as ACR20 reached and if recommended by the investigator, patients will have the possibility to enter an extension period
- The maximum exposure to treatment is 2 years.
- After 2 years patients will be able to continue treatment only if a documented favourable benefit/risk balance is established patient per patient by the investigator and a resignature of the ICF to warn the patient on potential long term risks.). |
|
| 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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