| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 17.1 |
| 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 topicallyapplied
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
|
|
| 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 preexisting
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.
|
|
| 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 | 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) | 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 |
| Argentina |
| Bosnia and Herzegovina |
| Czech Republic |
| Greece |
| India |
| Mexico |
| Monaco |
| Morocco |
| Philippines |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Slovakia |
| South Africa |
| Spain |
| Taiwan |
| Thailand |
| Tunisia |
| Ukraine |
| 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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