| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| rheumatoid arthritis |
| reumatoid artritis |
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| E.1.1.1 | Medical condition in easily understood language |
| rheumatoid arthritis |
| reumatoid artritis |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.1 |
| 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 |
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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 main objective of the study is to demonstrate non-inferiority of the response of MSKUS-assessed synovitis (i.e. B-mode and Doppler mode synovitis) to baricitinib treatment, alone plus combined with MTX (arm1 + arm2) vs. etanercept plus MTX (arm 3) in IR-MTX patients. Non-inferiority will be claimed if changes in MSKUS-assessed synovitis with baricitinib (alone and combined with MTX) after 12 weeks of treatment is at least 80% of changes in the etanercept + MTX group in the same period using a non-inferiority test for two means. |
| Undersøgelsen hovedformål er at demonstrere en non-inferiør respons af synovitis vurderet på baggrund af MSKUS (dvs. B-modus og Doppler modus synovitis) på baricitinib-behandling, alene og kombineret med MTX (arm1 + arm2) versus etanercept samt MTX (arm 3) hos IR-MTX patienter. Responsen vil blive anset for non-inferiør, hvis forandringerne i den MSKUS-vurderede synovitis med baricitinib (alene eller kombineret med MTX) efter 12 ugers behandling er mindst 80% af forandringerne i etanercept + MTX gruppen i samme periode under anvendelse af en non-inferioritets prøve for to midler. |
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| E.2.2 | Secondary objectives of the trial |
• To compare the grade of B-mode- and Doppler-detected residual synovitis in IR-MTX RA patients who achieve clinical remission or low disease activity (i.e. DAS28 <3.2) at 4 weeks, 12 weeks and 24 weeks on baricitinib + MTX vs baricitinib monotherapy vs + etanercept + MTX.
• To evaluate the predictive value of MSKUS-assessed response to baricitinib (monotherapy and combined with MTX) at week 4 in relation to clinical and MSKUS response at week 12 and 24.
• To histologically evaluate synovial biopsies, obtained at baseline (26, 27) in baricitinib + MTX treated patients in comparison to that observed in etanercept + MTX therapy, in correlation with the results obtained by MSKUS studies. The gene expression and synthesis of proinflammatory mediators (TNF, IL6, IL1, COX2, MCP1, pSTAT1, pSTAT2, pSTAT3, SOCS1, SOCS2, SOCS3, pERK, pAKT…) by real-time PCR and Western-Blot techniques will be assessed.
... |
• At sammenligne graden af B-mode- og Doppler-påvist resterende synovitis hos IR-MTX RA-patienter, der opnår klinisk remission eller lav sygdomsaktivitet (dvs. DAS28 <3.2) efter 4 uger, 12 uger og 24 uger på baricitinib + MTX vs baricitinib monoterapi vs + etanercept + MTX.
• At evaluere den forudsigelige værdi af MSKUS-vurderet respons på baricitinib (monoterapi og kombineret med MTX) i uge 4 i relation til klinisk og MSKUS-respons i uge 12 og 24.
• Til histologisk evaluering af synoviale biopsier opnået ved baseline (26, 27) hos patienter behandlet med baricitinib + MTX sammenlignet med dem, der blev observeret i etanercept + MTX-behandling, i sammenhæng med resultaterne opnået ved MSKUS-undersøgelser. Genekspression og syntese af proinflammatoriske mediatorer (TNF, IL6, IL1, COX2, MCP1, pSTAT1, pSTAT2, pSTAT3, SOCS1, SOCS2, SOCS3, pERK, pAKT ...) ved realtid PCR og Western-Blot teknikker vil blive vurderet.
... |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient able to provide written informed consent
2. Mentally competent to understand and willing to undergo the scheduled study procedures, including study questionnaires as established in the protocol.
3. Female or male, from 18 to 75 years of age at the moment of informed consent signature.
4. Patient with RA diagnosed according to 2010 ACR/EULAR Classification Criteria for RA.
5. Moderate to severe disease activity (according to Disease Activity Score for 28 joints (DAS28) ≥ 3.2).
6. Inadequate response to MTX, which must have been received during, at least, 3 months prior to baseline visit and be on a stable dose of ≤ 25 mg/week.
7. Patients who fulfils the pre-requisites for biologic and targeted synthetic disease modifying antirheumatic drugs (DMARD) therapy according to National recommendations/regulations (eg, absence of active infections, absence of latent tuberculosis, recommendations regarding previous cancer, vaccination recommendations,…).
8. Written acceptance to use highly effective contraception i.e. intrauterine device (IUD); hormonal therapy (progestin alone or combined with estrogen) associated with inhibition of ovulation such as oral pill, injection, implant, transdermal patch or vaginal ring; tubal ligation, partner’s vasectomy; or sexual abstinence for the entire duration of study participation including six months after stop of study treatment. |
1. Patienten skal være i stand til at udfylde en erklæring om informeret samtykke
2. Mentalt kompetent til af forstå og villig til at gennemgå de planlagte undersøgelsesprocedurer, inklusiv spørgeskemaer som angivet i protokollen.
3. Kvinde eller mand, mellem 18 og 75 år på det tidspunkt hvor det informerede samtykke underskrives.
4. Patient med RA diagnosticeret i overensstemmelse med ACR/EULAR klassifikationskriterier 2010 for RA.
5. Moderat til alvorlig sygdomsaktivitet (Ifølge sygdomsaktivitets score DAS for 28 led (DAS28) ≥ 3.2).
6. Utilstrækkelig respons på MTX, som skal være blevet administreret i mindst 3 måneder forud for udvælgelsesbesøget med en stabil dosis på ≤ 25 mg/uge.
7. Patienter som opfylder de forudgående krav for behandling med biologiske og målrettede syntetiske sygdomsmodificerende antireumatiske lægemidler (DMARD) i overensstemmelse med de nationale anbefalinger/retningslinje (f.eks. fravær af aktive infektioner, fravær af latent tuberkulose, anbefalinger angående tidligere cancer, anbefalinger angående vaccination...)
8. Skriftligt samtykke til at bruge meget effektiv prævention, dvs. intrauterin enhed (IUD); hormonbehandling (progestin alene eller kombineret med østrogen) forbundet med hæmning af ægløsning, såsom oral pille, injektion, implantat, transdermal plaster eller vaginal ring; tubal ligation, partners vasektomi; eller seksuel afholdenhedunder hele deltagelsen i undersøgelsen inklusiv 6 måneder efter undersøgelsesbehandlingens ophør.
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| E.4 | Principal exclusion criteria |
1. Patient considered by the investigator to be unsuitable for the study treatment and/or rescue medication (RM) based on the prescription drug labeling, their medical history, physical examination, concomitant medication (CM) and concomitant systemic diseases.
2. Complications during the period prior to randomisation, in the investigator's opinion.
3. Hypersensitivity or allergy to the study medication.
4. Patients taking any concomitant medication, which could be susceptible to interact with the study drugs.
5. Patients in treatment with any medication that could affect the evaluation of the study treatment’s efficacy. DMARDs other than methotrexate are not allowed at study inclusion. If the patient has received other DMARD, eg hidroxicloroquine, leflunomide, sulphasalazine,....These drugs must have been stopped at least 3 months before inclusion. Regarding NSAID or corticosteroids, concomitant stable doses of nonsteroidal anti-inflammatory drugs, analgesics for pain relief if necessary. or corticosteroids (≤ 7.5mg of prednisone or the equivalent daily) will be allowed during the trial period.
6. Patients on anticoagulant treatment
7. Pregnant or lactating women.
8. Patients and/or female partners of male patients not using highly effective method of birth control i.e. intrauterine device (IUD); hormonal therapy (progestin alone or combined with estrogen) associated with inhibition of ovulation such as oral pill, injection, implants, transdermal patch or vaginal ring; tubal ligation, partner’s vasectomy; or sexual abstinence.
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1. Patienter der af forskeren anses for at være uegnede til undersøgelsens behandling og/eller akutmedicinen (RM) baseret på receptmedicinens mærkning, den lægelige journal, fysisk undersøgelse, konkomitant medicinering (CM) eller konkomitant systemisk sygdom.
2. Komplikationer i perioden forud for randomiseringen efter forskerens vurdering.
3. Hypersensitivitet eller allergi overfor undersøgelsens lægemiddel.
4. Patienter som tager konkomitant medicin, der kan interagere med undersøgelsens lægemiddel.
5. Patienter i behandling med lægemidler, som kan påvirke evalueringen af undersøgelsesbehandlingens effektivitet. DMARD'er bortset fra methotrexat er ikke tilladt ved undersøgelse inkludering. Hvis patienten har modtaget andet DMARD, f.eks. Hidroxiclorokin, leflunomid, sulphasalazin, .... Disse lægemidler skal være stoppet mindst 3 måneder før inkludering. Med hensyn til NSAID eller kortikosteroider, samtidig stabile doser af ikke-steroide antiinflammatoriske lægemidler, smertestillende midler, hvis det er nødvendigt. eller kortikosteroider (≤7,5 mg prednison eller ækvivalent dagligt) vil være tilladt i forsøgsperioden.
6. Patienter på antikoagulerende behandling.
7. Gravide eller ammende kvinder.
8. Patienter og / eller kvindelige partnere hos mandlige patienter, der ikke bruger meget effektiv metode til prævention, dvs. intrauterin enhed (IUD); hormonbehandling (progestin alene eller kombineret med østrogen) forbundet med hæmning af ægløsning, såsom oral pille, injektion, implantater, transdermal plaster eller vaginal ring; tubal ligation, partners vasektomi; eller seksuel afholdenhed..
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy: The primary outcome considered in this trial is the decrease in join inflammation detected by MSKUS (B-mode and Doppler mode synovitis).
Safety: Safety evaluation will be assessed through physical examination, possible adverse events (related or not to the treatment under study) and analytical parameters. During each study visit all the safety variables must be recorded in medical records and e-CRF.
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Effektivitet: Det primære resultat af denne undersøgelse er mindskelse af inflammationen i led, påvist med MSKUS (B-modus og Doppler modus synovitis).
Sikkerhed: Sikkerheden vil blive vurderet ved fysisk undersøgelse, mulige bivirkninger (relateret eller ej til undersøgelsens behandling) og analytiske parametre. Ved alle undersøgelsens besøg må alle sikkerhedsvariable optegnes i lægejournal og e-CRF.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 4, 12, 24 weeks |
| Uger 4, 12, 24 |
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| E.5.2 | Secondary end point(s) |
Secondary: The secondary endpoints will be:
• Time-point of significant change in B-mode and Doppler synovitis according to treatment group (4 weeks, 12 weeks, 24 weeks).
• Presence and amount of subclinical B-mode and Doppler synovitis in patients reaching DAS28-defined clinical remission and low disease activity at 4 weeks, 12 weeks and 24 weeks, according to treatment group.
• Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI) at 4 weeks, 12 weeks and 24 weeks, according to treatment group.
• Correlation between presence of MSKUS-assessed synovitis, synovial histological alterations and the presence of proinflammatory citokines (TNF, IL6, IL1, COX2, MCP1, RANKL, OPG…) in serum and synovial tissue, at baseline in all patients and after 12 weeks in patients classified as non-responders, according to treatment group.
• Changes in PROM as assessed by the Health Assessment Questionnaire–Disability Index (HAQ-DI), from baseline to 24 weeks.
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De sekundære slutpunkter vil være:
• Tidspunktet for signifikant forandring i B-modus og Doppler synovitis for behandlingsgruppen (4 uger, 12 uger, 24 uger).
• Tilstedeværelse og mængde af subklinisk B-modus og Doppler synovitis hos patienter, som når den DAS28-definerede kliniske remission og lav sygdomsaktivitet ved 4 uger, 12 uger og 24 uger for behandlingsgruppen
• Simplified Disease Activity Index (SDAI) og Clinical Disease Activity Index (CDAI) ved 4 uger, 12 uger og 24 uger for behandlingsgruppen.
• For relevante patienter, korrelation mellem tilstedeværelse af synovitis vurderet med MSKUS, synoviale histologiske forandringer og tilstedeværelse af proinflammatoriske citokiner (TNF, IL6, IL1, COX2, MCP1, RANKL, OPG…) i serum og synovialvæv, ved undersøgelsesstart for alle patienter og efter 12 uger for patienter klassificeret som ikke-responderende i behandlingsgruppen
• Forandringer i PROM vurderet med Health Assessment Questionnaire–Disability Index (HAQ-DI), fra undersøgelsesstart til 24 uger.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 4, 12, 24 weeks |
| Uger 4, 12, 24 |
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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 | 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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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| LVLS: Last Patient Last Visit |
| Global LPLV |
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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 | 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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