E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
High IFN siganture in patients with rheumatoid arthritis |
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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 |
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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 efficacy of Anifrolumab compared to placebo on RA disease activity in patients with an increased type I IFN gene signature. (Achieving an ACR 20 response at week 24)
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E.2.2 | Secondary objectives of the trial |
To evaluate the effect of Anifrolumab compared to placebo on: •Absolute and relative change in the Simplified Disease Activity Index (SDAI) after 24 weeks •Absolute and relative change in Clinical Disease Activity Index (CDAI) at week 24 and at every visit before and after week 24 •Absolute and relative change in Disease Activity Score 28 (DAS28) after 24 weeks •Achieving a EULAR response (good, moderate) •Achieving a SDAI response (50%, 70%, 85%) •Achieving a CDAI response (50%, 70%, 85%) •Achieving an ACR response (20%, 50%, 70%) •Change in quality of life (SF-36) and physical function (HAQ) •Change in pain, fatigue and sleep (visual analog scale, VAS) •Proportion achieving a low disease activity state (CDAI≤10, SDAI≤11) after 24 weeks •Proportion achieving a remission state (CDAI≤2.8; SDAI≤3.3; ACR/EULAR Boolean) after 24 weeks •Proportion achieving DAS28≤3.2 after 24 weeks •Change in Kessler Psychological Distress Scale (K10) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•18 - 70 years at screening •Written informed consent •Weigh ≥50.0 kg and ≤100.0 kg at screening •Diagnosis of RA according to the 2010 ACR/EULAR classification criteria for RA •at least one conventional synthetic (cs)DMARD (methotrexate (MTX), leflunomide, sulfasalazine (SSZ)) regularly for at least 12 weeks, with stable doses for at least 8 weeks. •moderately to severely active RA •Received at least one TNF-inhibitor (TNFi) but not more than 3 biological (b)DMARDs and discontinued treatment because of an insufficient response after at least 3 months. •Oral Glucocorticoids (OCS) are allowed at stable doses of ≤10 mg /day prednisone or equivalent, if already used before the screening visit, dose must be stable for at least 2 weeks •High type I IFN gene signature test •Seronegative for HIV, hep. B surface antigen and hep. C ¬antibodies •Negative serum β-hCG test at screening (females of childbearing potential only). •Females of childbearing potential must use 2 effective methods of avoiding pregnancy •All males (sterilised or non-sterilised) who are sexually active must use condom (with spermicide where commercially available) •Male subjects must not donate sperm during the course of the study and for 12 weeks after the last dose of the investigational product. •Females with an intact cervix must have documentation of a normal Pap smear with no documented malignancy •Meets all of the following tuberculosis (TB) criteria: -No history of latent or active TB, exception: latent TB with documented completion of appropriate treatment -No signs or symptoms suggestive of active TB -No recent contact with a person with active TB -Negative QuantiFERON-tuberculosis Gold [QFT-G] test for tuberculosis within 3 months prior to randomisation •A chest radiograph with no evidence of current active infection within 12 weeks prior to signing of the informed consent |
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E.4 | Principal exclusion criteria |
General exclusion criteria: •Any condition that would interfere with evaluation of the investigational product or interpretation of patient safety or study results •Participation in another clinical study with an investigational product •Individuals involved with the conduct of the study, their employees, or immediate family members of such individuals •Lactating or pregnant females or females who intend to become pregnant •Current alcohol, drug or chemical abuse, or a history of such abuse •Major surgery within 8 weeks before signing ICF or elective major surgery planned during the study period •Low type I IFN transcript scores in peripheral whole blood (type I Interfern Gene signature test) •At screening (within 4 weeks before Week 0 [Day 0]), any of the following: -AST >2.0 × ULN -ALT >2.0 × ULN -Total bilirubin >ULN (unless due to Gilbert's syndrome) -Serum creatinine >2.0 mg/dL (or >181 μmol/L) -Urine protein/creatinine ratio >2.0 mg/mg (or >226.30 mg/mmol) -Neutrophil count <1000/μL (or <1.0 × 109/L) -Platelet count <150.000/μL (or <150 × 109/L) -Haemoglobin <8 g/dL (or <80 g/L) -Glycosylated haemoglobin (HbA1c) >8% (or >0.08) at screening (diabetic patients only)
Exclusion criteria related to con. Med.: •Receipt of any investigational product (small molecule or biologic agent) within 4 weeks or 5 half lives prior to signing of the ICF. •Prior receipt of Anifrolumab •Prior receipt of a JAK-inhibitor •known history of allergy or reaction to any component of the investigational product •Regular use of >1 NSAID within 2 weeks prior to Day 0 OR receipt of fluctuating doses of a NSAID within 2 weeks prior to Day 0 •Receipt of any of the following: -Intra-articular, intramuscular or intravenous glucocorticosteroids within 6 weeks prior to Day 0 -Any live or attenuated vaccine within 8 weeks prior to signing the ICF -BCG vaccine within 1 year prior signing the ICF -Blood transfusion within 4 weeks prior signing the ICF
Exclusion criteria related to other diseases: •History of any non RA disease that required treatment with oral or parenteral corticosteroids for > 2 weeks within the last 24 weeks prior signing the ICF
Exclusion criteria related to infection and malignancy risk factors: •Splenectomy •Any severe herpes infection at any time prior to Day 0 •Any herpes zoster infection that has not completely resolved within 12 weeks prior signing the ICF •Opportunistic infection requiring hospitalisation or parenteral antimicrobial treatment within 3 years of randomisation •Any of the following: -Clinically significant chronic infection within 8 weeks prior signing the ICF -Any infection requiring hospitalisation or treatment with intravenous anti infectives not completed at least 4 weeks prior signing the ICF •Any infection requiring oral anti-infectives (including antivirals) within 2 weeks prior to Day 0 •History of cancer, apart from: -Squamous or basal cell carcinoma of the skin treated with documented success of curative therapy ≥3 months prior to Week 0 (Day 0) -Cervical cancer in situ treated with apparent success with curative therapy ≥1 year prior to Week 0 (Day 0) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Achieving an ACR response of ≥20% after 24 weeks of treatment is the primary endpoint in this study. The ACR 20% response will be summarized by treatment group and the difference between groups may be estimated. A non responder imputation method will be used for the handling of missing data, i.e., patients who discontinue from treatment and/or the study for any reason, as well as patients who require rescue medication beyond the protocol allowed threshold, will be imputed as non-responders. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
To evaluate the effect of Anifrolumab compared to placebo on: •Absolute and relative change in the Simplified Disease Activity Index (SDAI) after 24 weeks •Absolute and relative change in Clinical Disease Activity Index (CDAI) at week 24 and at every visit before and after week 24 •Absolute and relative change in Disease Activity Score 28 (DAS28) after 24 weeks •Achieving a EULAR response (good, moderate) •Achieving a SDAI response (50%, 70%, 85%) •Achieving a CDAI response (50%, 70%, 85%) •Achieving an ACR response (20%, 50%, 70%) •Change in quality of life (SF-36) and physical function (HAQ) •Change in pain, fatigue and sleep (visual analog scale, VAS) •Proportion achieving a low disease activity state (CDAI≤10, SDAI≤11) after 24 weeks •Proportion achieving a remission state (CDAI≤2.8; SDAI≤3.3; ACR/EULAR Boolean) after 24 weeks •Proportion achieving DAS28≤3.2 after 24 weeks
Safety and tolerability endpoints: AEs (including adverse events of special interest [AESIs]), vital signs, physical examination, 12-lead electrocardiograms (ECG), and clinical laboratory tests (haematology, clinical chemistry, urinalysis) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Screening to end of study |
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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 | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
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 | No |
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 | 2 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 3 |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |