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 | 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 determine the preliminary tolerability and safety profile of multiple intravenous (i.v.) administrations of NI-0101 - To describe the Pharmacokinetic/Pharmacodynamic (PK/PD) profiles of NI-0101 - To determine NI-0101 preliminary efficacy - To explore specific biomarkers as predictors of treatment response - To explore the impact of the FcyRIIa genotype on the response to treatment - To assess the immunogenicity of NI-0101
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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 |
- Male and female patients - Age >= 18 years old - BMI: < 30 and > 18 - Diagnosis of RA according to 2010 ACR/EULAR criteria and with a disease duration of at least 6 months since diagnosis - Patient must present with active RA, characterized by at least 6 swollen joints out of 66 assessed and 6 tender jointsout of 68 assessed and by the presence of synovitis (measured by ultrasound) in at least one of the 6 swollen joints - C-reactive protein (CRP) level > 0.7 mg/dL or if the CRP level is between 0.3 mg/dL and 0.7 mg/dL (included) then patient must also present an ESR > 30mm/hr - Patients must have received MTX treatment for at least 3 months and have been on a stable dose of MTX for at least 6 weeks prior to start of screening - ACPA-positive RA patients - Women must be postmenopausal (> 12 months without menses) or surgically sterile or if considered of child bearing potential must be using at least a highly effective contraception method for at least for 4 weeks prior to the randomization date and agree to continue contraception for the duration of their participation in the study (until the end of follow up period). - Sexually active male patients must use a barrier method of contraception during the course of the study (and until the end of the follow up period), in addition to their partner(s) using another highly effective method - Patients must give written informed consent for study participation |
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E.4 | Principal exclusion criteria |
- A documented history of an autoimmune disease other than RA by ACR classification, or Sjögren syndrome - Administration of cytotoxic drugs and immune suppressants (other than MTX) within 3 months prior to screening - Previous multiple administrations of any biological DMARD or targeted synthetic DMARD - Known primary immunodeficiency - Pregnant or breastfeeding women - Suspicion of active or latent tuberculosis - HIV, HCV, HBV infection - Infection reported during screening not recovered 72h prior to first dose - History of anaphylactic reactions to any protein therapeutics or excipients - Any history of malignancy, excluding cured basal or squamous cell carcinoma of the skin, or cervical in situ carcinoma - Clinically significant cardiac disease requiring medication, such as congestive heart failure, unstable angina, myocardial infarction within 6 months prior to randomization - Moderate to severe renal insufficiency, clinically relevant liver function test abnormalities or pancytopenia - Major psychiatric or neurological disorder - Administration of anti-RANKL monoclonal antibody within 3 months prior to screening. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety: 1. Incidence, severity, causality and outcomes of AEs (serious and non-serious), with particular attention being paid to infusion-related reactions and infections 2. Withdrawals for safety issues 3. Evolution of laboratory parameters 4. Level of potential circulating antibodies against NI-0101 to determine immunogenicity; i.e. the development of anti-drug antibodies (ADA).
PK: 5. Descriptive non-compartmental PK analysis (NCA) 6. Exploratory compartmental PK analysis and population PK analysis 7. Detection of anti-drug antibodies (ADA) in human RA patient serum
PD: 8. Levels of CRP at all study visits prior to IMP infusion 9. Levels of inflammatory cytokines/chemokines at pre and post (week 2, 6 and 12) dose measured using ELISA and/or multiplex assays (e.g. MSD or equivalent).
Biomarker: 10. Multi Biomarker Disease Activity score (MBDA or Vectra DA®), calculated based on levels of 12 different biomarkers.
Efficacy: 11. DAS28-CRP/ESR score at Week 12 12. Proportion of patients achieving ACR20, ACR50 and ACR70 responses at Week 12 13. Proportion of patient achieving remission (defined as DAS28 < 2.6) at Week 12 14. Proportion of patients achieving EULAR good, moderate and no response at Week 12 15. Mean number of Tender Joint Count/Swollen Joint Count at week 12 and over time 16. Mean improvement from baseline to Week 12 in DAS28-CRP/ESR 17. Mean improvement from baseline to Week 12 in SDAI and CDAI scores 18. Mean improvement from baseline to Week 12 in HAQ-DI score 19. Mean improvement from baseline to Week 12 in SF-36 score |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety: 1. See E.5.1 2. See E.5.1 3. Day 0, 7, 14, 28, 42, 56, 70, 84, 112, 140, 168 4. Day 0, 84, 168
PK: 5-7. See E.5.1
PD: 8-9. See E.5.1
Biomarker: 10. The biomarker score will be measured pre-dose, week 2 and week 12 samples, the analysis is optional and will be performed at the end of the study, if considered relevant. Other exploratory biomarkers are included as part of the optional analysis.
Efficacy: 11-19. See E.5.1 |
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 22 |
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 |
Bosnia and Herzegovina |
Bulgaria |
Georgia |
Hungary |
Moldova, Republic of |
Poland |
Serbia |
United Kingdom |
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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
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End of the study is defined as last patient last visit, which will occur at the end of the follow up period. |
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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 | 15 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |