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 |
Rheumatoid Arthritis (RA) is a chronic progressive inflammatory disease
in the joints that often results in painful deformity and immobility,
especially in the fingers, wrists, feet, and ankles. |
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E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10003268 |
E.1.2 | Term | Arthritis rheumatoid |
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 |
The primary objective of the study is to evaluate the long-term safety of ABX464 given at 50mg once daily in patients with moderate to severe active Rheumatoid Arthritis. |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the long-term effects of ABX464 on Low Disease Activity (LDA) or remission (DAS28-ESR remission, ACR/EULAR remission, SDAI and CDAI remission);
- To evaluate the long-term effects of ABX464 on disease activity scores (DAS28 scores, simplified disease activity score [SDAI] and clinical disease activity score [CDAI]).
- To evaluate the long-term effects of ABX464 on the Patient Reported Outcomes (PRO), Healthy Assessment Questionnaire Disability Index (HAQ-DI) and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue;
- To evaluate the long-term effects of ABX464 on the American College of Rheumatology (ACR) 20/50/70 response and each of its components and the European League Against Rheumatism (EULAR) response (based on DAS28-CRP response).
- To evaluate the expression of miR-124 in total blood (determined by qPCR) at Week 52 and 104.
Echocardiography: - To evaluate the effect of ABX464 in cardiac function as assessed through echocardiograms. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
A patient will be eligible to participate in this study if ALL the following criteria are met:
- Patients previously enrolled in the ABX464-301 clinical study who have completed the ABX464-301 study;
- Patients are able and willing to comply with study visits and procedures as per protocol;
- Patients should understand, sign and date the written voluntary informed consent form at the enrolment visit prior to any protocol-specific procedures are performed;
- Females and males receiving the study treatment and their partners must agree to use a highly effective contraceptive method during the study and for 6 months after end of study or early termination. Contraception should be in place at least 2 weeks prior to study participation. Women must be surgically sterile or if of childbearing potential must use a highly effective contraceptive method. Women of childbearing potential (WOCBP) will enter the study after confirmed menstrual period and a negative pregnancy test. Highly effective methods of contraception include true abstinence, intrauterine device (IUD) or hormonal contraception aiming at inhibition of ovulation, intrauterine hormone releasing system, bilateral tubal ligation, vasectomized partner. True abstinence is defined when this is in line with the preferred and usual lifestyle of the patient. In each case of delayed menstrual period (over one month between menstruations) confirmation of absence of pregnancy is required. This recommendation also applies to WOCBP with infrequent or irregular menstrual cycle. Female and male patients must not be planning pregnancy and male patients should use condom and must not donate sperm during the trial and for 6 months post completion of their participation in the trial.
Criteria that should be met by patients at week 52 to be eligible for 52 additional weeks of study treatment. - Patients should be in clinical response. Clinical response is defined as: DAS28-CRP ≤ 2,6 for anti-TNFα naïve patients or DAS-28-CRP ≤ 3,2 for patients previously treated by anti-TNFα. - Patients able and willing to continue the study treatment and who are compliant with study visits and procedures and who signed the update of the written voluntary informed consent form |
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E.4 | Principal exclusion criteria |
The following criteria should be checked at the time of screening. If ANY exclusion criterion applies, the patient will not be included in the study:
- Any condition, which in the opinion of the investigator, could compromise the patient's safety or adherence to the study protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary safety endpoint
- Incidence of treatment-emergent adverse events in the ABX464 treated Patients, categorized by severity
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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) |
Main efficacy Endpoint:
- Proportion of patients achieving DAS28-ESR remission (DAS28 ESR < 2.6) at Week 52 and at Week 104
Other secondary endpoints:
- Proportion of patients achieving at Week 4, Week 12, Week 24, Week 36, Week 52, Week 65, Week 78, Week 91, and Week 104:
o Low Disease Activity (LDA) (DAS28 ESR ? 3.2)
o ACR/EULAR remission (TJC(28), SJC(28), CRP, and PtGA: all?1);
o SDAI remission (SDAI ? 3.3);
o CDAI remission (CDAI ? 2.8);
o ACR20/50/70 response;
o Categorical DAS28-CRP response. Proportion of patients achieving categorical DAS28-CRP response will be measured as moderate/good European League Against Rheumatism (EULAR) response at each assessment time point
- Time to onset of the LDA and DAS28-ESR remission;
- Time to onset of the ACR/EULAR remission;
- Change from Baseline in the following disease parameters at Week 4, Week 12, Week 24, Week 36, Week 52, Week 65, Week 78, Week 91, and Week 104:
o Individual components of the ACR20 response: CRP, TJC(28), SJC(28), Pain-VAS, PtGA, PrGA, HAQ-DI;
o DAS-28-CRP and DAS28-ESR scores;
o SDAI score;
o CDAI score;
o FACIT-Fatigue score;
Both baseline values from the primary randomized study ABX464-301 (Day 0) and from this open-label study ABX464-302 (Day 84 of ABX464-301) will be compared.
- Quantification of miR-124 expression in total blood (determined by qPCR) at Week 52 and Week 104.
- The number of incidences of treatment-emergent serious adverse events;
- The number of incidences of treatment-emergent adverse events of special interest;
- The number of incidences of adverse events leading to investigational product discontinuation;
- The number of incidences of clinically significant laboratory abnormalities;
- The number of incidences of all AE (causally related and non-related) and SAE, further categorized by severity.
The secondary endpoints for the echocardiography [10] are: - Absolute (%) change-from-previous echocardiogram of Left ventricle Ejection Fraction (EF) as measured by 2- or 3-dimensional echocardiography - Number of subjects with a clinically relevant reduction (change-from previous echocardiogram) of EF, defined as more than 10% absolute reduction to EF < 50% - Absolute (%) change in Global Longitudinal Strain - Number of subjects with a clinically relevant change of GLS, defined as a relative change-from-previous echocardiogram of >15% (e.g., -22% to -18%) - Number of subjects with an absolute reduction of LVER > 10% to EF >50% with a relative fall in GLS of > 15% - Number of subjects with an absolute reduction of LVEF <10% to ED <50% - Changes of other echocardiographic parameters as described in a standard protocol, including 2- and 3-dimensional volumes, RV size and systolic function and valve function. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
See E.5.2 for 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 | 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 | 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 | No |
E.8.1.1 | Randomised | No |
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 | 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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 20 |
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 | 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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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 | 3 |
E.8.9.1 | In the Member State concerned days | |
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 | 3 |