| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Rheumatoid Arthritis |
| Ревматоиден Артрит |
|
| E.1.1.1 | Medical condition in easily understood language |
| Rheumatoid Arthritis |
| Ревматоиден Артрит |
|
| 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 | 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 |
|
| 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 demonstrate comparative efficacy of AVT05 with EU-approved Simponi® (EU Simponi) as measured by DAS28-CRP at Week 16. |
|
| E.2.2 | Secondary objectives of the trial |
•To assess and compare additional efficacy measures of AVT05 and EU-Simponi in terms of DAS28-CRP, SDAI, CDAI and in terms of ACR20/50/70 and its individual components throughout the study.
•To assess and compare the safety, tolerability, and immunogenicity of AVT05 and EU Simponi throughout the study.
•To compare steady-state PK of AVT05 and EU Simponi. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Male or female subjects
2.Subjects must be 18-75 years of age inclusive at the time of signing the ICF
3.Subjects diagnosed with active RA according to American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 classification criteria for at least 4 months prior to Screening (Scr), and with a Clinical Disease Activity Index (CDAI) score >10.1 at Scr, who are capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol
4.Subjects with moderately to severely active RA as defined by≥6 swollen (out of 66) and≥6 tender (out of 68) joint counts, C reactive protein (CRP)>1 mg/L, and who fulfill at least 1 of the following criteria at Scr:
a)Positive rheumatoid factor
b)Positive anti-citrullinated peptide antibodies
c)Evidence of 1 joint erosion on radiological assessment of the hands, wrist of the dominant hand, or feet at Scr
5.Subjects must have taken MTX for≥12 weeks (W), at a stable dose of≥12.5 mg to 25 mg weekly in the last 4 W prior to Screening, and plan to remain on a stable dose throughout the study. Subjects who are on a dose of MTX of≥10 mg per W will be eligible if there is documented intolerance to further MTX dose escalation
6.Any concomitant non-steroidal anti-inflammatory drugs (NSAIDs) must be stable for at least 2 W prior to Day 1.
7.If receiving current treatment with oral corticosteroids, the dose must not exceed 10 mg/day prednisolone or equivalent; for≥4 W prior to Day 1 the dose must remain stable
8.Have a body weight of 50.0 to 100.0 kg (inclusive) and body mass index (BMI) of 18.5 to 32.0 kg/m2 (inclusive)
9..Supine systolic blood pressure of ≤140 mmHg and diastolic blood pressure of≤90mmHg obtained in at least 1 of up to 3 measurements, taken after 3 min in resting supine position. Other vital signs showing no clinically relevant deviations according to the investigator’s judgment
10.12-lead electrocardiogram (ECG) recording without signs of clinically relevant pathology or showing no clinically relevant deviations as judged by the investigator
11.Laboratory values for blood and urine within the normal range or showing no clinically relevant deviations as judged by the investigator.
NOTE: One repeat evaluation of clinical lab. tests, including CRP, will be permitted, at the discretion of the PI or delegate.
12.Tested negative for beta-D-glucan fungal antigen, hepatitis B surface antigen (HBsAg), anti-hepatitis B core antibodies (anti HBc), anti-hepatitis B surface antibody (anti-HBs), anti-hepatitis C virus(HCV) antibodies, and anti-human immunodeficiency virus(HIV) type 1 and type 2 antibodies at Scr
NOTE: Subjects with positive anti-HBs alone are eligible if they have documented history of vaccination.
13.Female subjects are eligible to participate if they are not pregnant, not breastfeeding, and at least ONE of the following conditions applies:
a.Is not a female of childbearing potential(FOCBP), defined as:
i.Surgically sterile (documented hysterectomy, bilateral salpingectomy, bilateral tubal ligation, or bilateral oophorectomy, as confirmed by review of the subject’s medical records, medical examination, or medical history interview), or
ii.Postmenopausal (defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone[FSH] level (>40 IU/L) in the postmenopausal range may be used to confirm a postmenopausal state in females not using hormonal contraception or hormonal replacement therapy[HRT]. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient). Female subjects on HRT and whose menopausal status is in doubt will be required to use 1 of the non-estrogen hormonal highly effective contraception methods (see Section 13.2.2 of the protocol), starting at Scr (from the signing of the ICF) until at least 6 months after the last dose of the study drug if they wish to continue their HRT during the study.
b.Is a FOCBP who agrees to use a highly effective method of contraception consistently and correctly, starting at Scr (from the signing of the ICF) until at least 6 months after the last dose of the study drug (see Section 13.2.2 of the protocol).
14.Non-sterilized male subjects with female partners of childbearing potential are eligible to participate if they agree to adhere to the contraception requirements (see Section 13.2.2 of the protocol), starting at Scr (from the signing of the ICF) until at least 6 months after the last dose of study drug.
15.In addition, subjects must refrain from donating sperm or eggs, starting at Screening (from the signing of the ICF) until at least 6 months after the the last dose of the study drug.
|
|
| E.4 | Principal exclusion criteria |
1.Prior treatment with biologics or Janus kinase (JAK) inhibitors that may be used as disease-modifying anti-rheumatic drugs.
2.Have a history of relevant drug and/or food allergies.
3.Have a history of hypersensitivity to golimumab or its constituents.
4.Have any past or concurrent medical conditions that could potentially increase the subject’s risks or that would interfere with the study evaluation, procedures, or study completion. Examples of these include medical history with evidence of clinically relevant pathology (eg, uncontrolled diabetes, malignancies, or demyelinating disorders).
5.RA with significant secondary involvement of any systemic organ (including, but not limited to vasculitis or pulmonary fibrosis) in the opinion of the investigator.
6.Major chronic inflammatory disease or connective tissue disease other than RA (eg, gout, reactive arthritis, psoriatic arthritis (PsA), seronegative spondyloarthropathy, Lyme disease), or any active autoimmune disease (eg, systemic lupus erythematosus, inflammatory bowel disease, scleroderma, inflammatory myopathy, mixed connective tissue disease, or any overlap syndrome) or diagnosis of juvenile idiopathic arthritis, and/or RA before the age of 16, or joint disease other than RA. Sjögren’s syndrome secondary to RA is allowed if the diagnosis is clearly documented.
7.Presence of chronic obstructive pulmonary disease. Childhood asthma and adult well-controlled asthma are allowed.
8.Presence of chronic heart failure of New York Heart Association (NYHA) class III or IV.
9.Presence of renal disease (defined as creatinine clearance <50 mL/min as calculated by Cockcroft-Gault formula).
10.Receipt of any investigational agent or drug within 60 days or 5 half-lives of the previous drug, whichever is longer, prior to study drug administration.
11.Treatment with intravenous (IV) gamma globulin or the Prosorba® Column within 6 months of the Screening Visit.
12.Previous treatment with any synthetic disease-modifying anti rheumatic drug (sDMARD) other than MTX (including injectable gold, sulfasalazine, antimalarials, D-penicillamine, cyclosporine, leflunomide, azathioprine, calcineurin inhibitors) within 3 months prior to Screening. Subjects who have received sDMARDs in the past must have recovered from all drug-related adverse events (AEs).
13.Subjects who received an intra-articular or parenteral corticosteroid injection within the 4 weeks prior to Screening.
14.Any current active infections, including localized infections, or any recent history (within 1 week prior to study drug administration) of active infections, cough or fever, or a history of recurrent or chronic (including opportunistic) infections.
15.Subject has a history of tuberculosis (TB) diagnosis or evidence of active or latent infection with Mycobacterium tuberculosis as defined by 1 of the following assessments:
a.Positive or indeterminate QuantiFERON®-TB Gold test result at Screening.
b.Chest radiograph (posterior anterior view) taken as part of the medical history within 12 weeks prior to Screening, read by a qualified radiologist or pulmonologist, with evidence of current active TB or old inactive TB.
c.Signs or symptoms suggesting active TB.
d.Recent close contact with active TB.
Note: A positive or indeterminate QuantiFERON®-TB Gold test result
shall not be retested but recognized as non-eligible. Subjects formerly
diagnosed with TB infection (not disease) due to a routine
QuantiFERON®-TB Gold test that returned a positive result, in whom
active disease was ruled out after appropriate testing and who had
received treatment according to local recommendations, may be
screened at the discretion of the investigator. In such cases, a positive
or indeterminate QuantiFERON®-TB Gold result will be allowed.
16.Donation of more than 500 mL of blood within the 8 weeks prior to study drug administration.
17.A recent history of major surgery (within the 3 months prior to randomization).
18.A history (within the previous 3 years) or evidence of alcohol abuse.
19.Vaccination with a live vaccine (with the exception of flu vaccine) within the 4 weeks prior to Screening or have the intention to receive a live vaccination up to 5 weeks after the last dose of study drug.
20.Any other condition which in the view of the investigator is likely to interfere with the study or put the subject at risk.
21.Any persons who are:
a.An employee of the study site, investigator, contract research organization (CRO), or the Sponsor.
b.A first-degree relative of an employee of the study site, the investigator, CRO, or the Sponsor. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| •Change from baseline in DAS28-CRP at Week 16. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
•Change from baseline in DAS28-CRP at Weeks 4, 8, 12, 24, 32, 40, 48, and 52.
•Percentage of subjects achieving ACR20/50/70 at Weeks 4, 8, 12, 16, 24, 32, 40, 48, and 52, in comparison to baseline.
•Percent change in DAS28-CRP from baseline at Weeks 4, 8, 12, 16, 24, 32, 40, 48, and 52.
•Change from baseline in all individual ACR core components: swollen joint count, tender joint count, Subject’s Assessment of Pain, Subject’s Assessment of Disease Activity, Physician’s Assessment of Disease Activity, Subject's Assessment of Activity Level, SDAI, CDAI, and CRP at Weeks 4, 8, 12, 16, 24, 32, 40, 48, and 52.
•Incidence, nature, and severity of AEs including ADRs, graded according to CTCAE and AESIs; clinical laboratory assessments (hematology, clinical biochemistry, coagulation, and urinalysis), vital signs, ECGs, physical examination findings, and injection site reactions.
•Detection of antibodies against AVT05 and EU-Simponi; titer and frequency of ADA and frequency (IC50) of NAbs.
•Serum trough concentrations at steady state. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
•Change from BL in DAS28-CRPat W 4,8,12,24,32,40,48,52
•%% of subjects achieving ACR20/50/70 at W 4,8,12,16,24,32,40,48,52.
•%% change in DAS28-CRP from BL at W 4,8,12,16,24,32,40,48,52
•Change from BL in all individual ACR core components, SDAI, CDAI, and CRP at W 4,8,12,16,24,32,40,48,52
•Incidence, nature, and severity of AEs including ADRs; clinical laboratory assessments, vital signs, ECGs, physical examination, injection site reactions: throughout the study
•Detection of antibodies against AVT05 and EU-Simponi; titer and frequency of ADA and frequency of NAbs: at W 1,4,8,16,24,32,40,48,52
•Serum trough concentrations at steady state: at W 1,4,8,16,24,32,40,48,52 |
|
| 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 | 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| 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 |
|
| 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
|
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 6 |
Print
