Efficacy, Safety and Immunogenicity of Enerceptan Compared to Enbrel in Rheumatoid Arthritis

Study Overview
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Brief Summary
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The purpose of this study is to asses the compared efficacy, safety and immunogenicity of ENERCEPTAN® with ENBREL® in combination with Methotrexate for the treatment of patients with rheumatoid arthritis.

Detailed Description
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Randomized, , non-inferiority, two parallel arms, 32 weeks, blind for the assessor. Subjects should be with inadequate response to methotrexate with stable dosis ≥ 15 and ≤ 25 mg/week 28 days before randomization. Randomization will be 2:1 Enerceptan® to Enbrel® with concomitant medication of MTX

Official Title
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Multicentric Evaluator-blinded Randomized Non-inferiority Study, to Asses the Compared Efficacy, Safety and Immunogenicity of Enerceptan® With Enbrel® in Combination With Methotrexate for the Treatment of Patients With Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Biological: Etanercept
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult men and women over 18 years, who present moderate to severe active RA (rheumatoid arthritis) , diagnosed according to ACR/ EULAR 2010 criteria, who have failed prior MTX (methotrexate) therapy. Functional class I to III. Moderate to severe disease activity, according to DAS28 (erythrosedimentation) ≥ 3.2. Must have at least a minimum of 6 tender joints and 8 swollen joints. If a patient has a joint surgery prior to the study, this joint is considered not evaluable throughout the study development. Must have at least, one erosion in the baseline radiograph. Local assessment centers either radiologist or rheumatologist to decide on this criterion will be accepted. Medical Indication to incorporate a biological treatment in their therapy. Treatment with MTX for at least 3 months on dose ≥15 mg/ week, stable over the last 28 days before the Day 1. Doses lower than 15 mg and greater or equal than 10 mg/ week are accepted in cases with previously documented intolerance. Subjects who have previously received treatment with a biologic (approved or investigational) except etanercept, may participate as long as the corresponding washout time has elapsed prior to the screening interview: At least 8 weeks for infliximab (T1/2 8 to 9.5 days) and for tocilizumab (T1/2 3to 12 days) 10 weeks for adalimumab (T1/2 10 to 20 days), Golimumab (T1/2 11 to 14 days), certolizumab (T1/2 14 days), abatacept (T1/2 14 days), 1 year for Rituximab (T1/2 77,5 days) 5 T1/2 for any other biological product, used for the treatment of rheumatoid arthritis, wether it has been used or not for research. Subjects who are receiving leflunomide must have a previous washout of 8 weeks before Day 1, except had have treatment with colestyramine, according to manufacturer indications. Can receive non steroidal anti inflammatory drugs (NSAIDs) or oral corticoids in doses < 10 mg of prednisone, but treatment must have been stable over the last 28 days. 8 Subjects must be able to self-inject or willing to have a previously assigned caregiver do it for them. 9 Subjects must be able to meet the schedule of visits, understand and comply with other protocol requirements. 10 Women of childbearing age must commit to be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 12 weeks after the last dose of Enbrel®/Enerceptan®. Suitable methods of contraception are oral contraceptives, IUDs (intrauterine device) , bilateral tubal ligation, vasectomy or double barrier methods such as condoms or spermicidal diaphragm, sponge, contraceptive foam or gel, heterosexual abstinence. Men should not conceive up to 12 weeks after stopping the MTX 11 Informed consent must be signed before making any study-specific procedure. Exclusion Criteria: Simultaneous treatment with other investigational drug or participation in another clinical study that the investigator considers inadvisable. Women who are pregnant or breastfeeding. Past history of nonresponsive to TNF (tumor necrosis factor) blocking agents or other biologic treatment. Chronic antibiotic therapy, if the investigator considers this may affect the safety of the subject or the assessment of the study results. Any previous or current serious medical conditions that, in the opinion of the investigator, constitute a contraindication for the study treatment, as: Administration of vaccines: Subjects who have received a live attenuated vaccine within 3 months prior to the randomization Visit (for example, varicella-zoster, oral polio, rabies, yellow fever vaccines.) Subjects who have received the BCG (bacillus Calmette-Guerin) vaccine within 12 months before the Selection. Presence of : a. At the time of the inclusion i. Active infections. ii. Fever (≥38 °C) or active, chronic or recurrent infections that require treatment with antibiotics, antiviral, or anti-fungal medications within 4 weeks prior to Screening Visit, or history of frequent recurrent infections unacceptable to the investigator's opinion. iii. Non-healing infected skin ulcers. b. In the previous time: i. Background of recurrent bacterial, viral, fungal (excluding superficial infections or nail bed mycosis), mycobacterial or other severe infections within the last month previous to selection. ii. Hospitalization for infection or Subjects who have received antibiotics intravenously within the last month or orally within the last 2 weeks. iii. Subjects with herpes zoster in the last 2 months. Past history of drug or alcohol abuse within the last year prior to the Screening Visit. Known hypersensitivity to the study drug or history of severe allergy or anaphylactic reaction to monoclonal antibodies or fusion or human proteins. Any condition that, in the investigator opinion, would not allow compliance with the guidelines of the study by the patient. The subject presents absolute contraindications for the use of etanercept, according to the prospectus Presence of significant laboratory abnormalities in the screening visit.

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Enbrel®<br>Enbrel® 50 mg injectable solution in autoinjector SureClick® contains: 50 mg etanercept and excipients/Once a week Methotrexate 15 to 25 mg /Once a week | Biological: Etanercept<br> <br> Drug: Methotrexate<br> <br> |
| Experimental: Enerceptan®.<br>Enerceptan®. Injectable Solution in prefilled syringes Source: GEMABIOTECH S. A. Formulation per unit: 1,0 ml of Enerceptan® contains 50 mg solution of Etanercept /Once a week Methotrexate 15 to 25 mg /Once a week | Biological: Etanercept<br> <br> Drug: Methotrexate<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ACR (American College of Rheumatology) 20 | The percentage of patients who achieved ACR20 at Week 32 is the primary end point. Signs and symptoms are assessed with a composite rating scale of the ACR (American College of Rheumatology) that includes 7 variables: Tender Joints Count Swollen Joints Count Levels of an acute phase reactant (CRP level) Patient's assessment of pain Patient's global assessment of disease activity Physician's global assessment of disease activity Patient's assessment of physical function | 32 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ACR (American College of Rheumatology) 50 | ACR50 is defined as the percentage of patients who achieve at least 50% improvement in both tender joint count and swollen joint count, and at least 50% improvement in at least 3 of the 5 other assessments. | 32 weeks of treatment | 
| ACR (American College of Rheumatology) 70 | ACR70 is defined as the percentage of patients who achieve at least 70% improvement in both tender joint counts and swollen joint counts and at least 70% improvement in at least 3 of the 5 other assessments of the ACR | 32 weeks of treatment | 
| DAS (Disease activity state) | It will be measured using the DAS (Disease activity state) 28. DAS28 is a composite score that includes 4 variables: Tender Joints Count (based on 28 joints) Swollen Joints Count (based on 28 joints) Patient's global assessment of disease activity Marker of inflammation: C REACTIVE PROTEIN | 32 weeks of treatment | 
| EULAR (European League Against Rheumatism) response criteria | Good response = Percentage of patients with an improvement of >1.2 and a present DAS score ≤3.2. Moderate response = Percentage of patients with either an improvement of >0.6 to ≤1.2 and a present score ≤5.1, or an improvement >1.2 and a present score >3.2 Non response = Percentage of patients with either an improvement of ≤0.6 or an improvement >0.6 to ≤1.2 and a present score >5.1 | 32 weeks of treatment | 
| Time to onset of benefit | ACR20, will be also analyzed at every clinic visit to allow an analysis of the time to onset of benefit for achievement of ACR | 32 weeks of treatment | 
| Change in modified van der Heijde Sharp score | • The Sharp method is a composite X-ray scoring system used to assess structural (joint) disease progression in rheumatoid arthritis. The method evaluates both joint erosions (JE) and joint space narrowing (JSN) in bilateral hand and foot joints | 32 weeks of treatment | 
| Physical function | • Improvement in physical function is assessed by change from baseline in HAQ (Health Assessment Questionnaire) at Week 32.The HAQ-DI (disability index) is composed of 8 categories as follows: dressing and grooming, arising, eating, walking, hygiene, reach, grip and activities, for which there are at least 2 questions by category. The patient will be asked to score how difficult he/she feels it is to perform such activities using a 0 to 3 scoring (0=without any difficulty, 1=with some difficulty, 2=with much difficulty and 3=unable to do). If the patient is using assistance for any of these activities, scoring may be adjusted. For each category, the highest score given for one of the question is attributed to the category. The total score is the sum of all categories' scores divided by the number of answered categories (at least 3 categories should be answered) | 32 weeks of treatment | 
| Functional Assessment of Chronic Illness Therapy Fatigue scale (FACIT-Fatigue) | The FACIT-Fatigue is a 13-item questionnaire rated 0 to 4. The patient will be asked to answer to 13 questions rated 0 to 4 (0=not at all, 1=a little bit, 2=some what, 3=quite a bit, 4=very much | 32 weeks of treatment | 
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]). | Infections, hematological disorders, neurologic disorders and malignancies. Adverse Drug Reactions. Incidence, seriousness and severity. Serum Hematological and chemistry values.Local Adverse Drug Reactions | 32 weeks of treatment | 
| Steady state concentration | Etanercept concentration measure | At week 16 and 32 | 
| Immunogenicity | Antibodies anti-Etanercept measure | At week 16 and 32 |