Clinical trial NCT03332719: Efficacy, Safety and Immunogenicity of Enerceptan Compared to Enbrel in Rheumatoid Arthritis
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Rheumatoid Arthritis
Lead sponsor: Gema Biotech S.A.
Sponsor class: INDUSTRY
Collaborators: name: QUID Quality in Drugs and Devices Latin American Consulting SRL
First posted: 2017-11-06
Enrollment: 168
Sex: ALL
Minimum age (years): 19
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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

Eligibility criteria: Inclusion Criteria:

1. 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.
2. Moderate to severe disease activity, according to DAS28 (erythrosedimentation) ≥ 3.2.
3. 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.
4. 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.
5. Medical Indication to incorporate a biological treatment in their therapy.
6. 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.
7. 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

   1. 8 weeks for infliximab (T1/2 8 to 9.5 days) and for tocilizumab (T1/2 3to 12 days)
   2. 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),
   3. 1 year for Rituximab (T1/2 77,5 days)
   4. 5 T1/2 for any other biological product, used for the treatment of rheumatoid arthritis, wether it has been used or not for research.
   5. 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.
   6. 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:

1. Simultaneous treatment with other investigational drug or participation in another clinical study that the investigator considers inadvisable.
2. Women who are pregnant or breastfeeding.
3. Past history of nonresponsive to TNF (tumor necrosis factor) blocking agents or other biologic treatment.
4. Chronic antibiotic therapy, if the investigator considers this may affect the safety of the subject or the assessment of the study results.
5. Any previous or current serious medical conditions that, in the opinion of the investigator, constitute a contraindication for the study treatment, as:
6. Administration of vaccines:

   1. 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.)
   2. Subjects who have received the BCG (bacillus Calmette-Guerin) vaccine within 12 months before the Selection.
7. 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.
8. Past history of drug or alcohol abuse within the last year prior to the Screening Visit.
9. Known hypersensitivity to the study drug or history of severe allergy or anaphylactic reaction to monoclonal antibodies or fusion or human proteins.
10. Any condition that, in the investigator opinion, would not allow compliance with the guidelines of the study by the patient.
11. The subject presents absolute contraindications for the use of etanercept, according to the prospectus
12. Presence of significant laboratory abnormalities in the screening visit.

Primary outcomes:
measure: ACR (American College of Rheumatology) 20
timeFrame: 32 weeks of treatment
Secondary outcomes:
measure: ACR (American College of Rheumatology) 50
timeFrame: 32 weeks of treatment
measure: ACR (American College of Rheumatology) 70
timeFrame: 32 weeks of treatment
measure: DAS (Disease activity state)
timeFrame: 32 weeks of treatment
measure: EULAR (European League Against Rheumatism) response criteria
timeFrame: 32 weeks of treatment
measure: Time to onset of benefit
timeFrame: 32 weeks of treatment
measure: Change in modified van der Heijde Sharp score
timeFrame: 32 weeks of treatment
measure: Physical function
timeFrame: 32 weeks of treatment
measure: Functional Assessment of Chronic Illness Therapy Fatigue scale (FACIT-Fatigue)
timeFrame: 32 weeks of treatment
measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]).
timeFrame: 32 weeks of treatment
measure: Steady state concentration
timeFrame: At week 16 and 32
measure: Immunogenicity
timeFrame: At week 16 and 32
Other outcomes:
Locations:
city: Bs As
country: Argentina
facility: Instituto Medico CER
Study officials:
affiliation: Instituto Médico CER
name: Jorge Velasco, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: PAMPA
name: Maria de los Angeles Correa, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: IARI
name: Maria Alicia Lazaro, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: CER San Juan
name: Rodolfo Pardo Hidalgo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: CAICI
name: Daniel Siri, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Centro Médico Privado de Reumatología
name: Alberto Jorge Spindler, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Centro Reumatologico Strusberg
name: Ingrid Strusberg, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: OMI
name: Patricio Tate, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Atención Integral en Reumatología
name: Horacio Oscar Venarotti, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Strusberg I, Mysler E, Citera G, Siri D, de Los Angeles Correa M, Lazaro MA, Pardo Hidalgo R, Spindler A, Tate P, Venarotti H, Velasco Zamora J, Klimovsky E, Federico A, Scheines E, Gonzalez E, Cordeiro L, Lago N. Efficacy, Safety, and Immunogenicity of Biosimilar Etanercept (Enerceptan) Versus Its Original Form in Combination With Methotrexate in Patients With Rheumatoid Arthritis: A Randomized, Multicenter, Evaluator-Blinded, Noninferiority Study. J Clin Rheumatol. 2021 Sep 1;27(6S):S173-S179. doi: 10.1097/RHU.0000000000001616.