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A 52-week, phase 3, multicentre, randomised, double blind, efficacy and safety study comparing GSK3196165 with placebo and with tofacitinib, in combination with methotrexate in participants with moderately to severely active rheumatoid arthritis who have an inadequate response to methotrexate

PHRR191204-002331

201790

2019-CT0515

A 52-week, phase 3, multicentre, randomised, double blind, efficacy and safety study comparing GSK3196165 with placebo and with tofacitinib, in combination with methotrexate in participants with moderately to severely active rheumatoid arthritis who have an inadequate response to methotrexate

This is a Phase 3, randomised, multicentre, double-blind, parallel group, placebo and active comparator (tofacitinib) controlled study, with primary objective to assess the efficacy and safety of GSK3196165 in combination with MTX in participants with moderately to severely active RA, who have an inadequate response to MTX.


The study consists of a screening phase of up to 6 weeks, a 52-week treatment phase and an 8-week safety follow-up visit. Upon successful screening, participants will be randomised to one of six intervention arms. Participants who complete this study may be eligible to participate in a long-term extension study to further evaluate the efficacy and safety of GSK3196165.


Approximately 3000-3400 participants will be screened to achieve between 1500 and 1700 randomly assigned to study intervention.

Participants will be randomised in a ratio of 6:6:3:1:1:1 to GSK3196165 150 mg SC weekly, GSK3196165 90 mg SC weekly, tofacitinib capsules 5 mg BID or placebo (3 arms) respectively, all in combination with oral or injectable MTX. At Week 12, the 3 placebo arms will switch from placebo to active intervention (either GSK3196165 150 mg SC weekly, GSK3196165 90 mg SC weekly, or tofacitinib capsules 5 mg BID).

A special committee of experts, called an “Independent Data Monitoring Committee (IDMC),” will function independently from GSK to monitor and evaluate all reported symptoms and adverse reactions throughout the study.

Regime Classification Priority
2017 - 2022 Research to enhance and extend healthy lives Environmental health
Start Date Duration in Months Target Completion Date Actual Completion Date
2020-03-31 15 2021-07-01 0000-00-00

Ongoing

Institution Classification Region LTO #
GlaxoSmithKline Research & Development Limited (UK) Private Business United Kingdom LTO-3000003797863
Institution Classification Region LTO #
IQVIA RDS Philippines, Inc. Private Business NCR LTO-3000003797863
Institution Region
GlaxoSmithKline Research & Development Limited (UK) United Kingdom
Name E-Mail Institution and Institution Address
Elena Lam QMNL.HealthRegistrymailbox@quintiles.com IQVIA RDS Phils. Inc., 7th Floor Unit 7A 8 Rockwell Building, Hidalgo Drive, Makati City 1210 Philippines
Name E-Mail Institution and Institution Address
Dr. Rashna Cama Rashna.Cama@quintiles.com IQVIA, 602, Natraj, M.V. Road Junction, Western Express Highway, Andheri East, Mumbai 400069
Name Expertise Affiliation
Allan E. Lanzon, MD Principal Investigator Mary Mediatrix Medical Center
Caroline G. Arroyo, MD Principal Investigator Iloilo Doctor's Hospital
Llewellyn T. Hao, MD Principal Investigator Davao Doctors Hospital
Maria Sheila Leynes, MD Principal Investigator Mary Mediatrix Medical Center
Melissa Aquino-Villamin, MD Principal Investigator St. Luke's Medical Center - Quezon City
Merle Y. Barba, MD Principal Investigator Cebu Doctors' University Hospital
Roger Dulos, MD Principal Investigator St. Paul's Hospital of Iloilo, Inc.
Rosario P. Baes, MD Principal Investigator Far Eastern University - Nicanor Reyes Memorial Foundation Hospital
Project Location Institutional Ethics Review Board
Mary Mediatrix Medical Center Mary Mediatrix Medical Center Research Ethics Review Committee
Iloilo Doctor's Hospital N/A
Davao Doctors Hospital Davao Doctors Hospital Ethics Review Committee
Mary Mediatrix Medical Center Mary Mediatrix Medical Center Research Ethics Review Committee
St. Luke's Medical Center - Quezon City St. Luke's Medical Center Institutional Ethics Review Board
Cebu Doctors' University Hospital Cebu Doctors' University Hospital - Institutional Ethics Review Committee
St. Paul's Hospital of Iloilo, Inc. St. Paul’s Hospital Iloilo – Institutional Ethics Review Board
Far Eastern University - Nicanor Reyes Memorial Foundation Hospital Far Eastern University - Nicanor Reyes Memorial Foundation Hospital Ethics Review Committee

Rheumatoid Arthritis 

To compare the efficacy of GSK3196165 at doses of 90 mg and 150 mg weekly versus placebo for the treatment of participants with moderately to severely active RA who are on a stable background of MTX and who have had an inadequate response to MTX.

  • Efficacy of GSK3196165 at doses of 90mg and 150 mg weekly versus tofacitinib for the treatment of participants with moderately to severely active RA who are on a stable background of MTX and who have had an inadequate response to MTX
  • Effect of GSK3196165 on Patient Reported Outcomes (PROs) versus placebo and the active comparator tofacitinib
  • Safety and tolerability of GSK3196165 versus placebo and the active comparator tofacitinib
  • To determine the immunogenic potential of GSK3196165

Pending

Clinical Trial

201790

20191011091020

2019-11-25

0000-00-00

44

Unspecified

Unspecified

2020-03-31

Inclusion Criteria:

AGE
(1)Age ≥18 years at the time of signing informed consent.

TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS
(2) Meets ACR/EULAR 2010 RA Classification Criteria (see study reference manual [SRM]) with a duration of RA disease of ≥6 months at time of screening and participant not diagnosed before 16 years of age.
(3) Must have active disease at both screening and baseline, as defined by having both:
a. ≥6/68 tender/painful joints (TJC), and
b. ≥6/66 swollen joints (SJC).
If surgical treatment of a joint has been performed, that joint cannot be counted in the TJC or SJC for enrolment purposes
(4) Must have a high sensitivity C-reactive protein (hsCRP) measurement ≥3 mg/L at screening.
(5) Must meet Class I, II or III of the ACR 1991 Revised Criteria for Global Functional Status in RA
(6) Must have at least 1 bone erosion present on hand/wrist or foot radiographs confirmed by central reading at screening.
(7) Must have inadequate response, despite currently taking Methotrexate (MTX): weekly 15-25 mg oral or injected, for at least 12 weeks at the maximum tolerated dose prior to Day 1, with no change in route of administration in this time. MTX dose must be stable and tolerated for at least 8 weeks prior to Day 1. A lower dose of ≥7.5 mg/week is acceptable if reduced for reasons of intolerance to MTX, e.g. nausea/vomiting, hepatic or hematologic toxicity, or per local requirement (there must be clear documentation in the medical record). Exception: A lower dose of 6 mg/week is allowed if the minimum locally approved or recommended dose is lower than 7.5 mg/week.

WEIGHT
(8) Body weight ≥40 kg

SEX
(9) Male or female participants are eligible to participate so long as they meet and agree to abide by the contraceptive criteria detailed in Appendix 4 of Protocol

INFORMED CONSENT
(10) Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

OTHER SAFETY-RELATED
(11) Willing to continue or initiate treatment with oral folic acid (at least 5 mg/week) or equivalent and be treated during the entire study (mandatory co-medication for MTX treatment).

Exclusion Criteria:

MEDICAL CONDITIONS
(1)Active infections (including localised infections), or history of recurrent infections (excluding recurrent fungal infections of the nail bed), or has required management of acute or chronic infections, as follows:
•Currently taking any suppressive anti-infective therapy for a chronic infection (such as pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria) OR
•Hospitalisation for treatment of infection within 26 weeks of Day 1 OR
•Use of parenteral (IV) or intramuscular (IM) antimicrobials (antibacterials, antivirals, antifungals, or antiparasitic agents) within 26 weeks of Day 1 or oral antimicrobials (apart from INH use for latent TB treatment) within 14 days of Day 1.
(2)Symptomatic herpes zoster within 3 months prior to screening.
(3)Hereditary or acquired immunodeficiency disorder, including immunoglobulin deficiency.
(4)Known infection with human immunodeficiency virus (HIV) or positive test at screening.
(5)History of infected joint prosthesis at any time, with the prosthesis still in situ. History of chronic leg ulcers, permanent in-dwelling catheters, chronic sinusitis, recurrent chest infections or recurrent urinary tract infections.
(6)Any baseline symptomatology that in the investigator’s opinion would confound the early detection of pulmonary alveolar proteinosis based upon clinical features, such as persistent cough (CTC Grade ≥2) or persistent dyspnoea (dyspnoea scale Grade ≥2).
(7)Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice, or cirrhosis.
(8)Current acute or chronic Hepatitis B and/or Hepatitis C.
(9)Current or history of renal disease or estimated glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) calculation (10)Breast cancer within the past 10 years or lymphoma, leukaemia, or any other malignancy within the past 5 years except for cervical carcinoma in situ that has been resected with no evidence of recurrence or metastatic disease, or basal cell or squamous epithelial cancers of the skin that have been resected with no evidence of recurrence or metastatic disease for at least 3 years.
(11)History of any lymphoproliferative disorder, such as Epstein Barr Virus (EBV) related lymphoproliferative disorder, or signs and symptoms suggestive of current lymphatic disease.
(12)History or presence of significant other concomitant illness according to the Investigator judgment such as, but not limited to cardiovascular (including Stage III or IV cardiac failure according to New York Heart Association classification, myocardial infarction within 12 months, unstable angina pectoris, uncontrolled hypertension, uncontrolled hypercholesterolemia), neurological, endocrinological, gastrointestinal (including diverticulitis), hepatic disease, metabolic, lymphatic disease, or previous renal transplant that would adversely affect the participant’s participation in this study.
(13)Any condition or contraindication as addressed in the local product information or local clinical practice for tofacitinib that would preclude the participant from participating in this protocol.
(14)History of other inflammatory rheumatologic or systemic autoimmune disorder, other than Sjögren’s syndrome secondary to RA, that may confound the evaluation of the effect of the study intervention such as mixed connective tissue disease, psoriatic arthritis, juvenile chronic arthritis, spondyloarthritis, Felty’s Syndrome, systemic lupus erythematosus, scleroderma, Crohn’s disease, ulcerative colitis, or vasculitis.
(15)Presence of fibromyalgia that, in the investigator’s opinion, would make it difficult to appropriately assess RA activity for the purposes of this study.
(16)Undergone any major surgery within 8 weeks prior to study entry or will require major surgery during the study that, in the opinion of the investigator in consultation with the medical monitor, would pose an unacceptable risk to the participant.
(17)Current or previous active Mycobacterium tuberculosis (TB) regardless of treatment.
(18)Evidence of latent TB (as documented by a positive QuantiFERON-TB Gold plus test or T-SPOT.TB test at screening, no findings on medical history or clinical examination consistent with active TB, and a normal chest radiograph) except for participants that either:
•Are willing to complete at least 4 weeks of anti-TB therapy as per WHO or national guidelines prior to randomisation and agree to complete the remainder of treatment while in the study OR
•Are documented as having evidence of satisfactory anti-TB treatment as per WHO or national guidelines within the last 5 years following review by a physician specialising in TB.
(19)Previous close contact with a person with active TB and did not receive satisfactory anti-tuberculosis treatment as per WHO or national guidelines.
(20)Significant allergies to humanised monoclonal antibodies.
(21)Clinically significant multiple or severe drug allergies or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear immunoglobulin A [IgA] dermatosis, toxic epidermal necrolysis, and exfoliative dermatitis).
(22)Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

PRIOR/CONCOMITANT THERAPY
(23)Any prior treatment antagonising GM-CSF or its receptor.
(24)Any prior treatment with targeted synthetic DMARDs (either experimental or approved), including Janus kinase (JAK) inhibitors (e.g. tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib).
(25)Any prior treatment with a biologic DMARD (either experimental or approved) which has been discontinued due to an inadequate response.
(26)Participants who are expected to be non-compliant with restrictions on medications and vaccinations prior to the study, during the study or during the 8-week safety follow-up of the study.

PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE
(27)Current enrolment or past participation within the last 42 days before randomisation in any other clinical study involving an investigational study treatment or any other type of medical research.
DIAGNOSTIC ASSESSMENTS
(28)Alanine transferase (ALT) or aspartate transaminase (AST) >1.5 x upper limit of normal (ULN).
(29)Bilirubin >1.5 x ULN (isolated bilirubin >1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
(30)Has a positive test for hepatitis B (HBV) defined as either:
•positive for hepatitis B surface antigen (HBsAg) or
•positive for hepatitis B core antibody (HBcAb) and positive for HBV deoxyribonucleic acid (DNA).
(31)Positive test for hepatitis C antibody at screening. Participants with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative hepatitis C RNA test is obtained.
(32)Haemoglobin ≤9 g/dL; white blood cell (WBC) count ≤3.0 x 109/L; platelet count ≤100 x 109/L; absolute neutrophil count (ANC) (33)Abnormal chest radiograph within 12 weeks of screening judged by the investigator as clinically-significant.
OTHER EXCLUSIONS
(34)Pregnant or lactating, or women planning to become pregnant or initiating breastfeeding.
(35)Current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or dependence within a year prior to Day 1.
(36)History of sensitivity to any of the study treatments, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.

Interventional

Otilimab (GSK3196165)

Comparison of different dosages of drug will be done. Participants will be randomized to one of six intervention arms in a ratio of 6:6:3:1:1:1 to GSK3196165 150 mg SC weekly, GSK3196165 90 mg SC weekly, tofacitinib capsules 5 mg BID or placebo (3 arms).

Date Amendment Classification Reason
2020-02-04 Amendments related to the protocol Referral Hub content, Documentation Folder V1.0, Referral Hub Screener Export dated 27 Aug 2019, Patient Information Sheet and Informed Consent Form for Optional Future Scientific Research V2.0
2020-02-04 Amendments related to the trial arrangements Change of the trial site or addition of new site
2020-02-10 Amendments related to the protocol Digital Informed Consent Form Screenshots ( Main Informed Consent Form Screenshots, Pregnant Partner Informed Consent Forms, Optional Genetic (DNA Research) Sub-study Informed Consent Forms)
2020-03-12 Amendments related to the protocol SecureConsent Glossary Terms for GlaxoSmithKline (GSK) 201790 V2.0, Introduction Video Storyboard GlaxoSmithKline (GSK)_201790 V2.0

Randomized

Double Blind

All participants will be centrally randomised using Interactive Response Technology (IRT). Participants will be randomised in a ratio of 6:6:3:1:1:1 to receive study intervention. Investigators will remain blinded to each participant’s assigned study intervention throughout the course of the study. To maintain this blind, all participants will receive oral capsules twice daily and once-weekly SC injections. Until such time as a matched placebo becomes available for GSK3196165, every SC injection must be delivered by an unblinded administrator and the syringe must be shielded from the participant to avoid unblinding. An unblinded pharmacist (or unblinded designee) will be responsible for the dispensation of the study intervention and will endeavour to ensure that there are no differences in time taken to dispense between the different intervention arms. While the study drug is supplied in vials, care will be taken to ensure that participants are not able to see the injection volume, syringe size or colour of liquid. The syringe should be prepared away from view of the participant, and appropriate shielding or masking of the syringe applied prior to administration. In addition, investigators and site staff will not have access to ongoing post-randomisation hsCRP/ESR analyses and should refrain from performing either routine ESR or CRP assessments unless clinically indicated for AE assessment. Furthermore, the results of the PK analyses of GSK3196165 will not be provided to the sites. Dose modifications to the oral study intervention will not be permitted in this study as it will have the potential to unblind the treatment assignments.In order to reduce bias, an independent joint assessor will perform all joint assessments. Unblinded monitors and in the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded study intervention records at the site(s) to verify that randomisation/dispensing has been done accurately.

Parallel

The purpose of the study is to determine whether GSK3196165 is superior to placebo in the treatment of participants with moderately to severely active RA despite MTX treatment (i.e. MTX-IR).

Phase III

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