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Efficacy and Safety Study of Sirukumab in Subjects With Polymyalgia Rheumatica

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ClinicalTrials.gov Identifier: NCT02899026
Recruitment Status : Withdrawn (GSK decision to return rights to sirukumab to Janssen and discontinue sirukumab development in polymyalgia rheumatica.)
First Posted : September 13, 2016
Last Update Posted : November 20, 2017
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:

Sirukumab is a human anti-IL-6 monoclonal antibody that selectively binds to the cytokine with high affinity that may have therapeutic benefit in the treatment of polymyalgia rheumatica (PMR) by interrupting multiple pathogenic pathways. Sirukumab inhibits IL-6-mediated signal transducer and activator of transcription 3 (STAT3) phosphorylation, resulting in the inhibition of the biological effect of IL-6. This study will evaluate the efficacy and safety of sirukumab to characterize the benefit-to-risk profile of sirukumab in the treatment of active PMR. The study will be conducted in 2 parts (Part A and Part B) and consists of the following phases: Screening phase, Part A: 52-week double-blind treatment phase, Part B: 52-week extension phase with no study drug administration and a 16-week follow-up phase if applicable.

Approximately 150 subjects with a diagnosis of PMR and active disease within 6 weeks of baseline will be randomized into Part A, the 52-week double-blind treatment phase, to receive one of two doses of sirukumab or placebo, each in addition to a pre-specified prednisone taper. The efficacy and safety of sirukumab in sustaining remission will be assessed at Week 52. Subjects completing Part A of the study who are in clinical remission will be eligible to enter Part B, the 52-week extension phase, designed to investigate the long-term maintenance of remission and safety following cessation of sirukumab treatment and to assess long-term corticosteroid use. Subjects will need to have follow-up safety evaluations for at least 16 weeks after receiving the last dose of study drug, applicable for those who have withdrawn prematurely from the study or who have completed Part A but are not eligible for Part B.


Condition or disease Intervention/treatment Phase
Polymyalgia Rheumatica Drug: Sirukumab Drug: Placebo to match sirukumab Drug: Prednisone /Prednisone placebo Phase 3

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Sirukumab in Subjects With Polymyalgia Rheumatica
Estimated Study Start Date : March 15, 2018
Estimated Primary Completion Date : August 26, 2020
Estimated Study Completion Date : August 26, 2021


Arm Intervention/treatment
Experimental: Part A: Sirukumab 100 mg SC + prednisone (6-week taper)
Eligible subjects will receive blinded Sirukumab 100 mg subcutaneously (SC) every 2 weeks (q2w) for 52 weeks plus a 6-week oral prednisone taper regimen
Drug: Sirukumab
Sirukumab will be provided as 1 millilitre (mL) Pre-filled Syringe (PFS), containing 100 mg/mL or 50 mg/mL of sirukumab, fitted with a spring-powered, disposable autoinjector device for single use SC administration of liquid biologic drug

Drug: Prednisone /Prednisone placebo
Prednisone will be provided as tablets with dosage level up to 20 mg/day. All subjects will receive 20 mg prednisone at Baseline (Randomization) and follow predefined taper regimen (6 weeks or 52 weeks) based on treatment assignment. Placebo to match prednisone will be provided as tablets

Experimental: Part A: Sirukumab 50 mg SC + prednisone (6-week taper)
Eligible subjects will receive blinded Sirukumab 50 mg SC q4w (with placebo SC injections q2w between sirukumab injections) for 52 weeks plus a 6-week oral prednisone taper regimen
Drug: Sirukumab
Sirukumab will be provided as 1 millilitre (mL) Pre-filled Syringe (PFS), containing 100 mg/mL or 50 mg/mL of sirukumab, fitted with a spring-powered, disposable autoinjector device for single use SC administration of liquid biologic drug

Drug: Placebo to match sirukumab
Placebo to match sirukumab will be provided as 1.0 mL PFS fitted with a spring-powered, disposable autoinjector device for single use SC administration of liquid biologic drug

Drug: Prednisone /Prednisone placebo
Prednisone will be provided as tablets with dosage level up to 20 mg/day. All subjects will receive 20 mg prednisone at Baseline (Randomization) and follow predefined taper regimen (6 weeks or 52 weeks) based on treatment assignment. Placebo to match prednisone will be provided as tablets

Placebo Comparator: Part A: Placebo SC + prednisone (52 week taper)
Eligible subjects will receive blinded placebo SC q2w for 52 weeks plus a blinded 52-week oral prednisone taper
Drug: Placebo to match sirukumab
Placebo to match sirukumab will be provided as 1.0 mL PFS fitted with a spring-powered, disposable autoinjector device for single use SC administration of liquid biologic drug

Drug: Prednisone /Prednisone placebo
Prednisone will be provided as tablets with dosage level up to 20 mg/day. All subjects will receive 20 mg prednisone at Baseline (Randomization) and follow predefined taper regimen (6 weeks or 52 weeks) based on treatment assignment. Placebo to match prednisone will be provided as tablets




Primary Outcome Measures :
  1. Proportion of subjects in sustained [ Time Frame: Week (wk) 52 ]
    Sustained remission at Week 52 is defined as having achieved all of the following: Remission by Week 12; Absence of disease flare following remission at Week 12 through Week 52; Completion of the assigned prednisone taper protocol; No requirement for rescue therapy at any time through Week 52. One flare before Week 12 is permitted if it can be successfully treated with a 5 mg/day prednisone add-on taper regimen in addition to the predefined taper schedule providing all other sustained remission criteria are met.


Secondary Outcome Measures :
  1. Part A: Cumulative prednisone dose at Week 52 [ Time Frame: Week 52 ]
    Cumulative prednisone dose at Week 52 (Part A)

  2. Part A&B: Cumulative prednisone dose over time [ Time Frame: Over 104 weeks ]
    Cumulative prednisone dose over time

  3. Part A&B: Proportion of subjects in sustained remission [ Time Frame: Week 12 to Week 52 (Part A) and to Week 104 (Part B) ]
    Subjects with sustained disease remission will be evaluated

  4. Part A&B: Proportion of subjects in remission while on a daily prednisone dose of 5mg [ Time Frame: Week 52 (Part A) and Week 76 (Part B) ]
    Subjects in remission while on a daily prednisone dose of 5mg will be evaluated

  5. Part B: Proportion of subjects in remission while off prednisone [ Time Frame: Week 76 (Part B) ]
    Proportion of subjects in remission while off prednisone at baseline of Part B and who remain off prednisone during the first 24 weeks of Part B

  6. Part A&B: Time to first PMR disease flare [ Time Frame: 52 weeks (Part A) and 104 weeks (Part B) ]
    Time to first PMR flare after remission

  7. Part A&B: Number of PMR disease flares per subject over time [ Time Frame: 52 weeks (Part A) and 104 weeks (Part B) ]
    PMR disease flare over time

  8. Part A: Change in PMR-activity score (AS) [ Time Frame: Week 12 and 52 ]
    Change in PMR-AS score from baseline to Week 12 and 52

  9. Part A: Proportion of subjects meeting PMR-AS remission criteria of <1.5 [ Time Frame: Week 12 and 52 ]
    Subjects withng PMR-AS remission criteria of <1.5

  10. Part A&B: Incidence of adverse events (AEs) and Serious AEs (SAEs) [ Time Frame: 52 weeks (Part A) and 104 weeks (Part B) ]
    All AEs and SAEs will be reported

  11. Part A: Incidence of GC-related AEs [ Time Frame: 52 weeks ]
    GC-related AEs will be reported

  12. Part A&B: Vital sign assessment as measure of safety [ Time Frame: Baseline (Week 0) to Week 52 (Part A) and Week 104 (Part B) ]
    Vital sign assessment includes systolic and diastolic blood pressure, pulse rate and body temperature

  13. Part A&B: Number of subjects having abnormal hematology parameters as a measure of safety [ Time Frame: Baseline (Week 0) to Week 52 (Part A) and Week 104 (Part B) ]
    Blood samples will be collected to measure hematological parameters such as platelet count, red blood cell (RBC) count, hemoglobin, hematocrit, white blood cell (WBC) count (including neutrophil count, lymphocyte count, monocyte count, eosinophil count and basophils count).

  14. Part A&B: Number of subjects having abnormal clinical chemistry parameters as a measure of safety [ Time Frame: Baseline (Week 0) to Week 52 (Part A) and Week 104 (Part B) ]
    Blood samples will be collected to measure serum chemistry parameters such as sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, glucose aspartate transaminase, alanine transaminase, alkaline phosphatase, calcium, phosphate, albumin, total protein, direct, indirect and total bilirubin

  15. Part A&B: Assessment of quality of life using the 36-item Short Form Health Survey version 2 (SF-36v2) (acute) [ Time Frame: 52 weeks (Part A) and 104 weeks (Part B) ]
    Patient report of quality of life

  16. Part A&B: Functional Assessment of Chronic Illness Therapy (FACIT )-Fatigue [ Time Frame: 52 weeks (Part A) and 104 weeks (Part B) ]
    Patient report of elements of fatigue

  17. Part A&B: Assessment of pain [ Time Frame: 52 weeks (Part A) and 104 weeks (Part B) ]
    Pain assessed by patient reported rating on a numeric rating scale from 0 to 10

  18. Part A&B: Assessment of steroid impact [ Time Frame: 52 weeks (Part A) and 104 weeks (Part B) ]
    Patient assessment of the side effects and impact of steroids on PMR symptoms over time

  19. Part A&B: Modified Health Assessment Questionnaire (MHAQ) [ Time Frame: 52 weeks (Part A) and 104 weeks (Part B) ]
    Patient reported outcome of disease-related disability, discomfort, and quality of life

  20. Part A&B: Assessment of Patient Global Impression of Change (PGIC) [ Time Frame: 52 weeks (Part A) and 104 weeks (Part B) ]
    Estimate of the magnitude of patient response to treatment at different time points by patient report

  21. Part A&B: Patient Global Assessment of Disease Activity (PtGA) [ Time Frame: 52 weeks (Part A) and 104 weeks (Part B) ]
    Patient report of PMR disease activity

  22. Part A&B: Duration of Morning Stiffness [ Time Frame: 52 weeks (Part A) and 104 weeks (Part B) ]
    Patient report of the duration of morning stiffness

  23. Part A&B: Physician Global Assessment of Disease Activity (PhGA) [ Time Frame: 52 weeks (Part A) and 104 weeks (Part B) ]
    Physician assessment of PMR disease activity on a scale of 0-100

  24. Part A&B: Pharmacokinetics: Serum concentrations of sirukumab [ Time Frame: 68 weeks ]
    Blood samples for Pharmacokinetic (PK) analysis of sirukumab serum concentrations will be collected at Baseline, wk 4, wk 8, wk 12, wk 16, wk 24, wk 36 and wk 52 in Part A; and at wk 60 and wk 68 (Part B)

  25. Part A&B: Serum anti-sirukumab antibodies [ Time Frame: 68 weeks ]
    Blood samples for antibodies analysis of sirukumab will be collected at Baseline, wk 24 and wk 52 in Part A; and at wk 68 in Part B



Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age >=50 years
  • Diagnosis of PMR based on the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2012 provisional PMR classification criteria, that is, at the time of PMR diagnosis, subjects should be aged 50 years or older, presenting with new-onset (<12 weeks of diagnosis) bilateral shoulder pain and abnormal acute-phase response, and are required to score 4 or more on the following criteria for the diagnosis of PMR: Morning stiffness duration >45 minutes (2 points) or Hip pain or limited range of motion (1 point) or Absence of rheumatic factor (RF) or anti-citrullinated protein antibody (ACPA) (2 points) or Absence of other joint involvement (1 point).
  • Active PMR within 6 weeks of randomization where active disease is defined by an ESR >=30 millimeter (mm)/hour (hr) or CRP >=1 mg/dL within 6 weeks of randomization AND the presence of at least one of the following at screening (within 6 weeks of randomization): Unequivocal symptoms of PMR, defined as shoulder and/or hip girdle pain associated with inflammatory stiffness or Other features judged by the clinician investigator to be consistent with PMR or PMR flares (e.g. fever of unknown origin).
  • Receiving oral prednisone 0-25 mg once daily (or equivalent) for PMR treatment at screening. Dosage of oral prednisone or equivalent, during the screening period can remain constant or be adjusted within the range of 0-25 mg prednisone equivalent based on investigator's discretion.
  • Willing and able to receive treatment with oral prednisone 20 mg once daily at randomization and undergo a pre-defined blinded prednisone taper.
  • No evidence of active or latent infection with Mycobacterium tuberculosis (TB)
  • Be able to read, understand, and complete study questionnaires.
  • Male and female subjects, where male subjects with female partners of child bearing potential must comply with the contraception requirements and not to donate sperm from the time of first dose of study medication until 4 months after the last dose of study medication. A female subject of child bearing potential must comply with contraception requirements.

Exclusion Criteria:

  • Features consistent with atypical PMR according to the investigator's clinical judgment. Investigators are encouraged to discuss with the medical monitor when there are questions regarding excluding subjects with atypical PMR. Atypical features or features that increase the likelihood of a non-PMR diagnosis may include some or all of the following: Age <60 years; Chronic onset (>2 months) at time of diagnosis; Lack of shoulder involvement; lack of inflammatory stiffness; prominent systemic features, weight loss, night pain, neurological signs; features of other rheumatic disease; Normal or extremely high acute-phase response; AND treatment dilemmas such as incomplete, poorly sustained or non-response to GCs, inability to reduce GCs, contraindications to GC therapy, the need for prolonged GC therapy (>2 years).
  • History or current diagnosis of Giant Cell Arteritis (GCA), or Large Vessel Vasculitis (LVV). If GCA/LVV is suspected, this should be ruled out by ultrasound or other imaging techniques (example. fluorodeoxy-glucose positron emission tomography) prior to entering the study.
  • Maintained on GCs for 2 years or more prior to Screening.
  • Other inflammatory rheumatic diseases with the exception of gout controlled on stable suppressive therapy and without flares for at least 2 years prior to screening and expected to remain on this therapy for the duration of the study.
  • Recent (within the past 12 weeks) or planned major surgery that would impact on study procedures or assessments.
  • Organ transplantation recipients (except corneas within 3 months prior to randomization visit).
  • Requires continued or repeated use of systemic GCs for conditions other than PMR.
  • Evidence of serious concomitant disease, which in the opinion of the investigator makes the subject unsuitable for participation in the study for either safety or efficacy.
  • Major ischemic event within 12 weeks of screening.
  • At screening, marked prolongation of corrected QT interval (QTc) > 450 millisecond (msec) [QTc by Bazett's formula (QTcB) or QTc by Fridericia's formula (QTcF)] or QTc > 480 msec in subjects with Bundle Branch Block. History of Torsade de Pointes, family history of long QT syndrome, history of second or third degree heart block.
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • History of or current active diverticulitis, inflammatory bowel disease, or other symptomatic gastro intestinal (GI) tract condition that might predispose to bowel perforation.
  • History of known demyelinating diseases such as multiple sclerosis or optic neuritis.
  • Active infections, or history of recurrent infections or required management of acute or chronic infections, as follows: currently on any suppressive therapy for a chronic infection and History or suspicion of chronic infection (e.g. joint infection) OR Hospitalization for treatment of infection within 60 days of the randomization visit OR Use of parenteral (intravenous [IV] or intramuscular [IM]) antimicrobials (antibacterials, antivirals, antifungals, or antiparasitic agents) within 60 days of randomization or oral antimicrobials within 30 days of randomization.
  • Primary or secondary immunodeficiency.
  • Human immunodeficiency syndrome (HIV) infection, hepatitis C.
  • Hepatitis B infection
  • Active malignancy or history of malignancy within previous 5 years.
  • Any other autoimmune disease.
  • Uncontrolled thyroid disease.
  • Uncontrolled psychiatric or emotional disorder.
  • Current history of suicidal ideation or past history of suicide attempt.
  • Has received prior treatment with any of the following: Systemic immunosuppressives within 4 weeks of randomization; Systemic GCs for conditions other than PMR within 8 weeks of randomization; Biologic agents targeted at reducing Tumor necrosis factor (TNF) alpha within 4-8 weeks of randomization, depending on the agent; B-cell depleting agents (e.g., rituximab) within 12 months prior to baseline or longer if B cell counts have not returned to the normal range or baseline levels; Any prior use of tocilizumab or other anti-IL-6 agents, Cytotoxic drugs such as cyclophosphamide, chlorambucil, nitrogen mustard, or other alkylating agents, Abatacept and Tofacitinib; Methotrexate use within 2 weeks of randomization; Methylprednisolone > 100 mg/day IV (or equivalent) within 8 weeks of randomization.
  • Has received, or is expected to receive, any live virus or bacterial vaccination within 3 months of randomization, during the study, or within 4 months after the last administration of study treatment. Have had a Bacille Calmette Guérin (BCG) vaccination within 12 months of screening.
  • Has received an investigational drug (including investigational vaccines) or used an investigational medical device within 3 months or 5 half-lives, whichever is longer, before randomization.
  • History of drug abuse, alcohol abuse within 3 years prior to screening.
  • History of severe allergic reactions to monoclonal antibodies, human proteins, or excipients.
  • History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation
  • Laboratory abnormalities at screening
  • A female subject who is pregnant or lactating.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02899026


Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02899026     History of Changes
Other Study ID Numbers: 205012
First Posted: September 13, 2016    Key Record Dates
Last Update Posted: November 20, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by GlaxoSmithKline:
Glucocorticosteroids
Sirukumab
Prednisone
Polymyalgia Rheumatica

Additional relevant MeSH terms:
Vasculitis, Central Nervous System
Vasculitis
Polymyalgia Rheumatica
Giant Cell Arteritis
Muscular Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Arteritis
Skin Diseases, Vascular
Skin Diseases
Autoimmune Diseases
Immune System Diseases
Prednisone
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents