Plain English Summary
Background and study aims
Rheumatoid arthritis is an autoimmune disease that affects the joints, in particular the hands, feet and wrists. The sufferers own immune system attacks the joints which, over time, can lead to damage to the joint, cartilage and nearby bone. Symptoms include pain, swelling (inflammation) and stiffness in the joints. Tocilizumab is a drug for rheumatoid arthritis which acts against an inflammatory protein called IL-6. We think that taking this drug results in improvements in the body cholesterol (lipid) profile as well as a reduction in inflammatory proteins released from fat tissue (adipokines). If treatment with tocilizimab decreases inflammatory proteins and improves cholesterol profiles, it may decrease the long term risk of heart disease and strokes in affected patients compared to drugs that are not associated with these changes.
Who can participate?
Participants of the 'ACT-NEUTS' study who were given tocilizimab.
What does the study involve?
The participants of the previous study (the 'ACT-NEUTS' study) are approached for this study. These patients all had blood samples collected at the start of this previous study and on three other occasions over the course of 12 months. We use the surplus blood samples collected as part of that original study to measure and compare blood levels of some inflammatory proteins from fat tissue ('adipokines') and cholesterol levels before and after this drug was administered. Information regarding blood pressure, smoking status, family history, rheumatoid arthritis disease severity, X-ray changes and other medications are obtained from the hospital medical records. No further blood sample collection or drug administration is performed during this study.
What are the possible benefits and risks of participating?
There are no immediate benefits to patients participating in the study, though outcomes of the study may influence treatment choices in rheumatoid arthritis in the future. We do not anticipate any risks to patients participating in the study.
Where is the study run from?
Aintree University Hospital NHS Foundation Trust (UK)
When is the study starting and how long is it expected to run for?
April 2014 to September 2015
Who is funding the study?
Obesity and Endocrinology Research Department, University of Liverpool
Who is the main contact?
Professor John Wilding
j.p.h.wilding@liverpool.ac.uk
Trial website
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
UoL001080
Study information
Scientific title
Observational study on the effects of IL-6 inhibitor therapy on adipokines in patients with rheumatoid arthritis
Acronym
Study hypothesis
To study whether IL-6 inhibitor therapy in rheumatoid arthritis is associated with metabolically favourable changes in adipokine and lipid profiles
Ethics approval
London City and East REC, 23/03/2015, ref: 15/LO/0544
Study design
Observational study involving analysing samples already collected from subjects with rheumatoid arthritis.
Primary study design
Observational
Secondary study design
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Condition
Rheumatoid arthritis
Intervention
Nineteen patients with rheumatoid arthritis participated in the ACT-NEUTS study in 2010-2011 (EUDRACT Number 2010-018331-18; REC Reference: 10/H0904/14), and were treated with the drug tocilizumab as part of the study.These individuals provided fasting blood samples prior to tocilizumab administration and at three timepoints thereafter (at approximately 3 months, 6 months and 12 months after tocilizumab therapy). Blood samples and clinical information as part of the study were collected, link-anonymised and securely stored within the university.
We intend to approach the participants of the ACT-NEUTS study through members of their usual healthcare team and request their consent to utilising the already collected samples as well as relevant clinical and pharmacological information for the purposes of our study. Other than the purpose of requesting informed consent, no further clinical contact with the patient is required for this study. No further blood sample collection or drug administration will be performed during this study.
For the patients who provide informed consent, plasma adipokines (leptin, adiponectin, resistin, visfatin, SPARC, TNF-alpha and IL-6), lipid profiles and other inflammatory markers will be measured in samples that were obtained for the ACT-NEUTS study Information regarding blood pressure, smoking status, family history, rheumatoid arthritis disease activity scores, radiographic changes and other medications will be obtained from the hospital medical records.
This study aims to analyse changes in anthropometric measures, disease activity score, lipid profiles and measured adipokines from baseline to twelve months of treatment with tocilizumab. We anticipate this study will be completed within a period of three months. This will be followed by dissemination and publication of results, and application for grants for future randomised controlled trials in this field.
Intervention type
Drug
Phase
Drug names
Tocilizumab
Primary outcome measure
1. Changes in circulating adipokine concentration
2. Change in metabolic syndrome determinants towards a favourable cardiovascular risk profile
Secondary outcome measures
1. Changes in anthropometric measures
2. Rheumatoid arthritis disease severity scores
3. Radiographic changes
Overall trial start date
01/04/2014
Overall trial end date
01/08/2016
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Male or non-pregnant, non-nursing female
2. ≥ 18 years of age
3. Diagnosis of moderate to severe active RA of ≥ 6 months duration
4. DAS28 ≥ 3.2 at screening and baseline
5. Receiving treatment on an outpatient basis
6. If inadequate response to a biologic DMARD, this treatment was discontinued
according to approximately 5-half lives for the agent, prior to receiving TCZ. That is, prior to randomization, have discontinued etanercept for ≥ 2 weeks, infliximab or adalimumab for ≥ 8 weeks, anakinra for ≥ 1 week; rituxamab > 24 weeks (or B-cell count has returned to levels prior to treatment and pt meets active disease criteria)
7. If continuing a non-biologic DMARD, dose was stable for at least 8 weeks.
8. In patients receiving an oral corticosteroid, the dose must have been stable for at least 25 out of 28 days prior to treatment (baseline).
9. Able and willing to give written informed consent and comply with the requirements of the study protocol
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
19
Participant exclusion criteria
Disease:
1. Major surgery (including joint surgery) within 8 weeks prior to screening or not recovered from prior surgery
2. Rheumatic autoimmune disease other than RA, including systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), scleroderma, polymyositis, or significant systemic involvement secondary to RA (e.g. vasculitis, pulmonary fibrosis or Felty’s syndrome). Patients with interstitial pulmonary disease and still able to tolerate MTX therapy are permitted, as is Sjögren’s Syndrome with RA
3. Functional class IV as defined by the ACR Classification of Functional Status in RA (largely or wholly incapacitated with patient bedridden or confined to wheel chair, permitting little or no self-care)
4. Prior history of or current inflammatory joint disease other than RA (e.g. gout, reactive arthritis, psoriasic arthritis, seronegative spondyloarthropathy, Lyme disease)
Drug-specific:
5. Treatment with any investigational agent within 4 weeks (or 5 half-lives of investigational agent, whichever is longer) before screening.
6. Previous treatment with any cell-depleting therapies, including investigational agents (e.g. CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19).
7. Treatment with leflunomide in combination with MTX (washout at least 12 weeks, 8 weeks with cholestyramine)
8. Treatment with IV gamma globulin, plasmapheresis or Prosorba® column within 6 months before baseline
9. Intraarticular or parenteral corticosteroids within 4 weeks prior to baseline
10. Immunization with a live/attenuated vaccine within 4 weeks prior to baseline
11. Previous treatment with TCZ
12. Any previous treatment with alkylating agents, such as cyclophosphamide or
chlorambucil, or with total lymphoid irradiation
Laboratory analyses (at screening):
13. Serum creatinine > 142 μmol/L (1.6 mg/dL) in female patients and > 168 μmol/L (1.9 mg/dL) in male patients and no active renal disease.
14. ALT (SGPT) or AST (SGOT) > 1.5 ULN (If initial sample yields ALT [SGPT] or AST [SGOT] > 1.5 ULN, a second sample may be taken and tested during the screening period)
15. Platelet count < 100 x 109/L (100,000/mm3)
16. Hemoglobin < 85 g/L (8.5 g/dL; 5.3 mmol/L)
17. WBC count < 2.0 x 109/L (2000/mm3), ANC < 1.0 x 109/L (1000/mm3)
18. ALC < 0.5 x 109/L (500/mm3)
19. Positive hepatitis B surface antigen (HBsAg) or hepatitis C antibody
20. Total bilirubin > ULN (If initial sample yields bilirubin > ULN, a second sample may
be taken and tested during the screening period) – unless diagnosis of Gilbert’s
syndrome
21. Triglycerides > 10 mmol/L (> 900 mg/dL) at screening (non-fasted)
General medical:
22. Pregnant women or nursing (breastfeeding) mothers
23. Females of child-bearing potential who were not using a reliable means of contraception, e.g. physical barrier (patient and partner), contraceptive pill or patch, spermicide and barrier, or IUD
24. History of severe allergic or anaphylactic reactions to human, humanized, or murine
monoclonal antibodies
25. CXR evidence of any clinically significant abnormality, per investigator evaluation
26. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus) or GI disease
27. In patients with a history of diverticulitis or diverticulosis requiring antibiotic treatment, the treating physician considered the benefit-risk ratio
28. A history of chronic ulcerative lower GI disease such as Crohn’s disease, ulcerative colitis or other symptomatic lower GI conditions that might predispose to perforation.
29. Uncontrolled disease states, such as asthma, psoriasis or inflammatory bowel disease where flares are commonly treated with oral or parenteral corticosteroids.
30. Current liver disease as determined by principal investigator. Patients with prior
history of ALT /AST (SGPT/SGOT) elevation were not excluded
31. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections (including but not limited to tuberculosis and atypical mycobacterial
disease, clinically significant abnormalities on CXR as determined by the investigator, hepatitis B and C, and herpes zoster, but excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening, or oral antibiotics within 2 weeks prior to screening
32. History of or active primary or secondary immunodeficiency
33. Evidence of active malignant disease, malignancies diagnosed within the previous 5
years (including hematological malignancies and solid tumors, except non-melanoma skin cancer that has been excised and cured), or breast cancer diagnosed within the previous 5 years
34. Active tuberculosis (TB) requiring treatment within the previous 3 years; patients
with no recurrence in 3 yrs are eligible.
35. Patient were screened for latent TB, prior to biologics use, as per local guidelines.
If screened positive, patients with latent tuberculosis should be treated with standard antimycobacterial therapy (at least 4 weeks) before initiating TCZ and have a negative CXR for active TB at screening.
36. HIV positive patient
37. History of alcohol, drug or chemical abuse within the 6 months prior to screening
38. Neuropathies or other painful conditions that might interfere with pain evaluation
39. Patients with lack of peripheral venous access
40. Body weight of > 130 kg
Recruitment start date
01/05/2015
Recruitment end date
01/08/2015
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Aintree University Hospital NHS Foundation Trust
Liverpool
L9 7AL
United Kingdom
Sponsor information
Organisation
University of Liverpool
Sponsor details
Research Support Office
2nd Floor Block D
Waterhouse Building
3 Brownlow Street
Liverpool
L69 3GL
United Kingdom
0151 794 8373
sponsor@liverpool.ac.uk
Sponsor type
University/education
Website
Funders
Funder type
University/education
Funder name
Obesity and Endocrinology Research Department, University of Liverpool
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
We intend to publish Sep 2015 onwards the study results-mainly what we find n terms of longitudinal associations of circulating adipokine concentrations following IL-6 inhibitor therapy. We will also publish associations with lipid profiles as well as disease activity scores if available in clinical records.
Intention to publish date
01/09/2015
Participant level data
Available on request
Basic results (scientific)
Publication list