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Trial registered on ANZCTR


Registration number
ACTRN12611000972921
Ethics application status
Approved
Date submitted
30/08/2011
Date registered
12/09/2011
Date last updated
8/01/2019
Date data sharing statement initially provided
8/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
The Hunter Humira and Endothelial Function in Early Rheumatoid Arthritis Trial
Scientific title
An Investigator-Initiated Phase 2, Single Centre, Double-Blind, Randomised, Controlled Trial of the Effect of Adalimumab Upon Endothelial Function in Patients with Early and Established Anti-CCP Antibody Positive Rheumatoid Arthritis.
Secondary ID [1] 262958 0
Nil
Universal Trial Number (UTN)
U1111-1124-1715
Trial acronym
Hunter HEART Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Rheumatoid Arthritis 270679 0
Cardiovascular Disease 270680 0
Condition category
Condition code
Musculoskeletal 270854 270854 0 0
Other muscular and skeletal disorders
Cardiovascular 270855 270855 0 0
Diseases of the vasculature and circulation including the lymphatic system
Inflammatory and Immune System 270930 270930 0 0
Rheumatoid arthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
24 weeks of adalimumab (Humira) 40 mg sub-cutaneous injections 2nd weekly plus "usual care".
Intervention code [1] 269298 0
Treatment: Drugs
Comparator / control treatment
24 weeks of placebo sub-cutaneous saline injections 2nd weekly plus "usual care".
Control group
Placebo

Outcomes
Primary outcome [1] 279534 0
EndoPAT assessments of endothelial function
Timepoint [1] 279534 0
Minus 2 weeks, Baseline, 4 weeks, 12 weeks, 24 weeks, and an additional assessment will be performed between weeks 36 and 48, 12 weeks after completion of the blinded phase of the study.
Secondary outcome [1] 287857 0
SphygmoCor assessments of arterial stiffness / compliance:
1. Carotid-femoral pulse wave velocity
2. Aortic augmentation index based upon radial artery pulse wave analysis
Timepoint [1] 287857 0
Minus 2 weeks, Baseline, 4 weeks, 12 weeks, 24 weeks, and an additional assessment will be performed between weeks 36 and 48, 12 weeks after completion of the blinded phase of the study.
Secondary outcome [2] 287858 0
Disease Activity Assessments - ESR, CRP, DAS28, DAS28 CRP, SDAI
Timepoint [2] 287858 0
Minus 2 weeks, Baseline, 4 weeks, 12 weeks, 24 weeks, and an additional assessment will be performed between weeks 36 and 48, 12 weeks after completion of the blinded phase of the study.
Secondary outcome [3] 287859 0
Functional assessment (Health Assessment Questionnaire score) and Work Instability Assessment (RA-WIS Questionnaire)
Timepoint [3] 287859 0
Minus 2 weeks, Baseline, 4 weeks, 12 weeks, 24 weeks, and an additional assessment will be performed between weeks 36 and 48, 12 weeks after completion of the blinded phase of the study.
Secondary outcome [4] 365474 0
Genotyping for "Shared Epitope" status from whole blood sample.
Timepoint [4] 365474 0
Baseline
Secondary outcome [5] 365475 0
Collection and storage of whole blood for Genome-Wide Array Study to search for genetic correlates of endothelial dysfunction and response to therapy.
Timepoint [5] 365475 0
Baseline assessment - visit 1.
Secondary outcome [6] 365476 0
This is an exploratory outcome. Serum cytokines and molecular markers as assessed by serum analysis.
Timepoint [6] 365476 0
Baseline 1, Baseline 2, Week 1, Week 4, Week 12, Week 24 and Week 36-48.

Eligibility
Key inclusion criteria
Group 1: Early Rheumatoid Arthritis: Anti-CCP (ACPA) positive rheumatoid arthritis of less than 1 year duration by onset of symptoms, age over 18 years, CRP > 15 mg/L or DAS28-CRP>3.20 within 1 week of enrolment.

Group 2: Established Rheumatoid Arthritis: Anti-CCP (ACPA) positive rheumatoid arthritis of greater than 1 year duration by onset of symptoms, age over 18 years, CRP>15 mg/L or DAS28-CRP>3.20 within one month of enrolment
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Disease Remission (ACR / EULAR 2010 Criteria) or CRP<15 mg/L
2. Anti-CCP antibody test negative
3. Serious malignancy within the last 5 years
4. Demyelinating Disease
5. Evidence of previous untreated TB infection

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Participants will be enrolled from clinical rheumatology practices and outpatients. After completing 2 baseline assessments participants will be randomly allocated to treatment or placebo arms for 24 weeks.
Participants will receive Placebo / Active drug in pre-randomised packages. Central randomisation by computer off-site at Abbvie Chicago and packages delivered blinded to John Hunter Hospital Pharmacy. Randomisation code kept on site in sealed opaque envelopes and numbered containers.

Assessments occur at minus 2 weeks, baseline and then 4 weeks, 12 weeks, 24 weeks during treatment. An additional assessment will be performed between weeks 36 and 48, 12 weeks after completion of the blinded phase of the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Abbott laboraties will prepare syringes pre-filled with either placebo saline or 40 mg adalimumab off site The syringes will be delivered to and dispensed by the hospital pharmacy.

The randomised syringes will be presented in a numbered container for the purpose of blinding. Randomisation (50:50 ratio) will be performed at the company laboratories in batches of syringes for 10 patients (5 x 24 week courses of 40 mg adalimumab and 5 x 24-week courses of saline placebo injections) within each group (Early / Established) to ensure equal recruitment into the placebo / adalimumab arms within each group through the early phase of the study.

The pre-filled syringes and randomisation table containing information regarding syringe contents will be delivered to and held by the John Hunter Hospital pharmacy. The pharmacy will provide the pre-filled syringes to study participants upon receipt of a study-specific prescription. The study participant, treating physician, research nurse, study technician and pharmacist will remain blinded to the contents of the pre-filled syringes until the indiviual patient has completed 24 weeks placebo / adalimumab or they have dropped out of the study.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
30/01/2012
Actual
31/01/2013
Date of last participant enrolment
Anticipated
Actual
15/07/2015
Date of last data collection
Anticipated
Actual
29/01/2016
Sample size
Target
60
Accrual to date
Final
60
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment postcode(s) [1] 4418 0
2305
Recruitment postcode(s) [2] 4419 0
2300
Recruitment postcode(s) [3] 4420 0
2298
Recruitment postcode(s) [4] 4421 0
2298
Recruitment postcode(s) [5] 25312 0
2291 - Merewether

Funding & Sponsors
Funding source category [1] 269762 0
Commercial sector/Industry
Name [1] 269762 0
Abbott Pharmaceuticals
Country [1] 269762 0
United States of America
Primary sponsor type
Individual
Name
A/Prof Stephen Oakley
Address
Rheumatology
Royal Newcastle Centre
Lookout Road
New Lambton
NSW
2305
Country
Australia
Secondary sponsor category [1] 268798 0
Hospital
Name [1] 268798 0
Royal Newcastle Centre
Address [1] 268798 0
Lookout Road
New Lambton
NSW
2305
Country [1] 268798 0
Australia
Other collaborator category [1] 252235 0
Individual
Name [1] 252235 0
Dr Gabor Major
Address [1] 252235 0
Rheumatology
Royal Newcastle Centre
Lookout Road
New Lambton
NSW
2305
Country [1] 252235 0
Australia
Other collaborator category [2] 252236 0
Individual
Name [2] 252236 0
Dr David Mathers
Address [2] 252236 0
Georgetown Arthritis
71 Georgetown Road
Geogetown
NSW
2298
Country [2] 252236 0
Australia
Other collaborator category [3] 252237 0
Individual
Name [3] 252237 0
Dr John van der Kallen
Address [3] 252237 0
Georgetown Arthritis
71 Georgetown Road
Geogetown
NSW
2298
Country [3] 252237 0
Australia
Other collaborator category [4] 252238 0
Individual
Name [4] 252238 0
Dr Mark Collins
Address [4] 252238 0
Georgetown Arthritis
71 Georgetown Road
Geogetown
NSW
2298
Country [4] 252238 0
Australia
Other collaborator category [5] 252239 0
Individual
Name [5] 252239 0
Dr Siva Ratnarajah
Address [5] 252239 0
25 William Street
Hamilton
NSW
2303
Country [5] 252239 0
Australia
Other collaborator category [6] 252240 0
Individual
Name [6] 252240 0
Dr John Glass
Address [6] 252240 0
50 Watt Street
Newcastle
NSW
2300
Country [6] 252240 0
Australia
Other collaborator category [7] 280485 0
Individual
Name [7] 280485 0
Dr Marc Toh
Address [7] 280485 0
Private Practice
Level 1, 41 Llewellyn St, Merewether NSW 2291
Country [7] 280485 0
Australia
Other collaborator category [8] 280486 0
Individual
Name [8] 280486 0
Dr Theo de Malmanche
Address [8] 280486 0
Hunter Area Pathology Service
John Hunter Hospital
Lookout Rd
New Lambton
NSW
2305
Country [8] 280486 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 271723 0
Hunter New England Area Health Service
Ethics committee address [1] 271723 0
Dr Nicole Gerrand
Manager, Research Ethics and Governance
Research Ethics and Governance Unit
Locked bag 1, New Lambton, NSW, 2305
Ethics committee country [1] 271723 0
Australia
Date submitted for ethics approval [1] 271723 0
30/09/2011
Approval date [1] 271723 0
20/06/2012
Ethics approval number [1] 271723 0
11/11/16/3.03

Summary
Brief summary
Introduction Rheumatoid arthritis is a severe destructive inflammatory arthritis that affects 1.5% of the population. The anti-CCP antibody positive subgroup experience a 50% increased risk of cardiovascular events that is directly related to the disease process although the mechanisms of this remain unclear. There is mounting evidence that a “window of opportunity” exists during which time treatment is more likely to achieve remission. It therefore seems possible that a similar window of opportunity might exist for the treatment of vascular disease in rheumatoid arthritis. New effective treatments for rheumatoid arthritis called the "Biologics" have become widely available over the last decade. This has resulted in dramatic improvements in the treatment of the arthritis. However, it remains unclear whether these treatments influence the risk of cardiovascular events. Pooled analyses of the large trials have not had sufficient power and are of insufficient duration to answer this question. Meta-analysis of the combined registry data found dramatic differences in the TNF-inhibitor treated group but these effects may be explained by confounding. Studies using assessments of pre-clinical vascular disease using imaging and physiological assessments of arterial stiffness seem more likely to show treatment effects but have thus far been inconclusive. Based upon studies in hypertension it is likely that studies utilising assessments of arterial stiffness and carotid artery wall thickness would require randomised controlled trials of considerable size and duration to detect treatment effects. Earlier pathological processes in vascular disease such as endothelial dysfunction are more likely to change quickly and detectably in response to treatment. However, studies have been inconclusive possibly due to the small sample sizes, insufficient study duration and because the studies evaluated subject with established and possibly irreversible disease. The Australian PBS funds Biologic drugs for patients with rheumatoid arthritis only after they have failed to respond to 6 months conventional DMARD therapy. This 6 month period presents an opportunity to evaluate the effects of TNF-inhibition (with adalimumab) upon vascular function in a randomised controlled trial while at the same time enhancing patient care. This phase 2, single-centre, double-blind randomised, placebo-controlled study will evaluate the effects of adalimumab upon endothelial function in early and established anti-CCP positive rheumatoid arthritis. Methods Two groups will be studied in a randomised, controlled trial: 1. 30 subjects with Early Anti-CCP Positive Rheumatoid Arthritis (<12 months disease duration, age 18-50 years) and ; 2. 30 subjects with Established Anti-CCP Positive Rheumatoid Arthritis (>12 mths disease duration, age>18 years) Subjects within each group will be randomised 1:1 to receive adalimumab / placebo for 24 weeks in addition to "usual care”.
Trial website
Not applicable
Trial related presentations / publications
Nil
Public notes

Contacts
Principal investigator
Name 33092 0
A/Prof Stephen Oakley
Address 33092 0
Rheumatology
Royal Newcastle Centre
Lookout Rd
New Lambton
2305
NSW
Country 33092 0
Australia
Phone 33092 0
+61 249 223 500
Fax 33092 0
+61 249 223 214
Email 33092 0
[email protected]
Contact person for public queries
Name 16339 0
Stephen Oakley
Address 16339 0
Rheumatology
Royal Newcastle Centre
Lookout Road
New Lambton
NSW
2305
Country 16339 0
Australia
Phone 16339 0
+61 249 223 500
Fax 16339 0
+61 249 223 214
Email 16339 0
[email protected]
Contact person for scientific queries
Name 7267 0
Stephen Oakley
Address 7267 0
Rheumatology
Royal Newcastle Centre
Lookout Road
New Lambton
NSW
2305
Country 7267 0
Australia
Phone 7267 0
+61 249 223 500
Fax 7267 0
+61 249 223 214
Email 7267 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
The scope of this study is quite narrow. The outcome assessments are very specific. No other studies appear to be collecting the same information and therefore there are currently no plans for data sharing. However, all requests for data sharing will be considered.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.