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Trial registered on ANZCTR


Registration number
ACTRN12615000557538
Ethics application status
Approved
Date submitted
8/12/2014
Date registered
29/05/2015
Date last updated
16/11/2020
Date data sharing statement initially provided
16/11/2020
Date results information initially provided
16/11/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
HUNTER HEART-RA-2 (HHRA-2) STUDY

A Randomised Controlled Trial Evaluating the Effects of Humira Upon Cardiovascular Risk as Measured by Endothelial Function in patients with Rheumatoid Arthritis who Test Positive for Anti-CCP Antibodies as well as those who Test Negative for Anti-CCP Antibodies.
Scientific title
HUNTER HEART-RA-2 (HHRA-2) STUDY

A Randomised Controlled Trial Evaluating the Effects of Humira Upon Endothelial Function in ACPA-Positive and ACPA-Negative Patients with Rheumatoid Arthritis.
Secondary ID [1] 285811 0
None
Universal Trial Number (UTN)
Trial acronym
HHRA-2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Rheumatoid Arthritis 293711 0
Cardiovascular Disease 293712 0
Condition category
Condition code
Musculoskeletal 294008 294008 0 0
Other muscular and skeletal disorders
Cardiovascular 294009 294009 0 0
Diseases of the vasculature and circulation including the lymphatic system
Inflammatory and Immune System 294010 294010 0 0
Rheumatoid arthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
24 weeks of adalimumab 40 mg sub-cutaneous injections 2nd weekly plus "usual care".

Adherence to treatment will be monitored and recorded by research staff during study assessments at weeks 12 and 24.
Intervention code [1] 290783 0
Treatment: Drugs
Comparator / control treatment
24 weeks of placebo sub-cutaneous saline injections 2nd weekly plus "usual care".

Adherence to treatment will be monitored and recorded by research staff during study assessments at weeks 12 and 24.
Control group
Placebo

Outcomes
Primary outcome [1] 293788 0
EndoPAT assessments of Endothelial function.
Timepoint [1] 293788 0
Baseline (pre-treatment), 12 weeks (trial period), 24 weeks (trial period) and then at 36 weeks (open label).
Secondary outcome [1] 311846 0
Carotid-Femoral Pulse Wave Velocity
Timepoint [1] 311846 0
Baseline (pre-treatment), weeks 12 and 24 (trial period) and week 36 (open-label)
Secondary outcome [2] 311847 0
Clinical Assessments of Disease Activity (DAS28, DAS28CRP, CDAI and SDAI)
Timepoint [2] 311847 0
Baseline (pre-treatment), weeks 12 and 24 (trial period) and week 36 (open-label)
Secondary outcome [3] 311848 0
Health Assessment Questionnaire (HAQ) Score
Timepoint [3] 311848 0
Baseline (pre-treatment), weeks 12 and 24 (trial period) and week 36 (open-label)
Secondary outcome [4] 311849 0
Peripheral Blood Analysis - mitochondrial DNA Neutrophil Extracellular Traps (NETS) in a subset of 10 patients before and after treatment.
Timepoint [4] 311849 0
Baseline (pre-treatment), weeks 12 and 24 (trial period) and week 36 (open-label)
Secondary outcome [5] 311850 0
Carotid Artery Ultrasound Carotid Intimal-Medial Thickness
Timepoint [5] 311850 0
Baseline (pre-treatment), weeks 12 and 24 (trial period) and week 36 (open-label)
Secondary outcome [6] 311851 0
Musculoskeletal Ultrasound
Grey scale and Power doppler grade of synovitis
40 joints
Timepoint [6] 311851 0
Baseline (pre-treatment), weeks 12 and 24 (trial period) and week 36 (open-label)
Secondary outcome [7] 311852 0
Serum Collection - cytokine analysis
Timepoint [7] 311852 0
Baseline (pre-treatment), weeks 12 and 24 (trial period) and week 36 (open-label)
Secondary outcome [8] 311853 0
Whole Blood collection and storage for later genetic analysis
Timepoint [8] 311853 0
Baseline
Secondary outcome [9] 311854 0
Shared epitope genetic analysis (whole blood)
Timepoint [9] 311854 0
Baseline
Secondary outcome [10] 314892 0
Aortic Pulse Wave Analysis
Timepoint [10] 314892 0
Baseline (pre-treatment), weeks 12, 24 and 36.
Secondary outcome [11] 314893 0
Rheumatoid Arthritis Work Instability Questionnaire Score (RA-WIS) Questionnaire
Timepoint [11] 314893 0
Baseline (pre-treatment), weeks 12, 24 and 36.
Secondary outcome [12] 314894 0
Australian Quality of Life Questionnaire (AQoL)
Timepoint [12] 314894 0
Baseline (pre-treatment), weeks 12, 24 and 36.
Secondary outcome [13] 314895 0
Ultrasound Carotid Artery Plaque Grade
Timepoint [13] 314895 0
Baseline (pre-treatment), weeks 12, 24 and 36.
Secondary outcome [14] 314896 0
Ultrasound Carotid Artery Wall Elasticity (Elastic Modulus)
Timepoint [14] 314896 0
Baseline (pre-treatment), weeks 12, 24 and 36.

Eligibility
Key inclusion criteria
Rheumatoid arthritis (as defined by 2010 American College of Rheumatology Criteria)
Anti-CCP (ACPA) positive or negative
Moderate or higher disease activity defined as 3 (or 4) variable DAS28 ESR (or DAS28 CRP) greater than 3.40.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Prior or current malignancy
2. Evidence of current or previous untreated infection with TB, hepatitis B, hepatitis C or HIV.
3. Demyelinating disease

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)
Potential subjects will be identified by investigators in rheumatology outpatients and private practice and allocation will remain concealed to each individual patient until they have completed 24 weeks of saline placebo or 40 mg adalimumab injections or if they have dropped out of the study.

Informed consent and enrolment will be performed by the principle investigator at Hunter New England Local Health District. Subjects will be screened for safety and undergo two baseline assessments of vascular function, disease activity and functional / work assessments. They will then be randomly assigned to receive 24 weeks of 40 mg adalimumab or saline placebo 2nd weekly sub-cutaneous injections in addition to "usual care" for a period of 24 weeks.

Adalimumab 40 and saline placebo pre-filled syringes will be prepared in and supplied by Abbott laboratories off-site and dispensed through the hospital pharmacy. The syringes will be labelled and dispensed in numbered containers so as to blind the investigators, research nurse / technician and patient to the contents of the syringe. A "randomisation table" will be provided to the hospital pharmacy to allow "unblinding" when each individual patient completes the study.

Subjects will undergo further assessments at 12 and 24 weeks during the treatment period. After the 24 week assessment subjects and their treating rheumatologist will be informed as to whether they recieved adalimumab or placebo. They will continue to receive "usual care from their rheumatologist. Subjects will undergo a final assessments at 36 weeks during open label treatment.
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 using a simple randomisation table created by computerised sequence generation. 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?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
3/08/2015
Actual
13/05/2016
Date of last participant enrolment
Anticipated
1/06/2016
Actual
24/11/2017
Date of last data collection
Anticipated
24/11/2017
Actual
24/11/2017
Sample size
Target
70
Accrual to date
Final
3
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment postcode(s) [1] 9018 0
2305 - New Lambton
Recruitment postcode(s) [2] 9019 0
2300 - Cooks Hill
Recruitment postcode(s) [3] 9020 0
2298 - Georgetown
Recruitment postcode(s) [4] 9021 0
2303 - Hamilton

Funding & Sponsors
Funding source category [1] 290371 0
Commercial sector/Industry
Name [1] 290371 0
Abbvie Inc
Country [1] 290371 0
United States of America
Primary sponsor type
Individual
Name
A/Prof Stephen Oakley
Address
Rheumatology
John Hunter Hospital
Lookout Rd
New Lambton
NSW 2305
Country
Australia
Secondary sponsor category [1] 289095 0
Individual
Name [1] 289095 0
Dr Gabor Major
Address [1] 289095 0
Rheumatology
John Hunter Hospital
Lookout Rd
New Lambton
NSW 2305
Country [1] 289095 0
Australia
Secondary sponsor category [2] 289096 0
Individual
Name [2] 289096 0
Dr David Mathers
Address [2] 289096 0
Georgetown Arthritis
71 Georgetown Rd
Georgetown
NSW 2298
Country [2] 289096 0
Australia
Secondary sponsor category [3] 289097 0
Individual
Name [3] 289097 0
Dr John van der Kallen
Address [3] 289097 0
Georgetown Arthritis Centre
71 Georgetown Rd
Georgetown
NSW 2298
Country [3] 289097 0
Australia
Secondary sponsor category [4] 289098 0
Individual
Name [4] 289098 0
Dr Mark Collins
Address [4] 289098 0
Georgetown Arthritis
71 Georgetown Rd
Georgetown
NSW 2298
Country [4] 289098 0
Australia
Other collaborator category [1] 278263 0
Individual
Name [1] 278263 0
Dr Siva Ratnarajah
Address [1] 278263 0
Dr Siva Ratnarajah
Private Consulting Rooms
25 William St
Hamilton
NSW 2303
Country [1] 278263 0
Australia
Other collaborator category [2] 278264 0
Individual
Name [2] 278264 0
Dr John Glass
Address [2] 278264 0
Rheumatology
John Hunter Hospital
Lookout Rd
New Lambton
NSW 2305
Country [2] 278264 0
Australia
Other collaborator category [3] 278265 0
Individual
Name [3] 278265 0
Dr Marc Toh
Address [3] 278265 0
Dr Marc Toh
Private Consulting Rooms
1/95 Union St
Cooks Hill
NSW 2300
Country [3] 278265 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292074 0
Hunter New England Local Health District
Ethics committee address [1] 292074 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] 292074 0
Australia
Date submitted for ethics approval [1] 292074 0
19/12/2014
Approval date [1] 292074 0
23/12/2015
Ethics approval number [1] 292074 0

Summary
Brief summary
Introduction

Rheumatoid arthritis is a severe destructive inflammatory arthritis that affects 1.5% of the population. They have a 50% increased risk of cardiovascular events that is directly related to the disease process although the mechanisms of this remain unclear.

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.

Our consortium have already conducted a small phase 2 study (Hunter HEART-RA has already evaluating the effect of adalimumab in anti-CCP antibody positive RA. This phase 2, single-centre, double-blind randomised, placebo-controlled study will evaluate the effects of adalimumab upon endothelial function anti-CCP positive and NEGATIVE rheumatoid arthritis.

Methods

1. 36 subjects with Anti-CCP Positive Rheumatoid Arthritis and ;

2. 34 subjects with Anti-CCP Negative Rheumatoid Arthritis (age>18 years)

Subjects within each group will be randomised 1:1 to receive adalimumab / placebo for 24 weeks in addition to "usual care”. During the 24-week trial subjects will undergo assessments of vascular function, rheumatoid arthritis disease activity, functional impairment and work disability. Assessments will occur at 0 (baseline), 12 and 24 weeks.

The primary response variable will be peripheral endothelial function as measured by EndoPAT.
Secondary response variable will include:
1. Arterial stiffness (Carotid-femoral pulse wave velocity, Central Aortic Augmentation Index as measured from the radial pulse wave analysis)
2. Carotid artery ultrasound (carotid initmal medial thickness, carotid plaque score and carotid wall elasticity)
3. Disease activity (ESR, CRP, joint counts, DAS28, SDAI)
4. Functional Ability (HAQ Questionnaire)
5. Work Disability (RA-WIS Questionnaire)
6. Australian Quality of Life (AQoL) Questionnaire
7. 40-joint musculoskeletal ultrasound.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 53366 0
A/Prof Stephen Oakley
Address 53366 0
Rheumatology
John Hunter Hospital
Lookout Rd
New Lambton
NSW 2305
Country 53366 0
Australia
Phone 53366 0
+61 2 2 4922 3500
Fax 53366 0
+61 249 223 562
Email 53366 0
[email protected]
Contact person for public queries
Name 53367 0
A/Prof Stephen Oakley
Address 53367 0
Rheumatology
John Hunter Hospital
Lookout Rd
New Lambton
NSW 2305
Country 53367 0
Australia
Phone 53367 0
+61 249 223 500
Fax 53367 0
+61 249 223 562
Email 53367 0
[email protected]
Contact person for scientific queries
Name 53368 0
A/Prof Stephen Oakley
Address 53368 0
Rheumatology
John Hunter Hospital
Lookout Rd
New Lambton
NSW 2305
Country 53368 0
Australia
Phone 53368 0
+61 249 223 500
Fax 53368 0
+61 249 223 562
Email 53368 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
There are no provisions for data sharing in the ethics approval and no collaborators.


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.