ANZCTR - Registration

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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

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]

None

Universal Trial Number (UTN)

Trial acronym

HHRA-2

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Rheumatoid Arthritis

Cardiovascular Disease

Condition category

Condition code

Musculoskeletal

Other muscular and skeletal disorders

Cardiovascular

Diseases of the vasculature and circulation including the lymphatic system

Inflammatory and Immune System

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]

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]

EndoPAT assessments of Endothelial function.

Timepoint [1]

Baseline (pre-treatment), 12 weeks (trial period), 24 weeks (trial period) and then at 36 weeks (open label).

Secondary outcome [1]

Carotid-Femoral Pulse Wave Velocity

Timepoint [1]

Baseline (pre-treatment), weeks 12 and 24 (trial period) and week 36 (open-label)

Secondary outcome [2]

Clinical Assessments of Disease Activity (DAS28, DAS28CRP, CDAI and SDAI)

Timepoint [2]

Baseline (pre-treatment), weeks 12 and 24 (trial period) and week 36 (open-label)

Secondary outcome [3]

Health Assessment Questionnaire (HAQ) Score

Timepoint [3]

Baseline (pre-treatment), weeks 12 and 24 (trial period) and week 36 (open-label)

Secondary outcome [4]

Peripheral Blood Analysis - mitochondrial DNA Neutrophil Extracellular Traps (NETS) in a subset of 10 patients before and after treatment.

Timepoint [4]

Baseline (pre-treatment), weeks 12 and 24 (trial period) and week 36 (open-label)

Secondary outcome [5]

Carotid Artery Ultrasound Carotid Intimal-Medial Thickness

Timepoint [5]

Baseline (pre-treatment), weeks 12 and 24 (trial period) and week 36 (open-label)

Secondary outcome [6]

Musculoskeletal Ultrasound
Grey scale and Power doppler grade of synovitis
40 joints

Timepoint [6]

Baseline (pre-treatment), weeks 12 and 24 (trial period) and week 36 (open-label)

Secondary outcome [7]

Serum Collection - cytokine analysis

Timepoint [7]

Baseline (pre-treatment), weeks 12 and 24 (trial period) and week 36 (open-label)

Secondary outcome [8]

Whole Blood collection and storage for later genetic analysis

Timepoint [8]

Baseline

Secondary outcome [9]

Shared epitope genetic analysis (whole blood)

Timepoint [9]

Baseline

Secondary outcome [10]

Aortic Pulse Wave Analysis

Timepoint [10]

Baseline (pre-treatment), weeks 12, 24 and 36.

Secondary outcome [11]

Rheumatoid Arthritis Work Instability Questionnaire Score (RA-WIS) Questionnaire

Timepoint [11]

Baseline (pre-treatment), weeks 12, 24 and 36.

Secondary outcome [12]

Australian Quality of Life Questionnaire (AQoL)

Timepoint [12]

Baseline (pre-treatment), weeks 12, 24 and 36.

Secondary outcome [13]

Ultrasound Carotid Artery Plaque Grade

Timepoint [13]

Baseline (pre-treatment), weeks 12, 24 and 36.

Secondary outcome [14]

Ultrasound Carotid Artery Wall Elasticity (Elastic Modulus)

Timepoint [14]

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]

2305 - New Lambton

Recruitment postcode(s) [2]

2300 - Cooks Hill

Recruitment postcode(s) [3]

2298 - Georgetown

Recruitment postcode(s) [4]

2303 - Hamilton

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Abbvie Inc

Address [1]

1 North Waukegan Road
North Chicago
IL 60064
UNITED STATES OF AMERICA

Country [1]

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]

Individual

Name [1]

Dr Gabor Major

Address [1]

Rheumatology
John Hunter Hospital
Lookout Rd
New Lambton
NSW 2305

Country [1]

Australia

Secondary sponsor category [2]

Individual

Name [2]

Dr David Mathers

Address [2]

Georgetown Arthritis
71 Georgetown Rd
Georgetown
NSW 2298

Country [2]

Australia

Secondary sponsor category [3]

Individual

Name [3]

Dr John van der Kallen

Address [3]

Georgetown Arthritis Centre
71 Georgetown Rd
Georgetown
NSW 2298

Country [3]

Australia

Secondary sponsor category [4]

Individual

Name [4]

Dr Mark Collins

Address [4]

Georgetown Arthritis
71 Georgetown Rd
Georgetown
NSW 2298

Country [4]

Australia

Other collaborator category [1]

Individual

Name [1]

Dr Siva Ratnarajah

Address [1]

Dr Siva Ratnarajah
Private Consulting Rooms
25 William St
Hamilton
NSW 2303

Country [1]

Australia

Other collaborator category [2]

Individual

Name [2]

Dr John Glass

Address [2]

Rheumatology
John Hunter Hospital
Lookout Rd
New Lambton
NSW 2305

Country [2]

Australia

Other collaborator category [3]

Individual

Name [3]

Dr Marc Toh

Address [3]

Dr Marc Toh
Private Consulting Rooms
1/95 Union St
Cooks Hill
NSW 2300

Country [3]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Hunter New England Local Health District

Ethics committee address [1]

Dr Nicole Gerrand
Manager, Research Ethics and Governance 
Research Ethics and Governance Unit
Locked bag 1, New Lambton, NSW, 2305

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

19/12/2014

Approval date [1]

23/12/2015

Ethics approval number [1]

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

A/Prof Stephen Oakley

Address

Rheumatology
John Hunter Hospital
Lookout Rd
New Lambton
NSW 2305

Country

Australia

Phone

+61 2 2 4922 3500

Fax

+61 249 223 562

Email

stephen.oakley@health.nsw.gov.au

Contact person for public queries

Name

Stephen Oakley

Address

Rheumatology
John Hunter Hospital
Lookout Rd
New Lambton
NSW 2305

Country

Australia

Phone

+61 249 223 500

Fax

+61 249 223 562

Email

stephen.oakley@hnehealth.nsw.gov.au

Contact person for scientific queries

Name

Stephen Oakley

Address

Rheumatology
John Hunter Hospital
Lookout Rd
New Lambton
NSW 2305

Country

Australia

Phone

+61 249 223 500

Fax

+61 249 223 562

Email

stephen.oakley@hnehealth.nsw.gov.au

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.