Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12613000039785
Ethics application status
Approved
Date submitted
11/01/2013
Date registered
14/01/2013
Date last updated
19/01/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomised trial of zoledronic acid for osteoarthritis of the knee
Scientific title
Patients with knee pain, knee osteoarthritis and bone marrow lesions, randomised to zoledronic acid or placebo, assessed by knee cartilage volume loss over 24 months, knee pain at 3, 6, 12, 18, and 24 months, and bone marrow lesion size over 6 and 24 months
Secondary ID [1] 281757 0
Nil
Universal Trial Number (UTN)
Trial acronym
ZAP2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Knee pain
 288070 0
Knee osteoarthritis 288081 0
Condition category
Condition code
Musculoskeletal 288441 288441 0 0
Osteoarthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Annual IV infusion of 100ml of fluid containing zoledronic acid (5mg/100mL) for 2 years
Intervention code [1] 286296 0
Treatment: Drugs
Comparator / control treatment
Annual IV infusion of 100ml of fluid containing placebo (0.9% NaCI 100mL) for 2 years
Control group
Placebo

Outcomes
Primary outcome [1] 288608 0
Magnetic resonance imaging assessment of cartilage volume loss
Timepoint [1] 288608 0
24 months following commencement of treatment
Secondary outcome [1] 300585 0
Knee pain as measured by visual analogue score and WOMAC
Timepoint [1] 300585 0
3, 6, 12, 18, and 24 months following the commencement of treatment
Secondary outcome [2] 300586 0
Magnetic resonance imaging assessment of bone marrow lesions
Timepoint [2] 300586 0
6 and 24 months following commencement of treatment

Eligibility
Key inclusion criteria
1) Males and females with significant knee pain on most days (defined as a pain score >= 40 mm on a 100-mm visual analogue scale (VAS)).

2) Aged >= 50 years old.

3) Bone marrow lesions present on MRI.

4) Meeting the American College of Rheumatology (ACR) criteria for symptomatic knee osteoarthritis.
Minimum age
50 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Prior use of bisphosphonates, except according to the washout schedule:
2 years (if use >48 weeks)
1 year (if used >8 weeks but <48 weeks)
6 months (if used >2 weeks but <8 weeks)
2 months (if used <2 weeks)
Any IV bisphosphonate within the prior 2 years

2) History of non-traumatic iritis or uveitis

3) Abnormal blood tests [serum calcium >2.75 mmol/L (11.0 mg/dL) or <2.00 mmol/L (8.0 mg/dL) or creatinine clearance < 35 ml/min]

4) Serum 25-hydroxyvitamin D concentrations <40 nmol/L

5) Use of any investigational drug(s) and/or devices within 30 days or 5 half-lives (whichever is longer) of the drug prior to randomisation

6) Prior diagnosis of cancer (metastatic cancer or cancer diagnosed < 2 years ago where treatment is still ongoing)

7) Poor dental fitness: A dental exam with appropriate preventative dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, corticosteroids, poor hygiene)

8) Severe knee osteoarthritis (joint space narrowing (JSN)) on X-ray of Grade 3 using the Osteoarthritis Research Society International (OARSI) atlas)

9) Other forms of arthritis in which disease is active and concomitant medication is used (e.g. rheumatoid arthritis or other inflammatory arthritis)

10) Patients who have undergone arthroscopy or open surgery in the index knee in the last 12 months

11) Women who are pregnant or breast feeding

12) Patients who have had a corticosteroid injection in the last 3 months or a hyaluronic acid injection in the last 6 months in the index knee

13) Planned joint replacement surgery

14) Contraindication to MRI scanning (for example, implanted pacemaker, metal sutures, presence of shrapnel or iron filings in the eye, claustrophobia, knee too large for coil)

15) Inability to give informed consent

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
20/06/2013
Actual
25/11/2013
Date of last participant enrolment
Anticipated
Actual
18/09/2015
Date of last data collection
Anticipated
18/09/2017
Actual
9/10/2017
Sample size
Target
264
Accrual to date
Final
263
Recruitment in Australia
Recruitment state(s)
NSW,SA,TAS,VIC

Funding & Sponsors
Funding source category [1] 286543 0
Government body
Name [1] 286543 0
National Health and Medical Research Council (NHMRC)
Country [1] 286543 0
Australia
Primary sponsor type
University
Name
Menzies Research Institute Tasmania, University of Tasmania
Address
Medical Science 1
17 Liverpool St
Hobart, TAS
7000
Country
Australia
Secondary sponsor category [1] 285330 0
Hospital
Name [1] 285330 0
Alfred Hospital, Monash University
Address [1] 285330 0
Department of Epidemiology & Preventive Medicine
Level 3, Burnet Building, Commerical Road
Melbourne, VIC
3004
Country [1] 285330 0
Australia
Secondary sponsor category [2] 285331 0
Hospital
Name [2] 285331 0
Royal North Shore Hospital, University of Sydney
Address [2] 285331 0
E25 - Royal North Shore Hospital
The University of Sydney
Sydney, NSW
2006
Country [2] 285331 0
Australia
Secondary sponsor category [3] 285332 0
Hospital
Name [3] 285332 0
The Queen Elizabeth Hospital
Address [3] 285332 0
Rheumatology Unit, The Queen Elizabeth Hospital
28 Woodville Road
Woodville, SA
5011
Country [3] 285332 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288612 0
Tasmania Health & Medical Human Research Ethics Committee (EC00337)
Ethics committee address [1] 288612 0
Office of Research Services
University of Tasmania
Private Bag 01
Hobart TAS 7001
Ethics committee country [1] 288612 0
Australia
Date submitted for ethics approval [1] 288612 0
03/12/2012
Approval date [1] 288612 0
09/01/2013
Ethics approval number [1] 288612 0
H0012941
Ethics committee name [2] 288613 0
Alfred Hospital Ethics Committee (EC00315)
Ethics committee address [2] 288613 0
Ethics committee country [2] 288613 0
Date submitted for ethics approval [2] 288613 0
Approval date [2] 288613 0
Ethics approval number [2] 288613 0
Ethics committee name [3] 288614 0
Northern Sydney Coast Human Research Ethics Committee (EC00112)
Ethics committee address [3] 288614 0
Ethics committee country [3] 288614 0
Date submitted for ethics approval [3] 288614 0
Approval date [3] 288614 0
Ethics approval number [3] 288614 0
Ethics committee name [4] 288615 0
Human Research Ethics Committtee (TQEH/LMH/MH) (EC00190)
Ethics committee address [4] 288615 0
Ethics committee country [4] 288615 0
Date submitted for ethics approval [4] 288615 0
Approval date [4] 288615 0
Ethics approval number [4] 288615 0

Summary
Brief summary
The aim of this study is to compare, using a randomised, placebo-controlled double-blind design over two years, the effect of an annual infusion of zoledronic acid to placebo on knee structural change assessed on MRI and knee pain in patients with knee osteoarthritis, significant knee pain and an MRI detected knee bone marrow lesion. We will recruit 264 subjects in Hobart, Melbourne, Sydney, and Adelaide. Eligible subjects will receive an annual identical intravenous infusion of zoledronic acid (5mg in normal saline) or placebo (normal saline), over two years. Outcome measures include cartilage loss over 24 months, knee pain at 3, 6, 12, 18, and 24 months, and bone marrow lesion size over 6 and 24 months.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 36954 0
Prof Graeme Jones
Address 36954 0
Medical Science 2
17 Liverpool St
Hobart, TAS
7000
Country 36954 0
Australia
Phone 36954 0
+61 03 6226 7705
Fax 36954 0
+61 03 6226 7704
Email 36954 0
g.jones@utas.edu.au
Contact person for public queries
Name 36955 0
Graeme Jones
Address 36955 0
Medical Science 2
17 Liverpool St
Hobart, TAS
7000
Country 36955 0
Australia
Phone 36955 0
+61 03 6226 7705
Fax 36955 0
+61 03 6226 7704
Email 36955 0
g.jones@utas.edu.au
Contact person for scientific queries
Name 36956 0
Graeme Jones
Address 36956 0
Medical Science 2
17 Liverpool St
Hobart, TAS
7000
Country 36956 0
Australia
Phone 36956 0
+61 03 6226 7705
Fax 36956 0
+61 03 6226 7704
Email 36956 0
g.jones@utas.edu.au

No information has been provided regarding IPD availability


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
SourceTitleYear of PublicationDOI
EmbaseA protocol for a multicentre, randomised, double-blind, placebo-controlled trial to compare the effect of annual infusions of zoledronic acid to placebo on knee structural change and knee pain over 24 months in knee osteoarthritis patients - ZAP2.2018https://dx.doi.org/10.1186/s12891-018-2143-2
EmbaseZoledronic acid plus methylprednisolone versus zoledronic acid or placebo in symptomatic knee osteoarthritis: a randomized controlled trial.2019https://dx.doi.org/10.1177/1759720X19880054
EmbaseEffect of Intravenous Zoledronic Acid on Tibiofemoral Cartilage Volume among Patients with Knee Osteoarthritis with Bone Marrow Lesions: A Randomized Clinical Trial.2020https://dx.doi.org/10.1001/jama.2020.2938
EmbaseThe association between change in bone marrow lesion size and change in tibiofemoral cartilage volume and knee symptoms.2021https://dx.doi.org/10.1093/rheumatology/keaa716
EmbaseProspects of Disease-Modifying Osteoarthritis Drugs.2022https://dx.doi.org/10.1016/j.cger.2021.11.010
N.B. These documents automatically identified may not have been verified by the study sponsor.