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Trial registered on ANZCTR


Registration number
ACTRN12612000776808
Ethics application status
Approved
Date submitted
20/07/2012
Date registered
23/07/2012
Date last updated
21/06/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Bisphosphonate Therapy with Zoledronic acid or Tenofovir Switching to Improve Low Bone Mineral Density in HIV-Infected Adults: a Strategic, Randomised Trial
Scientific title
Bisphosphonate Therapy with Zoledronic acid or Tenofovir Switching to Improve Low Bone Mineral Density in HIV-Infected Adults: a Strategic, Randomised Trial
Secondary ID [1] 280883 0
N/A
Universal Trial Number (UTN)
U1111-11328470
Trial acronym
ZeST
Linked study record

Health condition
Health condition(s) or problem(s) studied:
HIV 286952 0
osteopenia 286953 0
Condition category
Condition code
Inflammatory and Immune System 287290 287290 0 0
Other inflammatory or immune system disorders
Musculoskeletal 287291 287291 0 0
Osteoporosis
Infection 287296 287296 0 0
Acquired immune deficiency syndrome (AIDS / HIV)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants currently taking tenofovir as part of their stable HIV therapy, have no detectable HIV in the blood, have thin bones, and who could safely use either zoledronic acid or switch their tenofovir to another anti-HIV drug will be randmolmly assigned to either:

1. zoledronic acid 5 mg intravenous (IV) yearly (2 doses) OR
2. switch from tenofovir to another potent anti-HIV drug (without commencing zoledronic acid) selected by the study doctor at the first study visit.

Switch ARV: Dose amounts and frequency will depend on switch ARV selected by the study doctor, however at least daily. Mode of administration is oral for duration of the study (2 years).
Intervention code [1] 285315 0
Treatment: Drugs
Comparator / control treatment
switch from tenofovir to another potent antiretroviral (ARV)drug (without commencing a bisphosphonate)
Dose amounts and frequency will depend on switch ARV selected by the study doctor, mode of administration is oral.

The switch options include abacavir, raltegravir or a boosted protease inhibitor. A switch option will be chosen based on previous treatment exposure and side effects.
Control group
Active

Outcomes
Primary outcome [1] 287565 0
the effects of zoledronic acid 5 mg IV yearly to switching from tenofovir to another antiretroviral drug on lumbar spine BMD measured by Dual-energy X-ray absorptiometry [DEXA] scanning
Timepoint [1] 287565 0
2 years
Primary outcome [2] 287566 0
the effects of zoledronic acid 5 mg IV yearly to switching from tenofovir to another antiretroviral drug on hip BMD measured by Dual-energy X-ray absorptiometry [DEXA] scanning
Timepoint [2] 287566 0
2 years
Secondary outcome [1] 298411 0
To compare the randomised groups for mean percent change in hip BMD measured by Dual-energy X-ray absorptiometry [DEXA] scanning
Timepoint [1] 298411 0
2 years
Secondary outcome [2] 298412 0
To compare the randomised groups for incidence of osteoporosis (T-score <-2.5 at hip or spine) and of normal BMD (T-score >-1 at hip and spine) measured by Dual-energy X-ray absorptiometry [DEXA] scanning
Timepoint [2] 298412 0
2 years
Secondary outcome [3] 298413 0
To compare the randomised groups for fracture risk estimated with the Australian version of the FRAX equation
Timepoint [3] 298413 0
2 years
Secondary outcome [4] 298414 0
To compare the randomised groups for blood serum levels of C-Terminal telopeptide (CTx) and Procollagen type 1 N-terminal propeptide (P1NP)
Timepoint [4] 298414 0
2 years
Secondary outcome [5] 298415 0
To compare the randomised groups for fractures (except of the skull, and of the small bones of the hands and feet) by clinical assessment
Timepoint [5] 298415 0
2 years
Secondary outcome [6] 298416 0
To compare the randomised groups for clinical adverse events; all serious adverse events; AIDS; death; use of concomitant medications for toxicity; estimated glomerular filtration rate (eGFR, by MDRD equation; laboratory adverse events; virological failure by pathology tests and clinical assessment
Timepoint [6] 298416 0
2 years
Secondary outcome [7] 298417 0
To compare the randomised groups for modifications to ART (after baseline) by clinical assessment
Timepoint [7] 298417 0
2 years
Secondary outcome [8] 342387 0
Changes in BMD over 36 months
Timepoint [8] 342387 0
36 months

Eligibility
Key inclusion criteria
1. provision of written, informed consent
2. HIV infected adult equal to or greater than 18 years of age
3. stable and well-tolerated ART including tenofovir for the preceding 6 months
4. plasma HIV RNA <50 copies/ml for at least the preceding 3 months
5. eGFR >60ml/min (patients at higher risk of zoledronic acid/tenofovir nephrotoxicity)
6. spine or neck of femur T score = -1.0 measured by DXA (i.e. osteopenia)
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. prior bisphosphonate therapy
2. use of tenofovir for previously active chronic hepatitis B co-infection
3. requiring therapy for low BMD (e.g. prior fragility fracture; other metabolic bone disease)
4. other secondary causes of osteoporosis: hypogonadism (low total testosterone/oestrogen and luteinizing hormone >25% above upper normal limit); hypothyroidism (low T4 and elevated TSH); hyperparathyroidism (elevated parathyroid hormone); inhaled fluticasone in a patient receiving ritonavir; prednisolone equal to or greater than 7.5mg/d or equivalent
5. contra-indications to zoledronic acid (known hypersensitivity to bisphosphonates, hypocalcaemia, prior or current uveitis, eGFR<35 mL/min)
6. recent (within the last 2 months) or planned dental surgery (at investigators discretion)
7. previous virological failure, genotypic resistance, intolerance or contraindication to proposed switch antiretroviral drug
8. HLA-B*5701 positive (abacavir contra-indicated) or prior ischaemic cardiovascular disease if planning to switch from tenofovir to abacavir
9. concurrent use of any nephrotoxic drug
10. breast-feeding or pregnancy

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)
Eligible patients are allocated to intervention by central randomisation. A randomisation CRF and the screening DXA report is faxed to the central randomisation officer who has a medical doctor review the DXA to determine stratification.
Patients are stratified according to DXA site and severity of osteopenia. The randomisation officer will refer to the appropriate electronic stratum worksheet (1 worksheet per stratum) as instructed by the medical doctor and assign, in sequential order (from top to bottom) the next available randomised intervention.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Within each stratum, randomisation blocks were created.
An on-line number generator (http://graphpad.com/quickcalcs/RandMenu.cfm) was used to assign participants to one of two interventions (A or B) by a random order. This was repeated for each stratum.
Intervention A was designated as the ‘commence zoledronic acid treatment and continue tenofovir-containing ART’ arm, and B designated as the ‘switch from tenofovir to another potent antiretroviral drug’ arm.
The blocks will allow for even distribution of participants in each of the two arms within the 6 strata as the proportions within each stratum is unknown.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment outside Australia
Country [1] 9521 0
Spain
State/province [1] 9521 0
Barcelona

Funding & Sponsors
Funding source category [1] 285675 0
Government body
Name [1] 285675 0
National Health and Medical Research Council
Address [1] 285675 0
Level 1
16 Marcus Clarke Street
Canberra ACT 2601
Country [1] 285675 0
Australia
Primary sponsor type
Hospital
Name
St Vincents Hospital
Address
390 Victoria St
Darlinghurst
NSW 2010
Country
Australia
Secondary sponsor category [1] 284504 0
None
Name [1] 284504 0
Address [1] 284504 0
Country [1] 284504 0
Other collaborator category [1] 276955 0
Individual
Name [1] 276955 0
Professor Jennifer Hoy
Address [1] 276955 0
Infectious Diseases Unit
Level 2, Burnet Institute
The Alfred Hospital
85 Commercial Road
Melbourne VIC 3004
Country [1] 276955 0
Australia
Other collaborator category [2] 276956 0
Individual
Name [2] 276956 0
Professor Peter Ebeling
Address [2] 276956 0
Department of Medicine/ School of Clinical Sciences at Monash Health
Monash University
Level 5 / Block E,
Monash Medical Centre,
246 Clayton Road,
Clayton, VIC 3168
Australia
Country [2] 276956 0
Australia
Other collaborator category [3] 276957 0
Individual
Name [3] 276957 0
Professor Nicholas Pocock
Address [3] 276957 0
St Vincent's Clinic Nuclear Medicine, Level 5
438 Victoria St
Darlinghurst NSW 2010
Country [3] 276957 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 287662 0
St Vincents Hospital Sydney
Ethics committee address [1] 287662 0
St Vincent's Hospital
Delacy 15
Darlinghurst NSW 2010
Ethics committee country [1] 287662 0
Australia
Date submitted for ethics approval [1] 287662 0
Approval date [1] 287662 0
31/01/2012
Ethics approval number [1] 287662 0
HREC/11/SVH/201

Summary
Brief summary
The purpose of this study is to find out whether treatment with zoledronic acid or switching from tenofovir to another anti-HIV drug is more effective for improving low bone density over 24 months. These two options can improve low BMD in patients receiving tenofovir, but it is not yet known which one is the best as both strategies have their own advantages and disadvantages. Current evidence suggests that zoledronic acid may be better in terms of increasing bone density but it is not known for sure, hence the purpose of this study.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 34463 0
Prof Andrew Carr
Address 34463 0
St Vincents Hospital
Xavier, Level 4
390 Victoria St
Darlinghurst
NSW 2010
Country 34463 0
Australia
Phone 34463 0
+61 2 83823359
Fax 34463 0
Email 34463 0
andrew.carr@svha.org.au
Contact person for public queries
Name 17710 0
Ms Robyn Richardson
Address 17710 0
Clinical Research Program
C/- Immunology and Infectious Diseases Unit (IBAC)
Level 4, Xavier Building
St Vincent’s Hospital
390 Victoria Street
Darlinghurst NSW 2010
Country 17710 0
Australia
Phone 17710 0
+61 2 8382 3872
Fax 17710 0
+61 2 8382 3869
Email 17710 0
robyn.richardson@svha.org.au
Contact person for scientific queries
Name 8638 0
Prof Professor Andrew Carr
Address 8638 0
Clinical Research Program
C/- Immunology and Infectious Diseases Unit (IBAC)
Level 4, Xavier Building
St Vincent’s Hospital
390 Victoria Street
Darlinghurst NSW 2010
Country 8638 0
Australia
Phone 8638 0
+61 2 8382 3359
Fax 8638 0
+61 2 8382 3893
Email 8638 0
andrew.carr@svha.org.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary