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Comparing a Single-Dose vs. Twice Yearly Zoledronate in Patients With Early Stage Breast Cancer (REaCT-ZOL) (REaCT-ZOL)

Primary Purpose

Early-stage Breast Cancer

Status
Active
Phase
Phase 4
Locations
Canada
Study Type
Interventional
Intervention
Zoledronate
Sponsored by
Ottawa Hospital Research Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Early-stage Breast Cancer focused on measuring Adjuvant Zoledronate

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Commencing zoledronate within 3 months of starting neoadjuvant or adjuvant endocrine therapy or within 3 months of completion of neoadjuvant or adjuvant chemotherapy for early stage breast cancer
  • Patients receiving any intravenous or oral biphosphonates, or subcutaneous denosumab for the treatment of osteoporosis must discontinue treatment prior to baseline evaluation
  • ECOG performance status equal or less than 2 and life expectancy of more than 12 months
  • Serum creatinine greater than 30 ml/min and corrected serum calcium equal or greater than 2 mmol/l within 4 weeks before first zoledronate infusion
  • Age equal or greater than 18 years
  • Able to provide written consent

Exclusion Criteria:

  • Metastatic disease
  • History of osteonecrosis of the jaw
  • Known hypersensitivity to trial drug or hypersensitivity to any other component of the trial drug (e.g. fructose)
  • Any psychological, familial, sociological or geographical condition potentially hampering compliance with the trial protocol
  • Pregnancy or risk of pregnancy (this includes participants that are not willing to practice active contraception for the duration of the study)* *Women/men of child bearing potential must have agreed to use two effective contraceptive methods while on study. A women is considered to be of 'childbearing potential' if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods. 'effective contraception' also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as complete hysterectomy, bilateral oophorectomy or bilateral tubal ligation, or vasectomy/vasectomized partner. However, if at any point a previously celibate participant chooses to become heterosexually active during the period for use of contraceptive measures outlined in the protocol, she is responsible for beginning contraceptive measures. Examples of effective methods of contraception: Male condom plus spermicide; Cap plus spermicide; Diaphragm plus spermicide; intrauterine device (Copper T, Progesterone T; Levonorgestrel-releasing intrauterine system (i.e. Mirena); hormonal methods (implants, hormonal shot or injection, combined pill, minipill, patch).

Sites / Locations

  • Ottawa Hospital Research Institute

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Zoledronate one dose (4 mg)

Zoledronate 4 mg every 6 months x 3 years

Arm Description

One 4 mg dose of Zoledronate

One 4 mg dose of Zoledronate given every 6 months for 3 years

Outcomes

Primary Outcome Measures

Multiple Site Activation
Evaluating the feasibility of multiple site activation. Measured by the number of sites activated, as well as how long it takes to get the sites activated once the first site becomes active for accrual.
Time to Activate Six Sites
Evaluating the amount of time it takes to get six sites activated for participant accrual.
Medical Oncologist Active Participation
Evaluating the number of medical oncologists at each study site who actively participate in the trial. Active participation includes approaching eligible patients for the study, as well as following up with patients who are taking part in the study.
Patient Enrollment
Evaluating the number of patients enrolled across all of the active sites within 9 months of the sixth site being activated. Number of patients enrolled across all of the active sites.

Secondary Outcome Measures

Bone-Metastasis-Free Survival
Evaluate bone-metastasis-free Survival (Bone-DFS) defined as the time to first occurrence of bone metastasis (symptomatic or asymptomatic) or death from any cause.
Time to first bone metastasis
Evaluate the time to first bone metastasis (symptomatic or asymptomatic, excluding deaths). The time-to-disease will start from the randomization data and ends at occurrence of the event.
Fragility fractures rates
Evaluate fragility fracture rates. Fragility fractures rates; defined as fractures which result from a fall from a standing height or less, or that present in the absence of trauma (most common fragility fractures occur at the hip, wrist, spine, humerus or pelvis).
Direct Estimation of Health Utility Values
To evaluate patient quality of life using the EQ-5D-5L questionnaire, undertaken at the first Zoledronate treatment and either every year (Arm A) or every 6 months (Arm B) for 3 years. The EuroQol 5 Dimension 5 Level (EQ-5D-5L) questionnaire consists of two sections; the descriptive system and the visual analogue scale. The descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and has 5 levels associated with it (no problems, slight problems, moderate problems, severe problems and extreme problems). The scale range of 1-5 is used for the 5 dimensions where 1 is the best outcome and 5 is the worst outcome. The Visual Analogue scale records the respondent's self-rated health on a vertical, visual scale with endpoints labelled 'the best health you can imagine' at the top and 'the worst health you can imagine' at the bottom. This ranges 0-100 with 0 being the worst outcome and 100 being the best outcome.
Incremental Cost-Effectiveness Ratio
A statistic used in cost-effectiveness analysis to summarise the cost-effectiveness of a health care intervention. It is defined by the difference in cost between two possible interventions, divided by the difference in their effect.

Full Information

First Posted
September 6, 2018
Last Updated
May 10, 2023
Sponsor
Ottawa Hospital Research Institute
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1. Study Identification

Unique Protocol Identification Number
NCT03664687
Brief Title
Comparing a Single-Dose vs. Twice Yearly Zoledronate in Patients With Early Stage Breast Cancer (REaCT-ZOL)
Acronym
REaCT-ZOL
Official Title
A Randomised, Multicentre, Pragmatic Trial Comparing a Single-Dose vs. Twice Yearly Zoledronate in Patients With Early Stage Breast Cancer (REaCT-ZOL)
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
October 31, 2018 (Actual)
Primary Completion Date
April 2, 2020 (Actual)
Study Completion Date
December 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ottawa Hospital Research Institute

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
REaCT ZOL will compare one 4 mg dose of Zoledronate vs. one 4 mg dose of Zoledronate given every 6 months for 3 years.
Detailed Description
Breast cancer patients are at an increased risk of recurrence in bone and bone density loss (osteopenia/osteoporosis) and consequently fragility fractures due to: age, systemic therapy with aromatase inhibitors, and premature induction of menopause by chemotherapy or ovarian ablation. Bone is the most common site of breast cancer recurrence. The use of bone modifying agents, such as Zoledronate may reduce the risk of bone metastases and fragility fractures. Despite the widespread use of adjuvant Zoledronate, it is not known what the optimal number of infusions is to reduce the risk of bone metastases and the risk of fragility fractures. Indeed, the recent CCO and ASCO Practice Guideline, 'Bottom line recommendations' specifically states, "More research is recommended comparing different bone-modifying agents, doses, dosing intervals, and durations." In the metastatic setting, for nearly 2 decades biphosphonates (i.e. Zoledronate) have been given to patients every 3-4 weeks. This dosing interval was selected based on convenience of co-administration with standard anti-cancer agents and not on the long biological effect of these agents on osteoclasts, the cells responsible for excess bone breakdown. Furthermore, in the bone density preservation setting, despite the usual administration of Zoledronate once a year a single dose of Zoledronate was associated with a sustained increase in bone mineral density 5 years later. A recent systematic review in the adjuvant setting, showed that BTA at any particular dose or route of administration showed superiority over the other. In other words, the lowest dose appears to be just as good as the highest dose. This study will compare the single dose of Zoledronate to Zoledronate given every 6 months for 3 years. The primary outcome for this study will be feasibility of conducting this trial. The secondary outcome will assess bone-metastasis risk, fragility rates, quality of life, and cost-effectiveness. In this study it is hypothesized that a single dose of Zoledronate will be non-inferior to every 6 months in terms of bone-metastasis free survival, time to first bone metastasis and fragility fractures. It is also hypothesized that a single dose of Zoledronate will have less toxicities associated with Zoledronate compared to every 6 months.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Early-stage Breast Cancer
Keywords
Adjuvant Zoledronate

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
211 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Zoledronate one dose (4 mg)
Arm Type
Active Comparator
Arm Description
One 4 mg dose of Zoledronate
Arm Title
Zoledronate 4 mg every 6 months x 3 years
Arm Type
Active Comparator
Arm Description
One 4 mg dose of Zoledronate given every 6 months for 3 years
Intervention Type
Drug
Intervention Name(s)
Zoledronate
Other Intervention Name(s)
Zoledronic acid
Intervention Description
Administered intravenously (IV)
Primary Outcome Measure Information:
Title
Multiple Site Activation
Description
Evaluating the feasibility of multiple site activation. Measured by the number of sites activated, as well as how long it takes to get the sites activated once the first site becomes active for accrual.
Time Frame
12 months
Title
Time to Activate Six Sites
Description
Evaluating the amount of time it takes to get six sites activated for participant accrual.
Time Frame
12 months
Title
Medical Oncologist Active Participation
Description
Evaluating the number of medical oncologists at each study site who actively participate in the trial. Active participation includes approaching eligible patients for the study, as well as following up with patients who are taking part in the study.
Time Frame
Through to end of accrual, average 2 years
Title
Patient Enrollment
Description
Evaluating the number of patients enrolled across all of the active sites within 9 months of the sixth site being activated. Number of patients enrolled across all of the active sites.
Time Frame
9 months
Secondary Outcome Measure Information:
Title
Bone-Metastasis-Free Survival
Description
Evaluate bone-metastasis-free Survival (Bone-DFS) defined as the time to first occurrence of bone metastasis (symptomatic or asymptomatic) or death from any cause.
Time Frame
Through to end of study, average of 3 years
Title
Time to first bone metastasis
Description
Evaluate the time to first bone metastasis (symptomatic or asymptomatic, excluding deaths). The time-to-disease will start from the randomization data and ends at occurrence of the event.
Time Frame
Through to end of study, average of 3 years
Title
Fragility fractures rates
Description
Evaluate fragility fracture rates. Fragility fractures rates; defined as fractures which result from a fall from a standing height or less, or that present in the absence of trauma (most common fragility fractures occur at the hip, wrist, spine, humerus or pelvis).
Time Frame
Through to end of study, average of 3 years
Title
Direct Estimation of Health Utility Values
Description
To evaluate patient quality of life using the EQ-5D-5L questionnaire, undertaken at the first Zoledronate treatment and either every year (Arm A) or every 6 months (Arm B) for 3 years. The EuroQol 5 Dimension 5 Level (EQ-5D-5L) questionnaire consists of two sections; the descriptive system and the visual analogue scale. The descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and has 5 levels associated with it (no problems, slight problems, moderate problems, severe problems and extreme problems). The scale range of 1-5 is used for the 5 dimensions where 1 is the best outcome and 5 is the worst outcome. The Visual Analogue scale records the respondent's self-rated health on a vertical, visual scale with endpoints labelled 'the best health you can imagine' at the top and 'the worst health you can imagine' at the bottom. This ranges 0-100 with 0 being the worst outcome and 100 being the best outcome.
Time Frame
Through to end of study, average of 3 years
Title
Incremental Cost-Effectiveness Ratio
Description
A statistic used in cost-effectiveness analysis to summarise the cost-effectiveness of a health care intervention. It is defined by the difference in cost between two possible interventions, divided by the difference in their effect.
Time Frame
Through to study completion, an average of 3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Commencing zoledronate within 3 months of starting neoadjuvant or adjuvant endocrine therapy or within 3 months of completion of neoadjuvant or adjuvant chemotherapy for early stage breast cancer Patients receiving any intravenous or oral biphosphonates, or subcutaneous denosumab for the treatment of osteoporosis must discontinue treatment prior to baseline evaluation ECOG performance status equal or less than 2 and life expectancy of more than 12 months Serum creatinine greater than 30 ml/min and corrected serum calcium equal or greater than 2 mmol/l within 4 weeks before first zoledronate infusion Age equal or greater than 18 years Able to provide written consent Exclusion Criteria: Metastatic disease History of osteonecrosis of the jaw Known hypersensitivity to trial drug or hypersensitivity to any other component of the trial drug (e.g. fructose) Any psychological, familial, sociological or geographical condition potentially hampering compliance with the trial protocol Pregnancy or risk of pregnancy (this includes participants that are not willing to practice active contraception for the duration of the study)* *Women/men of child bearing potential must have agreed to use two effective contraceptive methods while on study. A women is considered to be of 'childbearing potential' if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods. 'effective contraception' also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as complete hysterectomy, bilateral oophorectomy or bilateral tubal ligation, or vasectomy/vasectomized partner. However, if at any point a previously celibate participant chooses to become heterosexually active during the period for use of contraceptive measures outlined in the protocol, she is responsible for beginning contraceptive measures. Examples of effective methods of contraception: Male condom plus spermicide; Cap plus spermicide; Diaphragm plus spermicide; intrauterine device (Copper T, Progesterone T; Levonorgestrel-releasing intrauterine system (i.e. Mirena); hormonal methods (implants, hormonal shot or injection, combined pill, minipill, patch).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mark Clemons, MD
Organizational Affiliation
Ottawa Hospital Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ottawa Hospital Research Institute
City
Ottawa
State/Province
Ontario
ZIP/Postal Code
K1H 8M2
Country
Canada

12. IPD Sharing Statement

Citations:
PubMed Identifier
33425673
Citation
Awan A, Ng T, Conter H, Raskin W, Stober C, Simos D, Pond G, Dhesy-Thind S, Mates M, Kumar V, Fergusson D, Hutton B, Saunders D, Vandermeer L, Clemons M; REaCT Investigators. Feasibility outcomes of a randomised, multicentre, pilot trial comparing standard 6-monthly dosing of adjuvant zoledronate with a single one-time dose in patients with early stage breast cancer. J Bone Oncol. 2020 Dec 13;26:100343. doi: 10.1016/j.jbo.2020.100343. eCollection 2021 Feb.
Results Reference
derived

Learn more about this trial

Comparing a Single-Dose vs. Twice Yearly Zoledronate in Patients With Early Stage Breast Cancer (REaCT-ZOL)

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