4-weekly Versus 12-weekly Administration of Bone-targeted Agents in Patients With Bone Metastases

Study Overview
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Brief Summary
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The current Rethinking Clinical Trials (REaCT) trial will compare two schedules(12- vs. 4-weekly) of bone-targeting agents (BTAs) to evaluate quality of life, pain and skeletal events within the Canadian Health Care System. This study will use an integrated consent model that involves oral consent rather than a written informed consent writing process as the study is comparing standard schedules and not a new administration schedule.

Detailed Description
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Bone metastases are common in patients with advanced breast and prostate cancers. Skeletal metastases can be associated with reduced Quality of Life (QoL), pain and skeletal-related events (SREs) (defined as pathological fractures, surgery/radiotherapy to bone, spinal cord compression and hypercalcaemia). Maintaining QoL while avoiding or delaying SREs are the main goals of therapy. Patients therefore receive bone-targeted agents (e.g. pamidronate, zoledronate and denosumab) which are typically given every 4 weeks. However, this 4 week dosing is based on convenience so the treatment could be given concurrently with chemotherapy. The half-life of these drugs in the bone is many months or even years. Hence studies have been performed evaluating 12-weekly therapy. These have confirmed similar palliative outcomes in the 4 vs 12-weekly groups for both breast and prostate cancer patients. However, there remains clinical equipoise about which dosing interval physicians prescribe. The current trial will compare these two schedules of bone-targeting agents (12- vs. 4-weekly) to evaluate quality of life, pain and skeletal events within the Canadian Health Care System. This study will use an integrated consent model that involves oral consent rather than a written informed consent writing process as the study is comparing standard schedules and not a new administration schedule.

Official Title
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A Pragmatic Randomised, Multicentre Trial Comparing 4-weekly Versus 12-weekly Administration of Bone-targeted Agents in Patients With Bone Metastases From Either Castration-resistant Prostate Cancer or Breast Cancer - The REaCT-BTA Study

Conditions
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Breast Cancer, Prostate Cancer, Metastasis

Intervention / Treatment
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* Drug: Pamidronate
* Drug: Denosumab
* Drug: Zoledronate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with either radiologically and/or histologically confirmed bone metastases from castrate resistant prostate cancer (36) or breast cancer. About to start or currently receiving BTA therapy. Serum creatinine >30 ml/min and corrected serum calcium ≥ 2 mmol/l Age ≥ 18 years. Able to provide verbal consent Exclusion Criteria: For CRPC patients - Definite contraindication for denosumab at baseline (e.g. hypocalcaemia [Albumin-corrected serum calcium < 2.0 mmol/l]). History of or current evidence of osteonecrosis of the jaw. Radiotherapy or surgery to the bone planned within 4 weeks after randomization. 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.

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 4 weekly bone-targeted agent x 1 year<br>Bone targeting agents as standard of care | Drug: Pamidronate<br>* Bone-targeted agent as standard of care<br>* Other names: Aredia;Drug: Denosumab<br>* Bone-targeted agent as standard of care<br>* Other names: Prolia;Drug: Zoledronate<br>* Bone-targeted agent as standard of care<br>* Other names: Zometa;|
| Active Comparator: 12 weekly bone-targeted agent x 1 year<br>Bone targeting agents as standard of care | Drug: Pamidronate<br>* Bone-targeted agent as standard of care<br>* Other names: Aredia;Drug: Denosumab<br>* Bone-targeted agent as standard of care<br>* Other names: Prolia;Drug: Zoledronate<br>* Bone-targeted agent as standard of care<br>* Other names: Zometa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Health related quality of life scores measured with European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Functional Domain (Physical Subdomain) | Units on a scale | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain will be measured through the EORTC-Quality of Life Questionnaire (QLQ)-BM22 (pain domain) | Units on a scale | 1 year | 
| Health related quality of life scores | Units on a scale | 1 year | 
| Time to development of symptomatic skeletal events (SSEs) | SSEs defined from the date of randomization until the first date a patient experiences an SSE (an on-study SSE is defined as: use of radiotherapy to relieve skeletal symptoms, new symptomatic pathological bone fractures (vertebral or non-vertebral), spinal cord compression, tumour related orthopedic surgical intervention, hypercalcaemia). Any patient who does not experience a SSE will be censored on the last date the patient can be confirmed as SSE-free. Multiple measurements will be aggregated to arrive at one reported value. | 2 year | 
| Total number of and time to subsequent on study SSE - to calculate Skeletal Morbidity Rates | Multiple measurements will be aggregated to arrive at one reported value. | 2 year | 
| For sites where Edmonton Symptom Assessment Scores (ESAS) are performed as standard of care, the ESAS scores will also be collected. | Units on a scale | 2 year | 
| Adverse events/ toxicity profiles will be compared between the two different approaches. |  | 2 year | 
| An economic analysis on Health Services Issues | We will perform a cost utility analysis alongside this pragmatic randomized controlled trial. The cost effectiveness of 4-week compared to 12-week BTA will be assessed in terms of the incremental cost per quality adjusted life year (QALY) gained from the perspective of health care system. Resource use and health utility will be measured from the trial at the follow up interviews. Health utility values would be estimated from the study questionnaires. | 1 year |