PRevEnting FracturEs in REnal Disease 1

Study Overview
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Brief Summary
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PREFERRED-1 is a pilot study for a large randomized, pragmatic, open-label, comparative-effectiveness trial. The pilot will enroll at least 60 patients from at least 6 different hemodialysis centres in Ontario, Canada. Patients on outpatient maintenance hemodialysis at high risk of fragility fracture, will be randomized 1:1 to a denosumab care pathway vs. usual care

Detailed Description
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Despite a fragility fracture risk that is >5-fold higher than those without chronic kidney disease (CKD), there is a lack of evidence on how to prevent fracture in patients on hemodialysis. Medications known to prevent fragility fracture in other populations, are either contraindicated in dialysis, or associated with severe side effects. Denosumab (Prolia) is one of the only Health Canada approved medications for fragility fracture prevention across the CKD stages. While small clinical trials inclusive of hemodialysis patients have noted that denosumab improves bone mineral density and reduces bone turnover, it remains unclear if this treatment effectively and safely prevents fragility fracture in this population. Instead of conducting an expensive traditional RCT where results might fail to apply to the real-world, we will embed a trial of denosumab into routine care. Our intervention will be delivered by healthcare staff, participants will be closely followed in their home dialysis unit, and baseline characteristics and outcomes will be captured using repurposed data held at ICES. The overall aim of the PREFERRED Program is to determine whether a denosumab care pathway vs. usual care (i.e., non-use of denosumab) alters the risk of fragility fracture in patients receiving in-centre hemodialysis. PREFERRED-1 is a pilot study that will inform the feasibility of conducting a large-scale, efficiently run, randomized-controlled trial in Canada to test whether denosumab reduces the risk of fragility fracture in patients receiving hemodialysis. The objectives of PREFERRED-1 are to: Prove that our streamlined methods of enrollment will facilitate patient recruitment across multiple centres in a timely way; Demonstrate there is good adherence to the trial protocol and that it was well-received by patients; Ensure that participants are adherent with treatment assignment (i.e., intervention group to denosumab, minimal cross-over to denosumab in non-use group); Confirm there are no 'signals' of unmanageable harm (i.e. hypocalcemia) that would prevent testing of this intervention on a larger scale. PREFERRED-1 will be deemed a success if: We can randomly allocate at least 60 patients from at least 6 hemodialysis centres within 6-months of the trial being activated at each centre. Demonstrate that patients randomly allocated to denosumab receive over 90% of their scheduled injections at 0, 6 and 12 months Patients randomly allocated to no denosumab (i.e. usual care) do not receive a prescription for denosumab. This high-risk innovative pragmatically approached trial focused on better treatments for fracture prevention in those with kidney disease will inform transformational change in the care of real-world patients; produce essential knowledge to safely prevent fracture in patients with kidney disease, and their associated costs to our healthcare system; foster the conduct of collaborative, multidisciplinary care for those with complex kidney disease.

Official Title
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Denosumab for the Prevention of Fragility Fractures in Hemodialysis: a Pilot Study for an Innovative, Randomized-controlled Trial, Embedded in Routine Care

Conditions
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Kidney Diseases, Dialysis; Complications, Fragility Fracture, Chronic Kidney Disease-Mineral and Bone Disorder

Intervention / Treatment
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* Drug: Denosumab 60 mg/ml
* Other: Calcium and vitamin D prophylaxis
* Diagnostic Test: Monitoring of post-injection calcium and phosphate


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Treating nephrologist/nurse practitioner in the dialysis unit deems that a prescription for study drug (denosumab) will be safe/reasonable in the potential participant. Age ≥40 years Access to denosumab through provincial drug benefits (i.e. evidence of receiving outpatient prescription medications through the Ontario Drug Benefits Program, Ontario Disability Support Program) Baseline albumin-corrected serum calcium ≥2.15 mmol/L, PTH ≥15 pmol/L (or 2-9x the upper limit of normal for the local laboratory), alkaline phosphatase (ALP) ≥80 IU/L. High risk of fragility fracture defined by: a) >20% 10-year risk of major osteoporotic fracture or >3% 10-year risk of hip fracture (using the World Health Organization's Fracture Risk Assessment Tool which is validated in hemodialysis), 41,42 OR b) a prior history of hip or vertebral fracture (where the later could have been asymptomatic and only observed radiographically), OR c) two or more fragility fractures of the humerus, wrist, and/or pelvis (e.g. 2 humerus fractures, humerus and wrist fracture).43 Exclusion criteria: Expected to recover kidney function, stop hemodialysis, pursue palliative care, or transfer to home or peritoneal dialysis within 12 months (as assessed by a health professional). Expected to start IV bisphosphonates (i.e. pamidronate or zoledronic acid). Current use of cinacalcet (Sensipar). Current use of an osteoporosis medication including: Denosumab Bisphosphonates Alendronate (Fosavance or Fosamax) Risedronate (Actonel or Actonel DR) Zoledronic acid (Aclasta) or Pamidronate Raloxifene (Evista) Oral or conjugated estrogen Topical, oral or injectable testosterone (Androgel, Testim, Fortesta, Androderm, testosterone enanthate and testosterone cypionate) Teriperatide (Forteo) Romosozumab (Evenity) Calcitonin (Calcimar) Of childbearing status History of femur fracture attributed to osteoporosis medication use (i.e. midshaft femoral fracture or atypical femoral fracture) Major dental surgery planned within the next 6 months (e.g. root canal). Known allergy or intolerance to denosumab. Expected to receive a parathyroidectomy for hyperparathyroidism in the next 12 months

Ages Eligible for Study
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Minimum Age: 40 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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>60 mg of denosumab (Prolia) will be administered every 6 months over a 15 - month period. Monitoring of serum calcium and phosphate will occur and bloodwork will be drawn for 7 weeks following each denosumab injection. Correction of vitamin D deficiency (if required), the adjustment of calcium dialysate and the provision of intravenous (IV) or oral (po) calcitriol/calcidiol will be administered as needed following each denosumab injection as described in the Beside Protocol. Once the study monitoring period is over, serum calcium monitoring and management will occur as per routine care in the dialysis centre. All intervention activities will occur during regularly scheduled hemodyalisis sessions. | Drug: Denosumab 60 mg/ml<br>* Details described in intervention arm/group description section.<br>* Other names: Prolia;Other: Calcium and vitamin D prophylaxis<br>* Details described in intervention arm/group description section.<br>Diagnostic Test: Monitoring of post-injection calcium and phosphate<br>* Details described in intervention arm/group description section.<br>|
| No Intervention: Usual care<br>Usual care participants will continue to receive the typical standard of care in their dialysis unit which includes their routine dialysis monitoring and bloodwork. They will not receive denosumab, calcium and vitamin prophylaxis. There will be no extra monitoring or bloodwork. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recruitment rate | Number or N (%) participants recruited within 4 months of trial initiation at each centre | 4 months | 
| Adherence to study intervention | N(%) participants randomized to the intervention receive >90% of their scheduled denosumab injections | 15 months | 
| Adherence to usual care | N(%) participants randomized to usual care who do not receive a prescription for denosumab | 15 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-related hypocalcemia as assessed by CTCAE v4.0 | N(%) with Grade 2: albumin-adjusted serum calcium < 2.00 to 1.75 mmol/L; Grade 3 albumin-adjusted serum calcium < 1.75 to 1.5 mmol/L; Grade 4: albumin-adjusted serum calcium < 1.5 mmol/L at 1, 2, 3 and 4 weeks following denosumab injection. | 4 weeks following denosumab injection | 
| Mean change in serum calcium | Mean (standard deviation), change in corrected serum calcium between baseline and last followup | 4 weeks following denosumab injection | 
| Median change in serum calcium | Median (interquartile range, IQR), change in corrected serum calcium between baseline and last followup | 4 weeks following denosumab injection | 
| Mean change in parathyroid hormone | Mean (standard deviation) change in parathyroid hormone between baseline and last followup | 4 weeks following denosumab injection | 
| Median change in parathyroid hormone | Median (IQR) change in parathyroid hormone between baseline and last followup | 4 weeks following denosumab injection | 
| Fragility fracture | N (%) with hospital encounter for fragility fracture of the hip, vertebrae, humerus, wrist, or pelvis at 15 months | 15 months | 
| Participant satisfaction with E-Platform | Mean (SD) Likert scale score (1=not satisfied, 5=very satisfied) | 15 months | 
| Participant satisfaction with E-Consent | Mean (SD) Likert scale score (1=not satisfied, 5=very satisfied) | 15 months | 
| Participant satisfaction with intervention | Mean (SD) Likert scale score in those randomized to intervention (1=not satisfied, 5=very satisfied) | 15 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pilot Study, Fracture, denosumab, hemodialysis, registries