PRevEnting FracturEs in REnal Disease - 1 (PREFERRED-1)

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

PREFERRED-1 is a pilot study designed to determine the feasibility of a large randomized, pragmatic, open-label, comparative-effectiveness trial of denosumab for the prevention of fragility fractures in people receiving hemodialysis. The pilot study will enroll at least 60 patients from across 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.

Primary outcomes include recruitment feasibility and treatment adherence. Secondary outcomes include safety and participant satisfaction with our protocol and processes.

Study Overview

• Status: Active, not recruiting
• Conditions: Kidney Diseases; Chronic Kidney Disease-Mineral and Bone Disorder; Fragility Fracture; Dialysis; Complications
• Intervention / Treatment: Drug: Denosumab 60 mg/ml; Other: Calcium and vitamin D prophylaxis; Diagnostic test: Monitoring of post-injection calcium and phosphate

Detailed Description

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, whether this treatment effectively and safely prevents fragility fracture in this population still remains unclear.

Instead of conducting an expensive traditional RCT where results might fail to apply to the "real-world", the study will embed a trial of denosumab into routine care. The intervention will be delivered by healthcare staff. Participants will be closely followed at the dialysis unit where the participant has dialysis treatments. Baseline characteristics and outcomes will be captured using routine care data including administrative health data.

The overarching 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 goal is to understand if individual level recruitment is feasible and timely, and if the intervention is acceptable to patients.

The objectives of PREFERRED-1 are to:

1. Examine whether streamlined methods of enrollment can facilitate recruitment across multiple centres in a timely way;
2. Demonstrate good adherence with the trial protocol and examine whether well-received by participants;
3. Ensure that participants are adherent with treatment assignment (i.e., intervention group to denosumab, minimal cross-over to denosumab in usual group);
4. Confirm there are no 'signals' of unmanageable harm (i.e. hypocalcemia) that would prevent testing of our intervention on a larger scale.

PREFERRED-1 will be deemed a success if:

• The study 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 the 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

1. inform transformational change in the care of real-world patients;
2. produce essential knowledge to safely prevent fracture in patients with kidney disease, and the associated costs to the healthcare system;
3. foster the conduct of collaborative, multidisciplinary care for those with complex kidney disease.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Kingston, Ontario, Canada, K7L 2V7
      • Kingston Health Sciences Centre
    • London, Ontario, Canada
      • London Health Sciences Centre
    • Ottawa, Ontario, Canada, K1Y 4E9
      • The Ottawa Hospital
    • Stratford, Ontario, Canada, N5A 2Y6
      • Huron Perth Healthcare Alliance - Stratford General Hospital
    • Toronto, Ontario, Canada, M5B 1W8
      • St. Michaels Hospital
    • Woodstock, Ontario, Canada, N4V 0A4
      • Woodstock hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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).
• High risk of fragility fracture defined by: a) ≥15% 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),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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Usual care; 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.
Experimental: Intervention; 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; Details described in intervention arm/group description section.; Other Names: Prolia; Other: Calcium and vitamin D prophylaxis; Details described in intervention arm/group description section.; Diagnostic test: Monitoring of post-injection calcium and phosphate; Details described in intervention arm/group description section.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recruitment rate	Number or N (%) of participants randomly allocated within 26 weeks of trial initiation at each centre.	26 weeks
Adherence to study intervention	Number (%) of participants randomized to the intervention who received >90% of their scheduled treatments to study end.	15 months
Adherence to usual care	Number (%) of participants randomized to usual care who received no prescription for denosumab to study end.	15 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fragility fracture	N (%) with hospital encounter for fragility fracture of the hip, vertebrae, humerus, wrist, or pelvis at 15 months	15 months
Treatment-related hypocalcemia as assessed by CTCAE v4.0	N (%) with hypocalcemia and symptomatic hypocalcemia [graded according to common terminology criteria for adverse events v 4.0 criteria (Grade 2, albumin-corrected serum calcium 1.75 to 1.99 mmol/L, Grade 3, 1.5 to 1.74 mmol/L, Grade 4, serum calcium <1.5 mmol/L)] within 7 weeks of denosumab. Symptomatic hypocalcemia will be defined by a calcium <2.00 mmol/L in the presence of new muscle cramps or paresthesia.	within 7 weeks following denosumab injection
Mean change in serum calcium	Mean change in serum calcium from baseline to 7 weeks post injection	7 weeks following denosumab injection
Median change in serum calcium	Median change in serum calcium from baseline to 7 weeks post injection	7 weeks following denosumab injection
Mean change in parathyroid hormone	Mean change in parathyroid hormone from baseline to 7 weeks post injection	7 weeks following denosumab injection
Median change in parathyroid hormone	Median change in parathyroid hormone from baseline to 7 weeks post injection	7 weeks following denosumab injection
Satisfaction with E-Platform and E-Consent Process	Patient satisfaction with e-platform, and e-consent process. (Likert Scale with 1=not satisfied to 5=very satisfied)	15 months
Satisfaction with intervention	Patient satisfaction with intervention (Likert Scale with 1=not satisfied, 5=very satisfied)	15 months

Collaborators and Investigators

• Sponsor: Western University, Canada
• Collaborators: Western University; The Kidney Foundation of Canada; Academic Medical Organization of Southwestern Ontario; ICES
• Investigators: Principal Investigator: Kristin K Clemens, MD, MSc, St. Joseph's Health Care London

Study record dates

Study Major Dates

• Study Start (Actual): June 11, 2022
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: September 21, 2021
• First Submitted That Met QC Criteria: October 14, 2021
• First Posted (Actual): October 27, 2021

Study Record Updates

• Last Update Posted (Actual): May 31, 2025
• Last Update Submitted That Met QC Criteria: May 26, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: hemodialysis; Fracture; Pilot Study; denosumab
• Additional Relevant MeSH Terms: Urogenital Diseases; Endocrine System Diseases; Musculoskeletal Diseases; Wounds and Injuries; Pathologic Processes; Nutrition Disorders; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Chronic Disease; Disease Attributes; Metabolic Diseases; Renal Insufficiency; Bone Diseases, Metabolic; Parathyroid Diseases; Avitaminosis; Deficiency Diseases; Malnutrition; Rickets; Calcium Metabolism Disorders; Vitamin D Deficiency; Hyperparathyroidism, Secondary; Hyperparathyroidism; Fractures, Bone; Kidney Diseases; Renal Insufficiency, Chronic; Bone Diseases; Chronic Kidney Disease-Mineral and Bone Disorder; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Bone Density Conservation Agents; Micronutrients; Vitamins; Denosumab; Calcium, Dietary; Calcium; Vitamin D
• Other Study ID Numbers: 3638

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No