PRevEnting FracturEs in REnal Disease 1

Kidney Diseases Clinical Trial

— PREFERRED-1  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05096195
• Other study ID #: 3638
• Status: Recruiting
• Phase: Phase 4
• Start date: June 11, 2022
• Est. completion date: December 2025

Study information

• Verified date: May 2024
• Source: Western University, Canada
• Contact: Jennifer Arnold
• Phone: 519-685-8500
• Email: Preferred1[@]sjhc.london.on.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

PREFERRED-1 is a pilot study for a large randomized, pragmatic, open-label, comparative-effectiveness trial. The pilot study 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

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. The 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:

1. Prove that the streamlined methods of enrollment will facilitate patient recruitment across multiple centres in a timely way;

2. Demonstrate there is good adherence to the trial protocol and that the trial protocol was well-received by patients;

3. Ensure that participants are adherent with treatment assignment (i.e., intervention group to denosumab, minimal cross-over to denosumab in non-use group);

4. 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:

• 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: December 2025
• Est. primary completion date: December 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Bone Diseases
• Chronic Kidney Disease-Mineral and Bone Disorder
• Dialysis; Complications
• Fractures, Bone
• Fragility Fracture
• Kidney Diseases
• Renal Insufficiency, Chronic

Intervention

Drug:
• Denosumab 60 mg/ml
Details described in intervention arm/group description section.

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.

Locations

Country	Name	City	State
Canada	Kingston Health Sciences Centre	Kingston	Ontario
Canada	London Health Sciences Centre	London	Ontario
Canada	The Ottawa Hospital	Ottawa	Ontario
Canada	Huron Perth Healthcare Alliance - Stratford General Hospital	Stratford	Ontario
Canada	St. Michaels Hospital	Toronto	Ontario
Canada	Woodstock Hospital	Woodstock	Ontario

Sponsors (5)

Lead Sponsor	Collaborator
Western University, Canada	Academic Medical Organization of Southwestern Ontario, ICES, The Kidney Foundation of Canada, Western University

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Recruitment rate	Number or N (%) participants recruited within 4 months of trial initiation at each centre	4 months
Primary	Adherence to study intervention	N(%) participants randomized to the intervention receive >90% of their scheduled denosumab injections	15 months
Primary	Adherence to usual care	N(%) participants randomized to usual care who do not receive a prescription for denosumab	15 months
Secondary	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
Secondary	Mean change in serum calcium	Mean (standard deviation), change in corrected serum calcium between baseline and last followup	4 weeks following denosumab injection
Secondary	Median change in serum calcium	Median (interquartile range, IQR), change in corrected serum calcium between baseline and last followup	4 weeks following denosumab injection
Secondary	Mean change in parathyroid hormone	Mean (standard deviation) change in parathyroid hormone between baseline and last followup	4 weeks following denosumab injection
Secondary	Median change in parathyroid hormone	Median (IQR) change in parathyroid hormone between baseline and last followup	4 weeks following denosumab injection
Secondary	Fragility fracture	N (%) with hospital encounter for fragility fracture of the hip, vertebrae, humerus, wrist, or pelvis at 15 months	15 months
Secondary	Participant satisfaction with E-Platform	Mean (SD) Likert scale score (1=not satisfied, 5=very satisfied)	15 months
Secondary	Participant satisfaction with E-Consent	Mean (SD) Likert scale score (1=not satisfied, 5=very satisfied)	15 months
Secondary	Participant satisfaction with intervention	Mean (SD) Likert scale score in those randomized to intervention (1=not satisfied, 5=very satisfied)	15 months