Clinical trial NCT05096195: PRevEnting FracturEs in REnal Disease - 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Kidney Diseases
Dialysis; Complications
Fragility Fracture
Chronic Kidney Disease-Mineral and Bone Disorder
Keywords: Pilot Study
Fracture
denosumab
hemodialysis
Lead sponsor: Western University, Canada
Sponsor class: OTHER
Collaborators: name: ICES
name: Academic Medical Organization of Southwestern Ontario
name: Western University
name: The Kidney Foundation of Canada
First posted: 2021-10-27
Enrollment: 60
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Recruitment rate
timeFrame: 26 weeks
measure: Adherence to study intervention
timeFrame: 15 months
measure: Adherence to usual care
timeFrame: 15 months
Secondary outcomes:
measure: Treatment-related hypocalcemia as assessed by CTCAE v4.0
timeFrame: within 7 weeks following denosumab injection
measure: Mean change in serum calcium
timeFrame: 7 weeks following denosumab injection
measure: Median change in serum calcium
timeFrame: 7 weeks following denosumab injection
measure: Mean change in parathyroid hormone
timeFrame: 7 weeks following denosumab injection
measure: Median change in parathyroid hormone
timeFrame: 7 weeks following denosumab injection
measure: Fragility fracture
timeFrame: 15 months
measure: Satisfaction with E-Platform and E-Consent Process
timeFrame: 15 months
measure: Satisfaction with intervention
timeFrame: 15 months
Other outcomes:
Locations:
city: Kingston
country: Canada
facility: Kingston Health Sciences Centre
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital
state: Ontario
city: Stratford
country: Canada
facility: Huron Perth Healthcare Alliance - Stratford General Hospital
state: Ontario
city: Toronto
country: Canada
facility: St. Michaels Hospital
state: Ontario
city: Woodstock
country: Canada
facility: Woodstock Hospital
state: Ontario
Study officials:
affiliation: St. Joseph's Health Care London
name: Kristin K Clemens, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References: