Better Evidence and Translation for Calciphylaxis

Study Overview
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Brief Summary
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This global platform study will evaluate multiple interventions, across several domains of therapeutic care, in adult patients with kidney failure and newly diagnosed calciphylaxis.

Detailed Description
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BEAT-Calci is a randomized, adaptive, multi-center, platform trial that will evaluate multiple interventions, across several domains of therapeutic care. The objective of the study is to establish high-quality evidence on the effect of a range of interventions in patients with kidney failure and newly diagnosed calciphylaxis. Calciphylaxis is a rare disease affecting 1-2 people in 10,000. The trial will commence with a Dialysis Membrane Domain and Pharmacotherapy Domain. The Pharmacotherapy Domain of BEAT-Calci is a placebo-controlled, double blind, response adaptive, randomised controlled trial that will investigate whether any of the pharmacotherapeutic agents is superior to placebo in improving outcomes. The Dialysis Membrane Domain of BEAT-Calci is an open-label, randomised controlled two-way comparison between two different dialysis technologies. The BEAT-Calci Wound Assessment Scale (BCWAS) is the primary endpoint for the trial. It is an 8-point ordinal categorical scale of disease outcomes and will be used to determine each participant's outcome. The trial will utilise a Bayesian adaptive sample size re-estimation approach for sample size calculations. The trial will continue to recruit until predefined superiority or futility rules are met. As the trial progresses, in response to information accumulating during the trial, there are various adaptations that can occur, including addition or removal of an intervention arm, response adaptive randomisation and addition of new therapeutic domains.

Official Title
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Better Evidence and Translation for Calciphylaxis

Conditions
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Calciphylaxis

Intervention / Treatment
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* Drug: Vitamin K1
* Drug: Magnesium citrate
* Drug: Sodium Thiosulfate
* Device: High Flux Dialyser
* Device: Medium Cut-off Dialyser
* Drug: Placebo injection (normal saline)
* Drug: Placebo capsule (Vitamin K1)
* Drug: Placebo tablet (Magnesium citrate)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Currently receiving haemodialysis, or peritoneal dialysis that can be converted to haemodialysis, with planned ongoing haemodialysis a minimum of three times per week for at least the duration of the protocolised calciphylaxis treatments within this trial Have a new calciphylaxis ulcer present for less than 10 weeks Age ≥ 18 years Eligible for randomisation in at least one recruiting domain The participant and treating physician are willing and able to perform trial procedures Exclusion Criteria: Nil

Ages Eligible for Study
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Minimum Age: 18 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: Sequential Assignment
Interventional Model Description: Adaptive, platform, randomized controlled trial, involving multiple interventions spanning several domains of therapeutic care.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo (Double-Blind Period)<br>Placebo Vitamin K1 Placebo Magnesium Citrate Placebo Sodium Thiosulphate | Drug: Placebo injection (normal saline)<br>* Placebo to be administered intravenously 3 times per week, during the subject's last hour of hemodialysis.<br>* Other names: 0.9% sodium chloride solution;Drug: Placebo capsule (Vitamin K1)<br>* Placebo to be administered 3 times per week following the subject's hemodialysis session.<br>* Other names: Matching placebo capsule;Drug: Placebo tablet (Magnesium citrate)<br>* Placebo to be administered 3 times per day. On dialysis days, administration of the middle daily dose should occur following the subject's hemodialysis session.<br>* Other names: Matching placebo tablet;|
| Experimental: Vitamin K1 (Double-Blind Period)<br>Dose: 10mg Vitamin K1 capsules, administered 3 times per week following the subject's hemodialysis session. Placebo Magnesium Citrate Placebo Sodium Thiosulphate | Drug: Vitamin K1<br>* Vitamin K1 capsule (10mg) to be administered 3 times per week following the subject's hemodialysis session.<br>* Other names: Phytonadione;Drug: Placebo injection (normal saline)<br>* Placebo to be administered intravenously 3 times per week, during the subject's last hour of hemodialysis.<br>* Other names: 0.9% sodium chloride solution;Drug: Placebo tablet (Magnesium citrate)<br>* Placebo to be administered 3 times per day. On dialysis days, administration of the middle daily dose should occur following the subject's hemodialysis session.<br>* Other names: Matching placebo tablet;|
| Experimental: Magnesium Citrate (Double-Blind Period)<br>Dose: 150mg Magnesium Citrate tablets, administered 3 times per day. On dialysis days, administration of the middle daily dose should occur following the subject's hemodialysis session. Placebo Vitamin K1 Placebo Sodium Thiosulphate | Drug: Magnesium citrate<br>* Magnesium Citrate tablet (150mg) to be administered 3 times per per day. On dialysis days, administration of the middle daily dose should occur following the subject's hemodialysis session.<br>Drug: Placebo injection (normal saline)<br>* Placebo to be administered intravenously 3 times per week, during the subject's last hour of hemodialysis.<br>* Other names: 0.9% sodium chloride solution;Drug: Placebo capsule (Vitamin K1)<br>* Placebo to be administered 3 times per week following the subject's hemodialysis session.<br>* Other names: Matching placebo capsule;|
| Experimental: Sodium Thiosulfate (Double-Blind Period)<br>Dose: 25g Sodium Thiosulfate injection, administered intravenously 3 times per week, during the subject's last hour of hemodialysis. Placebo Vitamin K1 Placebo Magnesium Citrate | Drug: Sodium Thiosulfate<br>* Sodium Thiosulfate injection (25g/100ml) to be administered intravenously 3 times per week, during the subject's last hour of hemodialysis.<br>* Other names: Intravenous Sodium Thiosulfate Injection;Drug: Placebo capsule (Vitamin K1)<br>* Placebo to be administered 3 times per week following the subject's hemodialysis session.<br>* Other names: Matching placebo capsule;Drug: Placebo tablet (Magnesium citrate)<br>* Placebo to be administered 3 times per day. On dialysis days, administration of the middle daily dose should occur following the subject's hemodialysis session.<br>* Other names: Matching placebo tablet;|
| Active Comparator: High Flux Hemodialysis<br>Hemodialysis using a high flux dialyser | Device: High Flux Dialyser<br>* Hemodialysis using a high flux dialyser.<br>* Other names: High Flux Hemodialysis;|
| Experimental: Medium Cut-off Hemodialysis<br>Hemodialysis using a medium cut-off dialyser | Device: Medium Cut-off Dialyser<br>* Hemodialysis using a medium cut-off dialyser.<br>* Other names: Medium Cut-off Hemodialysis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BEAT-Calci Wound Assessment Scale (BCWAS) - Baseline to Week 12 | To determine whether addition of the intervention changes the sentinel ulcer from Baseline to Week 12 on the BEAT-Calci Wound Assessment Scale. This is an 8-point ordinal categorical scale of change since baseline, which will be used to determine each participant's outcome. The scale is described as: Complete epithelialisation of the sentinel ulcer >50% reduction in sentinel ulcer surface area 20-50% reduction in sentinel ulcer surface area 0-20% reduction in sentinel ulcer surface area Any increase in sentinel ulcer surface area Development of new ulcers Amputation due to an ulcer All-cause death | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BEAT-Calci Wound Assessment Scale - Baseline to Week 26 | To determine whether addition of the intervention changes the sentinel ulcer from Baseline to Week 26 on the BEAT-Calci Wound Assessment Scale. This is an 8-point ordinal categorical scale of change since baseline, which will be used to determine each participant's outcome. The scale is described as: Complete epithelialisation of the sentinel ulcer >50% reduction in sentinel ulcer surface area 20-50% reduction in sentinel ulcer surface area 0-20% reduction in sentinel ulcer surface area Any increase in sentinel ulcer surface area Development of new ulcers Amputation due to an ulcer All-cause death | Week 26 | 
| Distribution of each of the individual components of the BCWAS, assessed at Weeks 4 | To determine whether addition of the intervention changes the distribution of each of the individual components of the BEAT-Calci Wound Assessment Scale, assessed at Weeks 4 Scale described as: Complete epithelialisation of the sentinel ulcer >50% reduction in sentinel ulcer surface area 20-50% reduction in sentinel ulcer surface area 0-20% reduction in sentinel ulcer surface area Any increase in sentinel ulcer surface area Development of new ulcers Amputation due to an ulcer All-cause death | Week 4 | 
| Distribution of each of the individual components of the BCWAS, assessed at Week 12 | To determine whether addition of the intervention changes the distribution of each of the individual components of the BEAT-Calci Wound Assessment Scale, assessed at Week 12 Scale described as: Complete epithelialisation of the sentinel ulcer >50% reduction in sentinel ulcer surface area 20-50% reduction in sentinel ulcer surface area 0-20% reduction in sentinel ulcer surface area Any increase in sentinel ulcer surface area Development of new ulcers Amputation due to an ulcer All-cause death | Week 12 | 
| Distribution of each of the individual components of the BCWAS, assessed at Week 26 | To determine whether addition of the intervention changes the distribution of each of the individual components of the BEAT-Calci Wound Assessment Scale, assessed at Week 26. Scale described as: Complete epithelialisation of the sentinel ulcer >50% reduction in sentinel ulcer surface area 20-50% reduction in sentinel ulcer surface area 0-20% reduction in sentinel ulcer surface area Any increase in sentinel ulcer surface area Development of new ulcers Amputation due to an ulcer All-cause death | Week 26 | 
| Bates-Jensen Wound Assessment Tool - from Baseline to Week 4 | To determine whether addition of the intervention changes the severity of sentinel ulcer from Baseline, assessed at Week 4 using the Bates-Jensen Wound Assessment Tool | Week 4 | 
| Bates-Jensen Wound Assessment Tool - from Baseline to Week 12 | To determine whether addition of the intervention changes the severity of sentinel ulcer from Baseline, assessed at Week 12, using the Bates-Jensen Wound Assessment Tool | Week 12 | 
| Bates-Jensen Wound Assessment Tool - from Baseline to Week 26 | To determine whether addition of the intervention changes the severity of sentinel ulcer from Baseline, assessed at Week 26, using the Bates-Jensen Wound Assessment Tool | Week 26 | 
| Sentinel ulcer surface area - from Baseline, assessed at Week 4 | To determine whether addition of the intervention changes the surface area of sentinel ulcer from Baseline, assessed at Week 4 | Week 4 | 
| Sentinel ulcer surface area - from Baseline, assessed at Week 12 | To determine whether addition of the intervention changes the surface area of sentinel ulcer from Baseline, assessed at Week 12 | Week 12 | 
| Sentinel ulcer surface area - from Baseline, assessed at Week 26 | To determine whether addition of the intervention changes the surface area of sentinel ulcer from Baseline, assessed at Week 26 | Week 26 | 
| All ulcers total surface area - from Baseline, assessed at Week 4 | To determine whether addition of the intervention changes the total surface area of all ulcers (not only the sentinel ulcer) from Baseline, assessed at Week 4 | Week 4 | 
| All ulcers total surface area - from Baseline, assessed at Week 12 | To determine whether addition of the intervention changes the total surface area of all ulcers (not only the sentinel ulcer) from Baseline, assessed at Week 12 | Week 12 | 
| All ulcers total surface area - from Baseline, assessed at Week 26 | To determine whether addition of the intervention changes the total surface area of all ulcers (not only the sentinel ulcer) from Baseline, assessed at Week 26 | Week 26 | 
| Change over time of self-reported pain | To determine whether addition of the intervention changes self-reported pain over time, assessed using the 0-to-10 Numerical Rating Scale | Week 26 | 
| Self-reported pain at week 12 | To determine whether addition of the intervention changes self-reported pain use at week 12 assessed using the 0-to-10 Numerical Rating Scale | Week 12 | 
| Change over time of analgesic use | To determine whether addition of the intervention changes analgesic use over time, as measured by cumulative weighted analgesia dose from baseline to week 26 | Week 26 | 
| Analgesic use week 12 | To determine whether addition of the intervention changes analgesic use over time, as measured by cumulative weighted analgesia dose from baseline to week 12 | Week 12 | 
| Composite self-reported pain and analgesic use over time | To determine whether addition of the intervention changes the composite outcome of self-reported pain (assessed using the 0-to-10 Numerical Rating Scale) and analgesic use over time | Week 26 | 
| Composite self-reported pain and analgesic use at week 12 | To determine whether addition of the intervention changes the composite outcome of self-reported pain (assessed using the 0-to-10 Numerical Rating Scale) and analgesic use at week 12 | Week 12 | 
| Change in self-reported quality of life from Baseline to Week 4 | To determine whether addition of the intervention changes self-reported quality of life from Baseline, assessed at Week 4, using the EuroQoL EQ-5D-5L instrument | Week 4 | 
| Change in self-reported quality of life from Baseline to Week 12 | To determine whether addition of the intervention changes self-reported quality of life from Baseline, assessed at Week 12, using the EuroQoL EQ-5D-5L instrument | Week 12 | 
| Change in self-reported quality of life from Baseline to Week 26 | To determine whether addition of the intervention changes self-reported quality of life from Baseline, assessed at Week 26 using the EuroQoL EQ-5D-5L instrument | Week 26 | 
| Time to first calciphylaxis-attributable infection from Baseline to Week 26 | Time in days to first calciphylaxis-attributable infection within 26 weeks post-randomisation | Week 26 | 
| All-cause hospitalisation days | Count of all cause hospitalisation days (excluding day admissions for dialysis treatment within 26 weeks post-randomisation | Weeks 0-26 | 
| Mortality | Incidence of mortality, as derived from hospital reports, within 5-years post-randomisation | Up to 5 years | 
| Kidney Transplantation | Incidence of kidney transplantation, as derived from hospital reports, within 5-years post-randomisation | Up to 5 years | 
| Calciphylaxis recurrence | Incidence of calciphylaxis recurrence as derived from hospital reports, within 5-years post-randomisation | Up to 5 years |