BEAT-Calci: Better Evidence and Translation for Calciphylaxis

Sponsor

University of Sydney (Other)

Overall Status

Recruiting

CT.gov ID

NCT05018221

Collaborator

Australasian Kidney Trials Network (Other), Northern Care Alliance NHS Foundation Trust (Other), Waitemata District Health Board (Other)

350

Enrollment

Locations

Arms

63.2

Anticipated Duration (Months)

18.4

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Calciphylaxis	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)	Phase 3

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

350 participants

Allocation:

Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

Adaptive, platform, randomized controlled trial, involving multiple interventions spanning several domains of therapeutic care.Adaptive, platform, randomized controlled trial, involving multiple interventions spanning several domains of therapeutic care.

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

Blinding of all parties will not be possible for all domains. The default position of the BEAT-Calci platform is that treatments determined by randomization will be blinded to as high a level is feasible. Within practical domains, a blind will be adopted, whereby participants, site personnel, trial investigators and outcome assessors will remain blinded to the treatment from the time of randomization until database lock of the comparisons to which that participant is contributing data. In blinded domains, randomization data will not be accessible by anyone else involved in the trial with the following exceptions: (1) data managers who work on the randomization and drug management system, (2) unblinded statistician(s) involved with the response adaptive randomization, and (3) the unblinded biostatistician who prepares reports for the IDMC. Information on the blind, or lack thereof, per domain will be described in the respective Domain-Specific Appendix.

Primary Purpose:

Treatment

Official Title:

Better Evidence and Translation for Calciphylaxis

Actual Study Start Date :

Aug 26, 2021

Anticipated Primary Completion Date :

Dec 1, 2026

Anticipated Study Completion Date :

Dec 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo (Double-Blind Period) Placebo Vitamin K1 Placebo Magnesium Citrate Placebo Sodium Thiosulphate	Drug: Placebo injection (normal saline) Placebo to be administered intravenously 3 times per week, during the subject's last hour of hemodialysis. Other Names: 0.9% sodium chloride solution Drug: Placebo capsule (Vitamin K1) Placebo to be administered 3 times per week following the subject's hemodialysis session. Other Names: Matching placebo capsule Drug: Placebo tablet (Magnesium citrate) 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. Other Names: Matching placebo tablet
Experimental: Vitamin K1 (Double-Blind Period) 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 Vitamin K1 capsule (10mg) to be administered 3 times per week following the subject's hemodialysis session. Other Names: Phytonadione Drug: Placebo injection (normal saline) Placebo to be administered intravenously 3 times per week, during the subject's last hour of hemodialysis. Other Names: 0.9% sodium chloride solution Drug: Placebo tablet (Magnesium citrate) 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. Other Names: Matching placebo tablet
Experimental: Magnesium Citrate (Double-Blind Period) 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 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. Drug: Placebo injection (normal saline) Placebo to be administered intravenously 3 times per week, during the subject's last hour of hemodialysis. Other Names: 0.9% sodium chloride solution Drug: Placebo capsule (Vitamin K1) Placebo to be administered 3 times per week following the subject's hemodialysis session. Other Names: Matching placebo capsule
Experimental: Sodium Thiosulfate (Double-Blind Period) 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 Sodium Thiosulfate injection (25g/100ml) to be administered intravenously 3 times per week, during the subject's last hour of hemodialysis. Other Names: Intravenous Sodium Thiosulfate Injection Drug: Placebo capsule (Vitamin K1) Placebo to be administered 3 times per week following the subject's hemodialysis session. Other Names: Matching placebo capsule Drug: Placebo tablet (Magnesium citrate) 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. Other Names: Matching placebo tablet
Active Comparator: High Flux Hemodialysis Hemodialysis using a high flux dialyser	Device: High Flux Dialyser Hemodialysis using a high flux dialyser. Other Names: High Flux Hemodialysis
Experimental: Medium Cut-off Hemodialysis Hemodialysis using a medium cut-off dialyser	Device: Medium Cut-off Dialyser Hemodialysis using a medium cut-off dialyser. Other Names: Medium Cut-off Hemodialysis

Outcome Measures

Primary Outcome Measures

BEAT-Calci Wound Assessment Scale (BCWAS) - Baseline to Week 12 [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

Secondary Outcome Measures

BEAT-Calci Wound Assessment Scale - Baseline to Week 26 [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
Distribution of each of the individual components of the BCWAS, assessed at Weeks 4 [Week 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
Distribution of each of the individual components of the BCWAS, assessed at Week 12 [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
Distribution of each of the individual components of the BCWAS, assessed at Week 26 [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
Bates-Jensen Wound Assessment Tool - from Baseline to Week 4 [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
Bates-Jensen Wound Assessment Tool - from Baseline to Week 12 [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
Bates-Jensen Wound Assessment Tool - from Baseline to Week 26 [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
Sentinel ulcer surface area - from Baseline, assessed at Week 4 [Week 4]
To determine whether addition of the intervention changes the surface area of sentinel ulcer from Baseline, assessed at Week 4
Sentinel ulcer surface area - from Baseline, assessed at Week 12 [Week 12]
To determine whether addition of the intervention changes the surface area of sentinel ulcer from Baseline, assessed at Week 12
Sentinel ulcer surface area - from Baseline, assessed at Week 26 [Week 26]
To determine whether addition of the intervention changes the surface area of sentinel ulcer from Baseline, assessed at Week 26
All ulcers total surface area - from Baseline, assessed at Week 4 [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
All ulcers total surface area - from Baseline, assessed at Week 12 [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
All ulcers total surface area - from Baseline, assessed at Week 26 [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
Change over time of self-reported pain [Week 26]
To determine whether addition of the intervention changes self-reported pain over time, assessed using the 0-to-10 Numerical Rating Scale
Self-reported pain at week 12 [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
Change over time of analgesic use [Week 26]
To determine whether addition of the intervention changes analgesic use over time, as measured by cumulative weighted analgesia dose from baseline to week 26
Analgesic use week 12 [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
Composite self-reported pain and analgesic use over time [Week 26]
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
Composite self-reported pain and analgesic use at week 12 [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
Change in self-reported quality of life from Baseline to Week 4 [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
Change in self-reported quality of life from Baseline to Week 12 [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
Change in self-reported quality of life from Baseline to Week 26 [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
Time to first calciphylaxis-attributable infection from Baseline to Week 26 [Week 26]
Time in days to first calciphylaxis-attributable infection within 26 weeks post-randomisation
All-cause hospitalisation days [Weeks 0-26]
Count of all cause hospitalisation days (excluding day admissions for dialysis treatment within 26 weeks post-randomisation
Mortality [Up to 5 years]
Incidence of mortality, as derived from hospital reports, within 5-years post-randomisation
Kidney Transplantation [Up to 5 years]
Incidence of kidney transplantation, as derived from hospital reports, within 5-years post-randomisation
Calciphylaxis recurrence [Up to 5 years]
Incidence of calciphylaxis recurrence as derived from hospital reports, within 5-years post-randomisation

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country
1	Auburn Hospital	Auburn	New South Wales	Australia
2	Blacktown Hospital	Blacktown	New South Wales	Australia
3	Concord Repatriation General Hospital	Concord	New South Wales	Australia
4	St George Hospital	Kogarah	New South Wales	Australia
5	Liverpool Hospital	Liverpool	New South Wales	Australia
6	Prince of Wales Hospital	Randwick	New South Wales	Australia
7	Westmead Hospital	Westmead	New South Wales	Australia
8	Sunshine Coast Hospital and Health Service	Birtinya	Queensland	Australia
9	Princess Alexandra Hospital	Brisbane	Queensland	Australia
10	Bundaberg Base Hospital	Bundaberg	Queensland	Australia
11	Cairns Hospital	Cairns	Queensland	Australia
12	Townsville Hospital	Townsville	Queensland	Australia
13	Royal Melbourne Hospital	Melbourne	Victoria	Australia
14	Sunshine Hospital (Western Health)	St Albans	Victoria	Australia
15	Armadale Hospital (East Metropolitan Health Services)	Armadale	Western Australia	Australia
16	Royal Perth Hospital (East Metropolitan Health Services)	Perth	Western Australia	Australia
17	Auckland City Hospital (Auckland DHB)	Grafton		New Zealand
18	Waikato Hospital (Waikato DHB)	Hamilton		New Zealand
19	North Shore Hospital (Waitemata DHB)	Takapuna		New Zealand