Better Evidence and Translation for Calciphylaxis (BEAT-Calci)

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

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

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.

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

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.

Dose: 10mg Vitamin K1 capsules, administered 3 times per week following the subject's hemodialysis session. Placebo Magnesium Citrate Placebo Sodium Thiosulphate

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

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

Vitamin K1 capsule (10mg) to be administered 3 times per week following the subject's hemodialysis session.

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.

Sodium Thiosulfate injection (25g/100ml) to be administered intravenously 3 times per week, during the subject's last hour of hemodialysis.

Placebo to be administered intravenously 3 times per week, during the subject's last hour of hemodialysis.

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.

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

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

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

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

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

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

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

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

To determine whether addition of the intervention changes the surface area of sentinel ulcer 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 12

To determine whether addition of the intervention changes the surface area of sentinel ulcer 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 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 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 26

To determine whether addition of the intervention changes self-reported pain over time, assessed using the 0-to-10 Numerical Rating Scale

To determine whether addition of the intervention changes self-reported pain use at week 12 assessed using the 0-to-10 Numerical Rating Scale

To determine whether addition of the intervention changes analgesic use over time, as measured by cumulative weighted analgesia dose from baseline to 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 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 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 at week 12

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

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

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

Count of all cause hospitalisation days (excluding day admissions for dialysis treatment within 26 weeks post-randomisation

Incidence of kidney transplantation, as derived from hospital reports, within 5-years post-randomisation

Incidence of calciphylaxis recurrence as derived from hospital reports, within 5-years post-randomisation

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

Trial data will be disseminated in the form of a publication to a relevant clinical journal and presentation at appropriate scientific conferences. Individual participant data that underlie the results reported, after de-identification (text, tables, figures, and appendices), may be shared with Investigators whose proposed use of the data has been approved by a review committee identified for this purpose.

No data should be released that would compromise the trial, unless specifically for safety reasons. There must be a strong scientific or other legitimate rationale for the data to be used for the requested purpose. Investigators should have a period of exclusivity in which to pursue their aims with the data, before key trial data are made available to other researchers. Adequate resources must be available in order to comply with the request, and the scientific aims of the study must justify the use of such resources. Data release complies with the relevant regulations from all relevant countries.