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    Clinical Trial Results:
    A Prospective Multicenter Phase 2/3 Clinical Trial with Sodium Thiosulfate for the Treatment of Calciphylaxis

    Summary
    EudraCT number
    		 2014-002128-28
    Trial protocol
    		 DE   AT  
    Global end of trial date
    30 May 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Jul 2019
    First version publication date
    04 Jul 2019
    Other versions
    Summary report(s)
    		 Clinical Study Report version 1.0 with Synopsis
    Appendix to Clinical Study Report
    CSR signature page Sponsor and Data Management
    CSR Signature Page Principal Investigator Site Feldkirch Austria
    CSR Signature Page Coordinating Investigator Site Salzburg Austria
    CSR Signature Page Principal Investigator Site Vienna Austria

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    STS-CSM-1/13
    Additional study identifiers
    ISRCTN number
    		 ISRCTN73380053
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Dr. Franz Köhler Chemie GmbH
    Sponsor organisation address
    Werner-von-Siemens-Str. 14-28, Bensheim, Germany, 64625
    Public contact
    Leitung Klinische Forschung, Dr. Franz Köhler Chemie GmbH, 0049 625110830,
    Scientific contact
    Leitung Klinische Forschung, Dr. Franz Köhler Chemie GmbH, 0049 625110830,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 Oct 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 May 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Percent reduction of the total wound area after 24 weeks (V4) compared to baseline (V0) as assessed by 2 independent, blinded dermatologists using a serial photo documentation. The mean value of both assessments will be taken.
    Protection of trial subjects
    During the run-in phase, measures for best supportive care that were considered obligatory were cautious necrosectomy (without debridement of wound margins) and support wound healing by keeping patients dry and treating peripheral edema. In addition, all participating study sites were free in their decision how to treat their calciphylaxis patients during the run-in phase. Patients who needed further treatment after the end of this clinical trial were treated according to the current best standard of care at the respective study site.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    14 Apr 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 5
    Worldwide total number of subjects
    5
    EEA total number of subjects
    5
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    2
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Territories: Austria, Germany, Switzerland Planned recruitment start date: 15-Jul-2015 Effective recruitment start date: 28-Jan-2016 First subject recruited on: 14-Apr-2016 Last subject recruited on: 17-Jan-2018 Clinical Trial stopped prematurely on: 30-May-2018

    Pre-assignment
    Screening details
    		 Dialysis patients with suspected calciphylaxis were asked to participate. During a run-in phase of 2-4 weeks with conventional wound management (c.w.m.) diagnosis of calciphylaxis was confirmed and efficacy of c.w.m. assessed. Patients with unconfirmed calciphylaxis or good response to c.w.m. after run-in phase were considered screening failures.

    Pre-assignment period milestones
    Number of subjects started
    		 5
    Number of subjects completed
    		 3

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 good response to conventional wound management: 1
    Reason: Number of subjects
    		 calciphylacis diagnosis not confirmed: 1
    Period 1
    Period 1 title
    V0
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Group A
    Arm description
    		 Patients with rapidly progressive disease under conventional wound management. Analysis to establish efficacy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sodium Thiosulfate (STS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose: 25 g Frequency: 3 times per week during haemodialysis Infusion start: 30 minutes before end of haemodialysis Infusion duration: 60 minutes

    Number of subjects in period 1 [1]
    		Group A
    Started
    3
    Treatment Start
    3
    Completed
    3
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Five subjects were screened and entered the run-in phase. Two of the five subjects proved to be ineligible and did not enter the baseline period. Therefore, only three subjects are reported in the baseline period.
    Period 2
    Period 2 title
    V1
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Group A
    Arm description
    		 Patients with rapidly progressive disease under conventional wound management. Analysis to establish efficacy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sodium Thiosulfate (STS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose: 25 g Frequency: 3 times per week during haemodialysis Infusion start: 30 minutes before end of haemodialysis Infusion duration: 60 minutes

    Number of subjects in period 2
    		Group A
    Started
    3
    Completed
    3
    Period 3
    Period 3 title
    V2
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Group A
    Arm description
    		 Patients with rapidly progressive disease under conventional wound management. Analysis to establish efficacy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sodium Thiosulfate (STS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose: 25 g Frequency: 3 times per week during haemodialysis Infusion start: 30 minutes before end of haemodialysis Infusion duration: 60 minutes

    Number of subjects in period 3
    		Group A
    Started
    3
    Completed
    3
    Period 4
    Period 4 title
    V3
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Group A
    Arm description
    		 Patients with rapidly progressive disease under conventional wound management. Analysis to establish efficacy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sodium Thiosulfate (STS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose: 25 g Frequency: 3 times per week during haemodialysis Infusion start: 30 minutes before end of haemodialysis Infusion duration: 60 minutes

    Number of subjects in period 4
    		Group A
    Started
    3
    Completed
    1
    Not completed
    2
         Adverse event, non-fatal
    1
         subject decided to discontinue hemodialysis
    1
    Period 5
    Period 5 title
    V4
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Group A
    Arm description
    		 Patients with rapidly progressive disease under conventional wound management. Analysis to establish efficacy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sodium Thiosulfate (STS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose: 25 g Frequency: 3 times per week during haemodialysis Infusion start: 30 minutes before end of haemodialysis Infusion duration: 60 minutes

    Number of subjects in period 5
    		Group A
    Started
    1
    Primary Endpoint Assessment
    1
    Completed
    1
    Period 6
    Period 6 title
    V5
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Group A
    Arm description
    		 Patients with rapidly progressive disease under conventional wound management. Analysis to establish efficacy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sodium Thiosulfate (STS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose: 25 g Frequency: 3 times per week during haemodialysis Infusion start: 30 minutes before end of haemodialysis Infusion duration: 60 minutes

    Investigational medicinal product name
    Sodium Thiosulfate (STS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose: 25 g Frequency: 3 times per week during haemodialysis Infusion start: 30 minutes before end of haemodialysis Infusion duration: 60 minutes

    Number of subjects in period 6
    		Group A
    Started
    1
    Completed
    1
    Period 7
    Period 7 title
    V6 / End of Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Group A
    Arm description
    		 Patients with rapidly progressive disease under conventional wound management. Analysis to establish efficacy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sodium Thiosulfate (STS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose: 25 g Frequency: 3 times per week during haemodialysis Infusion start: 30 minutes before end of haemodialysis Infusion duration: 60 minutes

    Number of subjects in period 7
    		Group A
    Started
    1
    End of Study
    2
    Completed
    2
    Joined
    1
         Early Termination Visit
    1
    Period 8
    Period 8 title
    Survival Follow Up 1
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Group A
    Arm description
    		 Patients with rapidly progressive disease under conventional wound management. Analysis to establish efficacy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sodium Thiosulfate (STS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose: 25 g Frequency: 3 times per week during haemodialysis Infusion start: 30 minutes before end of haemodialysis Infusion duration: 60 minutes

    Number of subjects in period 8
    		Group A
    Started
    2
    Completed
    1
    Not completed
    1
         Lost to follow-up
    1
    Period 9
    Period 9 title
    Survival Follow Up 2
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Group A
    Arm description
    		 Patients with rapidly progressive disease under conventional wound management. Analysis to establish efficacy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sodium Thiosulfate (STS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose: 25 g Frequency: 3 times per week during haemodialysis Infusion start: 30 minutes before end of haemodialysis Infusion duration: 60 minutes

    Number of subjects in period 9
    		Group A
    Started
    1
    Completed
    0
    Not completed
    1
         Subject's death
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 Patients with rapidly progressive disease under conventional wound management. Analysis to establish efficacy.

    Reporting group values
    		 Group A Total
    Number of subjects
    		 3 3
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 1 1
        From 65-84 years
    		 2 2
    Gender categorical
    Units: Subjects
        Female
    		 2 2
        Male
    		 1 1
    Ethnicity
    Units: Subjects
        white
    		 3 3
        black
    		 0 0
        asiatic
    		 0 0
        other
    		 0 0

    End points

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    End points reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 Patients with rapidly progressive disease under conventional wound management. Analysis to establish efficacy.
    Reporting group title
    Group A
    Reporting group description
    		 Patients with rapidly progressive disease under conventional wound management. Analysis to establish efficacy.
    Reporting group title
    Group A
    Reporting group description
    		 Patients with rapidly progressive disease under conventional wound management. Analysis to establish efficacy.
    Reporting group title
    Group A
    Reporting group description
    		 Patients with rapidly progressive disease under conventional wound management. Analysis to establish efficacy.
    Reporting group title
    Group A
    Reporting group description
    		 Patients with rapidly progressive disease under conventional wound management. Analysis to establish efficacy.
    Reporting group title
    Group A
    Reporting group description
    		 Patients with rapidly progressive disease under conventional wound management. Analysis to establish efficacy.
    Reporting group title
    Group A
    Reporting group description
    		 Patients with rapidly progressive disease under conventional wound management. Analysis to establish efficacy.
    Reporting group title
    Group A
    Reporting group description
    		 Patients with rapidly progressive disease under conventional wound management. Analysis to establish efficacy.
    Reporting group title
    Group A
    Reporting group description
    		 Patients with rapidly progressive disease under conventional wound management. Analysis to establish efficacy.

    Primary: Percent reduction of the total wound area after 24 weeks (v4) compared to baseline (V0).

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    End point title
    		 Percent reduction of the total wound area after 24 weeks (v4) compared to baseline (V0). [1]
    End point description
    Percent reduction of the total wound area after 24 weeks (V4) compared to baseline (V0) as assessed by 2 independent, blinded dermatologists using a serial photo documentation. The mean value of both assessments will be taken. Note: No statistical analysis of the primary endpoint was performed due to small sample size.
    End point type
    Primary
    End point timeframe
    Baseline (V0), 24 weeks (V4)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the study was terminated early due to recruitment problems, no statistical analysis plan was written and no statistical analysis was performed.
    End point values
    		 Group A Group A
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: square centimeter
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [2] - No statistical analysis of the primary endpoint was performed due to small sample size.
    [3] - No statistical analysis of the primary endpoint was performed due to small sample size.
    No statistical analyses for this end point

    Secondary: Total wound area at 8, 16, 36, 48 weeks compared to baseline (V0).

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    End point title
    		 Total wound area at 8, 16, 36, 48 weeks compared to baseline (V0).
    End point description
    Status of skin lesions Note: No statistical analysis of the secondary endpoints was performed due to small sample size. Lesion details can be found in attachment (table 1: Lesion Details (treated patients)).
    End point type
    Secondary
    End point timeframe
    Baseline, 8 weeks, 16 weeks, 36 weeks and 48 weeks after start of treatment
    End point values
    		 Group A Group A Group A Group A Group A
    Number of subjects analysed
    0 [4]
    0 [5]
    0 [6]
    0 [7]
    0 [8]
    Units: square centimeter
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    Attachments
    		 Table 1: Lesion Details (treated patients)
    Notes
    [4] - No statistical analysis was performed due to small sample size.
    [5] - No statistical analysis was performed due to small sample size.
    [6] - No statistical analysis was performed due to small sample size.
    [7] - No statistical analysis was performed due to small sample size.
    [8] - No statistical analysis was performed due to small sample size.
    No statistical analyses for this end point

    Secondary: Complete remission of wound area at any point

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    End point title
    		 Complete remission of wound area at any point
    End point description
    Status of skin lesions. Note: No statistical analysis of the secondary endpoints was performed due to small sample size. Occurrence was assessed using the results of the photo documentation of the lesions. Lesion details can be found in attachment of endpoint "Total wound area at 8, 16, 36, 48 weeks compared to baseline (V0)" (table 1: Lesion Details (treated patients)).
    End point type
    Secondary
    End point timeframe
    V0 (Baseline) to V6 (48 weeks / End of Treatment)
    End point values
    		 Group A Group A Group A Group A Group A Group A Group A
    Number of subjects analysed
    3
    0 [9]
    3
    1 [10]
    1
    1
    1 [11]
    Units: Occurrence
        Complete remission of wound area
    0
    0
    0
    0
    1
    0
    Notes
    [9] - No photodocumentation was scheduled for V1 (4 weeks). No further documentation available.
    [10] - Only one subject completed this arm.
    [11] - Early Termination Visit Subject 0103-001 (V3 in table 1) No photodocumentation of subject 0102-002.
    No statistical analyses for this end point

    Secondary: Qualitative Improvement of skin lesions at 8, 16, 24, 36, 48 weeks

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    End point title
    		 Qualitative Improvement of skin lesions at 8, 16, 24, 36, 48 weeks
    End point description
    Status of skin lesions. Qualitative improvement of skin lesions at 8, 16, 24, 36, 48 weeks as assessed by the revised Photographic Wound Assessment Tool (revPWAT) score and evaluation of a serial photo documentation through 2 independent, blinded dermatologists. Note: No statistical analysis of the secondary endpoints was performed due to small sample size. Lesion details can be found in attachment of endpoint "Total wound area at 8, 16, 36, 48 weeks compared to baseline (V0)" (table 1: Lesion Details (treated patients)).
    End point type
    Secondary
    End point timeframe
    V0 (Baseline), V2 (8 weeks), V3 (16 weeks), V4 (24 weeks), V5 (36 weeks), V6 (48 weeks, End of Treatment).
    End point values
    		 Group A Group A Group A Group A Group A Group A
    Number of subjects analysed
    0 [12]
    0 [13]
    0 [14]
    0 [15]
    0 [16]
    0 [17]
    Units: revPWAT score
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Notes
    [12] - No statistical analysis was performed due to small sample size.
    [13] - No statistical analysis was performed due to small sample size.
    [14] - No statistical analysis was performed due to small sample size.
    [15] - No statistical analysis was performed due to small sample size.
    [16] - No statistical analysis was performed due to small sample size.
    [17] - No statistical analysis was performed due to small sample size.
    No statistical analyses for this end point

    Secondary: Use of wound debridement

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    End point title
    		 Use of wound debridement
    End point description
    Status of skin lesions. Note: No statistical analysis of the secondary endpoints was performed due to small sample size. Data shown represent the documented corresponding concomitant procedures that were reported at the respective visit, if applicable. Results on subject level are contained in the CSR Appendix 16 that is attached in the Index section.
    End point type
    Secondary
    End point timeframe
    V0 (Start of Treatment) to V6 (week 48 / End of Study including Early Termination)
    End point values
    		 Group A Group A Group A Group A Group A Group A Group A
    Number of subjects analysed
    3
    3
    3
    1 [18]
    1
    1
    2 [19]
    Units: time(s)
        Wound debridement was performed
    0
    1
    1
    0
    0
    0
    0
    Notes
    [18] - Only one subject completed this arm.
    [19] - Early Termination Visit of subject 01-03-001.
    No statistical analyses for this end point

    Secondary: Reduction of pain in the areas of calciphylaxis after 4, 8, 16, 24, 36 and 48 weeks after start of STS treatment

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    End point title
    		 Reduction of pain in the areas of calciphylaxis after 4, 8, 16, 24, 36 and 48 weeks after start of STS treatment
    End point description
    Reduction of pain in the areas of calciphylaxis after 4, 8, 16, 24, 36 and 48 weeks after start of STS treatment was compared to baseline (V0) and assessed by a visual analogue scale (VAS) for pain (0-10). This was done directly before changing the wound dressing. Note: No statistical analysis was performed on secondary endpoints due to small sample size. A summary of the results is attached (table 2: Visual Analogue Scale for Pain (treated patients).
    End point type
    Secondary
    End point timeframe
    V0 (Baseline), V1 (4 weeks), V2 (8 weeks), V3 (16 weeks), V4 (24 weeks), V5 (36 weeks), V6 (48 weeks)
    End point values
    		 Group A Group A Group A Group A Group A Group A Group A
    Number of subjects analysed
    0 [20]
    0 [21]
    0 [22]
    0 [23]
    0 [24]
    0 [25]
    0 [26]
    Units: millimeter(s)
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Attachments
    		 Table 2: VAS for Pain (treated patients)
    Notes
    [20] - No statistical analysis was performed due to small sample size.
    [21] - No statistical analysis was performed due to small sample size.
    [22] - No statistical analysis was performed due to small sample size.
    [23] - No statistical analysis was performed due to small sample size.
    [24] - No statistical analysis was performed due to small sample size.
    [25] - No statistical analysis was performed due to small sample size.
    [26] - No statistical analysis was performed due to small sample size.
    No statistical analyses for this end point

    Secondary: Consumption of pain medication

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    End point title
    		 Consumption of pain medication
    End point description
    Pain evalutation. Consumption of pain medication (normalized to morphine equivalent with an appropriate conversion table) was assessed at VR, V0 and 4, 8, 16, 24, 36 and 48 weeks after start of STS treatment and compared to baseline (V0). Note: No statistical analysis was performed on secondary endpoints due to small sample size. Results on subject level are contained in the CSR Appendix 16 that is attached in the Index section.
    End point type
    Secondary
    End point timeframe
    VR (screening), V0 (baseline), V1 (4 weeks), V2 (8 weeks), V3 (16 weeks), V4 (24 weeks), V5 (36 weeks), V6 (48 weeks, End of Study)
    End point values
    		 Group A Group A Group A Group A Group A Group A Group A
    Number of subjects analysed
    0 [27]
    0 [28]
    0 [29]
    0 [30]
    0 [31]
    0 [32]
    0 [33]
    Units: milligram(s)
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Notes
    [27] - No statistical analysis was performed due to small sample size.
    [28] - No statistical analysis was performed due to small sample size.
    [29] - No statistical analysis was performed due to small sample size.
    [30] - No statistical analysis was performed due to small sample size.
    [31] - No statistical analysis was performed due to small sample size.
    [32] - No statistical analysis was performed due to small sample size.
    [33] - No statistical analysis was performed due to small sample size.
    No statistical analyses for this end point

    Secondary: Clinical global impression as assessed by the Clinical Global Impressions-Severity scale.

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    End point title
    		 Clinical global impression as assessed by the Clinical Global Impressions-Severity scale.
    End point description
    Clinical Global Impression. Change in clinical global impression as assessed by the Clinical Global Impressions-Improvement (CGI-I) score at each follow-up visit (after 4, 8, 16, 24, 36 and 48 weeks) compared to baseline (V0) and the Clinical Global Impression-Severity scale (CGI-S) through the investigators. The Clinical Global Impression-Severity scale (CGI-S) was assessed at each visit from visit V0 to V6 (i.e. after 4, 8, 16, 24, 36 and 48 weeks). No statistical analysis was performed due to small sample size. A summary of the results is attached (table 3: Clinical Global Impression (treated patients).
    End point type
    Secondary
    End point timeframe
    V0 (baseline), V1 (4 weeks), V2 (8 weeks), V3 (16 weeks), V4 (24 weeks), V5 (36 weeks), V6 (48 weeks / End of Study)
    End point values
    		 Group A Group A Group A Group A Group A Group A Group A
    Number of subjects analysed
    0 [34]
    0 [35]
    0 [36]
    0 [37]
    0 [38]
    0 [39]
    0 [40]
    Units: CGI-S scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Attachments
    		 Table 3: CGI (treated patients)
    Notes
    [34] - No statistical analysis was performed due to small sample size.
    [35] - No statistical analysis was performed due to small sample size.
    [36] - No statistical analysis was performed due to small sample size.
    [37] - No statistical analysis was performed due to small sample size.
    [38] - No statistical analysis was performed due to small sample size.
    [39] - No statistical analysis was performed due to small sample size.
    [40] - No statistical analysis was performed due to small sample size.
    No statistical analyses for this end point

    Secondary: Change in clinical global impression as assessed by the Clinical Global Impressions-Improvement (CGI-I) score at each follow-up visit (after 4, 8, 16, 24, 36 and 48 weeks) compared to baseline (V0) and the CGI-S.

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    End point title
    		 Change in clinical global impression as assessed by the Clinical Global Impressions-Improvement (CGI-I) score at each follow-up visit (after 4, 8, 16, 24, 36 and 48 weeks) compared to baseline (V0) and the CGI-S.
    End point description
    Change in clinical global impression as assessed by the Clinical Global Impressions-Improvement (CGI-I) score at each follow-up visit (after 4, 8, 16, 24, 36 and 48 weeks) compared to baseline (V0) and the Clinical Global Impression-Severity scale (CGI-S) through the investigators. The Clinical Global Impression-Severity scale (CGI-S) was assessed at each visit from visit V0 to V6 (i.e. after 4, 8, 16, 24, 36 and 48 weeks). A summary of the results is attached at endpoint "Clinical global impression as assessed by the Clinical Global Impressions-Severity scale" (table 3: Clinical Global Impression (treated patients).
    End point type
    Secondary
    End point timeframe
    V1 (4 weeks), V2 (8 weeks), V3 (16 weeks), V4 (24 weeks), V5 (36 weeks), V6 (48 weeks / End of Study)
    End point values
    		 Group A Group A Group A Group A Group A Group A
    Number of subjects analysed
    0 [41]
    0 [42]
    0 [43]
    0 [44]
    0 [45]
    0 [46]
    Units: CGI-I score
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Notes
    [41] - No statistical analysis was performed due to small sample size.
    [42] - No statistical analysis was performed due to small sample size.
    [43] - No statistical analysis was performed due to small sample size.
    [44] - No statistical analysis was performed due to small sample size.
    [45] - No statistical analysis was performed due to small sample size.
    [46] - No statistical analysis was performed due to small sample size.
    No statistical analyses for this end point

    Secondary: Improvement leading to eligibility of the patient for kidney transplantation.

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    End point title
    		 Improvement leading to eligibility of the patient for kidney transplantation.
    End point description
    Eligibility for kidney transplantation was given when the patient was being actively listed on a transplant waiting list. This did not occur for any patient in this clinical trial.
    End point type
    Secondary
    End point timeframe
    V0 (Baseline) to V6 (48 weeks / End of Study)
    End point values
    		 Group A Group A Group A Group A Group A Group A Group A
    Number of subjects analysed
    3
    3
    3
    1 [47]
    1
    1
    2 [48]
    Units: Occurrence
        Actively listed on a transplant waiting list
    0
    0
    0
    0
    0
    0
    0
    Notes
    [47] - Only one subject completed this arm.
    [48] - Early Termination Visit of Subject 01-03-001.
    No statistical analyses for this end point

    Secondary: Bone mineral density

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    End point title
    		 Bone mineral density
    End point description
    Measurement of bone mineral density was optional. Note: No statistical analysis was performed due to small sample size. Results on subject level are contained in the CSR Appendix 16 that is attached in the Index section.
    End point type
    Secondary
    End point timeframe
    V0 (Baseline), V6 (48 weeks / End of Study)
    End point values
    		 Group A Group A
    Number of subjects analysed
    0 [49]
    0 [50]
    Units: t/z-score
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [49] - No statistical analysis was performed due to small sample size.
    [50] - No statistical analysis was performed due to small sample size.
    No statistical analyses for this end point

    Secondary: Overall survival after start of STS treatment

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    End point title
    		 Overall survival after start of STS treatment
    End point description
    Median overall survival after start of STS treatment Note: No statistical analysis for secondary endpoints was performed due to small sample size. Results on subject level are contained in the CSR Appendix 16 that is attached in the Index section.
    End point type
    Secondary
    End point timeframe
    V0 (Baseline/Start of Treatment) - Survival Follow up 2
    End point values
    		 Group A
    Number of subjects analysed
    0 [51]
    Units: percent
        number (not applicable)
    Notes
    [51] - No analysis was performed due to small sample size.
    No statistical analyses for this end point

    Secondary: One-year survival rate

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    End point title
    		 One-year survival rate
    End point description
    Note: No statistical analysis for secondary endpoints was performed due to small sample size. Results on subject level are contained in the CSR Appendix 16 that is attached in the Index section.
    End point type
    Secondary
    End point timeframe
    VR (run-in phase) to SFU 2 (survival follow-up 12 months after End of Study)
    End point values
    		 Group A
    Number of subjects analysed
    0 [52]
    Units: percent
        number (not applicable)
    Notes
    [52] - No analysis was performed due to small sample size.
    No statistical analyses for this end point

    Other pre-specified: Safety Parameters

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    End point title
    		 Safety Parameters
    End point description
    The following safety parameters were monitored: Adverse events including Serious Adverse Events and Adverse Events of Special Interest, use of other concomitant medications, laboratory parameters (parathyroid hormone [PTH], total calcium, phosphorus, alkaline phosphatase, pH, CRP, leucocytes, hemoglobin, creatinine, albumin, Na, K, Cl, Mg, ASAT, ALAT, GGT, Amylase, Lipase, urea, uric acid, venous blood gas analysis, 1.25 vitamin D, 25 vitamin D, Physical examinations, ECG, vital signs (heart rate, blood pressure) and tolerability of STS treatment (dose reduction due to adverse event). Note: No statistical analysis was performed due to small sample size. Results on subject level are contained in the CSR Appendix 16 that is attached in the Index section.
    End point type
    Other pre-specified
    End point timeframe
    V0 (start of treatment) to V6 (End of Study)
    End point values
    		 Group A Group A Group A Group A Group A Group A Group A Group A Group A
    Number of subjects analysed
    0 [53]
    0 [54]
    0 [55]
    0 [56]
    0 [57]
    0 [58]
    0 [59]
    0 [60]
    0 [61]
    Units: unit(s)
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Notes
    [53] - No statistical analysis was performed due to small sample size.
    [54] - No statistical analysis was performed due to small sample size.
    [55] - No statistical analysis was performed due to small sample size.
    [56] - No statistical analysis was performed due to small sample size.
    [57] - No statistical analysis was performed due to small sample size.
    [58] - No statistical analysis was performed due to small sample size.
    [59] - No statistical analysis was performed due to small sample size.
    [60] - No statistical analysis was performed due to small sample size.
    [61] - No statistical analysis was performed due to small sample size.
    No statistical analyses for this end point

    Other pre-specified: Biobanking

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    End point title
    		 Biobanking
    End point description
    In order to establish a biobank for calciphylaxis, serum was collected for assessing further relevant parameters, e.g. inflammatory and calcification parameters and bone turn-over markers. The evaluation of these parameters was planned to be performed within 5 years after the end of the trial. Due to the small sample size this plan was not realized after the early termination of the study. The samples were discarded.
    End point type
    Other pre-specified
    End point timeframe
    VR (run-in phase), V0 (baseline), V2 (8 weeks), V3 (16 weeks), V4 (24 weeks), V6 (48 weeks, End of Study)
    End point values
    		 Group A Group A Group A Group A Group A
    Number of subjects analysed
    0 [62]
    0 [63]
    0 [64]
    0 [65]
    0 [66]
    Units: Serum sample(s)
    Notes
    [62] - No serum sample analysis was performed due to small sample size.
    [63] - No serum samples were analyzed due to small sample size.
    [64] - No serum samples were analyzed due to small sample size.
    [65] - No serum samples were analyzed due to small sample size.
    [66] - No serum samples were analyzed due to low sample size.
    No statistical analyses for this end point

    Other pre-specified: T50 test

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    End point title
    		 T50 test
    End point description
    The T50 test was planned to be conducted to obtain information on the calcification propensity by monitoring the maturation time (T50) of calciprotein particles in serum. The evaluation of these parameters was planned to be performed within 5 years after the end of the trial. Due to the small sample size this plan was not realized after the early termination of the study. The samples were discarded.
    End point type
    Other pre-specified
    End point timeframe
    VR (run-in phase), V0 (baseline), V2 (8 weeks), V3 (16 weeks), V4 (24 weeks), V6 (48 weeks, End of Study)
    End point values
    		 Group A Group A Group A Group A Group A
    Number of subjects analysed
    0 [67]
    0 [68]
    0 [69]
    0 [70]
    0 [71]
    Units: minute(s)
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    Notes
    [67] - No serum samples were analyzed due to small sample size.
    [68] - No serum samples were analyzed due to small sample size.
    [69] - No serum samples were analyzed due to small sample size.
    [70] - No serum samples were analyzed due to small sample size.
    [71] - No serum samples were analyzed due to small sample size.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From V0 (Baseline / Start of Treatment) to V6 (End of Study / End of Treatment)
    Adverse event reporting additional description
    Adverse events of special interest were defined as incidences of infections and sepsis, metabolic acidosis, ventricular tachycardia, hypotension and bone fractures.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 Patients with rapidly progressive disease under conventional wound management. Analysis to establish efficacy.

    Serious adverse events
    		 Group A
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 3 (33.33%)
         number of deaths (all causes)
    2
         number of deaths resulting from adverse events
    0
    Musculoskeletal and connective tissue disorders
    Fracture of femural neck
    Additional description: required inpatient hospitalization or prolongation of existing hospitalization
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Group A
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    Cardiac disorders
    Hypotension
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Atrial fibrillation
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Hypertensive crisis
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    General disorders and administration site conditions
    Cramps
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Otitis media right
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 3 (66.67%)
         occurrences all number
    2
    Vomiting
         subjects affected / exposed
    3 / 3 (100.00%)
         occurrences all number
    5
    Nausea during IMP administration
    Additional description: during STS administration
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Diarrhoea
    Additional description: Clostridium difficile associated
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Undulating vomiting
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Drug-induced liver injury
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Haematoma
    Additional description: periorbital left side
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Necrosis
    Additional description: related to calciphylaxis
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Infections and infestations
    Clostridium difficile infection
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Cytomegalovirus infection
    Additional description: of unknown origin
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Weight decreased
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Feb 2017
    In the submission process in Switzerland the Swissethics requested adaptations in the Clinical Study Protocol (CSP) that was previously approved in Austria and Germany. The substantial amendment aimed to harmonize the CSP in all participating countries. The substantial changes were: - change of responsible statistician - sponsor address - CRO name change - contact details for SAE reporting - additional information that if a biopsy report of a consisting wound is available at Screening (VR) and the diagnosis of calciphylaxis is confirmed or other causes for necroses and ulcerations were excluded, an additional biopsy is not required - establishing that all female subjects with childbearing potential have to perform a pregnancy test at every study visit - addition of definitions for the term post-menopausal and for effective methods of birth control in the exclusion criteria section - generalization of countries involved in the study

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    - early termination due to low recruitment - only 5 of 40 planned subjects were enrolled in 3 years. 3 started treatment. 1 completed the trial per protocol. - Due to small sample size no statistical analysis was performed.
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