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    Clinical Trial Results:
    Spinal anaesthesia with Chloroprocaine HCl 1% for elective lower limb procedures of short duration: a prospective, randomised, observer-blind study in adult patients

    Summary
    EudraCT number
    		 2014-003778-17
    Trial protocol
    		 IT  
    Global end of trial date
    02 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Aug 2021
    First version publication date
    21 Aug 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CHL.1/02-2014
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02481505
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Study: CRO-14-122
    Sponsors
    Sponsor organisation name
    Sintetica SA
    Sponsor organisation address
    Via Penate 5, Mendrisio, Switzerland, 6850
    Public contact
    Study Management, CROSS S.A., 0041 916300510, corporate@croalliance.com
    Scientific contact
    Study Management, CROSS S.A., 0041 916300510, corporate@croalliance.com
    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
    02 Dec 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study is to evaluate the effect of 3 doses of Chloroprocaine HCl 1% (30, 40 and 50 mg) for spinal anaesthesia in adult patients undergoing short duration elective surgery of the lower limb, in terms of time to complete regression of spinal block
    Protection of trial subjects
    According to exclusion criterion nr 10: Chronic pain syndromes: patients with chronic pain syndromes (taking opioids, antidepressants, anticonvulsant agents or chronic analgesic therapy). After the lumbar puncture and after verifying the spontaneous flow of liquor at the beginning and at the end of the procedure, two short aspirations will be done to verify the proper positioning of the needle. Barbotage must be avoided. In case of incomplete anaesthesia, sedative, analgesics or anaesthetics should be administered. Post-operative analgesia will be given to all patients, if necessary, according to the hospital standard procedures.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Jul 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 46
    Worldwide total number of subjects
    46
    EEA total number of subjects
    46
    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)
    46
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The enrollment period was around 5 months. Inclusion criteria: 1.male/female patients, 18-65 year old, scheduled for short duration (< 40 min) lower limb surgery requiring ≥ T12 metameric level of sensory block 2.BMI: 18-32 kg/m2 inclusive 3.(ASA) physical status I/II 4.written ICF before any study procedures 5.full procedure comprehension

    Pre-assignment
    Screening details
    		 There were no screening requirement other that the inclision/exclusion criteria. 46 patients were included in the study and randomized. 45 patients were treated and completed the study. All of them were considered in the full analysis. 1 patient was randomized but not treated due to lack of compliance, not included in the analysis.

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Investigator [1]
    Blinding implementation details
    For completeness, the study was observer blind, so the physician placing the spinal block will not be further involved in patient’s care and data recording. The assessment on patients was done by blinded Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dose 1
    Arm description
    		 patients receiving 30 mg of Chloroprocaine HCl 1% solution for injection
    Arm type
    		 Experimental

    Investigational medicinal product name
    Chloroprocaine HCl 1%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    30 mg of Chloroprocaine HCl 1% for spinal anaesthesia

    Arm title
    		 Dose 2
    Arm description
    		 Patients receiving 40 mg of Chloroprocaine HCl 1% solution for injection
    Arm type
    		 Experimental

    Investigational medicinal product name
    Chloroprocaine HCl 1%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    40 mg of Chloroprocaine HCl 1% for spinal anaesthesia

    Arm title
    		 Dose 3
    Arm description
    		 Patients receiving 50 mg of Chloroprocaine HCl 1% solution for injection
    Arm type
    		 Experimental

    Investigational medicinal product name
    Chloroprocaine HCl 1%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    50 mg of Chloroprocaine HCl 1% for spinal anaesthesia

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: For completeness, the study was observer blind, so the physician placing the spinal block will not be further involved in patient’s care and data recording. The assessment on patients was done by blinded Investigator
    Number of subjects in period 1 [2]
    		Dose 1 Dose 2 Dose 3
    Started
    15
    15
    15
    Completed
    15
    15
    15
    Notes
    [2] - 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: 46 patients were included in the study and randomized. 45 patients were treated and completed the study. All of them were considered in the full analysis. 1 patient was randomized but not treated due to lack of compliance, not included in the analysis. Not able to properly amend this section

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    		 -

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 45 45
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 45 45
        From 65-84 years
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 40.6 ( 12.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 18 18
        Male
    		 27 27
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    all randomised patients who fulfil the study protocol requirements in terms of study anaesthetic administration. Missing values of time to complete spinal block regression (Tea) will be replaced with the highest Tea detected in the corresponding treatment group. This analysis set will be used for sensitivity analysis.

    Subject analysis set title
    Per Protocol set (PP)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    all randomised patients who fulfil the study protocol requirements in terms of anaesthetic administration and primary efficacy evaluation, with no major deviations that could affect the primary efficacy results. This analysis set will be used for the primary efficacy analysis.

    Subject analysis set title
    PK Set 1 (PK 1)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    the PK set 1 will include all randomised patients who fulfil the study protocol requirements in terms of anaesthetic administration and have at least one post-dose blood PK sample collected.

    Subject analysis set title
    PK Set 2 (PK 2)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    the PK set 2 will include all randomised patients who fulfil the study protocol requirements in terms of anaesthetic administration and have the urine for PK analysis collected.

    Subject analysis set title
    Safety set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    all patients who receive at least one dose of the investigational medicinal product. This analysis set will be used for the safety analyses.

    Subject analysis set title
    Enrolled set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All enrolled subjects. This analysis set was used for demographic, baseline and background characteristics.

    Subject analysis sets values
    		 Full Analysis Set (FAS) Per Protocol set (PP) PK Set 1 (PK 1) PK Set 2 (PK 2) Safety set Enrolled set
    Number of subjects
    45
    39
    45
    43
    45
    46
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    45
    39
    45
    43
    45
    46
        From 65-84 years
    0
    0
    0
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    40.6 ( 12.6 )
    41.3 ( 12.5 )
    40.6 ( 12.6 )
    40.7 ( 12.9 )
    40.6 ( 12.6 )
    40.6 ( 12.5 )
    Gender categorical
    Units: Subjects
        Female
    18
    17
    18
    17
    18
    19
        Male
    27
    22
    27
    26
    27
    27

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Dose 1
    Reporting group description
    		 patients receiving 30 mg of Chloroprocaine HCl 1% solution for injection

    Reporting group title
    Dose 2
    Reporting group description
    		 Patients receiving 40 mg of Chloroprocaine HCl 1% solution for injection

    Reporting group title
    Dose 3
    Reporting group description
    		 Patients receiving 50 mg of Chloroprocaine HCl 1% solution for injection

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    all randomised patients who fulfil the study protocol requirements in terms of study anaesthetic administration. Missing values of time to complete spinal block regression (Tea) will be replaced with the highest Tea detected in the corresponding treatment group. This analysis set will be used for sensitivity analysis.

    Subject analysis set title
    Per Protocol set (PP)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    all randomised patients who fulfil the study protocol requirements in terms of anaesthetic administration and primary efficacy evaluation, with no major deviations that could affect the primary efficacy results. This analysis set will be used for the primary efficacy analysis.

    Subject analysis set title
    PK Set 1 (PK 1)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    the PK set 1 will include all randomised patients who fulfil the study protocol requirements in terms of anaesthetic administration and have at least one post-dose blood PK sample collected.

    Subject analysis set title
    PK Set 2 (PK 2)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    the PK set 2 will include all randomised patients who fulfil the study protocol requirements in terms of anaesthetic administration and have the urine for PK analysis collected.

    Subject analysis set title
    Safety set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    all patients who receive at least one dose of the investigational medicinal product. This analysis set will be used for the safety analyses.

    Subject analysis set title
    Enrolled set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All enrolled subjects. This analysis set was used for demographic, baseline and background characteristics.

    Primary: to evaluate the efficacy of the 3 Chloroprocaine HCl 1% doses D1, D2 and D3 in terms of time to complete regression of spinal block (Tea) (i.e. end of anaesthesia)_FAS

    		 Close Top of page
    End point title
    		 to evaluate the efficacy of the 3 Chloroprocaine HCl 1% doses D1, D2 and D3 in terms of time to complete regression of spinal block (Tea) (i.e. end of anaesthesia)_FAS
    End point description
    Time to regression of spinal block (Tea), defined as the time when Bromage score returns to 0 and sensitive perception returns to S1.
    End point type
    Primary
    End point timeframe
    at visit 2/day 1
    End point values
    		 Dose 1 Dose 2 Dose 3 Full Analysis Set (FAS)
    Number of subjects analysed
    15
    15
    15
    45
    Units: time (hh:mm)
        arithmetic mean (standard deviation)
    1.761 ( 0.348 )
    2.127 ( 0.457 )
    2.229 ( 0.379 )
    2.039 ( 0.438 )
    Attachments
    		 primary and secondary efficacy variables
    Statistical analysis title
    		 comparison of time to events_overall comparison
    Statistical analysis description
    Tea, Tsb, Tmb, Trs, TS1, Trmb, Tua, SBmax, TSBmax, Trd, Thd, Tuv, Tra and Tpa were summarised by dose level group and overall using descriptive statistics. Due to the small sample size, collected data will be compared using nonparametric tests. Above mentioned timings were analysed using the Kruskal-Wallis test. Pairwise comparisons between dose level groups were performed using the Wilcoxon rank-sum test.
    Comparison groups
    Dose 3 v Dose 2 v Dose 1
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.0092 [2]
    Method
    		 Kruskal-wallis
    Confidence interval
    Notes
    [1] - Comparisons were performed according to the following hierarchical order: 1. Overall comparison 2. D1 (30 mg) vs. D3 (50 mg) comparison 3. D2 (40 mg) vs. D3 (50 mg) comparison 4. D1 (30 mg) vs. D2 (40 mg) comparison Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary. However, if a null hypothesis of a comparison cannot be rejected, all the null hypotheses of the subsequent comparisons cannot be rejected.
    [2] - statistically significant
    Statistical analysis title
    		 comparison of time to events_D1 vs D3
    Statistical analysis description
    Tea, Tsb, Tmb, Trs, TS1, Trmb, Tua, SBmax, TSBmax, Trd, Thd, Tuv, Tra and Tpa were summarised by dose level group and overall using descriptive statistics. Due to the small sample size, collected data will be compared using nonparametric tests. Above mentioned timings were analysed using the Kruskal-Wallis test. Pairwise comparisons between dose level groups were performed using the Wilcoxon rank-sum test.
    Comparison groups
    Dose 1 v Dose 3
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.0063 [4]
    Method
    		 Wilcoxon rank-sum test
    Confidence interval
    Notes
    [3] - Comparisons were performed according to the following hierarchical order: 1. Overall comparison 2. D1 (30 mg) vs. D3 (50 mg) comparison 3. D2 (40 mg) vs. D3 (50 mg) comparison 4. D1 (30 mg) vs. D2 (40 mg) comparison Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary. However, if a null hypothesis of a comparison cannot be rejected, all the null hypotheses of the subsequent comparisons cannot be rejected.
    [4] - statistically significant
    Statistical analysis title
    		 comparison of time to events_D2 vs D3
    Statistical analysis description
    Tea, Tsb, Tmb, Trs, TS1, Trmb, Tua, SBmax, TSBmax, Trd, Thd, Tuv, Tra and Tpa were summarised by dose level group and overall using descriptive statistics. Due to the small sample size, collected data will be compared using nonparametric tests. Above mentioned timings were analysed using the Kruskal-Wallis test. Pairwise comparisons between dose level groups were performed using the Wilcoxon rank-sum test.
    Comparison groups
    Dose 3 v Dose 2
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.7423 [6]
    Method
    		 Wilcoxon rank-sum test
    Confidence interval
    Notes
    [5] - Comparisons were performed according to the following hierarchical order: 1. Overall comparison 2. D1 (30 mg) vs. D3 (50 mg) comparison 3. D2 (40 mg) vs. D3 (50 mg) comparison 4. D1 (30 mg) vs. D2 (40 mg) comparison Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary. However, if a null hypothesis of a comparison cannot be rejected, all the null hypotheses of the subsequent comparisons cannot be rejected.
    [6] - not statistically significant
    Statistical analysis title
    		 comparison of time to events_D1 vs D2
    Statistical analysis description
    Tea, Tsb, Tmb, Trs, TS1, Trmb, Tua, SBmax, TSBmax, Trd, Thd, Tuv, Tra and Tpa were summarised by dose level group and overall using descriptive statistics. Due to the small sample size, collected data will be compared using nonparametric tests. Above mentioned timings were analysed using the Kruskal-Wallis test. Pairwise comparisons between dose level groups were performed using the Wilcoxon rank-sum test.
    Comparison groups
    Dose 2 v Dose 1
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.0344 [8]
    Method
    		 Wilcoxon rank-sum test
    Confidence interval
    Notes
    [7] - Comparisons were performed according to the following hierarchical order: 1. Overall comparison 2. D1 (30 mg) vs. D3 (50 mg) comparison 3. D2 (40 mg) vs. D3 (50 mg) comparison 4. D1 (30 mg) vs. D2 (40 mg) comparison Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary. However, if a null hypothesis of a comparison cannot be rejected, all the null hypotheses of the subsequent comparisons cannot be rejected.
    [8] - statistically significant

    Primary: to evaluate the efficacy of the 3 Chloroprocaine HCl 1% doses D1, D2 and D3 in terms of time to complete regression of spinal block (Tea) (i.e. end of anaesthesia)_PP

    		 Close Top of page
    End point title
    		 to evaluate the efficacy of the 3 Chloroprocaine HCl 1% doses D1, D2 and D3 in terms of time to complete regression of spinal block (Tea) (i.e. end of anaesthesia)_PP
    End point description
    Time to regression of spinal block (Tea), defined as the time when Bromage score returns to 0 and sensitive perception returns to S1.
    End point type
    Primary
    End point timeframe
    at visit 2 / day 1
    End point values
    		 Dose 1 Dose 2 Dose 3 Per Protocol set (PP)
    Number of subjects analysed
    12
    13
    14
    39
    Units: time (hh:mm)
        arithmetic mean (standard deviation)
    1.813 ( 0.333 )
    2.119 ( 0.394 )
    2.218 ( 0.391 )
    2.061 ( 0.404 )
    Attachments
    		 Untitled (Filename: primary and secondary efficacy variables.PNG)
    Statistical analysis title
    		 comparison of time to events_overall comparison
    Statistical analysis description
    Tea, Tsb, Tmb, Trs, TS1, Trmb, Tua, SBmax, TSBmax, Trd, Thd, Tuv, Tra and Tpa were summarised by dose level group and overall using descriptive statistics. Due to the small sample size, collected data will be compared using nonparametric tests. Above mentioned timings were analysed using the Kruskal-Wallis test. Pairwise comparisons between dose level groups were performed using the Wilcoxon rank-sum test.
    Comparison groups
    Dose 3 v Dose 2 v Dose 1
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.0368 [10]
    Method
    		 Kruskal-wallis
    Confidence interval
    Notes
    [9] - Comparisons were performed according to the following hierarchical order: 1. Overall comparison 2. D1 (30 mg) vs. D3 (50 mg) comparison 3. D2 (40 mg) vs. D3 (50 mg) comparison 4. D1 (30 mg) vs. D2 (40 mg) comparison Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary. However, if a null hypothesis of a comparison cannot be rejected, all the null hypotheses of the subsequent comparisons cannot be rejected.
    [10] - statistically significant
    Statistical analysis title
    		 comparison of time to events_D1 vs D3
    Statistical analysis description
    Tea, Tsb, Tmb, Trs, TS1, Trmb, Tua, SBmax, TSBmax, Trd, Thd, Tuv, Tra and Tpa were summarised by dose level group and overall using descriptive statistics. Due to the small sample size, collected data will be compared using nonparametric tests. Above mentioned timings were analysed using the Kruskal-Wallis test. Pairwise comparisons between dose level groups were performed using the Wilcoxon rank-sum test.
    Comparison groups
    Dose 1 v Dose 3
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.0259 [12]
    Method
    		 Wilcoxon rank-sum test
    Confidence interval
    Notes
    [11] - Comparisons were performed according to the following hierarchical order: 1. Overall comparison 2. D1 (30 mg) vs. D3 (50 mg) comparison 3. D2 (40 mg) vs. D3 (50 mg) comparison 4. D1 (30 mg) vs. D2 (40 mg) comparison Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary. However, if a null hypothesis of a comparison cannot be rejected, all the null hypotheses of the subsequent comparisons cannot be rejected.
    [12] - statistically significant
    Statistical analysis title
    		 comparison of time to events_D2 vs D3
    Statistical analysis description
    Tea, Tsb, Tmb, Trs, TS1, Trmb, Tua, SBmax, TSBmax, Trd, Thd, Tuv, Tra and Tpa were summarised by dose level group and overall using descriptive statistics. Due to the small sample size, collected data will be compared using nonparametric tests. Above mentioned timings were analysed using the Kruskal-Wallis test. Pairwise comparisons between dose level groups were performed using the Wilcoxon rank-sum test.
    Comparison groups
    Dose 3 v Dose 2
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.8475 [14]
    Method
    		 Wilcoxon rank-sum test
    Confidence interval
    Notes
    [13] - Comparisons were performed according to the following hierarchical order: 1. Overall comparison 2. D1 (30 mg) vs. D3 (50 mg) comparison 3. D2 (40 mg) vs. D3 (50 mg) comparison 4. D1 (30 mg) vs. D2 (40 mg) comparison Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary. However, if a null hypothesis of a comparison cannot be rejected, all the null hypotheses of the subsequent comparisons cannot be rejected.
    [14] - not statistically significant
    Statistical analysis title
    		 comparison of time to events_D1 vs D2
    Statistical analysis description
    Tea, Tsb, Tmb, Trs, TS1, Trmb, Tua, SBmax, TSBmax, Trd, Thd, Tuv, Tra and Tpa were summarised by dose level group and overall using descriptive statistics. Due to the small sample size, collected data will be compared using nonparametric tests. Above mentioned timings were analysed using the Kruskal-Wallis test. Pairwise comparisons between dose level groups were performed using the Wilcoxon rank-sum test.
    Comparison groups
    Dose 2 v Dose 1
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 = 0.0553 [16]
    Method
    		 Wilcoxon rank-sum test
    Confidence interval
    Notes
    [15] - Comparisons were performed according to the following hierarchical order: 1. Overall comparison 2. D1 (30 mg) vs. D3 (50 mg) comparison 3. D2 (40 mg) vs. D3 (50 mg) comparison 4. D1 (30 mg) vs. D2 (40 mg) comparison Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary. However, if a null hypothesis of a comparison cannot be rejected, all the null hypotheses of the subsequent comparisons cannot be rejected.
    [16] - not statistically significant

    Secondary: To evaluate the efficacy of three Chloroprocaine HCl 1% doses at several timepoints_FAS

    		 Close Top of page
    End point title
    		 To evaluate the efficacy of three Chloroprocaine HCl 1% doses at several timepoints_FAS
    End point description
    Tsb: Time to onset of sensory block (min) Tmb: Time to onset of motor block (min) Trs: Time to readiness for surgery (min) Trmb: Time to resolution of motor block (h) Tua: Time to unassisted ambulation (h) TS1: Time to resolution of sensory block to S1 (h) (where S1 is the 1st sacral dermatomal level) TSBmax: Time to maximum level of sensory block (min) Trd: Time to regression of two dermatomers with respect to the maximum level of sensory block (h) Tuv: Time to first spontaneous urine voiding (h) Tra: Time to administration of rescue anaesthesia or rescue analgesia (h) Tpa: Time to first post-operative analgesia (h) Thd: Time to eligibility for home discharge (h)
    End point type
    Secondary
    End point timeframe
    At visit 2/day 1, timepoints described in the description since no enough space is foreseen here
    End point values
    		 Dose 1 Dose 2 Dose 3 Full Analysis Set (FAS)
    Number of subjects analysed
    15
    15
    15
    45
    Units: time (h or m)
    arithmetic mean (standard deviation)
        Tsb: Time to onset of sensory block (min)
    5.4 ( 3.0 )
    6.6 ( 3.4 )
    4.8 ( 2.0 )
    5.6 ( 2.8 )
        Tmb: Time to onset of motor block (min)
    6.3 ( 3.2 )
    6.0 ( 3.3 )
    4.4 ( 2.3 )
    5.6 ( 3.0 )
        Trs: Time to readiness for surgery (min)
    8.0 ( 4.1 )
    7.9 ( 4.7 )
    5.3 ( 2.0 )
    7.1 ( 3.9 )
        Trmb: Time to resolution of motor block (h)
    1.438 ( 0.409 )
    1.480 ( 0.400 )
    1.661 ( 0.459 )
    1.526 ( 0.425 )
        Tua: Time to unassisted ambulation (h)
    2.662 ( 0.789 )
    3.361 ( 1.120 )
    3.213 ( 0.856 )
    3.079 ( 0.960 )
        TS1: Time to resolution of sensory block to S1 (h)
    1.761 ( 0.348 )
    2.127 ( 0.457 )
    2.195 ( 0.386 )
    2.028 ( 0.435 )
        TSBmax: Time to maximum level of sensory block (mi
    0.224 ( 0.140 )
    0.235 ( 0.077 )
    0.234 ( 0.098 )
    0.231 ( 0.106 )
        Trd: Time to regression of two dermatomers with re
    0.687 ( 0.361 )
    0.851 ( 0.468 )
    0.695 ( 0.290 )
    0.744 ( 0.379 )
        Tuv: Time to first spontaneous urine voiding (h)
    2.530 ( 0.761 )
    3.361 ( 1.120 )
    3.067 ( 0.755 )
    2.986 ( 0.941 )
        Tra: Time to administration of rescue anaesthesia
    0.717 ( 0.397 )
    0.315 ( 0.049 )
    0 ( 0 )
    0.556 ( 0.358 )
        Tpa: Time to first post-operative analgesia (h)
    8.186 ( 10.815 )
    2.928 ( 1.228 )
    2.988 ( 1.167 )
    4.918 ( 6.996 )
        Thd: Time to eligibility for home discharge (h)
    3.021 ( 1.012 )
    3.545 ( 1.281 )
    3.530 ( 0.887 )
    3.366 ( 1.076 )
    Attachments
    		 Untitled (Filename: p-values efficacy variables.PNG)
    Statistical analysis title
    		 comparison of time to events_overall comparison
    Statistical analysis description
    Tsb, Tmb, Trs, TS1, Trmb, Tua, SBmax, TSBmax, Trd, Thd, Tuv, Tra and Tpa were summarised by dose level group and overall using descriptive statistics. Due to the small sample size, collected data will be compared using nonparametric tests. Above mentioned timings were analysed using the Kruskal-Wallis test. Pairwise comparisons between dose level groups were performed using the Wilcoxon rank-sum test.
    Comparison groups
    Dose 3 v Dose 2 v Dose 1
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 = 0.3732 [18]
    Method
    		 Kruskal-wallis
    Confidence interval
    Notes
    [17] - Comparisons were performed according to the following hierarchical order: 1. Overall comparison 2. D1 (30 mg) vs. D3 (50 mg) comparison 3. D2 (40 mg) vs. D3 (50 mg) comparison 4. D1 (30 mg) vs. D2 (40 mg) comparison Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary. However, if a null hypothesis of a comparison cannot be rejected, all the null hypotheses of the subsequent comparisons cannot be rejected.
    [18] - p-value for Tsb not statistically significant. The p-values for the other parameters are listed in the picture attached in the previous page
    Statistical analysis title
    		 comparison of time to events_D1 vs D3
    Statistical analysis description
    Tsb, Tmb, Trs, TS1, Trmb, Tua, SBmax, TSBmax, Trd, Thd, Tuv, Tra and Tpa were summarised by dose level group and overall using descriptive statistics. Due to the small sample size, collected data will be compared using nonparametric tests. Above mentioned timings were analysed using the Kruskal-Wallis test. Pairwise comparisons between dose level groups were performed using the Wilcoxon rank-sum test.
    Comparison groups
    Dose 1 v Dose 3
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 = 0.6862 [20]
    Method
    		 Wilcoxon rank-sum test
    Confidence interval
    Notes
    [19] - Comparisons were performed according to the following hierarchical order: 1. Overall comparison 2. D1 (30 mg) vs. D3 (50 mg) comparison 3. D2 (40 mg) vs. D3 (50 mg) comparison 4. D1 (30 mg) vs. D2 (40 mg) comparison Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary. However, if a null hypothesis of a comparison cannot be rejected, all the null hypotheses of the subsequent comparisons cannot be rejected.
    [20] - p-value for Tsb not statistically significant. The p-values for the other parameters are listed in the picture attached in the previous page
    Statistical analysis title
    		 comparison of time to events_D2 vs D3
    Statistical analysis description
    Tsb, Tmb, Trs, TS1, Trmb, Tua, SBmax, TSBmax, Trd, Thd, Tuv, Tra and Tpa were summarised by dose level group and overall using descriptive statistics. Due to the small sample size, collected data will be compared using nonparametric tests. Above mentioned timings were analysed using the Kruskal-Wallis test. Pairwise comparisons between dose level groups were performed using the Wilcoxon rank-sum test.
    Comparison groups
    Dose 2 v Dose 3
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    P-value
    		 = 0.1712 [22]
    Method
    		 Wilcoxon rank-sum test
    Confidence interval
    Notes
    [21] - Comparisons were performed according to the following hierarchical order: 1. Overall comparison 2. D1 (30 mg) vs. D3 (50 mg) comparison 3. D2 (40 mg) vs. D3 (50 mg) comparison 4. D1 (30 mg) vs. D2 (40 mg) comparison Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary. However, if a null hypothesis of a comparison cannot be rejected, all the null hypotheses of the subsequent comparisons cannot be rejected.
    [22] - p-value for Tsb not statistically significant. The p-values for the other parameters are listed in the picture attached in the previous page
    Statistical analysis title
    		 comparison of time to events_D1 vs D2
    Statistical analysis description
    Tsb, Tmb, Trs, TS1, Trmb, Tua, SBmax, TSBmax, Trd, Thd, Tuv, Tra and Tpa were summarised by dose level group and overall using descriptive statistics. Due to the small sample size, collected data will be compared using nonparametric tests. Above mentioned timings were analysed using the Kruskal-Wallis test. Pairwise comparisons between dose level groups were performed using the Wilcoxon rank-sum test.
    Comparison groups
    Dose 2 v Dose 1
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [23]
    P-value
    		 = 0.4058 [24]
    Method
    		 Wilcoxon rank-sum test
    Confidence interval
    Notes
    [23] - Comparisons were performed according to the following hierarchical order: 1. Overall comparison 2. D1 (30 mg) vs. D3 (50 mg) comparison 3. D2 (40 mg) vs. D3 (50 mg) comparison 4. D1 (30 mg) vs. D2 (40 mg) comparison Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary. However, if a null hypothesis of a comparison cannot be rejected, all the null hypotheses of the subsequent comparisons cannot be rejected.
    [24] - p-value for Tsb not statistically significant. The p-values for the other parameters are listed in the picture attached in the previous page

    Secondary: To evaluate the efficacy of three Chloroprocaine HCl 1% doses at several timepoints_PP

    		 Close Top of page
    End point title
    		 To evaluate the efficacy of three Chloroprocaine HCl 1% doses at several timepoints_PP
    End point description
    Tsb: Time to onset of sensory block (min) Tmb: Time to onset of motor block (min) Trs: Time to readiness for surgery (min) Trmb: Time to resolution of motor block (h) Tua: Time to unassisted ambulation (h) TS1: Time to resolution of sensory block to S1 (h) (where S1 is the 1st sacral dermatomal level) TSBmax: Time to maximum level of sensory block (min) Trd: Time to regression of two dermatomers with respect to the maximum level of sensory block (h) Tuv: Time to first spontaneous urine voiding (h) Tra: Time to administration of rescue anaesthesia or rescue analgesia (h) Tpa: Time to first post-operative analgesia (h) Thd: Time to eligibility for home discharge (h)
    End point type
    Secondary
    End point timeframe
    At visit 2/day 1, timepoints described in the description since no enough space is foreseen here
    End point values
    		 Dose 1 Dose 2 Dose 3 Per Protocol set (PP)
    Number of subjects analysed
    12
    13
    14
    39
    Units: time (h or m)
    arithmetic mean (standard deviation)
        Tsb: Time to onset of sensory block (min)
    5.3 ( 3.1 )
    6.9 ( 3.2 )
    4.6 ( 1.8 )
    5.6 ( 2.9 )
        Tmb: Time to onset of motor block (min)
    6.0 ( 3.1 )
    6.2 ( 3.3 )
    4.4 ( 2.4 )
    5.5 ( 3.0 )
        Trs: Time to readiness for surgery (min)
    7.2 ( 2.8 )
    7.4 ( 3.2 )
    5.1 ( 1.9 )
    6.5 ( 2.8 )
        Trmb: Time to resolution of motor block (h)
    1.508 ( 0.423 )
    1.488 ( 0.385 )
    1.610 ( 0.429 )
    1.538 ( 0.406 )
        Tua: Time to unassisted ambulation (h)
    2.744 ( 0.848 )
    3.432 ( 1.191 )
    3.252 ( 0.874 )
    3.156 ( 1.000 )
        TS1: Time to resolution of sensory block to S1 (h)
    1.813 ( 0.333 )
    2.119 ( 0.394 )
    2.218 ( 0.391 )
    2.061 ( 0.404 )
        TSBmax: Time to maximum level of sensory block (mi
    0.224 ( 0.151 )
    0.235 ( 0.082 )
    0.241 ( 0.097 )
    0.234 ( 0.110 )
        Trd: Time to regression of two dermatomers with re
    0.701 ( 0.392 )
    0.840 ( 0.446 )
    0.646 ( 0.228 )
    0.727 ( 0.371 )
        Tuv: Time to first spontaneous urine voiding (h)
    2.579 ( 0.830 )
    3.432 ( 1.191 )
    3.096 ( 0.775 )
    3.049 ( 0.987 )
        Tra: Time to administration of rescue anaesthesia
    0.800 ( 0.523 )
    0.350 ( 0 )
    0 ( 0 )
    0.650 ( 0.452 )
        Tpa: Time to first post-operative analgesia (h)
    10.322 ( 11.841 )
    3.091 ( 1.219 )
    3.051 ( 1.220 )
    5.580 ( 7.625 )
        Thd: Time to eligibility for home discharge (h)
    2.818 ( 0.786 )
    3.523 ( 1.370 )
    3.449 ( 0.861 )
    3.279 ( 1.060 )
    Attachments
    		 Untitled (Filename: primary and secondary efficacy variables.PNG)
    Untitled (Filename: p-values efficacy variables.PNG)
    Statistical analysis title
    		 comparison of time to events_overall comparison
    Statistical analysis description
    Tsb, Tmb, Trs, TS1, Trmb, Tua, SBmax, TSBmax, Trd, Thd, Tuv, Tra and Tpa were summarised by dose level group and overall using descriptive statistics. Due to the small sample size, collected data will be compared using nonparametric tests. Above mentioned timings were analysed using the Kruskal-Wallis test. Pairwise comparisons between dose level groups were performed using the Wilcoxon rank-sum test.
    Comparison groups
    Dose 2 v Dose 3 v Dose 1
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other [25]
    P-value
    		 = 0.1393 [26]
    Method
    		 Kruskal-wallis
    Confidence interval
    Notes
    [25] - Comparisons were performed according to the following hierarchical order: 1. Overall comparison 2. D1 (30 mg) vs. D3 (50 mg) comparison 3. D2 (40 mg) vs. D3 (50 mg) comparison 4. D1 (30 mg) vs. D2 (40 mg) comparison Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary. However, if a null hypothesis of a comparison cannot be rejected, all the null hypotheses of the subsequent comparisons cannot be rejected.
    [26] - p-value for Tsb not statistically significant. The p-values for the other parameters are listed in the picture attached in the previous page
    Statistical analysis title
    		 comparison of time to events_D1 vs D3
    Statistical analysis description
    Tsb, Tmb, Trs, TS1, Trmb, Tua, SBmax, TSBmax, Trd, Thd, Tuv, Tra and Tpa were summarised by dose level group and overall using descriptive statistics. Due to the small sample size, collected data will be compared using nonparametric tests. Above mentioned timings were analysed using the Kruskal-Wallis test. Pairwise comparisons between dose level groups were performed using the Wilcoxon rank-sum test.
    Comparison groups
    Dose 1 v Dose 3
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 other [27]
    P-value
    		 = 0.6917 [28]
    Method
    		 Wilcoxon rank-sum test
    Confidence interval
    Notes
    [27] - Comparisons were performed according to the following hierarchical order: 1. Overall comparison 2. D1 (30 mg) vs. D3 (50 mg) comparison 3. D2 (40 mg) vs. D3 (50 mg) comparison 4. D1 (30 mg) vs. D2 (40 mg) comparison Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary. However, if a null hypothesis of a comparison cannot be rejected, all the null hypotheses of the subsequent comparisons cannot be rejected.
    [28] - p-value for Tsb not statistically significant. The p-values for the other parameters are listed in the picture attached in the previous page
    Statistical analysis title
    		 comparison of time to events_D2 vs D3
    Statistical analysis description
    Tsb, Tmb, Trs, TS1, Trmb, Tua, SBmax, TSBmax, Trd, Thd, Tuv, Tra and Tpa were summarised by dose level group and overall using descriptive statistics. Due to the small sample size, collected data will be compared using nonparametric tests. Above mentioned timings were analysed using the Kruskal-Wallis test. Pairwise comparisons between dose level groups were performed using the Wilcoxon rank-sum test.
    Comparison groups
    Dose 3 v Dose 2
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 other [29]
    P-value
    		 = 0.0511 [30]
    Method
    		 Wilcoxon rank-sum test
    Confidence interval
    Notes
    [29] - Comparisons were performed according to the following hierarchical order: 1. Overall comparison 2. D1 (30 mg) vs. D3 (50 mg) comparison 3. D2 (40 mg) vs. D3 (50 mg) comparison 4. D1 (30 mg) vs. D2 (40 mg) comparison Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary. However, if a null hypothesis of a comparison cannot be rejected, all the null hypotheses of the subsequent comparisons cannot be rejected.
    [30] - p-value for Tsb not statistically significant. The p-values for the other parameters are listed in the picture attached in the previous page
    Statistical analysis title
    		 comparison of time to events_D1 vs D2
    Statistical analysis description
    Tsb, Tmb, Trs, TS1, Trmb, Tua, SBmax, TSBmax, Trd, Thd, Tuv, Tra and Tpa were summarised by dose level group and overall using descriptive statistics. Due to the small sample size, collected data will be compared using nonparametric tests. Above mentioned timings were analysed using the Kruskal-Wallis test. Pairwise comparisons between dose level groups were performed using the Wilcoxon rank-sum test.
    Comparison groups
    Dose 2 v Dose 1
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 other [31]
    P-value
    		 = 0.2446 [32]
    Method
    		 Wilcoxon rank-sum test
    Confidence interval
    Notes
    [31] - Comparisons were performed according to the following hierarchical order: 1. Overall comparison 2. D1 (30 mg) vs. D3 (50 mg) comparison 3. D2 (40 mg) vs. D3 (50 mg) comparison 4. D1 (30 mg) vs. D2 (40 mg) comparison Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary. However, if a null hypothesis of a comparison cannot be rejected, all the null hypotheses of the subsequent comparisons cannot be rejected.
    [32] - p-value for Tsb not statistically significant. The p-values for the other parameters are listed in the picture attached in the previous page

    Secondary: to assess the maximum level of sensory block_FAS

    		 Close Top of page
    End point title
    		 to assess the maximum level of sensory block_FAS
    End point description
    To evaluate the maximum level of sensory block according to the following metameric level: T2, T3, T4, T6, T7, T8, T10, T12 and L1
    End point type
    Secondary
    End point timeframe
    At visit 2/day 1
    End point values
    		 Dose 1 Dose 2 Dose 3 Full Analysis Set (FAS)
    Number of subjects analysed
    15
    15
    15
    45
    Units: number of patients
    number (not applicable)
        T2
    0
    2
    2
    4
        T3
    1
    0
    1
    2
        T4
    3
    2
    1
    6
        T6
    0
    1
    4
    5
        T7
    1
    0
    1
    2
        T8
    3
    3
    2
    8
        T10
    3
    1
    3
    7
        T12
    3
    5
    1
    9
        L1
    1
    1
    0
    2
    Attachments
    		 Untitled (Filename: max sensory block_FAS.PNG)
    Statistical analysis title
    		 comparison of SBmax_overall comparison
    Statistical analysis description
    The SBmax (maximum level of sensory block) was summarised by dose level group and overall using descriptive statistics. Due to the small sample size, collected data will be compared using nonparametric tests. The overall comparison was analysed using the Kruskal-Wallis test. Pairwise comparisons between dose level groups were performed using the Wilcoxon rank-sum test.
    Comparison groups
    Dose 1 v Dose 2 v Dose 3
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 other [33]
    P-value
    		 = 0.2591 [34]
    Method
    		 Kruskal-wallis
    Confidence interval
    Notes
    [33] - Comparisons were performed according to the following hierarchical order: 1. Overall comparison 2. D1 (30 mg) vs. D3 (50 mg) comparison 3. D2 (40 mg) vs. D3 (50 mg) comparison 4. D1 (30 mg) vs. D2 (40 mg) comparison Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary. However, if a null hypothesis of a comparison cannot be rejected, all the null hypotheses of the subsequent comparisons cannot be rejected.
    [34] - not statistically significant
    Statistical analysis title
    		 comparison of SBmax_D1 vs D3
    Statistical analysis description
    The SBmax (maximum level of sensory block) was summarised by dose level group and overall using descriptive statistics. Due to the small sample size, collected data will be compared using nonparametric tests. The overall comparison was analysed using the Kruskal-Wallis test. Pairwise comparisons between dose level groups were performed using the Wilcoxon rank-sum test.
    Comparison groups
    Dose 1 v Dose 3
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [35]
    P-value
    		 = 0.1591 [36]
    Method
    		 Wilcoxon rank-sum test
    Confidence interval
    Notes
    [35] - Comparisons were performed according to the following hierarchical order: 1. Overall comparison 2. D1 (30 mg) vs. D3 (50 mg) comparison 3. D2 (40 mg) vs. D3 (50 mg) comparison 4. D1 (30 mg) vs. D2 (40 mg) comparison Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary. However, if a null hypothesis of a comparison cannot be rejected, all the null hypotheses of the subsequent comparisons cannot be rejected.
    [36] - not statistically significant
    Statistical analysis title
    		 comparison of SBmax_D2 vs D3
    Statistical analysis description
    The SBmax (maximum level of sensory block) was summarised by dose level group and overall using descriptive statistics. Due to the small sample size, collected data will be compared using nonparametric tests. The overall comparison was analysed using the Kruskal-Wallis test. Pairwise comparisons between dose level groups were performed using the Wilcoxon rank-sum test.
    Comparison groups
    Dose 3 v Dose 2
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [37]
    P-value
    		 = 0.19 [38]
    Method
    		 Wilcoxon rank-sum test
    Confidence interval
    Notes
    [37] - Comparisons were performed according to the following hierarchical order: 1. Overall comparison 2. D1 (30 mg) vs. D3 (50 mg) comparison 3. D2 (40 mg) vs. D3 (50 mg) comparison 4. D1 (30 mg) vs. D2 (40 mg) comparison Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary. However, if a null hypothesis of a comparison cannot be rejected, all the null hypotheses of the subsequent comparisons cannot be rejected.
    [38] - not statistically significant
    Statistical analysis title
    		 comparison of SBmax_D1 vs D2
    Statistical analysis description
    The SBmax (maximum level of sensory block) was summarised by dose level group and overall using descriptive statistics. Due to the small sample size, collected data will be compared using nonparametric tests. The overall comparison was analysed using the Kruskal-Wallis test. Pairwise comparisons between dose level groups were performed using the Wilcoxon rank-sum test.
    Comparison groups
    Dose 1 v Dose 2
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [39]
    P-value
    		 = 0.9333 [40]
    Method
    		 Wilcoxon rank-sum test
    Confidence interval
    Notes
    [39] - Comparisons were performed according to the following hierarchical order: 1. Overall comparison 2. D1 (30 mg) vs. D3 (50 mg) comparison 3. D2 (40 mg) vs. D3 (50 mg) comparison 4. D1 (30 mg) vs. D2 (40 mg) comparison Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary. However, if a null hypothesis of a comparison cannot be rejected, all the null hypotheses of the subsequent comparisons cannot be rejected.
    [40] - not statistically significant

    Secondary: to assess the maximum level of sensory block_PP

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    End point title
    		 to assess the maximum level of sensory block_PP
    End point description
    To evaluate the maximum level of sensory block according to the following metameric level: T2, T3, T4, T6, T7, T8, T10, T12
    End point type
    Secondary
    End point timeframe
    at V2/ day 1
    End point values
    		 Dose 1 Dose 2 Dose 3 Per Protocol set (PP)
    Number of subjects analysed
    12
    13
    14
    39
    Units: number of patients
    number (not applicable)
        T2
    0
    1
    2
    3
        T3
    1
    0
    1
    2
        T4
    2
    2
    1
    5
        T6
    0
    1
    4
    5
        T7
    0
    0
    1
    1
        T8
    3
    3
    2
    8
        T10
    3
    1
    3
    7
        T12
    3
    5
    0
    8
    Attachments
    		 Untitled (Filename: max sensory block_PP.PNG)
    Statistical analysis title
    		 comparison of SBmax_overall comparison
    Statistical analysis description
    The SBmax (maximum level of sensory block) was summarised by dose level group and overall using descriptive statistics. Due to the small sample size, collected data will be compared using nonparametric tests. The overall comparison was analysed using the Kruskal-Wallis test. Pairwise comparisons between dose level groups were performed using the Wilcoxon rank-sum test
    Comparison groups
    Dose 3 v Dose 2 v Dose 1
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other [41]
    P-value
    		 = 0.1118 [42]
    Method
    		 Kruskal-wallis
    Confidence interval
    Notes
    [41] - Comparisons were performed according to the following hierarchical order: 1. Overall comparison 2. D1 (30 mg) vs. D3 (50 mg) comparison 3. D2 (40 mg) vs. D3 (50 mg) comparison 4. D1 (30 mg) vs. D2 (40 mg) comparison Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary. However, if a null hypothesis of a comparison cannot be rejected, all the null hypotheses of the subsequent comparisons cannot be rejected.
    [42] - not statistically significant
    Statistical analysis title
    		 comparison of SBmax_D1 vs D3
    Statistical analysis description
    The SBmax (maximum level of sensory block) was summarised by dose level group and overall using descriptive statistics. Due to the small sample size, collected data will be compared using nonparametric tests. The overall comparison was analysed using the Kruskal-Wallis test. Pairwise comparisons between dose level groups were performed using the Wilcoxon rank-sum test
    Comparison groups
    Dose 1 v Dose 3
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 other [43]
    P-value
    		 = 0.0843 [44]
    Method
    		 Wilcoxon rank-sum test
    Confidence interval
    Notes
    [43] - Comparisons were performed according to the following hierarchical order: 1. Overall comparison 2. D1 (30 mg) vs. D3 (50 mg) comparison 3. D2 (40 mg) vs. D3 (50 mg) comparison 4. D1 (30 mg) vs. D2 (40 mg) comparison Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary. However, if a null hypothesis of a comparison cannot be rejected, all the null hypotheses of the subsequent comparisons cannot be rejected.
    [44] - not statistically significant
    Statistical analysis title
    		 comparison of SBmax_D2 vs D3
    Statistical analysis description
    The SBmax (maximum level of sensory block) was summarised by dose level group and overall using descriptive statistics. Due to the small sample size, collected data will be compared using nonparametric tests. The overall comparison was analysed using the Kruskal-Wallis test. Pairwise comparisons between dose level groups were performed using the Wilcoxon rank-sum test
    Comparison groups
    Dose 3 v Dose 2
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 other [45]
    P-value
    		 = 0.0975 [46]
    Method
    		 Wilcoxon rank-sum test
    Confidence interval
    Notes
    [45] - Comparisons were performed according to the following hierarchical order: 1. Overall comparison 2. D1 (30 mg) vs. D3 (50 mg) comparison 3. D2 (40 mg) vs. D3 (50 mg) comparison 4. D1 (30 mg) vs. D2 (40 mg) comparison Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary. However, if a null hypothesis of a comparison cannot be rejected, all the null hypotheses of the subsequent comparisons cannot be rejected.
    [46] - not statistically significant
    Statistical analysis title
    		 comparison of SBmax_D1 vs D2
    Statistical analysis description
    The SBmax (maximum level of sensory block) was summarised by dose level group and overall using descriptive statistics. Due to the small sample size, collected data will be compared using nonparametric tests. The overall comparison was analysed using the Kruskal-Wallis test. Pairwise comparisons between dose level groups were performed using the Wilcoxon rank-sum test
    Comparison groups
    Dose 2 v Dose 1
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 other [47]
    P-value
    		 = 0.9119 [48]
    Method
    		 Wilcoxon rank-sum test
    Confidence interval
    Notes
    [47] - Comparisons were performed according to the following hierarchical order: 1. Overall comparison 2. D1 (30 mg) vs. D3 (50 mg) comparison 3. D2 (40 mg) vs. D3 (50 mg) comparison 4. D1 (30 mg) vs. D2 (40 mg) comparison Due to the hierarchical testing procedure, no formal adjustment of the alpha level is necessary. However, if a null hypothesis of a comparison cannot be rejected, all the null hypotheses of the subsequent comparisons cannot be rejected.
    [48] - not statistically significant

    Secondary: to assess the effectiveness of anaesthesia_FAS

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    End point title
    		 to assess the effectiveness of anaesthesia_FAS
    End point description
    to evaluated the proportion of patients who have reached an effective anaesthesia with an adequacy of spinal block
    End point type
    Secondary
    End point timeframe
    at V2/day 1
    End point values
    		 Dose 1 Dose 2 Dose 3 Full Analysis Set (FAS)
    Number of subjects analysed
    15
    15
    15
    45
    Units: number or patients
    number (not applicable)
        effective and adequate
    12
    13
    15
    40
        ineffective and inadequate
    3
    2
    0
    5
    Attachments
    		 Untitled (Filename: quality of spinal block_FAS.PNG)
    Untitled (Filename: effectiveness of anaesthesia_FAS.PNG)
    No statistical analyses for this end point

    Secondary: to assess the effectiveness of anaesthesia_PP

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    End point title
    		 to assess the effectiveness of anaesthesia_PP
    End point description
    to evaluated the proportion of patients who have reached an effective anaesthesia with an adequacy of spinal block
    End point type
    Secondary
    End point timeframe
    at V2/day 1
    End point values
    		 Dose 1 Dose 2 Dose 3 Per Protocol set (PP)
    Number of subjects analysed
    12
    13
    14
    39
    Units: number of patients
    number (not applicable)
        effective and adequate
    10
    12
    14
    36
        ineffective and inadequate
    2
    1
    0
    3
    Attachments
    		 Untitled (Filename: quality of spinal block_PP.PNG)
    Untitled (Filename: effectiveness of anaesthesia_PP.PNG)
    No statistical analyses for this end point

    Other pre-specified: To assess the concentration of chloroprocaine and its metabolite (CABA)

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    End point title
    		 To assess the concentration of chloroprocaine and its metabolite (CABA)
    End point description
    To assess the concentration of chloroprocaine and its metabolite 2-chloro-4-aminobenzoic acid (CABA) in plasma after administration of D1, D2 and D3. NOTE:Chlorporocaine was below the quantification limit (4.0ng/ml) at all time points for all arms. This is a pharmacokinetic variable
    End point type
    Other pre-specified
    End point timeframe
    Sampling times at day 1/ visit 2: Pre-dose (0)_within 60 minutes before IMP administration 5, 10 min post dose_with no deviation admitted 30 min_+/- 1 minute post dose 60 min_+/- 3 minutes post dose
    End point values
    		 Dose 1 Dose 2 Dose 3 PK Set 1 (PK 1)
    Number of subjects analysed
    15
    15
    15
    45
    Units: ng/ml
    geometric mean (standard deviation)
        CABA_time 0
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
        CABA_5 min
    16.127 ( 20.108 )
    20.411 ( 23.037 )
    24.887 ( 20.340 )
    20.475 ( 21.030 )
        CABA_10 min
    41.440 ( 31.778 )
    38.851 ( 25.492 )
    75.833 ( 67.635 )
    52.041 ( 47.689 )
        CABA_30 min
    57.459 ( 43.773 )
    67.180 ( 36.899 )
    97.647 ( 61.704 )
    74.095 ( 50.538 )
        CABA_60 min
    47.020 ( 41.381 )
    53.093 ( 31.803 )
    78.380 ( 48.403 )
    59.498 ( 42.435 )
    Attachments
    		 Untitled (Filename: CHL_CABA concentration_PK.pdf)
    No statistical analyses for this end point

    Other pre-specified: To assess the excretion of the CABA in urine

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    End point title
    		 To assess the excretion of the CABA in urine
    End point description
    To assess the excretion of the CABA in urine (as % of the administered dose). This is a pharmacokinetic variable
    End point type
    Other pre-specified
    End point timeframe
    at the time of first urine voiding at day 1/Visit 2 (day of surgery)
    End point values
    		 Dose 1 Dose 2 Dose 3 PK Set 2 (PK 2)
    Number of subjects analysed
    15
    14
    14
    43
    Units: % of administered dose
        arithmetic mean (standard deviation)
    1.70085 ( 0.96883 )
    1.75679 ( 0.93056 )
    1.658058 ( 1.29205 )
    1.70513 ( 1.04845 )
    No statistical analyses for this end point

    Other pre-specified: To evaluate the incidence of treatment emergent adverse events (TEAEs) throughout the study

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    End point title
    		 To evaluate the incidence of treatment emergent adverse events (TEAEs) throughout the study
    End point description
    To investigate the safety and tolerability of the administered Chloroprocaine HCl 1% doses on the basis of treatment emergent adverse events (TEAEs) throughout the study. This is a safety variable
    End point type
    Other pre-specified
    End point timeframe
    during the entire study period: from screening-visit 1 ( day -14 to day 1) to follow up visit (Day 7±1 ) post-surgery
    End point values
    		 Dose 1 Dose 2 Dose 3 Safety set
    Number of subjects analysed
    15
    15
    15
    45
    Units: number of TEAEs
        number (not applicable)
    0
    0
    0
    0
    No statistical analyses for this end point

    Other pre-specified: to evaluate the incidence of transient neurological symptoms (TNS)

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    End point title
    		 to evaluate the incidence of transient neurological symptoms (TNS)
    End point description
    To investigate the safety and tolerability of the administered Chloroprocaine HCl 1% doses on the basis of transient neurological symptoms (TNS) at 24 h (day 2) and 6±1 days (day 7±1) after spinal puncture (Tsp). This is a safety variable
    End point type
    Other pre-specified
    End point timeframe
    at 24 h (day 2) and 6±1 days (day 7±1) after spinal puncture (Tsp)
    End point values
    		 Dose 1 Dose 2 Dose 3 Safety set
    Number of subjects analysed
    15
    15
    15
    45
    Units: number of events
    number (not applicable)
        TNS_day 2_YES
    0
    0
    0
    0
        TNS_day 2_NO
    15
    15
    15
    45
        TNS_day 7±1_YES
    0
    0
    0
    0
        TNS_day 7±1_NO
    15
    15
    15
    45
    No statistical analyses for this end point

    Other pre-specified: to collect blood pressure (BP) for safety assessment

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    End point title
    		 to collect blood pressure (BP) for safety assessment
    End point description
    The complete safety end point is to investigate the safety and tolerability of the administered Chloroprocaine HCl 1% doses based on vital signs (blood pressure [BP], heart rate [HR] and peripheral oxygen saturation [SpO2]) check and ECG recording. It was split in 4 sub-endpoints for entering values for each parameter This is a safety variable
    End point type
    Other pre-specified
    End point timeframe
    systolic and diastolic blood pressure at screening, baseline and discharge
    End point values
    		 Dose 1 Dose 2 Dose 3 Safety set
    Number of subjects analysed
    15
    15
    15
    45
    Units: mmHg
    arithmetic mean (standard deviation)
        Systolic BP_screening
    120.0 ( 12.9 )
    126.0 ( 21.4 )
    121.6 ( 9.1 )
    122.5 ( 15.2 )
        Systolic BP_baseline
    116.9 ( 10.5 )
    127.9 ( 19.7 )
    125.5 ( 14.1 )
    123.4 ( 15.7 )
        Systolic BP_discharge
    116.9 ( 10.9 )
    124.7 ( 14.7 )
    121.7 ( 8.9 )
    121.1 ( 11.9 )
        Diastolic BP_screening
    81.5 ( 12.1 )
    78.9 ( 11.9 )
    80.5 ( 9.9 )
    80.3 ( 11.2 )
        Diastolic BP_baseline
    74.5 ( 10.3 )
    79.8 ( 10.9 )
    79.1 ( 13.3 )
    77.8 ( 11.6 )
        Diastolic BP_discharge
    75.5 ( 12.2 )
    79.0 ( 8.1 )
    82.0 ( 9.5 )
    78.8 ( 10.2 )
    No statistical analyses for this end point

    Other pre-specified: To assess the pain at the injection site and at the surgery site at different timepoints

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    End point title
    		 To assess the pain at the injection site and at the surgery site at different timepoints
    End point description
    To investigate the safety and tolerability of the administered Chloroprocaine HCl 1% doses on the basis of pain assessment at the site of injection and at the site of surgery performed immediately after regression of spinal block, at discharge (final visit/ETV), 24 h (day 2) and 6±1 days (day 7±1) after spinal puncture. This is a safety variable
    End point type
    Other pre-specified
    End point timeframe
    Pain assessment at these timepoints: immediately after regression of spinal block at discharge (final visit/ETV) 24 h (day 2) after spinal puncture 6±1 days (day 7±1) after spinal puncture
    End point values
    		 Safety set
    Number of subjects analysed
    45
    Units: number of patients experienced pain
    number (not applicable)
        Pain injection site_after regression_0
    45
        Pain injection site_after regression_1
    0
        Pain injection site_after regression_2
    0
        Pain injection site_after regression_3
    0
        Pain injection site_after regression_4
    0
        Pain injection site_after regression_5
    0
        Pain injection site_after regression_6
    0
        Pain injection site_after regression_7
    0
        Pain injection site_after regression_8
    0
        Pain injection site_after regression_9
    0
        Pain injection site_after regression_10
    0
        Pain injection site_discharge_0
    45
        Pain injection site_discharge_1
    0
        Pain injection site_discharge_2
    0
        Pain injection site_discharge_3
    0
        Pain injection site_discharge_4
    0
        Pain injection site_discharge_5
    0
        Pain injection site_discharge_6
    0
        Pain injection site_discharge_7
    0
        Pain injection site_discharge_8
    0
        Pain injection site_discharge_9
    0
        Pain injection site_discharge_10
    0
        Pain injection site_day2_0
    37
        Pain injection site_day2_1
    4
        Pain injection site_day2_2
    1
        Pain injection site_day2_3
    0
        Pain injection site_day2_4
    0
        Pain injection site_day2_5
    2
        Pain injection site_day2_6
    0
        Pain injection site_day2_7
    0
        Pain injection site_day2_8
    1
        Pain injection site_day2_9
    0
        Pain injection site_day2_10
    0
        Pain injection site_day 7±1_0
    44
        Pain injection site_day 7±1_1
    1
        Pain injection site_day 7±1_2
    0
        Pain injection site_day 7±1_3
    0
        Pain injection site_day 7±1_4
    0
        Pain injection site_day 7±1_5
    0
        Pain injection site_day 7±1_6
    0
        Pain injection site_day 7±1_7
    0
        Pain injection site_day 7±1_8
    0
        Pain injection site_day 7±1_9
    0
        Pain injection site_day 7±1_10
    0
        Pain surgery site_after regression_0
    13
        Pain surgery site_after regression_1
    2
        Pain surgery site_after regression_2
    8
        Pain surgery site_after regression_3
    4
        Pain surgery site_after regression_4
    9
        Pain surgery site_after regression_5
    5
        Pain surgery site_after regression_6
    2
        Pain surgery site_after regression_7
    1
        Pain surgery site_after regression_8
    1
        Pain surgery site_after regression_9
    0
        Pain surgery site_after regression_10
    0
        Pain surgery site_discharge_0
    17
        Pain surgery site_discharge_1
    6
        Pain surgery site_discharge_2
    7
        Pain surgery site_discharge_3
    14
        Pain surgery site_discharge_4
    1
        Pain surgery site_discharge_5
    0
        Pain surgery site_discharge_6
    0
        Pain surgery site_discharge_7
    0
        Pain surgery site_discharge_8
    0
        Pain surgery site_discharge_9
    0
        Pain surgery site_discharge_10
    0
        Pain surgery site_day2_0
    20
        Pain surgery site_day2_1
    3
        Pain surgery site_day2_2
    6
        Pain surgery site_day2_3
    6
        Pain surgery site_day2_4
    3
        Pain surgery site_day2_5
    3
        Pain surgery site_day2_6
    2
        Pain surgery site_day2_7
    2
        Pain surgery site_day2_8
    0
        Pain surgery site_day2_9
    0
        Pain surgery site_day2_10
    0
        Pain surgery site_day 7±1_0
    37
        Pain surgery site_day 7±1_1
    3
        Pain surgery site_day 7±1_2
    0
        Pain surgery site_day 7±1_3
    3
        Pain surgery site_day 7±1_4
    0
        Pain surgery site_day 7±1_5
    2
        Pain surgery site_day 7±1_6
    0
        Pain surgery site_day 7±1_7
    0
        Pain surgery site_day 7±1_8
    0
        Pain surgery site_day 7±1_9
    0
        Pain surgery site_day 7±1_10
    0
    Attachments
    		 Untitled (Filename: Pain assessment_Safety Set.pdf)
    No statistical analyses for this end point

    Other pre-specified: to collect heart rate (HR) for safety assessment

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    End point title
    		 to collect heart rate (HR) for safety assessment
    End point description
    The complete safety end point is to investigate the safety and tolerability of the administered Chloroprocaine HCl 1% doses based on vital signs (blood pressure [BP], heart rate [HR] and peripheral oxygen saturation [SpO2]) check and ECG recording. It was split in 4 sub-endpoints for entering values for each parameter This is a safety variable
    End point type
    Other pre-specified
    End point timeframe
    at screening, at baseline and at discharge
    End point values
    		 Dose 1 Dose 2 Dose 3 Safety set
    Number of subjects analysed
    15
    15
    15
    45
    Units: beats/min
    arithmetic mean (standard deviation)
        HR_screening
    62.2 ( 8.5 )
    67.5 ( 11.4 )
    70.7 ( 8.6 )
    66.8 ( 10.0 )
        HR_baseline
    63.1 ( 9.4 )
    71.0 ( 14.0 )
    71.7 ( 9.2 )
    68.6 ( 11.5 )
        HR_discharge
    64.9 ( 7.0 )
    66.9 ( 10.0 )
    67.0 ( 8.0 )
    66.2 ( 8.3 )
    No statistical analyses for this end point

    Other pre-specified: to collect peripheral oxygen saturation (SpO2) for safety assessment

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    End point title
    		 to collect peripheral oxygen saturation (SpO2) for safety assessment
    End point description
    The complete safety end point is to investigate the safety and tolerability of the administered Chloroprocaine HCl 1% doses based on vital signs (blood pressure [BP], heart rate [HR] and peripheral oxygen saturation [SpO2]) check and ECG recording. It was split in 4 sub-endpoints for entering values for each parameter. This is a safety variable.
    End point type
    Other pre-specified
    End point timeframe
    at screening, at baseline and at discharge
    End point values
    		 Dose 1 Dose 2 Dose 3 Safety set
    Number of subjects analysed
    15
    15
    15
    45
    Units: HbO2/circulating Hb
    arithmetic mean (standard deviation)
        SpO2 (%)_screening
    99.07 ( 0.96 )
    99.13 ( 1.25 )
    98.53 ( 1.36 )
    98.91 ( 1.20 )
        SpO2 (%)_baseline
    99.40 ( 0.91 )
    99.13 ( 0.83 )
    98.53 ( 1.51 )
    99.02 ( 1.16 )
        SpO2 (%)_discharge
    99.33 ( 0.72 )
    99.33 ( 0.90 )
    99.00 ( 1.07 )
    99.22 ( 0.90 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    during the entire study period: from Visit 1 Days -14/1 to Follow up visit (Day 7±1)
    Adverse event reporting additional description
    AEs were classified as pre-treatment AEs (PTAEs) and TEAEs according to the period of their occurrence, as follows: - PTAEs: all AEs occurring before the IMP spinal injection and not worsening after the IMP spinal injection; - TEAEs: all AEs occurring or worsening after the IMP spinal injection.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    CHL 30 mg
    Reporting group description
    		 subjects for safety set who received 30 mg of Chloroprocaine HCl 1%

    Reporting group title
    CHL 40 mg
    Reporting group description
    		 subjects for safety set who received 40 mg of Chloroprocaine HCl 1%

    Reporting group title
    CHL 50 mg
    Reporting group description
    		 subjects for safety set who received 50 mg of Chloroprocaine HCl 1%

    Serious adverse events
    		 CHL 30 mg CHL 40 mg CHL 50 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 CHL 30 mg CHL 40 mg CHL 50 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 15 (100.00%)
    13 / 15 (86.67%)
    13 / 15 (86.67%)
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    14 / 15 (93.33%)
    13 / 15 (86.67%)
    13 / 15 (86.67%)
         occurrences all number
    15
    13
    13
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    2 / 15 (13.33%)
    3 / 15 (20.00%)
    3 / 15 (20.00%)
         occurrences all number
    2
    3
    3
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    Diarrhoea
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    None reported
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