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    Clinical Trial Results:
    The effect of Canagliflozin 300mg, in subjects without diabetes after bariatric surgery, on glucose homeostasis (The CONTROL Study): A proof-of-concept, randomised, open-label, two period crossover study.

    Summary
    EudraCT number
    		 2019-004041-32
    Trial protocol
    		 GB  
    Global end of trial date
    31 Dec 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Jan 2025
    First version publication date
    05 Jan 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    0701
    Additional study identifiers
    ISRCTN number
    		 ISRCTN11342830
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Leicester
    Sponsor organisation address
    University Road, Leicester, United Kingdom, LE1 7RH
    Public contact
    Dr Dimitris Papamargaritis, Leicester Diabetes Centre, +44 01162588973, dimitris.papamargaritis@uhl-tr.nhs.uk
    Scientific contact
    Dr Dimitris Papamargaritis, Leicester Diabetes Centre, +44 01162588973, dimitris.papamargaritis@uhl-tr.nhs.uk
    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
    28 Nov 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Nov 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the effect of canagliflozin 300 mg (CANA300) on glucose levels, insulin and gut hormones after a meal in people without diabetes after weight-loss surgery. This was a randomised, open-label, two period, cross-over study comparing CANA300 with standard care in people after weight loss surgery.
    Protection of trial subjects
    In UK, more than 25% of the population is living with obesity and approximately 10% suffers from severe and complex obesity (defined as BMI≥35 kg/m2 with obesity related comorbidities). Bariatric surgery (BS) is currently the most effective method to achieve substantial weight loss and maintenance in people with severe and complex obesity. Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) account for more than 90% of bariatric procedures worldwide. Despite the successful weight loss and weight maintenance, some long-term complications can develop after both RYGB and SG, such as nutritional and vitamin deficiencies, early dumping syndrome and postprandial hyperinsulinaemic hypoglycaemia (PHH). PHH is a condition characterised by hypoglycaemic symptoms occurring 1-3 hours after a meal accompanied by a low glucose value, typically preceded by a high rise in both glucose and insulin concentration due to rapid gastric emptying and changes in glucose absorption post operatively. PHH has been described since 1940s as complication of gastric resection in people suffering from peptic ulcers and was named “late dumping”. The condition has recently warranted further attention due to the increased number of bariatric procedures worldwide. It is of note that recurrent PHH after BS is associated with reduced quality of life, high degree of functional disability (inability to work, drive, care for others) and weight regain. In addition, an increased rate of accidental deaths, syncopal episodes and seizures among people who have undergone BS has been reported, and it is speculated that this could be partially due to neuroglycopenic symptoms as result of severe PHH. In this study, all participants were people without known history of PHH and without frequent symptoms suggestive of hypoglycaemia in daily life.
    Background therapy
    		 People allocated to standard care treatment sequence were asked to continue their usual daily life without changing their diet and daily life habits.
    Evidence for comparator
    		 Treatment options for PHH after BS are limited, and people experiencing PHH are most commonly encouraged to follow dietary modifications consisting of small, frequent and low in carbohydrates meals. Medical treatments for PHH after BS include mainly acarbose but effectiveness can be limited, while the gastrointestinal side effects limits further its use. Canagliflozin is a Sodium-glucose co-transporter-2 (SGLT-2) inhibitor that is used worldwide for type 2 diabetes management. However, CANA300 once daily - the highest licensed dose - has a transient inhibitory effect on SGLT-1, on top of the relatively strong inhibition of SGLT-2. Mild to moderate pharmacological inhibition of SGLT-1 in the small intestine reduces postprandial excursion of glucose without causing severe diarrhoea or malabsorption. Indeed, CANA300 reduces the postprandial glucose excursions and insulin secretion and increases the postprandial glucose nadir in healthy individuals – this effect appears stronger with CANA300 compared to other available SGLT-2 inhibitors. So, if this effect on glucose homeostasis is also observed after BS then CANA300 could potentially be a treatment option for PHH after BS. Indeed, there are case reports and small observational studies where CANA300 has been successfully used to treat cases of PHH after BS. In addition, SGLT-2 inhibitors may increase glucagon secretion in normal healthy people, which could also play a role in preventing hypoglycaemic episodes in people on SGLT-2 inhibitors. Taking into account that CANA300 has also known cardiometabolic benefits (including weight loss), it could become an attractive option for PHH treatment after BS.
    Actual start date of recruitment
    10 Aug 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 24
    Worldwide total number of subjects
    24
    EEA total number of subjects
    0
    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)
    20
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited from the University Hospitals of Leicester NHS Trust, UK Recruitment open: 21/05/2021 First recruit: 10/08/2021 Last recruit: 13/04/2023 Recruitment closed: 13/04/2023

    Pre-assignment
    Screening details
    		 Participants were screened for eligibility by their age, ability to understand English and give consent, lack of diabetes diagnosis and whether they were at least one year after RYGB or SG surgery. We screened a total of 36 participants.

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 CANA 300mg
    Arm description
    		 Pooled data from visits 2 and 4, were used to analyse the treatment effect of canagliflozin 300mg, based on the two randomisation groups: Group A = canagliflozin 300mg and then standard care Group B = standard care and then canagliflozin 300 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Canagliflozin 300mg
    Investigational medicinal product code
    Other name
    Invokana
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one tablet of canagliflozin 300mg daily for 5 days

    Arm title
    		 Standard care
    Arm description
    		 Pooled data from visits 2 and 4, were used to analyse the treatment effect of standard care, based on the two randomisation groups: Group A = canagliflozin 300 mg and then standard care Group B = standard care and then canagliflozin 300 mg
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		CANA 300mg Standard care
    Started
    24
    24
    Visit 1-randomisation/baseline
    24
    24
    Visit 2 -mixed meal tolerance test
    22
    22
    Washout period of 3 weeks
    22
    22
    Visit 3-switching groups
    22
    22
    Visit 4-mixed meal tolerance test
    21
    21
    Completed
    21
    21
    Not completed
    3
    3
         Consent withdrawn by subject
    2
    2
         Adverse event, non-fatal
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall period
    Reporting group description
    		 24 participants attended the baseline visit, 14 of which had undergone Roux-en-Y Gastric Bypass (RYGB) and 10 who had undergone Sleeve gastrectomy (SG) bariatric surgery. Depending on the amount of missing data, less participants were included in the analysis of primary and secondary outcomes.

    Reporting group values
    		 Overall period Total
    Number of subjects
    		 24 24
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 20 20
        From 65-84 years
    		 4 4
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.8 ( 9.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 21 21
        Male
    		 3 3
    Ethnicity
    Units: Subjects
        White British
    		 22 22
        Indian
    		 1 1
        Other African background
    		 1 1
    Alcohol Status
    Units: Subjects
        Current
    		 21 21
        Ex-drinker
    		 1 1
        Never drank
    		 2 2
    Smoking history
    Units: Subjects
        Ex-smoker
    		 11 11
        Never smoked
    		 13 13
    Height
    Units: centimetre
        arithmetic mean (standard deviation)
    		 163.7 ( 7.6 ) -
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 96.8 ( 23.8 ) -
    Body fat
    Units: percent
        arithmetic mean (standard deviation)
    		 43 ( 10.5 ) -
    Systolic blood pressure
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 121 ( 16.2 ) -
    Diastolic blood pressure
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 74.9 ( 11.3 ) -
    HbA1c
    Units: percent
        arithmetic mean (standard deviation)
    		 5.4 ( 0.4 ) -
    Heart rate
    Units: bpm
        arithmetic mean (standard deviation)
    		 70.8 ( 8 ) -
    BMI
    Units: kilogram(s)/square metre
        arithmetic mean (standard deviation)
    		 36 ( 8.2 ) -

    End points

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    End points reporting groups
    Reporting group title
    CANA 300mg
    Reporting group description
    		 Pooled data from visits 2 and 4, were used to analyse the treatment effect of canagliflozin 300mg, based on the two randomisation groups: Group A = canagliflozin 300mg and then standard care Group B = standard care and then canagliflozin 300 mg

    Reporting group title
    Standard care
    Reporting group description
    		 Pooled data from visits 2 and 4, were used to analyse the treatment effect of standard care, based on the two randomisation groups: Group A = canagliflozin 300 mg and then standard care Group B = standard care and then canagliflozin 300 mg

    Primary: The difference in nadir glucose levels between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in nadir glucose levels between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test
    End point description
    The lowest plasma glucose value detected during visits 2,4 for CANA300 mg and standard care groups
    End point type
    Primary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: millimole(s)/litre
        arithmetic mean (standard deviation)
    3.75 ( 0.7 )
    3.41 ( 0.78 )
    Statistical analysis title
    		 Paired t-test
    Statistical analysis description
    Paired t-test to compare the mean difference in nadir glucose values between the CANA300 mg and standard care groups. The analysis subjects were 19 in total, given the paired nature of the crossover study. 12 subjects had undergone RYGB and 7 had undergone SG bariatric surgery. For all secondary outcomes with 19 participants reported, the number of participants having undergone RYGB and SG bariatric surgery, remains the same.
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.05
         upper limit
    		 0.65
    Variability estimate
    Standard error of the mean

    Secondary: Difference in fasting glucose levels between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 Difference in fasting glucose levels between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: millimole(s)/litre
        arithmetic mean (standard deviation)
    4.39 ( 0.46 )
    4.64 ( 0.45 )
    Statistical analysis title
    		 Paired t-test
    Statistical analysis description
    Paired t-test to compare the mean difference in fasting glucose values between the CANA300 mg and standard care The analysis subjects in are 19 in total, given the paired nature of the crossover study
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.37
         upper limit
    		 -0.13
    Variability estimate
    Standard error of the mean

    Secondary: Difference in peak glucose levels between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 Difference in peak glucose levels between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: millimole(s)/litre
        arithmetic mean (standard deviation)
    7.25 ( 1.33 )
    8.26 ( 1.41 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    Standard care v CANA 300mg
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.65
         upper limit
    		 -0.37
    Variability estimate
    Standard error of the mean

    Secondary: Difference in peak-nadir glucose levels between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 Difference in peak-nadir glucose levels between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: millimole(s)/litre
        arithmetic mean (standard deviation)
    3.49 ( 1.07 )
    4.85 ( 1.39 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.93
         upper limit
    		 -0.79
    Variability estimate
    Standard error of the mean

    Secondary: Difference in the max/min ratio of glucose levels between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 Difference in the max/min ratio of glucose levels between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: standardised ratio
        arithmetic mean (standard deviation)
    1.96 ( 0.3 )
    2.50 ( 0.49 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.77
         upper limit
    		 -0.32
    Variability estimate
    Standard error of the mean

    Secondary: The difference in glucose tAUC(0-180) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in glucose tAUC(0-180) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    16
    16
    Units: minutes × mmol/L
        arithmetic mean (standard deviation)
    919.88 ( 143.29 )
    960.23 ( 149.7 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.06
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -40.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -83.29
         upper limit
    		 2.58
    Variability estimate
    Standard error of the mean
    Notes
    [1] - For the secondary outcomes regarding AUC of 0-180,60-180 glucose calculations only, it was decided not to impute missing data, as 3 participants had to stop the MMTT due to hypoglycaemia. Therefore, the total number of participants was 16.

    Secondary: The difference in glucose tAUC(0-30) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in glucose tAUC(0-30) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: minutes × mmol/L
        arithmetic mean (standard deviation)
    177.71 ( 32.61 )
    204.51 ( 24.75 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -26.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -37.95
         upper limit
    		 -15.65
    Variability estimate
    Standard error of the mean

    Secondary: The difference in glucose positive iAUC(0-180) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in glucose positive iAUC(0-180) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    16
    16
    Units: minutes × mmol/L
        arithmetic mean (standard deviation)
    155.53 ( 74.93 )
    174.61 ( 71.74 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.25
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -19.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -52.79
         upper limit
    		 14.64
    Variability estimate
    Standard error of the mean

    Secondary: The difference in glucose net iAUC(0-180) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in glucose net iAUC(0-180) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    16
    16
    Units: minutes × mmol/L
        arithmetic mean (standard deviation)
    124.50 ( 104.87 )
    114.23 ( 124.14 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.56
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    10.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.43
         upper limit
    		 46.96
    Variability estimate
    Standard error of the mean

    Secondary: The difference in glucose positive iAUC(0-30) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in glucose positive iAUC(0-30) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: minutes × mmol/L
        arithmetic mean (standard deviation)
    45.87 ( 21.14 )
    65.39 ( 28.62 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -19.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28.53
         upper limit
    		 -10.51
    Variability estimate
    Standard error of the mean

    Secondary: The difference in glucose net iAUC(0-30) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in glucose net iAUC(0-30) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: minutes × mmol/L
        arithmetic mean (standard deviation)
    45.87 ( 21.14 )
    65.25 ( 28.94 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -19.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28.52
         upper limit
    		 -10.24
    Variability estimate
    Standard error of the mean

    Secondary: The difference in glucose negative iAUC(0-180) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in glucose negative iAUC(0-180) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    16
    16
    Units: minutes × mmol/L
        arithmetic mean (standard deviation)
    116.44 ( 109.84 )
    98.20 ( 128.10 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.29
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    18.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.17
         upper limit
    		 53.64
    Variability estimate
    Standard error of the mean

    Secondary: The difference in glucose negative iAUC(0-30) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in glucose negative iAUC(0-30) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: minutes × mmol/L
        arithmetic mean (standard deviation)
    45.87 ( 21.14 )
    65.19 ( 29.09 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -19.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28.52
         upper limit
    		 -10.12
    Variability estimate
    Standard error of the mean

    Secondary: Difference in fasting insulin levels between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 Difference in fasting insulin levels between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: mIU/L
        median (inter-quartile range (Q1-Q3))
    5.83 (4.3 to 8.72)
    6.87 (4.46 to 13.06)
    Statistical analysis title
    		 Wilcox signed rank test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.56
         upper limit
    		 -0.15

    Secondary: The difference in peak insulin levels between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in peak insulin levels between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: mIU/L
        arithmetic mean (standard deviation)
    102.74 ( 63.62 )
    123.73 ( 74.86 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.06
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -20.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -42.73
         upper limit
    		 0.75
    Variability estimate
    Standard error of the mean

    Secondary: The difference in insulin tAUC(0-180) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in insulin tAUC(0-180) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: minutes × mIU/L
        arithmetic mean (standard deviation)
    5699.72 ( 2984.15 )
    7086.81 ( 4211.69 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1387.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2512.97
         upper limit
    		 -261.22
    Variability estimate
    Standard error of the mean

    Secondary: The difference in insulin tAUC(0-30) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in insulin tAUC(0-30) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: minutes × mIU/L
        arithmetic mean (standard deviation)
    1753.95 ( 1003.54 )
    2276.17 ( 1508.77 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -522.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -867.69
         upper limit
    		 -176.75
    Variability estimate
    Standard error of the mean

    Secondary: The difference in insulin net iAUC(0-180) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in insulin net iAUC(0-180) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: minutes × mIU/L
        arithmetic mean (standard deviation)
    4410.79 ( 2276.53 )
    5490.73 ( 3484.68 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.07
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1079.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2243.87
         upper limit
    		 83.97
    Variability estimate
    Standard error of the mean

    Secondary: The difference in insulin net iAUC(0-30) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test

    		 Close Top of page
    End point title
    		 The difference in insulin net iAUC(0-30) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: minutes × mIU/L
        median (inter-quartile range (Q1-Q3))
    1416.44 (720.84 to 2093.01)
    1515.40 (1298.51 to 2586.68)
    Statistical analysis title
    		 Wilcox signed rank test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -477.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -825.3
         upper limit
    		 99.06

    Secondary: The difference in the ratio AUC insulin(0-180)/AUC glucose(0-180) between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in the ratio AUC insulin(0-180)/AUC glucose(0-180) between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    16
    16
    Units: mIU/mmol
        arithmetic mean (standard deviation)
    6.08 ( 3.26 )
    7.22 ( 4.36 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.09
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.45
         upper limit
    		 0.19
    Variability estimate
    Standard error of the mean

    Secondary: The difference in the ratio AUC insulin(0-30)/AUC glucose(0-30) between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in the ratio AUC insulin(0-30)/AUC glucose(0-30) between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: mIU/mmol
        median (inter-quartile range (Q1-Q3))
    7.62 (5.27 to 10.53)
    8.6 (6.27 to 13.03)
    Statistical analysis title
    		 Wilcox signed rank test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.23
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.98
         upper limit
    		 -0.94

    Secondary: The difference in the ratio net iAUC insulin(0-180)/iAUC glucose(0-180) between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in the ratio net iAUC insulin(0-180)/iAUC glucose(0-180) between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    16
    16
    Units: mIU/mmol
        median (inter-quartile range (Q1-Q3))
    21.33 (13.36 to 57.44)
    24.50 (18.64 to 47.04)
    Statistical analysis title
    		 Wilcox signed rank test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.78
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -2.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.57
         upper limit
    		 197.02

    Secondary: The difference in the ratio net iAUC insulin(0-30)/iAUC glucose(0-30) between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test

    		 Close Top of page
    End point title
    		 The difference in the ratio net iAUC insulin(0-30)/iAUC glucose(0-30) between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: mIU/mmol
        median (inter-quartile range (Q1-Q3))
    23.72 (19.14 to 47.77)
    21 (15.85 to 38.63)
    Statistical analysis title
    		 Wilcox signed rank test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.36
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    3.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.34
         upper limit
    		 7.96

    Secondary: The difference in the ratio AUC insulin(60-180)/AUC glucose(60-180) between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in the ratio AUC insulin(60-180)/AUC glucose(60-180) between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    16
    16
    Units: mIU/mmol
        median (inter-quartile range (Q1-Q3))
    2.19 (2.07 to 4.67)
    2.49 (2.11 to 6.08)
    Statistical analysis title
    		 Wilcox signed rank test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.08
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -0.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.59
         upper limit
    		 0.04

    Secondary: The difference in the ratio net iAUC insulin(60-180)/iAUC glucose(60-180) between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test

    		 Close Top of page
    End point title
    		 The difference in the ratio net iAUC insulin(60-180)/iAUC glucose(60-180) between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    16
    16
    Units: mIU/mmol
        median (inter-quartile range (Q1-Q3))
    10.52 (2.89 to 26.39)
    13.8 (2.11 to 34.73)
    Statistical analysis title
    		 Wilcox signed rank test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.23
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    3.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 61.05

    Secondary: The difference in fasting C-peptide levels between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in fasting C-peptide levels between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: picogram(s)/millilitre
        median (inter-quartile range (Q1-Q3))
    798.73 (630.03 to 1109.54)
    1044.56 (629.94 to 1261.11)
    Statistical analysis title
    		 Wilcox signed rank test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.16
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -61.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -171.7
         upper limit
    		 32.46

    Secondary: The difference in peak C-peptide levels between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in peak C-peptide levels between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: picogram(s)/millilitre
        median (inter-quartile range (Q1-Q3))
    4128.30 (3236.90 to 5296.95)
    4278.60 (3554.75 to 7243.80)
    Statistical analysis title
    		 Wilcox signed rank test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.07
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -495.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1275.7
         upper limit
    		 36.9

    Secondary: The difference in C-peptide tAUC(0-180) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in C-peptide tAUC(0-180) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: minutes × pg/mL
        median (inter-quartile range (Q1-Q3))
    393657.60 (305100.3 to 527728.9)
    408722.20 (349033.6 to 578742.8)
    Statistical analysis title
    		 Wilcox signed rank test
    Comparison groups
    Standard care v CANA 300mg
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -31195.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -75875.21
         upper limit
    		 9387.7

    Secondary: The difference in C-peptide tAUC(0-30) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in C-peptide tAUC(0-30) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: minutes × pg/mL
        median (inter-quartile range (Q1-Q3))
    83162.22 (59399.21 to 98316.15)
    87094.41 (70364.60 to 135148.88)
    Statistical analysis title
    		 Wilcox signed rank test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -15546.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -30245.51
         upper limit
    		 -7091.22

    Secondary: The difference in C-peptide net iAUC(0-180) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in C-peptide net iAUC(0-180) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: minutes × pg/mL
        arithmetic mean (standard deviation)
    269097 ( 106055.8 )
    300105.60 ( 137974 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.17
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -31008.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -76328.72
         upper limit
    		 14311.56
    Variability estimate
    Standard error of the mean

    Secondary: The difference in C-peptide net iAUC(0-30) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test

    		 Close Top of page
    End point title
    		 The difference in C-peptide net iAUC(0-30) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: minutes × pg/mL
        median (inter-quartile range (Q1-Q3))
    45287.46 (33097.44 to 69817.28)
    60668.44 (45645.12 to 105836.15)
    Statistical analysis title
    		 Wilcox signed rank test
    Comparison groups
    Standard care v CANA 300mg
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -15661.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -30537.07
         upper limit
    		 -5086.91

    Secondary: The difference in the ratio AUC C-peptide(0-180)/AUC glucose(0-180) between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in the ratio AUC C-peptide(0-180)/AUC glucose(0-180) between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    16
    16
    Units: (pg × L) / (mL × mmol)
        arithmetic mean (standard deviation)
    493.25 ( 169.47 )
    522.05 ( 207.82 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.32
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -28.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -87.96
         upper limit
    		 30.36
    Variability estimate
    Standard error of the mean

    Secondary: The difference in the ratio AUC C-peptide(0-30)/AUC glucose(0-30) between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in the ratio AUC C-peptide(0-30)/AUC glucose(0-30) between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4 
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: (pg × L) / (mL × mmol)
        median (inter-quartile range (Q1-Q3))
    409.49 (357.87 to 580.58)
    453.06 (366.33 to 453.06)
    Statistical analysis title
    		 Wilcox signed rank test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.38
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -16.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -78.5
         upper limit
    		 24.36

    Secondary: The difference in the ratio iAUC C-peptide(0-180)/iAUC glucose(0-180) between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in the ratio iAUC C-peptide(0-180)/iAUC glucose(0-180) between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    16
    16
    Units: (pg × L) / (mL × mmol)
        median (inter-quartile range (Q1-Q3))
    1644.65 (1037.30 to 2937.94)
    1309.24 (1007.74 to 2078.03)
    Statistical analysis title
    		 Wilcox signed rank test
    Comparison groups
    Standard care v CANA 300mg
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    67.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -310.75
         upper limit
    		 10092.43

    Secondary: The difference in the ratio iAUC C-peptide(0-30)/iAUC glucose(0-30) between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in the ratio iAUC C-peptide(0-30)/iAUC glucose(0-30) between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: (pg × L) / (mL × mmol)
        median (inter-quartile range (Q1-Q3))
    1147.10 (782.71 to 1718.39)
    937.28 (772.38 to 1561.57)
    Statistical analysis title
    		 Wilcox signed rank test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.19
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    119.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -61.98
         upper limit
    		 280.08

    Secondary: The difference in the ratio AUC C-peptide(60-180)/AUC glucose(60-180) between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in the ratio AUC C-peptide(60-180)/AUC glucose(60-180) between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    16
    16
    Units: (pg × L) / (mL × mmol)
        median (inter-quartile range (Q1-Q3))
    392.53 (304.32 to 580.52)
    357.78 (323.92 to 531.40)
    Statistical analysis title
    		 Wilcox signed rank test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.86
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -1.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -63.06
         upper limit
    		 34.43

    Secondary: The difference in the ratio iAUC C-peptide(60-180)/iAUC glucose(60-180) between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in the ratio iAUC C-peptide(60-180)/iAUC glucose(60-180) between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    16
    16
    Units: (pg × L) / (mL × mmol)
        median (inter-quartile range (Q1-Q3))
    698.76 (475.70 to 878.58)
    1016.46 (387.63 to 1708.40)
    Statistical analysis title
    		 Wilcox signed rank test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.09
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    756.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -110.82
         upper limit
    		 3162.2

    Secondary: The difference in fasting GLP-1 levels between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in fasting GLP-1 levels between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: pmol/L
        arithmetic mean (standard deviation)
    37.58 ( 16.32 )
    32.67 ( 15.91 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 t-test, 2-sided
    Parameter type
    		 Median difference (final values)
    Point estimate
    4.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 8.88
    Variability estimate
    Standard error of the mean

    Secondary: The difference in peak GLP-1 levels between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in peak GLP-1 levels between the two treatment options (CANA300 mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: pmol/L
        arithmetic mean (standard deviation)
    183.06 ( 83.38 )
    173.56 ( 81.05 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.55
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    9.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.36
         upper limit
    		 42.35
    Variability estimate
    Standard error of the mean

    Secondary: The difference in GLP-1 tAUC(0-180) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in GLP-1 tAUC(0-180) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: minutes × pmol/L
        arithmetic mean (standard deviation)
    15312.74 ( 5132.11 )
    12725.29 ( 3924.41 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2587.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1140.67
         upper limit
    		 4034.229
    Variability estimate
    Standard error of the mean

    Secondary: The difference in GLP-1 tAUC(0-30) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in GLP-1 tAUC(0-30) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: minutes × pmol/L
        arithmetic mean (standard deviation)
    3670.62 ( 1533.51 )
    3483.69 ( 1562.41 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    Standard care v CANA 300mg
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.38
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    186.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -252.73
         upper limit
    		 626.6
    Variability estimate
    Standard error of the mean

    Secondary: The difference in GLP-1 net iAUC(0-180) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in GLP-1 net iAUC(0-180) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: minutes × pmol/L
        arithmetic mean (standard deviation)
    8547.46 ( 4988.76 )
    6845.15 ( 4045.26 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1702.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 147.7
         upper limit
    		 3256.91
    Variability estimate
    Standard error of the mean

    Secondary: The difference in GLP-1 net iAUC(0-30) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test

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    End point title
    		 The difference in GLP-1 net iAUC(0-30) between the two treatment options (CANA300mg vs standard care) after the mixed meal tolerance test
    End point description
    End point type
    Secondary
    End point timeframe
    Visits 2,4
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    19
    19
    Units: minutes × pmol/L
        arithmetic mean (standard deviation)
    2543.08 ( 1495.8 )
    2503.67 ( 1545.62 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.86
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    39.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -425.32
         upper limit
    		 504.14
    Variability estimate
    Standard error of the mean

    Secondary: Difference in nadir glucose during CGM between the two treatment options (CANA 300mg vs standard care)

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    End point title
    		 Difference in nadir glucose during CGM between the two treatment options (CANA 300mg vs standard care)
    End point description
    End point type
    Secondary
    End point timeframe
    5 days after Visit 1 and 5 days after Visit 3
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    14
    14
    Units: millimole(s)/litre
        arithmetic mean (standard deviation)
    3.05 ( 0.68 )
    2.78 ( 0.65 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.35
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.33
         upper limit
    		 0.87
    Variability estimate
    Standard error of the mean

    Secondary: Difference in % time in interstitial glucose levels in CGM spent in< 3.9 mmol/l between the two treatment options (CANA 300mg vs standard care)

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    End point title
    		 Difference in % time in interstitial glucose levels in CGM spent in< 3.9 mmol/l between the two treatment options (CANA 300mg vs standard care)
    End point description
    End point type
    Secondary
    End point timeframe
    5 days after Visit 1 and 5 days after Visit 3
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    14
    14
    Units: percent
        median (inter-quartile range (Q1-Q3))
    0.81 (0.14 to 2.64)
    0.69 (0.30 to 1.16)
    Statistical analysis title
    		 Wilcox signed rank test
    Statistical analysis description
    Out of 14 participants with available CGM data, 8 had undergone RYGB and 6 SG bariatric surgery.
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.78
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    0.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.82
         upper limit
    		 3.62

    Secondary: Difference in % time in interstitial glucose levels in CGM spent between (3.9-10.0 mmol/l) between the two treatment options (CANA 300mg vs standard care)

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    End point title
    		 Difference in % time in interstitial glucose levels in CGM spent between (3.9-10.0 mmol/l) between the two treatment options (CANA 300mg vs standard care)
    End point description
    End point type
    Secondary
    End point timeframe
    5 days after Visit 1 and 5 days after Visit 3
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    14
    14
    Units: percent
        median (inter-quartile range (Q1-Q3))
    96.31 (95.21 to 98.36)
    96.63 (94.92 to 98.21)
    Statistical analysis title
    		 Wilcox signed rank test
    Comparison groups
    Standard care v CANA 300mg
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.62
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.74
         upper limit
    		 2.27

    Secondary: Difference in % time in interstitial glucose levels in CGM spent between (3.0-10.0) mmol/l between the two treatment options (CANA 300mg vs standard care

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    End point title
    		 Difference in % time in interstitial glucose levels in CGM spent between (3.0-10.0) mmol/l between the two treatment options (CANA 300mg vs standard care
    End point description
    End point type
    Secondary
    End point timeframe
    5 days after Visit 1 and 5 days after Visit 3
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    14
    14
    Units: percent
        median (inter-quartile range (Q1-Q3))
    98.62 (96.88 to 99.20)
    97.34 (96.66 to 98.50)
    Statistical analysis title
    		 Wilcox signed rank test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.14
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.22
         upper limit
    		 2.9

    Secondary: Difference in % time in interstitial glucose levels in CGM spent above 7.8 mmol/l between the two treatment options (CANA 300mg vs standard care)

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    End point title
    		 Difference in % time in interstitial glucose levels in CGM spent above 7.8 mmol/l between the two treatment options (CANA 300mg vs standard care)
    End point description
    End point type
    Secondary
    End point timeframe
    5 days after Visit 1 and 5 days after Visit 3
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    14
    14
    Units: percent
        arithmetic mean (standard deviation)
    9.46 ( 4.96 )
    13.01 ( 6.79 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.09
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.72
         upper limit
    		 0.62
    Variability estimate
    Standard error of the mean

    Secondary: Difference in % time in interstitial glucose levels in CGM spent above 10.0 mmol/l between the two treatment options (CANA 300mg vs standard care)

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    End point title
    		 Difference in % time in interstitial glucose levels in CGM spent above 10.0 mmol/l between the two treatment options (CANA 300mg vs standard care)
    End point description
    End point type
    Secondary
    End point timeframe
    5 days after Visit 1 and 5 days after Visit 3
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    14
    14
    Units: percent
        median (inter-quartile range (Q1-Q3))
    0.89 (0.53 to 2.52)
    2.42 (1.15 to 3.05)
    Statistical analysis title
    		 Wilcox signed rank test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.02
         upper limit
    		 0.26

    Secondary: Difference in % time in interstitial glucose levels in CGM spent in hypoglycemia (<= 3 .0 mmol/l) between the two treatment options (CANA 300mg vs standard care)

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    End point title
    		 Difference in % time in interstitial glucose levels in CGM spent in hypoglycemia (<= 3 .0 mmol/l) between the two treatment options (CANA 300mg vs standard care)
    End point description
    End point type
    Secondary
    End point timeframe
    5 days after Visit 1 and 5 days after Visit 3
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    14
    14
    Units: percent
        median (inter-quartile range (Q1-Q3))
    0.00 (0.00 to 0.55)
    0.11 (0.00 to 0.28)
    Statistical analysis title
    		 Wilcox signed rank test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.82
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 0.58

    Secondary: Difference in % time in interstitial glucose levels in CGM spent between (3.9-7.8) mmol/l between the two treatment options (CANA 300mg vs standard care)

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    End point title
    		 Difference in % time in interstitial glucose levels in CGM spent between (3.9-7.8) mmol/l between the two treatment options (CANA 300mg vs standard care)
    End point description
    End point type
    Secondary
    End point timeframe
    5 days after Visit 1 and 5 days after Visit 3
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    14
    14
    Units: percent
        arithmetic mean (standard deviation)
    88.23 ( 4.15 )
    85.78 ( 6.28 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.16
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.12
         upper limit
    		 6
    Variability estimate
    Standard error of the mean

    Secondary: Difference in mean interstitial glucose in CGM between the two treatment options (CANA300 mg vs standard care)

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    End point title
    		 Difference in mean interstitial glucose in CGM between the two treatment options (CANA300 mg vs standard care)
    End point description
    End point type
    Secondary
    End point timeframe
    5 days after Visit 1 and 5 days after Visit 3
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    14
    14
    Units: millimole(s)/litre
        arithmetic mean (standard deviation)
    6.03 ( 0.57 )
    6.40 ( 0.58 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.08
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.79
         upper limit
    		 0.05
    Variability estimate
    Standard error of the mean

    Secondary: Difference in standard deviation (SD) of the mean interstitial glucose in CGM between the two treatment options (CANA300 mg vs standard care

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    End point title
    		 Difference in standard deviation (SD) of the mean interstitial glucose in CGM between the two treatment options (CANA300 mg vs standard care
    End point description
    End point type
    Secondary
    End point timeframe
    5 days after Visit 1 and 5 days after Visit 3
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    14
    14
    Units: millimole(s)/litre
        arithmetic mean (standard deviation)
    1.25 ( 0.20 )
    1.36 ( 0.32 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    Standard care v CANA 300mg
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.21
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.07
    Variability estimate
    Standard error of the mean

    Secondary: Difference in the coefficient of variation (CV) of the mean interstitial glucose in CGM between the two treatment options (CANA300 mg vs standard care)

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    End point title
    		 Difference in the coefficient of variation (CV) of the mean interstitial glucose in CGM between the two treatment options (CANA300 mg vs standard care)
    End point description
    End point type
    Secondary
    End point timeframe
    5 days after Visit 1 and 5 days after Visit 3
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    14
    14
    Units: index
        arithmetic mean (standard deviation)
    0.21 ( 0.03 )
    0.21 ( 0.04 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    CANA 300mg v Standard care
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.79
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.02
    Variability estimate
    Standard error of the mean

    Secondary: Difference in mean amplitude glucose excursion (MAGE) in CGM between the two treatment options (CANA300 mg vs standard care)

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    End point title
    		 Difference in mean amplitude glucose excursion (MAGE) in CGM between the two treatment options (CANA300 mg vs standard care)
    End point description
    End point type
    Secondary
    End point timeframe
    5 days after Visit 1 and 5 days after Visit 3
    End point values
    		 CANA 300mg Standard care
    Number of subjects analysed
    14
    14
    Units: index
        arithmetic mean (standard deviation)
    3.45 ( 0.53 )
    3.84 ( 0.88 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    Standard care v CANA 300mg
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.08
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.84
         upper limit
    		 0.05
    Variability estimate
    Standard error of the mean

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Between visits 2-6
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 no dictionary used
    Dictionary version
    NA
    Reporting groups
    Reporting group title
    All participants randomised
    Reporting group description
    		 -

    Serious adverse events
    		 All participants randomised
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 24 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 All participants randomised
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 24 (66.67%)
    Nervous system disorders
    Stabbing sensation in head
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Bells’ Palsy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Brain Fog
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    General disorders and administration site conditions
    Rash at tourniquet site
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Rash on stomach at CGM site
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Feeling hot
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Ear Infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Dizziness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    1
    Gastrointestinal disorders
    Stomach Cramps
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Dumping syndrome symptoms
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Diarrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Bloating
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Sore Throat
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Itchy lesions R leg
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Discomforting left axilla
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Psychiatric disorders
    Worsening of depression
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Renal and urinary disorders
    UTI
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Endocrine disorders
    Hypoglycaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    1
    Hypoglycaemia symptoms
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Chest tightness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Right upper quadrant ache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Infections and infestations
    Sore Throat
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    1
    Ear Infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Increased appetite
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
         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
    08 Jun 2021
    SA01 Within this amendment we have updated the current recruitment strategy outlined within the study protocol to include additional ways to promote and advertise the study using research registry databases (such as UHL research registry) and relevant charities (such as Obesity UK) to target a wider population which will support recruitment to time and target projections. A Patient Information Leaflet (PIL) has been produced and will be used as a study advertising material but will also support study mail outs to reduce printing costs/overburden of information on patients via 'cold call' mailings. We have updated the patient reply slip due to the addition of the Patient Information Leaflet. Change made within the current study Consent form to revise Participant ID to Participant Screening ID. We will also take this opportunity to inform the MHRA of changes made within the protocol around pregnancy reporting as per REC comments on Protocol v2.0 (original study submission). Details of the changes made within the protocol include the process of reporting pregnancies to sponsor and the responsibility of the study team to follow up participants according to sponsor SOP and guidelines.
    12 Oct 2021
    SA02 Within this amendment, we have updated the current exclusion criteria outlined within the study protocol around the use of oral steroids and intolerance to the Mixed Meal Tolerance Test. This proposed amendment was discussed at the recent Data Safety Monitoring Committee and all DSMC Members agree with the PI that these statements should be amended. The current statement around the use of steroids excludes patients on any form of steroids therefore we are updating this to exclude patients on oral or injectable steroids only (topical or inhaled corticosteriods are allowed). We are also excluding those patients with a severe lactose intolerance - severity will be assessed by a clinician during screening visit to determine if a patient should be excluded or not.
    23 Aug 2023
    SA03 With this amendment we have updated the main statistical analysis primary and secondary outcomes. We have also updated the description of subgroup analyses.

    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.
    Although REC and HRA approvals were in place, the start of the trial was delayed because of COVID-19. The study had 5 core study visits in which participants were required to attend on site and these visits could not be adapted to virtual visits.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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