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    Clinical Trial Results:
    Effect on fasting plasma glucose (FPG) of once daily oral administration during 28 days of O304 suspension in subjects with Type 2 Diabetes (T2D). A single-centre, randomised, parallel-group, double-blinded, placebo controlled Phase IIa study (TELLUS).

    Summary
    EudraCT number
    		 2016-002183-13
    Trial protocol
    		 SE  
    Global end of trial date
    09 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Jun 2021
    First version publication date
    04 Jun 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    O304-2016-02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Betagenon AB
    Sponsor organisation address
    Tvistevägen 48C, Umeå, Sweden, 907 36
    Public contact
    CEO, Betagenon AB, 0046 070277 89 97, thomas.edlund@betagenon.com
    Scientific contact
    CEO, Betagenon AB, 0046 070277 89 97, thomas.edlund@betagenon.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 Aug 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Aug 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to assess the effect of O304 on FPG levels after 28 days of treatment in subjects with T2D, as compared to placebo.
    Protection of trial subjects
    The study was performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Conference of Harmonization (ICH)/Good Clinical Practice (GCP), European Union (EU) Clinical Trials Directive, and applicable local regulatory requirements. It was the responsibility of the Investigator to give each potential study patient adequate verbal and written information before any study specific assessments were performed. The information included the objectives and procedures of the study as well as any risks or inconvenience involved. It was emphasised that participation in the study was voluntary and that the patient could withdraw from participation at any time and for any reason, without any prejudice. All patients were given the opportunity to ask questions about the study and was given sufficient time to consider participation before signing the ICF. Before performing any study-related procedures the ICF was signed and personally dated by the patient and by the Investigator. A copy of the patient information including the signed ICF was provided to the patient. Documentation of the patient information and the date of informed consent were recorded in the medical records and in the CRF. The patient information sheet and the signed ICF were filed by the Investigator.
    Background therapy
    		 All patients used their prescribed product and dose of metformin. This was not supplied by the Sponsor.
    Evidence for comparator
    		 Main inclusion criteria: Male and female patients, 18-80 years of age, with uncomplicated T2D, on stable T2D treatment with metformin monotherapy for ≥ 3 months. Study patients were on stable (i.e. no dose adjustment) metformin treatment for at least 3 months prior to inclusion in the study. No other diabetes medications than metformin was allowed.
    Actual start date of recruitment
    20 Sep 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 65
    Worldwide total number of subjects
    65
    EEA total number of subjects
    65
    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)
    24
    From 65 to 84 years
    41
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Main inclusion criteria: Male and female patients, 18-80 years of age, with uncomplicated T2D, on stable T2D treatment with metformin monotherapy for ≥ 3 months.

    Pre-assignment
    Screening details
    		 A screening visit was performed within 3 weeks before randomisation and the start of IMP administration.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Carer, Subject
    Blinding implementation details
    This was a double-blind study and the allocation of treatments was not disclosed until clean file had been declared and the database has been locked on 14 September 2017. Placebo and O304 suspension were of identical appearance.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 O304
    Arm description
    		 Patients were treated with O304 for a period of 28 days. During the treatment period, there were weekly visits to the clinic, where blood sampling for FPG, safety, and exploratory parameters were collected. During the visits to the clinic, IMP for the next period was dispensed and the patients received the IMP dose for that day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    O304
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Test product: O304 oral suspension, 20 mg/ml. Dose: 1000 mg (50 ml) once daily in the morning.

    Arm title
    		 Placebo
    Arm description
    		 Patients were treated with Placebo for a period of 28 days. During the treatment period, there were weekly visits to the clinic, where blood sampling for FPG, safety, and exploratory parameters were collected. During the visits to the clinic, IMP for the next period was dispensed and the patients received the IMP dose for that day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Reference product: Placebo oral suspension. Dose: 50 ml once daily in the morning.

    Number of subjects in period 1
    		O304 Placebo
    Started
    33
    32
    Completed
    31
    28
    Not completed
    2
    4
         Physician decision
    1
    1
         Consent withdrawn by subject
    1
    1
         Adverse event, non-fatal
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    O304
    Reporting group description
    		 Patients were treated with O304 for a period of 28 days. During the treatment period, there were weekly visits to the clinic, where blood sampling for FPG, safety, and exploratory parameters were collected. During the visits to the clinic, IMP for the next period was dispensed and the patients received the IMP dose for that day.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients were treated with Placebo for a period of 28 days. During the treatment period, there were weekly visits to the clinic, where blood sampling for FPG, safety, and exploratory parameters were collected. During the visits to the clinic, IMP for the next period was dispensed and the patients received the IMP dose for that day.

    Reporting group values
    		 O304 Placebo Total
    Number of subjects
    		 33 32 65
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 66.15 ( 9.65 ) 64.59 ( 8.12 ) -
    Gender categorical
    Units: Subjects
        Female
    		 9 8 17
        Male
    		 24 24 48

    End points

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    End points reporting groups
    Reporting group title
    O304
    Reporting group description
    		 Patients were treated with O304 for a period of 28 days. During the treatment period, there were weekly visits to the clinic, where blood sampling for FPG, safety, and exploratory parameters were collected. During the visits to the clinic, IMP for the next period was dispensed and the patients received the IMP dose for that day.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients were treated with Placebo for a period of 28 days. During the treatment period, there were weekly visits to the clinic, where blood sampling for FPG, safety, and exploratory parameters were collected. During the visits to the clinic, IMP for the next period was dispensed and the patients received the IMP dose for that day.

    Primary: Difference in FPG (Fasting Plasma Glucose)

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    End point title
    		 Difference in FPG (Fasting Plasma Glucose)
    End point description
    Primary objective: To assess the effect of O304 on FPG levels after 28 days of treatment in subjects with T2D, as compared to placebo. Primary endpoint: The primary endpoint is the mean difference in FPG (mmol/L) after 28 days of treatment. However, due to that compliance with magnetic resonance imaging (MRI) analysis of calf muscle at screen was used as an inclusion criteria, FPG at baseline could not be used as inclusion criteria. The study did not show a statistically significant effect on the primary endpoint -change in FPG during 28 days of treatment with O304 as compared to placebo. However, within- treatment comparisons showed a statistically significant reduction of FPG, insulin and HOMA-IR from baseline to Day 28 in the O304 group but not in the placebo group. The table presents descriptive statistics of actual FPG values over time, by treatment (FAS).
    End point type
    Primary
    End point timeframe
    FPG levels were collected from the screening visit to study day 40.
    End point values
    		 O304 Placebo
    Number of subjects analysed
    33
    32
    Units: mmol/L
    arithmetic mean (standard deviation)
        Screening
    9.35 ( 1.85 )
    8.62 ( 1.24 )
        Day 1
    8.82 ( 1.95 )
    8.15 ( 1.13 )
        Day 7
    9.11 ( 2.08 )
    8.41 ( 1.39 )
        Day 14
    9.17 ( 1.85 )
    8.40 ( 1.29 )
        Day 21
    9.03 ( 2.17 )
    8.25 ( 1.74 )
        Day 28
    8.64 ( 2.41 )
    8.01 ( 1.16 )
        Day 40
    9.29 ( 2.12 )
    8.22 ( 1.21 )
    Statistical analysis title
    		 Absolute change from baseline to Day 28
    Statistical analysis description
    Sample size was calculated with a two-sample T-test, assuming a standard deviation of 0.8 and a mean fasting glucose value of 8.0 mmol/l in the placebo group. This would give a possibility to detect a difference of 0.7 mmol/l in mean blood glucose with 92% power. Mean difference in change in FPG was compared between the treatment groups by means of analysis of covariance with treatment, age, gender, and weight at baseline as covariates. Other parameters are presented with descriptive statistics
    Comparison groups
    O304 v Placebo
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.356
    Method
    		 t-test, 2-sided
    Confidence interval
         level
    		 95%
    Variability estimate
    Standard deviation

    Secondary: Occurrence and frequency of Adverse Events (AEs)

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    End point title
    		 Occurrence and frequency of Adverse Events (AEs)
    End point description
    Secondary objective: To assess safety and tolerability [of O304] after 28 days treatment in subjects with T2D, as compared to placebo. Secondary endpoint: Safety and tolerability will be assessed by occurrence and frequency of Adverse Events (AEs). A total of 87 AEs were reported for 42 patients (64.6%), with a slightly higher frequency in the placebo group. There was one reported SAE in this study. Two (2) patients, including the one with the SAE, were withdrawn from the placebo group due to AEs.
    End point type
    Secondary
    End point timeframe
    AEs were collected from first administration of IMP to study day 40.
    End point values
    		 O304 Placebo
    Number of subjects analysed
    33
    32
    Units: Number of AEs
        No. of patients with at least one AE
    19
    23
        No. of AEs
    38
    49
        No. of patients with at least one SAE
    0
    1
        No. of SAEs
    0
    1
        No. of patients with at least one related AE
    15
    10
        No. of related AEs
    18
    20
        No of patients with AEs leading to discontinuation
    0
    2
    No statistical analyses for this end point

    Secondary: Changes in laboratory parameters

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    End point title
    		 Changes in laboratory parameters
    End point description
    Secondary objective: To assess safety and tolerability [of O304] after 28 days treatment in subjects with T2D, as compared to placebo. Secondary endpoint: Safety and tolerability will be assessed by changes in laboratory parameters. No effects were seen on laboratory safety parameters.
    End point type
    Secondary
    End point timeframe
    Safety blood samples were collected from screening to study day 28.
    End point values
    		 O304 Placebo
    Number of subjects analysed
    33
    32
    Units: No. of clinically significant changes
        Clinically significant changes
    0
    0
    No statistical analyses for this end point

    Secondary: Changes in vital signs

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    End point title
    		 Changes in vital signs
    End point description
    Secondary objective: To assess safety and tolerability [of O304] after 28 days treatment in subjects with T2D, as compared to placebo. Secondary endpoint: Safety and tolerability will be assessed by changes in vital signs. No effects were seen on vital signs.
    End point type
    Secondary
    End point timeframe
    Vital signs (systolic/diastolic blood pressure and heart rate) were collected from screening to study day 40.
    End point values
    		 O304 Placebo
    Number of subjects analysed
    33
    32
    Units: No. of clinically significant changes
        Clinically significant changes
    0
    0
    No statistical analyses for this end point

    Secondary: Changes in physical examination

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    End point title
    		 Changes in physical examination
    End point description
    Secondary objective: To assess safety and tolerability [of O304] after 28 days treatment in subjects with T2D, as compared to placebo. Secondary endpoint: Safety and tolerability will be assessed by changes in physical examination. No effects were seen on physical examination findings.
    End point type
    Secondary
    End point timeframe
    Physical examination (head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen, lymph nodes, extremities) including weight were checked at screening and study day 40.
    End point values
    		 O304 Placebo
    Number of subjects analysed
    33
    32
    Units: No. of clinically significant changes
        Clinically significant changes
    0
    0
    No statistical analyses for this end point

    Secondary: Cmax

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    End point title
    		 Cmax [1]
    End point description
    Secondary objective: To assess the exposure of O304 in subjects with T2D and potential relationship to secondary and explorative PD variables. Secondary endpoint: The following exposure parameter will be assessed after the last multiple dose: Cmax. There was little difference between maximum and minimum concentrations during the dosage interval; mean Cmax was 55.5 μg/ml and mean Cmin 45.4 μg/ml. On the other hand, the serum levels varied greatly between patients.
    End point type
    Secondary
    End point timeframe
    PK samples were collected from study day 7 to study day 40.
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint reports PK parameters for patients who received the test product O304, not for the placebo group.
    End point values
    		 O304
    Number of subjects analysed
    31
    Units: μg/ml
    median (full range (min-max))
        Cmax
    55.70 (28.10 to 89.30)
    No statistical analyses for this end point

    Secondary: Cmin

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    End point title
    		 Cmin [2]
    End point description
    Secondary objective: To assess the exposure of O304 in subjects with T2D and potential relationship to secondary and explorative PD variables. Secondary endpoint: The following exposure parameter will be assessed after the last multiple dose: Cmin. There was little difference between maximum and minimum concentrations during the dosage interval; mean Cmax was 55.5 μg/ml and mean Cmin 45.4 μg/ml. On the other hand, the serum levels varied greatly between patients.
    End point type
    Secondary
    End point timeframe
    PK samples were collected from study day 7 to study day 40.
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint reports PK parameters for patients who received the test product O304, not for the placebo group.
    End point values
    		 O304
    Number of subjects analysed
    31
    Units: μg/ml
    median (full range (min-max))
        Cmin
    46.60 (22.20 to 74.00)
    No statistical analyses for this end point

    Secondary: Css

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    End point title
    		 Css [3]
    End point description
    Secondary objective: To assess the exposure of O304 in subjects with T2D and potential relationship to secondary and explorative PD variables. Secondary endpoint: The following exposure parameter will be assessed after the last multiple dose: Css. Css was calculated as AUCtau/24. Average concentrations during the dosage interval; (Css) ranged from 24.6 to 82.9 μg/ml.
    End point type
    Secondary
    End point timeframe
    PK samples were collected from study day 7 to study day 40.
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint reports PK parameters for patients who received the test product O304, not for the placebo group.
    End point values
    		 O304
    Number of subjects analysed
    31
    Units: μg/ml
    median (full range (min-max))
        Css
    52.74 (24.56 to 82.88)
    No statistical analyses for this end point

    Secondary: AUCtau

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    End point title
    		 AUCtau [4]
    End point description
    Secondary objective: To assess the exposure of O304 in subjects with T2D and potential relationship to secondary and explorative PD variables. Secondary endpoint: The following exposure parameters will be assessed after the last multiple dose: AUCtau. The actual sampling times were used in the calculations. The linear trapezoidal rule was used for calculation of AUC, and the estimated concentration at 24 hours was used in the calculation of AUCtau.
    End point type
    Secondary
    End point timeframe
    PK samples were collected from study day 7 to study day 40.
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint reports PK parameters for patients who received the test product O304, not for the placebo group.
    End point values
    		 O304
    Number of subjects analysed
    31
    Units: μg/ml·h
    median (full range (min-max))
        AUCtau
    1265.7 (589.38 to 1989.2)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were collected from first IMP treatment to study day 40 (end of study).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    O304
    Reporting group description
    		 Patients were treated with O304 for a period of 28 days. During the treatment period, there were weekly visits to the clinic, where blood sampling for FPG, safety, and exploratory parameters were collected. During the visits to the clinic, IMP for the next period was dispensed and the patients received the IMP dose for that day.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients were treated with Placebo for a period of 28 days. During the treatment period, there were weekly visits to the clinic, where blood sampling for FPG, safety, and exploratory parameters were collected. During the visits to the clinic, IMP for the next period was dispensed and the patients received the IMP dose for that day.

    Serious adverse events
    		 O304 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 O304 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 33 (57.58%)
    23 / 32 (71.88%)
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Contusion
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Joint injury
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Limb injury
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    2
    Chest discomfort
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    3 / 33 (9.09%)
    7 / 32 (21.88%)
         occurrences all number
    4
    11
    Tension headache
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 32 (3.13%)
         occurrences all number
    2
    1
    Oedema mucosal
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Social circumstances
    Dental prosthesis user
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 32 (3.13%)
         occurrences all number
    1
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 32 (3.13%)
         occurrences all number
    1
    1
    Diarrhoea
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 32 (3.13%)
         occurrences all number
    4
    1
    Dyspepsia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Faeces hard
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 32 (0.00%)
         occurrences all number
    2
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Mouth ulceration
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Tooth infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Nasal congestion
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    5 / 33 (15.15%)
    11 / 32 (34.38%)
         occurrences all number
    6
    13
    Psychiatric disorders
    Nightmare
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Back pain
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 32 (6.25%)
         occurrences all number
    1
    2
    Muscle spasms
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 32 (6.25%)
         occurrences all number
    2
    2
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Neck pain
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    Infections and infestations
    Folliculitis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Aug 2016
    Amendment No. 1 was approved and implemented before inclusion of the first patient in the study. The following changes were made to the Final CSP version 1.0, as a response to requests from the Swedish Medical Product Agency (MPA) following the initial CTA: • The benefit/risk section was expanded. A discussion of exposure margins (to Cmax and AUC) at the anticipated exposure from the clinical dose to the NOAEL in the non-clinical safety studies was added. • A full PK profile following the last dose of IMP on Day 28 was added, resulting in some modified wording of secondary objectives and endpoints. The original protocol only included pre-dose sampling at several occasions during the study. As a result of this change, Visit 6 (Day 28) became a full-day visit to the clinic and an additional visit was added on Day 29 for the 24-hour PK sampling. • Revised restrictions for concomitant medications to avoid potential interactions both from the perspective of O304 as a victim and as a perpetrator were added.
    10 Nov 2016
    Amendment No. 2 was approved and implemented before inclusion of the first patient in the study. The following changes were made to the Revised Final CSP version 2.0: • To facilitate recruitment, a second study site was added (CTC Linköping). • The screening period was prolonged from 14 to 21 days. • The time window of ± 1 day for study Day 27 was deleted since the 28-day treatment period was not to be exceeded. • A section for definition of re-screening procedures and criteria was added. • Changes were made in exclusion criterion no. 5: Creatinine clearance determined according to the Cockroft-Gault method was replaced by an estimated glomerular filtration rate (eGFR) (cystatin-C), and the limit for total bilirubin was changed from2.0 mg/dL to >2xULN. • To achieve consistent image quality, a restriction regarding food intake prior to the MRI assessments was added. • A change was made in the section concerning concomitant medication: Substitution therapy with vitamin B12, folic acid and thyroxin were allowed if the dose has been stable for four weeks prior to first dose of IMP. • Text was added to state that only 1 sample PK sample would be analysed for patients in the placebo group. • Measurement of B lactate was removed from the tests performed at screening.
    13 Dec 2016
    Amendment No. 3 applied to patients Nos. 1015 –1066. The text in this report reflects the last version of the CSP, version 4.0. The following changes were made to the Revised Final CSP version 3.0: • Changes to the MRI protocol (exploratory analyses) protocol were introduced. Novel results, obtained after the initiation of the clinical study, demonstrate that O304 protects mice on a high-fat induced diet against body weight gain and body fat gain, without affecting muscle mass, indicating that O304 increases energy expenditure. An additional examination to assess the volume of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) depots in the remaining patients was therefore added. • A new procedure for reading the MRI images was also introduced to assure that any incidental findings, possibly meeting exclusion criterion No. 9 (“Any clinically significant incidental finding at the MRI scan performed before randomisation”) were discovered before randomisation.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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