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    Clinical Trial Results:
    Pilot randomised controlled trial of SITAgliptin for Depressive Symptoms in type 2 diabetes

    Summary
    EudraCT number
    		 2015-004527-32
    Trial protocol
    		 GB  
    Global end of trial date
    08 Aug 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Aug 2020
    First version publication date
    30 Aug 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SITADS
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    King's College London
    Sponsor organisation address
    The Strand, London, United Kingdom, WC2R 2LS
    Public contact
    Prof Khalida Ismail , King's College London, 0044 02078483545, khalida.2.ismail@kcl.ac.uk
    Scientific contact
    Prof Khalida Ismail , King's College London, 0044 02078483545, khalida.2.ismail@kcl.ac.uk
    Sponsor organisation name
    King's College Hospital NHS Foundation Trust
    Sponsor organisation address
    Denmark Hill, London, United Kingdom, SE5 9RS
    Public contact
    Prof Khalida Ismail, King's College London, 0044 02078483545, khalida.2.ismail@kcl.ac.uk
    Scientific contact
    Prof Khalida Ismail, King's College London, 0044 02078483545, khalida.2.ismail@kcl.ac.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
    08 Aug 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Jun 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate whether sitagliptin improves depressive symptoms improve in patients with type 2 diabetes. To investigate whether sitagliptin improves blood glucose control and reduces systemic inflammation in patients with type 2 diabetes.
    Protection of trial subjects
    Patients are free to withdraw consent for study treatment and/or consent to participate in the study at any time and without the prejudice to further treatment. Patients who withdraw from study treatment, but are willing to continue to participate in the follow-up visits, should be followed according to the procedures outlined in the protocol.
    Background therapy
    		 Eligible participants will already be prescribed a minimum of one first-line anti-diabetes agent (metformin or sulphonylurea) for at least 3 months. This ensures that this trial accords with NICE Guidelines on the treatment of T2D. Adherence with current diabetes treatment will be assessed using the Brief Adherence Rating Scale. At baseline, consenting participants will not be prescribed any concomitant anti-depressant treatment or incretin-based diabetes therapy. During the trial, however, commencement of additional glucose-lowering therapy (including insulin) will be permitted if prescribed by GP or diabetes specialist. The only exception is the commencement of other incretin-based therapy, which will not be permitted due to potential interaction with sitagliptin. Commencement of other treatment for depression (pharmacological or psychotherapeutic) by GP or specialist mental health services will also be permitted during the trial and measured as an outcome.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Jan 2018
    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
    United Kingdom: 44
    Worldwide total number of subjects
    44
    EEA total number of subjects
    44
    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)
    40
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment duration January 2018 to January 2019. Potential participants were identified from the registers of participating GP surgeries in the London boroughs of Southwark, Lewisham, Lambeth and Bromley.

    Pre-assignment
    Screening details
    		 General Practices searched for patients with a diagnosis of type 2 diabetes for at least 6 months, aged 18-75 and with last recorded HbA1c 53-86 mmol/mol. Patients were then contacted by the GP and invited to meet the study team for a screening visit. All patients provided signed and dated informed consent before enrollment.

    Pre-assignment period milestones
    Number of subjects started
    		 153 [1]
    Number of subjects completed
    		 44

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 screen fail: 109
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Pre-assignment period includes scree failures who were not enrolled
    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
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sitagliptin
    Arm description
    		 Sitagliptin 100mg oral (PO) once per day (OD)
    Arm type
    		 Experimental

    Investigational medicinal product name
    sitagliptin
    Investigational medicinal product code
    Other name
    Januvia
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    100mg per day for up to 12 weeks

    Arm title
    		 Placebo
    Arm description
    		 placebo PO OD
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    PO OD

    Number of subjects in period 1
    		Sitagliptin Placebo
    Started
    22
    22
    Completed
    16
    20
    Not completed
    6
    2
         Consent withdrawn by subject
    5
    2
         Adverse event, non-fatal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sitagliptin
    Reporting group description
    		 Sitagliptin 100mg oral (PO) once per day (OD)

    Reporting group title
    Placebo
    Reporting group description
    		 placebo PO OD

    Reporting group values
    		 Sitagliptin Placebo Total
    Number of subjects
    		 22 22 44
    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)
    		 59.9 ± 9.6 57.7 ± 6.8 -
    Gender categorical
    Units: Subjects
        Female
    		 10 10 20
        Male
    		 12 12 24
    Current medication regime
    Units: Subjects
        Metformin/gliclazide monotherapy
    		 15 13 28
        Dual therapy
    		 7 9 16
    Any previous macrovascular complication
    Defined as any previous heart attack, stroke, coronary artery bypass graft, carotid revascularisation or peripheral arterial revascularisation
    Units: Subjects
        Yes
    		 4 3 7
        No
    		 18 19 37
    Retinopathy present
    Units: Subjects
        Yes
    		 6 5 11
        No
    		 16 17 33
    Diabetes Duration
    Units: Years
        arithmetic mean (standard deviation)
    		 6.45 ± 4.4 7.41 ± 4.9 -
    Fasting glucose
    Units: mg/L
        arithmetic mean (standard deviation)
    		 8.8 ± 3.5 8.1 ± 2.5 -
    HOMA-IR
    Homeostasis Model Assessment of Insulin Resistance
    Units: percent
        arithmetic mean (full range (min-max))
    		 6.63 (1.78 to 23.54) 5.34 (3.07 to 8.29) -
    HbA1c
    Units: mmol/mol
        arithmetic mean (standard deviation)
    		 62.2 ± 7.0 60.2 ± 6.3 -
    Hypoglycaemia symptoms score
    Units: Score
        arithmetic mean (standard deviation)
    		 36.1 ± 9.4 31.0 ± 12.8 -
    BMI
    body mass index
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 31.7 ± 5.9 31.8 ± 4.2 -
    Total cholesterol
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 4.39 ± 0.8 4.35 ± 1.1 -
    Baseline hs-CRP
    Units: mg/L
        arithmetic mean (full range (min-max))
    		 4.75 (0.98 to 7.23) 2.40 (1.05 to 5.95) -
    Systolic BP
    blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 131.6 ± 14.8 127.1 ± 14.8 -
    Diastolic BP
    blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 79.3 ± 11.2 76.2 ± 9.7 -
    PHQ-9 score
    Patient Health Questionnaire for baseline depressive symptoms (0-27)
    Units: Score
        arithmetic mean (standard deviation)
    		 15.5 ± 4.3 13.8 ± 4.6 -
    QIDS-SR-16 score
    16-item Quick Inventory of Depressive Symptomatology (0-27)
    Units: Score
        arithmetic mean (standard deviation)
    		 13.7 ± 4.4 12.4 ± 4.8 -

    End points

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    End points reporting groups
    Reporting group title
    Sitagliptin
    Reporting group description
    		 Sitagliptin 100mg oral (PO) once per day (OD)

    Reporting group title
    Placebo
    Reporting group description
    		 placebo PO OD

    Primary: Change in depressive symptoms

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    End point title
    		 Change in depressive symptoms
    End point description
    Primary: change in depressive symptoms after 12 weeks as measured by the Patient Health Questionnaire-9 (PHQ-9) and Quick Inventory of Depressive Symptomatology (QIDS-SR-16).
    End point type
    Primary
    End point timeframe
    Baseline to 12 weeks
    End point values
    		 Sitagliptin Placebo
    Number of subjects analysed
    16
    20
    Units: score
    arithmetic mean (confidence interval 95%)
        QIDS-SR-16
    10.25 (7.63 to 12.87)
    9.10 (6.91 to 11.29)
        PHQ-9
    9.94 (6.85 to 13.03)
    9.05 (5.97 to 12.13)
    Attachments
    		 Changes in QIDS-SR-16 score during study
    Changes in PHQ-9 score during study
    Statistical analysis title
    		 Difference between groups QIDS-SR-16
    Statistical analysis description
    The primary treatment analyses will compare the difference in depressive symptoms after 12 weeks between the two groups after adjusting for baseline outcome scores (“ANCOVA” approach.) A linear mixed model using STATA’s xtmixed command will be used for estimation.
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.017
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    3.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 6
    Variability estimate
    Standard deviation
    Dispersion value
    0.71
    Statistical analysis title
    		 Difference between groups PHQ-9 Score
    Statistical analysis description
    The primary treatment analyses will compare the difference in depressive symptoms after 12 weeks between the two groups after adjusting for baseline outcome scores (“ANCOVA” approach.) A linear mixed model using STATA’s xtmixed command will be used for estimation.
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.37
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.85
         upper limit
    		 4.98
    Variability estimate
    Standard deviation
    Dispersion value
    0.35

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to 24 weeks
    Adverse event reporting additional description
    Every 4 weeks, participants will be asked to report any adverse events to the investigators.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Sitagliptin
    Reporting group description
    		 Sitagliptin 100mg oral (PO) once per day (OD)

    Reporting group title
    Placebo
    Reporting group description
    		 placebo PO OD

    Serious adverse events
    		 Sitagliptin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 22 (4.55%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    transient ischemic attack
    Additional description: hospitalisation due to possible transient ischemic attack
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    unilateral deafness
    Additional description: an incident of unilateral deafness (which attributed by an ear-nose-throat specialist to a diuretic medication [furosemide]),
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    osteoarthritis
    Additional description: of right hip
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         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
    		 Sitagliptin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 22 (40.91%)
    11 / 22 (50.00%)
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 22 (9.09%)
         occurrences all number
    2
    2
    Paraesthesia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    2
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 22 (9.09%)
         occurrences all number
    1
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 22 (9.09%)
         occurrences all number
    2
    2
    Dyspepsia
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    2
    Constipation
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    2 / 22 (9.09%)
    6 / 22 (27.27%)
         occurrences all number
    2
    6
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 22 (9.09%)
    6 / 22 (27.27%)
         occurrences all number
    2
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jan 2017
    Protocol v2.0 Update to endpoint timings
    25 Jul 2017
    Protocol v3.0 Imp dosing updated to 2 x 50mg capsules Change to code break mechanism Inclusion/Exclusion criteria clarification
    27 Jun 2019
    Protocol v4.1, recruitment stopped at 44 rather than 60 patients

    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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    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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