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    Clinical Trial Results:
    DPP-4 inhibition with sitagliptin and the risk for hypoglycaemia in the fasting state in subjects with type 2 diabetes treated to fasting plasma glucose targets with insulin glargine and metformin

    Summary
    EudraCT number
    		 2016-004480-39
    Trial protocol
    		 DE  
    Global end of trial date
    17 Jul 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 May 2021
    First version publication date
    15 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DPP4-Hypo
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03359590
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Profil Institut für Stoffwechselforschung GmbH
    Sponsor organisation address
    Hellersbergstr. 9, Neuss, Germany, 41460
    Public contact
    Project Development, Profil Institut für Stoffwechselforschung GmbH, +49 21314018219, eric.zijlstra@profil.com
    Scientific contact
    Project Development, Profil Institut für Stoffwechselforschung GmbH, +49 21314018219, eric.zijlstra@profil.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
    18 Nov 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Jul 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jul 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    to test the influence of DPP-4 inhibition (comparing sitagliptin 100 mg per day versus placebo in a cross-over design) on (a) the risk to develop hypoglycemia and on (b) hormonal responses and recovery from hypoglycemia in the case that they occur
    Protection of trial subjects
    Trial-related risks are mainly associated with an increased risk of hypoglycaemia due to therapy intensification with basal insulin titration. Mitigation strategies implemented in the protocol reduce the potential risks of treatment and trial-related procedures. Subjects that are required to washout oral anti-diabetes medication before starting the insulin titration period may temporarily experience more pronounced fluctuations of their plasma glucose levels, with a tendency to elevated glucose levels. As the washout period is relatively short (1 week) and is followed by an intensification of their diabetes treatment thereafter, this risk is considered low.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Mar 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
    Germany: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    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
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment from the own database; advertisement on homepage

    Pre-assignment
    Screening details
    		 - HbA1c) ≤8.5% - Total insulin dose <1.2 U/kg/day - on stable treatment with insulin glargine (any dose) and metformin (≥1500 mg/day or at highest tolerated dose) for at least 3 months prior to inclusion - All subjects underwent 1–16 weeks outpatient insulin titration during each treatment period.

    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
    Blinding implementation details
    blinded dosing bottles

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Sitagliptin arm
    Arm description
    		 Januvia 100 mg/d
    Arm type
    		 Experimental

    Investigational medicinal product name
    Januvia
    Investigational medicinal product code
    Sitagliptin
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50 mg tablets; 100 mg/d

    Arm title
    		 Placebo arm
    Arm description
    		 Placebo matching Januvia
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matching Januvia, 2 tablets (50 mg) once a day

    Number of subjects in period 1
    		Sitagliptin arm Placebo arm
    Started
    20
    20
    Completed
    17
    19
    Not completed
    3
    1
         Adverse event, non-fatal
    1
    -
         Protocol deviation
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 20 20
    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
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (standard deviation)
    		 59.0 ± 6.17 -
    Gender categorical
    Units: Subjects
        Female
    		 5 5
        Male
    		 15 15
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 92.32 ± 13.79 -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 178.1 ± 9.20 -
    Waist circumference
    Units: cm
        arithmetic mean (standard deviation)
    		 105.9 ± 9.02 -
    HbA1c
    Units: percent
        arithmetic mean (standard deviation)
    		 7.35 ± 0.661 -
    BMI
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 29.19 ± 4.139 -

    End points

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    End points reporting groups
    Reporting group title
    Sitagliptin arm
    Reporting group description
    		 Januvia 100 mg/d

    Reporting group title
    Placebo arm
    Reporting group description
    		 Placebo matching Januvia

    Primary: Hypoglycaemic episodes

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    End point title
    		 Hypoglycaemic episodes
    End point description
    End point type
    Primary
    End point timeframe
    during in-house periods
    End point values
    		 Sitagliptin arm Placebo arm
    Number of subjects analysed
    16
    18
    Units: numbers
    91
    103
    Statistical analysis title
    		 Primary Endpoint
    Comparison groups
    Sitagliptin arm v Placebo arm
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.389
    Method
    		 ANOVA
    Confidence interval
    Notes
    [1] - Difference between sitagliptin and placebo regarding the number of chemical hypoglycaemic episodes.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Only treatment-emergent adverse events (TEAEs) are reported, occurring after randomisation. No AEs were reported for the washout period.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Sitagliptin arm
    Reporting group description
    		 -

    Reporting group title
    Placebo arm
    Reporting group description
    		 -

    Serious adverse events
    		 Sitagliptin arm Placebo arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Coronary heart disease
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         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 arm Placebo arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 17 (70.59%)
    11 / 19 (57.89%)
    Investigations
    Electrocardiogram ST segment depression
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 19 (5.26%)
         occurrences all number
    2
    1
    Decapitation
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Infusion site thrombosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Traumatic amputation
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Orthostatic intolerance
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Syncope
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Cardiac disorders
    Cardiovascular disorder
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Coronary artery disease
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Tachyarrhythmia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Nervous system disorders
    Allodynia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 19 (5.26%)
         occurrences all number
    1
    4
    Headache
         subjects affected / exposed
    6 / 17 (35.29%)
    3 / 19 (15.79%)
         occurrences all number
    6
    3
    Ear and labyrinth disorders
    Ear discomfort
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 17 (5.88%)
    4 / 19 (21.05%)
         occurrences all number
    1
    4
    Nausea
         subjects affected / exposed
    3 / 17 (17.65%)
    1 / 19 (5.26%)
         occurrences all number
    3
    1
    Vomiting
         subjects affected / exposed
    2 / 17 (11.76%)
    2 / 19 (10.53%)
         occurrences all number
    3
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Rhinitis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 19 (10.53%)
         occurrences all number
    1
    2
    Back pain
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Fibromyalgia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Intervertebral disc displacement
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Muscle contractions involuntary
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Dec 2017
    Issued due to BfArM objections

    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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