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    Clinical Trial Results:
    Rotation for Optimal Targeting of Albuminuria and Treatment Evaluation

    Summary
    EudraCT number
    		 2015-005691-26
    Trial protocol
    		 NL   DK  
    Global end of trial date
    19 May 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Jul 2023
    First version publication date
    29 Jul 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    26201501252
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Dutch Trial Register (LTR): NL5458
    Sponsors
    Sponsor organisation name
    University Medical Center Groningen
    Sponsor organisation address
    Hanzeplein 1, Groningen, Netherlands,
    Public contact
    N/A, University Medical Center Groningen, h.j.lambers.heerspink@umcg.nl
    Scientific contact
    N/A, University Medical Center Groningen, h.j.lambers.heerspink@umcg.nl
    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 Jan 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 May 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    19 May 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    A better understanding on the individual response to different albuminuria lowering drugs and a better understanding why these drugs, of which some are developed for another indication, may help to tailor optimal therapy. Therefore in this study individual patients will be subjected to four different drug classes that have all been shown to reduce albuminuria on a group level. The drug that induces the strongest albuminuria-lowering response will be repeated in a fifth treatment period to assess whether the albuminuria lowering effect can be confirmed in a second treatment period to ascertain the consistency of the individual response.
    Protection of trial subjects
    ETHICAL CONSIDERATIONS Regulation statement: The study was conducted in accordance with the Declaration of Helsinki (latest version adopted by the 64th WMA General Assembly in Fortaleza, Brazil, October 2013) and the Medical Research Involving Human Subjects Act (WMO). The Medical Ethical Committee of the University Medical Center in Groningen and of the Capital Region in Denmark, approved the study for initiation in The Netherlands and in Denmark, respectively. Benefits and risks assessment, group relatedness: There was no direct benefit to the patient’s health be expected from this study. Participation in the study is on a free-will base. Patients will receive restitution of all costs of transportation. Patients will not receive priority for treatment of other diseases in the clinic during this study. Participation in the proposed study was accompanied with only minor risks, if any at all. Compensation for injury: The patients were covered by the existing law of product liability insurance for the study medication as well as the law of patient insurance. All patients received written information about this insurance.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Feb 2017
    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
    Denmark: 25
    Country: Number of subjects enrolled
    Netherlands: 1
    Worldwide total number of subjects
    26
    EEA total number of subjects
    26
    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)
    17
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 26 participants with type 1 diabetes and albuminuria were recruited from Steno Diabetes Center Copenhagen, Denmark and Ziekenhuis Groep Twente, Almelo, Netherlands. Coordination of the study centers were performed by the University Medical Center Groningen, Netherlands.

    Pre-assignment
    Screening details
    		 Adult participants with type 1 or type 2 diabetes with a urinary albumin to creatinine ratio (UACR) between 30 and 500 mg/g and estimated glomerular filtration rate >=45 mL/min/1.73 m2 were eligible.

    Period 1
    Period 1 title
    First treatment
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Telmisartan
    Arm description
    		 4-week open label treatment with telmisartan 80 mg, before crossing over to next arm, in random order.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Micardis
    Investigational medicinal product code
    Other name
    TELMISARTAN
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    80 mg, once dialy

    Arm title
    		 Empagliflozin
    Arm description
    		 4-week treatment with empagliflozin 25 mg, before crossing over to next arm, in random order.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Jardiance
    Investigational medicinal product code
    Other name
    EMPAGLIFLOZIN
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 MG, ONCE daily

    Arm title
    		 Baricitinib
    Arm description
    		 4-week treatment with baricitinib 2 mg, before crossing over to next arm, in random order.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Olumiant
    Investigational medicinal product code
    Other name
    Baricitinib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 mg, once daily

    Arm title
    		 Linagliptin
    Arm description
    		 4-week treatment with linagliptin 5 mg, before crossing over to next arm, in random order.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Trajenta
    Investigational medicinal product code
    Other name
    LINAGLIPTIN
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5 mg, once daily

    Number of subjects in period 1
    		Telmisartan Empagliflozin Baricitinib Linagliptin
    Started
    26
    26
    26
    26
    Completed
    26
    26
    26
    26
    Period 2
    Period 2 title
    Confirmation
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not blinded

    Arms
    Arm title
    		 Confirmation
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Micardis
    Investigational medicinal product code
    Other name
    TELMISARTAN
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    80 mg, once dialy

    Investigational medicinal product name
    Jardiance
    Investigational medicinal product code
    Other name
    EMPAGLIFLOZIN
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 MG, ONCE daily

    Investigational medicinal product name
    Olumiant
    Investigational medicinal product code
    Other name
    Baricitinib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 mg, once daily

    Investigational medicinal product name
    Trajenta
    Investigational medicinal product code
    Other name
    LINAGLIPTIN
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5 mg, once daily

    Number of subjects in period 2
    		Confirmation
    Started
    26
    Completed
    26

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    First treatment
    Reporting group description
    		 -

    Reporting group values
    		 First treatment Total
    Number of subjects
    		 26 26
    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)
    		 60 ( 12 ) -
    Gender categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 19 19
    Race
    Units: Subjects
        White
    		 26 26
        Non-white
    		 0 0
    Current smokers
    Units: Subjects
        Smoker
    		 3 3
        Non-smoker
    		 23 23
    Diuretics treatment
    Units: Subjects
        Thiazide
    		 10 10
        Loop
    		 15 15
        No diuretics
    		 1 1
    Metformin treatment
    Units: Subjects
        Metformin
    		 2 2
        No metformin
    		 24 24
    Insulin treatment
    Units: Subjects
        Insulin
    		 26 26
        No insulin
    		 0 0
    HbA1c
    Glycated hemoglobin
    Units: mmol/mol
        arithmetic mean (standard deviation)
    		 60 ( 7 ) -
    UACR
    Urinary albumin/creatinine ratio
    Units: mg/g
        median (inter-quartile range (Q1-Q3))
    		 92 (65 to 282) -
    BMI
    Body mass index
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 29 ( 5 ) -
    Serum creatinine
    Units: µmol/l
        arithmetic mean (standard deviation)
    		 88 ( 23 ) -
    eGFR
    Estimated creatinine-derived glomerular filtration rate
    Units: ml/min/1.73m^2
        arithmetic mean (standard deviation)
    		 79 ( 18 ) -
    Systolic blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 138 ( 13 ) -
    Diastolic blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 79 ( 18 ) -

    End points

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    End points reporting groups
    Reporting group title
    Telmisartan
    Reporting group description
    		 4-week open label treatment with telmisartan 80 mg, before crossing over to next arm, in random order.

    Reporting group title
    Empagliflozin
    Reporting group description
    		 4-week treatment with empagliflozin 25 mg, before crossing over to next arm, in random order.

    Reporting group title
    Baricitinib
    Reporting group description
    		 4-week treatment with baricitinib 2 mg, before crossing over to next arm, in random order.

    Reporting group title
    Linagliptin
    Reporting group description
    		 4-week treatment with linagliptin 5 mg, before crossing over to next arm, in random order.
    Reporting group title
    Confirmation
    Reporting group description
    		 -

    Primary: Change in UACR across 4 weeks of treatment

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    End point title
    		 Change in UACR across 4 weeks of treatment
    End point description
    The study comprised four consecutive crossover treatment periods of 4 weeks, in random order, each with 4-week washout periods in between. At the end of the 4-week rotation schedule, participants proceeded to a 4-week confirmatory treatment period during which they were treated with their individual best UACR-lowering drug.
    End point type
    Primary
    End point timeframe
    Change across 4 weeks
    End point values
    		 Telmisartan Empagliflozin Baricitinib Linagliptin Confirmation
    Number of subjects analysed
    26
    26
    26
    26
    26
    Units: percent
        arithmetic mean (confidence interval 95%)
    -22.6 (-32.5 to -11.4)
    4.7 (-9.7 to 21.4)
    -6.5 (-19.1 to 8.1)
    -9.5 (-21.4 to 4.3)
    -15.0 (-26.7 to -1.4)
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    Telmisartan v Empagliflozin v Baricitinib v Linagliptin v Confirmation
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    14 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    2.1
    Reporting groups
    Reporting group title
    Full dataset
    Reporting group description
    		 -

    Serious adverse events
    		 Full dataset
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 26 (15.38%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Eye disorders
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Full dataset
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 26 (100.00%)
    Vascular disorders
    Foot ulcer
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Hypertension
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Orthostatic hypotension
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Vertigo
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Intermittent lower limb paresthesia
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Neuropathy peripheral
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    General disorders and administration site conditions
    Peripheral edema
         subjects affected / exposed
    4 / 26 (15.38%)
         occurrences all number
    4
    Thirst
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Dry mouth
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Eye disorders
    Iritis
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Glaucoma
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Retinopathy
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    3 / 26 (11.54%)
         occurrences all number
    3
    Constipation
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Colorectal polype
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Dyspnoea
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Cough
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Irritated foreskin
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Eczema
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Insulin pump failure
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Renal and urinary disorders
    Polyuria
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Muscular pain
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Arthralgia
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Exacerbation of arthritic pains
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Dislocation of clavicle
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Infections and infestations
    Cystitis bacterial
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Influenza like illness
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Foot wart
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Borrelia infection
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Hypoglycaemia
         subjects affected / exposed
    4 / 26 (15.38%)
         occurrences all number
    4
    Blood glucose fluctuation
         subjects affected / exposed
    3 / 26 (11.54%)
         occurrences all number
    3

    More information

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

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

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/36657986
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