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    Clinical Trial Results:
    ENSAYO CLÍNICO DE FASE II, ABIERTO, UNICÉNTRICO, PILOTO PARA EVALUAR LAS CARACTERÍSTICAS FARMACOCINÉTICAS, SEGURIDAD Y TOLERABILIDAD, TRAS LA CONVERSIÓN DE UN RÉGIMEN INMUNOSUPRESOR CON PROGRAF® A TACROLIMUS DE LIBERACIÓN PROLONGADA (ADVAGRAF®) EN PACIENTES CON TRASPLANTE PULMONAR ESTABLE

    Summary
    EudraCT number
    		 2009-015863-15
    Trial protocol
    		 ES  
    Global end of trial date
    29 Aug 2011

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Dec 2021
    First version publication date
    29 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TX-PULMON09
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    VHIR
    Sponsor organisation address
    Passeig Vall dHebron 119-129, Barcelona, Spain, 08035
    Public contact
    Joaquin Lopez-Soriano, VHIR, joaquin.lopez.soriano@vhir.org
    Scientific contact
    Dr Antonio Roman, VHIR, aroman@vhebron.net
    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
    29 Aug 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Aug 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Determinar y comparar el perfil farmacocinético de tacrolimus en pacientes con trasplante de pulmón estable tras la conversión 1:1 de tacrolimus (Prograf®) a tacrolimus de liberación prolongada (Advagraf®). The purpose of this study was to establish and compare the PK profile of tacrolimus in stable adult lung transplantation patients before and after conversion (1:1) from twice-daily to once-daily dosing.
    Protection of trial subjects
    The study was approved by the local ethics committee and conducted in accordance with the Declaration of Helsinki. Each patient gave written informed consent before enrolment in the study. Corticosteroids were started in the operating room and before initiating lung perfusion.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 May 2010
    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
    Spain: 19
    Worldwide total number of subjects
    19
    EEA total number of subjects
    19
    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)
    19
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The inclusion criteria were adult LT patients, more than 180 days of post-LT follow-up, and stable tacrolimus dose with C0 between 5 and 15 ng/mL

    Period 1
    Period 1 title
    TAC-BID
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 TACROLIMUS TWICE
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tacrolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Buccal use
    Dosage and administration details
    Tacrolimus dosage was modified as follows: mean daily dose of TAC BID before switching (day -14) was 4.8+/-2.2 mg. After conversion to QD, mean daily dose was increased to 5.2+/-2.6, 5.4+/-3.0, and 5.6+/-3.1 mg on days +60, +90 and +180, respectively.

    Investigational medicinal product name
    Corticosteroids
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Corticosteroids were started in the operating room and before initiating lung perfusion. The initial dose was 10 mg/kg followed by 6 mg/kg the first postoperative day. This drug was decreased to 0.5 mg/kg during the first week, and dose ranged from 0.5 to 0.1 mg/kg per day thereafter

    Investigational medicinal product name
    Antimetabolite drugs
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Mycophenolate mofetil [MMF], mycophenolic acid, or azathioprine at the operation room

    Arm title
    		 TACROLIMUS SINGLE DOSE
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tacrolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Buccal use
    Dosage and administration details
    Tacrolimus dosage was modified as follows: mean daily dose of TAC BID before switching (day -14) was 4.8+/-2.2 mg. After conversion to QD, mean daily dose was increased to 5.2+/-2.6, 5.4+/-3.0, and 5.6+/-3.1 mg on days +60, +90 and +180, respectively.

    Investigational medicinal product name
    Corticosteroids
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Corticosteroids were started in the operating room and before initiating lung perfusion. The initial dose was 10 mg/kg followed by 6 mg/kg the first postoperative day. This drug was decreased to 0.5 mg/kg during the first week, and dose ranged from 0.5 to 0.1 mg/kg per day thereafter

    Investigational medicinal product name
    Antimetabolite drugs
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Mycophenolate mofetil [MMF], mycophenolic acid, or azathioprine at the operation room

    Number of subjects in period 1
    		TACROLIMUS TWICE TACROLIMUS SINGLE DOSE
    Started
    19
    19
    Completed
    19
    19
    Period 2
    Period 2 title
    TAC-QD
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 TAC QD
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tacrolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Buccal use
    Dosage and administration details
    Tacrolimus dosage was modified as follows: mean daily dose of TAC BID before switching (day -14) was 4.8+/-2.2 mg. After conversion to QD, mean daily dose was increased to 5.2+/-2.6, 5.4+/-3.0, and 5.6+/-3.1 mg on days +60, +90 and +180, respectively.

    Number of subjects in period 2
    		TAC QD
    Started
    19
    Completed
    19

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TACROLIMUS TWICE
    Reporting group description
    		 -

    Reporting group title
    TACROLIMUS SINGLE DOSE
    Reporting group description
    		 -

    Reporting group values
    		 TACROLIMUS TWICE TACROLIMUS SINGLE DOSE Total
    Number of subjects
    		 19 19 19
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 19 19 19
    Gender categorical
    Units: Subjects
        Female
    		 9 9 9
        Male
    		 10 10 10

    End points

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    End points reporting groups
    Reporting group title
    TACROLIMUS TWICE
    Reporting group description
    		 -

    Reporting group title
    TACROLIMUS SINGLE DOSE
    Reporting group description
    		 -
    Reporting group title
    TAC QD
    Reporting group description
    		 -

    Primary: AUC 24h

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    End point title
    		 AUC 24h
    End point description
    End point type
    Primary
    End point timeframe
    24 hours
    End point values
    		 TACROLIMUS TWICE TACROLIMUS SINGLE DOSE
    Number of subjects analysed
    19
    19
    Units: unit(s)
        arithmetic mean (standard deviation)
    279.8 ± 57.7
    278.7 ± 52.5
    Statistical analysis title
    		 AUC 0-24
    Comparison groups
    TACROLIMUS TWICE v TACROLIMUS SINGLE DOSE
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.9217
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Wilcoxon test
    Confidence interval

    Secondary: Cmax 0-24

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    End point title
    		 Cmax 0-24
    End point description
    End point type
    Secondary
    End point timeframe
    24 hours
    End point values
    		 TACROLIMUS TWICE TACROLIMUS SINGLE DOSE
    Number of subjects analysed
    19
    19
    Units: nanogram(s)/millilitre
        arithmetic mean (standard deviation)
    20.1 ± 4.0
    19.1 ± 3.2
    Statistical analysis title
    		 Cmax 0-24
    Comparison groups
    TACROLIMUS TWICE v TACROLIMUS SINGLE DOSE
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.7482
    Method
    		 Schuirmann double t-test
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All the study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Total adverse events
    Reporting group description
    		 -

    Serious adverse events
    		 Total adverse events
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 19 (15.79%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Nervous system disorders
    Ischaemic cerebral infarction
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Urinary sepsis
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Total adverse events
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 19 (100.00%)
    Nervous system disorders
    Sciatica
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Transient ischaemic attack
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    General disorders and administration site conditions
    Abdominal pain
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Tremor
         subjects affected / exposed
    3 / 19 (15.79%)
         occurrences all number
    3
    Insomnia
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Libido decreased
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Hypertension
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Peripheral oedema
         subjects affected / exposed
    3 / 19 (15.79%)
         occurrences all number
    3
    Eye disorders
    Cataract
         subjects affected / exposed
    3 / 19 (15.79%)
         occurrences all number
    3
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    4 / 19 (21.05%)
         occurrences all number
    4
    Respiratory, thoracic and mediastinal disorders
    Bronchitis
         subjects affected / exposed
    5 / 19 (26.32%)
         occurrences all number
    5
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Fungal infection
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Renal and urinary disorders
    Pyelonephritis
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Cholecystitis acute
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Movement disorder
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Infections and infestations
    Papilloma
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Weight gain
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1

    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.
    A potential limitation of the study design is the short follow-up period (6 months), which is insufficient to show differences in efficacy between TAC BID and TAC QD. Also of note was the exclusion of patients with cystic fibrosis

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/24492423
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