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    Clinical Trial Results:
    Phase II, open, one-site, pilot Clinical trial for assessing the pharmacokinetic characteristics, safety and tolerability after conversion of the immuno-suppressive regimen with Advagraf® to Envarsus® in patients with stable pulmonary transplant.

    Summary
    EudraCT number
    		 2015-005519-34
    Trial protocol
    		 ES  
    Global end of trial date
    09 May 2017

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

    Trial information

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    Trial identification
    Sponsor protocol code
    ENVARUS
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    VHIR
    Sponsor organisation address
    Passeig Vall Hebron 119-129, Barcelona, Spain, 08035
    Public contact
    Joaquin Lopez Soriano, Fundació Hospital Universitari Vall d'Hebron - Institut de Recerca (VHIR), 0034 934894779, joaquin.lopez.soriano@vhir.org
    Scientific contact
    Antonio Román - Servicio de Neumología, Fundació Hospital Universitari Vall d'Hebron - Institut de Recerca (VHIR), 0034 934893000, 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
    09 May 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 May 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Determinate and compare the tacrolimus pharmacokinetic profile in stable pulmonary transplant patients after the conversion 1:0.7 from Advagraf® to Envarsus®
    Protection of trial subjects
    Patients had been in postoperative follow-up for more than 6 months. On day 16 after enrollment, patients were admitted to the hospital for determination of their 24-hour pharmacokinetic profile. Patients with chronic allograft dysfunction and those with an episode of acute cellular rejection in the previous 3 months were excluded from the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jan 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
    Spain: 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)
    16
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 At recruitment, patients remained under ODT for 30 days per protocol. On day 16 after enrollment, patients were admitted to the hospital for determination of their 24-hour pharmacokinetic profile. On day 31, patients were switched from ODT to LCPTin a 1:0.7 (mg/mg) conversion ratio, according to manufacturer's recommendations.

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 20
    Number of subjects completed
    		 20

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

    Arms
    Arm title
    		 ODT treatment
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tacrolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    ODT: Oral Daily Treatment per 30 days LCPT: Oral once-daily extended-release formulation, in ratio 0.7:1 (mg:mg) compared to ODT. The dose of tacrolimus had to remain stable with an individualized target level of Cmin between 5 and 15 ng/mL in 2 determinations performed before enrollment,with a minimum interval of 6 days between them.

    Number of subjects in period 1
    		ODT treatment
    Started
    20
    Completed
    20
    Period 2
    Period 2 title
    LCPT
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 LCTP switch
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tacrolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    ODT: Oral Daily Tretament per 30 days LCPT: Oral once-daily extended-release formulation, in ratio 0.7:1 (mg:mg) compared to ODT. The dose of tacrolimus had to remain stable with an individualized target level of Cmin between 5 and 15 ng/mL in 2 determinations performed before enrollment,with a minimum interval of 6 days between them.

    Number of subjects in period 2
    		LCTP switch
    Started
    20
    Completed
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ODT
    Reporting group description
    		 -

    Reporting group values
    		 ODT Total
    Number of subjects
    		 20 20
    Age categorical
    Units: Subjects
        Adults
    		 20 20
    Gender categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 13 13
    Subject analysis sets

    Subject analysis set title
    ODT to LCTP conversion
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Afert recruitment, patients remained under ODT for 30 days per protocol. On day 16 after enrollment, patients were admitted to the hospital for determination of their 24-hour pharmacokinetic profile. On day 31, patients were switched from ODT to LCPTin a 1:0.7 (mg/mg) conversion ratio, according to manufacturer's recommendations in Europe as well as previous data in renal transplant

    Subject analysis sets values
    		 ODT to LCTP conversion
    Number of subjects
    20
    Age categorical
    Units: Subjects
        Adults
    20
    Age continuous
    Units:
        
    ±
    Gender categorical
    Units: Subjects
        Female
    7
        Male
    13

    End points

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    End points reporting groups
    Reporting group title
    ODT treatment
    Reporting group description
    		 -
    Reporting group title
    LCTP switch
    Reporting group description
    		 -

    Subject analysis set title
    ODT to LCTP conversion
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Afert recruitment, patients remained under ODT for 30 days per protocol. On day 16 after enrollment, patients were admitted to the hospital for determination of their 24-hour pharmacokinetic profile. On day 31, patients were switched from ODT to LCPTin a 1:0.7 (mg/mg) conversion ratio, according to manufacturer's recommendations in Europe as well as previous data in renal transplant

    Primary: AUC 0-24

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    End point title
    		 AUC 0-24
    End point description
    End point type
    Primary
    End point timeframe
    All study
    End point values
    		 ODT treatment LCTP switch
    Number of subjects analysed
    20
    20
    Units: units
        number (confidence interval 95%)
    253.97 (225 to 282.94)
    282.44 (169 to 452)
    Statistical analysis title
    		 AUC 0-24
    Comparison groups
    ODT treatment v LCTP switch
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1762
    Method
    		 ANOVA
    Confidence interval

    Primary: Cmin 0-24

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    End point title
    		 Cmin 0-24
    End point description
    End point type
    Primary
    End point timeframe
    All the study
    End point values
    		 ODT treatment LCTP switch
    Number of subjects analysed
    20
    20
    Units: ng/mL
        number (confidence interval 95%)
    6.85 (5.99 to 7.7)
    7.75 (6.83 to 8.66)
    Statistical analysis title
    		 C min at 0-24
    Comparison groups
    ODT treatment v LCTP switch
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1552
    Method
    		 ANOVA
    Confidence interval

    Primary: Cmax 0-24

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    End point title
    		 Cmax 0-24
    End point description
    End point type
    Primary
    End point timeframe
    All the study
    End point values
    		 ODT treatment LCTP switch
    Number of subjects analysed
    20
    20
    Units: ng/L
        arithmetic mean (confidence interval 95%)
    18.70 (16.07 to 21.32)
    17.57 (15.81 to 19.33)
    Statistical analysis title
    		 Cmax 0-24 h
    Comparison groups
    LCTP switch v ODT treatment
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.849
    Method
    		 ANOVA
    Confidence interval

    Primary: Tmax 0-24 h

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    End point title
    		 Tmax 0-24 h
    End point description
    End point type
    Primary
    End point timeframe
    All the study
    End point values
    		 ODT treatment LCTP switch
    Number of subjects analysed
    20
    20
    Units: hour
        arithmetic mean (confidence interval 95%)
    2.07 (1 to 4.08)
    5.28 (3 to 8.07)
    Statistical analysis title
    		 Tmax 0-24 hour
    Comparison groups
    ODT treatment v LCTP switch
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    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
    4 / 20 (20.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Cardiac disorders
    Atypical atrial flutte
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic lung allograft dysfunction
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Facial herpes
         subjects affected / exposed
    1 / 20 (5.00%)
         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
    16 / 20 (80.00%)
    Nervous system disorders
    Insomnia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Lupus anticoagulant hypoprothrombinaemia syndrome
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Hypertension
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Venous insufficiency
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Tonsillitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Eye disorders
    Blurred vision
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Gastroenteritis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Diarrhea
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Nausea
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Prostatic hyperplasia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Bronchitis
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    4
    Upper respiratory fungal infection
         subjects affected / exposed
    10 / 20 (50.00%)
         occurrences all number
    10
    transitory worsening of respiratory function
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Papule
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Renal and urinary disorders
    Worsening of renal function
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Ankle edema
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Intermitent claudication
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Achiles tendinopathy
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Musculoskeletal pain
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    4
    Infections and infestations
    Perianal streptococcal infection
         subjects affected / exposed
    1 / 20 (5.00%)
         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, which prevents efficacy and safety from being assessed in the long term. The study population (mainly white) may not be representative of other ethnicities.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29965950
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