Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43865   clinical trials with a EudraCT protocol, of which   7286   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A PILOT, PHASE II STUDY WITH A PROSPECTIVE, RANDOMIZED, CROSS-OVER, PLACEBO-CONTROLLED, DOUBLE-BLIND DESIGN TO ASSESS THE SHORT-TERM EFFECTS OF TOLVAPTAN PLUS PLACEBO VS TOLVAPTAN PLUS OCTREOTIDE LAR COMBINATION THERAPY IN ADPKD PATIENTS WITH NORMAL KIDNEY FUNCTION OR HYPERFILTRATION

    Summary
    EudraCT number
    		 2017-004701-40
    Trial protocol
    		 IT  
    Global end of trial date
    08 Apr 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Jun 2023
    First version publication date
    04 Jun 2023
    Other versions
    Summary report(s)
    		 Article
    Supplemental material

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    TOOL
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03541447
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Istituto di Ricerche Farmacologiche Mario Negri IRCCS
    Sponsor organisation address
    Via G.B. Camozzi 3, Ranica, Italy,
    Public contact
    UOC Regulatory, Ethical and Legal Affairs, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 035 0354535308, nadia.rubis@marionegri.it
    Scientific contact
    UOC Regulatory, Ethical and Legal Affairs, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, +39 0354535308, nadia.rubis@marionegri.it
    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
    20 Oct 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Apr 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Apr 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of 4-week Tolvaptan and Octreotide LAR combination therapy as compared to Tolvaptan and Placebo combination therapy on GFR, as assessed by the Iohexol Plasma Clearance Technique, in 20 ADPKD patients with normal kidney function (GFR: >80 and <120 ml/min/1.73m2) or hyperfiltration (GFR >120 ml/min/1.73m2).
    Protection of trial subjects
    This study was conducted in conformance with the Declaration of Helsinki, Good Clinical Practice standards, and applicable country regulations regarding ethical committee review, informed consent, protection of human subjects participating in biomedical research, and privacy.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jun 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
    Italy: 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

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Overall, 75 potentially eligible patients were identified and referred to the Clinical Research Center: 34 signed the written informed consent to study participation. Then, 22 eligible patients entered the run-in phase between January 22, 2019, and July 2, 2021 and 20 were finally randomized: ten to each treatment sequence.

    Pre-assignment
    Screening details
    		 Potentially eligible patients were identified from the database of the ADPKD Outpatient Clinics of the Unit of Nephrology of the ASST and were referred to the Clinical Research Center for Rare Diseases Aldo e Cele Daccò of the Istituto di Ricerche Farmacologiche Mario Negri IRCCS in Ranica (Italy).

    Period 1
    Period 1 title
    First treatment period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Arm title
    		 Tolvaptan-Placebo
    Arm description
    		 All patients received a first 4-week treatment period with tolvaptan. Tolvaptan was started at the dose of 45 mg in the morning and 15 mg in the afternoon. Then, morning and afternoon doses were up-titrated every 2 days to 60 and 30 mg and then to 90 and 30 mg, respectively, according to tolerability. By completion of this 4-week titration period, participants were randomly allocated using a 1:1 randomization ratio to 4-week treatment periods with tolvaptan. During these two treatment periods, tolvaptan was administered at the maintenance dose achieved at the end of the titration period. According to the randomization plan, at the start of one of the two treatment periods, tolvaptan was combined with two 20-mg i.m. injections of octreotide- LAR, whereas at the start of the other treatment period, tolvaptan was combined with two i.m. injections of 0.9% NaCl solution (placebo for octreotide-LAR).
    Arm type
    		 Placebo

    Investigational medicinal product name
    0.9% NaCl
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Two i.m. injections of 0.9% NaCl solution (placebo for octreotide-LAR).

    Investigational medicinal product name
    Tolvaptan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All patients received a first 4-week treatment period with tolvaptan. Tolvaptan was started at the dose of 45 mg in the morning and 15 mg in the afternoon. Then, morning and afternoon doses were up-titrated every 2 days to 60 and 30 mg and then to 90 and 30 mg, respectively, according to tolerability.

    Number of subjects in period 1
    		Tolvaptan-Placebo
    Started
    19
    Completed
    19
    Period 2
    Period 2 title
    Second treatment period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Arm title
    		 Tolvaptan-Octreotide LAR
    Arm description
    		 All patients received a first 4-week treatment period with tolvaptan. Tolvaptan was started at the dose of 45 mg in the morning and 15 mg in the afternoon. Then, morning and afternoon doses were up-titrated every 2 days to 60 and 30 mg and then to 90 and 30 mg, respectively, according to tolerability. By completion of this 4-week titration period, participants were randomly allocated using a 1:1 randomization ratio to 4-week treatment periods with tolvaptan. During these two treatment periods, tolvaptan was administered at the maintenance dose achieved at the end of the titration period. According to the andomization plan, at the start of one of the two treatment periods, tolvaptan was combined with two 20-mg i.m. injections of octreotide-LAR, whereas at the start of the other treatment period, tolvaptan was combined with two i.m. injections of 0.9% NaCl solution (placebo for octreotide-LAR).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tolvaptan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All patients received a first 4-week treatment period with tolvaptan. Tolvaptan was started at the dose of 45 mg in the morning and 15 mg in the afternoon. Then, morning and afternoon doses were up-titrated every 2 days to 60 and 30 mg and then to 90 and 30 mg, respectively, according to tolerability.

    Investigational medicinal product name
    Octreotide LAR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Two 20-mg i.m. injections of octreotide-LAR

    Number of subjects in period 2
    		Tolvaptan-Octreotide LAR
    Started
    19
    Completed
    19

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    First treatment period
    Reporting group description
    		 -

    Reporting group values
    		 First treatment period Total
    Number of subjects
    		 19 19
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 19 19
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 41 ± 12 -
    Gender categorical
    Units: Subjects
        Female
    		 9 9
        Male
    		 10 10
    Diabetes
    Units: Subjects
        Diabetes
    		 7 7
        Non diabetes
    		 12 12
    Smoke
    Units: Subjects
        Current smokers
    		 8 8
        Never smoked
    		 7 7
        Former smokers
    		 4 4
    Mayo class
    Units: Subjects
        1A
    		 2 2
        1B
    		 4 4
        1C
    		 5 5
        1D
    		 7 7
        1E
    		 1 1
    BMI
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 24.2 ± 3.6 -
    Systolic BP
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 128 ± 8 -
    Diastolic BP
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 82 ± 7 -
    Heart rate
    Units: bpm
        arithmetic mean (standard deviation)
    		 67 ± 11 -
    Creatinine
    Units: md/dl
        arithmetic mean (standard deviation)
    		 0.9 ± 0.1 -
    Glomerular Filtration rate
    By Iohexol plasma clearance
    Units: ml/min/1.73m2
        arithmetic mean (standard deviation)
    		 85.13 ± 13 -
    Renal blood flow
    Units: ml/min/1.73m2
        arithmetic mean (standard deviation)
    		 707 ± 211 -
    Renal plasmna flow
    Units: ml/min/1.73m2
        arithmetic mean (standard deviation)
    		 431 ± 110 -
    Renal vascular resistance
    Units: dynXs/cm5
        median (inter-quartile range (Q1-Q3))
    		 11.675 (9.967 to 14.621) -
    Total Kidney Volume
    Units: ml
        median (inter-quartile range (Q1-Q3))
    		 1142 (850 to 1859) -
    Cystic kidney volume
    Units: ml
        median (inter-quartile range (Q1-Q3))
    		 738 (407 to 1413) -
    24 H urine protein
    Units: g/24H
        median (inter-quartile range (Q1-Q3))
    		 0.1 (0.06 to 0.13) -
    24H Urine albumin
    Units: ug/min
        median (inter-quartile range (Q1-Q3))
    		 14 (6 to 24) -
    24 H Urine sodium
    Units: mEq/24H
        arithmetic mean (standard deviation)
    		 149 ± 57 -
    24H Urine potassium
    Units: mEq/24H
        arithmetic mean (standard deviation)
    		 62 ± 21 -
    24H Urine urea
    Units: g/24H
        arithmetic mean (standard deviation)
    		 25 ± 8 -
    24H Urine creatinine
    Units: mg/24H
        arithmetic mean (standard deviation)
    		 1540 ± 423 -
    Phospahte
    Units: mg/dl
        arithmetic mean (standard deviation)
    		 3.2 ± 0.4 -
    Calcium
    Units: mg/dl
        arithmetic mean (standard deviation)
    		 9 ± 0.2 -
    Sodium
    Units: mEq/dl
        arithmetic mean (standard deviation)
    		 139 ± 2 -
    Potassium
    Units: mEq/dl
        arithmetic mean (standard deviation)
    		 3.8 ± 0.3 -
    Glucose
    Units: mg/dl
        arithmetic mean (standard deviation)
    		 88 ± 7 -
    Protein
    Units: g/dl
        arithmetic mean (standard deviation)
    		 6.6 ± 0.4 -
    Total cholesterol
    Units: mg/dl
        arithmetic mean (standard deviation)
    		 176 ± 33 -
    LDL
    Units: mg/dl
        arithmetic mean (standard deviation)
    		 113 ± 30 -
    HDL
    Units: mg/dl
        arithmetic mean (standard deviation)
    		 50 ± 13 -
    Triglycerides
    Units: mg/dl
        arithmetic mean (standard deviation)
    		 80 ± 41 -
    Albumin
    Units: g/dl
        arithmetic mean (standard deviation)
    		 3.8 ± 0.2 -
    Hemoglobin
    Units: g/dl
        arithmetic mean (standard deviation)
    		 12.7 ± 1.4 -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Tolvaptan-Placebo
    Reporting group description
    		 All patients received a first 4-week treatment period with tolvaptan. Tolvaptan was started at the dose of 45 mg in the morning and 15 mg in the afternoon. Then, morning and afternoon doses were up-titrated every 2 days to 60 and 30 mg and then to 90 and 30 mg, respectively, according to tolerability. By completion of this 4-week titration period, participants were randomly allocated using a 1:1 randomization ratio to 4-week treatment periods with tolvaptan. During these two treatment periods, tolvaptan was administered at the maintenance dose achieved at the end of the titration period. According to the randomization plan, at the start of one of the two treatment periods, tolvaptan was combined with two 20-mg i.m. injections of octreotide- LAR, whereas at the start of the other treatment period, tolvaptan was combined with two i.m. injections of 0.9% NaCl solution (placebo for octreotide-LAR).
    Reporting group title
    Tolvaptan-Octreotide LAR
    Reporting group description
    		 All patients received a first 4-week treatment period with tolvaptan. Tolvaptan was started at the dose of 45 mg in the morning and 15 mg in the afternoon. Then, morning and afternoon doses were up-titrated every 2 days to 60 and 30 mg and then to 90 and 30 mg, respectively, according to tolerability. By completion of this 4-week titration period, participants were randomly allocated using a 1:1 randomization ratio to 4-week treatment periods with tolvaptan. During these two treatment periods, tolvaptan was administered at the maintenance dose achieved at the end of the titration period. According to the andomization plan, at the start of one of the two treatment periods, tolvaptan was combined with two 20-mg i.m. injections of octreotide-LAR, whereas at the start of the other treatment period, tolvaptan was combined with two i.m. injections of 0.9% NaCl solution (placebo for octreotide-LAR).

    Primary: Primary Comparison GFR

    		 Close Top of page
    End point title
    		 Primary Comparison GFR
    End point description
    The GFR was stable (Delta GFR: 0 [25 to 4] ml/min per 1.73 m2) during the 1-month run-in period whereas it significantly decreased by 3 (21 to 5) ml/min per 1.73 m2 during the 1-month tolvaptan and placebo treatment period (P=0.01) and by 7 (3–14) ml/min per 1.73 m2 during the 1-month dual treatment period (P=0.03). GFR changes during the two treatment periods differed by 2 (25 to 14) ml/min per 1.73 m2. The difference, however, was not significant (P=0.28).
    End point type
    Primary
    End point timeframe
    Baseline compared to 1 month after Tolvaptan and Octreotide–Long-Acting Release and Tolvaptan and Placebo
    End point values
    		 Tolvaptan-Placebo Tolvaptan-Octreotide LAR
    Number of subjects analysed
    19
    19
    Units: ml/min per 1.73m2
    arithmetic mean (standard deviation)
        Pre
    83 ± 13
    85 ± 15
        Post
    79 ± 14
    78 ± 12
    Statistical analysis title
    		 Primary comparisons endpoint
    Statistical analysis description
    The primary and secondary efficacy variables of this cross-over study were analyzed by paired t test (or Wilcoxon signed-rank test, in case of departure from normality assumptions) and, in a multivariable, exploratory approach, by using a linear mixed model for repeated measures (PROC MIXED, SAS version 9.2; SAS Institute Inc., Cary, NC), with sequence, period, and treatment as fixed effects and participant as random effect.
    Comparison groups
    Tolvaptan-Placebo v Tolvaptan-Octreotide LAR
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.28 [1]
    Method
    		 unpaired t-test
    Confidence interval
    Notes
    [1] - H0 : diff = 0 where diff = delta1-delta2, delta1 = GFR 1 month octreotide - GFR baseline octreotide delta2 = GFR 1 month placebo - GFR baseline placebo.

    Primary: Coprimary Comparisons GFR

    		 Close Top of page
    End point title
    		 Coprimary Comparisons GFR
    End point description
    During the first week treatment period, the GFR significantly decreased by 3 (0–7) ml/min per 1.73 m2 with tolvaptan and placebo therapy (P=0.006) and by 10 (26 to 16) ml/min per 1.73 m2 with dual therapy (P,0.001). Both changes significantly differed from the GFR changes were observed during the run-in period (P=0.03 and P=0.001, respectively). Notably, the GFR reduction achieved by tolvaptan and octreotide-LAR add-on therapy exceeded the reduction achieved by tolvaptan and placebo by 3 (0–12) ml/min per 1.73 m2 (Figure 1B), and the excess reduction was statistically significant (P=0.01).
    End point type
    Primary
    End point timeframe
    Baseline compared to 1 week after Tolvaptan and Octreotide–Long-Acting Release and Tolvaptan and Placebo
    End point values
    		 Tolvaptan-Placebo Tolvaptan-Octreotide LAR
    Number of subjects analysed
    19
    19
    Units: ml/min per 1.73m2
    arithmetic mean (standard deviation)
        Pre
    83 ± 13
    85 ± 13
        Post
    78 ± 13
    75 ± 11
    Statistical analysis title
    		 Coprimary comparisons endpoint
    Comparison groups
    Tolvaptan-Octreotide LAR v Tolvaptan-Placebo
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01 [2]
    Method
    		 unpaired t-test
    Confidence interval
    Notes
    [2] - H0 : diff = 0 where diff = delta1-delta2, delta1 = GFR 1 week octreotide - GFR baseline octreotide delta2 = GFR 1 week placebo - GFR baseline placebo.

    Secondary: Total Kidney Volume TKV

    		 Close Top of page
    End point title
    		 Total Kidney Volume TKV
    End point description
    TKV nonsignificantly decreased by 4 (-23 to 48) ml during the 1-month tolvaptan and placebo treatment period (P50.73), whereas it decreased significantly by 41 (25–77) ml during the 1-month treatment period with tolvaptan and octreotide-LAR (P <.001). TKV changes during the two treatment periods differed by 39.1613.3 ml, and the difference was statistically significant (P=0.01). Similar results were obtained by measuring height-adjusted TKV (data not shown). Changes in cystic kidney volume paralleled changes in TKV.
    End point type
    Secondary
    End point timeframe
    Baseline compared to 1 week after Tolvaptan and Octreotide–Long-Acting Release and Tolvaptan and Placebo
    End point values
    		 Tolvaptan-Placebo Tolvaptan-Octreotide LAR
    Number of subjects analysed
    19
    19
    Units: ml
    arithmetic mean (standard deviation)
        Pre
    1318 ± 623
    1295 ± 623
        Post
    1313 ± 625
    1185 ± 519
    No statistical analyses for this end point

    Secondary: Cystics Kidney Volume (CKV)

    		 Close Top of page
    End point title
    		 Cystics Kidney Volume (CKV)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline compared to 1 week after Tolvaptan and Octreotide–Long-Acting Release and Tolvaptan and Placebo
    End point values
    		 Tolvaptan-Placebo Tolvaptan-Octreotide LAR
    Number of subjects analysed
    19
    19
    Units: ml
    arithmetic mean (standard deviation)
        Pre
    889 ± 557
    836 ± 505
        Post
    883 ± 545
    737 ± 452
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    The adverse events will be reported during whole study up to 30 days after last dose of study drug.
    Adverse event reporting additional description
    Regarding the non-serious adverse event please refer to table 3 of the article attached
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Overall
    Reporting group description
    		 -

    Serious adverse events
    		 Overall
    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
    Investigations
    Elevated transaminase levels
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Elevated CPK levels
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    COVID-19
         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
    		 Overall
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 19 (100.00%)
    Renal and urinary disorders
    Polyuria
         subjects affected / exposed
    19 / 19 (100.00%)
         occurrences all number
    19

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Nov 2020
    Changing in inclusion/exclusion criteria due to recruitment slow rate

    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/36754009
    For support, Contact us.
    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.

    European Medicines Agency © 1995-Mon Apr 29 17:29:37 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA