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   43839   clinical trials with a EudraCT protocol, of which   7280   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:
    Phase II randomized, placebo-controlled, double blind clinical trial of valsartan for attenuating disease evolution in early sarcomeric HCM

    Summary
    EudraCT number
    2015-002283-16
    Trial protocol
    DK  
    Global end of trial date
    01 May 2020

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

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    1P50HL112349
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01912534
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    National Institutes of Health
    Sponsor organisation address
    10 Center Dr, Bethesda, United States,
    Public contact
    Kristin Burns, Heart Development and Structural Diseases Branch / Division of Cardiovascular Sciences National Hea, 001 301-594-6859, kristin.burns@nih.gov
    Scientific contact
    Kristin Burns, Heart Development and Structural Diseases Branch / Division of Cardiovascular Sciences National Hear, 001 301-594-6859, kristin.burns@nih.gov
    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
    13 Nov 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 May 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    01 May 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of Valsartan in young patients in an early stage of hypertrophic cardiomyopathy.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Jul 2014
    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: 10
    Country: Number of subjects enrolled
    United States: 137
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Brazil: 27
    Worldwide total number of subjects
    178
    EEA total number of subjects
    10
    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)
    10
    Adolescents (12-17 years)
    57
    Adults (18-64 years)
    111
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    Study was conducted at multiple centers in 4 countries between 1 July 2014 (first subject first visit) and 26 July 2019 (last subject last visit).

    Pre-assignment
    Screening details
    The most common reasons for not progressing to randomization were not meeting eligibility criteria (n=28) or consent withdrawal (n=19). In total, 178 subjects were randomized and received study treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Valsartan
    Arm description
    Subjects entered into an active run-in phase during which increasing doses of valsartan were administered as tolerated until reaching weight-based target dose (80–320 mg daily). Valsartan or placebo was thereafter administered for two years.
    Arm type
    Active comparator

    Investigational medicinal product name
    Valsartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects entered into an active run-in phase during which increasing doses of valsartan were administered as tolerated until reaching weight-based target dose (80–320 mg daily). Valsartan was thereafter administered for two years.

    Arm title
    Placebo
    Arm description
    Subjects entered into an active run-in phase during which increasing doses of valsartan were administered as tolerated until reaching weight-based target dose (80–320 mg daily). Placebo matched to valsartan was thereafter administered for two years
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects entered into an active run-in phase during which increasing doses of valsartan were administered as tolerated until reaching weight-based target dose (80–320 mg daily). Valsartan or placebo was thereafter administered for two years.

    Number of subjects in period 1
    Valsartan Placebo
    Started
    88
    90
    Completed
    84
    83
    Not completed
    4
    7
         Consent withdrawn by subject
    3
    6
         Death in pedestrian accident
    1
    -
         Adverse event, non-fatal
    -
    1

    Baseline characteristics

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

    Reporting group values
    Overall treatment period Total
    Number of subjects
    178 178
    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)
    23.3 ± 10.0 -
    Gender categorical
    Units: Subjects
        Female
    69 69
        Male
    109 109

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Valsartan
    Reporting group description
    Subjects entered into an active run-in phase during which increasing doses of valsartan were administered as tolerated until reaching weight-based target dose (80–320 mg daily). Valsartan or placebo was thereafter administered for two years.

    Reporting group title
    Placebo
    Reporting group description
    Subjects entered into an active run-in phase during which increasing doses of valsartan were administered as tolerated until reaching weight-based target dose (80–320 mg daily). Placebo matched to valsartan was thereafter administered for two years

    Primary: Primary composite end point

    Close Top of page
    End point title
    Primary composite end point
    End point description
    The primary objective of VANISH was to investigate whether treatment with valsartan attenuated phenotypic progression in early sarcomeric HCM by assessing changes in multiple metrics of cardiac structure and function from baseline to end of study (Year 2). Metrics included BSA-indexed LV mass and BSA-indexed left atrial (LA) volume (decrease considered improvement), BSA-indexed LV end diastolic and end systolic volumes (increase considered improvement), BSA-adjusted maximal LV wall thickness (decrease considered improvement), age-adjusted age-adjusted mitral annulus diastolic (e’) and systolic (s’) velocities (increase considered improvement); and log-transformed serum TnT and NTproBNP levels (decrease considered improvement). These changes were converted to z-scores for change for each metric and averaged together to produce the composite z-score for each patient, the prespecified primary outcome. A positive composite z-score indicates a greater than average improvement.
    End point type
    Primary
    End point timeframe
    2 years
    End point values
    Valsartan Placebo
    Number of subjects analysed
    84
    83
    Units: z-score
        median (inter-quartile range (Q1-Q3))
    0.136 (0.049 to 0.223)
    -0.095 (-0.192 to 0.002)
    Statistical analysis title
    Primary endpoint
    Statistical analysis description
    Our analyses of the composite z-score and its components were based on mixed model linear regressions, adjusting through random effects for clustering within sites and within families. Models compared changes in the outcome between the treatment groups and were adjusted for pre-specified patient characteristics.
    Comparison groups
    Valsartan v Placebo
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    Mixed models analysis
    Confidence interval

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Valsartan
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Serious adverse events
    Valsartan Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 88 (9.09%)
    10 / 90 (11.11%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Pedestrian accident
    Additional description: Death (pedestrian accident) / unrelated to hypertrophic cardiomyopathy and study drug/ severity=5
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac disorders
    ICD placement
         subjects affected / exposed
    1 / 88 (1.14%)
    3 / 90 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 88 (1.14%)
    2 / 90 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ICD malfunction
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inducible ventricular tachycardia
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Premature ventricular complexes
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Severe anemia
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervical cancer
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hysterectomy
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Viral syndrome
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.5%
    Non-serious adverse events
    Valsartan Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    52 / 88 (59.09%)
    48 / 90 (53.33%)
    Cardiac disorders
    overall non-serious
         subjects affected / exposed
    52 / 88 (59.09%)
    48 / 90 (53.33%)
         occurrences all number
    52
    48

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Nov 2013
    1. Clarification of the visit information for subjects that may require a longer active-run phase; 2. Clarification of the visit information for children ≤16 years and <35 kg in the active-run; 3. Clarification of the dose adjustment guidelines for children who reach 17 years of age or whose body weight increases from <35 kg to ≥ 35 kg in the maintenance phase; 4. Clarification of the adverse event reporting timeframe to the DCC; 5. Clarification of the acquisition and handling of blood samples; 6. Clarification of the roles for the management of the investigational drugs; and 7. Clarification of the potential risk that valsartan administration may contribute to the development of obstructive physiology.
    26 Aug 2014
    1. Change in nomenclature to clarify that subjects designated as overt HCM may have borderline left ventricular hypertrophy and not meet standard clinical criteria for a diagnosis of HCM. The cohort previously designated "overt HCM" will now be designated "Group 1". The cohort previously designated as "preclinical HCM" will now be designated "Group 2". 2. Section 5.2: Clarification of Inclusion Criteria: All Group 1 subjects regardless of age may be eligible based on either LV wall thickness in mm ( >/= 12 mm and </= 20 mm) or z score (>/= 3 and </=14) criteria. Group 1 z-score cap should be </=14 (not 10) to correlate with LVWT 20 mm. 3. Section 5.3: Subject Exclusion Criteria Addition of concomitant or prior use of Spironolactone, Lithium, or Aliskiren 4. Section 5.3: Subject Exclusion Criteria- Clarification prior ARB/ACE-use is permitted if medications have been discontinued or can be discontinued/ not needed for clinical care. A minimum 2-week washout period should be performed before proceeding to baseline studies. 5. Section 5.3: Subject Exclusion Criteria - Clarification of echocardiographic core lab eligibility 6. Section 5.3: Subject Exclusion Criteria - Clarify the exclusion for hypertension to exclude only those with uncontrolled, persistent hypertension (SBP>160 and/or DBP>90) 7. Section 7.7: Clarification of FitBit distribution 8. Section 8.2.2: Restrictions regarding concomitant treatment Addition of Spironolactone, Lithium, or Aliskiren to the list of restricted medications. 9. Section 9.1: Recording and Reporting of Adverse Events - Modification to remove independent medical monitor adjudication. 10. Section 10.4: Adjudication Procedures- Clarification of the process for adjudicating clinical events 11. Section 22.1 Appendix 1: Participating Sites Modifications to update the participating sites and investigators 12. We would like to expand our internet advertising strategy to include social media. We have included Face
    23 Feb 2015
    1. Minor grammatical/style changes were made throughout 2. Page 5, Section 1.2: Protocol Synopsis • Edited to reflect changes in eligibility (listed below) • Edited to reflect that baseline studies are considered current for up to six months 3. Page 14, Section 4.1 Trial Schema • Figure 4 updated to reflect changes in eligibility (listed below) 4. Page 15, Section 5.1: Subject Selection • Edited to reflect changes in group 2 eligibility (listed below) 5. Page 15-16, Section 5.2: Amendment of Inclusion Criteria • Genetic testing not performed by a laboratory not listed in the inclusion criteria will be reviewed by the Clinical Coordinating Center to determine eligibility. • The upper age range for Group 1 subjects will be increased from 30 to 45 years • The maximal LV wall thickness for Group 1 subjects will be increased from 20 to 25 mm or a z-score of 18 Rationale: Experience during the first 6 months of study enrollment indicated that the target population for this trial, as defined by original inclusion/exclusion criteria, is exceedingly rare. Even in the specialty HCM centers participating in the trial, the target population represents a very low prevalence group. As such, we recognize the need to modify eligibility criteria to facilitate enrollment. After detailed review of site screening logs, it was determined that allowing inclusion of subjects up to age 45 years, subjects with a maximal LV wall thickness of up 25mm, and subjects with primary prevention ICD devices will substantially increase the yield of eligible subjects without compromising study safety and design. • A LV wall thickness z-score of 1.5-2.9 combined with LV thickness to dimension ratio ≥0.19 (as determined by rapid assessment by the echocardiographic core laboratory) will qualify subjects for Group 2 Rationale: The combination of an upper normal LV wall thickness combined with an increased thickness:dimension ratio is anticipated to accurately discriminat
    23 Jan 2017
    Added additional performance sites
    15 Jun 2018
    The protocol has been updated in the following sections: -Section 1.2 - Protocol Synopsis -Section 6.1 - Subject Participation -Section 8.4 - Procedures for Monitoring Subject Compliance These changes relate to patients that have their Year 2 visit out of window and the timeframe in which they continue taking study drug. The protocol changes indicate that patients will continue taking study medication up until their Year 2 visit, even if the visit occurs out of window. If a patient has an out of window Year 2 visit, the patient should continue study medication until the visit occurs. This is to ensure that Year 2 studies are performed on therapy and preserve the reliability/interpretability of their results.

    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/34556856
    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 © 1995-2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA