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    Clinical Trial Results:
    A randomized, double-blind, active-controlled study to assess the effect of sacubitril/valsartan compared with enalapril to improve erectile function in patients with heart failure with reduced ejection fraction (HFrEF) and erectile dystunction (ED)

    Summary
    EudraCT number
    		 2018-000220-33
    Trial protocol
    		 DE  
    Global end of trial date
    25 May 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Jun 2022
    First version publication date
    04 Jun 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLCZ696BDE03
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03917459
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Dislcosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    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
    25 May 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 May 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to demonstrate the superiority of sacubitril/valsartan compared to enalapril regarding improvement in erectile function and ability in male patients with chronic heart failure and erectile dysfunction using the International Index of Erectile Function (IIEF-15) questionnaire at the end of the study.
    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
    16 Apr 2019
    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
    Germany: 27
    Worldwide total number of subjects
    27
    EEA total number of subjects
    27
    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)
    10
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Thirteen patients were randomized to the LCZ696 group, 14 were randomized to the Enalapril group. Twelve patients in the LCZ696 group and 13 patients in the enalapril group completed the study. One patient from the LCZ696 group discontinued due to Adverse Event. One patient from the enalapril group discontinued due to subject decision.

    Pre-assignment
    Screening details
    		 Thirteen patients were randomized to the LCZ696 group, 14 were randomized to the Enalapril group. Twelve patients in the LCZ696 group and 13 patients in the enalapril group completed the study. One patient from the LCZ696 group discontinued due to Adverse Event. One patient from the enalapril group discontinued due to subject decision.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LCZ696
    Arm description
    		 LCZ696 200 mg (sacubitril/valsartan 97 mg/103 mg bid)
    Arm type
    		 Experimental

    Investigational medicinal product name
    sacubitril/valsartan
    Investigational medicinal product code
    LCZ696
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LCZ696 200 mg

    Investigational medicinal product name
    Placebo to match sacubitril/valsartan
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg

    Investigational medicinal product name
    sacubitril/valsartan
    Investigational medicinal product code
    LCZ696
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LCZ696 100 mg

    Investigational medicinal product name
    sacubitril/valsartan
    Investigational medicinal product code
    LCZ696
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LCZ696 50 mg

    Investigational medicinal product name
    Placebo to match sacubitril/valsartan
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg

    Investigational medicinal product name
    Placebo to match sacubitril/valsartan
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50 mg

    Arm title
    		 Enalapril
    Arm description
    		 Enalapril 10 mg bid
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Enalapril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Enalapril 10 mg

    Investigational medicinal product name
    Placebo to match Enalapril
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg

    Investigational medicinal product name
    Placebo to match Enalapril
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5 mg

    Investigational medicinal product name
    Placebo to match Enalapril
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5 mg

    Investigational medicinal product name
    Enalapril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Enalapril 2.5 mg

    Investigational medicinal product name
    Enalapril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Enalapril 5 mg

    Number of subjects in period 1
    		LCZ696 Enalapril
    Started
    13
    14
    Completed
    12
    13
    Not completed
    1
    1
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LCZ696
    Reporting group description
    		 LCZ696 200 mg (sacubitril/valsartan 97 mg/103 mg bid)

    Reporting group title
    Enalapril
    Reporting group description
    		 Enalapril 10 mg bid

    Reporting group values
    		 LCZ696 Enalapril Total
    Number of subjects
    		 13 14 27
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 7 3 10
        From 65-84 years
    		 6 11 17
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Count of Participants
        arithmetic mean (standard deviation)
    		 63.5 ± 9.18 66.5 ± 7.80 -
    Sex: Female, Male
    Gender
    Units: Participants
        Female
    		 0 0 0
        Male
    		 13 14 27
    Race (NIH/OMB)
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 13 14 27
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    LCZ696
    Reporting group description
    		 LCZ696 200 mg (sacubitril/valsartan 97 mg/103 mg bid)

    Reporting group title
    Enalapril
    Reporting group description
    		 Enalapril 10 mg bid

    Primary: Erectile function score using Index of Erectile Function (IIEF-15)

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    End point title
    		 Erectile function score using Index of Erectile Function (IIEF-15)
    End point description
    The International Index of Erectile Function (IIEF-15) was used to assess erectile function score in male patients with chronic heart failure. IIEF-15 is a patient self-reported assessment of erectile dysfunction (ED) and consists of 15 questions assessing five main principles associated with ED: erectile function, orgasmic function, sexual desire, intercourse satisfaction and overall satisfaction. For erectile function score, questions 1-5 and 15 were evaluated and summed. For each question, 0-5 points could be achieved with 5 being the highest score assigned, which corresponded to the most favorable outcome.
    End point type
    Primary
    End point timeframe
    Week 12 (3 months)
    End point values
    		 LCZ696 Enalapril
    Number of subjects analysed
    12
    13
    Units: Percentage score
        least squares mean (standard error)
    15.1 ± 2.15
    12.2 ± 2.00
    Statistical analysis title
    		 LCZ696 vs Enalapril
    Comparison groups
    LCZ696 v Enalapril
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3432
    Method
    		 Mixed Model Repeated Measures (MMRM)
    Parameter type
    		 LS mean of treatment difference
    Point estimate
    2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.29
         upper limit
    		 9.01

    Secondary: Summary of change from baseline in Self-reported frequency of sexual activity per week

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    End point title
    		 Summary of change from baseline in Self-reported frequency of sexual activity per week
    End point description
    Assessment of early-onset effect and end of study effect, regarding improvement in sexual activity, using patient's self-reported frequency of sexual activity per week. Patient was asked to complete a diary assessing sexual activity on a weekly basis
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, Week 12
    End point values
    		 LCZ696 Enalapril
    Number of subjects analysed
    13
    14
    Units: Number
    arithmetic mean (standard deviation)
        Week 4:
    -1.6 ± 1.59
    -1.1 ± 1.97
        Week 12:
    -1.4 ± 3.13
    -2.0 ± 3.07
    No statistical analyses for this end point

    Secondary: Summary of change from baseline in NT-proBNP levels

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    End point title
    		 Summary of change from baseline in NT-proBNP levels
    End point description
    Change in n-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels compared to baseline assessed at Week 4 and Week 12
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, Week 12
    End point values
    		 LCZ696 Enalapril
    Number of subjects analysed
    13
    14
    Units: pg/mL
    median (full range (min-max))
        Week 4
    -369.0 (-4884.0 to 1590.0)
    -43.50 (-198.0 to 7819.0)
        Week 12
    -208.50 (-6962.0 to 2683.0)
    -189.00 (-826.0 to 1744.0)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of approximately 2 years, 1 month.
    Adverse event reporting additional description
    Any sign or symptom that occurs during the study treatment plus the 30 days post treatment
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Enalapril
    Reporting group description
    		 Enalapril

    Reporting group title
    LCZ696
    Reporting group description
    		 LCZ696

    Serious adverse events
    		 Enalapril LCZ696
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 13 (7.69%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 13 (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: 5%
    Non-serious adverse events
    		 Enalapril LCZ696
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 14 (35.71%)
    7 / 13 (53.85%)
    Investigations
    Blood potassium decreased
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Hypotension
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Dental caries
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Toothache
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Fluid retention
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Gout
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jan 2019
    The classification of the clinical phase of the trial was adjusted. In addition, exclusion criterion 33 was modified and the end of the study was defined in more detail.

    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.
    This study was early terminated on 25-May-2021. 27 patients were randomized instead of planned 200 patients. The reason for preliminary study stop was recruitment issues. There were no safety issues in the study.
    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.

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