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CompletedNCT02690974PARASAILUpdated Jun 7, 2019Results posted

Description of Tolerability of LCZ696 (Sacubitril / Valsartan) in Heart Failure With Reduced Ejection Fraction (HFrEF) Treated in Real Life Setting

A Phase 4 interventional study of LCZ696 (sacubitril/valsartan) in Hearth Failure With Reduced Ejection Fraction (HFrEF), sponsored by Novartis Pharmaceuticals. Completed at 32 sites in Canada. Open to participants aged 18 Years to 80 Years. Per ClinicalTrials.gov, last updated 2019-06-07.

Sponsored by Novartis Pharmaceuticals · Phase 4, Interventional, and Supportive care

Phase
Phase 4
Study type
Interventional
Enrollment
302
Allocation
Not applicable
Ages
18 Years to 80 Years
Sex
All
01

Study summary

The primary purpose of the study was to describe the tolerability of treatment with the optimal dose of LCZ696 (97 mg sacubitril / 103 mg valsartan bid), over six (6) months, in patients with heart failure with reduced ejection fraction (HFrEF) in Canada.

The study was also to describe the overall tolerability, effectiveness and safety of LCZ696 for the management of HFrEF over 12 months of treatment, as well as describe the patterns of LCZ696 up and down dose titrations occurring during the management of patients with HFrEF.

02

Conditions studied

  • Hearth Failure With Reduced Ejection Fraction (HFrEF)

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Keywords

  • HFrEF,
  • ACEi,
  • ACE inhibitor,
  • ARBs,
  • systolic heart failure,
  • chronic heart failure,
  • CHF,
  • reduced EF,
  • Ejection Fraction
03

In context

Heart Failure

5,701 studies on the registry are indexed under Heart Failure; 1,220 are open to participants now.

This study's enrollment of 302 is above the median of 72 across 3,736 interventional studies indexed under Heart Failure.

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Lead sponsor

Novartis Pharmaceuticals is the lead sponsor of 2,673 studies on the registry; 228 are open to participants now.

Of its 576 completed or terminated interventional studies of FDA-regulated products, 431 (75%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years to 80 Years
Sexes eligible
All
Accepts healthy volunteers
No

Eligibility criteria

Key Inclusion Criteria:

  1. Written informed consent must be obtained before any assessment is performed.
  2. Age ≥ 18 years and ≤ 80 years.
  3. Males or females.
  4. Diagnosis of Heart Failure NYHA class II-III.
  5. Diagnosis of Heart Failure with reduced Ejection Fraction (LVEF =\< 40%) and NYHA class II or III.
  6. Stable on any dose of ACEI or ARB prior to enrolment in the study
  7. Stable on any dose of a beta-blocker prior to enrolment in the study.
  8. Eligible for treatment with LCZ696 as per Canadian product monograph.
  9. Treated as an outpatient.
  10. Signed an informed consent agreeing to participate in the study.

Key Exclusion Criteria:

  1. Symptomatic hypotension and/or a SBP \< 100 mmHg at baseline visit.
  2. Estimated GFR \< 30 mL/min/1.73m\^2 as measured by the simplified Modification of Diet in Renal Disease (MDRD) formula at baseline visit.
  3. Known history of angioedema related to previous ACEI or ARBs therapy, or history of hereditary or idiopathic angioedema.
  4. Requirement of concomitant treatment with both ACEIs and ARBs.
  5. Concurrent participation in other clinical trials or receiving other investigational drugs within 30 days of enrollment.
  6. Hypersensitivity to the active substances, sacubitril or valsartan, or to any of the excipients.
  7. Concomitant use of aliskiren-containing drugs in patients with diabetes mellitus (type 1 or type 2) or moderate to severe renal impairment (GFR \<60ml/min/1.73m\^2).
  8. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes.
  9. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
  10. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
  11. Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment. Effective contraception methods are described in the protocol.
05

Study design

Phase
Phase 4
Primary purpose
Supportive care
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrollment
302 participants (actual)

Study arms

  • Other
    LCZ696 (sacubitril / valsartan)

    All patients were initiated on either LCZ696 at 24 mg sacubitril / 26 mg valsartan or LCZ696 at 49 mg sacubitril / 51 mg valsartan bid for 2-4 weeks and were up-titrated to the next higher dose for another 2 - 4 weeks as applicable.

    Drug: LCZ696 (sacubitril/valsartan)

Interventions

  • DrugLCZ696 (sacubitril/valsartan)

    All patients were treated with the LCZ696 (sacubitril and valsartan) tablets

06

What researchers measure

Primary outcomes

  1. Percentage of Participants on LCZ696 200 mg Bid at Month 6

    The tolerability of LCZ696 was defined as the percentage of patients on LCZ696 at the dose of 97 mg sacubitril / 103 mg valsartan twice daily (bid) who did not experience down titration or treatment discontinuation because of adverse events while on this dose at month 6. Only descriptive analysis done.

    Time frame: Month 6

Secondary outcomes

  1. Percentage of Participants on LCZ696 200 mg Bid at Month 12

    The tolerability of LCZ696 was defined as the percentage of patients on LCZ696 at the dose of 97 mg sacubitril / 103 mg valsartan twice daily (bid) who did not experience down titration or treatment discontinuation because of adverse events while on this dose at month 12. Only descriptive analysis done.

    Time frame: Month 12

  2. Percentage of Participants Requiring Down-titration From LCZ696 200 mg

    The impact of the titration scheme on the tolerability of patients maintained on LCZ696 97 mg sacubitril / 103 mg valsartan bid was defined as the percentage of patients on LCZ696 200mg requiring down-titration. Only descriptive analysis done.

    Time frame: Month 12

  3. Percentage of Participants With Down-titration Changes From LCZ696 200 mg During 12 Months of Treatment

    The impact of the titration scheme on the tolerability of patients maintained on LCZ696 97 mg sacubitril / 103 mg valsartan bid was defined as the number of down-titration during the 12 months treatment period. Dow-titration schemes considered for the analysis are 200 mg to 100 mg; 100 mg to 50 mg; and 50 mg to 0 mg (i.e. treatment discontinuation). The down-titration scheme of 50mg to 0 mg was taken in account in this analysis to ensure to reflect all actual changes in dose. Only descriptive analysis done.

    Time frame: Month 12

  4. Change From Baseline in the Six Minute Walk Test (6MWT) at Month 6 and Month 12

    The impact of LCZ696 on functional exercise capacity was measured by the Six Minute Walk Test at 6 and 12 months. The 6MWT measures the distance an individual is able to walf over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. The individual is able to self-pace and rest as needed as they traverse back and forth along a marked walkway. Only descriptive analysis done.

    Time frame: Baseline, Month 6 and Month 12

  5. Time to Each Up-titration to LCZ696 100 mg and LCZ696 200 mg

    To describe the time of up-titration for each dose (24 mg sacubitril / 26 mg valsartan bid and 49 mg sacubitril / 51 mg valsartan bid) of LCZ696. Only descriptive analysis done.

    Time frame: Baseline, Week 2, Week 4, Month 3, Month 6 and Month 12

  6. Median Time to Reach LCZ696 200 mg

    To describe the time of up-titration for each dose (24 mg sacubitril / 26 mg valsartan bid and 49 mg sacubitril / 51 mg valsartan bid) of LCZ696. Only descriptive analysis done.

    Time frame: Baseline, Week 2, Week 4, Month 3, Month 6 and Month 12

  7. Percentage of Participants on Guideline Recommended Dose of Beta-blockers and MRAs Over Time

    To describe the adherence to guideline recommended dosing of beta-blockers and MRAs at 6 and 12 months of treatment of LCZ696. Only descriptive analysis done.

    Time frame: Baseline, Month 6 and Month 12

07

Results

Posted Jun 7, 2019

Participant flow

This study was conducted in 32 study centers in Canada

Participant flow — Overall Study
MilestoneLCZ696 (Sacubitril / Valsartan)
Started302
Completed262
Not completed40
Withdrew: Adverse event16
Withdrew: Death9
Withdrew: Subject/guardian decision4
Withdrew: Lost to follow-up3
Withdrew: Withdrawal of informed consent3
Withdrew: Physician decision2
Withdrew: Non-compliance with study treatment1
Withdrew: Protocol-defined stopping criteria1
Withdrew: Protocol deviation1

Outcome measures

PrimaryPercentage of Participants on LCZ696 200 mg Bid at Month 6

The tolerability of LCZ696 was defined as the percentage of patients on LCZ696 at the dose of 97 mg sacubitril / 103 mg valsartan twice daily (bid) who did not experience down titration or treatment discontinuation because of adverse events while on this dose at month 6. Only descriptive analysis done.

Time frame:
Month 6
Reported as:
Number · Percentage of Participants
Percentage of Participants on LCZ696 200 mg Bid at Month 6
Percentage of ParticipantsLCZ696 (Sacubitril / Valsartan)
Percentage of Participants on LCZ696 200 mg Bid at Month 664.6 (59.18 to 69.96)
SecondaryPercentage of Participants on LCZ696 200 mg Bid at Month 12

The tolerability of LCZ696 was defined as the percentage of patients on LCZ696 at the dose of 97 mg sacubitril / 103 mg valsartan twice daily (bid) who did not experience down titration or treatment discontinuation because of adverse events while on this dose at month 12. Only descriptive analysis done.

Time frame:
Month 12
Reported as:
Number · Percentage of Participants
Percentage of Participants on LCZ696 200 mg Bid at Month 12
Percentage of ParticipantsLCZ696 (Sacubitril / Valsartan)
Percentage of Participants on LCZ696 200 mg Bid at Month 1262.3 (56.78 to 67.72)
SecondaryPercentage of Participants Requiring Down-titration From LCZ696 200 mg

The impact of the titration scheme on the tolerability of patients maintained on LCZ696 97 mg sacubitril / 103 mg valsartan bid was defined as the percentage of patients on LCZ696 200mg requiring down-titration. Only descriptive analysis done.

Time frame:
Month 12
Reported as:
Number · Percentage of Participants
Percentage of Participants Requiring Down-titration From LCZ696 200 mg
Percentage of ParticipantsLCZ696 (Sacubitril / Valsartan)
Percentage of Participants Requiring Down-titration From LCZ696 200 mg11.92 (8.27 to 15.58)
SecondaryPercentage of Participants With Down-titration Changes From LCZ696 200 mg During 12 Months of Treatment

The impact of the titration scheme on the tolerability of patients maintained on LCZ696 97 mg sacubitril / 103 mg valsartan bid was defined as the number of down-titration during the 12 months treatment period. Dow-titration schemes considered for the analysis are 200 mg to 100 mg; 100 mg to 50 mg; and 50 mg to 0 mg (i.e. treatment discontinuation). The down-titration scheme of 50mg to 0 mg was taken in account in this analysis to ensure to reflect all actual changes in dose. Only descriptive analysis done.

Time frame:
Month 12
Reported as:
Count of participants · Participants
Percentage of Participants With Down-titration Changes From LCZ696 200 mg During 12 Months of Treatment
ParticipantsLCZ696 (Sacubitril / Valsartan)
200 mg dose level188
100 mg dose level44
50 mg dose level28
SecondaryChange From Baseline in the Six Minute Walk Test (6MWT) at Month 6 and Month 12

The impact of LCZ696 on functional exercise capacity was measured by the Six Minute Walk Test at 6 and 12 months. The 6MWT measures the distance an individual is able to walf over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. The individual is able to self-pace and rest as needed as they traverse back and forth along a marked walkway. Only descriptive analysis done.

Time frame:
Baseline, Month 6 and Month 12
Reported as:
Mean · Meter (m)
Change From Baseline in the Six Minute Walk Test (6MWT) at Month 6 and Month 12
Meter (m)LCZ696 (Sacubitril / Valsartan)
Value at Baseline (Day 1)392.62 ± 139.3277
Change from Baseline at Month 611.99 ± 67.5725
Change from Baseline at Month 128.19 ± 71.3619
SecondaryTime to Each Up-titration to LCZ696 100 mg and LCZ696 200 mg

To describe the time of up-titration for each dose (24 mg sacubitril / 26 mg valsartan bid and 49 mg sacubitril / 51 mg valsartan bid) of LCZ696. Only descriptive analysis done.

Time frame:
Baseline, Week 2, Week 4, Month 3, Month 6 and Month 12
Reported as:
Mean · Days
Time to Each Up-titration to LCZ696 100 mg and LCZ696 200 mg
DaysLCZ696 (Sacubitril / Valsartan)
50- 100 mg bid level21.44 ± 23.1799
100- 200 mg bid level27.37 ± 28.5601
50- 200 mg bid level46.61 ± 36.9439
SecondaryMedian Time to Reach LCZ696 200 mg

To describe the time of up-titration for each dose (24 mg sacubitril / 26 mg valsartan bid and 49 mg sacubitril / 51 mg valsartan bid) of LCZ696. Only descriptive analysis done.

Time frame:
Baseline, Week 2, Week 4, Month 3, Month 6 and Month 12
Reported as:
Median · Days
Median Time to Reach LCZ696 200 mg
DaysLCZ696 (Sacubitril / Valsartan)
Median Time to Reach LCZ696 200 mg37.00 (35.00 to 42.00)
SecondaryPercentage of Participants on Guideline Recommended Dose of Beta-blockers and MRAs Over Time

To describe the adherence to guideline recommended dosing of beta-blockers and MRAs at 6 and 12 months of treatment of LCZ696. Only descriptive analysis done.

Time frame:
Baseline, Month 6 and Month 12
Reported as:
Count of participants · Participants
Percentage of Participants on Guideline Recommended Dose of Beta-blockers and MRAs Over Time
ParticipantsLCZ696 (Sacubitril / Valsartan)
Baseline298
Month 6272
Month 12261

Adverse events

Collected over Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 1 year.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
LCZ696 (Sacubitril / Valsartan)9/302 (3%)47/302 (15.6%)98/302 (32.5%)
Most frequent serious events
Showing 10 of 52
Most frequent serious events
EventLCZ696 (Sacubitril / Valsartan)
Cardiac failure congestiveCardiac disorders13/302
PneumoniaInfections and infestations6/302
Acute myocardial infarctionCardiac disorders3/302
Cardiac arrestCardiac disorders3/302
Cardiac failureCardiac disorders3/302
Ventricular tachycardiaCardiac disorders3/302
DeathGeneral disorders3/302
GastroenteritisInfections and infestations2/302
DehydrationMetabolism and nutrition disorders2/302
HyponatraemiaMetabolism and nutrition disorders2/302
Most frequent other events
Most frequent other events
EventLCZ696 (Sacubitril / Valsartan)
DizzinessNervous system disorders45/302
HypotensionVascular disorders31/302
CoughRespiratory, thoracic and mediastinal disorders20/302
FatigueGeneral disorders19/302
DiarrhoeaGastrointestinal disorders18/302

Baseline characteristics

Full Analysis Set (FAS)

Age, Continuous
Age, Continuous(Years)LCZ696 (Sacubitril / Valsartan)
Mean64.47 ± 10.7659
Sex: Female, Male
Sex: Female, Male(Participants)LCZ696 (Sacubitril / Valsartan)
Female62
Male240
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)LCZ696 (Sacubitril / Valsartan)
Caucasian271
Black8
Asian15
Native American4
Unknown or Not Reported4
08

Study locations

32 sites
  • Novartis Investigative Site
    Edmonton, Alberta T5H 3V9, Canada
  • Novartis Investigative Site
    New Westminster, British Columbia V3L 3W4, Canada
  • Novartis Investigative Site
    Vancouver, British Columbia V6Z 1Y6, Canada
  • Novartis Investigative Site
    Winnipeg, Manitoba R2H 2A6, Canada
  • Novartis Investigative Site
    Moncton, New Brunswick E1C 2Z3, Canada
  • Novartis Investigative Site
    Moncton, New Brunswick E1G 1A7, Canada
  • Novartis Investigative Site
    St. John's, Newfoundland and Labrador A1B 3V6, Canada
  • Novartis Investigative Site
    Burlington, Ontario L7M 4Y1, Canada
  • Novartis Investigative Site
    Cambridge, Ontario N1R 6V6, Canada
  • Novartis Investigative Site
    London, Ontario N6A 5A5, Canada
  • Novartis Investigative Site
    Mississauga, Ontario L5K 2L3, Canada
  • Novartis Investigative Site
    Newmarket, Ontario L3Y 2P6, Canada
  • Novartis Investigative Site
    Newmarket, Ontario L3Y 8C3, Canada
  • Novartis Investigative Site
    Ottawa, Ontario K1Y 4W7, Canada
  • Novartis Investigative Site
    Peterborough, Ontario K9J 0B2, Canada
  • Novartis Investigative Site
    Sarnia, Ontario N7T 4X3, Canada
  • Novartis Investigative Site
    Scarborough, Ontario M1E 5E9, Canada
  • Novartis Investigative Site
    Scarborough, Ontario M1P 2V5, Canada
  • Novartis Investigative Site
    Sudbury, Ontario P3E 3B8, Canada
  • Novartis Investigative Site
    Sudbury, Ontario P3E 5M9, Canada
  • Novartis Investigative Site
    Toronto, Ontario M6R 1B5, Canada
  • Novartis Investigative Site
    Waterloo, Ontario N2T 0C1, Canada
  • Novartis Investigative Site
    Weston, Ontario M9N 1W4, Canada
  • Novartis Investigative Site
    Greenfield Park, Quebec J4V 2G8, Canada
  • Novartis Investigative Site
    Joliette, Quebec J6E 6J2, Canada
  • Novartis Investigative Site
    Montreal, Quebec H1T 3Y7, Canada
  • Novartis Investigative Site
    St-Jean-sur-Richelieu, Quebec J3A 1J2, Canada
  • Novartis Investigative Site
    Terrebonne, Quebec J6V 2H2, Canada
  • Novartis Investigative Site
    Brossard, J4Z 2K9, Canada
  • Novartis Investigative Site
    Hamilton, L8L 0A9, Canada
  • Novartis Investigative Site
    Quebec, GIV 4G5, Canada
  • Novartis Investigative Site
    St-Lambert, J4P 2J2, Canada
09

References and documents

Study documents

  • Statistical analysis plan · Jul 4, 2017
  • Study protocol · Sep 12, 2016

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Jun 7, 2019, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT02690974
Lead sponsor
Novartis Pharmaceuticals
Responsible party
Sponsor
First posted
Feb 24, 2016
Start date
Mar 8, 2016
Primary completion
Jun 7, 2017
Completion
Nov 29, 2017
Results posted
Jun 7, 2019
Last update
Jun 7, 2019

Study contacts

Novartis Pharmaceuticals
study director · Novartis Pharmaceuticals

Oversight

Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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