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

Prospective, Multi-center, Open lAbel, Post-appRovAl Study AImed at Characterizing the Use of LCZ696 at 97 mg Sacubitril / 103 mg Valsartan Bid in Patients With HFrEF

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.

Study Overview

• Status: Completed
• Conditions: Hearth Failure With Reduced Ejection Fraction (HFrEF)
• Intervention / Treatment: Drug: LCZ696 (sacubitril/valsartan)

• Study Type: Interventional
• Enrollment (Actual): 302
• Phase: Phase 4

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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); All patients were treated with the LCZ696 (sacubitril and valsartan) tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Month 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Month 12
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.	Month 12
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.	Month 12
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.	Baseline, Month 6 and Month 12
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.	Baseline, Week 2, Week 4, Month 3, Month 6 and Month 12
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.	Baseline, Week 2, Week 4, Month 3, Month 6 and Month 12
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.	Baseline, Month 6 and Month 12

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): March 8, 2016
• Primary Completion (Actual): June 7, 2017
• Study Completion (Actual): November 29, 2017

Study Registration Dates

• First Submitted: February 15, 2016
• First Submitted That Met QC Criteria: February 19, 2016
• First Posted (Estimate): February 24, 2016

Study Record Updates

• Last Update Posted (Actual): June 7, 2019
• Last Update Submitted That Met QC Criteria: March 5, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: Ejection Fraction; HFrEF,; CHF,; ACEi,; ACE inhibitor,; ARBs,; systolic heart failure,; chronic heart failure,; reduced EF,
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Valsartan; Sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: CLCZ696BCA02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No