An Open-label Extension Study Evaluating Safety and Tolerability of LCZ696 in Subjects Who Completed PARAGON-HF in Japan.

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03909295
• Collaborator: (none)
• Enrollment: 52
• Locations: 17
• Arm: 1
• Actual Duration (Months): 6.4
• Patients Per Site: 3.1
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This study evaluated the safety and tolerability of LCZ696 treatment in Japanese heart failure patients (NYHA Class II-IV) with preserved ejection fraction after CLCZ696D2301 (PARAGON-HF).

Condition or Disease	Intervention/Treatment	Phase
Heart Failure With Preserved Ejection Fraction (HFpEF)	Drug: LCZ696	Phase 3

Detailed Description

This study was an open-label extension study following the PARAGON-HF. Patients who have completed the PARAGON-HF were eligible to participate. During the study, open-label LCZ696 was taken in addition to background treatments of comorbidities. All subjects were treated with LCZ696 (sacubitril/valsartan) at maximally tolerated dosed with a target dose of 200 mg b.i.d (twice a day).

The subject were to continue to receive LCZ696 until it became commercially available, or for a period up to 24 months from the first patient enrolled in this study whichever came first. However, this study was terminated early based on the pre-defined early termination criteria of "the primary endpoint of PARAGONHF was not met" in the protocol.

Study Design

• Study Type: Interventional
• Actual Enrollment: 52 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Open-label Study to Evaluate the Safety and Tolerability of LCZ696 Treatment in Japanese Heart Failure Patients (NYHA Class II-IV) With Preserved Ejection Fraction After CLCZ696D2301 (PARAGON-HF)
• Actual Study Start Date: May 7, 2019
• Actual Primary Completion Date: Nov 19, 2019
• Actual Study Completion Date: Nov 19, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LCZ696 Starting dose was either 50 mg b.i.d. or 100 mg b.i.d. largely depending on the last dose level taken by the patient at the time of completing PARAGON-HF and patient condition. The dose level was gradually up-titrated with the goal of reaching the target dose of 200 mg b.i.d. as soon as tolerated by the patient	Drug: LCZ696; Starting dose was either 50 mg b.i.d. or 100 mg b.i.d. largely depending on the last dose level taken by the patient at the time of completing PARAGON-HF and patient condition. The dose level was gradually up-titrated with the goal of reaching the target dose of 200 mg b.i.d. as soon as tolerated by the patient; Other Names: Sacubitril/valsartan

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events and Serious Adverse Events [Up to 27 weeks]

   An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study. Any sign or symptom that occured from first dose of study treatment until end of study treatment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Signed informed consent must be obtained before any assessment is performed.

• Patients who have completed LCZ696D2301 and are able to be safely enrolled into this study as judged by the investigator.

Exclusion Criteria:

• Patients who discontinued study drug treatment during LCZ696D2301 due to an event or intercurrent illness. Eligibility can be re-considered if the event has resolved and no longer represents a risk to the patient and the patient can safely tolerate the administration of LCZ696 per the investigator's assessment.

• Any medical condition that in the opinion of the investigator is likely to prevent the patient from safely tolerating LCZ696 or complying with the requirements of the study.

• Patients who have experience of angioedema event(s) which occurred and reported by the investigator during LCZ696D2301.

• Pregnant or nursing (lactating) women.

• Women of childbearing potential unless they are using highly effective methods of contraception.

Other protocol-defined inclusion/exclusion may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Seto-city	Aichi	Japan	489-8642
2	Novartis Investigative Site	Chikushino-city	Fukuoka	Japan	818-8516
3	Novartis Investigative Site	Ogaki-city	Gifu	Japan	503-8502
4	Novartis Investigative Site	Maebashi city	Gunma	Japan	371 8511
5	Novartis Investigative Site	Kanazawa	Ishikawa	Japan	920 8650
6	Novartis Investigative Site	Morioka	Iwate	Japan	020 0066
7	Novartis Investigative Site	Kanonji-city	Kagawa	Japan	769-1695
8	Novartis Investigative Site	Takamatsu city	Kagawa	Japan	760 8557
9	Novartis Investigative Site	Yokohama-city	Kanagawa	Japan	227-8501
10	Novartis Investigative Site	Yokohama-city	Kanagawa	Japan	236 0051
11	Novartis Investigative Site	Sendai city	Miyagi	Japan	980 8574
12	Novartis Investigative Site	Kashihara city	Nara	Japan	634 8522
13	Novartis Investigative Site	Sayama-city	Saitama	Japan	350-1305
14	Novartis Investigative Site	Kusatsu city	Shiga	Japan	525 8585
15	Novartis Investigative Site	Hachioji-city	Tokyo	Japan	192-0918
16	Novartis Investigative Site	Itabashi-ku	Tokyo	Japan	173-8610
17	Novartis Investigative Site	Shinagawa-ku	Tokyo	Japan	142-8666

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Dec 17, 2018
• Statistical Analysis Plan - Dec 17, 2019

More Information

Additional Information:

• A Plain Language Trial Summary is available on novartisclinicaltrials.com

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03909295
• Other Study ID Numbers: CLCZ696D1301E1
• First Posted: Apr 10, 2019
• Last Update Posted: Oct 8, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: heart failure with preserved ejection fraction, Japanese patients, extension study, long-term safety and tolerability, open-label
• Additional relevant MeSH terms: Heart Failure; Valsartan; Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

Recruitment Details	A total of 52 participants were enrolled across 17 centers in Japan.
Pre-assignment Detail	This study was terminated early based on the pre defined early termination criteria of "the primary endpoint of PARAGON-HF (CLCZ696D2301) was not met" in the protocol.

Arm/Group Title	LCZ696
Arm/Group Description	Starting dose was either 50 mg b.i.d. or 100 mg b.i.d. largely depending on the last dose level taken by the patient at the time of completing PARAGON-HF and patient condition. The dose level was gradually up-titrated with the goal of reaching the target dose of 200 mg b.i.d. as soon as tolerated by the patient
Period Title: Overall Study
STARTED	52
Safety Set (SAF)	52
COMPLETED	0
NOT COMPLETED	52

Baseline Characteristics

Arm/Group Title	LCZ696
Arm/Group Description	Starting dose was either 50 mg b.i.d. or 100 mg b.i.d. largely depending on the last dose level taken by the patient at the time of completing PARAGON-HF and patient condition. The dose level was gradually up-titrated with the goal of reaching the target dose of 200 mg b.i.d. as soon as tolerated by the patient
Overall Participants	52
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	77.37 (7.608)
Sex: Female, Male (Count of Participants)
Female	23 44.2%
Male	29 55.8%
Race/Ethnicity, Customized (Count of Participants)
Asian	52 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events and Serious Adverse Events
Description	An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study. Any sign or symptom that occured from first dose of study treatment until end of study treatment.
Time Frame	Up to 27 weeks

Outcome Measure Data

Analysis Population Description

Safety set (SAF) included all participants who received at least one dose of study drug

Arm/Group Title	LCZ696 50 mg
Arm/Group Description	Starting dose was either 50 mg b.i.d. or 100 mg b.i.d. largely depending on the last dose level taken by the patient at the time of completing PARAGON-HF and patient condition. The dose level was gradually up-titrated with the goal of reaching the target dose of 200 mg b.i.d. as soon as tolerated by the patient
Measure Participants	52
Participants experiencing Adverse Events	40 76.9%
Participants experiencing Serious Adverse Events	8 15.4%

Adverse Events

Time Frame	Adverse events were collected from first dose of study treatment until end of study treatment (up to 27 weeks).
Adverse Event Reporting Description	Any sign or symptom that occured from first dose of study treatment until end of study treatment (27 weeks).
Arm/Group Title	LCZ696
Arm/Group Description	Starting dose was either 50 mg b.i.d. or 100 mg b.i.d. largely depending on the last dose level taken by the patient at the time of completing PARAGON-HF and patient condition. The dose level was gradually up-titrated with the goal of reaching the target dose of 200 mg b.i.d. as soon as tolerated by the patient
All Cause Mortality
	LCZ696
	Affected / at Risk (%)	# Events
Total	0/52 (0%)
Serious Adverse Events
	LCZ696
	Affected / at Risk (%)	# Events
Total	8/52 (15.4%)
Cardiac disorders
Atrial fibrillation	1/52 (1.9%)
Cardiac failure chronic	1/52 (1.9%)
Eye disorders
Macular fibrosis	1/52 (1.9%)
Gastrointestinal disorders
Inguinal hernia	1/52 (1.9%)
Nausea	1/52 (1.9%)
Infections and infestations
Gastroenteritis	1/52 (1.9%)
Injury, poisoning and procedural complications
Spinal compression fracture	1/52 (1.9%)
Nervous system disorders
Embolic stroke	1/52 (1.9%)
Headache	1/52 (1.9%)
Other (Not Including Serious) Adverse Events
	LCZ696
	Affected / at Risk (%)	# Events
Total	16/52 (30.8%)
Gastrointestinal disorders
Diarrhoea	5/52 (9.6%)
Infections and infestations
Nasopharyngitis	7/52 (13.5%)
Metabolism and nutrition disorders
Hypokalaemia	4/52 (7.7%)
Vascular disorders
Hypotension	3/52 (5.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.