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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| LCZ696 (sacubitril / valsartan) | Other | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| LCZ696 (sacubitril/valsartan) | Drug | All patients were treated with the LCZ696 (sacubitril and valsartan) tablets |
|
| 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 |
| 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 |
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Key Inclusion Criteria:
Key Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Novartis Pharmaceuticals | Novartis Pharmaceuticals | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Novartis Investigative Site | Edmonton | Alberta | T5H 3V9 | Canada | ||
| Novartis Investigative Site |
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Approximately 300 patients with HFrEF were planned for enrolling into the study. A total of 302 patients received at least one dose of LCZ696 and were included in the Full Analysis Set (FAS). The analysis of the primary endpoint was based on the FAS.
This study was conducted in 32 study centers in Canada
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| Title | Milestones | Reasons Not Completed | ||||
|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| SAP | No | Yes | No | Statistical Analysis Plan | Jul 4, 2017 | Oct 16, 2018 |
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| 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 |
| 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 | Greater Sudbury | Ontario | P3E 3B8 | Canada |
| Novartis Investigative Site | Greater Sudbury | Ontario | P3E 5M9 | 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 Village | Ontario | M1E 5E9 | Canada |
| Novartis Investigative Site | Scarborough Village | Ontario | M1P 2V5 | 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 | Saint-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 | Québec | GIV 4G5 | Canada |
| Novartis Investigative Site | Saint-Lambert | J4P 2J2 | Canada |
|
| COMPLETED |
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| NOT COMPLETED |
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Full Analysis Set (FAS)
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | |||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | Years |
| ||||||||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| |||||||||||||||||||||||
| Race/Ethnicity, Customized | Number | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered. | Posted | Number | 95% Confidence Interval | Percentage of Participants | Month 6 |
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| Secondary | 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. | The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered. | Posted | Number | 95% Confidence Interval | Percentage of Participants | Month 12 |
|
| ||||||||||||||||||||||||||
| Secondary | 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. | The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered. | Posted | Number | 95% Confidence Interval | Percentage of Participants | Month 12 |
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| ||||||||||||||||||||||||||
| Secondary | 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. | The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered. | Posted | Count of Participants | Participants | Month 12 |
|
| |||||||||||||||||||||||||||
| Secondary | 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. | The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered. | Posted | Mean | Standard Deviation | Meter (m) | Baseline, Month 6 and Month 12 |
|
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| Secondary | 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. | The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered. | Posted | Mean | Standard Deviation | Days | Baseline, Week 2, Week 4, Month 3, Month 6 and Month 12 |
|
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| Secondary | 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. | The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered. | Posted | Median | 95% Confidence Interval | Days | Baseline, Week 2, Week 4, Month 3, Month 6 and Month 12 |
|
| ||||||||||||||||||||||||||
| Secondary | 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. | The Safety Analysis Set (FAS), which consisted of all participants with an observed value, was considered. | Posted | Count of Participants | Participants | Baseline, Month 6 and Month 12 |
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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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. | 9 | 302 | 47 | 302 | 98 | 302 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA (20.0) | Systematic Assessment |
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| Acute myocardial infarction | Cardiac disorders | MedDRA (20.0) | Systematic Assessment |
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| Angina pectoris | Cardiac disorders | MedDRA (20.0) | Systematic Assessment |
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| Atrial fibrillation | Cardiac disorders | MedDRA (20.0) | Systematic Assessment |
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| Atrial tachycardia | Cardiac disorders | MedDRA (20.0) | Systematic Assessment |
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| Bradyarrhythmia | Cardiac disorders | MedDRA (20.0) | Systematic Assessment |
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| Cardiac arrest | Cardiac disorders | MedDRA (20.0) | Systematic Assessment |
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| Cardiac failure | Cardiac disorders | MedDRA (20.0) | Systematic Assessment |
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| Cardiac failure acute | Cardiac disorders | MedDRA (20.0) | Systematic Assessment |
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| Cardiac failure congestive | Cardiac disorders | MedDRA (20.0) | Systematic Assessment |
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| Congestive cardiomyopathy | Cardiac disorders | MedDRA (20.0) | Systematic Assessment |
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| Nodal arrhythmia | Cardiac disorders | MedDRA (20.0) | Systematic Assessment |
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| Ventricular tachycardia | Cardiac disorders | MedDRA (20.0) | Systematic Assessment |
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| Gastrooesophageal reflux disease | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
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| Volvulus | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
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| Death | General disorders | MedDRA (20.0) | Systematic Assessment |
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| Multiple organ dysfunction syndrome | General disorders | MedDRA (20.0) | Systematic Assessment |
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| Sudden death | General disorders | MedDRA (20.0) | Systematic Assessment |
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| Cholecystitis chronic | Hepatobiliary disorders | MedDRA (20.0) | Systematic Assessment |
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| Bacteraemia | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
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| Bronchitis | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
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| Diverticulitis | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
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| Gastroenteritis | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
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| Infective exacerbation of bronchiectasis | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
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| Osteomyelitis | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
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| Pneumococcal sepsis | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
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| Pneumonia | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
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| Postoperative wound infection | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
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| Post procedural complication | Injury, poisoning and procedural complications | MedDRA (20.0) | Systematic Assessment |
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| Brain natriuretic peptide increased | Investigations | MedDRA (20.0) | Systematic Assessment |
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| White blood cell count increased | Investigations | MedDRA (20.0) | Systematic Assessment |
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| Dehydration | Metabolism and nutrition disorders | MedDRA (20.0) | Systematic Assessment |
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| Fluid overload | Metabolism and nutrition disorders | MedDRA (20.0) | Systematic Assessment |
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| Hyponatraemia | Metabolism and nutrition disorders | MedDRA (20.0) | Systematic Assessment |
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| Colon cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (20.0) | Systematic Assessment |
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| Squamous cell carcinoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (20.0) | Systematic Assessment |
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| Tongue neoplasm malignant stage unspecified | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (20.0) | Systematic Assessment |
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| Cerebrovascular accident | Nervous system disorders | MedDRA (20.0) | Systematic Assessment |
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| Intracranial mass | Nervous system disorders | MedDRA (20.0) | Systematic Assessment |
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| Ischaemic stroke | Nervous system disorders | MedDRA (20.0) | Systematic Assessment |
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| Presyncope | Nervous system disorders | MedDRA (20.0) | Systematic Assessment |
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| Device malfunction | Product Issues | MedDRA (20.0) | Systematic Assessment |
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| Adjustment disorder | Psychiatric disorders | MedDRA (20.0) | Systematic Assessment |
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| Delirium | Psychiatric disorders | MedDRA (20.0) | Systematic Assessment |
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| Suicidal ideation | Psychiatric disorders | MedDRA (20.0) | Systematic Assessment |
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| Acute kidney injury | Renal and urinary disorders | MedDRA (20.0) | Systematic Assessment |
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| Renal failure | Renal and urinary disorders | MedDRA (20.0) | Systematic Assessment |
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| Laryngeal mass | Respiratory, thoracic and mediastinal disorders | MedDRA (20.0) | Systematic Assessment |
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| Pleural effusion | Respiratory, thoracic and mediastinal disorders | MedDRA (20.0) | Systematic Assessment |
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| Pulmonary oedema | Respiratory, thoracic and mediastinal disorders | MedDRA (20.0) | Systematic Assessment |
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| Orthostatic hypotension | Vascular disorders | MedDRA (20.0) | Systematic Assessment |
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| Peripheral ischaemia | Vascular disorders | MedDRA (20.0) | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
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| Fatigue | General disorders | MedDRA (20.0) | Systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA (20.0) | Systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (20.0) | Systematic Assessment |
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| Hypotension | Vascular disorders | MedDRA (20.0) | Systematic Assessment |
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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.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | Novartis Pharmaceuticals | 862-778-8300 | Novartis.email@novartis.com |
| SAP_000.pdf |
| Prot | Yes | No | No | Study Protocol | Sep 12, 2016 | Oct 16, 2018 | Prot_001.pdf |
| ID | Term |
|---|---|
| D054143 | Heart Failure, Systolic |
| ID | Term |
|---|---|
| D006333 | Heart Failure |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| C549068 | sacubitril and valsartan sodium hydrate drug combination |
| C000717211 | sacubitril |
| D000068756 | Valsartan |
| ID | Term |
|---|---|
| D013777 | Tetrazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D014633 | Valine |
| D000597 | Amino Acids, Branched-Chain |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
| D000601 | Amino Acids, Essential |
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| Asian |
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| Native American |
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| Unknown or Not Reported |
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