PARAGON-HF: Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Completed

CT.gov ID

NCT01920711

Collaborator

(none)

4,822

Enrollment

717

Locations

Arms

58.6

Actual Duration (Months)

6.7

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study was to evaluate the effect of LCZ696 compared to valsartan in the reduction of cardiovascular death and heart failure(HF) hospitalizations in patients with HF with preserved ejection fraction.

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

Detailed Description

This was a multicenter, randomized, double-blind, parallel group, active-controlled, study to evaluate the efficacy and safety of sacubitril/valsartan compared to valsartan, on morbidity and mortality in heart failure patients (NYHA Class II-IV) with preserved ejection fraction. Specifically, the study evaluated the effect of sacubitril/valsartan compared to the active comparator valsartan in the reduction of the rate of CV death and total HF hospitalizations in patients with HFpEF. The trial consisted of two periods: (1) a single-blind treatment run-in epoch that lasted from 3 to 8 weeks, in which patients received valsartan 80 mg bid, followed by sacubitril/valsartan 100 mg bid and (2) a double-blind randomized treatment epoch (sacubitril/valsartan 200 mg bid or valsartan 160 mg bid). In this study, investigators were responsible for assessing and submitting all events which could potentially fulfill the criteria for the primary, secondary, or other clinical endpoints to a Clinical Endpoint Committee (CEC). Investigator reported events were assessed by the CEC for adjudication.

For angioedema or angioedema-like events, investigators completed an Adjudication Questionnaire for an Angioedema-like Event form. All angioedema reports were forwarded to an Angioedema Adjudication Committee (AAC) by Novartis for assessment.

Study Design

Study Type:

Interventional

Actual Enrollment :

4822 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

A Multicenter, Randomized, Double-blind, Parallel Group, Active-controlled Study to Evaluate the Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients (NYHA Class II-IV) With Preserved Ejection Fraction (PARAGON-HF)

Actual Study Start Date :

Jul 18, 2014

Actual Primary Completion Date :

Jun 7, 2019

Actual Study Completion Date :

Jun 7, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LCZ696 Single Blind Run-in Period (3-8 weeks): Patients will start on Valsartan 80 mg b.i.d. for 1-2 weeks followed by LCZ696 100 mg b.i.d. for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients can only be randomized from the run-in period if they meet all of the run-in safety criteria. Target dose of LCZ696 during the double blind period is 200 mg b.i.d.	Drug: LCZ696 LCZ696 50mg, 100mg and 200 mg dosage strengths will be available for dose adjustments.
Active Comparator: Valsartan Single Blind Run-in Period (3-8 weeks): Patients will start on Valsartan 80 mg b.i.d. for 1-2 weeks followed by LCZ696 100 mg b.i.d. for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients can only be randomized from the run-in period if they meet all of the run-in safety criteria. Target dose of Valsartan during the double blind period is 160 mg b.i.d.	Drug: Valsartan Valsartan 40mg, 80mg and 160mg dosage strengths will be available for dose adjustments.

Arm

Intervention/Treatment

Experimental: LCZ696

Single Blind Run-in Period (3-8 weeks): Patients will start on Valsartan 80 mg b.i.d. for 1-2 weeks followed by LCZ696 100 mg b.i.d. for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients can only be randomized from the run-in period if they meet all of the run-in safety criteria. Target dose of LCZ696 during the double blind period is 200 mg b.i.d.

Drug: LCZ696

LCZ696 50mg, 100mg and 200 mg dosage strengths will be available for dose adjustments.

Active Comparator: Valsartan

Single Blind Run-in Period (3-8 weeks): Patients will start on Valsartan 80 mg b.i.d. for 1-2 weeks followed by LCZ696 100 mg b.i.d. for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients can only be randomized from the run-in period if they meet all of the run-in safety criteria. Target dose of Valsartan during the double blind period is 160 mg b.i.d.

Drug: Valsartan

Valsartan 40mg, 80mg and 160mg dosage strengths will be available for dose adjustments.

Outcome Measures

Primary Outcome Measures

Cumulative Number of Primary Composite Events of Cardiovascular (CV) Death and Total (First and Recurrent) HF Hospitalizations. [Total follow up time (up to 57 months)]
The primary objective of this study is to compare LCZ696 to valsartan in reducing the rate of the composite endpoint of CV death and total (first and recurrent) HF hospitalizations, in HF patients (New York Heart Association [NYHA] Class II-IV) with preserved ejection fraction (left ventricular ejection fraction [LVEF] ≥45%). The treatment arm with the lower rate of events will be deemed as having a successful response.

Secondary Outcome Measures

Change in the Clinical Summary Score From Baseline to Month 8 by Kansas City Cardiomyopathy Questionnaire (KCCQ) [Baseline, 8 months]
The KCCQ is a validated instrument for self-assessment of quality of life and health status in heart failure (HF) patients. The clinical summary score, which is derived from the physical limitations and heart failure (HF) symptoms domains of the KCCQ is a valid measure for assessing the patient's health aspects that may be influenced by CV medications. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. Evaluation of change from baseline to month 8 in KCCQ a most sensitive, specific, and responsive health-related quality of life measure for heart failure symptoms and physical limitations.
Change From Baseline to Month 8 in New York Heart Association (NYHA) Functional Class [Baseline, 8 months]
Evaluation of change from baseline to Month 8 in NYHA functional class, a well established grading scale used to classify a heart failure's (HF) patients' level of functionality based on the signs and symptoms of HF exhibited by the patient.
Participants With First Occurrence of a Composite Renal Endpoint [Randomization to total follow-up time (up to 57 months)]
Analyis of composite renal endpoint defined as renal death, or reaching ESRD, or ≥50% decline in eGFR relative to baseline, using Cox's proportional hazards model.
All-cause Mortality [Randomization to total follow up time (up to 57 months)]
Analysis for all-cause mortality using Cox's proportional hazards model.

Eligibility Criteria

Criteria

Ages Eligible for Study:

50 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Left ventricular ejection fraction (LVEF) ≥45% by echo during screening epoch or within 6 months prior to study entry.
Symptom(s) of heart failure (HF) and requiring treatment with diuretic(s) for HF at least 30 days prior to study entry.
Current symptom(s) of HF (NYHA class II-IV)
Structural heart disease (left atrial enlargement or left ventricular hypertrophy) documented by echocardiogram.
Elevated NT-proBNP

Exclusion Criteria:

Any prior measurement of LVEF < 40%.
Acute coronary syndrome (including MI), cardiac surgery, other major CV surgery within 3 months , or urgent percutaneous coronary intervention within 3 months or and elective PCI within 30 days prior to entry.
Any clinical event within the 6 months prior to entry could have reduced the LVEF (e.g., MI, CABG), unless an echo measurement performed after the event confirms a LVEF ≥45%.
Current acute decompensated HF requiring therapy.
Patients who require treatment with 2 or more of the following: an angiotensin converting enzyme inhibitor (ACEI), an angiotensin receptor blocker (ARB) or a renin inhibitor.
Alternative reason for shortness of breath such as: significant pulmonary disease or severe COPD, hemoglobin (Hgb) <10 g/dl, or body mass index (BMI) > 40 kg/m2.
Systolic blood pressure (SBP) ≥ 180 mmHg at entry, or SBP >150 mmHg and <180 mmHg at entry unless the patient is receiving 3 or more antihypertensive drugs, or SBP < 110 mmHg at entry.

Other protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Huntsville	Alabama	United States	35801
2	Novartis Investigative Site	Mobile	Alabama	United States	36608
3	Novartis Investigative Site	Muscle Shoals	Alabama	United States	35662
4	Novartis Investigative Site	Little Rock	Arkansas	United States	72204
5	Novartis Investigative Site	Beverly Hills	California	United States	90211
6	Novartis Investigative Site	Los Angeles	California	United States	90073
7	Novartis Investigative Site	Northridge	California	United States	91325
8	Novartis Investigative Site	Orange	California	United States	92868
9	Novartis Investigative Site	San Diego	California	United States	92161
10	Novartis Investigative Site	Santa Ana	California	United States	92704
11	Novartis Investigative Site	Denver	Colorado	United States	80220
12	Novartis Investigative Site	Hartford	Connecticut	United States	06105
13	Novartis Investigative Site	New Haven	Connecticut	United States	06520-8062
14	Novartis Investigative Site	Stamford	Connecticut	United States	06905
15	Novartis Investigative Site	West Haven	Connecticut	United States	06516
16	Novartis Investigative Site	Bradenton	Florida	United States	34209
17	Novartis Investigative Site	Gainesville	Florida	United States	32608
18	Novartis Investigative Site	Lake Worth	Florida	United States	33461
19	Novartis Investigative Site	Miami	Florida	United States	33143
20	Novartis Investigative Site	Tallahassee	Florida	United States	32308
21	Novartis Investigative Site	Atlanta	Georgia	United States	30309
22	Novartis Investigative Site	Atlanta	Georgia	United States	30310-1495
23	Novartis Investigative Site	Covington	Georgia	United States	30014
24	Novartis Investigative Site	Cumming	Georgia	United States	30041
25	Novartis Investigative Site	Chicago	Illinois	United States	60611
26	Novartis Investigative Site	Chicago	Illinois	United States	60637
27	Novartis Investigative Site	Evanston	Illinois	United States	60201
28	Novartis Investigative Site	Hazel Crest	Illinois	United States	60429
29	Novartis Investigative Site	Lombard	Illinois	United States	60148
30	Novartis Investigative Site	Maywood	Illinois	United States	60153
31	Novartis Investigative Site	Oakbrook Terrace	Illinois	United States	60181
32	Novartis Investigative Site	Peoria	Illinois	United States	61602
33	Novartis Investigative Site	Quincy	Illinois	United States	62301
34	Novartis Investigative Site	Louisville	Kentucky	United States	40206
35	Novartis Investigative Site	Baton Rouge	Louisiana	United States	70808
36	Novartis Investigative Site	Hammond	Louisiana	United States	70403
37	Novartis Investigative Site	Lafayette	Louisiana	United States	70508
38	Novartis Investigative Site	Slidell	Louisiana	United States	70458
39	Novartis Investigative Site	Biddeford	Maine	United States	04005
40	Novartis Investigative Site	Portland	Maine	United States	04102
41	Novartis Investigative Site	Baltimore	Maryland	United States	21229
42	Novartis Investigative Site	Baltimore	Maryland	United States	21287
43	Novartis Investigative Site	Columbia	Maryland	United States	21044
44	Novartis Investigative Site	Boston	Massachusetts	United States	02118
45	Novartis Investigative Site	Boston	Massachusetts	United States
46	Novartis Investigative Site	Ann Arbor	Michigan	United States	48105
47	Novartis Investigative Site	Detroit	Michigan	United States	48202
48	Novartis Investigative Site	Grand Blanc	Michigan	United States	48439
49	Novartis Investigative Site	Saginaw	Michigan	United States	48601
50	Novartis Investigative Site	Minneapolis	Minnesota	United States	55417
51	Novartis Investigative Site	Minneapolis	Minnesota	United States	55433
52	Novartis Investigative Site	Minneapolis	Minnesota	United States	55455
53	Novartis Investigative Site	Saint Cloud	Minnesota	United States	56303
54	Novartis Investigative Site	Saint Paul	Minnesota	United States	55102
55	Novartis Investigative Site	Belzoni	Mississippi	United States	39038
56	Novartis Investigative Site	Jackson	Mississippi	United States	39216
57	Novartis Investigative Site	Saint Louis	Missouri	United States	63110
58	Novartis Investigative Site	Saint Louis	Missouri	United States	63136
59	Novartis Investigative Site	Kalispell	Montana	United States	59901 3158
60	Novartis Investigative Site	Lincoln	Nebraska	United States	68506
61	Novartis Investigative Site	Lebanon	New Hampshire	United States	03756
62	Novartis Investigative Site	Morristown	New Jersey	United States	07960
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64	Novartis Investigative Site	Ridgewood	New Jersey	United States	07450
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67	Novartis Investigative Site	Brooklyn	New York	United States	11215
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69	Novartis Investigative Site	Buffalo	New York	United States	14215
70	Novartis Investigative Site	Flushing	New York	United States	11355
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72	Novartis Investigative Site	Northport	New York	United States	11768
73	Novartis Investigative Site	Rochester	New York	United States	14642
74	Novartis Investigative Site	Saratoga Springs	New York	United States	12866
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80	Novartis Investigative Site	Tulsa	Oklahoma	United States	74133
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85	Novartis Investigative Site	Warwick	Rhode Island	United States	02886
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87	Novartis Investigative Site	Rapid City	South Dakota	United States	57701
88	Novartis Investigative Site	Sioux Falls	South Dakota	United States	57104
89	Novartis Investigative Site	Knoxville	Tennessee	United States	37917
90	Novartis Investigative Site	Memphis	Tennessee	United States	38104
91	Novartis Investigative Site	Nashville	Tennessee	United States	37203
92	Novartis Investigative Site	Nashville	Tennessee	United States	37212
93	Novartis Investigative Site	Beaumont	Texas	United States	77702
94	Novartis Investigative Site	Dallas	Texas	United States	75216
95	Novartis Investigative Site	Dallas	Texas	United States	75231
96	Novartis Investigative Site	Dallas	Texas	United States	75235
97	Novartis Investigative Site	Houston	Texas	United States	77030
98	Novartis Investigative Site	Houston	Texas	United States	77094
99	Novartis Investigative Site	Livingston	Texas	United States	77351
100	Novartis Investigative Site	McKinney	Texas	United States	75069
101	Novartis Investigative Site	San Antonio	Texas	United States	78234
102	Novartis Investigative Site	Tomball	Texas	United States	77375
103	Novartis Investigative Site	Salt Lake City	Utah	United States	84124
104	Novartis Investigative Site	Salt Lake City	Utah	United States	84132
105	Novartis Investigative Site	White River Junction	Vermont	United States	05009
106	Novartis Investigative Site	Seattle	Washington	United States	98122
107	Novartis Investigative Site	Seattle	Washington	United States	98195
108	Novartis Investigative Site	Madison	Wisconsin	United States	53705
109	Novartis Investigative Site	Madison	Wisconsin	United States	53792-1615
110	Novartis Investigative Site	Milwaukee	Wisconsin	United States	53215
111	Novartis Investigative Site	Caba	Buenos Aires	Argentina	1407
112	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1056ABJ
113	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1280AEB
114	Novartis Investigative Site	Quilmes	Buenos Aires	Argentina	B1878GEG
115	Novartis Investigative Site	Ramos Mejia	Buenos Aires	Argentina	B1704ETD
116	Novartis Investigative Site	Caba	Capital Federal	Argentina	C1179AAB
117	Novartis Investigative Site	Posadas	Misiones	Argentina	N3300AHX
118	Novartis Investigative Site	Ciudad de Salta	Provincia De Salta	Argentina	A4406BPF
119	Novartis Investigative Site	Tucuman	San Miguel De Tucuman	Argentina	T4000ICL
120	Novartis Investigative Site	Rosario	Santa Fe	Argentina	2000
121	Novartis Investigative Site	Rosario	Santa Fe	Argentina	3080
122	Novartis Investigative Site	Rosario	Santa Fe	Argentina	S2000DSV
123	Novartis Investigative Site	Rosario	Santa Fe	Argentina	S2000QID
124	Novartis Investigative Site	San Miguel de Tucuman	Tucuman	Argentina	T4000IFL
125	Novartis Investigative Site	Buenos Aires		Argentina	C1425AGP
126	Novartis Investigative Site	Buenos Aires		Argentina	C1428DCO
127	Novartis Investigative Site	Caba		Argentina	C1119ACN
128	Novartis Investigative Site	Cordoba		Argentina	X5000AAX
129	Novartis Investigative Site	Cordoba		Argentina	X5000EVQ
130	Novartis Investigative Site	Cordoba		Argentina	X5009BSN
131	Novartis Investigative Site	Cordoba		Argentina	X5016KET
132	Novartis Investigative Site	Cordoba		Argentina	X5022CPU
133	Novartis Investigative Site	Formosa		Argentina	P3600
134	Novartis Investigative Site	San Luis		Argentina	D5702JRS
135	Novartis Investigative Site	Santa Fe		Argentina	S3000FWO
136	Novartis Investigative Site	Southport	Queensland	Australia	4215
137	Novartis Investigative Site	Bedford Park	South Australia	Australia	5041
138	Novartis Investigative Site	Bundoora	Victoria	Australia	3083
139	Novartis Investigative Site	Epping	Victoria	Australia	3076
140	Novartis Investigative Site	Geelong	Victoria	Australia	3220
141	Novartis Investigative Site	Innsbruck	Tyrol	Austria	6020
142	Novartis Investigative Site	Braunau		Austria	A5280
143	Novartis Investigative Site	Graz		Austria	8020
144	Novartis Investigative Site	Graz		Austria	A-8036
145	Novartis Investigative Site	Großgmain		Austria	5084
146	Novartis Investigative Site	Linz		Austria	4010
147	Novartis Investigative Site	Vienna		Austria	1130
148	Novartis Investigative Site	Wien		Austria	A 1090
149	Novartis Investigative Site	Aalst		Belgium	9300
150	Novartis Investigative Site	Antwerpen		Belgium	2060
151	Novartis Investigative Site	Brasschaat		Belgium	2930
152	Novartis Investigative Site	Bruxelles		Belgium	1200
153	Novartis Investigative Site	De Pinte		Belgium	9840
154	Novartis Investigative Site	Genk		Belgium	3600
155	Novartis Investigative Site	Gent		Belgium	9000
156	Novartis Investigative Site	Hasselt		Belgium	3500
157	Novartis Investigative Site	Huy		Belgium	4500
158	Novartis Investigative Site	Kortrijk		Belgium	8500
159	Novartis Investigative Site	Leuven		Belgium	3000
160	Novartis Investigative Site	Ottignies		Belgium	1340
161	Novartis Investigative Site	Goiania	GO	Brazil	74605-020
162	Novartis Investigative Site	Belo Horizonte	MG	Brazil	30150-221
163	Novartis Investigative Site	Uberlandia	Minas Gerais	Brazil	38411 186
164	Novartis Investigative Site	Curitiba	Parana	Brazil	80730 150
165	Novartis Investigative Site	Campina Grande do Sul	PR	Brazil	83430-000
166	Novartis Investigative Site	Porto Alegre	RS	Brazil	90035-003
167	Novartis Investigative Site	Porto Alegre	RS	Brazil	90880-480
168	Novartis Investigative Site	Liberdade	Sao Paulo	Brazil	01504-001
169	Novartis Investigative Site	Blumenau	SC	Brazil	89020 430
170	Novartis Investigative Site	Campinas	SP	Brazil	13020-431
171	Novartis Investigative Site	Campinas	SP	Brazil	13060-904
172	Novartis Investigative Site	Ribeirao Preto	SP	Brazil	14055-370
173	Novartis Investigative Site	Sao Jose do Rio Preto	SP	Brazil	15090 000
174	Novartis Investigative Site	Sao Paulo	SP	Brazil	08270-070
175	Novartis Investigative Site	Burgas		Bulgaria	8127
176	Novartis Investigative Site	Pazardzhik		Bulgaria	4400
177	Novartis Investigative Site	Pleven		Bulgaria	5800
178	Novartis Investigative Site	Plovdiv		Bulgaria	4000
179	Novartis Investigative Site	Plovdiv		Bulgaria	4002
180	Novartis Investigative Site	Shumen		Bulgaria	9700
181	Novartis Investigative Site	Silistra		Bulgaria	7500
182	Novartis Investigative Site	Sliven		Bulgaria	8800
183	Novartis Investigative Site	Smolian		Bulgaria	4700
184	Novartis Investigative Site	Sofia		Bulgaria	1000
185	Novartis Investigative Site	Sofia		Bulgaria	1202
186	Novartis Investigative Site	Sofia		Bulgaria	1233
187	Novartis Investigative Site	Sofia		Bulgaria	1309
188	Novartis Investigative Site	Sofia		Bulgaria	1407
189	Novartis Investigative Site	Sofia		Bulgaria	1527
190	Novartis Investigative Site	Sofia		Bulgaria	1606
191	Novartis Investigative Site	Sofia		Bulgaria	1784
192	Novartis Investigative Site	Varna		Bulgaria	9010
193	Novartis Investigative Site	Veliko Tarnovo		Bulgaria	5000
194	Novartis Investigative Site	Calgary	Alberta	Canada	T2N 4Z6
195	Novartis Investigative Site	Victoria	British Columbia	Canada	V8R4R2
196	Novartis Investigative Site	St. John	Newfoundland and Labrador	Canada	A1B 3V6
197	Novartis Investigative Site	Halifax	Nova Scotia	Canada	B3H 2Y9
198	Novartis Investigative Site	Cambridge	Ontario	Canada	N1R 6V6
199	Novartis Investigative Site	Hamilton	Ontario	Canada	L8L 2X2
200	Novartis Investigative Site	Ottawa	Ontario	Canada	K1Y 4W7
201	Novartis Investigative Site	Toronto	Ontario	Canada	M5B 1W8
202	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 1X5
203	Novartis Investigative Site	Toronto	Ontario	Canada	M5S 1B2
204	Novartis Investigative Site	Weston	Ontario	Canada	M9N 1W4
205	Novartis Investigative Site	Montreal	Quebec	Canada	H1T 1C8
206	Novartis Investigative Site	Montreal	Quebec	Canada	H3G 1A4
207	Novartis Investigative Site	Montreal	Quebec	Canada	H3T 1E2
208	Novartis Investigative Site	Sainte Foy	Quebec	Canada	G1V 4G5
209	Novartis Investigative Site	Sherbrooke	Quebec	Canada	J1G 2E8
210	Novartis Investigative Site	Thetford Mines	Quebec	Canada	G6G 2V4
211	Novartis Investigative Site	Trois Rivieres	Quebec	Canada	G8Z 3R9
212	Novartis Investigative Site	Beijing	Beijing	China	100037
213	Novartis Investigative Site	Beijing	Beijing	China	100039
214	Novartis Investigative Site	Beijing	Beijing	China	100044
215	Novartis Investigative Site	Beijing	Beijing	China	100730
216	Novartis Investigative Site	Chongqing	Chongqing	China	400010
217	Novartis Investigative Site	Lanzhou	Gansu	China	730030
218	Novartis Investigative Site	Guangzhou	Guangdong	China	51000
219	Novartis Investigative Site	Guangzhou	Guangdong	China	510080
220	Novartis Investigative Site	Guangzhou	Guangdong	China	510515
221	Novartis Investigative Site	Nanning	Guangxi	China	530021
222	Novartis Investigative Site	Changsha	Hunan	China	410003
223	Novartis Investigative Site	Nanjing	Jiangsu	China	210009
224	Novartis Investigative Site	Nanjing	Jiangsu	China	210029
225	Novartis Investigative Site	Suzhou	Jiangsu	China	215004
226	Novartis Investigative Site	Wuxi	Jiangsu	China
227	Novartis Investigative Site	Nanchang	Jiangxi	China	330006
228	Novartis Investigative Site	Changchun	Jilin	China	130022
229	Novartis Investigative Site	Jilin	Jilin	China	132000
230	Novartis Investigative Site	Shenyang	Liaoning	China	110003
231	Novartis Investigative Site	Shenyang	Liaoning	China	110016
232	Novartis Investigative Site	Shanghai	Shanghai	China	200032
233	Novartis Investigative Site	Shanghai	Shanghai	China	200120
234	Novartis Investigative Site	Shanghai	Shanghai	China
235	Novartis Investigative Site	Xi'an	Shanxi	China	710032
236	Novartis Investigative Site	Xian	Shanxi	China	710061
237	Novartis Investigative Site	Chengdu	Sichuan	China	610041
238	Novartis Investigative Site	Tianjin	Tianjin	China	300121
239	Novartis Investigative Site	Wulumuqi	Xinjiang	China	830054
240	Novartis Investigative Site	Hangzhou	Zhejiang	China	310009
241	Novartis Investigative Site	Hangzhou	Zhejiang	China	310013
242	Novartis Investigative Site	Hangzhou	Zhejiang	China	310016
243	Novartis Investigative Site	Beijing		China	100029
244	Novartis Investigative Site	Beijing		China	100034
245	Novartis Investigative Site	Chongqing		China	400037
246	Novartis Investigative Site	Jinan		China	250012
247	Novartis Investigative Site	Nanjing		China	210036
248	Novartis Investigative Site	Shanghai		China	200025
249	Novartis Investigative Site	Shanghai		China	200031
250	Novartis Investigative Site	Shanghai		China	200080
251	Novartis Investigative Site	Medellin	Antioquia	Colombia	050036
252	Novartis Investigative Site	Barranquilla	Atlantico	Colombia
253	Novartis Investigative Site	Barranquilla		Colombia	080020
254	Novartis Investigative Site	Barranquilla		Colombia
255	Novartis Investigative Site	Florida Blanca		Colombia
256	Novartis Investigative Site	Varazdin	HRV	Croatia	42000
257	Novartis Investigative Site	Rijeka		Croatia	51000
258	Novartis Investigative Site	Zadar		Croatia	23000
259	Novartis Investigative Site	Zagreb		Croatia	10000
260	Novartis Investigative Site	Brandys nad Labem	Czech Republic	Czechia	250 01
261	Novartis Investigative Site	Brno	Czech Republic	Czechia	60200
262	Novartis Investigative Site	Ivancice	Czech Republic	Czechia	66491
263	Novartis Investigative Site	Kladno	Czech Republic	Czechia	272 80
264	Novartis Investigative Site	Liberec	Czech Republic	Czechia	460 05
265	Novartis Investigative Site	Louny	Czech Republic	Czechia
266	Novartis Investigative Site	Ostrava	Czech Republic	Czechia	70200
267	Novartis Investigative Site	Plzen	Czech Republic	Czechia	30100
268	Novartis Investigative Site	Praha 4	Czech Republic	Czechia	140 21
269	Novartis Investigative Site	Roznov pod Radhostem	Czech Republic	Czechia	756 61
270	Novartis Investigative Site	Svitavy	Czech Republic	Czechia	568 25
271	Novartis Investigative Site	Trebic	Czech Republic	Czechia	674 01
272	Novartis Investigative Site	Usti nad Labem	Czech Republic	Czechia	400 01
273	Novartis Investigative Site	Znojmo	Czech Republic	Czechia	66902
274	Novartis Investigative Site	Policska	CZE	Czechia	57201
275	Novartis Investigative Site	Praha 2	CZE	Czechia	128 08
276	Novartis Investigative Site	Usti nad Labem	CZE	Czechia	400 01
277	Novartis Investigative Site	CZE		Czechia	11000
278	Novartis Investigative Site	Kolin		Czechia	280 20
279	Novartis Investigative Site	Marianske lazne		Czechia	353 01
280	Novartis Investigative Site	Uherske Hradiste		Czechia	68601
281	Novartis Investigative Site	Esbjerg		Denmark	DK-6700
282	Novartis Investigative Site	Glostrup		Denmark	2600
283	Novartis Investigative Site	Herlev		Denmark	2730
284	Novartis Investigative Site	Hvidovre		Denmark	2650
285	Novartis Investigative Site	Randers		Denmark	8930
286	Novartis Investigative Site	Svendborg		Denmark	5700
287	Novartis Investigative Site	Viborg		Denmark	DK-8800
288	Novartis Investigative Site	Jyvaskyla		Finland	40620
289	Novartis Investigative Site	Oulu		Finland	90220
290	Novartis Investigative Site	Tampere		Finland	33520
291	Novartis Investigative Site	Bayonne	Bayonne Cedex	France	64109
292	Novartis Investigative Site	Montpellier cedex 5	Herault	France	34059
293	Novartis Investigative Site	Besancon Cedex		France	25030
294	Novartis Investigative Site	Beziers Cedex		France	34525
295	Novartis Investigative Site	Bordeaux Cedex		France	33075
296	Novartis Investigative Site	Grenoble		France	38043
297	Novartis Investigative Site	Lyon		France	F-69001
298	Novartis Investigative Site	Paris cedex 10		France	75010
299	Novartis Investigative Site	Poitiers		France	86000
300	Novartis Investigative Site	Pontoise		France	F-95300
301	Novartis Investigative Site	Rennes Cedex 9		France	35033
302	Novartis Investigative Site	Toulouse Cedex		France	31059
303	Novartis Investigative Site	Tourcoing		France	59208
304	Novartis Investigative Site	Vandoeuvre Les Nancy		France	54511
305	Novartis Investigative Site	Dresden	Sachsen	Germany	01099
306	Novartis Investigative Site	Aachen		Germany	52074
307	Novartis Investigative Site	Bad Homburg		Germany	61348
308	Novartis Investigative Site	Bad Krozingen		Germany	79189
309	Novartis Investigative Site	Bamberg		Germany	96049
310	Novartis Investigative Site	Berlin Buch		Germany	13125
311	Novartis Investigative Site	Berlin		Germany	10789
312	Novartis Investigative Site	Berlin		Germany	12157
313	Novartis Investigative Site	Berlin		Germany	12683
314	Novartis Investigative Site	Berlin		Germany	13086
315	Novartis Investigative Site	Berlin		Germany	13353
316	Novartis Investigative Site	Berlin		Germany	13405
317	Novartis Investigative Site	Chemnitz		Germany	09126
318	Novartis Investigative Site	Chemnitz		Germany	09130
319	Novartis Investigative Site	Dessau-Roßlau		Germany	06846
320	Novartis Investigative Site	Dresden		Germany	01277
321	Novartis Investigative Site	Dresden		Germany	01307
322	Novartis Investigative Site	Dresden		Germany	01309
323	Novartis Investigative Site	Duisburg		Germany	47137
324	Novartis Investigative Site	Eilenburg		Germany	D 04838
325	Novartis Investigative Site	Elsterwerda		Germany	04910
326	Novartis Investigative Site	Essen		Germany	45355
327	Novartis Investigative Site	Frankfurt		Germany	60594
328	Novartis Investigative Site	Frankfurt		Germany	65929
329	Novartis Investigative Site	Hamburg		Germany	20099
330	Novartis Investigative Site	Hamburg		Germany	20246
331	Novartis Investigative Site	Hamburg		Germany	22041
332	Novartis Investigative Site	Hamburg		Germany	22765
333	Novartis Investigative Site	Hassloch		Germany	67454
334	Novartis Investigative Site	Heidenau		Germany	01809
335	Novartis Investigative Site	Heppenheim		Germany	64646
336	Novartis Investigative Site	Homburg		Germany	66421
337	Novartis Investigative Site	Ingelheim		Germany	55218
338	Novartis Investigative Site	Jena		Germany	07740
339	Novartis Investigative Site	Kassel		Germany	34121
340	Novartis Investigative Site	Kleve		Germany	47533
341	Novartis Investigative Site	Koblenz		Germany	56068
342	Novartis Investigative Site	Koeln		Germany	51065
343	Novartis Investigative Site	Leipzig		Germany	04103
344	Novartis Investigative Site	Loehne		Germany	32584
345	Novartis Investigative Site	Ludwigshafen		Germany	67071
346	Novartis Investigative Site	Lutherstadt Wittenberg		Germany	06886
347	Novartis Investigative Site	Lüneburg		Germany	21339
348	Novartis Investigative Site	Mainz		Germany	55116
349	Novartis Investigative Site	Meißen		Germany	01662
350	Novartis Investigative Site	Memmingen		Germany	87700
351	Novartis Investigative Site	Muehldorf Am Inn		Germany	84453
352	Novartis Investigative Site	Muehldorf		Germany	84453
353	Novartis Investigative Site	Muenster		Germany	48149
354	Novartis Investigative Site	Munchen		Germany	81675
355	Novartis Investigative Site	Munich		Germany	80638
356	Novartis Investigative Site	Nienburg		Germany	31582
357	Novartis Investigative Site	Northeim		Germany	37154
358	Novartis Investigative Site	Oschatz		Germany	04758
359	Novartis Investigative Site	Papenburg		Germany	26871
360	Novartis Investigative Site	Reinfeld		Germany	23858
361	Novartis Investigative Site	Riesa		Germany	01589
362	Novartis Investigative Site	Rodgau		Germany	63110
363	Novartis Investigative Site	Siegen		Germany	57072
364	Novartis Investigative Site	Ulm		Germany	89077
365	Novartis Investigative Site	Wermsdorf		Germany	04779
366	Novartis Investigative Site	Weyhe		Germany	28844
367	Novartis Investigative Site	Witten		Germany	58455
368	Novartis Investigative Site	Wuerzburg		Germany	97080
369	Novartis Investigative Site	Athens	Attica	Greece	15562
370	Novartis Investigative Site	Athens	GR	Greece	14233
371	Novartis Investigative Site	Ioannina	GR	Greece	455 00
372	Novartis Investigative Site	Larissa	GR	Greece	411 10
373	Novartis Investigative Site	Athens		Greece	115 27
374	Novartis Investigative Site	Athens		Greece	12462
375	Novartis Investigative Site	Thessaloniki		Greece	54642
376	Novartis Investigative Site	Thessaloniki		Greece	GR 54636
377	Novartis Investigative Site	Guatemala City		Guatemala	01010
378	Novartis Investigative Site	Guatemala City		Guatemala	01011
379	Novartis Investigative Site	Guatemala City		Guatemala	01015
380	Novartis Investigative Site	Guatemala City		Guatemala	10110
381	Novartis Investigative Site	Zalaegerszeg	Zala	Hungary	8900
382	Novartis Investigative Site	Budapest		Hungary	1042
383	Novartis Investigative Site	Budapest		Hungary	1085
384	Novartis Investigative Site	Budapest		Hungary	1134
385	Novartis Investigative Site	Budapest		Hungary	1145
386	Novartis Investigative Site	Budapest		Hungary	H 1096
387	Novartis Investigative Site	Cegled		Hungary	2700
388	Novartis Investigative Site	Kistarcsa		Hungary	2143
389	Novartis Investigative Site	Mako		Hungary	6900
390	Novartis Investigative Site	Nyiregyháza		Hungary	4400
391	Novartis Investigative Site	Pecs		Hungary	7623
392	Novartis Investigative Site	Pecs		Hungary	7635
393	Novartis Investigative Site	Pécs		Hungary	7623
394	Novartis Investigative Site	Szeged		Hungary	H 6725
395	Novartis Investigative Site	Szekesfehervar		Hungary	H-8000
396	Novartis Investigative Site	Guntur	Andhra Pradesh	India	522001
397	Novartis Investigative Site	Vishakhapatnam	Andhra Pradesh	India	532 002
398	Novartis Investigative Site	New Delhi	Delhi	India	110 060
399	Novartis Investigative Site	Ahmedabad	Gujarat	India	380054
400	Novartis Investigative Site	Surat	Gujarat	India	395 002
401	Novartis Investigative Site	Chandigarh	Haryana	India	160 030
402	Novartis Investigative Site	Gurgaon	Haryana	India	122001
403	Novartis Investigative Site	Kochi	Kerala	India	683 594
404	Novartis Investigative Site	Pune	Maharashtra	India	411 030
405	Novartis Investigative Site	Ludhiana	Punjab	India	141002
406	Novartis Investigative Site	Bikaner	Rajasthan	India	334003
407	Novartis Investigative Site	Chennai	Tamil NADU	India	600037
408	Novartis Investigative Site	Chennai	Tamil Nadu	India	600081
409	Novartis Investigative Site	Madurai	Tamil NADU	India	625107
410	Novartis Investigative Site	Kolkata	West Bengal	India	700 020
411	Novartis Investigative Site	New Delhi		India	110025
412	Novartis Investigative Site	Hadera		Israel	38100
413	Novartis Investigative Site	Hadera		Israel
414	Novartis Investigative Site	Haifa		Israel	3339419
415	Novartis Investigative Site	Haifa		Israel	3525408
416	Novartis Investigative Site	Lower Galilee		Israel	15208
417	Novartis Investigative Site	Nahariya		Israel	22100
418	Novartis Investigative Site	Petach Tikva		Israel	49100
419	Novartis Investigative Site	Ramat Gan		Israel	52621
420	Novartis Investigative Site	Rehovot		Israel	76100
421	Novartis Investigative Site	Tel Giborim, Holon		Israel	58100
422	Novartis Investigative Site	Aosta	AO	Italy	11100
423	Novartis Investigative Site	Cortona	AR	Italy	52044
424	Novartis Investigative Site	Bergamo	BG	Italy	24127
425	Novartis Investigative Site	Treviglio	BG	Italy	24047
426	Novartis Investigative Site	Bologna	BO	Italy	40138
427	Novartis Investigative Site	Brescia	BS	Italy	25123
428	Novartis Investigative Site	Cona	FE	Italy	44100
429	Novartis Investigative Site	Pozzilli	IS	Italy	86077
430	Novartis Investigative Site	Monza	MB	Italy	20900
431	Novartis Investigative Site	Messina	ME	Italy	98125
432	Novartis Investigative Site	Milano	MI	Italy	20162
433	Novartis Investigative Site	Vimercate	MI	Italy	200059
434	Novartis Investigative Site	Padova	PD	Italy	35128
435	Novartis Investigative Site	Perugia	PG	Italy	06100
436	Novartis Investigative Site	Perugia	PG	Italy	06129
437	Novartis Investigative Site	Pavia	PV	Italy	27100
438	Novartis Investigative Site	Ariccia	RM	Italy	00041
439	Novartis Investigative Site	Roma	RM	Italy	00163
440	Novartis Investigative Site	Roma	RM	Italy	00189
441	Novartis Investigative Site	Sassari	SS	Italy	07100
442	Novartis Investigative Site	Trieste	TS	Italy	34142
443	Novartis Investigative Site	Trieste	TS	Italy	34149
444	Novartis Investigative Site	Palmanova	UD	Italy	33057
445	Novartis Investigative Site	San Daniele Del Friuli	UD	Italy	33038
446	Novartis Investigative Site	Saronno	Va	Italy	21047
447	Novartis Investigative Site	Venezia	VE	Italy	30174
448	Novartis Investigative Site	Milano		Italy	20149
449	Novartis Investigative Site	Napoli		Italy	80131
450	Novartis Investigative Site	Seto-city	Aichi	Japan	489-8642
451	Novartis Investigative Site	Chikushino-city	Fukuka	Japan	818-8516
452	Novartis Investigative Site	Ogaki-city	Gifu	Japan	503-8502
453	Novartis Investigative Site	Maebashi city	Gunma	Japan	371 8511
454	Novartis Investigative Site	Amagasaki city	Hyogo	Japan	660 8550
455	Novartis Investigative Site	Kanazawa	Ishikawa	Japan	920 8650
456	Novartis Investigative Site	Morioka	Iwate	Japan	020 0066
457	Novartis Investigative Site	Kanonji-city	Kagawa	Japan	769-1695
458	Novartis Investigative Site	Takamatsu city	Kagawa	Japan	760 8557
459	Novartis Investigative Site	Yokohama-city	Kanagawa	Japan	227-8501
460	Novartis Investigative Site	Yokohama-city	Kanagawa	Japan	236 0051
461	Novartis Investigative Site	Sendai city	Miyagi	Japan	980 8574
462	Novartis Investigative Site	Kashihara city	Nara	Japan	634 8522
463	Novartis Investigative Site	Sayama-city	Saitama	Japan	350-1305
464	Novartis Investigative Site	Kusatsu city	Shiga	Japan	525 8585
465	Novartis Investigative Site	Chiyoda-ku	Tokyo	Japan	101-8309
466	Novartis Investigative Site	Hachioji-city	Tokyo	Japan	192-0918
467	Novartis Investigative Site	Itabashi-ku	Tokyo	Japan	173-8610
468	Novartis Investigative Site	Shinagawa-ku	Tokyo	Japan	142-8666
469	Novartis Investigative Site	Gyeonggi do	Bucheon Si	Korea, Republic of	422-711
470	Novartis Investigative Site	Cheongju si	Chungcheongbuk Do	Korea, Republic of	28644
471	Novartis Investigative Site	Wonju	Gangwon-do	Korea, Republic of	26427
472	Novartis Investigative Site	Bundang Gu	Gyeonggi Do	Korea, Republic of	13620
473	Novartis Investigative Site	Seoul	Korea	Korea, Republic of	05505
474	Novartis Investigative Site	Incheon	KOR	Korea, Republic of	22332
475	Novartis Investigative Site	Seoul	KOR	Korea, Republic of	08308
476	Novartis Investigative Site	Daegu		Korea, Republic of	705 718
477	Novartis Investigative Site	Seoul		Korea, Republic of	02841
478	Novartis Investigative Site	Seoul		Korea, Republic of	03080
479	Novartis Investigative Site	Seoul		Korea, Republic of	03722
480	Novartis Investigative Site	Seoul		Korea, Republic of	06351
481	Novartis Investigative Site	Torreon	Coahulia	Mexico	27000
482	Novartis Investigative Site	Mexico	Distrito Federal	Mexico	14080
483	Novartis Investigative Site	Leon	Guanajuato	Mexico	37530
484	Novartis Investigative Site	Zapopan	Jalisco	Mexico	45200
485	Novartis Investigative Site	San Juan del Rio	Queretaro	Mexico	76800
486	Novartis Investigative Site	San Luis Potosi	San Luis Potosí	Mexico	78240
487	Novartis Investigative Site	Culiacan	Sinaloa	Mexico	80230
488	Novartis Investigative Site	Aguascalientes		Mexico	20230
489	Novartis Investigative Site	Queretaro		Mexico	76000
490	Novartis Investigative Site	San Luis Potosi		Mexico	78200
491	Novartis Investigative Site	San Luis Potosí		Mexico	78200
492	Novartis Investigative Site	Apeldoorn	DZ	Netherlands	7334
493	Novartis Investigative Site	Den Haag	NL	Netherlands	2597 AX
494	Novartis Investigative Site	Almelo	PP	Netherlands	7609
495	Novartis Investigative Site	Arnhem		Netherlands	6815 AD
496	Novartis Investigative Site	Blaricum		Netherlands	1261 AN
497	Novartis Investigative Site	Den Haag		Netherlands	2512 VA
498	Novartis Investigative Site	Ede		Netherlands	6716 RP
499	Novartis Investigative Site	Gouda		Netherlands	2803 HH
500	Novartis Investigative Site	Groningen		Netherlands	9713 GZ
501	Novartis Investigative Site	Hardenberg		Netherlands	7770 AA
502	Novartis Investigative Site	Harderwijk		Netherlands	3840 AC
503	Novartis Investigative Site	Nijmegen		Netherlands	6500 HB
504	Novartis Investigative Site	Rotterdam		Netherlands	3015 CE
505	Novartis Investigative Site	Sneek		Netherlands	8601 ZK
506	Novartis Investigative Site	Tilburg		Netherlands	5022 GC
507	Novartis Investigative Site	Loerenskog		Norway	NO 1478
508	Novartis Investigative Site	Oslo		Norway	0450
509	Novartis Investigative Site	Stavanger		Norway	4068
510	Novartis Investigative Site	Tromsoe		Norway	NO-9038
511	Novartis Investigative Site	Bellavista	Lima	Peru	CALLAO 02
512	Novartis Investigative Site	Cercado De Lima	Lima	Peru	01
513	Novartis Investigative Site	Jesus Maria	Lima	Peru	11
514	Novartis Investigative Site	Miraflores	Lima	Peru	18
515	Novartis Investigative Site	San Isidro	Lima	Peru	27
516	Novartis Investigative Site	Lipa City	Batangas	Philippines	4217
517	Novartis Investigative Site	Quezon City	Manila	Philippines	1100
518	Novartis Investigative Site	Quezon City		Philippines	1100
519	Novartis Investigative Site	Quezon City		Philippines	1102
520	Novartis Investigative Site	Lodz	Lodzkie	Poland	90 549
521	Novartis Investigative Site	Gdynia		Poland	81-157
522	Novartis Investigative Site	Gdynia		Poland	81-548
523	Novartis Investigative Site	Grodzisk Mazowiecki		Poland	05 825
524	Novartis Investigative Site	Katowice		Poland	40-645
525	Novartis Investigative Site	Krakow		Poland	30-015
526	Novartis Investigative Site	Krakow		Poland	31 501
527	Novartis Investigative Site	Lublin		Poland	20-363
528	Novartis Investigative Site	Sandomierz		Poland	27 600
529	Novartis Investigative Site	Staszów		Poland	28-200
530	Novartis Investigative Site	Torun		Poland	87-100
531	Novartis Investigative Site	Warszawa/Anin		Poland	04-761
532	Novartis Investigative Site	Warszawa		Poland	02-097
533	Novartis Investigative Site	Warszawa		Poland	04-154
534	Novartis Investigative Site	Zabrze		Poland	41 800
535	Novartis Investigative Site	Zamosc		Poland	22-400
536	Novartis Investigative Site	Pitesti	Arges	Romania	110438
537	Novartis Investigative Site	Bucuresti	District 1	Romania	014461
538	Novartis Investigative Site	Craiova	Jud. Dolj	Romania	200497
539	Novartis Investigative Site	Sibiu	Jud. Iasi	Romania	550371
540	Novartis Investigative Site	Timisoara	Timis	Romania	300125
541	Novartis Investigative Site	Timisoara	Timis	Romania	300362
542	Novartis Investigative Site	Arad		Romania	310158
543	Novartis Investigative Site	Baia Mare		Romania	430222
544	Novartis Investigative Site	Bucharest		Romania	050098
545	Novartis Investigative Site	Bucuresti		Romania	062272
546	Novartis Investigative Site	Targu Mures		Romania	540142
547	Novartis Investigative Site	Targu Mures		Romania	540143
548	Novartis Investigative Site	Timisoara		Romania	300041
549	Novartis Investigative Site	Ekaterinburg		Russian Federation	620028
550	Novartis Investigative Site	Ekaterinburg		Russian Federation	620137
551	Novartis Investigative Site	Ivanovo		Russian Federation	153012
552	Novartis Investigative Site	Izhevsk		Russian Federation	426009
553	Novartis Investigative Site	Izhevsk		Russian Federation	426063
554	Novartis Investigative Site	Kemerovo		Russian Federation	650029
555	Novartis Investigative Site	Kemerovo		Russian Federation	650099
556	Novartis Investigative Site	Kirov		Russian Federation	610027
557	Novartis Investigative Site	Kirov		Russian Federation	610035
558	Novartis Investigative Site	Moscow		Russian Federation	101990
559	Novartis Investigative Site	Moscow		Russian Federation	117198
560	Novartis Investigative Site	Moscow		Russian Federation	121309
561	Novartis Investigative Site	Moscow		Russian Federation	121552
562	Novartis Investigative Site	N.Novgorod		Russian Federation	603005
563	Novartis Investigative Site	Perm		Russian Federation	614990
564	Novartis Investigative Site	Rostov on Don		Russian Federation	344022
565	Novartis Investigative Site	Rostov-on-Don		Russian Federation	344068
566	Novartis Investigative Site	Saint Petersburg		Russian Federation	194044
567	Novartis Investigative Site	Saint Petersburg		Russian Federation	197022
568	Novartis Investigative Site	Saint Petersburg		Russian Federation	197341
569	Novartis Investigative Site	Saint Petersburg		Russian Federation	199106
570	Novartis Investigative Site	Saint-Petersburg		Russian Federation	192257
571	Novartis Investigative Site	Saratov		Russian Federation	410012
572	Novartis Investigative Site	Sestroretsk		Russian Federation	197706
573	Novartis Investigative Site	Smolensk		Russian Federation	214018
574	Novartis Investigative Site	St Petersburg		Russian Federation	196601
575	Novartis Investigative Site	St-Petersburg		Russian Federation	194295
576	Novartis Investigative Site	St.- Petersburg		Russian Federation	197110
577	Novartis Investigative Site	Yaroslavl		Russian Federation	150003
578	Novartis Investigative Site	Belgrade		Serbia	11000
579	Novartis Investigative Site	Beograd		Serbia	11040
580	Novartis Investigative Site	Niska Banja		Serbia	18205
581	Novartis Investigative Site	Nis		Serbia	18000
582	Novartis Investigative Site	Singapore		Singapore	119074
583	Novartis Investigative Site	Singapore		Singapore	169609
584	Novartis Investigative Site	Singapore		Singapore	308433
585	Novartis Investigative Site	Singapore		Singapore	529889
586	Novartis Investigative Site	Singapore		Singapore	768828
587	Novartis Investigative Site	Brezno	Slovak Republic	Slovakia	977 42
588	Novartis Investigative Site	Komarno	Slovak Republic	Slovakia	94501
589	Novartis Investigative Site	Levice	Slovak Republic	Slovakia	93401
590	Novartis Investigative Site	Namestovo	Slovak Republic	Slovakia	02901
591	Novartis Investigative Site	Povazska Bystrica	Slovak Republic	Slovakia	01701
592	Novartis Investigative Site	Presov	Slovak Republic	Slovakia	08001
593	Novartis Investigative Site	Bardejov		Slovakia	085 01
594	Novartis Investigative Site	Bratislava		Slovakia	821 07
595	Novartis Investigative Site	Bratislava		Slovakia	831 01
596	Novartis Investigative Site	Bratislava		Slovakia	833 48
597	Novartis Investigative Site	Bratislava		Slovakia	841 07
598	Novartis Investigative Site	Bratislava		Slovakia	842 31
599	Novartis Investigative Site	Bratislava		Slovakia	851 01
600	Novartis Investigative Site	Kosice		Slovakia	040 01
601	Novartis Investigative Site	Levice		Slovakia	934 01
602	Novartis Investigative Site	Lucenec		Slovakia	984 01
603	Novartis Investigative Site	Lucenec		Slovakia	98439
604	Novartis Investigative Site	Nitra		Slovakia	949 01
605	Novartis Investigative Site	Nitra		Slovakia	949 88
606	Novartis Investigative Site	Nove Zamky		Slovakia	940 01
607	Novartis Investigative Site	Nove Zamky		Slovakia	94002
608	Novartis Investigative Site	Piestany		Slovakia	921 01
609	Novartis Investigative Site	Presov		Slovakia	080 01
610	Novartis Investigative Site	Svidnik		Slovakia	089 01
611	Novartis Investigative Site	Trebisov		Slovakia	075 01
612	Novartis Investigative Site	Zilina		Slovakia	012 07
613	Novartis Investigative Site	Golnik		Slovenia	4204
614	Novartis Investigative Site	Ljubljana		Slovenia	1000
615	Novartis Investigative Site	Bloemfontein	Free State	South Africa	9301
616	Novartis Investigative Site	Soweto	Gauteng	South Africa	2013
617	Novartis Investigative Site	Durban	Kwa-Zulu Natal	South Africa	4052
618	Novartis Investigative Site	Alberton		South Africa	1449
619	Novartis Investigative Site	Bloemfontein		South Africa	9301
620	Novartis Investigative Site	Cape Town		South Africa	7500
621	Novartis Investigative Site	Cape Town		South Africa	7531
622	Novartis Investigative Site	Cape Town		South Africa	7925
623	Novartis Investigative Site	Durban		South Africa	4001
624	Novartis Investigative Site	Tongaat		South Africa	3300
625	Novartis Investigative Site	Western Cape		South Africa	7130
626	Novartis Investigative Site	Worcester		South Africa	6850
627	Novartis Investigative Site	Almeria	Andalucia	Spain	04120
628	Novartis Investigative Site	Cordoba	Andalucia	Spain	14004
629	Novartis Investigative Site	Malaga	Andalucia	Spain	29010
630	Novartis Investigative Site	Marbella	Andalucia	Spain	29600
631	Novartis Investigative Site	Sanlúcar de Barrameda	Andalucia	Spain	11540
632	Novartis Investigative Site	Sevilla	Andalucia	Spain	41013
633	Novartis Investigative Site	Sevilla	Andalucia	Spain	41014
634	Novartis Investigative Site	Sant Joan Despi	Barcelona	Spain	08970
635	Novartis Investigative Site	Villamartin	Cadiz	Spain	11650
636	Novartis Investigative Site	Santander	Cantabria	Spain	39008
637	Novartis Investigative Site	Aranda de Duero	Castilla Y Leon	Spain	09400
638	Novartis Investigative Site	Leon	Castilla Y Leon	Spain	24071
639	Novartis Investigative Site	Lerida	Cataluna	Spain	25198
640	Novartis Investigative Site	Badalona	Catalunya	Spain	08916
641	Novartis Investigative Site	Barcelona	Catalunya	Spain	08003
642	Novartis Investigative Site	Alzira	Comunidad Valenciana	Spain	46600
643	Novartis Investigative Site	Valencia	Comunidad Valenciana	Spain	46010
644	Novartis Investigative Site	Valencia	Comunidad Valenciana	Spain	46014
645	Novartis Investigative Site	Valencia	Comunidad Valenciana	Spain	46026
646	Novartis Investigative Site	Merida	Extremadura	Spain	06800
647	Novartis Investigative Site	A Coruna	Galicia	Spain	15006
648	Novartis Investigative Site	Santiago de Compostela	Galicia	Spain	15706
649	Novartis Investigative Site	Olot	Girona	Spain	17800
650	Novartis Investigative Site	Mostoles	Madrid	Spain	28935
651	Novartis Investigative Site	El Palmar	Murcia	Spain	30120
652	Novartis Investigative Site	Ciudad Real		Spain	13005
653	Novartis Investigative Site	Madrid		Spain	28009
654	Novartis Investigative Site	Madrid		Spain	28034
655	Novartis Investigative Site	Madrid		Spain	28040
656	Novartis Investigative Site	Madrid		Spain	28046
657	Novartis Investigative Site	Madrid		Spain	28222
658	Novartis Investigative Site	Danderyd		Sweden	182 88
659	Novartis Investigative Site	Falun		Sweden	791 82
660	Novartis Investigative Site	Goteborg		Sweden	413 45
661	Novartis Investigative Site	Karlstad		Sweden	652 30
662	Novartis Investigative Site	Lund		Sweden	222 21
663	Novartis Investigative Site	Orebro		Sweden	701 85
664	Novartis Investigative Site	Stockholm		Sweden	17176
665	Novartis Investigative Site	Vasteras		Sweden	72189
666	Novartis Investigative Site	Basel		Switzerland	4031
667	Novartis Investigative Site	Bern		Switzerland	3010
668	Novartis Investigative Site	Biel		Switzerland	2502
669	Novartis Investigative Site	Lausanne		Switzerland	1011
670	Novartis Investigative Site	Zurich		Switzerland	8091
671	Novartis Investigative Site	Tainan	Taiwan ROC	Taiwan	70403
672	Novartis Investigative Site	Changhua		Taiwan	50006
673	Novartis Investigative Site	Kaohsiung		Taiwan	80756
674	Novartis Investigative Site	New Taipei		Taiwan	22060
675	Novartis Investigative Site	Taichung		Taiwan	40447
676	Novartis Investigative Site	Tainan		Taiwan	71004
677	Novartis Investigative Site	Taipei		Taiwan	10002
678	Novartis Investigative Site	Taipei		Taiwan	11217
679	Novartis Investigative Site	Yilan		Taiwan	26058
680	Novartis Investigative Site	Istanbul	TUR	Turkey	34098
681	Novartis Investigative Site	Haydarpasa Istanbul		Turkey	34668
682	Novartis Investigative Site	Istanbul		Turkey	34304
683	Novartis Investigative Site	Izmir		Turkey	35040
684	Novartis Investigative Site	Izmir		Turkey	35340
685	Novartis Investigative Site	Kocaeli		Turkey	41380
686	Novartis Investigative Site	Pendik / Istanbul		Turkey	34899
687	Novartis Investigative Site	Sivas		Turkey	58140
688	Novartis Investigative Site	High Wycombe	Buckinghamshire	United Kingdom	HP11 2TT
689	Novartis Investigative Site	Stockton on Tees	Cleveland	United Kingdom	TS19 8PE
690	Novartis Investigative Site	Darlington	Co Durham	United Kingdom	DL3 8SQ
691	Novartis Investigative Site	Durham	County Durham	United Kingdom	DH1 5TW
692	Novartis Investigative Site	Torquay	Devon	United Kingdom	TQ2 7AA
693	Novartis Investigative Site	Dorchester	Dorset	United Kingdom	DT1 2JY
694	Novartis Investigative Site	Peterborough	GBR	United Kingdom	PE3 6DA
695	Novartis Investigative Site	Basingstoke	Hampshire	United Kingdom	RG24 9NA
696	Novartis Investigative Site	Portsmouth	Hampshire	United Kingdom	PO6 3LY
697	Novartis Investigative Site	Oldham	Lancashire	United Kingdom	OL1 2JH
698	Novartis Investigative Site	Harrow	Middlesex	United Kingdom	HA1 3UJ
699	Novartis Investigative Site	Portadown	Nothern Ireland	United Kingdom	BT63 5QQ
700	Novartis Investigative Site	Wansford	Peterborough	United Kingdom	PE8 6PL
701	Novartis Investigative Site	Glasgow	Scotland	United Kingdom	G12 8TA
702	Novartis Investigative Site	Taunton	Somerset	United Kingdom	TA1 5DA
703	Novartis Investigative Site	Gateshead	Tyne And Wear	United Kingdom	NE9 6SX
704	Novartis Investigative Site	Clydebank	West Dumbartonshire	United Kingdom	G81 4HX
705	Novartis Investigative Site	Cheshire		United Kingdom	CW1 4QJ
706	Novartis Investigative Site	Coventry		United Kingdom	CV2 2DX
707	Novartis Investigative Site	Dundee		United Kingdom	DD1 9SY
708	Novartis Investigative Site	Glasgow		United Kingdom	G20 0XA
709	Novartis Investigative Site	Hull		United Kingdom	HU16 5JQ
710	Novartis Investigative Site	London		United Kingdom	SE5 9RS
711	Novartis Investigative Site	London		United Kingdom	SW 6NP
712	Novartis Investigative Site	Newport		United Kingdom	NP20 2UB
713	Novartis Investigative Site	Nottingham		United Kingdom	NG5 1PB
714	Novartis Investigative Site	Sheffield		United Kingdom	S5 7AU
715	Novartis Investigative Site	Swindon		United Kingdom	SN3 6BB
716	Novartis Investigative Site	Wiltshire		United Kingdom	SN15 2SB
717	Novartis Investigative Site	Wrexham		United Kingdom	LL13 7TD

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

More Information

Publications

None provided.

Responsible Party:

Novartis Pharmaceuticals

ClinicalTrials.gov Identifier:

NCT01920711

Other Study ID Numbers:

CLCZ696D2301
2013-001747-31

First Posted:

Aug 12, 2013

Last Update Posted:

Sep 29, 2020

Last Verified:

Sep 1, 2020

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Novartis Pharmaceuticals

Heart failure

preserved ejection fraction

diastolic heart failure

Additional relevant MeSH terms:

Heart Failure

Valsartan

Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

Recruitment Details	4822 patients were randomized at 755 sites in 43 countries. 2419 participants were randomized into the LCZ696 treatment group and 2403 were randomized into the valsartan treatment group.
Pre-assignment Detail

Arm/Group Title	LCZ696	Valsartan
Arm/Group Description	Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients followed by Valsartan 80 mg bid for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of LCZ696 during the double blind period was 200 mg bid	Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients, followed by Valsartan 80 mg bid. for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of Valsartan during the double blind period was 160 mg bid
Period Title: Overall Study
STARTED	2419	2403
COMPLETED	2055	2030
NOT COMPLETED	364	373

Baseline Characteristics

Arm/Group Title	LCZ696	Valsartan	Total
Arm/Group Description	Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients followed by Valsartan 80 mg bid for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of LCZ696 during the double blind period was 200 mg bid	Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients, followed by Valsartan 80 mg bid. for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of Valsartan during the double blind period was 160 mg bid	Total of all reporting groups
Overall Participants	2419	2403	4822
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	415 17.2%	415 17.3%	830 17.2%
>=65 years	2004 82.8%	1988 82.7%	3992 82.8%
Sex: Female, Male (Count of Participants)
Female	1247 51.6%	1244 51.8%	2491 51.7%
Male	1172 48.4%	1159 48.2%	2331 48.3%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	1975 81.6%	1958 81.5%	3933 81.6%
Black	52 2.1%	50 2.1%	102 2.1%
Asian	297 12.3%	310 12.9%	607 12.6%
Native American	28 1.2%	23 1%	51 1.1%
Pacific Islander	0 0%	1 0%	1 0%
Other	67 2.8%	61 2.5%	128 2.7%

Outcome Measures

1. Primary Outcome

Title	Cumulative Number of Primary Composite Events of Cardiovascular (CV) Death and Total (First and Recurrent) HF Hospitalizations.
Description	The primary objective of this study is to compare LCZ696 to valsartan in reducing the rate of the composite endpoint of CV death and total (first and recurrent) HF hospitalizations, in HF patients (New York Heart Association [NYHA] Class II-IV) with preserved ejection fraction (left ventricular ejection fraction [LVEF] ≥45%). The treatment arm with the lower rate of events will be deemed as having a successful response.
Time Frame	Total follow up time (up to 57 months)

Outcome Measure Data

Analysis Population Description
Full Analysis Set - This was the primary efficacy population applied in efficacy analyses for all efficacy endpoints.

Arm/Group Title	LCZ696	Valsartan
Arm/Group Description	Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients followed by Valsartan 80 mg bid for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of LCZ696 during the double blind period was 200 mg bid	Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients, followed by Valsartan 80 mg bid. for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of Valsartan during the double blind period was 160 mg bid
Measure Participants	2407	2389
Primary Composite Events	894	1009
Total Hospitalizations for heart failure	690	797
Cardiovascular death	204	212

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696, Valsartan
	Comments	Primary Composite Events
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0587
	Comments	1-sided p-value 0.0294
	Method	Proportional Rates Model (LWYY)
	Comments	Treatment as fixed-effect factor and stratified by region and with robust variance estimate.

Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.8698
	Confidence Interval	(2-Sided) 95% 0.7526 to 1.0052
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LCZ696, Valsartan
	Comments	Total Hospitalizations for heart failure
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0556
	Comments	1-sided p-value 0.0278
	Method	Joint Frality Model
	Comments	Treatment and region as fixed-effect factors

Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.8511
	Confidence Interval	(2-Sided) 95% 0.7216 to 1.0039
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LCZ696, Valsartan
	Comments	Cardiovascular Death
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.6241
	Comments	1-sided p-value 0.3120
	Method	Cox's proportional hazard model
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.9531
	Confidence Interval	(2-Sided) 95% 0.7863 to 1.1551
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in the Clinical Summary Score From Baseline to Month 8 by Kansas City Cardiomyopathy Questionnaire (KCCQ)
Description	The KCCQ is a validated instrument for self-assessment of quality of life and health status in heart failure (HF) patients. The clinical summary score, which is derived from the physical limitations and heart failure (HF) symptoms domains of the KCCQ is a valid measure for assessing the patient's health aspects that may be influenced by CV medications. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. Evaluation of change from baseline to month 8 in KCCQ a most sensitive, specific, and responsive health-related quality of life measure for heart failure symptoms and physical limitations.
Time Frame	Baseline, 8 months

Outcome Measure Data

Analysis Population Description
Full Analysis Set-This was the primary efficacy population applied in efficacy analyses for all efficacy endpoints.

Arm/Group Title	LCZ696	Valsartan
Arm/Group Description	Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients followed by Valsartan 80 mg bid for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of LCZ696 during the double blind period was 200 mg bid	Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients, followed by Valsartan 80 mg bid. for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of Valsartan during the double blind period was 160 mg bid
Measure Participants	2407	2389
Least Squares Mean (Standard Error) [Points on a scale]	-1.5073 (0.3709)	-2.5338 (0.3729)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696, Valsartan
	Comments	Clinical Summary Score
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0510
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Least Squares Mean of Difference
	Estimated Value	1.0264
	Confidence Interval	(2-Sided) 95% -0.0047 to 2.0576
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline to Month 8 in New York Heart Association (NYHA) Functional Class
Description	Evaluation of change from baseline to Month 8 in NYHA functional class, a well established grading scale used to classify a heart failure's (HF) patients' level of functionality based on the signs and symptoms of HF exhibited by the patient.
Time Frame	Baseline, 8 months

Outcome Measure Data

Analysis Population Description
Full Analysis Set - This was the primary efficacy population applied in efficacy analyses for all efficacy endpoints. However, this endpoint only includes those participants who had assessments completed for both Baseline and Month 8 visits; as that is the only way a change could be calculated and analyzed.

Arm/Group Title	LCZ696	Valsartan
Arm/Group Description	Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients followed by Valsartan 80 mg bid for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of LCZ696 during the double blind period was 200 mg bid	Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients, followed by Valsartan 80 mg bid. for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of Valsartan during the double blind period was 160 mg bid
Measure Participants	2407	2389
Improved (n=2316, 2302)	347 14.3%	289 12%
Unchanged (n=2316, 2302)	1767 73%	1792 74.6%
Worsened (n=2316, 2302)	202 8.4%	221 9.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696, Valsartan
	Comments	NYHA Class Change
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0035
	Comments
	Method	Repeated measures cumulative odds model
	Comments	The response variable is the change from baseline to any scheduled time points up to Month 8.

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.4475
	Confidence Interval	(2-Sided) 95% 1.1294 to 1.8552
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Participants With First Occurrence of a Composite Renal Endpoint
Description	Analyis of composite renal endpoint defined as renal death, or reaching ESRD, or ≥50% decline in eGFR relative to baseline, using Cox's proportional hazards model.
Time Frame	Randomization to total follow-up time (up to 57 months)

Outcome Measure Data

Analysis Population Description
Full Analysis Set -This was the primary efficacy population applied in efficacy analyses for all efficacy endpoints.

Arm/Group Title	LCZ696	Valsartan
Arm/Group Description	Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients followed by Valsartan 80 mg bid for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of LCZ696 during the double blind period was 200 mg bid	Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients, followed by Valsartan 80 mg bid. for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of Valsartan during the double blind period was 160 mg bid
Measure Participants	2407	2389
Composite renal endpoint	33 1.4%	64 2.7%
Renal Death	1 0%	1 0%
Reaching ESRD	7 0.3%	12 0.5%
>=50% decline in eGFR from baseline	27 1.1%	60 2.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696, Valsartan
	Comments	Composite renal endpoint
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0014
	Comments
	Method	Cox's proportional hazards model
	Comments	Treatment as fixed factor and stratified by region.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.5041
	Confidence Interval	(2-Sided) 95% 0.3312 to 0.7673
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LCZ696, Valsartan
	Comments	Renal Death
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.9588
	Comments
	Method	Cox's proportional hazards model
	Comments	Treatment as fixed factor and stratified by region.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.9295
	Confidence Interval	(2-Sided) 95% 0.0581 to 14.861
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LCZ696, Valsartan
	Comments	Reaching ESRD
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.2484
	Comments
	Method	Cox's proportional hazards model
	Comments	Treatment as fixed factor and stratified by region.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.5774
	Confidence Interval	(2-Sided) 95% 0.2272 to 1.4672
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	LCZ696, Valsartan
	Comments	>=50% decline in eGFR from baseline
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	Cox's proportional hazards model
	Comments	Treatment as fixed factor and stratified by region.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.4407
	Confidence Interval	(2-Sided) 95% 0.2798 to 0.6942
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	All-cause Mortality
Description	Analysis for all-cause mortality using Cox's proportional hazards model.
Time Frame	Randomization to total follow up time (up to 57 months)

Outcome Measure Data

Analysis Population Description
Full Analysis Set -This was the primary efficacy population applied in efficacy analyses for all efficacy endpoints.

Arm/Group Title	LCZ696	Valsartan
Arm/Group Description	Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients followed by Valsartan 80 mg bid for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of LCZ696 during the double blind period was 200 mg bid	Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients, followed by Valsartan 80 mg bid. for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of Valsartan during the double blind period was 160 mg bid
Measure Participants	2407	2389
Number [Participants]	342 14.1%	349 14.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696, Valsartan
	Comments	All-cause mortality
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.6846
	Comments
	Method	Cox's proportional hazards model
	Comments	Treatment as fixed factor and stratified by region.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.9696
	Confidence Interval	(2-Sided) 95% 0.8352 to 1.1255
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

	LCZ696		Valsartan		All Patients
Time Frame	Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 5 years.
Adverse Event Reporting Description	Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.

Arm/Group Title	LCZ696		Valsartan		All Patients
Arm/Group Description	Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients followed by Valsartan 80 mg bid for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of LCZ696 during the double blind period was 200 mg bid		Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients, followed by Valsartan 80 mg bid. for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of Valsartan during the double blind period was 160 mg bid		Total patients
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	347/2419 (14.3%)		357/2402 (14.9%)		704/4821 (14.6%)
Serious Adverse Events
	LCZ696		Valsartan		All Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1424/2419 (58.9%)		1416/2402 (59%)		2840/4821 (58.9%)
Blood and lymphatic system disorders
Acquired haemophilia	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Anaemia	68/2419 (2.8%)		67/2402 (2.8%)		135/4821 (2.8%)
Anaemia macrocytic	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Anaemia megaloblastic	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Anaemia vitamin B12 deficiency	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Autoimmune haemolytic anaemia	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Blood loss anaemia	2/2419 (0.1%)		7/2402 (0.3%)		9/4821 (0.2%)
Coagulopathy	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Disseminated intravascular coagulation	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Hypercoagulation	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Hypersplenism	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Immune thrombocytopenic purpura	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Iron deficiency anaemia	5/2419 (0.2%)		6/2402 (0.2%)		11/4821 (0.2%)
Leukocytosis	1/2419 (0%)		6/2402 (0.2%)		7/4821 (0.1%)
Leukopenia	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Lymphadenitis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Lymphadenopathy	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Lymphadenopathy mediastinal	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Microcytic anaemia	3/2419 (0.1%)		1/2402 (0%)		4/4821 (0.1%)
Nephrogenic anaemia	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Neutropenia	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Normochromic normocytic anaemia	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Pancytopenia	1/2419 (0%)		3/2402 (0.1%)		4/4821 (0.1%)
Splenic infarction	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Splenitis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Thrombocytopenia	6/2419 (0.2%)		1/2402 (0%)		7/4821 (0.1%)
Thrombocytosis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Cardiac disorders
Acute coronary syndrome	11/2419 (0.5%)		13/2402 (0.5%)		24/4821 (0.5%)
Acute left ventricular failure	14/2419 (0.6%)		15/2402 (0.6%)		29/4821 (0.6%)
Acute myocardial infarction	60/2419 (2.5%)		54/2402 (2.2%)		114/4821 (2.4%)
Adams-Stokes syndrome	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Angina pectoris	42/2419 (1.7%)		50/2402 (2.1%)		92/4821 (1.9%)
Angina unstable	50/2419 (2.1%)		43/2402 (1.8%)		93/4821 (1.9%)
Aortic valve disease	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Aortic valve incompetence	2/2419 (0.1%)		2/2402 (0.1%)		4/4821 (0.1%)
Aortic valve stenosis	4/2419 (0.2%)		3/2402 (0.1%)		7/4821 (0.1%)
Arrhythmia	4/2419 (0.2%)		4/2402 (0.2%)		8/4821 (0.2%)
Arrhythmia supraventricular	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Arteriosclerosis coronary artery	4/2419 (0.2%)		4/2402 (0.2%)		8/4821 (0.2%)
Atrial fibrillation	162/2419 (6.7%)		145/2402 (6%)		307/4821 (6.4%)
Atrial flutter	31/2419 (1.3%)		23/2402 (1%)		54/4821 (1.1%)
Atrial tachycardia	7/2419 (0.3%)		2/2402 (0.1%)		9/4821 (0.2%)
Atrial thrombosis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Atrioventricular block	6/2419 (0.2%)		4/2402 (0.2%)		10/4821 (0.2%)
Atrioventricular block complete	8/2419 (0.3%)		11/2402 (0.5%)		19/4821 (0.4%)
Atrioventricular block first degree	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Atrioventricular block second degree	4/2419 (0.2%)		3/2402 (0.1%)		7/4821 (0.1%)
Bradyarrhythmia	3/2419 (0.1%)		3/2402 (0.1%)		6/4821 (0.1%)
Bradycardia	27/2419 (1.1%)		24/2402 (1%)		51/4821 (1.1%)
Bundle branch block left	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Cardiac amyloidosis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Cardiac arrest	17/2419 (0.7%)		30/2402 (1.2%)		47/4821 (1%)
Cardiac asthma	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Cardiac discomfort	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Cardiac failure	340/2419 (14.1%)		380/2402 (15.8%)		720/4821 (14.9%)
Cardiac failure acute	85/2419 (3.5%)		77/2402 (3.2%)		162/4821 (3.4%)
Cardiac failure chronic	26/2419 (1.1%)		30/2402 (1.2%)		56/4821 (1.2%)
Cardiac failure congestive	86/2419 (3.6%)		83/2402 (3.5%)		169/4821 (3.5%)
Cardiac fibrillation	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Cardiac flutter	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Cardiac tamponade	2/2419 (0.1%)		2/2402 (0.1%)		4/4821 (0.1%)
Cardiac valve disease	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Cardiac ventricular disorder	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Cardio-respiratory arrest	15/2419 (0.6%)		13/2402 (0.5%)		28/4821 (0.6%)
Cardiogenic shock	12/2419 (0.5%)		6/2402 (0.2%)		18/4821 (0.4%)
Cardiomegaly	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Cardiomyopathy	0/2419 (0%)		3/2402 (0.1%)		3/4821 (0.1%)
Cardiopulmonary failure	4/2419 (0.2%)		1/2402 (0%)		5/4821 (0.1%)
Cardiorenal syndrome	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Cardiovascular disorder	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Cardiovascular insufficiency	1/2419 (0%)		3/2402 (0.1%)		4/4821 (0.1%)
Chronic left ventricular failure	3/2419 (0.1%)		1/2402 (0%)		4/4821 (0.1%)
Congestive cardiomyopathy	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Cor pulmonale	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Coronary artery disease	24/2419 (1%)		27/2402 (1.1%)		51/4821 (1.1%)
Coronary artery occlusion	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Coronary artery stenosis	5/2419 (0.2%)		2/2402 (0.1%)		7/4821 (0.1%)
Hypertensive heart disease	1/2419 (0%)		3/2402 (0.1%)		4/4821 (0.1%)
Intracardiac mass	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Ischaemic cardiomyopathy	4/2419 (0.2%)		1/2402 (0%)		5/4821 (0.1%)
Left ventricular dysfunction	0/2419 (0%)		3/2402 (0.1%)		3/4821 (0.1%)
Left ventricular failure	6/2419 (0.2%)		5/2402 (0.2%)		11/4821 (0.2%)
Microvascular coronary artery disease	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Mitral valve calcification	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Mitral valve incompetence	7/2419 (0.3%)		8/2402 (0.3%)		15/4821 (0.3%)
Mitral valve prolapse	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Myocardial infarction	32/2419 (1.3%)		35/2402 (1.5%)		67/4821 (1.4%)
Myocardial ischaemia	7/2419 (0.3%)		11/2402 (0.5%)		18/4821 (0.4%)
Myocardial rupture	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Myocarditis	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Nodal rhythm	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Palpitations	3/2419 (0.1%)		4/2402 (0.2%)		7/4821 (0.1%)
Pericardial effusion	3/2419 (0.1%)		4/2402 (0.2%)		7/4821 (0.1%)
Pericarditis	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Pericarditis constrictive	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Pulseless electrical activity	3/2419 (0.1%)		1/2402 (0%)		4/4821 (0.1%)
Right ventricular dysfunction	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Right ventricular failure	0/2419 (0%)		3/2402 (0.1%)		3/4821 (0.1%)
Sinoatrial block	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Sinus arrest	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Sinus bradycardia	1/2419 (0%)		8/2402 (0.3%)		9/4821 (0.2%)
Sinus node dysfunction	18/2419 (0.7%)		12/2402 (0.5%)		30/4821 (0.6%)
Sinus tachycardia	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Stress cardiomyopathy	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Supraventricular extrasystoles	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Supraventricular tachycardia	6/2419 (0.2%)		3/2402 (0.1%)		9/4821 (0.2%)
Systolic dysfunction	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Tachyarrhythmia	3/2419 (0.1%)		0/2402 (0%)		3/4821 (0.1%)
Tachycardia	3/2419 (0.1%)		1/2402 (0%)		4/4821 (0.1%)
Torsade de pointes	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Tricuspid valve incompetence	0/2419 (0%)		3/2402 (0.1%)		3/4821 (0.1%)
Trifascicular block	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Ventricular arrhythmia	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Ventricular dyssynchrony	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Ventricular extrasystoles	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Ventricular fibrillation	4/2419 (0.2%)		5/2402 (0.2%)		9/4821 (0.2%)
Ventricular tachycardia	9/2419 (0.4%)		4/2402 (0.2%)		13/4821 (0.3%)
Congenital, familial and genetic disorders
Atrial septal defect	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Congenital coronary artery malformation	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Congenital megaureter	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Gastrointestinal arteriovenous malformation	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
LUMBAR syndrome	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Phimosis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Vertebral artery hypoplasia	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Ear and labyrinth disorders
Deafness unilateral	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Sudden hearing loss	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Tinnitus	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Vertigo	6/2419 (0.2%)		3/2402 (0.1%)		9/4821 (0.2%)
Vertigo positional	5/2419 (0.2%)		1/2402 (0%)		6/4821 (0.1%)
Vestibular ischaemia	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Endocrine disorders
Goitre	0/2419 (0%)		3/2402 (0.1%)		3/4821 (0.1%)
Hypercorticoidism	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Hyperparathyroidism	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Hyperthyroidism	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Hypothyroidism	3/2419 (0.1%)		3/2402 (0.1%)		6/4821 (0.1%)
Inappropriate antidiuretic hormone secretion	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Parathyroid hyperplasia	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Eye disorders
Amaurosis fugax	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Blindness unilateral	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Cataract	14/2419 (0.6%)		12/2402 (0.5%)		26/4821 (0.5%)
Cataract diabetic	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Conjunctival haemorrhage	1/2419 (0%)		3/2402 (0.1%)		4/4821 (0.1%)
Entropion	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Eye pain	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Glaucoma	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Macular degeneration	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Macular fibrosis	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Maculopathy	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Narrow anterior chamber angle	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Neovascular age-related macular degeneration	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Pterygium	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Retinal detachment	1/2419 (0%)		3/2402 (0.1%)		4/4821 (0.1%)
Retinal haemorrhage	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Retinal vein occlusion	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Vision blurred	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Visual acuity reduced	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Vitreous haemorrhage	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Gastrointestinal disorders
Abdominal distension	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Abdominal hernia	3/2419 (0.1%)		1/2402 (0%)		4/4821 (0.1%)
Abdominal pain	6/2419 (0.2%)		8/2402 (0.3%)		14/4821 (0.3%)
Abdominal pain lower	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Abdominal pain upper	3/2419 (0.1%)		4/2402 (0.2%)		7/4821 (0.1%)
Abdominal wall haematoma	2/2419 (0.1%)		2/2402 (0.1%)		4/4821 (0.1%)
Anal fissure	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Anal fistula	1/2419 (0%)		3/2402 (0.1%)		4/4821 (0.1%)
Anal haemorrhage	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Anal incontinence	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Appendiceal mucocoele	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Ascites	8/2419 (0.3%)		9/2402 (0.4%)		17/4821 (0.4%)
Chronic gastritis	2/2419 (0.1%)		3/2402 (0.1%)		5/4821 (0.1%)
Colitis	5/2419 (0.2%)		3/2402 (0.1%)		8/4821 (0.2%)
Colitis ischaemic	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Colitis microscopic	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Colitis ulcerative	3/2419 (0.1%)		0/2402 (0%)		3/4821 (0.1%)
Constipation	2/2419 (0.1%)		6/2402 (0.2%)		8/4821 (0.2%)
Crohn's disease	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Dental caries	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Diabetic gastroenteropathy	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Diaphragmatic hernia	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Diarrhoea	13/2419 (0.5%)		14/2402 (0.6%)		27/4821 (0.6%)
Dieulafoy's vascular malformation	0/2419 (0%)		3/2402 (0.1%)		3/4821 (0.1%)
Diverticular perforation	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Diverticulum	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Diverticulum intestinal	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Diverticulum intestinal haemorrhagic	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Duodenal polyp	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Duodenal ulcer	3/2419 (0.1%)		4/2402 (0.2%)		7/4821 (0.1%)
Duodenal ulcer haemorrhage	1/2419 (0%)		3/2402 (0.1%)		4/4821 (0.1%)
Duodenitis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Dyspepsia	3/2419 (0.1%)		2/2402 (0.1%)		5/4821 (0.1%)
Dysphagia	2/2419 (0.1%)		3/2402 (0.1%)		5/4821 (0.1%)
Enteritis	3/2419 (0.1%)		1/2402 (0%)		4/4821 (0.1%)
Erosive oesophagitis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Faecaloma	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Faeces discoloured	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Femoral hernia	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Gastric disorder	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Gastric haemorrhage	1/2419 (0%)		3/2402 (0.1%)		4/4821 (0.1%)
Gastric polyps	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Gastric ulcer	8/2419 (0.3%)		3/2402 (0.1%)		11/4821 (0.2%)
Gastric ulcer haemorrhage	2/2419 (0.1%)		4/2402 (0.2%)		6/4821 (0.1%)
Gastritis	3/2419 (0.1%)		7/2402 (0.3%)		10/4821 (0.2%)
Gastritis erosive	1/2419 (0%)		7/2402 (0.3%)		8/4821 (0.2%)
Gastritis haemorrhagic	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Gastrointestinal haemorrhage	29/2419 (1.2%)		32/2402 (1.3%)		61/4821 (1.3%)
Gastrointestinal perforation	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Gastrointestinal polyp haemorrhage	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Gastrointestinal ulcer	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Gastrointestinal ulcer haemorrhage	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Gastrointestinal wall thickening	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Gastrooesophageal reflux disease	4/2419 (0.2%)		3/2402 (0.1%)		7/4821 (0.1%)
Haematemesis	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Haematochezia	4/2419 (0.2%)		3/2402 (0.1%)		7/4821 (0.1%)
Haemorrhagic erosive gastritis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Haemorrhoidal haemorrhage	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Haemorrhoids	5/2419 (0.2%)		3/2402 (0.1%)		8/4821 (0.2%)
Hiatus hernia	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Ileus	2/2419 (0.1%)		3/2402 (0.1%)		5/4821 (0.1%)
Ileus paralytic	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Impaired gastric emptying	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Incarcerated inguinal hernia	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Incarcerated umbilical hernia	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Inguinal hernia	10/2419 (0.4%)		13/2402 (0.5%)		23/4821 (0.5%)
Inguinal hernia, obstructive	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Intestinal haemorrhage	1/2419 (0%)		3/2402 (0.1%)		4/4821 (0.1%)
Intestinal infarction	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Intestinal ischaemia	3/2419 (0.1%)		3/2402 (0.1%)		6/4821 (0.1%)
Intestinal obstruction	5/2419 (0.2%)		5/2402 (0.2%)		10/4821 (0.2%)
Intestinal perforation	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Intestinal polyp	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Intestinal strangulation	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Intra-abdominal haematoma	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Intra-abdominal haemorrhage	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Irritable bowel syndrome	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Large intestinal obstruction	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Large intestine perforation	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Large intestine polyp	5/2419 (0.2%)		4/2402 (0.2%)		9/4821 (0.2%)
Lower gastrointestinal haemorrhage	1/2419 (0%)		6/2402 (0.2%)		7/4821 (0.1%)
Mallory-Weiss syndrome	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Melaena	7/2419 (0.3%)		6/2402 (0.2%)		13/4821 (0.3%)
Mouth haemorrhage	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Nausea	12/2419 (0.5%)		5/2402 (0.2%)		17/4821 (0.4%)
Obstructive pancreatitis	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Oesophageal haemorrhage	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Oesophageal perforation	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Oesophageal ulcer	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Pancreatitis	2/2419 (0.1%)		3/2402 (0.1%)		5/4821 (0.1%)
Pancreatitis acute	5/2419 (0.2%)		9/2402 (0.4%)		14/4821 (0.3%)
Pancreatitis chronic	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Pancreatitis necrotising	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Pancreatitis relapsing	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Peptic ulcer haemorrhage	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Peritoneal haemorrhage	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Portal hypertensive gastropathy	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Proctitis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Rectal haemorrhage	9/2419 (0.4%)		4/2402 (0.2%)		13/4821 (0.3%)
Rectal polyp	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Rectal prolapse	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Retroperitoneal haematoma	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Salivary gland calculus	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Small intestinal haemorrhage	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Small intestinal obstruction	7/2419 (0.3%)		5/2402 (0.2%)		12/4821 (0.2%)
Subileus	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Toothache	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Umbilical hernia	2/2419 (0.1%)		2/2402 (0.1%)		4/4821 (0.1%)
Upper gastrointestinal haemorrhage	7/2419 (0.3%)		11/2402 (0.5%)		18/4821 (0.4%)
Varices oesophageal	3/2419 (0.1%)		2/2402 (0.1%)		5/4821 (0.1%)
Vomiting	9/2419 (0.4%)		11/2402 (0.5%)		20/4821 (0.4%)
General disorders
Adverse drug reaction	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Asthenia	12/2419 (0.5%)		21/2402 (0.9%)		33/4821 (0.7%)
Cardiac death	3/2419 (0.1%)		6/2402 (0.2%)		9/4821 (0.2%)
Catheter site haemorrhage	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Chest discomfort	4/2419 (0.2%)		1/2402 (0%)		5/4821 (0.1%)
Chest pain	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Concomitant disease progression	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Condition aggravated	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Death	34/2419 (1.4%)		23/2402 (1%)		57/4821 (1.2%)
Disuse syndrome	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Euthanasia	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Fatigue	4/2419 (0.2%)		4/2402 (0.2%)		8/4821 (0.2%)
Gait disturbance	3/2419 (0.1%)		3/2402 (0.1%)		6/4821 (0.1%)
General physical health deterioration	9/2419 (0.4%)		5/2402 (0.2%)		14/4821 (0.3%)
Hyperthermia	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Ill-defined disorder	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Impaired healing	3/2419 (0.1%)		0/2402 (0%)		3/4821 (0.1%)
Impaired self-care	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Implant site haemorrhage	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Incarcerated hernia	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Influenza like illness	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Lithiasis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Malaise	2/2419 (0.1%)		2/2402 (0.1%)		4/4821 (0.1%)
Mass	1/2419 (0%)		3/2402 (0.1%)		4/4821 (0.1%)
Medical device discomfort	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Multiple organ dysfunction syndrome	10/2419 (0.4%)		7/2402 (0.3%)		17/4821 (0.4%)
Necrosis	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Non-cardiac chest pain	42/2419 (1.7%)		37/2402 (1.5%)		79/4821 (1.6%)
Oedema	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Oedema peripheral	6/2419 (0.2%)		12/2402 (0.5%)		18/4821 (0.4%)
Pain	1/2419 (0%)		3/2402 (0.1%)		4/4821 (0.1%)
Peripheral swelling	1/2419 (0%)		3/2402 (0.1%)		4/4821 (0.1%)
Pyrexia	8/2419 (0.3%)		13/2402 (0.5%)		21/4821 (0.4%)
Stenosis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Sudden cardiac death	15/2419 (0.6%)		16/2402 (0.7%)		31/4821 (0.6%)
Sudden death	21/2419 (0.9%)		22/2402 (0.9%)		43/4821 (0.9%)
Surgical failure	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Swelling	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Systemic inflammatory response syndrome	1/2419 (0%)		5/2402 (0.2%)		6/4821 (0.1%)
Treatment noncompliance	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Ulcer haemorrhage	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Unevaluable event	0/2419 (0%)		3/2402 (0.1%)		3/4821 (0.1%)
Vascular stent stenosis	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Hepatobiliary disorders
Bile duct obstruction	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Bile duct stenosis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Bile duct stone	5/2419 (0.2%)		4/2402 (0.2%)		9/4821 (0.2%)
Biliary colic	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Biliary dyskinesia	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Cholangitis	4/2419 (0.2%)		4/2402 (0.2%)		8/4821 (0.2%)
Cholangitis acute	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Cholecystitis	14/2419 (0.6%)		11/2402 (0.5%)		25/4821 (0.5%)
Cholecystitis acute	8/2419 (0.3%)		9/2402 (0.4%)		17/4821 (0.4%)
Cholecystitis chronic	5/2419 (0.2%)		2/2402 (0.1%)		7/4821 (0.1%)
Cholelithiasis	17/2419 (0.7%)		19/2402 (0.8%)		36/4821 (0.7%)
Cholelithiasis migration	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Cholestasis	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Chronic hepatic failure	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Cirrhosis alcoholic	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Cryptogenic cirrhosis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Gallbladder disorder	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Gallbladder rupture	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Haemobilia	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Hepatic cirrhosis	4/2419 (0.2%)		6/2402 (0.2%)		10/4821 (0.2%)
Hepatic cyst	5/2419 (0.2%)		6/2402 (0.2%)		11/4821 (0.2%)
Hepatic failure	3/2419 (0.1%)		4/2402 (0.2%)		7/4821 (0.1%)
Hepatic function abnormal	5/2419 (0.2%)		5/2402 (0.2%)		10/4821 (0.2%)
Hepatic lesion	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Hepatic mass	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Hepatic steatosis	10/2419 (0.4%)		10/2402 (0.4%)		20/4821 (0.4%)
Hepatitis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Hepatitis acute	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Hepatobiliary disease	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Hepatocellular injury	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Hepatomegaly	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Hepatorenal syndrome	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Hepatosplenomegaly	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Jaundice	8/2419 (0.3%)		5/2402 (0.2%)		13/4821 (0.3%)
Jaundice cholestatic	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Liver disorder	1/2419 (0%)		4/2402 (0.2%)		5/4821 (0.1%)
Liver injury	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Nonalcoholic fatty liver disease	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Portal hypertension	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Portal vein thrombosis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Primary biliary cholangitis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Steatohepatitis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Immune system disorders
Anaphylactic reaction	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Anaphylactic shock	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Drug hypersensitivity	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Food allergy	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Sarcoidosis	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Infections and infestations
Abdominal sepsis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Abdominal wall abscess	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Abscess jaw	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Abscess limb	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Abscess neck	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Abscess oral	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Acinetobacter bacteraemia	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Acute endocarditis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Amoebiasis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Anal abscess	0/2419 (0%)		3/2402 (0.1%)		3/4821 (0.1%)
Appendicitis	2/2419 (0.1%)		4/2402 (0.2%)		6/4821 (0.1%)
Arthritis bacterial	3/2419 (0.1%)		6/2402 (0.2%)		9/4821 (0.2%)
Arthritis infective	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Aspergillus infection	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Bacteraemia	6/2419 (0.2%)		7/2402 (0.3%)		13/4821 (0.3%)
Bacterial disease carrier	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Bacterial infection	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Bacterial rhinitis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Bacterial sepsis	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Beta haemolytic streptococcal infection	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Biliary sepsis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Biliary tract infection	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Bone abscess	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Bronchiolitis	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Bronchitis	32/2419 (1.3%)		41/2402 (1.7%)		73/4821 (1.5%)
Bronchitis viral	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Campylobacter infection	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Cellulitis	30/2419 (1.2%)		25/2402 (1%)		55/4821 (1.1%)
Chest wall abscess	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Cholangitis infective	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Chronic sinusitis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Clostridium colitis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Clostridium difficile colitis	6/2419 (0.2%)		3/2402 (0.1%)		9/4821 (0.2%)
Clostridium difficile infection	3/2419 (0.1%)		2/2402 (0.1%)		5/4821 (0.1%)
Colonic abscess	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Complicated appendicitis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Cystitis	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Cystitis bacterial	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Cystitis escherichia	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Cytomegalovirus infection	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Dengue fever	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Device related infection	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Diabetic foot infection	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Diabetic gangrene	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Diarrhoea infectious	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Diverticulitis	3/2419 (0.1%)		9/2402 (0.4%)		12/4821 (0.2%)
Eczema infected	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Embolic pneumonia	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Endocarditis	2/2419 (0.1%)		3/2402 (0.1%)		5/4821 (0.1%)
Enteritis infectious	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Enterococcal bacteraemia	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Enterococcal sepsis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Epididymitis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Epiglottitis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Erysipelas	11/2419 (0.5%)		7/2402 (0.3%)		18/4821 (0.4%)
Escherichia bacteraemia	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Escherichia sepsis	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Escherichia urinary tract infection	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Gangrene	3/2419 (0.1%)		3/2402 (0.1%)		6/4821 (0.1%)
Gastroenteritis	21/2419 (0.9%)		16/2402 (0.7%)		37/4821 (0.8%)
Gastroenteritis bacterial	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Gastroenteritis clostridial	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Gastroenteritis norovirus	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Gastroenteritis salmonella	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Gastroenteritis viral	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Gastrointestinal viral infection	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Genital herpes zoster	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Haematoma infection	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Helicobacter infection	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Hepatitis E	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Herpes zoster	2/2419 (0.1%)		4/2402 (0.2%)		6/4821 (0.1%)
Hordeolum	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Human anaplasmosis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Infected skin ulcer	2/2419 (0.1%)		4/2402 (0.2%)		6/4821 (0.1%)
Infection	1/2419 (0%)		3/2402 (0.1%)		4/4821 (0.1%)
Infectious pleural effusion	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Infective exacerbation of bronchiectasis	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Infective exacerbation of chronic obstructive airways disease	2/2419 (0.1%)		3/2402 (0.1%)		5/4821 (0.1%)
Influenza	16/2419 (0.7%)		11/2402 (0.5%)		27/4821 (0.6%)
Intervertebral discitis	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Intestinal sepsis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Intracranial infection	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Klebsiella sepsis	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Labyrinthitis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Laryngitis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Liver abscess	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Localised infection	4/2419 (0.2%)		5/2402 (0.2%)		9/4821 (0.2%)
Lower respiratory tract infection	11/2419 (0.5%)		12/2402 (0.5%)		23/4821 (0.5%)
Lower respiratory tract infection viral	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Lung abscess	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Lung infection	12/2419 (0.5%)		11/2402 (0.5%)		23/4821 (0.5%)
Lymphangitis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Mediastinitis	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Medical device site infection	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Meningitis enterococcal	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Nasopharyngitis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Necrotising fasciitis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Nosocomial infection	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Oesophageal candidiasis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Ophthalmic herpes zoster	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Oral candidiasis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Oral herpes	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Orchitis	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Osteomyelitis	7/2419 (0.3%)		3/2402 (0.1%)		10/4821 (0.2%)
Otitis media	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Pelvic abscess	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Periodontitis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Peritonitis	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Peritonitis bacterial	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Pharyngitis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Pneumococcal sepsis	3/2419 (0.1%)		0/2402 (0%)		3/4821 (0.1%)
Pneumonia	162/2419 (6.7%)		178/2402 (7.4%)		340/4821 (7.1%)
Pneumonia bacterial	4/2419 (0.2%)		5/2402 (0.2%)		9/4821 (0.2%)
Pneumonia influenzal	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Pneumonia mycoplasmal	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Pneumonia pneumococcal	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Pneumonia respiratory syncytial viral	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Pneumonia streptococcal	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Pneumonia viral	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Post procedural infection	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Postoperative wound infection	3/2419 (0.1%)		3/2402 (0.1%)		6/4821 (0.1%)
Pseudomembranous colitis	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Pulmonary sepsis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Pulmonary tuberculosis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Pyelonephritis	3/2419 (0.1%)		3/2402 (0.1%)		6/4821 (0.1%)
Pyelonephritis acute	4/2419 (0.2%)		3/2402 (0.1%)		7/4821 (0.1%)
Pyelonephritis chronic	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Rectal abscess	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Renal abscess	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Respiratory moniliasis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Respiratory syncytial virus bronchitis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Respiratory syncytial virus infection	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Respiratory tract infection	19/2419 (0.8%)		21/2402 (0.9%)		40/4821 (0.8%)
Respiratory tract infection bacterial	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Respiratory tract infection viral	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Salmonellosis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Sepsis	34/2419 (1.4%)		37/2402 (1.5%)		71/4821 (1.5%)
Septic encephalopathy	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Septic necrosis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Septic shock	21/2419 (0.9%)		16/2402 (0.7%)		37/4821 (0.8%)
Severe acute respiratory syndrome	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Shunt infection	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Skin bacterial infection	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Skin infection	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Soft tissue infection	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Staphylococcal bacteraemia	0/2419 (0%)		3/2402 (0.1%)		3/4821 (0.1%)
Staphylococcal infection	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Staphylococcal sepsis	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Streptococcal bacteraemia	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Streptococcal sepsis	0/2419 (0%)		3/2402 (0.1%)		3/4821 (0.1%)
Syphilis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Tooth abscess	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Tracheobronchitis	2/2419 (0.1%)		2/2402 (0.1%)		4/4821 (0.1%)
Tuberculosis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Tuberculous pleurisy	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Tubo-ovarian abscess	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Upper respiratory tract infection	5/2419 (0.2%)		6/2402 (0.2%)		11/4821 (0.2%)
Urethritis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Urinary tract infection	54/2419 (2.2%)		68/2402 (2.8%)		122/4821 (2.5%)
Urosepsis	11/2419 (0.5%)		14/2402 (0.6%)		25/4821 (0.5%)
Vestibular neuronitis	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Viral infection	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Viral upper respiratory tract infection	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Wound abscess	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Wound infection	2/2419 (0.1%)		3/2402 (0.1%)		5/4821 (0.1%)
Injury, poisoning and procedural complications
Abdominal injury	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Accident	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Accidental overdose	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Acetabulum fracture	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Alcohol poisoning	0/2419 (0%)		3/2402 (0.1%)		3/4821 (0.1%)
Anaemia postoperative	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Anastomotic leak	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Anastomotic ulcer	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Animal bite	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Ankle fracture	7/2419 (0.3%)		4/2402 (0.2%)		11/4821 (0.2%)
Arterial bypass occlusion	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Arteriovenous fistula thrombosis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Avulsion fracture	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Bone contusion	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Brain herniation	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Carbon monoxide poisoning	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Cardiac function disturbance postoperative	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Cervical vertebral fracture	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Chest injury	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Clavicle fracture	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Comminuted fracture	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Complications of transplanted kidney	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Concussion	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Contusion	4/2419 (0.2%)		3/2402 (0.1%)		7/4821 (0.1%)
Coronary bypass stenosis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Craniocerebral injury	3/2419 (0.1%)		4/2402 (0.2%)		7/4821 (0.1%)
Cystitis radiation	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Extra dose administered	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Extradural haematoma	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Eye injury	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Facial bones fracture	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Fall	33/2419 (1.4%)		26/2402 (1.1%)		59/4821 (1.2%)
Femoral neck fracture	5/2419 (0.2%)		8/2402 (0.3%)		13/4821 (0.3%)
Femur fracture	11/2419 (0.5%)		20/2402 (0.8%)		31/4821 (0.6%)
Foot fracture	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Fracture	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Fractured coccyx	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Gastrointestinal stoma complication	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Hand fracture	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Head injury	5/2419 (0.2%)		6/2402 (0.2%)		11/4821 (0.2%)
Hip fracture	13/2419 (0.5%)		14/2402 (0.6%)		27/4821 (0.6%)
Humerus fracture	5/2419 (0.2%)		7/2402 (0.3%)		12/4821 (0.2%)
Hypobarism	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Incision site haematoma	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Incisional hernia	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Injury	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Joint dislocation	2/2419 (0.1%)		3/2402 (0.1%)		5/4821 (0.1%)
Ligament injury	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Ligament sprain	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Limb crushing injury	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Limb injury	4/2419 (0.2%)		1/2402 (0%)		5/4821 (0.1%)
Lower limb fracture	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Lumbar vertebral fracture	3/2419 (0.1%)		2/2402 (0.1%)		5/4821 (0.1%)
Meniscus injury	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Multiple injuries	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Muscle strain	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Nerve root injury cervical	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Overdose	4/2419 (0.2%)		2/2402 (0.1%)		6/4821 (0.1%)
Patella fracture	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Pelvic fracture	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Periprosthetic fracture	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Post procedural complication	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Post procedural haematoma	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Post procedural haemorrhage	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Post procedural myocardial infarction	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Post-traumatic pain	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Postoperative hypotension	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Postoperative respiratory failure	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Postoperative wound complication	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Procedural pneumothorax	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Procedural vomiting	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Pubis fracture	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Radiation proctitis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Radius fracture	7/2419 (0.3%)		1/2402 (0%)		8/4821 (0.2%)
Respiratory fume inhalation disorder	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Rib fracture	11/2419 (0.5%)		6/2402 (0.2%)		17/4821 (0.4%)
Road traffic accident	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Scapula fracture	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Sedation complication	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Skin abrasion	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Skin laceration	6/2419 (0.2%)		2/2402 (0.1%)		8/4821 (0.2%)
Spinal compression fracture	3/2419 (0.1%)		8/2402 (0.3%)		11/4821 (0.2%)
Spinal fracture	6/2419 (0.2%)		2/2402 (0.1%)		8/4821 (0.2%)
Splenic rupture	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Stomal hernia	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Subdural haematoma	7/2419 (0.3%)		8/2402 (0.3%)		15/4821 (0.3%)
Subdural haemorrhage	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Tendon rupture	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Thoracic vertebral fracture	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Tibia fracture	2/2419 (0.1%)		2/2402 (0.1%)		4/4821 (0.1%)
Toxicity to various agents	2/2419 (0.1%)		8/2402 (0.3%)		10/4821 (0.2%)
Traumatic haematoma	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Traumatic haemothorax	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Traumatic intracranial haemorrhage	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Traumatic liver injury	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Ulna fracture	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Upper limb fracture	2/2419 (0.1%)		2/2402 (0.1%)		4/4821 (0.1%)
Vascular graft occlusion	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Vascular pseudoaneurysm	1/2419 (0%)		3/2402 (0.1%)		4/4821 (0.1%)
Vascular pseudoaneurysm ruptured	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Wound	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Wound complication	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Investigations
Alanine aminotransferase increased	2/2419 (0.1%)		2/2402 (0.1%)		4/4821 (0.1%)
Anticoagulation drug level above therapeutic	2/2419 (0.1%)		4/2402 (0.2%)		6/4821 (0.1%)
Aspartate aminotransferase increased	4/2419 (0.2%)		2/2402 (0.1%)		6/4821 (0.1%)
Bleeding time abnormal	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Blood alkaline phosphatase increased	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Blood bilirubin increased	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Blood creatine phosphokinase increased	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Blood creatinine increased	1/2419 (0%)		4/2402 (0.2%)		5/4821 (0.1%)
Blood glucose abnormal	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Blood glucose decreased	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Blood glucose fluctuation	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Blood glucose increased	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Blood osmolarity decreased	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Blood pressure decreased	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Blood pressure increased	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Blood sodium decreased	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Blood urea increased	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Brain natriuretic peptide increased	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Cardiac output decreased	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Coagulation time prolonged	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Electrocardiogram QT prolonged	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Electrocardiogram repolarisation abnormality	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
General physical condition abnormal	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Glomerular filtration rate decreased	0/2419 (0%)		3/2402 (0.1%)		3/4821 (0.1%)
Haemoglobin decreased	0/2419 (0%)		3/2402 (0.1%)		3/4821 (0.1%)
Heart rate decreased	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Heart rate irregular	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Hepatic enzyme increased	7/2419 (0.3%)		6/2402 (0.2%)		13/4821 (0.3%)
Inflammatory marker increased	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Influenza virus test positive	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
International normalised ratio increased	3/2419 (0.1%)		2/2402 (0.1%)		5/4821 (0.1%)
Lipase increased	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Myocardial necrosis marker increased	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Platelet count decreased	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Precancerous cells present	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Prostatic specific antigen increased	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Pulse absent	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Respiratory rate increased	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Transaminases increased	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Troponin I increased	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Troponin T increased	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Troponin increased	0/2419 (0%)		4/2402 (0.2%)		4/4821 (0.1%)
Urine output decreased	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Ventilation/perfusion scan abnormal	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Visual field tests abnormal	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Weight decreased	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Metabolism and nutrition disorders
Cachexia	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Cardiometabolic syndrome	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Decreased appetite	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Dehydration	18/2419 (0.7%)		26/2402 (1.1%)		44/4821 (0.9%)
Diabetes mellitus	9/2419 (0.4%)		8/2402 (0.3%)		17/4821 (0.4%)
Diabetes mellitus inadequate control	4/2419 (0.2%)		3/2402 (0.1%)		7/4821 (0.1%)
Diabetic complication	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Diabetic ketoacidosis	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Diabetic metabolic decompensation	3/2419 (0.1%)		9/2402 (0.4%)		12/4821 (0.2%)
Electrolyte imbalance	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Failure to thrive	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Fluid overload	8/2419 (0.3%)		8/2402 (0.3%)		16/4821 (0.3%)
Fluid retention	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Folate deficiency	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Gout	5/2419 (0.2%)		11/2402 (0.5%)		16/4821 (0.3%)
Haemochromatosis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Hyperammonaemia	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Hypercalcaemia	2/2419 (0.1%)		2/2402 (0.1%)		4/4821 (0.1%)
Hypercholesterolaemia	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Hyperglycaemia	10/2419 (0.4%)		16/2402 (0.7%)		26/4821 (0.5%)
Hyperglycaemic hyperosmolar nonketotic syndrome	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Hyperkalaemia	19/2419 (0.8%)		42/2402 (1.7%)		61/4821 (1.3%)
Hypernatraemia	3/2419 (0.1%)		0/2402 (0%)		3/4821 (0.1%)
Hyperuricaemia	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Hypoalbuminaemia	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Hypocalcaemia	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Hypoglycaemia	20/2419 (0.8%)		6/2402 (0.2%)		26/4821 (0.5%)
Hypokalaemia	8/2419 (0.3%)		14/2402 (0.6%)		22/4821 (0.5%)
Hypomagnesaemia	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Hyponatraemia	17/2419 (0.7%)		17/2402 (0.7%)		34/4821 (0.7%)
Hypoosmolar state	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Hypophosphataemia	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Hypovolaemia	4/2419 (0.2%)		1/2402 (0%)		5/4821 (0.1%)
Iron deficiency	0/2419 (0%)		4/2402 (0.2%)		4/4821 (0.1%)
Ketoacidosis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Lactic acidosis	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Malnutrition	0/2419 (0%)		3/2402 (0.1%)		3/4821 (0.1%)
Marasmus	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Metabolic acidosis	3/2419 (0.1%)		3/2402 (0.1%)		6/4821 (0.1%)
Type 2 diabetes mellitus	5/2419 (0.2%)		8/2402 (0.3%)		13/4821 (0.3%)
Musculoskeletal and connective tissue disorders
Acquired claw toe	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Arthralgia	4/2419 (0.2%)		7/2402 (0.3%)		11/4821 (0.2%)
Arthritis	5/2419 (0.2%)		3/2402 (0.1%)		8/4821 (0.2%)
Back pain	11/2419 (0.5%)		11/2402 (0.5%)		22/4821 (0.5%)
Bursitis	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
CREST syndrome	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Chest wall haematoma	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Chondrocalcinosis	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Costochondritis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Dactylitis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Dupuytren's contracture	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Exostosis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Fibromyalgia	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Flank pain	3/2419 (0.1%)		0/2402 (0%)		3/4821 (0.1%)
Foot deformity	3/2419 (0.1%)		1/2402 (0%)		4/4821 (0.1%)
Gouty arthritis	3/2419 (0.1%)		1/2402 (0%)		4/4821 (0.1%)
Haemarthrosis	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Intervertebral disc degeneration	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Intervertebral disc disorder	0/2419 (0%)		3/2402 (0.1%)		3/4821 (0.1%)
Intervertebral disc protrusion	9/2419 (0.4%)		5/2402 (0.2%)		14/4821 (0.3%)
Joint effusion	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Kyphosis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Lumbar spinal stenosis	4/2419 (0.2%)		5/2402 (0.2%)		9/4821 (0.2%)
Mobility decreased	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Muscle spasms	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Muscular weakness	3/2419 (0.1%)		4/2402 (0.2%)		7/4821 (0.1%)
Musculoskeletal chest pain	0/2419 (0%)		3/2402 (0.1%)		3/4821 (0.1%)
Musculoskeletal pain	2/2419 (0.1%)		2/2402 (0.1%)		4/4821 (0.1%)
Myalgia	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Myositis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Myositis ossificans	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Neck pain	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Osteitis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Osteitis deformans	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Osteoarthritis	31/2419 (1.3%)		28/2402 (1.2%)		59/4821 (1.2%)
Osteochondrosis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Osteonecrosis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Osteoporosis	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Pain in extremity	2/2419 (0.1%)		6/2402 (0.2%)		8/4821 (0.2%)
Pathological fracture	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Periarthritis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Periostitis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Polymyalgia rheumatica	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Pseudarthrosis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Rheumatoid arthritis	0/2419 (0%)		3/2402 (0.1%)		3/4821 (0.1%)
Rotator cuff syndrome	6/2419 (0.2%)		3/2402 (0.1%)		9/4821 (0.2%)
Scleroderma	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Spinal osteoarthritis	6/2419 (0.2%)		4/2402 (0.2%)		10/4821 (0.2%)
Spinal pain	3/2419 (0.1%)		6/2402 (0.2%)		9/4821 (0.2%)
Spinal stenosis	5/2419 (0.2%)		6/2402 (0.2%)		11/4821 (0.2%)
Spondylolisthesis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Synovial cyst	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Tenosynovitis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute lymphocytic leukaemia	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Acute myeloid leukaemia	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Acute promyelocytic leukaemia	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Adenocarcinoma	0/2419 (0%)		3/2402 (0.1%)		3/4821 (0.1%)
Adenocarcinoma gastric	3/2419 (0.1%)		1/2402 (0%)		4/4821 (0.1%)
Adenocarcinoma of colon	3/2419 (0.1%)		4/2402 (0.2%)		7/4821 (0.1%)
Anal cancer stage 0	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
B-cell lymphoma	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Basal cell carcinoma	11/2419 (0.5%)		11/2402 (0.5%)		22/4821 (0.5%)
Benign gastrointestinal neoplasm	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Benign lung neoplasm	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Benign pancreatic neoplasm	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Bile duct cancer	1/2419 (0%)		3/2402 (0.1%)		4/4821 (0.1%)
Bladder cancer	2/2419 (0.1%)		5/2402 (0.2%)		7/4821 (0.1%)
Bladder neoplasm	2/2419 (0.1%)		2/2402 (0.1%)		4/4821 (0.1%)
Bladder transitional cell carcinoma	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Bone cancer	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Bowen's disease	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Brain neoplasm	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Brain neoplasm malignant	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Breast angiosarcoma	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Breast cancer	6/2419 (0.2%)		8/2402 (0.3%)		14/4821 (0.3%)
Breast neoplasm	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Bronchial carcinoma	4/2419 (0.2%)		1/2402 (0%)		5/4821 (0.1%)
Carcinoma in situ of skin	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Central nervous system lymphoma	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Cholangiocarcinoma	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Chronic lymphocytic leukaemia	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Chronic myeloid leukaemia	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Clear cell renal cell carcinoma	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Colon adenoma	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Colon cancer	5/2419 (0.2%)		4/2402 (0.2%)		9/4821 (0.2%)
Colon cancer metastatic	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Colon neoplasm	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Colorectal cancer	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Diffuse large B-cell lymphoma	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Endometrial adenocarcinoma	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Endometrial cancer	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Fibroma	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Gallbladder cancer	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Gallbladder neoplasm	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Gastric cancer	3/2419 (0.1%)		4/2402 (0.2%)		7/4821 (0.1%)
Gastric neoplasm	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Gastrointestinal carcinoma	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Gastrointestinal neoplasm	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Gastrointestinal stromal tumour	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Gastrointestinal tract adenoma	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Glioblastoma	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Haemangioma of liver	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Hepatic cancer	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Hepatic cancer metastatic	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Hepatic neoplasm	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Hepatocellular carcinoma	5/2419 (0.2%)		2/2402 (0.1%)		7/4821 (0.1%)
Hormone-refractory prostate cancer	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Intestinal adenocarcinoma	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Invasive breast carcinoma	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Invasive lobular breast carcinoma	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Invasive papillary breast carcinoma	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Kaposi's sarcoma	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Laryngeal cancer	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Laryngeal squamous cell carcinoma	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Leiomyoma	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Lip and/or oral cavity cancer	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Lip squamous cell carcinoma	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Lipoma	3/2419 (0.1%)		2/2402 (0.1%)		5/4821 (0.1%)
Lung adenocarcinoma	1/2419 (0%)		3/2402 (0.1%)		4/4821 (0.1%)
Lung cancer metastatic	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Lung carcinoma cell type unspecified stage II	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Lung neoplasm	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Lung neoplasm malignant	8/2419 (0.3%)		10/2402 (0.4%)		18/4821 (0.4%)
Lymphoma	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Lymphoproliferative disorder	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Malignant mediastinal neoplasm	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Malignant melanoma	7/2419 (0.3%)		6/2402 (0.2%)		13/4821 (0.3%)
Malignant neoplasm of unknown primary site	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Malignant pleural effusion	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Mantle cell lymphoma	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Mediastinum neoplasm	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Meningioma	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Mesothelioma	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Metastases to bone	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Metastases to central nervous system	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Metastases to liver	3/2419 (0.1%)		4/2402 (0.2%)		7/4821 (0.1%)
Metastases to lung	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Metastases to lymph nodes	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Metastasis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Metastatic carcinoma of the bladder	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Metastatic lymphoma	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Metastatic malignant melanoma	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Metastatic squamous cell carcinoma	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Monoclonal gammopathy	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Myelodysplastic syndrome	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Myeloid leukaemia	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Myeloproliferative neoplasm	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Neoplasm malignant	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Neoplasm skin	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Non-Hodgkin's lymphoma	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Non-small cell lung cancer	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Oesophageal adenocarcinoma	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Oesophageal carcinoma	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Oncologic complication	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Oral haemangioma	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Oropharyngeal cancer	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Oropharyngeal squamous cell carcinoma	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Ovarian cancer	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Ovarian epithelial cancer	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Pancreatic carcinoma	4/2419 (0.2%)		2/2402 (0.1%)		6/4821 (0.1%)
Pancreatic neoplasm	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Papillary thyroid cancer	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Papilloma	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Parathyroid tumour benign	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Penile cancer	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Plasma cell myeloma	0/2419 (0%)		3/2402 (0.1%)		3/4821 (0.1%)
Prostate cancer	7/2419 (0.3%)		8/2402 (0.3%)		15/4821 (0.3%)
Prostate cancer metastatic	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Prostatic adenoma	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Rectal adenocarcinoma	2/2419 (0.1%)		3/2402 (0.1%)		5/4821 (0.1%)
Rectal cancer	6/2419 (0.2%)		4/2402 (0.2%)		10/4821 (0.2%)
Rectal cancer metastatic	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Rectal cancer recurrent	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Rectal neoplasm	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Renal cancer	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Renal cell carcinoma	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Renal neoplasm	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Sarcoma uterus	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Schwannoma	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Seborrhoeic keratosis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Skin cancer	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Skin neoplasm bleeding	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Small cell lung cancer	2/2419 (0.1%)		2/2402 (0.1%)		4/4821 (0.1%)
Squamous cell carcinoma	6/2419 (0.2%)		8/2402 (0.3%)		14/4821 (0.3%)
Squamous cell carcinoma of lung	4/2419 (0.2%)		1/2402 (0%)		5/4821 (0.1%)
Transitional cell carcinoma	0/2419 (0%)		4/2402 (0.2%)		4/4821 (0.1%)
Transitional cell carcinoma recurrent	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Tumour compression	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Tumour embolism	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Tumour haemorrhage	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Ureteral neoplasm	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Ureteric cancer	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Uterine cancer	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Uterine leiomyoma	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Vaginal adenocarcinoma	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Vaginal cancer	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Waldenstrom's macroglobulinaemia	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Nervous system disorders
Altered state of consciousness	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Amyotrophic lateral sclerosis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Aphasia	1/2419 (0%)		4/2402 (0.2%)		5/4821 (0.1%)
Ataxia	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Brain hypoxia	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Brain injury	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Brain oedema	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Brain stem stroke	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Carotid artery aneurysm	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Carotid artery disease	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Carotid artery stenosis	9/2419 (0.4%)		7/2402 (0.3%)		16/4821 (0.3%)
Carpal tunnel syndrome	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Central nervous system lesion	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Cerebellar haematoma	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Cerebellar infarction	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Cerebellar ischaemia	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Cerebral arteriosclerosis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Cerebral artery embolism	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Cerebral cyst	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Cerebral haemorrhage	5/2419 (0.2%)		6/2402 (0.2%)		11/4821 (0.2%)
Cerebral infarction	17/2419 (0.7%)		18/2402 (0.7%)		35/4821 (0.7%)
Cerebral ischaemia	3/2419 (0.1%)		3/2402 (0.1%)		6/4821 (0.1%)
Cerebral thrombosis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Cerebrospinal fluid leakage	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Cerebrovascular accident	39/2419 (1.6%)		42/2402 (1.7%)		81/4821 (1.7%)
Cerebrovascular disorder	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Cerebrovascular insufficiency	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Cervical radiculopathy	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Cervicobrachial syndrome	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Cognitive disorder	7/2419 (0.3%)		2/2402 (0.1%)		9/4821 (0.2%)
Coma	1/2419 (0%)		4/2402 (0.2%)		5/4821 (0.1%)
Dementia	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Dementia Alzheimer's type	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Dementia with Lewy bodies	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Depressed level of consciousness	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Diabetic ketoacidotic hyperglycaemic coma	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Diabetic neuropathy	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Dizziness	17/2419 (0.7%)		11/2402 (0.5%)		28/4821 (0.6%)
Dysarthria	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Embolic stroke	5/2419 (0.2%)		4/2402 (0.2%)		9/4821 (0.2%)
Encephalopathy	1/2419 (0%)		6/2402 (0.2%)		7/4821 (0.1%)
Epilepsy	0/2419 (0%)		3/2402 (0.1%)		3/4821 (0.1%)
Facial paralysis	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Generalised tonic-clonic seizure	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Guillain-Barre syndrome	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Haemorrhage intracranial	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Haemorrhagic cerebral infarction	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Haemorrhagic stroke	3/2419 (0.1%)		3/2402 (0.1%)		6/4821 (0.1%)
Haemorrhagic transformation stroke	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Headache	3/2419 (0.1%)		10/2402 (0.4%)		13/4821 (0.3%)
Hemiparesis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Hemiplegia	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Hepatic encephalopathy	1/2419 (0%)		5/2402 (0.2%)		6/4821 (0.1%)
Hydrocephalus	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Hypoaesthesia	3/2419 (0.1%)		0/2402 (0%)		3/4821 (0.1%)
Hypoglycaemic coma	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Hypoxic-ischaemic encephalopathy	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
IIIrd nerve paralysis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Intracranial aneurysm	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Intracranial haematoma	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Intracranial pressure increased	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Ischaemic cerebral infarction	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Ischaemic stroke	32/2419 (1.3%)		29/2402 (1.2%)		61/4821 (1.3%)
Lacunar infarction	4/2419 (0.2%)		2/2402 (0.1%)		6/4821 (0.1%)
Lacunar stroke	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Lethargy	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Loss of consciousness	3/2419 (0.1%)		3/2402 (0.1%)		6/4821 (0.1%)
Lumbar radiculopathy	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Lumbosacral radiculopathy	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Metabolic encephalopathy	6/2419 (0.2%)		3/2402 (0.1%)		9/4821 (0.2%)
Migraine	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Mixed dementia	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Motor dysfunction	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Movement disorder	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Multiple system atrophy	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Myasthenia gravis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Myasthenic syndrome	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Myelopathy	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Myoclonus	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Nervous system disorder	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Neuralgia	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Neuropathy peripheral	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Normal pressure hydrocephalus	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Parkinson's disease	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Parkinsonism	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Peripheral sensorimotor neuropathy	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Polyneuropathy	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Post herpetic neuralgia	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Post stroke epilepsy	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Posterior reversible encephalopathy syndrome	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Presyncope	3/2419 (0.1%)		3/2402 (0.1%)		6/4821 (0.1%)
Pseudoradicular syndrome	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Radiculopathy	2/2419 (0.1%)		2/2402 (0.1%)		4/4821 (0.1%)
Resting tremor	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Sciatica	4/2419 (0.2%)		4/2402 (0.2%)		8/4821 (0.2%)
Seizure	6/2419 (0.2%)		2/2402 (0.1%)		8/4821 (0.2%)
Sensory disturbance	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Somnolence	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Speech disorder	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Spinal cord compression	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Spinal cord disorder	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Spondylitic myelopathy	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Status epilepticus	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Stroke in evolution	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Subarachnoid haemorrhage	3/2419 (0.1%)		4/2402 (0.2%)		7/4821 (0.1%)
Syncope	41/2419 (1.7%)		57/2402 (2.4%)		98/4821 (2%)
Thalamus haemorrhage	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Thrombotic cerebral infarction	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Thrombotic stroke	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Toxic encephalopathy	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Transient ischaemic attack	34/2419 (1.4%)		26/2402 (1.1%)		60/4821 (1.2%)
Tremor	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Trigeminal neuralgia	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Unresponsive to stimuli	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Uraemic encephalopathy	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
VIth nerve paresis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Vascular dementia	2/2419 (0.1%)		2/2402 (0.1%)		4/4821 (0.1%)
Vascular parkinsonism	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Vertebrobasilar insufficiency	4/2419 (0.2%)		2/2402 (0.1%)		6/4821 (0.1%)
Vertigo CNS origin	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Product Issues
Device battery issue	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Device breakage	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Device damage	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Device defective	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Device dislocation	2/2419 (0.1%)		2/2402 (0.1%)		4/4821 (0.1%)
Device failure	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Device leakage	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Device loosening	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Device malfunction	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Device occlusion	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Lead dislodgement	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Psychiatric disorders
Acute stress disorder	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Adjustment disorder	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Adjustment disorder with mixed anxiety and depressed mood	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Agitation	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Alcoholism	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Anxiety	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Anxiety disorder	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Behaviour disorder	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Completed suicide	4/2419 (0.2%)		2/2402 (0.1%)		6/4821 (0.1%)
Confusional state	6/2419 (0.2%)		7/2402 (0.3%)		13/4821 (0.3%)
Delirium	7/2419 (0.3%)		11/2402 (0.5%)		18/4821 (0.4%)
Delirium febrile	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Delusion	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Depressed mood	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Depression	6/2419 (0.2%)		7/2402 (0.3%)		13/4821 (0.3%)
Disorientation	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Hallucination	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Major depression	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Mental disorder	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Mental disorder due to a general medical condition	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Mental status changes	3/2419 (0.1%)		5/2402 (0.2%)		8/4821 (0.2%)
Organic brain syndrome	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Paranoia	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Personality disorder	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Somatic symptom disorder	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Suicidal ideation	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Suicide attempt	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Renal and urinary disorders
Acute kidney injury	90/2419 (3.7%)		110/2402 (4.6%)		200/4821 (4.1%)
Anuria	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Azotaemia	3/2419 (0.1%)		3/2402 (0.1%)		6/4821 (0.1%)
Bladder diverticulum	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Bladder neck obstruction	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Bladder prolapse	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Calculus bladder	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Calculus urethral	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Calculus urinary	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Chronic kidney disease	13/2419 (0.5%)		14/2402 (0.6%)		27/4821 (0.6%)
Dysuria	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
End stage renal disease	3/2419 (0.1%)		3/2402 (0.1%)		6/4821 (0.1%)
Glomerulonephritis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Glomerulonephropathy	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Haematuria	5/2419 (0.2%)		8/2402 (0.3%)		13/4821 (0.3%)
Haemorrhage urinary tract	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Hydronephrosis	2/2419 (0.1%)		3/2402 (0.1%)		5/4821 (0.1%)
Nephrolithiasis	3/2419 (0.1%)		5/2402 (0.2%)		8/4821 (0.2%)
Nephropathy toxic	0/2419 (0%)		3/2402 (0.1%)		3/4821 (0.1%)
Nephrotic syndrome	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Oliguria	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Prerenal failure	1/2419 (0%)		3/2402 (0.1%)		4/4821 (0.1%)
Proteinuria	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Renal artery stenosis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Renal colic	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Renal cyst	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Renal disorder	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Renal failure	31/2419 (1.3%)		29/2402 (1.2%)		60/4821 (1.2%)
Renal impairment	24/2419 (1%)		48/2402 (2%)		72/4821 (1.5%)
Renal infarct	3/2419 (0.1%)		0/2402 (0%)		3/4821 (0.1%)
Renal injury	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Renal mass	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Renal pain	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Renal tubular necrosis	0/2419 (0%)		3/2402 (0.1%)		3/4821 (0.1%)
Renal vein stenosis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Ureteric obstruction	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Ureterolithiasis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Urethral stenosis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Urinary incontinence	1/2419 (0%)		3/2402 (0.1%)		4/4821 (0.1%)
Urinary retention	8/2419 (0.3%)		8/2402 (0.3%)		16/4821 (0.3%)
Urinary tract obstruction	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Reproductive system and breast disorders
Adenomyosis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Benign prostatic hyperplasia	8/2419 (0.3%)		5/2402 (0.2%)		13/4821 (0.3%)
Breast calcifications	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Breast cyst	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Breast mass	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Cervical dysplasia	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Cervical polyp	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Endometrial hyperplasia	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Endometrial thickening	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Erectile dysfunction	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Metrorrhagia	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Ovarian cyst	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Postmenopausal haemorrhage	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Prostatic haemorrhage	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Prostatic obstruction	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Prostatitis	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Scrotal inflammation	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Spermatocele	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Uterine polyp	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Uterine prolapse	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Vaginal haemorrhage	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Vaginal prolapse	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	12/2419 (0.5%)		14/2402 (0.6%)		26/4821 (0.5%)
Acute respiratory distress syndrome	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Acute respiratory failure	20/2419 (0.8%)		24/2402 (1%)		44/4821 (0.9%)
Aspiration	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Asthma	9/2419 (0.4%)		10/2402 (0.4%)		19/4821 (0.4%)
Atelectasis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Bronchial hyperreactivity	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Bronchial obstruction	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Bronchiectasis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Bronchitis chronic	0/2419 (0%)		3/2402 (0.1%)		3/4821 (0.1%)
Bronchospasm	2/2419 (0.1%)		2/2402 (0.1%)		4/4821 (0.1%)
Chronic obstructive pulmonary disease	42/2419 (1.7%)		67/2402 (2.8%)		109/4821 (2.3%)
Chronic respiratory failure	3/2419 (0.1%)		4/2402 (0.2%)		7/4821 (0.1%)
Cough	3/2419 (0.1%)		3/2402 (0.1%)		6/4821 (0.1%)
Dyspnoea	42/2419 (1.7%)		64/2402 (2.7%)		106/4821 (2.2%)
Dyspnoea at rest	0/2419 (0%)		3/2402 (0.1%)		3/4821 (0.1%)
Dyspnoea exertional	4/2419 (0.2%)		5/2402 (0.2%)		9/4821 (0.2%)
Emphysema	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Epistaxis	4/2419 (0.2%)		4/2402 (0.2%)		8/4821 (0.2%)
Haemoptysis	2/2419 (0.1%)		5/2402 (0.2%)		7/4821 (0.1%)
Haemothorax	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Hydrothorax	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Hypercapnia	2/2419 (0.1%)		2/2402 (0.1%)		4/4821 (0.1%)
Hypoventilation	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Hypoxia	2/2419 (0.1%)		6/2402 (0.2%)		8/4821 (0.2%)
Interstitial lung disease	4/2419 (0.2%)		3/2402 (0.1%)		7/4821 (0.1%)
Laryngeal haemorrhage	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Laryngeal oedema	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Laryngospasm	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Lung disorder	1/2419 (0%)		3/2402 (0.1%)		4/4821 (0.1%)
Mediastinal mass	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Nasal septum deviation	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Obstructive airways disorder	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Organising pneumonia	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Orthopnoea	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Pharyngeal haemorrhage	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Pickwickian syndrome	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Pleural effusion	17/2419 (0.7%)		15/2402 (0.6%)		32/4821 (0.7%)
Pleurisy	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Pneumonia aspiration	7/2419 (0.3%)		11/2402 (0.5%)		18/4821 (0.4%)
Pneumonitis	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Pneumothorax	4/2419 (0.2%)		1/2402 (0%)		5/4821 (0.1%)
Presbyphonia	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Pulmonary alveolar haemorrhage	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Pulmonary arterial hypertension	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Pulmonary congestion	0/2419 (0%)		5/2402 (0.2%)		5/4821 (0.1%)
Pulmonary embolism	16/2419 (0.7%)		17/2402 (0.7%)		33/4821 (0.7%)
Pulmonary eosinophilia	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Pulmonary fibrosis	3/2419 (0.1%)		0/2402 (0%)		3/4821 (0.1%)
Pulmonary hypertension	4/2419 (0.2%)		9/2402 (0.4%)		13/4821 (0.3%)
Pulmonary mass	3/2419 (0.1%)		4/2402 (0.2%)		7/4821 (0.1%)
Pulmonary oedema	7/2419 (0.3%)		16/2402 (0.7%)		23/4821 (0.5%)
Respiratory acidosis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Respiratory arrest	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Respiratory depression	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Respiratory distress	1/2419 (0%)		3/2402 (0.1%)		4/4821 (0.1%)
Respiratory failure	29/2419 (1.2%)		32/2402 (1.3%)		61/4821 (1.3%)
Respiratory tract congestion	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Sleep apnoea syndrome	4/2419 (0.2%)		5/2402 (0.2%)		9/4821 (0.2%)
Status asthmaticus	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Tracheal stenosis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Vocal cord polyp	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Wheezing	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Skin and subcutaneous tissue disorders
Angioedema	5/2419 (0.2%)		1/2402 (0%)		6/4821 (0.1%)
Blister	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Butterfly rash	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Decubitus ulcer	3/2419 (0.1%)		1/2402 (0%)		4/4821 (0.1%)
Dermatitis	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Dermatitis exfoliative generalised	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Diabetic foot	2/2419 (0.1%)		5/2402 (0.2%)		7/4821 (0.1%)
Diabetic wound	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Eczema	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Eczema asteatotic	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Erythema	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Haemorrhage subcutaneous	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Hyperhidrosis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Intertrigo	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Ischaemic skin ulcer	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Neurodermatitis	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Purpura	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Rash	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Rash maculo-papular	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Rash pruritic	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Rhinophyma	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Skin lesion	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Skin ulcer	5/2419 (0.2%)		3/2402 (0.1%)		8/4821 (0.2%)
Subcutaneous emphysema	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Urticaria	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Vasculitic ulcer	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Social circumstances
Immobile	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Living in residential institution	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Vascular disorders
Accelerated hypertension	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Angiopathy	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Aortic aneurysm	2/2419 (0.1%)		8/2402 (0.3%)		10/4821 (0.2%)
Aortic aneurysm rupture	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Aortic dissection	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Aortic rupture	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Aortic stenosis	13/2419 (0.5%)		12/2402 (0.5%)		25/4821 (0.5%)
Aortic thrombosis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Arterial occlusive disease	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Arteriosclerosis	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Bleeding varicose vein	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Blood pressure fluctuation	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Circulatory collapse	3/2419 (0.1%)		2/2402 (0.1%)		5/4821 (0.1%)
Deep vein thrombosis	4/2419 (0.2%)		7/2402 (0.3%)		11/4821 (0.2%)
Dry gangrene	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Essential hypertension	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Extremity necrosis	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Haematoma	7/2419 (0.3%)		8/2402 (0.3%)		15/4821 (0.3%)
Haemorrhage	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Haemorrhagic infarction	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Hypertension	16/2419 (0.7%)		25/2402 (1%)		41/4821 (0.9%)
Hypertensive crisis	4/2419 (0.2%)		8/2402 (0.3%)		12/4821 (0.2%)
Hypertensive emergency	1/2419 (0%)		3/2402 (0.1%)		4/4821 (0.1%)
Hypertensive urgency	6/2419 (0.2%)		1/2402 (0%)		7/4821 (0.1%)
Hypotension	52/2419 (2.1%)		47/2402 (2%)		99/4821 (2.1%)
Hypovolaemic shock	1/2419 (0%)		2/2402 (0.1%)		3/4821 (0.1%)
Iliac artery embolism	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Intermittent claudication	2/2419 (0.1%)		1/2402 (0%)		3/4821 (0.1%)
Ischaemia	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Jugular vein thrombosis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Leriche syndrome	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Lymphoedema	0/2419 (0%)		4/2402 (0.2%)		4/4821 (0.1%)
Orthostatic hypertension	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Orthostatic hypotension	5/2419 (0.2%)		9/2402 (0.4%)		14/4821 (0.3%)
Peripheral arterial occlusive disease	18/2419 (0.7%)		7/2402 (0.3%)		25/4821 (0.5%)
Peripheral artery aneurysm	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Peripheral artery occlusion	2/2419 (0.1%)		2/2402 (0.1%)		4/4821 (0.1%)
Peripheral artery stenosis	3/2419 (0.1%)		4/2402 (0.2%)		7/4821 (0.1%)
Peripheral artery thrombosis	2/2419 (0.1%)		2/2402 (0.1%)		4/4821 (0.1%)
Peripheral coldness	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Peripheral embolism	3/2419 (0.1%)		3/2402 (0.1%)		6/4821 (0.1%)
Peripheral ischaemia	8/2419 (0.3%)		7/2402 (0.3%)		15/4821 (0.3%)
Peripheral vascular disorder	5/2419 (0.2%)		2/2402 (0.1%)		7/4821 (0.1%)
Peripheral venous disease	2/2419 (0.1%)		0/2402 (0%)		2/4821 (0%)
Phlebitis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Post thrombotic syndrome	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Shock	0/2419 (0%)		1/2402 (0%)		1/4821 (0%)
Shock haemorrhagic	2/2419 (0.1%)		5/2402 (0.2%)		7/4821 (0.1%)
Subclavian artery stenosis	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Subclavian artery thrombosis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Temporal arteritis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Thrombosis	1/2419 (0%)		1/2402 (0%)		2/4821 (0%)
Varicose ulceration	0/2419 (0%)		2/2402 (0.1%)		2/4821 (0%)
Venous thrombosis	1/2419 (0%)		0/2402 (0%)		1/4821 (0%)
Other (Not Including Serious) Adverse Events
	LCZ696		Valsartan		All Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2005/2419 (82.9%)		1995/2402 (83.1%)		4000/4821 (83%)
Blood and lymphatic system disorders
Anaemia	166/2419 (6.9%)		214/2402 (8.9%)		380/4821 (7.9%)
Cardiac disorders
Angina pectoris	87/2419 (3.6%)		82/2402 (3.4%)		169/4821 (3.5%)
Atrial fibrillation	248/2419 (10.3%)		239/2402 (10%)		487/4821 (10.1%)
Bradycardia	53/2419 (2.2%)		85/2402 (3.5%)		138/4821 (2.9%)
Cardiac failure	225/2419 (9.3%)		269/2402 (11.2%)		494/4821 (10.2%)
Palpitations	62/2419 (2.6%)		56/2402 (2.3%)		118/4821 (2.4%)
Ear and labyrinth disorders
Vertigo	77/2419 (3.2%)		60/2402 (2.5%)		137/4821 (2.8%)
Eye disorders
Cataract	84/2419 (3.5%)		70/2402 (2.9%)		154/4821 (3.2%)
Gastrointestinal disorders
Abdominal pain	53/2419 (2.2%)		54/2402 (2.2%)		107/4821 (2.2%)
Constipation	100/2419 (4.1%)		86/2402 (3.6%)		186/4821 (3.9%)
Diarrhoea	177/2419 (7.3%)		180/2402 (7.5%)		357/4821 (7.4%)
Nausea	93/2419 (3.8%)		87/2402 (3.6%)		180/4821 (3.7%)
Vomiting	70/2419 (2.9%)		58/2402 (2.4%)		128/4821 (2.7%)
General disorders
Asthenia	60/2419 (2.5%)		58/2402 (2.4%)		118/4821 (2.4%)
Fatigue	98/2419 (4.1%)		107/2402 (4.5%)		205/4821 (4.3%)
Non-cardiac chest pain	98/2419 (4.1%)		92/2402 (3.8%)		190/4821 (3.9%)
Oedema peripheral	166/2419 (6.9%)		183/2402 (7.6%)		349/4821 (7.2%)
Pyrexia	59/2419 (2.4%)		54/2402 (2.2%)		113/4821 (2.3%)
Infections and infestations
Bronchitis	177/2419 (7.3%)		197/2402 (8.2%)		374/4821 (7.8%)
Cellulitis	61/2419 (2.5%)		41/2402 (1.7%)		102/4821 (2.1%)
Influenza	110/2419 (4.5%)		109/2402 (4.5%)		219/4821 (4.5%)
Nasopharyngitis	207/2419 (8.6%)		177/2402 (7.4%)		384/4821 (8%)
Pneumonia	100/2419 (4.1%)		97/2402 (4%)		197/4821 (4.1%)
Respiratory tract infection	48/2419 (2%)		60/2402 (2.5%)		108/4821 (2.2%)
Upper respiratory tract infection	145/2419 (6%)		139/2402 (5.8%)		284/4821 (5.9%)
Urinary tract infection	243/2419 (10%)		268/2402 (11.2%)		511/4821 (10.6%)
Injury, poisoning and procedural complications
Contusion	57/2419 (2.4%)		72/2402 (3%)		129/4821 (2.7%)
Fall	106/2419 (4.4%)		90/2402 (3.7%)		196/4821 (4.1%)
Investigations
Blood creatinine increased	63/2419 (2.6%)		65/2402 (2.7%)		128/4821 (2.7%)
Glomerular filtration rate decreased	85/2419 (3.5%)		93/2402 (3.9%)		178/4821 (3.7%)
Weight decreased	71/2419 (2.9%)		82/2402 (3.4%)		153/4821 (3.2%)
Metabolism and nutrition disorders
Diabetes mellitus	52/2419 (2.1%)		62/2402 (2.6%)		114/4821 (2.4%)
Gout	76/2419 (3.1%)		88/2402 (3.7%)		164/4821 (3.4%)
Hyperkalaemia	238/2419 (9.8%)		298/2402 (12.4%)		536/4821 (11.1%)
Hyperuricaemia	62/2419 (2.6%)		75/2402 (3.1%)		137/4821 (2.8%)
Hypokalaemia	110/2419 (4.5%)		100/2402 (4.2%)		210/4821 (4.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	152/2419 (6.3%)		153/2402 (6.4%)		305/4821 (6.3%)
Back pain	149/2419 (6.2%)		170/2402 (7.1%)		319/4821 (6.6%)
Muscle spasms	36/2419 (1.5%)		49/2402 (2%)		85/4821 (1.8%)
Musculoskeletal pain	63/2419 (2.6%)		58/2402 (2.4%)		121/4821 (2.5%)
Osteoarthritis	92/2419 (3.8%)		92/2402 (3.8%)		184/4821 (3.8%)
Pain in extremity	81/2419 (3.3%)		75/2402 (3.1%)		156/4821 (3.2%)
Nervous system disorders
Dizziness	229/2419 (9.5%)		192/2402 (8%)		421/4821 (8.7%)
Headache	114/2419 (4.7%)		126/2402 (5.2%)		240/4821 (5%)
Syncope	42/2419 (1.7%)		62/2402 (2.6%)		104/4821 (2.2%)
Psychiatric disorders
Depression	68/2419 (2.8%)		70/2402 (2.9%)		138/4821 (2.9%)
Insomnia	75/2419 (3.1%)		54/2402 (2.2%)		129/4821 (2.7%)
Renal and urinary disorders
Acute kidney injury	64/2419 (2.6%)		65/2402 (2.7%)		129/4821 (2.7%)
Chronic kidney disease	33/2419 (1.4%)		50/2402 (2.1%)		83/4821 (1.7%)
Haematuria	71/2419 (2.9%)		77/2402 (3.2%)		148/4821 (3.1%)
Renal failure	85/2419 (3.5%)		108/2402 (4.5%)		193/4821 (4%)
Renal impairment	287/2419 (11.9%)		331/2402 (13.8%)		618/4821 (12.8%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	57/2419 (2.4%)		68/2402 (2.8%)		125/4821 (2.6%)
Cough	188/2419 (7.8%)		146/2402 (6.1%)		334/4821 (6.9%)
Dyspnoea	217/2419 (9%)		236/2402 (9.8%)		453/4821 (9.4%)
Epistaxis	42/2419 (1.7%)		71/2402 (3%)		113/4821 (2.3%)
Skin and subcutaneous tissue disorders
Pruritus	46/2419 (1.9%)		51/2402 (2.1%)		97/4821 (2%)
Vascular disorders
Hypertension	225/2419 (9.3%)		314/2402 (13.1%)		539/4821 (11.2%)
Hypotension	529/2419 (21.9%)		379/2402 (15.8%)		908/4821 (18.8%)

Limitations/Caveats

[Not Specified]

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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.

Results Point of Contact

Name/Title	Study Director
Organization	Novartis Pharmaceuticals
Phone	862-778-8300
Email	Novartis.email@novartis.com

Responsible Party:

Novartis Pharmaceuticals

ClinicalTrials.gov Identifier:

NCT01920711

Other Study ID Numbers:

CLCZ696D2301
2013-001747-31

First Posted:

Aug 12, 2013

Last Update Posted:

Sep 29, 2020

Last Verified:

Sep 1, 2020

PARAGON-HF: Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction

Study Details

Study Description

Brief Summary

Detailed Description

Study Design

Arms and Interventions

Outcome Measures

Primary Outcome Measures

Secondary Outcome Measures

Eligibility Criteria

Criteria

Inclusion Criteria:

Exclusion Criteria:

Contacts and Locations

Locations

Sponsors and Collaborators

Investigators

Study Documents (Full-Text)

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Study Results

Participant Flow

Baseline Characteristics

Outcome Measures

Outcome Measure Data

Statistical Analysis 1

Statistical Analysis 2

Statistical Analysis 3

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Statistical Analysis 2

Statistical Analysis 3

Statistical Analysis 4

Outcome Measure Data

Statistical Analysis 1

Adverse Events

All Cause Mortality

Serious Adverse Events

Other (Not Including Serious) Adverse Events

Limitations/Caveats

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Results Point of Contact