PIONEER 6: A Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02692716
• Collaborator: (none)
• Enrollment: 3,183
• Locations: 229
• Arms: 2
• Actual Duration (Months): 20.2
• Patients Per Site: 13.9
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

This trial is conducted globally. The aim of the trial is to investigate the cardiovascular safety of oral semaglutide in subjects with type 2 diabetes.

Condition or Disease	Intervention/Treatment	Phase
Diabetes; Diabetes Mellitus, Type 2	Drug: semaglutide; Drug: placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 3183 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes
• Actual Study Start Date: Jan 17, 2017
• Actual Primary Completion Date: Sep 25, 2018
• Actual Study Completion Date: Sep 25, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Oral semaglutide	Drug: semaglutide; For oral use once daily.
Placebo Comparator: Placebo	Drug: placebo; For oral use once daily.

Outcome Measures

Primary Outcome Measures

1. Time From Randomisation to First Occurrence of a Major Adverse Cardiovascular Event (MACE) Composite Endpoint Consisting of: Cardiovascular Death, Non-fatal Myocardial Infarction or Non-fatal Stroke [Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.]

   Number of participants experiencing a first event of a MACE, defined as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

Secondary Outcome Measures

1. Time From Randomisation to First Occurrence of an Expanded Composite Cardiovascular Endpoint Consisting of: Cardiovascular Death, Non-fatal Myocardial Infarction, Non-fatal Stroke, UAP Requiring Hospitalisation or Hospitalisation for Heart Failure [Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.]

   Participants experiencing first occurrence of an expanded composite CV endpoint [defined as cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, UAP (unstable angina pectoris) requiring hospitalisation or heart failure requiring hospitalisation] are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

2. Time From Randomisation to First Occurrence of Each of the Individual Components in the Expanded Composite Cardiovascular Endpoint [Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.]

   Participants experiencing an event onset for each individual component of the expanded composite cardiovascular outcomes (defined as cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, unstable angina requiring hospitalisation or heart failure requiring hospitalisation) are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

3. Time From Randomisation to First Occurrence of a Composite Endpoint Consisting of: All-cause Death, Non-fatal Myocardial Infarction or Nonfatal Stroke [Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.]

   Participants experiencing first occurrence of a composite CV endpoint (defined as all-cause death, non-fatal myocardial infarction or nonfatal stroke) are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

4. Time From Randomisation to First Occurrence of Fatal or Non-fatal Myocardial Infarction [Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.]

   Number of participants experiencing a first event of a fatal or non-fatal myocardial infarction are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

5. Time From Randomisation to First Occurrence of Fatal or Non-fatal Stroke [Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.]

   Number of participants experiencing a first event of a fatal or non-fatal stroke are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

6. Time From Randomisation to All-cause Death [Maximum treatment duration is dependent on event rates and is expected to be no longer than 19 months + 5 weeks of follow-up period.]

   Number of all-cause deaths in the study are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

7. Time to First AE Leading to Permanent Trial Product Discontinuation [Maximum treatment duration is dependent on event rates and is expected to be no longer than 19 months + 38 days of ascertainment window.]

   Number of participants who permanently discontinued trial product in ths study are presented. Results are based on the on-treatment observation period which starts at the date of first dose on trial product; ends on last date on trial product +38 days (ascertainment window).

8. Number of Serious Adverse Events [Maximum treatment duration is dependent on event rates and is expected to be no longer than 19 months + 38 days of ascertainment window.]

   Number of serious adverse events were recorded from week 0 to week 87 in the study. Results are based on the on-treatment observation period which started at the date of first dose on trial product and ended on last date on trial product +38 days (ascertainment window).

9. Change in Eye Examination Category [Week -3, End of treatment]

   Participants with eye examination findings, normal, abnormal non clinically significant (NCS) and abnormal clinically significant (CS) at baseline (week -3) and end of treatment visit (week 83) are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

10. Change in Pulse Rate [Week 0, End of treatment]

    Change from baseline (week 0) in pulse rate measured at the end of treatment visit (week 83) is reported. Results are based on the on-treatment observation period which started at the date of first dose on trial product, ended on last date on trial product +38 days (ascertainment window).

11. Change in Systolic and Diastolic Blood Pressure [Week 0, End of treatment]

    Change from baseline (week 0) in systolic and diastolic blood pressure measured at the end of treatment visit (week 83) is reported. Results are based on the on-treatment observation period which started at the date of first dose on trial product, ended on last date on trial product +38 days (ascertainment window).

12. Change in Glycosylated Haemoglobin (HbA1c) [Week 0, End of treatment]

    Change from baseline (week 0) in HbA1c measured at the end of treatment visit (week 83) is reported. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

13. Change in Body Weight [Week 0, End of treatment]

    Change from baseline (week 0) in body weight measured at the end of treatment visit (week 83) is reported. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

14. Change in Total Cholesterol - Ratio to Baseline [Week 0, End of treatment]

    Change from baseline (week 0) in total cholesterol (mmol/L) at the end of treatment (week 83) visit is presented as ratio to baseline. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

15. Change in LDL-cholesterol - Ratio to Baseline [Week 0, End of treatment]

    Change from baseline (week 0) in LDL cholesterol (mmol/L) at end of treatment visit (week 83) is presented as ratio to baseline. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

16. Change in HDL-cholesterol - Ratio to Baseline [Week 0, End of treatment]

    Change from baseline (week 0) in HDL cholesterol (mmol/L) at end of treatment visit (week 83) is presented as ratio to baseline. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

17. Change in Triglycerides - Ratio to Baseline [Week 0, End of treatment]

    Change from baseline (week 0) in triglycerides (mmol/L) at end of treatment visit (week 83) is presented as ratio to baseline. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Male or female diagnosed with type 2 diabetes

• Age at least 50 years at screening and presence of cardiovascular disease, or age at least 60 years at screening and presence of at least one cardiovascular risk factor

Exclusion Criteria:

• Current or previous (within 90 days prior to screening) treatment with any GLP-1 (glucagon-like peptide-1) receptor agonist, DPP-4 (dipeptidyl peptidase-4) inhibitor or pramlintide

• Family or personal history of multiple endocrine neoplasia type 2 (MEN 2) or medullary thyroid carcinoma (MTC)

• History of pancreatitis (acute or chronic)

• History of major surgical procedures involving the stomach potentially affecting absorption of trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery)

• Subjects presently classified as being in New York Heart Association (NYHA) Class IV heart failure

• Planned coronary, carotid or peripheral artery revascularisation known on the day of screening

• Any of the following: myocardial infarction, stroke or hospitalisation for unstable angina or transient ischaemic attack within the past 60 days prior to screening

• Chronic or intermittent hemodialysis or peritoneal dialysis or severe renal impairment (corresponding to eGFR (glomerular filtration rate, estimated) below 30 mL/min/1.73 m^2)

• History or presence of malignant neoplasms within the last 5 years (except basal and squamous cell skin cancer and carcinoma in situ)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novo Nordisk Investigational Site	Little Rock	Arkansas	United States	72211
2	Novo Nordisk Investigational Site	Searcy	Arkansas	United States	72143
3	Novo Nordisk Investigational Site	Concord	California	United States	94520
4	Novo Nordisk Investigational Site	Huntington Beach	California	United States	92648
5	Novo Nordisk Investigational Site	La Jolla	California	United States	92037
6	Novo Nordisk Investigational Site	La Mesa	California	United States	91942
7	Novo Nordisk Investigational Site	Lancaster	California	United States	93534
8	Novo Nordisk Investigational Site	Monterey	California	United States	93940
9	Novo Nordisk Investigational Site	San Diego	California	United States	92111
10	Novo Nordisk Investigational Site	San Ramon	California	United States	94583
11	Novo Nordisk Investigational Site	Ventura	California	United States	93003
12	Novo Nordisk Investigational Site	Boca Raton	Florida	United States	33433
13	Novo Nordisk Investigational Site	New Port Richey	Florida	United States	34652
14	Novo Nordisk Investigational Site	Roswell	Georgia	United States	30076
15	Novo Nordisk Investigational Site	Savannah	Georgia	United States	31406
16	Novo Nordisk Investigational Site	Honolulu	Hawaii	United States	96814
17	Novo Nordisk Investigational Site	Springfield	Illinois	United States	62702
18	Novo Nordisk Investigational Site	Indianapolis	Indiana	United States	46254
19	Novo Nordisk Investigational Site	Michigan City	Indiana	United States	46360
20	Novo Nordisk Investigational Site	Muncie	Indiana	United States	47304
21	Novo Nordisk Investigational Site	Council Bluffs	Iowa	United States	51501
22	Novo Nordisk Investigational Site	Lexington	Kentucky	United States	40502
23	Novo Nordisk Investigational Site	Lexington	Kentucky	United States	40503
24	Novo Nordisk Investigational Site	Louisville	Kentucky	United States	40213
25	Novo Nordisk Investigational Site	Monroe	Louisiana	United States	71203
26	Novo Nordisk Investigational Site	Slidell	Louisiana	United States	70461-4231
27	Novo Nordisk Investigational Site	Canton	Michigan	United States	48187
28	Novo Nordisk Investigational Site	Troy	Michigan	United States	48098
29	Novo Nordisk Investigational Site	Omaha	Nebraska	United States	68114
30	Novo Nordisk Investigational Site	Omaha	Nebraska	United States	68198
31	Novo Nordisk Investigational Site	Las Vegas	Nevada	United States	89128
32	Novo Nordisk Investigational Site	Nashua	New Hampshire	United States	03063
33	Novo Nordisk Investigational Site	Albany	New York	United States	12203
34	Novo Nordisk Investigational Site	Albany	New York	United States	12206
35	Novo Nordisk Investigational Site	North Massapequa	New York	United States	11758-1802
36	Novo Nordisk Investigational Site	Westfield	New York	United States	14787
37	Novo Nordisk Investigational Site	Asheville	North Carolina	United States	28803
38	Novo Nordisk Investigational Site	Greenville	North Carolina	United States	27834
39	Novo Nordisk Investigational Site	Wilmington	North Carolina	United States	28401
40	Novo Nordisk Investigational Site	Fargo	North Dakota	United States	58104
41	Novo Nordisk Investigational Site	Cleveland	Ohio	United States	44195
42	Novo Nordisk Investigational Site	Columbus	Ohio	United States	43203
43	Novo Nordisk Investigational Site	Maumee	Ohio	United States	43537
44	Novo Nordisk Investigational Site	Beaver	Pennsylvania	United States	15009
45	Novo Nordisk Investigational Site	Philadelphia	Pennsylvania	United States	19114
46	Novo Nordisk Investigational Site	Anderson	South Carolina	United States	29621
47	Novo Nordisk Investigational Site	Moncks Corner	South Carolina	United States	29461
48	Novo Nordisk Investigational Site	Myrtle Beach	South Carolina	United States	29572
49	Novo Nordisk Investigational Site	Spartanburg	South Carolina	United States	29303
50	Novo Nordisk Investigational Site	Chattanooga	Tennessee	United States	37404
51	Novo Nordisk Investigational Site	Chattanooga	Tennessee	United States	37411
52	Novo Nordisk Investigational Site	Kingsport	Tennessee	United States	37660
53	Novo Nordisk Investigational Site	Knoxville	Tennessee	United States	37938
54	Novo Nordisk Investigational Site	Nashville	Tennessee	United States	37203
55	Novo Nordisk Investigational Site	Nashville	Tennessee	United States	37212
56	Novo Nordisk Investigational Site	Arlington	Texas	United States	76012-4637
57	Novo Nordisk Investigational Site	Austin	Texas	United States	78705
58	Novo Nordisk Investigational Site	Austin	Texas	United States	78731
59	Novo Nordisk Investigational Site	Austin	Texas	United States	78749
60	Novo Nordisk Investigational Site	Dallas	Texas	United States	75230
61	Novo Nordisk Investigational Site	Dallas	Texas	United States	75231
62	Novo Nordisk Investigational Site	Dallas	Texas	United States	75390-9302
63	Novo Nordisk Investigational Site	Hurst	Texas	United States	76054
64	Novo Nordisk Investigational Site	Midland	Texas	United States	79707
65	Novo Nordisk Investigational Site	Round Rock	Texas	United States	78681
66	Novo Nordisk Investigational Site	San Antonio	Texas	United States	78220
67	Novo Nordisk Investigational Site	San Antonio	Texas	United States	78228-6205
68	Novo Nordisk Investigational Site	Waco	Texas	United States	76710
69	Novo Nordisk Investigational Site	South Burlington	Vermont	United States	05403
70	Novo Nordisk Investigational Site	Norfolk	Virginia	United States	23510-2015
71	Novo Nordisk Investigational Site	Winchester	Virginia	United States	22601-3834
72	Novo Nordisk Investigational Site	Annaba		Algeria	23000
73	Novo Nordisk Investigational Site	Oran		Algeria	31000
74	Novo Nordisk Investigational Site	Setif		Algeria	19000
75	Novo Nordisk Investigational Site	Tizi Ouzou		Algeria	16015
76	Novo Nordisk Investigational Site	Buenos Aires		Argentina	B1704ETD
77	Novo Nordisk Investigational Site	Buenos Aires		Argentina	C1428ART
78	Novo Nordisk Investigational Site	Caba		Argentina	C1120AAC
79	Novo Nordisk Investigational Site	Caba		Argentina	C1428ART
80	Novo Nordisk Investigational Site	Caba		Argentina	C1440AAD
81	Novo Nordisk Investigational Site	Cordoba		Argentina	5000
82	Novo Nordisk Investigational Site	Lanus Este		Argentina	B1824KAJ
83	Novo Nordisk Investigational Site	Curitiba	Parana	Brazil	80030-110
84	Novo Nordisk Investigational Site	Mogi das Cruzes	Sao Paulo	Brazil	08780-090
85	Novo Nordisk Investigational Site	São José dos Campos	Sao Paulo	Brazil	12243-280
86	Novo Nordisk Investigational Site	São Paulo	Sao Paulo	Brazil	01228-200
87	Novo Nordisk Investigational Site	Calgary	Alberta	Canada	T2V 4J2
88	Novo Nordisk Investigational Site	Edmonton	Alberta	Canada	T6H 2L4
89	Novo Nordisk Investigational Site	Brampton	Ontario	Canada	L6T 0G1
90	Novo Nordisk Investigational Site	Brampton	Ontario	Canada	L6Z 4N5
91	Novo Nordisk Investigational Site	Concord	Ontario	Canada	L4K 4M2
92	Novo Nordisk Investigational Site	Toronto	Ontario	Canada	M5G 2C4
93	Novo Nordisk Investigational Site	Montreal	Quebec	Canada	H4A 3T2
94	Novo Nordisk Investigational Site	Aarhus N		Denmark	8200
95	Novo Nordisk Investigational Site	Esbjerg		Denmark	6700
96	Novo Nordisk Investigational Site	Hellerup		Denmark	2900
97	Novo Nordisk Investigational Site	Hvidovre		Denmark	2650
98	Novo Nordisk Investigational Site	Odense		Denmark	5000
99	Novo Nordisk Investigational Site	Bochum		Germany	44791
100	Novo Nordisk Investigational Site	Dresden		Germany	01307
101	Novo Nordisk Investigational Site	Elsterwerda		Germany	04910
102	Novo Nordisk Investigational Site	Essen		Germany	45219
103	Novo Nordisk Investigational Site	Falkensee		Germany	14612
104	Novo Nordisk Investigational Site	Hamburg		Germany	22607
105	Novo Nordisk Investigational Site	Ludwigshafen		Germany	67059
106	Novo Nordisk Investigational Site	Münster		Germany	48145
107	Novo Nordisk Investigational Site	Oldenburg I. Holst		Germany	23758
108	Novo Nordisk Investigational Site	Oldenburg		Germany	23758
109	Novo Nordisk Investigational Site	Rehlingen-Siersburg		Germany	66780
110	Novo Nordisk Investigational Site	Saint Ingbert-Oberwürzbach		Germany	66386
111	Novo Nordisk Investigational Site	Hyderabad	Andhra Pradesh	India	500034
112	Novo Nordisk Investigational Site	Hyderbad	Andhra Pradesh	India	500 012
113	Novo Nordisk Investigational Site	Ahmedabad	Gujarat	India	380006
114	Novo Nordisk Investigational Site	Ahmedabad	Gujarat	India	380052
115	Novo Nordisk Investigational Site	Kochi	Kerala	India	682041
116	Novo Nordisk Investigational Site	Kozhikode	Kerala	India	673017
117	Novo Nordisk Investigational Site	Thiruvananthapuram	Kerala	India	695031
118	Novo Nordisk Investigational Site	Goa	Maharashtra	India	403 202
119	Novo Nordisk Investigational Site	Mumbai	Maharashtra	India	400008
120	Novo Nordisk Investigational Site	Mumbai	Maharashtra	India	400012
121	Novo Nordisk Investigational Site	Pune	Maharashtra	India	411001
122	Novo Nordisk Investigational Site	Pune	Maharashtra	India	411004
123	Novo Nordisk Investigational Site	New Dehli	New Delhi	India	110029
124	Novo Nordisk Investigational Site	Ludhiana	Punjab	India	141008
125	Novo Nordisk Investigational Site	Chennai	Tamil Nadu	India	600086
126	Novo Nordisk Investigational Site	Kolkata	West Bengal	India	700054
127	Novo Nordisk Investigational Site	New Delhi		India	110001
128	Novo Nordisk Investigational Site	New Delhi		India	110017
129	Novo Nordisk Investigational Site	Pune		India	411011
130	Novo Nordisk Investigational Site	Haifa		Israel	35152
131	Novo Nordisk Investigational Site	Holon		Israel	58100
132	Novo Nordisk Investigational Site	Jerusalem		Israel	91120
133	Novo Nordisk Investigational Site	Nahariya		Israel	22100
134	Novo Nordisk Investigational Site	Petah-Tikva		Israel	49100
135	Novo Nordisk Investigational Site	Rishon Le Zion		Israel	75650
136	Novo Nordisk Investigational Site	Tel Aviv		Israel	6937947
137	Novo Nordisk Investigational Site	Tel-Aviv		Israel	64239
138	Novo Nordisk Investigational Site	Bergamo		Italy	24127
139	Novo Nordisk Investigational Site	Catanzaro		Italy	88100
140	Novo Nordisk Investigational Site	Chieti		Italy	66100
141	Novo Nordisk Investigational Site	Milano		Italy	20132
142	Novo Nordisk Investigational Site	Palermo		Italy	90127
143	Novo Nordisk Investigational Site	Roma		Italy	00133
144	Novo Nordisk Investigational Site	Roma		Italy	00161
145	Novo Nordisk Investigational Site	Ipoh, Perak		Malaysia	30990
146	Novo Nordisk Investigational Site	Kota Bharu, Kelantan		Malaysia	16150
147	Novo Nordisk Investigational Site	Kota Bharu		Malaysia	15586
148	Novo Nordisk Investigational Site	Kota Samarahan		Malaysia	94300
149	Novo Nordisk Investigational Site	Kuala Lumpur		Malaysia	50400
150	Novo Nordisk Investigational Site	Kuala Lumpur		Malaysia	59100
151	Novo Nordisk Investigational Site	Kuching		Malaysia	93586
152	Novo Nordisk Investigational Site	Melaka		Malaysia	75400
153	Novo Nordisk Investigational Site	Putrajaya		Malaysia	62250
154	Novo Nordisk Investigational Site	Seremban		Malaysia	70300
155	Novo Nordisk Investigational Site	Guadalajara	Jalisco	Mexico	44600
156	Novo Nordisk Investigational Site	Guadalajara	Jalisco	Mexico	44650
157	Novo Nordisk Investigational Site	Guadalajara	Jalisco	Mexico	44670
158	Novo Nordisk Investigational Site	Monterrey	Nuevo León	Mexico	64460
159	Novo Nordisk Investigational Site	Merida	Yucatan	Mexico	97070
160	Novo Nordisk Investigational Site	San Luis Potosi		Mexico	78200
161	Novo Nordisk Investigational Site	Almere		Netherlands	1311RL
162	Novo Nordisk Investigational Site	Amsterdam		Netherlands	1066 EC
163	Novo Nordisk Investigational Site	Eindhoven		Netherlands	5631 BM
164	Novo Nordisk Investigational Site	Hoogeveen		Netherlands	7909 AA
165	Novo Nordisk Investigational Site	Nijmegen		Netherlands	6525 GA
166	Novo Nordisk Investigational Site	Krakow		Poland	31-261
167	Novo Nordisk Investigational Site	Krakow		Poland	31-271
168	Novo Nordisk Investigational Site	Lublin		Poland	20-044
169	Novo Nordisk Investigational Site	Poznan		Poland	60-589
170	Novo Nordisk Investigational Site	Warszawa		Poland	01-192
171	Novo Nordisk Investigational Site	Oradea	Bihor	Romania	410025
172	Novo Nordisk Investigational Site	Targu Mures	Mures	Romania	540142
173	Novo Nordisk Investigational Site	Tirgu Mures	Mures	Romania	540142
174	Novo Nordisk Investigational Site	Bucharest		Romania	010507
175	Novo Nordisk Investigational Site	Bucharest		Romania	010627
176	Novo Nordisk Investigational Site	Bucharest		Romania	020359
177	Novo Nordisk Investigational Site	Bucharest		Romania	020475
178	Novo Nordisk Investigational Site	Bucharest		Romania
179	Novo Nordisk Investigational Site	Galati		Romania	800098
180	Novo Nordisk Investigational Site	Bloemfontein	Free State	South Africa	9301
181	Novo Nordisk Investigational Site	Johannesburg	Gauteng	South Africa	1827
182	Novo Nordisk Investigational Site	Johannesburg	Gauteng	South Africa	2013
183	Novo Nordisk Investigational Site	Lenasia	Gauteng	South Africa	1827
184	Novo Nordisk Investigational Site	Pretoria	Gauteng	South Africa	0181
185	Novo Nordisk Investigational Site	Durban	KwaZulu-Natal	South Africa	4001
186	Novo Nordisk Investigational Site	Durban	KwaZulu-Natal	South Africa	4450
187	Novo Nordisk Investigational Site	Middleburg	Mpumalanga	South Africa	1055
188	Novo Nordisk Investigational Site	Cape Town	Western Cape	South Africa	7925
189	Novo Nordisk Investigational Site	Alcala de Henares		Spain	28805
190	Novo Nordisk Investigational Site	Badalona		Spain	08916
191	Novo Nordisk Investigational Site	Fuenlabrada - Madrid		Spain	28942
192	Novo Nordisk Investigational Site	Madrid		Spain	28046
193	Novo Nordisk Investigational Site	Málaga		Spain	29006
194	Novo Nordisk Investigational Site	Palma de Mallorca		Spain	07198
195	Novo Nordisk Investigational Site	Pontevedra		Spain	36071
196	Novo Nordisk Investigational Site	Sevilla		Spain	41003
197	Novo Nordisk Investigational Site	Sevilla		Spain	41010
198	Novo Nordisk Investigational Site	Valencia		Spain	46014
199	Novo Nordisk Investigational Site	Valencia		Spain	46026
200	Novo Nordisk Investigational Site	Kaohsiung City		Taiwan	833
201	Novo Nordisk Investigational Site	Taichung City		Taiwan	407
202	Novo Nordisk Investigational Site	Tainan city		Taiwan	710
203	Novo Nordisk Investigational Site	Taipei		Taiwan	100
204	Novo Nordisk Investigational Site	Bangkok		Thailand	10330
205	Novo Nordisk Investigational Site	Bangkok		Thailand	10400
206	Novo Nordisk Investigational Site	Bangkok		Thailand	10700
207	Novo Nordisk Investigational Site	Chiang Mai		Thailand	50200
208	Novo Nordisk Investigational Site	Klong Luang, Pathumthani		Thailand	12120
209	Novo Nordisk Investigational Site	Nakhon Ratchasima		Thailand	30000
210	Novo Nordisk Investigational Site	Ankara		Turkey	06100
211	Novo Nordisk Investigational Site	Ankara		Turkey	06500
212	Novo Nordisk Investigational Site	Antalya		Turkey	07058
213	Novo Nordisk Investigational Site	Aydin		Turkey	09010
214	Novo Nordisk Investigational Site	Denizli		Turkey	20070
215	Novo Nordisk Investigational Site	Gaziantep		Turkey	27070
216	Novo Nordisk Investigational Site	Istanbul		Turkey	34371
217	Novo Nordisk Investigational Site	Istanbul		Turkey	34760
218	Novo Nordisk Investigational Site	Izmir		Turkey	35100
219	Novo Nordisk Investigational Site	Izmir		Turkey	35340
220	Novo Nordisk Investigational Site	Rize		Turkey	53020
221	Novo Nordisk Investigational Site	Aberdeen		United Kingdom	AB25 2ZD
222	Novo Nordisk Investigational Site	Bristol		United Kingdom	BS10 5NB
223	Novo Nordisk Investigational Site	Dundee		United Kingdom	DD1 9SY
224	Novo Nordisk Investigational Site	Edinburgh		United Kingdom	EH4 2XU
225	Novo Nordisk Investigational Site	Exeter		United Kingdom	EX2 5DW
226	Novo Nordisk Investigational Site	Guildford		United Kingdom	GU2 7XX
227	Novo Nordisk Investigational Site	Norfolk		United Kingdom	NR4 7UQ
228	Novo Nordisk Investigational Site	Swansea		United Kingdom	SA2 8PP
229	Novo Nordisk Investigational Site	Watford		United Kingdom	WD18 0HB

Sponsors and Collaborators

• Novo Nordisk A/S

Investigators

• Study Director: Global Clinical Registry (GCR, 1452), Novo Nordisk A/S

Study Documents (Full-Text)

• Study Protocol - Feb 11, 2019
• Statistical Analysis Plan - Feb 11, 2019

More Information

Additional Information:

• Clinical Trials at Novo Nordisk

Publications

None provided.

• Responsible Party: Novo Nordisk A/S
• ClinicalTrials.gov Identifier: NCT02692716
• Other Study ID Numbers: NN9924-4221; 2015-003563-10; U1111-1173-0750; NL56580.091.16
• First Posted: Feb 26, 2016
• Last Update Posted: Jul 20, 2022
• Last Verified: Jul 1, 2022

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2

Study Results

Participant Flow

Recruitment Details	The study was conducted at 214 sites in 21 countries: Algeria (4), Argentina (6), Brazil (1), Canada (7), Denmark (5), Germany (10), India (16), Israel (8), Italy (7), Malaysia (10), Mexico (6), Netherlands (5), Poland (5), Romania (8), South Africa (9), Spain (9), Taiwan (4), Thailand (7), Turkey (9) and United Kingdom (9), United Stated (69).
Pre-assignment Detail	Data presented in "participant flow" is based on the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product.

Arm/Group Title	Oral Semaglutide	Placebo
Arm/Group Description	Participants were to take once-daily semaglutide tablets in a dose escalation manner for upto 82 weeks: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 9 to upto week 82.	Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Period Title: Overall Study
STARTED	1591	1592
Full Analysis Set (FAS)	1591	1592
Exposed	1591	1591
COMPLETED	1586	1586
NOT COMPLETED	5	6

Baseline Characteristics

Arm/Group Title	Oral Semaglutide	Placebo	Total
Arm/Group Description	Participants were to take once-daily semaglutide tablets in a dose escalation manner for upto 82 weeks: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 9 to upto week 82.	Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.	Total of all reporting groups
Overall Participants	1591	1592	3183
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	66 (7)	66 (7)	66 (7)
Sex: Female, Male (Count of Participants)
Female	507 31.9%	500 31.4%	1007 31.6%
Male	1084 68.1%	1092 68.6%	2176 68.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	253 15.9%	261 16.4%	514 16.1%
Not Hispanic or Latino	1338 84.1%	1331 83.6%	2669 83.9%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	1148 72.2%	1152 72.4%	2300 72.3%
Black or African American	89 5.6%	103 6.5%	192 6%
Asian	324 20.4%	306 19.2%	630 19.8%
American Indian or Alaska native	14 0.9%	15 0.9%	29 0.9%
Native Hawaiian or Other Pacific Islander	5 0.3%	1 0.1%	6 0.2%
Other	11 0.7%	15 0.9%	26 0.8%
Baseline cardiovasular disease (CVD)/chronic kidney disease (CKD) risk details (Count of Participants)
Established CVD and/or CKD, age ≥ 50 years	1350 84.9%	1345 84.5%	2695 84.7%
Evidence of CV risk factors, age ≥ 60 years	241 15.1%	247 15.5%	488 15.3%

Outcome Measures

1. Primary Outcome

Title	Time From Randomisation to First Occurrence of a Major Adverse Cardiovascular Event (MACE) Composite Endpoint Consisting of: Cardiovascular Death, Non-fatal Myocardial Infarction or Non-fatal Stroke
Description	Number of participants experiencing a first event of a MACE, defined as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.
Time Frame	Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = full analysis set (FAS) which comprised all randomised participants.

Arm/Group Title	Oral Semaglutide	Placebo
Arm/Group Description	Participants were to take once-daily semaglutide tablets in a dose escalation manner for upto 82 weeks: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 9 to upto week 82.	Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Measure Participants	1591	1592
Count of Participants [Participants]	61 3.8%	76 4.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide, Placebo
	Comments	Data from the in-trial observation period. Time from randomisation to first event adjudication committee (EAC) confirmed MACE was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of cardiovascular disease at screening. Participants were censored at the end of their in-trial observation period.
	Type of Statistical Test	Non-Inferiority
	Comments	This hypothesis was controlled for multiplicity. Non-inferiority of oral semaglutide versus placebo was considered confirmed if the upper limit of the two-sided 95% confidence interval for the HR was strictly below 1.8.
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments	Unadjusted two-sided p-value for test of no difference from the non-inferiority margin (non-inferiority).
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.79
	Confidence Interval	(2-Sided) 95%; 0.57 to 1.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide, Placebo
	Comments	Data from the in-trial observation period. Time from randomisation to first EAC-confirmed MACE was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of cardiovascular disease at screening. Participants were censored at the end of their in-trial observation period.
	Type of Statistical Test	Superiority
	Comments	This hypothesis was controlled for multiplicity.
Statistical Test of Hypothesis	p-Value	= 0.1749
	Comments	Unadjusted two-sided p-value from test of no difference from 1 (superiority).
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.79
	Confidence Interval	(2-Sided) 95%; 0.57 to 1.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Time From Randomisation to First Occurrence of an Expanded Composite Cardiovascular Endpoint Consisting of: Cardiovascular Death, Non-fatal Myocardial Infarction, Non-fatal Stroke, UAP Requiring Hospitalisation or Hospitalisation for Heart Failure
Description	Participants experiencing first occurrence of an expanded composite CV endpoint [defined as cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, UAP (unstable angina pectoris) requiring hospitalisation or heart failure requiring hospitalisation] are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.
Time Frame	Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = FAS which comprised all randomised participants.

Arm/Group Title	Oral Semaglutide	Placebo
Arm/Group Description	Participants were to take once-daily semaglutide tablets in a dose escalation manner for upto 82 weeks: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 9 to upto week 82.	Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Measure Participants	1591	1592
Count of Participants [Participants]	83 5.2%	100 6.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide, Placebo
	Comments	Data from the in-trial observation period. Time from randomisation to first EAC-confirmed expanded cardiovascular outcome was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of cardiovascular disease at screening. Participants were censored at the end of their in-trial observation period.
	Type of Statistical Test	Other
	Comments	This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis	p-Value	= 0.1827
	Comments	Unadjusted two-sided p-value for test of no difference from 1.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.61 to 1.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Time From Randomisation to First Occurrence of Each of the Individual Components in the Expanded Composite Cardiovascular Endpoint
Description	Participants experiencing an event onset for each individual component of the expanded composite cardiovascular outcomes (defined as cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, unstable angina requiring hospitalisation or heart failure requiring hospitalisation) are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.
Time Frame	Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = FAS which comprised all randomised participants.

Arm/Group Title	Oral Semaglutide	Placebo
Arm/Group Description	Participants were to take once-daily semaglutide tablets in a dose escalation manner for upto 82 weeks: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 9 to upto week 82.	Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Measure Participants	1591	1592
Cardiovascular death	15 0.9%	30 1.9%
Non-fatal myocardial infarction	37 2.3%	31 1.9%
Non-fatal stroke	12 0.8%	16 1%
Unstable angina requiring hospitalisation	11 0.7%	7 0.4%
Heart failure requiring hospitalisation	21 1.3%	24 1.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide, Placebo
	Comments	Data from the in-trial observation period. Time from randomisation to first EAC-confirmed cardiovascular death (including undetermined cause of death) was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of cardiovascular disease at screening. Participants were censored at the end of their in-trial observation period.
	Type of Statistical Test	Other
	Comments	This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis	p-Value	= 0.0261
	Comments	Unadjusted two-sided p-value for test of no difference from 1.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.49
	Confidence Interval	(2-Sided) 95%; 0.27 to 0.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide, Placebo
	Comments	Data from the in-trial observation period. Time from randomisation to first EAC-confirmed non-fatal myocardial infarction was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of cardiovascular disease at screening. Participants were censored at the end of their in-trial observation period.
	Type of Statistical Test	Other
	Comments	This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis	p-Value	= 0.5044
	Comments	Unadjusted two-sided p-value for test of no difference from 1.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.18
	Confidence Interval	(2-Sided) 95%; 0.73 to 1.90
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide, Placebo
	Comments	Data from the in-trial observation period. Time from randomisation to first EAC-confirmed non-fatal stroke was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of cardiovascular disease at screening. Participants were censored at the end of their in-trial observation period.
	Type of Statistical Test	Other
	Comments	This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis	p-Value	= 0.4350
	Comments	Unadjusted two-sided p-value for test of no difference from 1
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95%; 0.35 to 1.57
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide, Placebo
	Comments	Data from the in-trial observation period. Time from randomisation to first EAC-confirmed unstable angina pectoris requiring hospitalisation was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of cardiovascular disease at screening. Participants were censored at the end of their in-trial observation period.
	Type of Statistical Test	Other
	Comments	This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis	p-Value	= 0.3605
	Comments	Unadjusted two-sided p-value for test of no difference from 1.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.56
	Confidence Interval	(2-Sided) 95%; 0.60 to 4.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide, Placebo
	Comments	Data from the in-trial observation period. Time from randomisation to first EAC-confirmed hospitalisation for heart failure was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of cardiovascular disease at screening. Participants were censored at the end of their in-trial observation period.
	Type of Statistical Test	Other
	Comments	This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis	p-Value	= 0.6227
	Comments	Unadjusted two-sided p-value for test of no difference from 1.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.86
	Confidence Interval	(2-Sided) 95%; 0.48 to 1.55
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Time From Randomisation to First Occurrence of a Composite Endpoint Consisting of: All-cause Death, Non-fatal Myocardial Infarction or Nonfatal Stroke
Description	Participants experiencing first occurrence of a composite CV endpoint (defined as all-cause death, non-fatal myocardial infarction or nonfatal stroke) are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.
Time Frame	Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = FAS which comprised all randomised participants.

Arm/Group Title	Oral Semaglutide	Placebo
Arm/Group Description	Participants were to take once-daily semaglutide tablets in a dose escalation manner for upto 82 weeks: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 9 to upto week 82.	Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Measure Participants	1591	1592
Count of Participants [Participants]	69 4.3%	89 5.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide, Placebo
	Comments	Data from the in-trial observation period. Time from randomisation to first EAC-confirmed all-cause death, non-fatal myocardial infarction or non-fatal stroke was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of cardiovascular disease at screening. Participants were censored at the end of their in-trial observation period.
	Type of Statistical Test	Other
	Comments	This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis	p-Value	= 0.0952
	Comments	Unadjusted two-sided p-value for test of no difference from 1.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.56 to 1.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Time From Randomisation to First Occurrence of Fatal or Non-fatal Myocardial Infarction
Description	Number of participants experiencing a first event of a fatal or non-fatal myocardial infarction are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.
Time Frame	Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = FAS which comprised all randomised participants.

Arm/Group Title	Oral Semaglutide	Placebo
Arm/Group Description	Participants were to take once-daily semaglutide tablets in a dose escalation manner for upto 82 weeks: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 9 to upto week 82.	Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Measure Participants	1591	1592
Count of Participants [Participants]	37 2.3%	35 2.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide, Placebo
	Comments	Data from the on-treatment observation period. Time from first dose of trial product to first EAC-confirmed fatal or non-fatal myocardial infarction was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of cardiovascular disease at screening. Participants were censored at the end of their on-treatment observation period.
	Type of Statistical Test	Other
	Comments	This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis	p-Value	0.8583
	Comments	Unadjusted two-sided p-value for test of no difference from 1.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 0.66 to 1.66
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Time From Randomisation to First Occurrence of Fatal or Non-fatal Stroke
Description	Number of participants experiencing a first event of a fatal or non-fatal stroke are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.
Time Frame	Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = FAS which comprised all randomised participants.

Arm/Group Title	Oral Semaglutide	Placebo
Arm/Group Description	Participants were to take once-daily semaglutide tablets in a dose escalation manner for upto 82 weeks: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 9 to upto week 82.	Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Measure Participants	1591	1592
Count of Participants [Participants]	13 0.8%	17 1.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide, Placebo
	Comments	Data from the in-trial observation period. Time from randomisation to first EAC-confirmed fatal or non-fatal stroke was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of cardiovascular disease at screening. Participants were censored at the end of their in-trial observation period.
	Type of Statistical Test	Other
	Comments	This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis	p-Value	0.4485
	Comments	Unadjusted two-sided p-value for test of no difference from 1.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.37 to 1.56
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Time From Randomisation to All-cause Death
Description	Number of all-cause deaths in the study are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.
Time Frame	Maximum treatment duration is dependent on event rates and is expected to be no longer than 19 months + 5 weeks of follow-up period.

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = FAS which comprised all randomised participants.

Arm/Group Title	Oral Semaglutide	Placebo
Arm/Group Description	Participants were to take once-daily semaglutide tablets in a dose escalation manner for upto 82 weeks: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 9 to upto week 82.	Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Measure Participants	1591	1592
Count of Participants [Participants]	23 1.4%	45 2.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide, Placebo
	Comments	Data from the in-trial observation period. Time from randomisation to first EAC-confirmed all-cause death was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of cardiovascular disease at screening. Participants were censored at the end of their in-trial observation period.
	Type of Statistical Test	Other
	Comments	This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis	p-Value	0.0078
	Comments	Unadjusted two-sided p-value for test of no difference from 1.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.51
	Confidence Interval	(2-Sided) 95%; 0.31 to 0.84
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Time to First AE Leading to Permanent Trial Product Discontinuation
Description	Number of participants who permanently discontinued trial product in ths study are presented. Results are based on the on-treatment observation period which starts at the date of first dose on trial product; ends on last date on trial product +38 days (ascertainment window).
Time Frame	Maximum treatment duration is dependent on event rates and is expected to be no longer than 19 months + 38 days of ascertainment window.

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = FAS which comprised all randomised participants.

Arm/Group Title	Oral Semaglutide	Placebo
Arm/Group Description	Participants were to take once-daily semaglutide tablets in a dose escalation manner for upto 82 weeks: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 9 to upto week 82.	Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Measure Participants	1591	1592
Count of Participants [Participants]	184 11.6%	104 6.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide, Placebo
	Comments	Data from date of first dose of trial product to date of end of treatment visit. Time from first dose to first AE leading to permanent trial product discontinuation was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of cardiovascular disease at screening. Participants were censored at the date of their end of treatment visit or at their end of study date, whichever came first.
	Type of Statistical Test	Other
	Comments	This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Unadjusted two-sided p-value for test of no difference from 1.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.81
	Confidence Interval	(2-Sided) 95%; 1.42 to 2.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Number of Serious Adverse Events
Description	Number of serious adverse events were recorded from week 0 to week 87 in the study. Results are based on the on-treatment observation period which started at the date of first dose on trial product and ended on last date on trial product +38 days (ascertainment window).
Time Frame	Maximum treatment duration is dependent on event rates and is expected to be no longer than 19 months + 38 days of ascertainment window.

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = FAS which comprised all randomised participants.

Arm/Group Title	Oral Semaglutide	Placebo
Arm/Group Description	Participants were to take once-daily semaglutide tablets in a dose escalation manner for upto 82 weeks: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 9 to upto week 82.	Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Measure Participants	1591	1592
Number [Events]	545	618

10. Secondary Outcome

Title	Change in Eye Examination Category
Description	Participants with eye examination findings, normal, abnormal non clinically significant (NCS) and abnormal clinically significant (CS) at baseline (week -3) and end of treatment visit (week 83) are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.
Time Frame	Week -3, End of treatment

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = FAS which comprised all randomised participants. Number Analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide	Placebo
Arm/Group Description	Participants were to take once-daily semaglutide tablets in a dose escalation manner for upto 82 weeks: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 9 to upto week 82.	Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Measure Participants	1591	1592
Left eye fundoscopy (week -3): Normal	848 53.3%	843 53%
Left eye fundoscopy (week -3): Abnormal NCS	657 41.3%	673 42.3%
Left eye fundoscopy (week -3): Abnormal CS	86 5.4%	74 4.6%
Right eye fundoscopy (week -3): Normal	845 53.1%	858 53.9%
Right eye fundoscopy (week -3): Abnormal NCS	659 41.4%	661 41.5%
Right eye fundoscopy (week -3): Abnormal CS	86 5.4%	72 4.5%
Left eye fundoscopy (EOT): Normal	783 49.2%	790 49.6%
Left eye fundoscopy (EOT): Abnormal NCS	599 37.6%	597 37.5%
Left eye fundoscopy (EOT): Abnormal CS	83 5.2%	62 3.9%
Right eye fundoscopy (EOT): Normal	780 49%	787 49.4%
Right eye fundoscopy (EOT): Abnormal NCS	601 37.8%	599 37.6%
Right eye fundoscopy (EOT): Abnormal CS	81 5.1%	64 4%

11. Secondary Outcome

Title	Change in Pulse Rate
Description	Change from baseline (week 0) in pulse rate measured at the end of treatment visit (week 83) is reported. Results are based on the on-treatment observation period which started at the date of first dose on trial product, ended on last date on trial product +38 days (ascertainment window).
Time Frame	Week 0, End of treatment

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide	Placebo
Arm/Group Description	Participants were to take once-daily semaglutide tablets in a dose escalation manner for upto 82 weeks: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 9 to upto week 82.	Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Measure Participants	1345	1411
Mean (Standard Deviation) [Beats/minute]	4 (11)	-0 (11)

12. Secondary Outcome

Title	Change in Systolic and Diastolic Blood Pressure
Description	Change from baseline (week 0) in systolic and diastolic blood pressure measured at the end of treatment visit (week 83) is reported. Results are based on the on-treatment observation period which started at the date of first dose on trial product, ended on last date on trial product +38 days (ascertainment window).
Time Frame	Week 0, End of treatment

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide	Placebo
Arm/Group Description	Participants were to take once-daily semaglutide tablets in a dose escalation manner for upto 82 weeks: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 9 to upto week 82.	Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Measure Participants	1345	1411
Systolic blood pressure	-5 (18)	-2 (18)
Diastolic blood pressure	-1 (11)	-2 (10)

13. Secondary Outcome

Title	Change in Glycosylated Haemoglobin (HbA1c)
Description	Change from baseline (week 0) in HbA1c measured at the end of treatment visit (week 83) is reported. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.
Time Frame	Week 0, End of treatment

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide	Placebo
Arm/Group Description	Participants were to take once-daily semaglutide tablets in a dose escalation manner for upto 82 weeks: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 9 to upto week 82.	Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Measure Participants	1489	1473
Mean (Standard Deviation) [Percentage of HbA1c]	-1.0 (1.4)	-0.3 (1.3)

14. Secondary Outcome

Title	Change in Body Weight
Description	Change from baseline (week 0) in body weight measured at the end of treatment visit (week 83) is reported. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.
Time Frame	Week 0, End of treatment

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide	Placebo
Arm/Group Description	Participants were to take once-daily semaglutide tablets in a dose escalation manner for upto 82 weeks: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 9 to upto week 82.	Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Measure Participants	1510	1493
Mean (Standard Deviation) [Kg]	-4.2 (5.7)	-0.8 (4.5)

15. Secondary Outcome

Title	Change in Total Cholesterol - Ratio to Baseline
Description	Change from baseline (week 0) in total cholesterol (mmol/L) at the end of treatment (week 83) visit is presented as ratio to baseline. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.
Time Frame	Week 0, End of treatment

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide	Placebo
Arm/Group Description	Participants were to take once-daily semaglutide tablets in a dose escalation manner for upto 82 weeks: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 9 to upto week 82.	Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Measure Participants	1472	1469
Geometric Mean (Geometric Coefficient of Variation) [Ratio of total cholesterol]	0.97 (21.9)	0.98 (21.1)

16. Secondary Outcome

Title	Change in LDL-cholesterol - Ratio to Baseline
Description	Change from baseline (week 0) in LDL cholesterol (mmol/L) at end of treatment visit (week 83) is presented as ratio to baseline. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.
Time Frame	Week 0, End of treatment

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide	Placebo
Arm/Group Description	Participants were to take once-daily semaglutide tablets in a dose escalation manner for upto 82 weeks: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 9 to upto week 82.	Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Measure Participants	1466	1467
Geometric Mean (Geometric Coefficient of Variation) [Ratio of LDL-cholesterol]	0.96 (36.6)	0.97 (34.5)

17. Secondary Outcome

Title	Change in HDL-cholesterol - Ratio to Baseline
Description	Change from baseline (week 0) in HDL cholesterol (mmol/L) at end of treatment visit (week 83) is presented as ratio to baseline. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.
Time Frame	Week 0, End of treatment

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide	Placebo
Arm/Group Description	Participants were to take once-daily semaglutide tablets in a dose escalation manner for upto 82 weeks: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 9 to upto week 82.	Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Measure Participants	1468	1467
Geometric Mean (Geometric Coefficient of Variation) [Ratio of HDL-cholesterol]	1.05 (16.9)	1.02 (15.9)

18. Secondary Outcome

Title	Change in Triglycerides - Ratio to Baseline
Description	Change from baseline (week 0) in triglycerides (mmol/L) at end of treatment visit (week 83) is presented as ratio to baseline. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.
Time Frame	Week 0, End of treatment

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide	Placebo
Arm/Group Description	Participants were to take once-daily semaglutide tablets in a dose escalation manner for upto 82 weeks: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 9 to upto week 82.	Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Measure Participants	1468	1467
Geometric Mean (Geometric Coefficient of Variation) [Ratio of triglycerides]	0.92 (41.8)	0.97 (39.8)

Adverse Events

Time Frame	Week 0 to 87. SAEs and other AEs were based on the on-treatment observation period, i.e., the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication. All-cause mortality were based on the in-trial observation period, i.e., the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product.
Adverse Event Reporting Description	Systematic collection of AEs was limited to SAEs, AEs leading to permanent discontinuation of trial product, medication errors leading to SAEs, severe hypoglycaemic episodes, hepatic events, pregnancies and AEs related to technical complaints and were summarised. Non-serious AEs not fulfilling the above criteria were not systematically collected.
Arm/Group Title	Oral Semaglutide		Placebo
Arm/Group Description	Participants were to take once-daily semaglutide tablets in a dose escalation manner for upto 82 weeks: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 9 to upto week 82.		Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
All Cause Mortality
	Oral Semaglutide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/1591 (1.4%)		45/1591 (2.8%)
Serious Adverse Events
	Oral Semaglutide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	301/1591 (18.9%)		358/1591 (22.5%)
Blood and lymphatic system disorders
Anaemia	2/1591 (0.1%)	2	2/1591 (0.1%)	2
Autoimmune haemolytic anaemia	1/1591 (0.1%)	1	0/1591 (0%)	0
Iron deficiency anaemia	2/1591 (0.1%)	2	1/1591 (0.1%)	1
Leukocytosis	1/1591 (0.1%)	1	0/1591 (0%)	0
Splenic haemorrhage	1/1591 (0.1%)	1	0/1591 (0%)	0
Cardiac disorders
Acute coronary syndrome	1/1591 (0.1%)	1	0/1591 (0%)	0
Acute left ventricular failure	2/1591 (0.1%)	2	2/1591 (0.1%)	2
Acute myocardial infarction	21/1591 (1.3%)	25	22/1591 (1.4%)	25
Angina pectoris	8/1591 (0.5%)	9	7/1591 (0.4%)	7
Angina unstable	19/1591 (1.2%)	20	15/1591 (0.9%)	18
Arrhythmia	1/1591 (0.1%)	1	1/1591 (0.1%)	1
Arteriosclerosis coronary artery	1/1591 (0.1%)	1	0/1591 (0%)	0
Arteriospasm coronary	0/1591 (0%)	0	1/1591 (0.1%)	1
Atrial fibrillation	6/1591 (0.4%)	8	14/1591 (0.9%)	14
Atrial flutter	3/1591 (0.2%)	3	1/1591 (0.1%)	1
Atrioventricular block complete	0/1591 (0%)	0	1/1591 (0.1%)	1
Atrioventricular block first degree	1/1591 (0.1%)	1	0/1591 (0%)	0
Atrioventricular block second degree	3/1591 (0.2%)	3	1/1591 (0.1%)	1
Bradycardia	1/1591 (0.1%)	1	0/1591 (0%)	0
Cardiac arrest	5/1591 (0.3%)	6	0/1591 (0%)	0
Cardiac failure	2/1591 (0.1%)	2	7/1591 (0.4%)	8
Cardiac failure acute	2/1591 (0.1%)	3	2/1591 (0.1%)	2
Cardiac failure chronic	5/1591 (0.3%)	5	8/1591 (0.5%)	9
Cardiac failure congestive	9/1591 (0.6%)	12	9/1591 (0.6%)	11
Cardiac flutter	0/1591 (0%)	0	1/1591 (0.1%)	1
Cardio-respiratory arrest	1/1591 (0.1%)	1	3/1591 (0.2%)	3
Cardiogenic shock	0/1591 (0%)	0	1/1591 (0.1%)	1
Cardiomyopathy	1/1591 (0.1%)	1	0/1591 (0%)	0
Cardiopulmonary failure	0/1591 (0%)	0	1/1591 (0.1%)	1
Cardiorenal syndrome	0/1591 (0%)	0	1/1591 (0.1%)	1
Coronary artery disease	9/1591 (0.6%)	9	13/1591 (0.8%)	13
Coronary artery stenosis	1/1591 (0.1%)	1	3/1591 (0.2%)	3
Coronary artery thrombosis	0/1591 (0%)	0	1/1591 (0.1%)	1
Degenerative aortic valve disease	1/1591 (0.1%)	1	0/1591 (0%)	0
Hypertensive heart disease	0/1591 (0%)	0	1/1591 (0.1%)	1
Ischaemic cardiomyopathy	1/1591 (0.1%)	1	1/1591 (0.1%)	1
Left ventricular failure	0/1591 (0%)	0	4/1591 (0.3%)	4
Mitral valve incompetence	1/1591 (0.1%)	1	0/1591 (0%)	0
Myocardial infarction	11/1591 (0.7%)	11	9/1591 (0.6%)	9
Myocardial ischaemia	2/1591 (0.1%)	2	3/1591 (0.2%)	3
Myocarditis	1/1591 (0.1%)	1	0/1591 (0%)	0
Prinzmetal angina	0/1591 (0%)	0	1/1591 (0.1%)	1
Pulseless electrical activity	0/1591 (0%)	0	1/1591 (0.1%)	1
Sinus node dysfunction	0/1591 (0%)	0	1/1591 (0.1%)	1
Supraventricular tachycardia	0/1591 (0%)	0	1/1591 (0.1%)	1
Tachycardia	1/1591 (0.1%)	1	0/1591 (0%)	0
Ventricular fibrillation	1/1591 (0.1%)	1	0/1591 (0%)	0
Ventricular tachycardia	0/1591 (0%)	0	1/1591 (0.1%)	1
Ear and labyrinth disorders
Vertigo	0/1591 (0%)	0	1/1591 (0.1%)	1
Endocrine disorders
Hyperthyroidism	0/1591 (0%)	0	1/1591 (0.1%)	1
Thyroid mass	0/1591 (0%)	0	1/1591 (0.1%)	1
Eye disorders
Cataract	8/1591 (0.5%)	8	5/1591 (0.3%)	6
Retinal tear	1/1591 (0.1%)	1	0/1591 (0%)	0
Retinopathy proliferative	0/1591 (0%)	0	1/1591 (0.1%)	1
Gastrointestinal disorders
Abdominal pain	2/1591 (0.1%)	2	2/1591 (0.1%)	2
Abdominal pain upper	1/1591 (0.1%)	1	0/1591 (0%)	0
Colitis	1/1591 (0.1%)	1	0/1591 (0%)	0
Colitis ischaemic	2/1591 (0.1%)	2	0/1591 (0%)	0
Constipation	0/1591 (0%)	0	1/1591 (0.1%)	1
Diarrhoea	4/1591 (0.3%)	4	0/1591 (0%)	0
Duodenal ulcer	0/1591 (0%)	0	1/1591 (0.1%)	1
Duodenal ulcer haemorrhage	1/1591 (0.1%)	1	1/1591 (0.1%)	1
Dyspepsia	1/1591 (0.1%)	1	0/1591 (0%)	0
Gastric ulcer	1/1591 (0.1%)	1	0/1591 (0%)	0
Gastritis	1/1591 (0.1%)	1	0/1591 (0%)	0
Gastroduodenitis	1/1591 (0.1%)	1	0/1591 (0%)	0
Gastrointestinal haemorrhage	1/1591 (0.1%)	1	1/1591 (0.1%)	2
Gastrointestinal polyp haemorrhage	0/1591 (0%)	0	1/1591 (0.1%)	1
Gastrooesophageal reflux disease	1/1591 (0.1%)	1	0/1591 (0%)	0
Haematochezia	1/1591 (0.1%)	1	0/1591 (0%)	0
Haemorrhoids	1/1591 (0.1%)	1	0/1591 (0%)	0
Impaired gastric emptying	0/1591 (0%)	0	1/1591 (0.1%)	1
Inguinal hernia	2/1591 (0.1%)	2	2/1591 (0.1%)	2
Intestinal ischaemia	0/1591 (0%)	0	1/1591 (0.1%)	1
Intestinal mass	0/1591 (0%)	0	1/1591 (0.1%)	1
Large intestine polyp	1/1591 (0.1%)	1	0/1591 (0%)	0
Lower gastrointestinal haemorrhage	2/1591 (0.1%)	2	1/1591 (0.1%)	1
Nausea	2/1591 (0.1%)	2	1/1591 (0.1%)	1
Oesophageal haemorrhage	1/1591 (0.1%)	1	0/1591 (0%)	0
Oesophageal varices haemorrhage	0/1591 (0%)	0	1/1591 (0.1%)	1
Oesophagitis	0/1591 (0%)	0	1/1591 (0.1%)	1
Oesophagitis ulcerative	0/1591 (0%)	0	1/1591 (0.1%)	1
Pancreatitis	1/1591 (0.1%)	1	1/1591 (0.1%)	1
Pancreatitis acute	0/1591 (0%)	0	1/1591 (0.1%)	1
Pancreatitis chronic	0/1591 (0%)	0	1/1591 (0.1%)	1
Peptic ulcer haemorrhage	0/1591 (0%)	0	1/1591 (0.1%)	1
Salivary gland calculus	0/1591 (0%)	0	1/1591 (0.1%)	1
Umbilical hernia	2/1591 (0.1%)	2	1/1591 (0.1%)	1
Vomiting	4/1591 (0.3%)	4	0/1591 (0%)	0
General disorders
Asthenia	3/1591 (0.2%)	3	0/1591 (0%)	0
Chest pain	1/1591 (0.1%)	1	2/1591 (0.1%)	2
Death	1/1591 (0.1%)	1	3/1591 (0.2%)	3
Drowning	0/1591 (0%)	0	1/1591 (0.1%)	1
Fatigue	1/1591 (0.1%)	1	0/1591 (0%)	0
Hernia pain	0/1591 (0%)	0	1/1591 (0.1%)	1
Non-cardiac chest pain	9/1591 (0.6%)	11	7/1591 (0.4%)	9
Oedema peripheral	1/1591 (0.1%)	1	0/1591 (0%)	0
Peripheral swelling	0/1591 (0%)	0	1/1591 (0.1%)	1
Pyrexia	0/1591 (0%)	0	1/1591 (0.1%)	1
Sudden cardiac death	0/1591 (0%)	0	2/1591 (0.1%)	2
Systemic inflammatory response syndrome	1/1591 (0.1%)	1	0/1591 (0%)	0
Vascular stent restenosis	0/1591 (0%)	0	1/1591 (0.1%)	1
Hepatobiliary disorders
Bile duct stone	1/1591 (0.1%)	1	0/1591 (0%)	0
Biliary fistula	0/1591 (0%)	0	1/1591 (0.1%)	1
Cholangitis acute	1/1591 (0.1%)	1	0/1591 (0%)	0
Cholecystitis	1/1591 (0.1%)	1	2/1591 (0.1%)	2
Cholecystitis acute	3/1591 (0.2%)	3	2/1591 (0.1%)	2
Cholecystitis chronic	1/1591 (0.1%)	1	0/1591 (0%)	0
Cholelithiasis	2/1591 (0.1%)	2	4/1591 (0.3%)	4
Drug-induced liver injury	0/1591 (0%)	0	1/1591 (0.1%)	1
Gallbladder polyp	0/1591 (0%)	0	1/1591 (0.1%)	1
Hepatic cirrhosis	1/1591 (0.1%)	1	1/1591 (0.1%)	1
Hepatic steatosis	1/1591 (0.1%)	1	2/1591 (0.1%)	2
Hepatitis	1/1591 (0.1%)	1	0/1591 (0%)	0
Liver disorder	1/1591 (0.1%)	1	0/1591 (0%)	0
Immune system disorders
Anaphylactic reaction	0/1591 (0%)	0	1/1591 (0.1%)	1
Infections and infestations
Abscess limb	1/1591 (0.1%)	1	0/1591 (0%)	0
Anal abscess	0/1591 (0%)	0	1/1591 (0.1%)	1
Biliary sepsis	0/1591 (0%)	0	1/1591 (0.1%)	1
Bronchitis	1/1591 (0.1%)	1	3/1591 (0.2%)	4
Campylobacter gastroenteritis	1/1591 (0.1%)	1	0/1591 (0%)	0
Carbuncle	1/1591 (0.1%)	1	0/1591 (0%)	0
Cellulitis	9/1591 (0.6%)	9	7/1591 (0.4%)	7
Cholecystitis infective	0/1591 (0%)	0	1/1591 (0.1%)	1
Device related infection	1/1591 (0.1%)	1	2/1591 (0.1%)	3
Diabetic foot infection	1/1591 (0.1%)	1	0/1591 (0%)	0
Diabetic gangrene	1/1591 (0.1%)	1	0/1591 (0%)	0
Diverticulitis	3/1591 (0.2%)	3	2/1591 (0.1%)	2
Empyema	1/1591 (0.1%)	1	0/1591 (0%)	0
Endocarditis bacterial	1/1591 (0.1%)	1	0/1591 (0%)	0
Erysipelas	0/1591 (0%)	0	3/1591 (0.2%)	3
Escherichia pyelonephritis	0/1591 (0%)	0	1/1591 (0.1%)	1
Folliculitis	0/1591 (0%)	0	1/1591 (0.1%)	1
Gallbladder empyema	1/1591 (0.1%)	1	0/1591 (0%)	0
Gangrene	0/1591 (0%)	0	1/1591 (0.1%)	1
Gastroenteritis	5/1591 (0.3%)	5	5/1591 (0.3%)	5
Gastroenteritis viral	1/1591 (0.1%)	1	0/1591 (0%)	0
Herpes zoster	0/1591 (0%)	0	1/1591 (0.1%)	1
Infective tenosynovitis	1/1591 (0.1%)	1	0/1591 (0%)	0
Influenza	2/1591 (0.1%)	2	1/1591 (0.1%)	1
Injection site abscess	1/1591 (0.1%)	1	0/1591 (0%)	0
Intervertebral discitis	0/1591 (0%)	0	1/1591 (0.1%)	1
Lower respiratory tract infection	2/1591 (0.1%)	2	0/1591 (0%)	0
Ludwig angina	0/1591 (0%)	0	1/1591 (0.1%)	1
Meningitis	1/1591 (0.1%)	1	0/1591 (0%)	0
Murine typhus	1/1591 (0.1%)	1	0/1591 (0%)	0
Myelitis	1/1591 (0.1%)	1	0/1591 (0%)	0
Oral infection	0/1591 (0%)	0	1/1591 (0.1%)	1
Osteomyelitis	5/1591 (0.3%)	5	1/1591 (0.1%)	1
Periorbital cellulitis	0/1591 (0%)	0	1/1591 (0.1%)	1
Pneumonia	12/1591 (0.8%)	13	21/1591 (1.3%)	21
Pneumonia acinetobacter	1/1591 (0.1%)	1	0/1591 (0%)	0
Pneumonia escherichia	0/1591 (0%)	0	1/1591 (0.1%)	1
Pneumonia influenzal	1/1591 (0.1%)	1	0/1591 (0%)	0
Pneumonia klebsiella	0/1591 (0%)	0	1/1591 (0.1%)	1
Pneumonia streptococcal	1/1591 (0.1%)	1	0/1591 (0%)	0
Post procedural cellulitis	0/1591 (0%)	0	1/1591 (0.1%)	1
Post procedural infection	0/1591 (0%)	0	1/1591 (0.1%)	1
Post procedural pneumonia	1/1591 (0.1%)	1	0/1591 (0%)	0
Postoperative wound infection	0/1591 (0%)	0	2/1591 (0.1%)	2
Pulmonary tuberculosis	1/1591 (0.1%)	1	0/1591 (0%)	0
Pyelonephritis	0/1591 (0%)	0	1/1591 (0.1%)	1
Pyelonephritis acute	1/1591 (0.1%)	1	2/1591 (0.1%)	2
Rectal abscess	0/1591 (0%)	0	1/1591 (0.1%)	1
Sepsis	3/1591 (0.2%)	3	6/1591 (0.4%)	6
Septic shock	2/1591 (0.1%)	2	3/1591 (0.2%)	3
Sialoadenitis	0/1591 (0%)	0	2/1591 (0.1%)	2
Sinusitis	1/1591 (0.1%)	1	0/1591 (0%)	0
Staphylococcal bacteraemia	0/1591 (0%)	0	1/1591 (0.1%)	1
Tinea pedis	0/1591 (0%)	0	1/1591 (0.1%)	1
Tonsillitis	0/1591 (0%)	0	1/1591 (0.1%)	1
Upper respiratory tract infection	1/1591 (0.1%)	1	1/1591 (0.1%)	1
Upper respiratory tract infection bacterial	1/1591 (0.1%)	1	0/1591 (0%)	0
Urinary tract infection	3/1591 (0.2%)	3	5/1591 (0.3%)	5
Urosepsis	2/1591 (0.1%)	2	3/1591 (0.2%)	5
Wound sepsis	1/1591 (0.1%)	1	0/1591 (0%)	0
Injury, poisoning and procedural complications
Accidental overdose	1/1591 (0.1%)	1	0/1591 (0%)	0
Ankle fracture	1/1591 (0.1%)	1	1/1591 (0.1%)	1
Brain contusion	1/1591 (0.1%)	1	0/1591 (0%)	0
Cervical vertebral fracture	0/1591 (0%)	0	1/1591 (0.1%)	1
Chemical peritonitis	0/1591 (0%)	0	1/1591 (0.1%)	1
Comminuted fracture	0/1591 (0%)	0	1/1591 (0.1%)	1
Coronary artery restenosis	0/1591 (0%)	0	1/1591 (0.1%)	1
Ear injury	0/1591 (0%)	0	1/1591 (0.1%)	1
Facial bones fracture	0/1591 (0%)	0	1/1591 (0.1%)	1
Fall	5/1591 (0.3%)	5	11/1591 (0.7%)	11
Femoral neck fracture	0/1591 (0%)	0	2/1591 (0.1%)	2
Femur fracture	2/1591 (0.1%)	2	1/1591 (0.1%)	1
Foot fracture	0/1591 (0%)	0	1/1591 (0.1%)	1
Forearm fracture	0/1591 (0%)	0	1/1591 (0.1%)	1
Foreign body in ear	1/1591 (0.1%)	1	0/1591 (0%)	0
Graft haemorrhage	0/1591 (0%)	0	1/1591 (0.1%)	1
Hip fracture	2/1591 (0.1%)	2	1/1591 (0.1%)	1
Humerus fracture	0/1591 (0%)	0	2/1591 (0.1%)	2
Injury corneal	0/1591 (0%)	0	1/1591 (0.1%)	1
Joint dislocation	1/1591 (0.1%)	1	0/1591 (0%)	0
Joint injury	1/1591 (0.1%)	1	0/1591 (0%)	0
Laceration	0/1591 (0%)	0	1/1591 (0.1%)	1
Limb injury	0/1591 (0%)	0	1/1591 (0.1%)	1
Open globe injury	1/1591 (0.1%)	1	1/1591 (0.1%)	1
Patella fracture	1/1591 (0.1%)	1	0/1591 (0%)	0
Pelvic fracture	1/1591 (0.1%)	1	0/1591 (0%)	0
Post procedural bile leak	0/1591 (0%)	0	1/1591 (0.1%)	1
Post procedural complication	0/1591 (0%)	0	2/1591 (0.1%)	2
Post procedural haematuria	2/1591 (0.1%)	2	0/1591 (0%)	0
Postoperative thoracic procedure complication	1/1591 (0.1%)	1	0/1591 (0%)	0
Radius fracture	1/1591 (0.1%)	1	1/1591 (0.1%)	1
Rib fracture	1/1591 (0.1%)	1	0/1591 (0%)	0
Road traffic accident	2/1591 (0.1%)	2	1/1591 (0.1%)	1
Spinal compression fracture	1/1591 (0.1%)	1	2/1591 (0.1%)	2
Subdural haematoma	3/1591 (0.2%)	3	0/1591 (0%)	0
Subdural haemorrhage	0/1591 (0%)	0	1/1591 (0.1%)	1
Tendon injury	1/1591 (0.1%)	1	0/1591 (0%)	0
Tendon rupture	0/1591 (0%)	0	1/1591 (0.1%)	1
Thermal burn	0/1591 (0%)	0	1/1591 (0.1%)	1
Upper limb fracture	1/1591 (0.1%)	1	0/1591 (0%)	0
Vascular pseudoaneurysm	0/1591 (0%)	0	2/1591 (0.1%)	2
Investigations
Blood creatinine increased	0/1591 (0%)	0	1/1591 (0.1%)	1
Blood potassium increased	0/1591 (0%)	0	1/1591 (0.1%)	1
Clostridium test positive	1/1591 (0.1%)	1	0/1591 (0%)	0
Ejection fraction decreased	1/1591 (0.1%)	1	0/1591 (0%)	0
Hepatic enzyme increased	0/1591 (0%)	0	1/1591 (0.1%)	1
Troponin increased	0/1591 (0%)	0	1/1591 (0.1%)	1
Metabolism and nutrition disorders
Dehydration	3/1591 (0.2%)	3	2/1591 (0.1%)	2
Diabetes mellitus	0/1591 (0%)	0	1/1591 (0.1%)	1
Diabetes mellitus inadequate control	1/1591 (0.1%)	1	3/1591 (0.2%)	3
Diabetic ketoacidosis	2/1591 (0.1%)	2	0/1591 (0%)	0
Hyperglycaemia	2/1591 (0.1%)	2	4/1591 (0.3%)	4
Hyperglycaemic hyperosmolar nonketotic syndrome	2/1591 (0.1%)	2	1/1591 (0.1%)	1
Hyperkalaemia	1/1591 (0.1%)	1	1/1591 (0.1%)	1
Hypervolaemia	0/1591 (0%)	0	1/1591 (0.1%)	1
Hypoglycaemia	5/1591 (0.3%)	5	4/1591 (0.3%)	4
Hypokalaemia	1/1591 (0.1%)	1	0/1591 (0%)	0
Hyponatraemia	1/1591 (0.1%)	1	1/1591 (0.1%)	1
Hypovolaemia	0/1591 (0%)	0	1/1591 (0.1%)	1
Lactic acidosis	3/1591 (0.2%)	3	2/1591 (0.1%)	2
Latent autoimmune diabetes in adults	0/1591 (0%)	0	1/1591 (0.1%)	1
Musculoskeletal and connective tissue disorders
Arthritis	1/1591 (0.1%)	1	0/1591 (0%)	0
Arthropathy	1/1591 (0.1%)	1	1/1591 (0.1%)	1
Back pain	0/1591 (0%)	0	2/1591 (0.1%)	2
Bursitis	1/1591 (0.1%)	1	1/1591 (0.1%)	1
Intervertebral disc protrusion	1/1591 (0.1%)	1	0/1591 (0%)	0
Lumbar spinal stenosis	0/1591 (0%)	0	2/1591 (0.1%)	2
Muscular weakness	0/1591 (0%)	0	1/1591 (0.1%)	1
Musculoskeletal chest pain	1/1591 (0.1%)	1	1/1591 (0.1%)	1
Neck pain	2/1591 (0.1%)	2	1/1591 (0.1%)	1
Osteoarthritis	6/1591 (0.4%)	6	10/1591 (0.6%)	10
Pain in extremity	0/1591 (0%)	0	1/1591 (0.1%)	1
Pathological fracture	1/1591 (0.1%)	1	0/1591 (0%)	0
Polymyalgia rheumatica	0/1591 (0%)	0	1/1591 (0.1%)	1
Rhabdomyolysis	1/1591 (0.1%)	1	1/1591 (0.1%)	1
Rotator cuff syndrome	0/1591 (0%)	0	2/1591 (0.1%)	2
Sacroiliitis	0/1591 (0%)	0	1/1591 (0.1%)	1
Spinal column stenosis	0/1591 (0%)	0	1/1591 (0.1%)	1
Spinal osteoarthritis	1/1591 (0.1%)	1	0/1591 (0%)	0
Trigger finger	1/1591 (0.1%)	1	0/1591 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma gastric	1/1591 (0.1%)	1	2/1591 (0.1%)	2
Adenocarcinoma of colon	4/1591 (0.3%)	4	1/1591 (0.1%)	1
Adenocarcinoma pancreas	0/1591 (0%)	0	2/1591 (0.1%)	2
B-cell lymphoma	0/1591 (0%)	0	1/1591 (0.1%)	1
Basal cell carcinoma	0/1591 (0%)	0	1/1591 (0.1%)	2
Bladder cancer	0/1591 (0%)	0	1/1591 (0.1%)	1
Bladder transitional cell carcinoma	0/1591 (0%)	0	1/1591 (0.1%)	1
Breast cancer	0/1591 (0%)	0	1/1591 (0.1%)	1
Carcinoid tumour of the appendix	1/1591 (0.1%)	1	0/1591 (0%)	0
Cholangiocarcinoma	0/1591 (0%)	0	2/1591 (0.1%)	2
Choroid melanoma	0/1591 (0%)	0	1/1591 (0.1%)	1
Chronic myelomonocytic leukaemia	0/1591 (0%)	0	1/1591 (0.1%)	1
Colon cancer	1/1591 (0.1%)	1	0/1591 (0%)	0
Diffuse large B-cell lymphoma	1/1591 (0.1%)	1	1/1591 (0.1%)	1
Endometrial adenocarcinoma	0/1591 (0%)	0	1/1591 (0.1%)	1
Haemangioma	0/1591 (0%)	0	1/1591 (0.1%)	1
Hepatic cancer	0/1591 (0%)	0	1/1591 (0.1%)	1
Hepatocellular carcinoma	2/1591 (0.1%)	2	1/1591 (0.1%)	1
Light chain disease	1/1591 (0.1%)	1	0/1591 (0%)	0
Lip squamous cell carcinoma	0/1591 (0%)	0	1/1591 (0.1%)	1
Lung adenocarcinoma	2/1591 (0.1%)	2	0/1591 (0%)	0
Lung cancer metastatic	2/1591 (0.1%)	2	0/1591 (0%)	0
Lymphoma	0/1591 (0%)	0	1/1591 (0.1%)	1
Malignant peritoneal neoplasm	0/1591 (0%)	0	1/1591 (0.1%)	1
Medullary thyroid cancer	1/1591 (0.1%)	1	0/1591 (0%)	0
Mesothelioma malignant	0/1591 (0%)	0	1/1591 (0.1%)	1
Metastases to liver	0/1591 (0%)	0	1/1591 (0.1%)	1
Metastases to lung	1/1591 (0.1%)	1	0/1591 (0%)	0
Metastatic malignant melanoma	1/1591 (0.1%)	1	0/1591 (0%)	0
Non-Hodgkin's lymphoma	1/1591 (0.1%)	1	0/1591 (0%)	0
Pancreatic carcinoma	0/1591 (0%)	0	1/1591 (0.1%)	1
Pancreatic carcinoma metastatic	2/1591 (0.1%)	2	1/1591 (0.1%)	1
Pancreatic neuroendocrine tumour metastatic	1/1591 (0.1%)	1	0/1591 (0%)	0
Papillary renal cell carcinoma	1/1591 (0.1%)	1	0/1591 (0%)	0
Penile squamous cell carcinoma	0/1591 (0%)	0	1/1591 (0.1%)	1
Pituitary tumour benign	2/1591 (0.1%)	2	0/1591 (0%)	0
Plasma cell myeloma	1/1591 (0.1%)	1	0/1591 (0%)	0
Polycythaemia vera	1/1591 (0.1%)	1	0/1591 (0%)	0
Prostate cancer	0/1591 (0%)	0	4/1591 (0.3%)	4
Prostate cancer metastatic	1/1591 (0.1%)	1	0/1591 (0%)	0
Prostate cancer stage III	1/1591 (0.1%)	1	0/1591 (0%)	0
Prostate cancer stage IV	1/1591 (0.1%)	1	0/1591 (0%)	0
Rectal adenocarcinoma	0/1591 (0%)	0	1/1591 (0.1%)	1
Renal neoplasm	1/1591 (0.1%)	1	1/1591 (0.1%)	1
Small cell carcinoma	0/1591 (0%)	0	1/1591 (0.1%)	1
Squamous cell carcinoma of lung	0/1591 (0%)	0	1/1591 (0.1%)	1
Squamous cell carcinoma of the tongue	0/1591 (0%)	0	2/1591 (0.1%)	2
Thyroid cancer metastatic	1/1591 (0.1%)	1	0/1591 (0%)	0
Nervous system disorders
Carotid artery occlusion	2/1591 (0.1%)	2	0/1591 (0%)	0
Carotid artery stenosis	4/1591 (0.3%)	4	4/1591 (0.3%)	5
Cerebellar infarction	1/1591 (0.1%)	1	0/1591 (0%)	0
Cerebral infarction	1/1591 (0.1%)	1	1/1591 (0.1%)	1
Cerebral ischaemia	0/1591 (0%)	0	1/1591 (0.1%)	1
Cerebrovascular accident	0/1591 (0%)	0	1/1591 (0.1%)	1
Dementia with Lewy bodies	0/1591 (0%)	0	1/1591 (0.1%)	1
Diabetic neuropathy	0/1591 (0%)	0	1/1591 (0.1%)	1
Dizziness	2/1591 (0.1%)	2	2/1591 (0.1%)	2
Dyspraxia	0/1591 (0%)	0	1/1591 (0.1%)	1
Encephalopathy	2/1591 (0.1%)	2	0/1591 (0%)	0
Headache	0/1591 (0%)	0	1/1591 (0.1%)	1
Hemiparesis	2/1591 (0.1%)	3	0/1591 (0%)	0
Hypoaesthesia	1/1591 (0.1%)	1	1/1591 (0.1%)	1
Hypoglycaemic seizure	1/1591 (0.1%)	1	0/1591 (0%)	0
Hypoglycaemic unconsciousness	9/1591 (0.6%)	11	6/1591 (0.4%)	8
Ischaemic cerebral infarction	0/1591 (0%)	0	2/1591 (0.1%)	2
Ischaemic stroke	9/1591 (0.6%)	9	11/1591 (0.7%)	12
Lacunar infarction	0/1591 (0%)	0	1/1591 (0.1%)	1
Lacunar stroke	1/1591 (0.1%)	1	0/1591 (0%)	0
Lumbosacral plexopathy	0/1591 (0%)	0	1/1591 (0.1%)	1
Migraine	0/1591 (0%)	0	1/1591 (0.1%)	1
Myasthenia gravis	0/1591 (0%)	0	1/1591 (0.1%)	1
Neuritis	1/1591 (0.1%)	2	0/1591 (0%)	0
Neurotoxicity	0/1591 (0%)	0	1/1591 (0.1%)	1
Optic neuritis	1/1591 (0.1%)	1	0/1591 (0%)	0
Parkinsonism	0/1591 (0%)	0	1/1591 (0.1%)	1
Seizure	0/1591 (0%)	0	2/1591 (0.1%)	2
Spondylitic myelopathy	0/1591 (0%)	0	1/1591 (0.1%)	1
Syncope	7/1591 (0.4%)	7	4/1591 (0.3%)	4
Transient ischaemic attack	3/1591 (0.2%)	3	6/1591 (0.4%)	6
VIth nerve paralysis	1/1591 (0.1%)	1	0/1591 (0%)	0
Vascular dementia	0/1591 (0%)	0	1/1591 (0.1%)	1
Product Issues
Device malfunction	1/1591 (0.1%)	1	0/1591 (0%)	0
Psychiatric disorders
Alcoholism	1/1591 (0.1%)	1	0/1591 (0%)	0
Bipolar disorder	0/1591 (0%)	0	1/1591 (0.1%)	1
Confusional state	1/1591 (0.1%)	1	0/1591 (0%)	0
Depression	1/1591 (0.1%)	1	0/1591 (0%)	0
Drug dependence	1/1591 (0.1%)	1	1/1591 (0.1%)	1
Mania	0/1591 (0%)	0	1/1591 (0.1%)	1
Mental status changes	0/1591 (0%)	0	1/1591 (0.1%)	1
Renal and urinary disorders
Acute kidney injury	13/1591 (0.8%)	14	14/1591 (0.9%)	18
Acute prerenal failure	0/1591 (0%)	0	1/1591 (0.1%)	1
Azotaemia	0/1591 (0%)	0	1/1591 (0.1%)	1
Bladder prolapse	1/1591 (0.1%)	1	0/1591 (0%)	0
Chronic kidney disease	1/1591 (0.1%)	1	5/1591 (0.3%)	5
Diabetic nephropathy	0/1591 (0%)	0	1/1591 (0.1%)	1
Haematuria	2/1591 (0.1%)	2	2/1591 (0.1%)	2
Hydronephrosis	1/1591 (0.1%)	1	1/1591 (0.1%)	1
IgA nephropathy	1/1591 (0.1%)	1	0/1591 (0%)	0
Nephrolithiasis	2/1591 (0.1%)	2	2/1591 (0.1%)	2
Renal failure	1/1591 (0.1%)	1	2/1591 (0.1%)	2
Renal impairment	1/1591 (0.1%)	1	0/1591 (0%)	0
Ureterolithiasis	3/1591 (0.2%)	3	2/1591 (0.1%)	2
Urethral stenosis	0/1591 (0%)	0	1/1591 (0.1%)	1
Urinary incontinence	0/1591 (0%)	0	1/1591 (0.1%)	1
Reproductive system and breast disorders
Benign prostatic hyperplasia	3/1591 (0.2%)	3	2/1591 (0.1%)	2
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	1/1591 (0.1%)	1	0/1591 (0%)	0
Acute respiratory failure	0/1591 (0%)	0	2/1591 (0.1%)	3
Aspiration	1/1591 (0.1%)	1	0/1591 (0%)	0
Asthma	0/1591 (0%)	0	2/1591 (0.1%)	2
Bronchial hyperreactivity	1/1591 (0.1%)	1	0/1591 (0%)	0
Bronchospasm	0/1591 (0%)	0	1/1591 (0.1%)	1
Chronic obstructive pulmonary disease	8/1591 (0.5%)	11	4/1591 (0.3%)	4
Dyspnoea	1/1591 (0.1%)	2	2/1591 (0.1%)	2
Haemothorax	1/1591 (0.1%)	1	0/1591 (0%)	0
Hypoxia	0/1591 (0%)	0	1/1591 (0.1%)	1
Idiopathic pulmonary fibrosis	1/1591 (0.1%)	1	0/1591 (0%)	0
Lung disorder	1/1591 (0.1%)	1	0/1591 (0%)	0
Obstructive airways disorder	1/1591 (0.1%)	1	0/1591 (0%)	0
Organising pneumonia	0/1591 (0%)	0	1/1591 (0.1%)	1
Pharyngeal oedema	1/1591 (0.1%)	1	0/1591 (0%)	0
Pleural effusion	1/1591 (0.1%)	2	1/1591 (0.1%)	1
Pneumonitis	0/1591 (0%)	0	1/1591 (0.1%)	1
Pulmonary embolism	2/1591 (0.1%)	2	2/1591 (0.1%)	2
Pulmonary oedema	2/1591 (0.1%)	2	0/1591 (0%)	0
Respiratory failure	2/1591 (0.1%)	2	2/1591 (0.1%)	2
Sleep apnoea syndrome	0/1591 (0%)	0	1/1591 (0.1%)	1
Skin and subcutaneous tissue disorders
Angioedema	0/1591 (0%)	0	1/1591 (0.1%)	1
Dermatomyositis	0/1591 (0%)	0	1/1591 (0.1%)	1
Diabetic foot	2/1591 (0.1%)	2	6/1591 (0.4%)	7
Skin ulcer	1/1591 (0.1%)	1	4/1591 (0.3%)	4
Vasculitic ulcer	0/1591 (0%)	0	1/1591 (0.1%)	1
Surgical and medical procedures
Aortic aneurysm repair	1/1591 (0.1%)	1	0/1591 (0%)	0
Cardiac pacemaker insertion	1/1591 (0.1%)	1	0/1591 (0%)	0
Cataract operation	1/1591 (0.1%)	1	1/1591 (0.1%)	1
Cholecystectomy	0/1591 (0%)	0	1/1591 (0.1%)	1
Finger repair operation	0/1591 (0%)	0	1/1591 (0.1%)	1
Gastric bypass	0/1591 (0%)	0	1/1591 (0.1%)	1
Glaucoma surgery	1/1591 (0.1%)	1	0/1591 (0%)	0
Hip arthroplasty	1/1591 (0.1%)	1	0/1591 (0%)	0
Implantable defibrillator insertion	1/1591 (0.1%)	1	0/1591 (0%)	0
Joint arthroplasty	1/1591 (0.1%)	1	0/1591 (0%)	0
Knee arthroplasty	0/1591 (0%)	0	1/1591 (0.1%)	1
Spinal fusion surgery	0/1591 (0%)	0	2/1591 (0.1%)	2
Subdural haematoma evacuation	0/1591 (0%)	0	1/1591 (0.1%)	1
Transurethral prostatectomy	1/1591 (0.1%)	1	0/1591 (0%)	0
Trapeziectomy	0/1591 (0%)	0	1/1591 (0.1%)	1
Vascular disorders
Aortic aneurysm	0/1591 (0%)	0	1/1591 (0.1%)	1
Aortic dissection	1/1591 (0.1%)	1	0/1591 (0%)	0
Aortic stenosis	1/1591 (0.1%)	1	1/1591 (0.1%)	1
Arteriosclerosis	0/1591 (0%)	0	1/1591 (0.1%)	1
Deep vein thrombosis	3/1591 (0.2%)	3	1/1591 (0.1%)	1
Hypertension	1/1591 (0.1%)	1	1/1591 (0.1%)	1
Hypertensive crisis	0/1591 (0%)	0	1/1591 (0.1%)	1
Hypertensive emergency	0/1591 (0%)	0	1/1591 (0.1%)	1
Hypotension	5/1591 (0.3%)	5	3/1591 (0.2%)	3
Malignant hypertension	1/1591 (0.1%)	1	0/1591 (0%)	0
Orthostatic hypotension	1/1591 (0.1%)	1	3/1591 (0.2%)	3
Peripheral arterial occlusive disease	2/1591 (0.1%)	2	7/1591 (0.4%)	7
Peripheral artery dissection	1/1591 (0.1%)	1	0/1591 (0%)	0
Peripheral artery occlusion	1/1591 (0.1%)	1	0/1591 (0%)	0
Peripheral artery stenosis	3/1591 (0.2%)	3	1/1591 (0.1%)	1
Peripheral ischaemia	1/1591 (0.1%)	1	3/1591 (0.2%)	3
Peripheral vascular disorder	3/1591 (0.2%)	3	2/1591 (0.1%)	2
Thrombosis	0/1591 (0%)	0	1/1591 (0.1%)	1
Other (Not Including Serious) Adverse Events
	Oral Semaglutide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1591 (0%)		0/1591 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

At the end of the trial, one or more scientific publications may be prepared collaboratively by the investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or communication for up to 60 days to protect intellectual property.