Trial Outcomes & Findings for Trial to Reduce Cardiovascular Events With Aranesp® Therapy (TREAT) (NCT NCT00093015)

Last Updated: 2022-11-08

Results Overview

Time from randomization to the first confirmed composite event. Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

4038 participants

Primary outcome timeframe

Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first

Results posted on

2022-11-08

Participant Flow

First Subject Enrolled: 25 Aug 2004 Last Subject Enrolled: 04 Dec 2007

Participant milestones

Participant milestones
Measure	Placebo Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was \<9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL.	Darbepoetin Alfa Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed.
Overall Study STARTED	2026	2012
Overall Study Received Study Medication	2019	2004
Overall Study COMPLETED	1361	1348
Overall Study NOT COMPLETED	665	664

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was \<9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL.	Darbepoetin Alfa Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed.
Overall Study Withdrawal by Subject	194	171
Overall Study Lost to Follow-up	96	108
Overall Study Death	375	385

Baseline Characteristics

Trial to Reduce Cardiovascular Events With Aranesp® Therapy (TREAT)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Darbepoetin Alfa n=2012 Participants Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed.	Placebo n=2026 Participants Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was \<9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL.	Total n=4038 Participants Total of all reporting groups
Age, Continuous	67.2 Years STANDARD_DEVIATION 10.7 • n=5 Participants	67.5 Years STANDARD_DEVIATION 10.6 • n=7 Participants	67.4 Years STANDARD_DEVIATION 10.6 • n=5 Participants
Sex: Female, Male Female	1178 Participants n=5 Participants	1134 Participants n=7 Participants	2312 Participants n=5 Participants
Sex: Female, Male Male	834 Participants n=5 Participants	892 Participants n=7 Participants	1726 Participants n=5 Participants
Race/Ethnicity, Customized White or Caucasian	1270 Participants n=5 Participants	1300 Participants n=7 Participants	2570 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	414 Participants n=5 Participants	401 Participants n=7 Participants	815 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic or Latino	273 Participants n=5 Participants	265 Participants n=7 Participants	538 Participants n=5 Participants
Race/Ethnicity, Customized Asian	35 Participants n=5 Participants	43 Participants n=7 Participants	78 Participants n=5 Participants
Race/Ethnicity, Customized Japanese	8 Participants n=5 Participants	3 Participants n=7 Participants	11 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	1 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	4 Participants n=5 Participants	5 Participants n=7 Participants	9 Participants n=5 Participants
Race/Ethnicity, Customized Aborigine	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized Other	5 Participants n=5 Participants	4 Participants n=7 Participants	9 Participants n=5 Participants
History of cardiovascular disease With history of cardiovascular disease	1287 Participant n=5 Participants	1355 Participant n=7 Participants	2642 Participant n=5 Participants
History of cardiovascular disease Without history of cardiovascular disease	725 Participant n=5 Participants	671 Participant n=7 Participants	1396 Participant n=5 Participants
Baseline proteinuria level >= 1 g/g creat	686 Participants n=5 Participants	711 Participants n=7 Participants	1397 Participants n=5 Participants
Baseline proteinuria level < 1 g/g creat	1324 Participants n=5 Participants	1315 Participants n=7 Participants	2639 Participants n=5 Participants

PRIMARY outcome

Timeframe: Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first

Population: The analysis followed intent-to-treat principles. Subjects were analyzed as randomized using all available follow-up information.

Outcome measures

Outcome measures
Measure	Placebo n=2026 Participants Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was \<9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL.	Darbepoetin Alfa n=2012 Participants Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed.
Time to All-cause Mortality or Cardiovascular (CV) Events Including Hospitalization Due to Acute Myocardial Ischemia, Congestive Heart Failure (CHF), Myocardial Infarction (MI), and Cerebrovascular Accident (CVA)	602 Participants	632 Participants

PRIMARY outcome

Population: The analysis followed intent-to-treat principles. Subjects were analyzed as randomized using all available follow-up information.

Time from randomization to first event of all-cause mortality or ESRD. Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized.

Outcome measures

Outcome measures
Measure	Placebo n=2026 Participants Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was \<9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL.	Darbepoetin Alfa n=2012 Participants Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed.
Time to All-cause Mortality or End Stage Renal Disease (ESRD)	618 Participants	652 Participants

SECONDARY outcome

Population: The analysis followed intent-to-treat principles. Subjects were analyzed as randomized using all available follow-up information.

Time from randomization to all-cause mortality. Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized.

Outcome measures

Outcome measures
Measure	Placebo n=2026 Participants Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was \<9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL.	Darbepoetin Alfa n=2012 Participants Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed.
Time to All-cause Mortality	395 Participants	412 Participants

SECONDARY outcome

Population: The analysis followed intent-to-treat principles. Subjects were analyzed as randomized using all available follow-up information.

Time from randomization to cardiovascular (CV) mortality. Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized.

Outcome measures

Outcome measures
Measure	Placebo n=2026 Participants Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was \<9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL.	Darbepoetin Alfa n=2012 Participants Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed.
Time to Cardiovascular Mortality	250 Participants	259 Participants

SECONDARY outcome

Population: The analysis followed intent-to-treat principles. Subjects were analyzed as randomized using all available follow-up information.

Time from randomization to fatal or non-fatal myocardial infarction (MI). Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized.

Outcome measures

Outcome measures
Measure	Placebo n=2026 Participants Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was \<9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL.	Darbepoetin Alfa n=2012 Participants Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed.
Time to Myocardial Infarction	129 Participants	124 Participants

SECONDARY outcome

Population: The analysis followed intent-to-treat principles. Subjects were analyzed as randomized using all available follow-up information.

Time from randomization to fatal or non-fatal cerebrovascular accident (CVA). Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized.

Outcome measures

Outcome measures
Measure	Placebo n=2026 Participants Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was \<9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL.	Darbepoetin Alfa n=2012 Participants Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed.
Time to Cerebrovascular Accident	53 Participants	101 Participants

SECONDARY outcome

Population: The analysis followed intent-to-treat principles. Subjects were analyzed as randomized using all available follow-up information.

Time from randomization to fatal or non-fatal congestive heart failure(CHF). Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized.

Outcome measures

Outcome measures
Measure	Placebo n=2026 Participants Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was \<9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL.	Darbepoetin Alfa n=2012 Participants Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed.
Time to Congestive Heart Failure	229 Participants	205 Participants

SECONDARY outcome

Population: The analysis followed intent-to-treat principles. Subjects were analyzed as randomized using all available follow-up information.

Time from randomization to end stage renal disease (ESRD). Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized.

Outcome measures

Outcome measures
Measure	Placebo n=2026 Participants Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was \<9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL.	Darbepoetin Alfa n=2012 Participants Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed.
Time to End Stage Renal Disease	330 Participants	338 Participants

SECONDARY outcome

Population: Subjects were analyzed as randomized using all available eGFR measurements, except eGFR measurements measured after subjects develop ESRD since creatinine measurements were no longer reliable or meaningful for eGFR calculation.

GFR was estimated using the following MDRD formula: 186 x \[Serum creatinine\]\^(-1.154) x \[Age\]\^(-0.203) x \[0.742 if subject is female\] x \[1.210 if subject is black\]. Change from baseline in eGFR at week 49 for each treatment group are presented. The treatment effect of the rate of decline in eGFR per year was estimated using the mixed model.

Outcome measures

Outcome measures
Measure	Placebo n=2026 Participants Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was \<9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL.	Darbepoetin Alfa n=2012 Participants Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed.
Rate of Decline in Estimated Glomerular Filtration Rate (eGFR) Relative to Baseline	-1.89 mL/min/1.73m^2 Standard Deviation 10.60	-1.30 mL/min/1.73m^2 Standard Deviation 10.81

SECONDARY outcome

Timeframe: Baseline and week 25

Population: Subjects with both the baseline and at least post-baseline measurement at week 25 for FACT-fatigue were included in the analysis and were analyzed as randomized. Last observation carried forward (LOCF) using last non-missing post-baseline value was used for missing post-baseline data for subjects who were still on study.

Change in patient reported fatigue measured by the Functional Assessment of Cancer Therapy (FACT) - Fatigue scale from baseline to week 25. Range and direction of scale: 0 = most fatigue; 52 = least fatigue

Outcome measures

Outcome measures
Measure	Placebo n=1769 Participants Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was \<9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL.	Darbepoetin Alfa n=1762 Participants Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed.
Change in Patient Reported Fatigue Relative to Baseline at Week 25	2.8 Units on a scale Standard Deviation 10.3	4.2 Units on a scale Standard Deviation 10.5

SECONDARY outcome

Population: The analysis followed intent-to-treat principles. Subjects were analyzed as randomized using all available follow-up information.

Time from randomization to hospitalization due to acute myocardial ischemia. Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized.

Outcome measures

Outcome measures
Measure	Placebo n=2026 Participants Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was \<9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL.	Darbepoetin Alfa n=2012 Participants Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed.
Time to Hospitalization Due to Acute Myocardial Ischemia	49 Participants	41 Participants

Adverse Events

Placebo

Serious events: 1219 serious events

Other events: 1547 other events

Deaths: 0 deaths

Darbepoetin Alfa

Serious events: 1235 serious events

Other events: 1571 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Amgen Inc.

Phone: 866-572-6436

Results disclosure agreements

Principal investigator is a sponsor employee The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multi-center studies, the investigator agrees not to publish any results before the first multi-center publication.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=2019 participants at risk	Darbepoetin Alfa n=2004 participants at risk
Blood and lymphatic system disorders Anaemia	5.1% 102/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	2.8% 57/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Gastrointestinal disorders Constipation	7.6% 154/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	6.5% 130/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Gastrointestinal disorders Diarrhoea	14.0% 283/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	13.9% 279/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Gastrointestinal disorders Nausea	11.2% 227/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	11.5% 231/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Gastrointestinal disorders Vomiting	9.4% 190/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	10.0% 200/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
General disorders Asthenia	8.2% 166/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	7.0% 140/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
General disorders Fatigue	17.4% 351/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	16.1% 322/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
General disorders Oedema	6.2% 126/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	6.2% 124/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
General disorders Oedema peripheral	20.7% 417/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	20.7% 414/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Infections and infestations Bronchitis	8.4% 169/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	8.1% 163/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Infections and infestations Influenza	5.7% 115/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	5.4% 108/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Infections and infestations Nasopharyngitis	8.9% 179/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	10.5% 210/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Infections and infestations Sinusitis	4.5% 91/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	5.6% 112/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Infections and infestations Upper respiratory tract infection	9.0% 182/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	9.2% 185/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Infections and infestations Urinary tract infection	12.2% 247/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	13.1% 262/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Injury, poisoning and procedural complications Contusion	4.6% 93/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	5.5% 111/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Injury, poisoning and procedural complications Fall	6.7% 135/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	8.2% 165/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Investigations Blood pressure increased	5.1% 102/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	5.4% 109/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Metabolism and nutrition disorders Gout	4.7% 94/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	5.3% 106/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Metabolism and nutrition disorders Hyperglycaemia	4.7% 95/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	5.0% 101/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Metabolism and nutrition disorders Hyperkalaemia	5.3% 106/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	5.5% 110/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Metabolism and nutrition disorders Hypoglycaemia	10.6% 215/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	11.2% 225/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Musculoskeletal and connective tissue disorders Arthralgia	12.3% 249/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	12.8% 257/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Musculoskeletal and connective tissue disorders Back pain	13.2% 266/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	11.1% 223/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Musculoskeletal and connective tissue disorders Muscle spasms	6.6% 134/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	6.4% 129/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	5.8% 117/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	5.9% 119/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Musculoskeletal and connective tissue disorders Pain in extremity	14.3% 289/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	14.6% 293/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Nervous system disorders Dizziness	10.2% 206/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	11.3% 226/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Nervous system disorders Headache	8.0% 161/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	9.6% 192/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Respiratory, thoracic and mediastinal disorders Cough	11.7% 236/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	10.7% 214/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Respiratory, thoracic and mediastinal disorders Dyspnoea	15.2% 307/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	12.9% 259/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Skin and subcutaneous tissue disorders Rash	4.0% 80/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	5.5% 111/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Vascular disorders Hypertension	14.9% 301/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	16.6% 332/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Vascular disorders Hypotension	4.4% 88/2019 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	5.5% 110/2004 • Differential follow-up up to 4.6 years The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.