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Clinical Trial Results:
A Study Comparing Dulaglutide With Insulin Glargine on Glycemic Control in Participants With Type 2 Diabetes (T2D) and Moderate or Severe Chronic Kidney Disease (CKD) (AWARD-7)

Summary
EudraCT number	2012-000829-44
Trial protocol	ES HU
Global end of trial date	20 Dec 2016

Results information
Results version number	v1
This version publication date	31 Dec 2017
First version publication date	31 Dec 2017
Other versions	v2

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

H9X-MC-GBDX

ISRCTN number

US NCT number

NCT01621178

WHO universal trial number (UTN)

Other trial identifiers

Trial ID: 13798

Sponsor organisation name

Eli Lilly and Company

Sponsor organisation address

Lilly Corporate Center, Indianapolis, United States, 46285

Public contact

Available Mon - Fri 9 AM - 5 PM EST, Eli Lilly and Company, 1 877-CTLilly,

Scientific contact

Available Mon - Fri 9 AM - 5 PM EST, Eli Lilly and Company, 1 877-285-4559,

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

20 Dec 2016

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

20 Dec 2016

Was the trial ended prematurely?

Main objective of the trial

The purpose of this study is to determine the glycemic efficacy and safety of dulaglutide compared to insulin glargine in the treatment of participants with type 2 diabetes and moderate or severe chronic kidney disease.

Protection of trial subjects

This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.

Background therapy

Evidence for comparator

Actual start date of recruitment

02 Jul 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 183

Country: Number of subjects enrolled

Romania: 37

Country: Number of subjects enrolled

Hungary: 55

Country: Number of subjects enrolled

Ukraine: 40

Country: Number of subjects enrolled

Brazil: 141

Country: Number of subjects enrolled

Poland: 5

Country: Number of subjects enrolled

Mexico: 53

Country: Number of subjects enrolled

South Africa: 51

Country: Number of subjects enrolled

Spain: 12

Worldwide total number of subjects

577

EEA total number of subjects

109

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

270

From 65 to 84 years

307

85 years and over

Subject disposition

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Recruitment details

Screening details

All randomized participants, except for 1, in the dulaglutide group, were treated with at least 1 dose of study drug and comprised the ITT population. One participant did not receive study drug because after randomization the physician determined that the participant would be unable to successfully comply with the protocol.

Period 1 title

Randomization Period

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Insulin Glargine

Arm description

Insulin glargine was administered subcutaneously (SC) at bedtime per a modified forced-titration treat-to-target algorithm. Participants were instructed to administer their titrated prandial insulin lispro dose SC with the three most significant meals of the day.

Arm type

Active comparator

Investigational medicinal product name

Insulin Glargine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Dulaglutide 0.75 mg

Arm description

0.75 milligram (mg) of dulaglutide was administered once weekly as a SC injection. Participants were instructed to administer their titrated prandial insulin lispro dose SC with the three most significant meals of the day.

Arm type

Experimental

Investigational medicinal product name

Dulaglutide 0.75 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Dulaglutide 0.75 mg was administered once weekly as a SC injection. Participants were instructed to administer their titrated prandial insulin lispro dose SC with the three most significant meals of the day.

Dulaglutide 1.5 mg

Arm description

1.5 mg of dulaglutide was administered once weekly as a SC injection. Participants were instructed to administer their titrated prandial insulin lispro dose SC with the three most significant meals of the day.

Arm type

Experimental

Investigational medicinal product name

Dulaglutide 1.5 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Dulaglutide 1.5 mg was administered once weekly as a SC injection. Participants were instructed to administer their titrated prandial insulin lispro dose SC with the three most significant meals of the day.

Number of subjects in period 1	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Started	194	190	193
Received at least one dose of study drug	194	190	193
Modified Intent to Treat Population	194	190	193
Completed	194	190	193

Period 2 title

Treatment Period

Is this the baseline period?

Yes ^[1]

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Insulin Glargine

Arm description

Insulin glargine was administered SC at bedtime per a modified forced-titration treat-to-target algorithm. Participants were instructed to administer their titrated prandial insulin lispro dose SC with the three most significant meals of the day.

Arm type

Experimental

Investigational medicinal product name

Insulin Glargine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Dulaglutide 0.75 mg

Arm description

Dulaglutide 0.75 mg administered once weekly as a SC injection. Participants were instructed to administer their titrated prandial insulin lispro dose SC with the three most significant meals of the day.

Arm type

Experimental

Investigational medicinal product name

Dulaglutide 0.75

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Dulaglutide 1.5 mg

Arm description

Dulaglutide 1.5 mg administered once weekly as a SC injection. Participants were instructed to administer their titrated prandial insulin lispro dose SC with the three most significant meals of the day.

Arm type

Experimental

Investigational medicinal product name

Dulaglutide 1.5 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Notes
[1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
Justification: The baseline period consists of the intent to treat population in period 2. One participant did not receive study drug because after randomization the physician determined that the participant would be unable to successfully comply with the protocol.

Number of subjects in period 2	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Started	194	190	193
Received at least one dose of study drug	194	190	192
Modified intent to treat population	186	180	183
Completed	163	160	157
Not completed	31	30	36
Adverse event, serious fatal	6	7	2
Consent withdrawn by subject	14	17	18
Physician decision	5	2	7
Adverse event, non-fatal	5	2	8
Lost to follow-up	1	2	1

Baseline characteristics

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Reporting group title

Insulin Glargine

Reporting group description

Reporting group title

Dulaglutide 0.75 mg

Reporting group description

Reporting group title

Dulaglutide 1.5 mg

Reporting group description

Reporting group values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg	Total
Number of subjects	194	190	193	577
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	94	89	87	270
From 65-84 years	100	101	106	307
85 years and over	0	0	0	0
Gender categorical
Units: Subjects
Female	101	86	89	276
Male	93	104	104	301
Body Weight
Body weight was analyzed on all randomized participants who received at least 1 dose of study drug.
Units: kilogram (kg)
arithmetic mean (standard deviation)	88.20 ( 18.5 )	90.88 ( 18.3 )	88.14 ( 16.0 )	-
Body Mass Index (BMI)
BMI was analyzed on all randomized participants who received at least 1 dose of study drug.
Units: kilogram/square meter (kg/m^2)
arithmetic mean (standard deviation)	32 ( 5.3 )	33 ( 5.5 )	32 ( 4.8 )	-
Hemoglobin A1C (HbA1c) at Baseline
HbA1c was analyzed on all randomized participants who received at least 1 dose of study drug.
Units: Percentage of HbA1c
arithmetic mean (standard deviation)	8.56 ( 0.9 )	8.57 ( 1.0 )	8.59 ( 0.8 )	-
Duration of Diabetes
Duration of diabetes was analyzed on all randomized participants who received at least 1 dose of study drug.
Units: years
arithmetic mean (standard deviation)	18 ( 8.7 )	18 ( 8.8 )	18 ( 8.7 )	-
Duration of Chronic Kidney Disease (CKD) Stage 3 or Higher
Duration of CKD was analyzed on all randomized participants who received at least 1 dose of study drug.
Units: years
arithmetic mean (standard deviation)	3.47 ( 3.9 )	4.03 ( 4.8 )	4.18 ( 5.6 )	-
Estimated Glomerular Filtration Rate (eGFR)
eGFR was analyzed on all randomized participants who received at least 1 dose of study drug.
Units: milliliter/minute/1.73 square meter
arithmetic mean (standard deviation)	38.5 ( 12.9 )	38.3 ( 12.3 )	38.1 ( 13.2 )	-

End points

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Reporting group title

Insulin Glargine

Reporting group description

Reporting group title

Dulaglutide 0.75 mg

Reporting group description

Reporting group title

Dulaglutide 1.5 mg

Reporting group description

Reporting group title

Insulin Glargine

Reporting group description

Reporting group title

Dulaglutide 0.75 mg

Reporting group description

Reporting group title

Dulaglutide 1.5 mg

Reporting group description

Primary: Change from Baseline in Hemoglobin A1c (HbA1c)

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End point title

Change from Baseline in Hemoglobin A1c (HbA1c)

End point description

HbA1c is a form of hemoglobin that is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. Least square (LS) means in HbA1c were calculated using a restricted maximum likelihood (REML) based mixed-effects model for repeated measures (MMRM) with the change in HbA1c as the dependent variable and treatment, macroalbuminuria (MA) region, Baseline CKD Severity, week, treatment*week, baseline HbA1c (%), log baseline eGFR (within CKD severity), and participant was the random effect. Covariance structure = Unstructured. Only measurements prior to rescue or study drug discontinuation were used.

End point type

Primary

End point timeframe

Baseline, 26 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	175 ^[1]	149 ^[2]	138 ^[3]
Units: percentage of HbA1c
least squares mean (standard error)	-1.13 ( 0.12 )	-1.12 ( 0.12 )	-1.19 ( 0.13 )

Notes
[1] - All randomized participants who received (rec'd) one dose of study drug and had evaluable HbA1c data
[2] - All randomized participants who received one dose of study drug and had evaluable HbA1c data.
[3] - All randomized participants who received one dose of study drug and had evaluable HbA1c data.

Dulaglutide 1.5 mg Statistical Analysis

Statistical analysis description

All participants were included in the statistical analysis at week 26.

Comparison groups

Insulin Glargine v Dulaglutide 1.5 mg

Number of subjects included in analysis

313

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[4]

P-value

< 0.001

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.05

Confidence interval

level

95%

sides

2-sided

lower limit

-0.26

upper limit

0.15

Notes
[4] - Non-Inferiority to Glargine with a 0.4% margin.

Dulaglutide 0.75 mg Statistical Analysis

Statistical analysis description

All participants were included in the statistical analysis at week 26.

Comparison groups

Insulin Glargine v Dulaglutide 0.75 mg

Number of subjects included in analysis

324

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[5]

P-value

< 0.001

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.18

upper limit

0.22

Notes
[5] - Non-Inferiority to Glargine with a 0.4% margin

Secondary: Percentage of Participants whose HbA1c was <7.0%

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End point title

Percentage of Participants whose HbA1c was <7.0%

End point description

Percentage of participants whose HbA1c was <7.0% based on last observation carried forward (LOCF). Only measurement prior to rescue or study drug discontinuation were used.

End point type

Secondary

End point timeframe

26 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	182 ^[6]	164 ^[7]	152 ^[8]
Units: percentage of participants
number (not applicable)	34.6	31.7	37.5

Notes
[6] - All randomized participants who received at least 1 dose of study drug and had evaluable HbA1c data.
[7] - All randomized participants who received at least 1 dose of study drug and had evaluable HbA1c data.
[8] - All randomized participants who received at least 1 dose of study drug and had evaluable HbA1c data.

No statistical analyses for this end point

Secondary: Percentage of Participants whose HbA1c was <8.0%

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End point title

Percentage of Participants whose HbA1c was <8.0%

End point description

Percentage of Participants whose HbA1c was <8.0% based on last observation carried forward (LOCF). Only measurement prior to rescue or study drug discontinuation were used.

End point type

Secondary

End point timeframe

26 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	182 ^[9]	164 ^[10]	152 ^[11]
Units: percentage of participants
number (not applicable)	75.3	72.6	78.3

Notes
[9] - All randomized participants who received at least 1 dose of study drug and had evaluable HbA1c data.
[10] - All randomized participants who received at least 1 dose of study drug and had evaluable HbA1c data.
[11] - All randomized participants who received at least 1 dose of study drug and had evaluable HbA1c data.

No statistical analyses for this end point

Secondary: Change from Baseline in 8-Point Self-Monitored Plasma Glucose (SMPG)

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End point title

Change from Baseline in 8-Point Self-Monitored Plasma Glucose (SMPG)

End point description

The daily mean of 8-point SMPG profile at Week 26 is presented. Participants were required to perform two 8-point SMPG profiles over a 1-week period at 3 separate times throughout the study. LS means were calculated using the MMRM model including the corresponding baseline value as a continuous covariate, as well as baseline HbA1c, MA-region, treatment, week, treatment*week, baseline CKD severity, and log baseline eGFR (within CKD severity). The two 8-point SMPG profiles were collected on two non-consecutive days (pre-meal and 2-hour postprandial SMPG x [morning, midday, and evening meals in one day] + bedtime + 5 hours after bedtime). Only measurement prior to rescue or study drug discontinuation were used.

End point type

Secondary

End point timeframe

Baseline, 26 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	128 ^[12]	107 ^[13]	102 ^[14]
Units: milligrams/deciliter (mg/dL)
least squares mean (standard error)	-37.6 ( 3.41 )	-31.7 ( 3.53 )	-33.7 ( 3.77 )

Notes
[12] - All randomized participants who received at least 1 dose of study drug & had evaluable HbA1c & SMPG.
[13] - All randomized participants who received at least 1 dose of study drug & had evaluable HbA1c & SMPG.
[14] - All randomized participants who received at least 1 dose of study drug & had evaluable HbA1c & SMPG.

No statistical analyses for this end point

Secondary: Change from Baseline in Fasting Glucose (FG)

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End point title

Change from Baseline in Fasting Glucose (FG)

End point description

LS means were calculated using MMRM with the change in FG as the dependent variable and treatment, MA -region, Baseline CKD Severity, week, treatment*week, baseline FG, baseline HbA1c (%), log baseline eGFR (within CKD severity), and participant was the random effect. Covariance structure = Unstructured. Only measurement prior to rescue or study drug discontinuation were used.

End point type

Secondary

End point timeframe

Baseline, 26 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	162 ^[15]	145 ^[16]	132 ^[17]
Units: milligram/deciliter (mg/dL)
least squares mean (standard deviation)	-19.1 ( 6.00 )	17.7 ( 6.14 )	23.1 ( 6.50 )

Notes
[15] - All randomized participants who received at least 1 dose of study drug & had evaluable HbA1c & FG.
[16] - All randomized participants who received at least 1 dose of study drug & had evaluable HbA1c & FG.
[17] - All randomized participants who received at least 1 dose of study drug & had evaluable HbA1c & FG.

No statistical analyses for this end point

Secondary: Change From Baseline in Mean Daily Insulin Lispro Dose

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End point title

Change From Baseline in Mean Daily Insulin Lispro Dose

End point description

The mean daily insulin was based on a 4-week interval prior to week 26 assessments. LS means were calculated using a REML based mixed-effects model for repeated measures (MMRM) with the change in HbA1c as the dependent variable and treatment, MA-region, Baseline HbA1c, baseline mean daily insulin, baseline CKD Severity, week, treatment*week, baseline HbA1c (%), log baseline eGFR (within CKD severity), and participant was the random effect. Covariance structure = Unstructured. Only measurements prior to rescue or study drug discontinuation were used.

End point type

Secondary

End point timeframe

26 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	177 ^[18]	154 ^[19]	141 ^[20]
Units: Units/day (U/day)
least squares mean (standard error)	16.64 ( 2.76 )	26.16 ( 2.80 )	18.12 ( 3.00 )

Notes
[18] - All randomized participants who rec'd 1 dose of study drug & had evaluable insulin lispro dose data.
[19] - All randomized participants who rec'd 1 dose of study drug & had evaluable insulin lispro dose data.
[20] - All randomized participants who rec'd 1 dose of study drug & had evaluable insulin lispro dose data.

No statistical analyses for this end point

Secondary: Percentage of Participants With Estimated Average Glucose <154 mg/dL

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End point title

Percentage of Participants With Estimated Average Glucose <154 mg/dL

End point description

Percentage of Participants With Estimated Average Glucose <154 milligram/deciliter (mg/dL) was based on last observation carried forward (LOCF). Only measurements prior to rescue and study discontinuation were used.

End point type

Secondary

End point timeframe

26 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	134 ^[21]	118 ^[22]	110 ^[23]
Units: percentage of participants
number (not applicable)	64.9	52.5	56.4

Notes
[21] - All randomized participants who had 1 dose of study drug & had evaluable estimated average glucose.
[22] - All randomized participants who had 1 dose of study drug & had evaluable estimated average glucose.
[23] - All randomized participants who had 1 dose of study drug & had evaluable estimated average glucose.

No statistical analyses for this end point

Secondary: Change from Baseline in Serum Creatinine (sCr)

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End point title

Change from Baseline in Serum Creatinine (sCr)

End point description

Change from baseline in serum creatinine (sCr) levels after treatment.

End point type

Secondary

End point timeframe

Baseline, 26 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	176 ^[24]	169 ^[25]	163 ^[26]
Units: mg/dL
median (inter-quartile range (Q1-Q3))	0.10 (-0.04 to 0.28)	0.02 (-0.15 to 0.15)	0.04 (-0.14 to 0.20)

Notes
[24] - All randomized participants who received at least 1 dose of study drug and had evaluable sCr data.
[25] - All randomized participants who received at least 1 dose of study drug and had evaluable sCr data.
[26] - All randomized participants who received at least 1 dose of study drug and had evaluable sCr data..

No statistical analyses for this end point

Secondary: Change from Baseline in estimated Glomerular Filtration Rate (eGFR)

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End point title

Change from Baseline in estimated Glomerular Filtration Rate (eGFR)

End point description

The change in estimated glomerular filtration rate (eGFR) by using CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation.

End point type

Secondary

End point timeframe

Baseline, 26 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	176 ^[27]	169 ^[28]	163 ^[29]
Units: milliliter/minute/1.73m2 (mL/min/1.73m2)
median (inter-quartile range (Q1-Q3))	-2.5 (-6.0 to 1.0)	-1.0 (-4.5 to 3.0)	-1.0 (-5.5 to 3.0)

Notes
[27] - All randomized participants who received at least 1 dose of study drug and had evaluable eGFR data.
[28] - All randomized participants who received at least 1 dose of study drug and had evaluable eGFR data.
[29] - All randomized participants who received at least 1 dose of study drug and had evaluable eGFR data.

No statistical analyses for this end point

Secondary: Change from Baseline in estimated Creatinine Clearance (eCrCl)

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End point title

Change from Baseline in estimated Creatinine Clearance (eCrCl)

End point description

Estimated creatinine clearance (eCrCl) was calculated by Cockcroft-Gault [Cockcroft and Gault 1976] equation using baseline estimated lean body weight.

End point type

Secondary

End point timeframe

Baseline, 26 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	176 ^[30]	169 ^[31]	163 ^[32]
Units: milliliter/minute (ml/min)
median (inter-quartile range (Q1-Q3))	-2.0 (-4.0 to 0.5)	-1.0 (-3.5 to 2.0)	-0.5 (-4.0 to 2.0)

Notes
[30] - All randomized participants who received at least 1 dose of study drug and had evaluable eCrCl data.
[31] - All randomized participants who received at least 1 dose of study drug and had evaluable eCrCl data.
[32] - All randomized participants who received at least 1 dose of study drug and had evaluable eCrCl data.

No statistical analyses for this end point

Secondary: Change from Baseline in Urinary Albumin to Creatinine Ratio (UACR)

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End point title

Change from Baseline in Urinary Albumin to Creatinine Ratio (UACR)

End point description

The change from baseline in Urinary Albumin to Creatinine Ratio (UACR).

End point type

Secondary

End point timeframe

Baseline, 26 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	181 ^[33]	175 ^[34]	175 ^[35]
Units: gram/kilogram (g/kg)
median (inter-quartile range (Q1-Q3))	-1.3 (-71.7 to 62.0)	-11.1 (-147.8 to 33.2)	-10.2 (-180.5 to 53.1)

Notes
[33] - All randomized participants who received at least 1 dose of study drug and had evaluable UACR data.
[34] - All randomized participants who received at least 1 dose of study drug and had evaluable UACR data.
[35] - All randomized participants who received at least 1 dose of study drug and had evaluable UACR data.

No statistical analyses for this end point

Secondary: Change from Baseline in Body Weight

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End point title

Change from Baseline in Body Weight

End point description

LS means were calculated from a REML based MMRM model: Change from Baseline = treatment , week, treatment*Week, MA-region, Baseline HbA1c (%), Baseline Body Weight (kg), Baseline CKD Severity, Log Baseline eGFR (within CKD severity), where participant enters the model as a random effect. Covariance structure = Unstructured. Only measurement and prior to rescue or study drug discontinuation were used.

End point type

Secondary

End point timeframe

Baseline, 26 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	175 ^[36]	151 ^[37]	140 ^[38]
Units: kilogram (kg)
least squares mean (standard error)	1.11 ( 0.346 )	-2.02 ( 0.357 )	-2.81 ( 0.374 )

Notes
[36] - All randomized participants who rec'd 1 dose of study drug & had evaluable HbA1c & body weight.
[37] - All randomized participants who rec'd 1 dose of study drug & had evaluable HbA1c & body weight.
[38] - All randomized participants who rec'd 1 dose of study drug & had evaluable HbA1c & body weight.

No statistical analyses for this end point

Secondary: Percentage of Participants with Self-Reported Hypoglycemic Events (HE)

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End point title

Percentage of Participants with Self-Reported Hypoglycemic Events (HE)

End point description

Hypoglycemic events (HE) were classified as severe (defined as an episode requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions), documented symptomatic (defined as any time a participant feels that he/she is experiencing symptoms and/or signs associated with hypoglycemia, and has a plasma glucose level of ≤3.9 mmol/L (≤70 mg/dL), nocturnal (defined as any hypoglycemic event that occurs between bedtime and waking). The number of self-reported hypoglycemic events was summarized cumulatively at 26 weeks. A summary of other nonserious AEs, and all SAEs, regardless of causality, is located in the Reported Adverse Events section. Only measurements prior to rescue and study discontinuation was used.

End point type

Secondary

End point timeframe

Baseline through 26 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	194 ^[39]	189 ^[40]	190 ^[41]
Units: percentage of participants
number (not applicable)
Total Hypo	71.6	50.8	43.2
Documented Symptomatic Hypo	60.3	40.7	31.6
Severe Hypo	4.1	1.1	0
Nocturnal Hypo	38.1	15.9	13.2

Notes
[39] - All randomized participants who received at least 1 dose of study drug and evaluable HE data.
[40] - All randomized participants who received at least 1 dose of study drug and evaluable HE data.
[41] - All randomized participants who received at least 1 dose of study drug and evaluable HE data.

No statistical analyses for this end point

Secondary: Rate of Hypoglycemic Events

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End point title

Rate of Hypoglycemic Events

End point description

Hypoglycemic events (HE) were classified as total HE rate, documented symptomatic hypoglycemia, severe hypoglycemia, and nocturnal. The 1-year adjusted rate of HEs was summarized cumulatively at 26 weeks. A summary of other nonserious AEs, and all SAEs, regardless of causality, is located in the Reported Adverse Events section. Only measurements prior to rescue and study discontinuation were used.

End point type

Secondary

End point timeframe

Baseline through 26 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	194 ^[42]	189 ^[43]	190 ^[44]
Units: Events/Participant/Year
arithmetic mean (standard deviation)
Total HE Rate	17.07 ( 27.70 )	7.76 ( 20.39 )	5.45 ( 12.54 )
Documented Symptomatic HE Rate	11.34 ( 22.04 )	4.86 ( 13.37 )	4.19 ( 11.58 )
Severe HE Rate	0.10 ( 0.56 )	0.03 ( 0.31 )	0.00 ( 0.00 )
Nocturnal HE Rate	3.06 ( 7.26 )	0.73 ( 2.25 )	0.63 ( 2.26 )

Notes
[42] - All randomized participants who received at least 1 dose of study drug & had evaluable HE rate.
[43] - All randomized participants who received at least 1 dose of study drug & had evaluable HE rate.
[44] - All randomized participants who received at least 1 dose of study drug & had evaluable HE rate.

No statistical analyses for this end point

Secondary: Change from Baseline in HbA1c

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End point title

Change from Baseline in HbA1c

End point description

HbA1c is a form of hemoglobin that is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. LS means in HbA1c were calculated using a REML based mixed-effects model for repeated measures (MMRM) with the change in HbA1c as the dependent variable and treatment, MA region, Baseline CKD Severity, week, treatment*week, baseline HbA1c (%), log baseline eGFR (within CKD severity), and participant was the random effect. Covariance structure = Unstructured. Only measurements prior to rescue and study discontinuation were used.

End point type

Secondary

End point timeframe

Baseline, 52 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	153 ^[45]	132 ^[46]	130 ^[47]
Units: percentage of HbA1c
least squares mean (standard error)	-1.00 ( 0.12 )	-1.10 ( 0.12 )	-1.10 ( 0.13 )

Notes
[45] - All randomized participants who received at least 1 dose of study drug and had evaluable HbA1c data.
[46] - All randomized participants who received at least 1 dose of study drug and had evaluable HbA1c data.
[47] - All randomized participants who received at least 1 dose of study drug and had evaluable HbA1c data.

No statistical analyses for this end point

Secondary: Percentage of Participants Whose HbA1c is <7.0%

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End point title

Percentage of Participants Whose HbA1c is <7.0%

End point description

Percentage of participants whose HbA1c was <7.0% based on last observation carried forward (LOCF). Only measurements prior to rescue and study discontinuation were used.

End point type

Secondary

End point timeframe

52 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	182 ^[48]	164 ^[49]	152 ^[50]
Units: percentage of participants
number (not applicable)	29.1	33.5	32.9

Notes
[48] - All randomized participants who had received at least 1 dose of study drug & had evaluable HbA1c.
[49] - All randomized participants who had received at least 1 dose of study drug & had evaluable HbA1c.
[50] - All randomized participants who had received at least 1 dose of study drug & had evaluable HbA1c.

No statistical analyses for this end point

Secondary: Percentage of Participants Whose HbA1c is <8.0%

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End point title

Percentage of Participants Whose HbA1c is <8.0%

End point description

Percentage of participants whose HbA1c was <8.0% based on last observation carried forward (LOCF). Only measurements prior to rescue and study discontinuation were used.

End point type

Secondary

End point timeframe

Baseline, 52 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	182 ^[51]	164 ^[52]	152 ^[53]
Units: percentage of participants
number (not applicable)	70.3	69.5	69.1

Notes
[51] - All randomized participants who received at least 1 dose of study drug & had evaluable HbA1c data.
[52] - All randomized participants who received at least 1 dose of study drug & had evaluable HbA1c data.
[53] - All randomized participants who received at least 1 dose of study drug & had evaluable HbA1c data.

No statistical analyses for this end point

Secondary: Change From Baseline in 8-Point SMPG

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End point title

Change From Baseline in 8-Point SMPG

End point description

The daily mean of 8-point SMPG profile at Week 52 is presented. Participants were required to perform two 8-point SMPG profiles over a 1-week period at 5 separate times throughout the study. LS means were calculated using the MMRM model including the corresponding baseline value as a continuous covariate, as well as baseline HbA1c, MA-region, treatment, week, treatment*week, baseline CKD severity, and log baseline eGFR (within CKD severity).The two 8-point SMPG profiles were collected on two non-consecutive days (pre-meal and 2-hour postprandial SMPG x [morning, midday, and evening meals in one day] + bedtime + 5 hours after bedtime). Only measurements prior to rescue and study discontinuation were used.

End point type

Secondary

End point timeframe

Baseline, 52 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	118 ^[54]	96 ^[55]	102 ^[56]
Units: mg/dL
least squares mean (standard error)	-40.5 ( 3.59 )	-30.0 ( 3.75 )	-27.2 ( 3.93 )

Notes
[54] - All randomized participants who had at least 1 dose of study drug & had evaluable HbA1c & SMPG data.
[55] - All randomized participants who had at least 1 dose of study drug & had evaluable HbA1c & SMPG data
[56] - All randomized participants who had at least 1 dose of study drug & had evaluable HbA1c & SMPG data

No statistical analyses for this end point

Secondary: Change From Baseline in FG

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End point title

Change From Baseline in FG

End point description

End point type

Secondary

End point timeframe

Baseline, 52 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	152 ^[57]	132 ^[58]	131 ^[59]
Units: mg/dL
least squares mean (standard error)	-6.4 ( 6.38 )	20.8 ( 6.58 )	28.3 ( 6.87 )

Notes
[57] - All randomized participants who received 1 dose of study drug and had evaluable HbA1c and FG data.
[58] - All randomized participants who received 1 dose of study drug and had evaluable HbA1c and FG data.
[59] - All randomized participants who recieved 1 dose of study drug and had evaluable HbA1c and FG data.

No statistical analyses for this end point

Secondary: Change in Mean Daily Insulin Lispro Dose

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End point title

Change in Mean Daily Insulin Lispro Dose

End point description

The mean daily insulin was based on a 4-week interval prior to week 52 assessments. LS means were calculated using a REML based mixed-effects model for repeated measures (MMRM) with the change in HbA1c as the dependent variable and treatment, MA-region, Baseline HbA1c, baseline mean daily insulin, baseline CKD Severity, week, treatment*week, baseline HbA1c (%), log baseline eGFR (within CKD severity), and participant was the random effect. Covariance structure = Unstructured. Only measurements prior to rescue and study discontinuation were used.

End point type

Secondary

End point timeframe

Baseline, 52 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	159 ^[60]	140 ^[61]	132 ^[62]
Units: U/day
least squares mean (standard error)	16.84 ( 2.87 )	27.46 ( 2.93 )	20.05 ( 3.13 )

Notes
[60] - All randomized participants who had 1 dose of study drug & evaluable HbA1c & Lispro dose data.
[61] - All randomized participants who had 1 dose of study drug & evaluable HbA1c & Lispro dose data.
[62] - All randomized participants who had 1 dose of study drug & evaluable HbA1c & Lispro dose data.

No statistical analyses for this end point

Secondary: Percentage of Participants With Estimated Average Glucose <154 mg/dL

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End point title

Percentage of Participants With Estimated Average Glucose <154 mg/dL

End point description

End point type

Secondary

End point timeframe

Baseline, 52 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	137 ^[63]	122 ^[64]	116 ^[65]
Units: percentage of participants
number (not applicable)	73.7	57.4	50.9

Notes
[63] - All randomized participants who had evaluable HbA1c and average self-monitored plasma glucose data.
[64] - All randomized participants who had evaluable HbA1c and average self-monitored plasma glucose data.
[65] - All randomized participants who had evaluable HbA1c and average self-monitored plasma glucose data.

No statistical analyses for this end point

Secondary: Change From Baseline in sCr

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End point title

Change From Baseline in sCr

End point description

Change from baseline in sCr levels after treatment.

End point type

Secondary

End point timeframe

Baseline, 52 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	164 ^[66]	160 ^[67]	157 ^[68]
Units: mg/dL
median (inter-quartile range (Q1-Q3))	0.12 (-0.05 to 0.38)	0.04 (-0.11 to 0.27)	0.07 (-0.11 to 0.21)

Notes
[66] - All randomized participants who had evaluable baseline and post-baseline sCr data.
[67] - All randomized participants had evaluable baseline and post-baseline sCr data.
[68] - All randomized participants who had evaluable baseline and post-baseline sCr data.

No statistical analyses for this end point

Secondary: Change From Baseline in eGFR

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End point title

Change From Baseline in eGFR

End point description

The change in eGFR by using CKD-EPI equation.

End point type

Secondary

End point timeframe

Baseline, 52 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	164 ^[69]	160 ^[70]	157 ^[71]
Units: mL/min/1.73m2
median (inter-quartile range (Q1-Q3))	-3.3 (-7.5 to 1.0)	-1.5 (-5.5 to 2.5)	-2.0 (-6.0 to 2.5)

Notes
[69] - All randomized participants who and had evaluable baseline and post baseline eGFR data.
[70] - All randomized participants who and had evaluable baseline and post baseline eGFR data.
[71] - All randomized participants who and had evaluable baseline and post baseline eGFR data.

No statistical analyses for this end point

Secondary: Change From Baseline in eCrCl

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End point title

Change From Baseline in eCrCl

End point description

eCrCl was calculated by Cockcroft-Gault [Cockcroft and Gault 1976] equation using baseline estimated lean body weight.

End point type

Secondary

End point timeframe

Baseline, 52 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	164 ^[72]	160 ^[73]	157 ^[74]
Units: mL/min
median (inter-quartile range (Q1-Q3))	-2.5 (-5.8 to 0.5)	-1.3 (-4.0 to 1.5)	-1.5 (-5.0 to 1.5)

Notes
[72] - All randomized participants who study drug and had evaluable baseline and post-baseline eCrCl data.
[73] - All randomized participants who study drug and had evaluable baseline and post-baseline eCrCl data.
[74] - All randomized participants who study drug and had evaluable baseline and post-baseline eCrCl data.

No statistical analyses for this end point

Secondary: Change From Baseline in UACR

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End point title

Change From Baseline in UACR

End point description

The change from baseline in UACR

End point type

Secondary

End point timeframe

Baseline, 52 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	165 ^[75]	162 ^[76]	159 ^[77]
Units: g/kg
median (inter-quartile range (Q1-Q3))	3.5 (-56.2 to 138.1)	-3.0 (-88.5 to 87.6)	-11.5 (-158.0 to 42.9)

Notes
[75] - All randomized participants who had evaluable baseline and post-baseline UACR data.
[76] - All randomized participants who had evaluable baseline and post-baseline UACR data.
[77] - All randomized participants who had evaluable baseline and post-baseline UACR data.

No statistical analyses for this end point

Secondary: Change From Baseline in Body Weight

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End point title

Change From Baseline in Body Weight

End point description

LS means were calculated from a REML based MMRM model: Change from Baseline = treatment , week, treatment*Week, MA-region, Baseline HbA1c (%), Baseline Body Weight (kg), Baseline CKD Severity, Log Baseline eGFR (within CKD severity), where participant enters the model as a random effect. Covariance structure = Unstructured. Only measurements prior to rescue and study discontinuation were used.

End point type

Secondary

End point timeframe

Baseline, 52 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	158 ^[78]	137 ^[79]	132 ^[80]
Units: kg
least squares mean (standard error)	1.57 ( 0.429 )	-1.71 ( 0.448 )	-2.66 ( 0.467 )

Notes
[78] - All randomized participants who rec'd 1 dose of study drug & had evaluable HbA1c & body weight.
[79] - All randomized participants who rec'd 1 dose of study drug & had evaluable HbA1c & body weight.
[80] - All randomized participants who rec'd 1 dose of study drug & had evaluable HbA1c & body weight.

No statistical analyses for this end point

Secondary: Rate of Hypoglycemic Events (HE)

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End point title

Rate of Hypoglycemic Events (HE)

End point description

HE were classified as total HE rate, documented symptomatic hypoglycemia, severe hypoglycemia, and nocturnal. The 1-year adjusted rate of HEs was summarized cumulatively at 52 weeks. A summary of other nonserious AEs, and all SAEs, regardless of causality, is located in the Reported Adverse Events section. Only measurements prior to rescue and study discontinuation were used.

End point type

Secondary

End point timeframe

Baseline, 52 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	194 ^[81]	189 ^[82]	190 ^[83]
Units: Events/Participant/Year
arithmetic mean (standard deviation)
Total	14.36 ( 22.20 )	7.59 ( 17.81 )	5.82 ( 13.70 )
Documented Symptomatic	9.62 ( 17.72 )	4.34 ( 9.30 )	4.44 ( 12.23 )
Severe	0.09 ( 0.37 )	0.03 ( 0.21 )	0.00 ( 0.00 )
Nocturnal	2.48 ( 5.10 )	0.76 ( 0.09 )	0.70 ( 2.29 )

Notes
[81] - All randomized participants who received at least 1 dose of study drug & had evaluable HE data.
[82] - All randomized participants who received at least 1 dose of study drug & had evaluable HE data.
[83] - All randomized participants who received at least 1 dose of study drug & had evaluable HE data.

No statistical analyses for this end point

Secondary: Percentage of Participants with Allergic/Hypersensitivity Reactions

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End point title

Percentage of Participants with Allergic/Hypersensitivity Reactions

End point description

Percentage of Participants with Allergic/Hypersensitivity Reactions: Angioedema Standardized MedDRA Query (SMQ), Anaphylactic Reaction SMQ, or Severe Cutaneous Adverse Reactions SMQ

End point type

Secondary

End point timeframe

Baseline through 52 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	194 ^[84]	190 ^[85]	192 ^[86]
Units: events
number (not applicable)
Angdioedema SMQ	1	2	2
Angiodema	0	0	1
Eyelid edema	0	1	0
Face edema	0	1	1
Uticaria	1	0	0
Anaphylactic Reaction SMQ	1	0	0
Circulatory Collapse	1	0	0
Severe Cutaneous Adverse Reactions SMQ	0	0	0

Notes
[84] - All randomized participants who received at least one dose of study drug.
[85] - All randomized participants who received at least one dose of study drug.
[86] - All randomized participants who received at least one dose of study drug.

No statistical analyses for this end point

Secondary: Percentage of Participants with Self-Reported Hypoglycemic Events (HE)

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End point title

Percentage of Participants with Self-Reported Hypoglycemic Events (HE)

End point description

Hypoglycemic events (HE) were classified as severe (defined as an episode requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions), documented symptomatic (defined as any time a participant feels that he/she is experiencing symptoms and/or signs associated with hypoglycemia, and has a plasma glucose level of ≤3.9 mmol/L (≤70 mg/dL), nocturnal (defined as any hypoglycemic event that occurs between bedtime and waking). The number of self-reported hypoglycemic events was summarized cumulatively at 52 weeks. A summary of other nonserious AEs, and all SAEs, regardless of causality, is located in the Reported Adverse Events section. Only measurements prior to rescue and study discontinuation was used.

End point type

Secondary

End point timeframe

Baseline, 52 Weeks

End point values	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Number of subjects analysed	194 ^[87]	189 ^[88]	190 ^[89]
Units: percentage of participants
Total HE	75	60	50
Documented Symptomatic HE	63	48	41
Severe HE	6	3	0
Nocturnal HE	48	24	21

Notes
[87] - All randomized participants who received at least 1 dose of study drug and had evaluable HE data.
[88] - All randomized participants who received at least 1 dose of study drug and had evaluable HE data.
[89] - All randomized participants who received at least 1 dose of study drug and had evaluable HE data.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Entire Study

Adverse event reporting additional description

H9X-MC-GBDX

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

Insulin Glargine

Reporting group description

Reporting group title

Dulaglutide 0.75 mg

Reporting group description

Reporting group title

Dulaglutide 1.5 mg

Reporting group description

Serious adverse events	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Total subjects affected by serious adverse events
subjects affected / exposed	56 / 194 (28.87%)	48 / 190 (25.26%)	41 / 192 (21.35%)
number of deaths (all causes)	6	9	3
number of deaths resulting from adverse events	0	1	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
bladder neoplasm
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	0 / 190 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
gastric cancer
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
circulatory collapse
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
deep vein thrombosis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
hypertension
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
hypertensive crisis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
hypotension
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
peripheral arterial occlusive disease
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	0 / 190 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
peripheral ischaemia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	0 / 190 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
peripheral vascular disorder
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	2 / 190 (1.05%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
chest pain
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	0 / 190 (0.00%)	3 / 192 (1.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
death
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
ischaemic ulcer
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	0 / 190 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
non-cardiac chest pain
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	1 / 190 (0.53%)	2 / 192 (1.04%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
oedema peripheral
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	0 / 190 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
pacemaker generated arrhythmia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
pyrexia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
sudden death
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Immune system disorders
drug hypersensitivity
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
acute pulmonary oedema
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
aspiration
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
colpocele
alternative dictionary used: MedDRA 19.1
subjects affected / exposed ^[1]	1 / 101 (0.99%)	0 / 86 (0.00%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
dyspnoea
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
epistaxis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
pleural effusion
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
pulmonary embolism
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	0 / 190 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
respiratory distress
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
respiratory failure
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
blood creatinine increased
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	2 / 194 (1.03%)	3 / 190 (1.58%)	3 / 192 (1.56%)
occurrences causally related to treatment / all	0 / 3	0 / 3	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
glomerular filtration rate decreased
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
haemoglobin decreased
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
red blood cell sedimentation rate increased
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
accidental overdose
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ankle fracture
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
concussion
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
fall
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	2 / 194 (1.03%)	0 / 190 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
foot fracture
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
postpericardiotomy syndrome
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
road traffic accident
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
tendon rupture
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	0 / 190 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
toxicity to various agents
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
wrist fracture
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
acute coronary syndrome
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	2 / 194 (1.03%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
acute myocardial infarction
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	4 / 194 (2.06%)	6 / 190 (3.16%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 4	1 / 6	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
angina pectoris
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
angina unstable
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	3 / 194 (1.55%)	2 / 190 (1.05%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
atrial fibrillation
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	0 / 190 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
cardiac arrest
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
cardiac failure
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	1 / 190 (0.53%)	3 / 192 (1.56%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
cardiac failure acute
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
cardiac failure congestive
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	2 / 194 (1.03%)	2 / 190 (1.05%)	2 / 192 (1.04%)
occurrences causally related to treatment / all	0 / 2	1 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
coronary artery disease
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
coronary artery occlusion
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
heart valve incompetence
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	0 / 190 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
ischaemic cardiomyopathy
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
myocardial infarction
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
myocardial ischaemia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
palpitations
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	0 / 190 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
carotid artery stenosis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
cerebrovascular accident
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	2 / 192 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
cervical radiculopathy
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
iiird nerve paralysis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ischaemic stroke
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	2 / 192 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
myoclonus
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
presyncope
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
sciatica
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
syncope
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	1 / 190 (0.53%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
transient ischaemic attack
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	0 / 190 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
anaemia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
retinal artery occlusion
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
visual acuity reduced
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
abdominal pain
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 0	2 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
abdominal pain lower
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
colitis ischaemic
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	0 / 190 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
diarrhoea
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	0 / 190 (0.00%)	2 / 192 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
gastritis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
gastrointestinal haemorrhage
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
gastrooesophageal reflux disease
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
nausea
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
pancreatitis acute
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	2 / 192 (1.04%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
vomiting
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	1 / 1	2 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
cholecystitis acute
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	2 / 190 (1.05%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
portal vein thrombosis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
diabetic foot
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	0 / 190 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
skin ulcer
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
acute kidney injury
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	2 / 194 (1.03%)	5 / 190 (2.63%)	3 / 192 (1.56%)
occurrences causally related to treatment / all	0 / 2	1 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
chronic kidney disease
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	2 / 194 (1.03%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
end stage renal disease
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	2 / 194 (1.03%)	2 / 190 (1.05%)	2 / 192 (1.04%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
haematuria
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
prerenal failure
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	0 / 190 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
renal injury
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
tubulointerstitial nephritis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
urethral haemorrhage
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
musculoskeletal chest pain
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
osteoarthritis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	0 / 190 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
pain in extremity
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
rhabdomyolysis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	2 / 190 (1.05%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
Infections and infestations
abdominal abscess
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
appendicitis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
cellulitis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	3 / 194 (1.55%)	0 / 190 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
clostridium difficile colitis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
diverticulitis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
gastroenteritis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
gastroenteritis viral
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
groin abscess
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
localised infection
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
osteomyelitis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	1 / 190 (0.53%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
pneumonia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	3 / 194 (1.55%)	3 / 190 (1.58%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
pneumonia haemophilus
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
pneumonia legionella
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
pseudomembranous colitis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	0 / 190 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
pyelonephritis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	0 / 190 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
sepsis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	0 / 190 (0.00%)	2 / 192 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
tonsillitis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
tracheobronchitis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
urinary tract infection
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	3 / 194 (1.55%)	2 / 190 (1.05%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
wound infection
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	0 / 190 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
dehydration
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	2 / 192 (1.04%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
fluid retention
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	1 / 190 (0.53%)	0 / 192 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
hyperglycaemia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	0 / 194 (0.00%)	0 / 190 (0.00%)	2 / 192 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
hypoglycaemia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	13 / 194 (6.70%)	6 / 190 (3.16%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	14 / 17	5 / 7	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
hyponatraemia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	1 / 194 (0.52%)	0 / 190 (0.00%)	1 / 192 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Notes
[1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Colpocele is a gender-specific SAE in females and is the correct N presented.

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Insulin Glargine	Dulaglutide 0.75 mg	Dulaglutide 1.5 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	130 / 194 (67.01%)	134 / 190 (70.53%)	144 / 192 (75.00%)
Investigations
blood creatinine increased
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	90 / 194 (46.39%)	71 / 190 (37.37%)	74 / 192 (38.54%)
occurrences all number	124	102	106
glomerular filtration rate decreased
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	26 / 194 (13.40%)	20 / 190 (10.53%)	17 / 192 (8.85%)
occurrences all number	29	25	22
weight increased
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	16 / 194 (8.25%)	9 / 190 (4.74%)	9 / 192 (4.69%)
occurrences all number	18	9	10
Vascular disorders
hypertension
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	20 / 194 (10.31%)	13 / 190 (6.84%)	14 / 192 (7.29%)
occurrences all number	20	13	14
Nervous system disorders
dizziness
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	10 / 194 (5.15%)	11 / 190 (5.79%)	8 / 192 (4.17%)
occurrences all number	12	12	11
Blood and lymphatic system disorders
anaemia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	10 / 194 (5.15%)	3 / 190 (1.58%)	5 / 192 (2.60%)
occurrences all number	10	3	5
General disorders and administration site conditions
oedema peripheral
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	15 / 194 (7.73%)	12 / 190 (6.32%)	10 / 192 (5.21%)
occurrences all number	16	13	10
Gastrointestinal disorders
constipation
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	6 / 194 (3.09%)	10 / 190 (5.26%)	12 / 192 (6.25%)
occurrences all number	6	10	13
diarrhoea
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	14 / 194 (7.22%)	30 / 190 (15.79%)	31 / 192 (16.15%)
occurrences all number	17	37	49
nausea
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	9 / 194 (4.64%)	27 / 190 (14.21%)	38 / 192 (19.79%)
occurrences all number	9	38	52
vomiting
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	9 / 194 (4.64%)	16 / 190 (8.42%)	26 / 192 (13.54%)
occurrences all number	9	22	42
Respiratory, thoracic and mediastinal disorders
cough
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	15 / 194 (7.73%)	7 / 190 (3.68%)	7 / 192 (3.65%)
occurrences all number	17	7	8
Musculoskeletal and connective tissue disorders
back pain
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	7 / 194 (3.61%)	8 / 190 (4.21%)	10 / 192 (5.21%)
occurrences all number	8	8	10
Infections and infestations
influenza
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	10 / 194 (5.15%)	15 / 190 (7.89%)	12 / 192 (6.25%)
occurrences all number	10	18	12
nasopharyngitis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	12 / 194 (6.19%)	9 / 190 (4.74%)	11 / 192 (5.73%)
occurrences all number	15	12	12
sinusitis
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	11 / 194 (5.67%)	4 / 190 (2.11%)	2 / 192 (1.04%)
occurrences all number	13	4	2
upper respiratory tract infection
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	20 / 194 (10.31%)	13 / 190 (6.84%)	8 / 192 (4.17%)
occurrences all number	26	15	9
urinary tract infection
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	19 / 194 (9.79%)	10 / 190 (5.26%)	13 / 192 (6.77%)
occurrences all number	25	12	16
Metabolism and nutrition disorders
decreased appetite
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	3 / 194 (1.55%)	5 / 190 (2.63%)	11 / 192 (5.73%)
occurrences all number	3	6	11
hyperkalaemia
alternative dictionary used: MedDRA 19.1
subjects affected / exposed	13 / 194 (6.70%)	8 / 190 (4.21%)	12 / 192 (6.25%)
occurrences all number	15	10	14

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Study Comparing Dulaglutide With Insulin Glargine on Glycemic Control in Participants With Type 2 Diabetes (T2D) and Moderate or Severe Chronic Kidney Disease (CKD) (AWARD-7)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from Baseline in Hemoglobin A1c (HbA1c)

Primary: Change from Baseline in Hemoglobin A1c (HbA1c)

Secondary: Percentage of Participants whose HbA1c was <7.0%

Secondary: Percentage of Participants whose HbA1c was <7.0%

Secondary: Percentage of Participants whose HbA1c was <8.0%

Secondary: Percentage of Participants whose HbA1c was <8.0%

Secondary: Change from Baseline in 8-Point Self-Monitored Plasma Glucose (SMPG)

Secondary: Change from Baseline in 8-Point Self-Monitored Plasma Glucose (SMPG)

Secondary: Change from Baseline in Fasting Glucose (FG)

Secondary: Change from Baseline in Fasting Glucose (FG)

Secondary: Change From Baseline in Mean Daily Insulin Lispro Dose

Secondary: Change From Baseline in Mean Daily Insulin Lispro Dose

Secondary: Percentage of Participants With Estimated Average Glucose <154 mg/dL

Secondary: Percentage of Participants With Estimated Average Glucose <154 mg/dL

Secondary: Change from Baseline in Serum Creatinine (sCr)

Secondary: Change from Baseline in Serum Creatinine (sCr)

Secondary: Change from Baseline in estimated Glomerular Filtration Rate (eGFR)

Secondary: Change from Baseline in estimated Glomerular Filtration Rate (eGFR)

Secondary: Change from Baseline in estimated Creatinine Clearance (eCrCl)

Secondary: Change from Baseline in estimated Creatinine Clearance (eCrCl)

Secondary: Change from Baseline in Urinary Albumin to Creatinine Ratio (UACR)

Secondary: Change from Baseline in Urinary Albumin to Creatinine Ratio (UACR)

Secondary: Change from Baseline in Body Weight

Secondary: Change from Baseline in Body Weight

Secondary: Percentage of Participants with Self-Reported Hypoglycemic Events (HE)

Secondary: Percentage of Participants with Self-Reported Hypoglycemic Events (HE)

Secondary: Rate of Hypoglycemic Events

Secondary: Rate of Hypoglycemic Events

Secondary: Change from Baseline in HbA1c

Secondary: Change from Baseline in HbA1c

Secondary: Percentage of Participants Whose HbA1c is <7.0%

Secondary: Percentage of Participants Whose HbA1c is <7.0%

Secondary: Percentage of Participants Whose HbA1c is <8.0%

Secondary: Percentage of Participants Whose HbA1c is <8.0%

Secondary: Change From Baseline in 8-Point SMPG

Secondary: Change From Baseline in 8-Point SMPG

Secondary: Change From Baseline in FG

Secondary: Change From Baseline in FG

Secondary: Change in Mean Daily Insulin Lispro Dose

Secondary: Change in Mean Daily Insulin Lispro Dose

Secondary: Percentage of Participants With Estimated Average Glucose <154 mg/dL

Secondary: Percentage of Participants With Estimated Average Glucose <154 mg/dL

Secondary: Change From Baseline in sCr

Secondary: Change From Baseline in sCr

Secondary: Change From Baseline in eGFR

Secondary: Change From Baseline in eGFR

Secondary: Change From Baseline in eCrCl

Secondary: Change From Baseline in eCrCl

Secondary: Change From Baseline in UACR

Secondary: Change From Baseline in UACR

Secondary: Change From Baseline in Body Weight

Secondary: Change From Baseline in Body Weight

Secondary: Rate of Hypoglycemic Events (HE)

Secondary: Rate of Hypoglycemic Events (HE)

Secondary: Percentage of Participants with Allergic/Hypersensitivity Reactions

Secondary: Percentage of Participants with Allergic/Hypersensitivity Reactions

Secondary: Percentage of Participants with Self-Reported Hypoglycemic Events (HE)

Secondary: Percentage of Participants with Self-Reported Hypoglycemic Events (HE)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Study Comparing Dulaglutide With Insulin Glargine on Glycemic Control in Participants With Type 2 Diabetes (T2D) and Moderate or Severe Chronic Kidney Disease (CKD) (AWARD-7)