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Clinical Trial Results:
A 24-Week International, Multi-center, Randomized, Parallel-group, Double-blind Trial to Evaluate Metformin Extended Release Monotherapy Compared to Metformin Immediate Release Monotherapy in Adult Subjects with Type 2 Diabetes who have Inadequate Glycemic Control with Diet and Exercise

Summary
EudraCT number	2012-004531-23
Trial protocol	CZ DE HU GB PL
Global end of trial date	01 Jun 2016

Results information
Results version number	v1(current)
This version publication date	16 Jun 2017
First version publication date	16 Jun 2017
Other versions

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

CV181-206

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Bristol-Myers Squibb International Corporation

Sponsor organisation address

Chaussée de la Hulpe 185, Brussels, Belgium, 1170

Public contact

EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com

Scientific contact

EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com

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

01 Jun 2016

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

01 Jun 2016

Was the trial ended prematurely?

Main objective of the trial

To determine if monotherapy with 2000 mg metformin extended release is non-inferior to monotherapy with 2000 mg immediate release in adult patients with type 2 diabetes who have inadequate glycemic control with diet and exercise

Protection of trial subjects

The study was conducted in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

21 May 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Czech Republic: 47

Country: Number of subjects enrolled

Canada: 169

Country: Number of subjects enrolled

Germany: 26

Country: Number of subjects enrolled

Hungary: 270

Country: Number of subjects enrolled

Poland: 138

Country: Number of subjects enrolled

Puerto Rico: 95

Country: Number of subjects enrolled

Romania: 345

Country: Number of subjects enrolled

South Africa: 118

Country: Number of subjects enrolled

United Kingdom: 89

Country: Number of subjects enrolled

United States: 439

Worldwide total number of subjects

1736

EEA total number of subjects

915

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)

1366

From 65 to 84 years

365

85 years and over

Subject disposition

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Recruitment details

1736 enrolled at 148 study sites in North America, Europe, and South Africa. Lead in period=794. Reasons not entered: 1 AE, 17 WC, 4 lost to FU, 3 NC, 911 SC, 4 ARS, 1 other. Adverse event=-AE, Withdrew consent=WC, Follow-up=FU, poor/non-compliance=NC, No longer met study criteria=SC, Administrative reason by sponsor=ARS.

Screening details

570 completed lead-in period and were eligible for randomization. 568 randomized. Non-randomized: 1 AE, 27 WC, 3 lost to FU, 7 NC, 159 SC, 8 ARS, 3 other.

Period 1 title

Double Blind Treatment - All treated

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer

Blinding implementation details

Randomized subjects who took at least one dose of double-blind study medication in the treatment group to which they were randomized.

Are arms mutually exclusive

Yes

Metformin XR

Arm description

Arm type

Experimental

Investigational medicinal product name

Placebo for Metformin Hydrochloride Modified Release (Metformin XR)

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Placebo for Metformin XR modified release is a plain, white to off-white, capsule-shaped, biconvex tablet. Subjects randomized to double-blind treatment with metformin XR were titrated from 500 mg orally once daily (evening) to 2000 mg orally once daily (evening) over the first 3 weeks of the 24-week double-blind treatment period (as tolerated). In order to maintain blinding, subjects received 4 metformin XR tablets daily in the evening (combination of active and placebo) throughout the 24-week double-blind treatment period. Subjects randomized to treatment with metformin XR also received placebo tablets for metformin IR throughout the 24-week double-blind treatment period (2 tablets each morning and 2 tablets each evening).

Investigational medicinal product name

Metformin Hydrochloride Modified Release (Metformin XR)

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Metformin XR modified release is a plain, white to off-white, capsule-shaped, biconvex tablet. Subjects randomized to double-blind treatment with metformin XR were titrated from 500 mg orally once daily (evening) to 2000 mg orally once daily (evening) over the first 3 weeks of the 24-week double-blind treatment period (as tolerated). In order to maintain blinding, subjects received 4 metformin XR tablets daily in the evening (combination of active and placebo) throughout the 24-week double-blind treatment period. Subjects randomized to treatment with metformin XR also received placebo tablets for metformin IR throughout the 24-week double-blind treatment period (2 tablets each morning and 2 tablets each evening).

Metformin IR

Arm description

Arm type

Experimental

Investigational medicinal product name

Metformin Hydrochloride (Metformin IR)

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Metformin IR is a white to off-white, round, biconvex, bevel-edged film-coated tablet with no markings. Subjects randomized to double-blind treatment with metformin IR were titrated from 500 mg orally daily (morning) to a total daily dose of 2000 mg orally (divided between morning and evening) over the first 3 weeks of the 24-week double-blind treatment period (as tolerated). In order to maintain blinding, subjects received 4 metformin IR tablets daily (2 tablets each morning and 2 tablets each evening; combination of active and placebo) throughout the 24-week double-blind treatment period. Subjects randomized to treatment with metformin IR also received placebo tablets for metformin XR throughout the 24-week double-blind treatment period (4 tablets each evening).

Investigational medicinal product name

Placebo for Metformin Hydrochloride (Metformin IR)

Investigational medicinal product code

Other name

Pharmaceutical forms

Modified-release tablet

Routes of administration

Oral use

Dosage and administration details

Placebo for Metformin IR is a white to off-white, round, biconvex, bevel-edged film-coated tablet with no markings. Subjects randomized to double-blind treatment with metformin IR were titrated from 500 mg orally daily (morning) to a total daily dose of 2000 mg orally (divided between morning and evening) over the first 3 weeks of the 24-week double-blind treatment period (as tolerated). In order to maintain blinding, subjects received 4 metformin IR tablets daily (2 tablets each morning and 2 tablets each evening; combination of active and placebo) throughout the 24-week double-blind treatment period. Subjects randomized to treatment with metformin IR also received placebo tablets for metformin XR throughout the 24-week double-blind treatment period (4 tablets each evening).

Number of subjects in period 1	Metformin XR	Metformin IR
Started	283	285
Completed	268	271
Not completed	15	14
Removed due to site non-compliance	15	14

Period 2 title

Double Blind - Compliant Randomized

Is this the baseline period?

Yes ^[1]

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer

Are arms mutually exclusive

Yes

Metformin XR

Arm description

Subjects received Metformin XR and Placebo matching with Metformin XR Metformin Extended Release (XR) 500 mg tablets (500-2000 mg per day) by mouth twice daily (BID) for 24 weeks Placebo matching with Metformin XR 0 mg tablets by mouth twice daily (BID) for 24 weeks. Population includes all randomized subjects who took at least one dose of double-blind study medication in the treatment group to which they were randomized, excluding 15 randomized subjects due to site non-compliance.

Arm type

Experimental

Investigational medicinal product name

Placebo for Metformin Hydrochloride Modified Release (Metformin XR)

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Metformin Hydrochloride Modified Release (Metformin XR)

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Metformin IR

Arm description

Subjects received Metformin IR and Placebo matching with Metformin IR. Metformin Immediate Release (IR) 500 mg tablets (500-2000 mg per day) by mouth twice daily (BID) for 24 weeks Placebo matching with Metformin IR 0 mg tablets by mouth twice daily (BID) for 24 weeks. Population includes all randomized subjects who took at least one dose of double-blind study medication in the treatment group to which they were randomized, excluding 14 randomized subjects due to site non-compliance.

Arm type

Experimental

Investigational medicinal product name

Metformin Hydrochloride (Metformin IR)

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Placebo for Metformin Hydrochloride (Metformin IR)

Investigational medicinal product code

Other name

Pharmaceutical forms

Modified-release tablet

Routes of administration

Oral 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: Baseline period only refers to those randomized and treated subjects from compliant sites.

Number of subjects in period 2 ^[2]	Metformin XR	Metformin IR
Started	268	271
Completed	245	245
Not completed	23	26
Adverse event, serious fatal	1	-
Subject Withdrew Consent	4	5
Adverse event, non-fatal	6	1
Other	6	10
Subject Request to Discontinue Treatment	2	-
Poor/Non-compliance	1	-
Lost to follow-up	3	10

Notes
[2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Out of 1736 subjects who were enrolled only 568 subjects were treated.

Period 3 title

Off Treatment Follow-Up

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Metformin XR

Arm description

Subjects did not received any treatment during the off-treatment follow-up period. These subjects originally received Metformin XR and Placebo matching with Metformin XR Metformin Extended Release (XR) 500 mg tablets (500-2000 mg per day) by mouth twice daily (BID) for 24 weeks Placebo matching with Metformin XR 0 mg tablets by mouth twice daily (BID) for 24 weeks.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Metformin IR

Arm description

Subjects did not received any treatment during the off-treatment follow-up period. These subjects originally received Metformin IR and Placebo matching with Metformin IR. Metformin Immediate Release (IR) 500 mg tablets (500-2000 mg per day) by mouth twice daily (BID) for 24 weeks Placebo matching with Metformin IR 0 mg tablets by mouth twice daily (BID) for 24 weeks.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 3 ^[3]	Metformin XR	Metformin IR
Started	9	1
Completed	6	1
Not completed	3	0
Subject Withdrew Consent	1	-
Other	2	-

Notes
[3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Not all subjects entered the Follow-Up period.

Baseline characteristics

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Reporting group title

Metformin XR

Reporting group description

Reporting group title

Metformin IR

Reporting group description

Reporting group values	Metformin XR	Metformin IR	Total
Number of subjects	268	271	539
Age Categorical
Units: Subjects
< 65 years	198	226	424
>= 65 years	70	45	115
Age Continuous
Units: years
arithmetic mean (standard deviation)	56.8 ± 10.69	55.3 ± 10.34	-
Gender, Male/Female
Units: Subjects
Female	122	122	244
Male	146	149	295
Race/Ethnicity, Customized
Units: Subjects
White	227	225	452
Black or African American	22	19	41
Asian	17	20	37
Other	2	7	9

End points

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Reporting group title

Metformin XR

Reporting group description

Reporting group title

Metformin IR

Reporting group description

Reporting group title

Metformin XR

Reporting group description

Reporting group title

Metformin IR

Reporting group description

Reporting group title

Metformin XR

Reporting group description

Reporting group title

Metformin IR

Reporting group description

Primary: Adjusted mean change from baseline in HbA1c

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End point title

Adjusted mean change from baseline in HbA1c

End point description

Mean change in glycated hemoglobin (HbA1c) from baseline to Week 24 in the double-blind treatment period.

End point type

Primary

End point timeframe

Week 24

End point values	Metformin XR	Metformin IR
Number of subjects analysed	237	237
Units: percent
arithmetic mean (standard error)	-0.93 ± 0.0485	-0.96 ± 0.048

Adjusted mean change from baseline in HbA1c

Comparison groups

Metformin XR v Metformin IR

Number of subjects included in analysis

474

Analysis specification

Pre-specified

Analysis type

^[1]

Method

Parameter type

Mean difference (final values)

Point estimate

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

0.17

Variability estimate

Standard error of the mean

Dispersion value

0.0687

Notes
[1] - The study provided 90% power to demonstrate noninferiority in change from baseline mean HbA1c at Week 24, with an assumed standard deviation (SD) of 1.0%, a non-inferiority margin of 0.3%, and 2-sided alpha of 0.05 for the primary comparison

Primary: Number of Subjects With Death, Serious Adverse Events (SAEs), SAEs Related to Study Therapy, SAEs Leading to Discontinuation, Adverse Events (AEs) Related to Study Therapy, and AEs Leading to Discontinuation

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End point title

Number of Subjects With Death, Serious Adverse Events (SAEs), SAEs Related to Study Therapy, SAEs Leading to Discontinuation, Adverse Events (AEs) Related to Study Therapy, and AEs Leading to Discontinuation ^[2]

End point description

SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Treated subjects; All subjects who took at least one dose of double-blind study medication in the treatment group they were randomized to unless subjects had never received the double-blind study medication they were randomized. Those subjects were included in the treatment group based on the first treatment received.

End point type

Primary

End point timeframe

Date of first dose (Day 1) up to 30 post last dose of study drug (approx. 28 weeks)

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive summary statistics were planned for this outcome measure.

End point values	Metformin XR	Metformin IR
Number of subjects analysed	283	285
Units: subjects
Death	1	0
SAE	8	10
SAEs Related to Study Therapy	1	1
SAEs Leading to Discontinuation	0	1
AEs Related to Study Therapy	30	25
AEs Leading to Discontinuation	10	7

No statistical analyses for this end point

Secondary: Mean change in fasting plasma glucose (FPG)

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End point title

Mean change in fasting plasma glucose (FPG)

End point description

The mean change in fasting plasma glucose (FPG) from baseline to Week 24 in the double-blind treatment period was assessed. The lack of glycemic control criteria for initiation of rescue medication during Week 12 to Week 24 was having a FPG > 200 mg/dL (11.1 mmol/L). mg/dL = milligrams per deciliter; mmol/L = millimole per Liter

End point type

Secondary

End point timeframe

Week 24

End point values	Metformin XR	Metformin IR
Number of subjects analysed	228	229
Units: mg/dL
arithmetic mean (standard error)	-21.1 ± 1.803	-20.6 ± 1.789

No statistical analyses for this end point

Secondary: Mean change in Mean Daily Glucose (MDG)

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End point title

Mean change in Mean Daily Glucose (MDG)

End point description

The mean change in Mean Daily Glucose (MDG) from baseline to Week 24 in the double-blind treatment period was assessed. Prior to the Day 1 visit (between Week -1 and Day 1) and in the week before the Week 24/Study Termination and Rescue or Early Treatment Termination visit, subjects performed 7-point finger stick blood glucose monitoring (before and 2 hours after 3 meals per day, and at bedtime) for 3 consecutive days in order to determine their MDG.

End point type

Secondary

End point timeframe

Week 24

End point values	Metformin XR	Metformin IR
Number of subjects analysed	211	218
Units: mg/dL
arithmetic mean (standard error)	-24.68 ± 1.5813	-27.05 ± 1.555

No statistical analyses for this end point

Secondary: Percent of subjects with HbA1c < 7%

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End point title

Percent of subjects with HbA1c < 7%

End point description

Percent of subjects achieving a therapeutic glycemic response (defined as HbA1c < 7.0%) at Week 24 in the double-blind treatment period.

End point type

Secondary

End point timeframe

Week 24

End point values	Metformin XR	Metformin IR
Number of subjects analysed	237	237
Units: percent of subjects
number (confidence interval 95%)	70.9 (65.5 to 76.3)	72 (66.3 to 77.7)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up to 30 days after the last dose of the study drug

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

Metformin IR

Reporting group description

Metformin Immediate Release (IR) 500 mg, tablets (500-2000 mg per day), orally, BID and Placebo matching with Metformin IR 0 mg, tablets, orally, BID for 24 weeks.

Reporting group title

Metformin XR

Reporting group description

Metformin Extended Release (XR) 500 mg, tablets (500-2000 mg per day), orally, twice daily (BID) and placebo matching with Metformin XR 0 mg, tablets, orally, BID for 24 weeks.

Serious adverse events	Metformin IR	Metformin XR
Total subjects affected by serious adverse events
subjects affected / exposed	10 / 285 (3.51%)	8 / 283 (2.83%)
number of deaths (all causes)	1	0
number of deaths resulting from adverse events	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant melanoma in situ
subjects affected / exposed	0 / 285 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Prostatic adenoma
subjects affected / exposed	1 / 285 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	0 / 285 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Delayed recovery from anaesthesia
subjects affected / exposed	0 / 285 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Laceration
subjects affected / exposed	1 / 285 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Overdose
subjects affected / exposed	0 / 285 (0.00%)	2 / 283 (0.71%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Angina unstable
subjects affected / exposed	0 / 285 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Cerebral haemorrhage
subjects affected / exposed	0 / 285 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	1 / 285 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Hypocoagulable state
subjects affected / exposed	0 / 285 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Diplopia
subjects affected / exposed	1 / 285 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain lower
subjects affected / exposed	1 / 285 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 285 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	1 / 285 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	1 / 285 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 285 (0.00%)	1 / 283 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Ureterolithiasis
subjects affected / exposed	1 / 285 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Pulmonary tuberculosis
subjects affected / exposed	1 / 285 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 285 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Diabetes mellitus inadequate control
subjects affected / exposed	1 / 285 (0.35%)	0 / 283 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Metformin IR	Metformin XR
Total subjects affected by non serious adverse events
subjects affected / exposed	33 / 285 (11.58%)	39 / 283 (13.78%)
Investigations
Glomerular filtration rate decreased
subjects affected / exposed	13 / 285 (4.56%)	14 / 283 (4.95%)
occurrences all number	15	18
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	22 / 285 (7.72%)	25 / 283 (8.83%)
occurrences all number	36	32

More information

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Were there any global substantial amendments to the protocol? Yes

17 Apr 2013

This amendment clarified the language for the enrollment period and the lead-in period.

08 Aug 2013

This amendment added the following exclusion criteria: 1) Moderate or severe impairment of renal function defined as eGFR < 60 mL/min/1.73 m2 (estimated by MDRD) 2) Administration of any other investigational drug or participation in any interventional clinical study within 30 days of planned screening to this study 3) Subject is a participating investigator, study coordinator, employee of an investigator or immediate family member of any of the aforementioned) Additionally, this amendment revised language for discontinuation due to increased serum creatinine; added criteria for discontinuation of study drug due to impairment of renal function based on eGFR; and clarified that a 12-lead ECG would be obtained during the Lead-in Period.

19 Jun 2014

This amendment revised the inclusion enrollment and randomization criteria for HbA1c (lower limit of HbA1c was changed from >=7.2% to >=7.0%, and the upper limit was changed from <= 9.0% to <= 9.2%), clarified the definition of “treatment naïve” for inclusion criteria, allowed for optional pre-screening, and clarified the IVRS contact at Week -1.

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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Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Adjusted mean change from baseline in HbA1c

Primary: Adjusted mean change from baseline in HbA1c

Primary: Number of Subjects With Death, Serious Adverse Events (SAEs), SAEs Related to Study Therapy, SAEs Leading to Discontinuation, Adverse Events (AEs) Related to Study Therapy, and AEs Leading to Discontinuation

Primary: Number of Subjects With Death, Serious Adverse Events (SAEs), SAEs Related to Study Therapy, SAEs Leading to Discontinuation, Adverse Events (AEs) Related to Study Therapy, and AEs Leading to Discontinuation

Secondary: Mean change in fasting plasma glucose (FPG)

Secondary: Mean change in fasting plasma glucose (FPG)

Secondary: Mean change in Mean Daily Glucose (MDG)

Secondary: Mean change in Mean Daily Glucose (MDG)

Secondary: Percent of subjects with HbA1c < 7%

Secondary: Percent of subjects with HbA1c < 7%

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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