Trial Outcomes & Findings for Linagliptin in Combination With Metformin in Treatment Naive Patients With Type 2 Diabetes Mellitus and Insufficient Glycaemic Control (NCT NCT01438814)

NCT ID: NCT01438814

Last Updated: 2014-11-25

Results Overview

Adjusted mean change in HbA1c from baseline at Week 14 was analysed using an ANCOVA model. The Model included treatment and continuous baseline HbA1c.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 689 participants
• Primary outcome timeframe: Baseline and 14 weeks
• Results posted on: 2014-11-25

Participant Flow

Participant milestones

Measure	Lina 5mg + Met qd Patients treated with Linagliptin 5mg in combination with metformin once daily.	Met Bid Patients treated with metformin alone twice daily.
Overall Study STARTED	344	345
Overall Study COMPLETED	330	331
Overall Study NOT COMPLETED	14	14

Reasons for withdrawal

Measure	Lina 5mg + Met qd Patients treated with Linagliptin 5mg in combination with metformin once daily.	Met Bid Patients treated with metformin alone twice daily.
Overall Study Adverse Event	3	3
Overall Study Protocol Violation	1	2
Overall Study Lost to Follow-up	4	3
Overall Study Withdrawal by Subject	4	2
Overall Study Other	2	4

Baseline Characteristics

Linagliptin in Combination With Metformin in Treatment Naive Patients With Type 2 Diabetes Mellitus and Insufficient Glycaemic Control

Baseline characteristics by cohort

Measure	Lina 5mg + Met qd n=344 Participants Patients treated with Linagliptin 5mg in combination with metformin once daily.	Met Bid n=345 Participants Patients treated with metformin alone twice daily.	Total n=689 Participants Total of all reporting groups
Age, Continuous	53.1 years STANDARD_DEVIATION 10.7 • n=5 Participants	52.9 years STANDARD_DEVIATION 10.7 • n=7 Participants	53.0 years STANDARD_DEVIATION 10.7 • n=5 Participants
Sex: Female, Male Female	175 Participants n=5 Participants	187 Participants n=7 Participants	362 Participants n=5 Participants
Sex: Female, Male Male	169 Participants n=5 Participants	158 Participants n=7 Participants	327 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and 14 weeks

Population: FAS1000mg with last observation carried forward (LOCF): all patients randomised and treated who had a baseline at least 1 on-treatment HbA1c value and who tolerated a daily metformin dose of at least 1000 mg at the end of the titration phase.

Adjusted mean change in HbA1c from baseline at Week 14 was analysed using an ANCOVA model. The Model included treatment and continuous baseline HbA1c.

Outcome measures

Measure	Lina 5mg + Met qd n=298 Participants Patients treated with Linagliptin 5mg in combination with metformin once daily.	Met Bid n=341 Participants Patients treated with metformin alone twice daily.
Change From Baseline in Glycosylated Hemoglobin A1c (HbA1c) After 14 Weeks Treatment	-0.99 percent Standard Error 0.05	-0.98 percent Standard Error 0.04

SECONDARY outcome

Timeframe: 14 weeks

Population: Patients from FAS1000 with non-completer considered as failure (NCF) having a baseline HbA1c\>=7.0%.

The proportion of patients who achieved all the targets in a composite endpoint (HbA1c below 7.0% after 14 weeks of treatment; no occurrence of pre-specified moderate or severe gastrointestinal (GI) side effects of metformin, as assessed by the investigators during 14 weeks of treatment)

Outcome measures

Measure	Lina 5mg + Met qd n=257 Participants Patients treated with Linagliptin 5mg in combination with metformin once daily.	Met Bid n=306 Participants Patients treated with metformin alone twice daily.
Composite Endpoint of Occurrence of Treat to Target Efficacy Response, That is an HbA1c Under Treatment of <7.0% After 14 Weeks of Treatment, on no Occurrence of Moderate or Severe Gastrointestinal (GI) Side Effects During 14 Weeks of Treatment	119 participants	148 participants

SECONDARY outcome

Timeframe: 14 weeks

Population: Patients from FAS1000

Proportion of patients who experienced at least one metformin pre-specified moderate or severe GI side effect during 14 weeks

Outcome measures

Measure	Lina 5mg + Met qd n=298 Participants Patients treated with Linagliptin 5mg in combination with metformin once daily.	Met Bid n=341 Participants Patients treated with metformin alone twice daily.
Occurence of Metformin Pre-specified Moderate to Severe GI Side Effects Assessed by Investigators During 14 Weeks of Treatment	25 participants	28 participants

SECONDARY outcome

Timeframe: Baseline and 14 weeks

Population: Patients from FAS1000 with LOCF

Means are adjusted by treatment, continuous baseline HbA1c and continuous baseline fasting plasma glucose.

Outcome measures

Measure	Lina 5mg + Met qd n=298 Participants Patients treated with Linagliptin 5mg in combination with metformin once daily.	Met Bid n=338 Participants Patients treated with metformin alone twice daily.
Change From Baseline in Fasting Plasma Glucose (FPG) After 14 Weeks of Treatment	-24.5 mg/dL Standard Error 1.5	-26.6 mg/dL Standard Error 1.4

SECONDARY outcome

Timeframe: 14 weeks

Population: Patients from FAS1000 and having GI adverse events which were assessed for severity by the investigator.

Patients could experience multiple events, therefore, multiple answers were possible for each patient.

Outcome measures

Measure	Lina 5mg + Met qd n=157 Events Patients treated with Linagliptin 5mg in combination with metformin once daily.	Met Bid n=219 Events Patients treated with metformin alone twice daily.
Metformin Pre-specified GI Symptom Intensity Score Assessed by Investigators During 14 Weeks of Treatment Mild	114 events	153 events
Metformin Pre-specified GI Symptom Intensity Score Assessed by Investigators During 14 Weeks of Treatment Moderate	37 events	65 events
Metformin Pre-specified GI Symptom Intensity Score Assessed by Investigators During 14 Weeks of Treatment Severe	6 events	1 events

SECONDARY outcome

Timeframe: 14 weeks

Population: Patients from the FAS1000 using original results (OR) and having GI adverse events which were assessed for severity by the patient.

The intensity of the GI side effects was also assessed by the patients using VAS scaled from 0 to 10; higher scores indicate more severe events. Means are adjusted by treatment and continuous baseline HbA1c.

Outcome measures

Measure	Lina 5mg + Met qd n=154 Participants Patients treated with Linagliptin 5mg in combination with metformin once daily.	Met Bid n=209 Participants Patients treated with metformin alone twice daily.
Metformin Pre-specified GI Symptom Intensity Score Assessed by Patients During 14 Weeks of Treatment	4.9 units on a scale Standard Error 0.2	4.4 units on a scale Standard Error 0.2

SECONDARY outcome

Timeframe: 14 weeks

Population: Patients from FAS1000 (NCF) having a baseline HbA1c\>=6.5%.

The proportion of patients who achieved all the targets in a composite endpoint (HbA1c below 6.5% after 14 weeks of treatment; no occurrence of pre-specified moderate or severe GI side effects of metformin, as assessed by the investigators during 14 weeks of treatment).

Outcome measures

Measure	Lina 5mg + Met qd n=291 Participants Patients treated with Linagliptin 5mg in combination with metformin once daily.	Met Bid n=338 Participants Patients treated with metformin alone twice daily.
Composite Endpoint of Occurrence of Treat to Target Efficacy Response, That is an HbA1c Under Treatment of <6.5% After 14 Weeks of Treatment, and no Occurrence of Moderate or Severe Metformin Pre-specified GI Side Effects Assessed by Investigators	83 participants	95 participants

SECONDARY outcome

Timeframe: 14 weeks

Population: Patients from FAS1000 (NCF)

The proportion of patients who achieved a relative efficacy response (HbA1c lowering by at least 0.5% after 14 weeks of treatment).

Outcome measures

Measure	Lina 5mg + Met qd n=298 Participants Patients treated with Linagliptin 5mg in combination with metformin once daily.	Met Bid n=341 Participants Patients treated with metformin alone twice daily.
Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 14 Weeks of Treatment)	211 participants	257 participants

SECONDARY outcome

Timeframe: 14 weeks

Population: Patients from the FAS1000 (NCF)

The proportion of patients who achieved a relative efficacy response (HbA1c lowering by at least 0.8% after 14 weeks of treatment).

Outcome measures

Measure	Lina 5mg + Met qd n=298 Participants Patients treated with Linagliptin 5mg in combination with metformin once daily.	Met Bid n=341 Participants Patients treated with metformin alone twice daily.
Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.8% After 14 Weeks of Treatment)	162 participants	187 participants

SECONDARY outcome

Timeframe: 14 weeks

Population: Patients from FAS1000 (NCF)

The proportion of patients who achieved all the targets in a composite endpoint (HbA1c lowered by at least 0.5% after 14 weeks of treatment; no occurrence of pre-specified moderate or severe GI side effects of metformin, as assessed by the investigators during 14 weeks of treatment).

Outcome measures

Measure	Lina 5mg + Met qd n=298 Participants Patients treated with Linagliptin 5mg in combination with metformin once daily.	Met Bid n=341 Participants Patients treated with metformin alone twice daily.
Composite Endpoint of Occurence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 14 Weeks of Treatment) and no Occurence of Moderate and Severe Metformin Pre-specified GI Side Effects Assessed by the Investigators During 14 Weeks	194 participants	236 participants

SECONDARY outcome

Timeframe: Baseline and 14 weeks

Population: FAS1000 having values for weight at baseline and week 14.

Means are adjusted by treatment, continuous baseline HbA1c and continuous baseline weight

Outcome measures

Measure	Lina 5mg + Met qd n=287 Participants Patients treated with Linagliptin 5mg in combination with metformin once daily.	Met Bid n=324 Participants Patients treated with metformin alone twice daily.
Change From Baseline in Body Weight by Visit at Week 14	-0.44 kg Standard Error 0.14	-1.05 kg Standard Error 0.13

SECONDARY outcome

Timeframe: 14 weeks

Population: Patients from FAS1000 (NCF)

The proportion of patients who achieved all the targets in a composite endpoint (HbA1c lowered by at least 0.8% after 14 weeks of treatment; no occurrence of pre-specified moderate or severe GI side effects of metformin, as assessed by the investigators during 14 weeks of treatment).

Outcome measures

Measure	Lina 5mg + Met qd n=298 Participants Patients treated with Linagliptin 5mg in combination with metformin once daily.	Met Bid n=341 Participants Patients treated with metformin alone twice daily.
Composite Endpoint of Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.8% After 14 Weeks of Treatment) and no Occurrence of Moderate and Severe Metformin Pre-specified GI Side Effects Assessed by Investigators During 14 Weeks	149 participants	175 participants

SECONDARY outcome

Timeframe: Baseline, 2 weeks and 8 weeks

Population: Patients from FAS1000 (LOCF)

Means are adjusted by treatment and continuous baseline HbA1c

Outcome measures

Measure	Lina 5mg + Met qd n=298 Participants Patients treated with Linagliptin 5mg in combination with metformin once daily.	Met Bid n=341 Participants Patients treated with metformin alone twice daily.
Change From Baseline in HbA1c Over Time At week 2	-0.28 percent Standard Error 0.02	-0.25 percent Standard Error 0.02
Change From Baseline in HbA1c Over Time At week 8	-0.84 percent Standard Error 0.04	-0.78 percent Standard Error 0.04

Adverse Events

Lina 5mg + Met qd

Serious events: 2 serious events

Other events: 101 other events

Deaths: 0 deaths

Met Bid

Serious events: 7 serious events

Other events: 121 other events

Deaths: 0 deaths

Serious adverse events

Measure	Lina 5mg + Met qd n=344 participants at risk Patients treated with Linagliptin 5mg in combination with metformin once daily.	Met Bid n=345 participants at risk Patients treated with metformin alone twice daily.
Gastrointestinal disorders Abdominal pain	0.00% 0/344 • 14 weeks	0.29% 1/345 • 14 weeks
Gastrointestinal disorders Epiploic appendagitis	0.00% 0/344 • 14 weeks	0.29% 1/345 • 14 weeks
Gastrointestinal disorders Pancreatitis acute	0.29% 1/344 • 14 weeks	0.00% 0/345 • 14 weeks
Hepatobiliary disorders Biliary dilatation	0.00% 0/344 • 14 weeks	0.29% 1/345 • 14 weeks
Hepatobiliary disorders Cholecystitis acute	0.00% 0/344 • 14 weeks	0.29% 1/345 • 14 weeks
Infections and infestations Acute tonsillitis	0.00% 0/344 • 14 weeks	0.29% 1/345 • 14 weeks
Infections and infestations Appendicitis	0.29% 1/344 • 14 weeks	0.00% 0/345 • 14 weeks
Infections and infestations Cellulitis	0.00% 0/344 • 14 weeks	0.58% 2/345 • 14 weeks
Injury, poisoning and procedural complications Comminuted fracture	0.00% 0/344 • 14 weeks	0.29% 1/345 • 14 weeks
Injury, poisoning and procedural complications Road traffic accident	0.00% 0/344 • 14 weeks	0.29% 1/345 • 14 weeks
Nervous system disorders Balance disorder	0.00% 0/344 • 14 weeks	0.29% 1/345 • 14 weeks
Nervous system disorders Dizziness	0.00% 0/344 • 14 weeks	0.29% 1/345 • 14 weeks
Respiratory, thoracic and mediastinal disorders Vocal cord leukoplakia	0.00% 0/344 • 14 weeks	0.29% 1/345 • 14 weeks

Other adverse events

Measure	Lina 5mg + Met qd n=344 participants at risk Patients treated with Linagliptin 5mg in combination with metformin once daily.	Met Bid n=345 participants at risk Patients treated with metformin alone twice daily.
Gastrointestinal disorders Abdominal pain	6.7% 23/344 • 14 weeks	8.4% 29/345 • 14 weeks
Gastrointestinal disorders Diarrhoea	18.0% 62/344 • 14 weeks	21.4% 74/345 • 14 weeks
Gastrointestinal disorders Nausea	6.7% 23/344 • 14 weeks	7.0% 24/345 • 14 weeks
Infections and infestations Urinary tract infection	4.9% 17/344 • 14 weeks	9.9% 34/345 • 14 weeks

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim Pharmaceuticals

Phone: 1-800-243-0127

Email: clintriage.rdg@boehringer-ingelheim.com

Results disclosure agreements

• Principal investigator is a sponsor employee Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.
• Publication restrictions are in place

Restriction type: OTHER