MARLINA - T2D : Efficacy, Safety & Modification of Albuminuria in Type 2 Diabetes Subjects With Renal Disease With LINAgliptin - Study Results

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double-Blind; Primary Purpose: Treatment
Condition:	Diabetes Mellitus, Type 2
Interventions:	Drug: Placebo Drug: Linagliptin 5mg

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
360 patients were randomised and treated (Placebo: 178 patients, Linagliptin: 182 patients.)

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Randomized, double-blind, placebo controlled, parallel group study to evaluate glycemic and renal efficacy of once daily administration of Linagliptin 5 milligram (mg) for 24 weeks in type 2 diabetes patients, with micro- or macroalbuminuria on top of current treatment with Angiotensin Converting Enzyme inhibitor or Angiotensin Receptor Blocker

Reporting Groups

	Description
Placebo	Patients received 1 matching placebo tablet to Linagliptin 5 mg, administered orally, once every day for 24 weeks during the double blind treatment period.
Linagliptin 5 mg	Patients received 1 tablet of Linagliptin 5 mg, administered orally, once every day for 24 weeks during the double blind treatment period.

Participant Flow: Overall Study

	Placebo	Linagliptin 5 mg
STARTED	178	182
COMPLETED	170	175
NOT COMPLETED	8	7
Adverse Event	3	4
Protocol Violation	0	1
Lost to Follow-up	3	1
Withdrawal by Subject	2	0
Other Reason	0	1

Baseline Characteristics

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Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Treated Set (TS) - including all patients treated with at least one dose of randomised trial medication.

Reporting Groups

	Description
Placebo	Patients received 1 matching placebo tablet to Linagliptin 5 mg, administered orally, once every day for 24 weeks during the double blind treatment period.
Linagliptin 5 mg	Patients received 1 tablet of Linagliptin 5 mg, administered orally, once every day for 24 weeks during the double blind treatment period.
Total	Total of all reporting groups

Baseline Measures

	Placebo	Linagliptin 5 mg	Total
Overall Participants Analyzed [Units: Participants]	178	182	360

Age [Units: Years] Mean (Standard Deviation)	60.1 (9.3)	61.0 (10.0)	60.6 (9.6)

Gender [Units: Participants] Count of Participants
Female	65 36.5%	66 36.3%	131 36.4%
Male	113 63.5%	116 63.7%	229 63.6%

Outcome Measures

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1. Primary:

HbA1c Change From Baseline After 24 Weeks Double-blind Randomized Treatment [ Time Frame: Baseline and 24 weeks ]

Measure Type	Primary
Measure Title	HbA1c Change From Baseline After 24 Weeks Double-blind Randomized Treatment
Measure Description	Change from baseline in Glycated haemoglobin (HbA1c) [%] after 24 weeks of treatment with double- blind trial medication. The term “baseline” refers to the last observation before the start of any randomised trial treatment. The number of participants analysed displays the number of participants with available data at the timepoint of interest.
Time Frame	Baseline and 24 weeks

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full Analysis Set (FAS) - including all randomised patients who were treated with at least one dose of study drug, had a baseline HbA1c and a baseline Urinary albumin creatinine ratio (UACR), and at least one on treatment HbA1c or UACR assessment. Observed Case (OC): Values after the use of rescue medication were set to missing.

Reporting Groups

	Description
Placebo	Patients received 1 matching placebo tablet to Linagliptin 5 mg, administered orally, once every day for 24 weeks during the double blind treatment period.
Linagliptin 5 mg	Patients received 1 tablet of Linagliptin 5 mg, administered orally, once every day for 24 weeks during the double blind treatment period.

Measured Values

	Placebo	Linagliptin 5 mg
Participants Analyzed [Units: Participants]	156	161
HbA1c Change From Baseline After 24 Weeks Double-blind Randomized Treatment [Units: Percentage of HbA1c] Least Squares Mean (Standard Error)	-0.03 (0.06)	-0.63 (0.06)

Statistical Analysis 1 for HbA1c Change From Baseline After 24 Weeks Double-blind Randomized Treatment

Groups ^[1]	All groups
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	<0.0001
Mean Difference (Final Values) ^[5]	-0.60
95% Confidence Interval	-0.78 to -0.43
Standard Error of the mean	(0.09)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Superiority of Linagliptin 5 mg vs. placebo: change in HbA1c is analysed using mixed model repeated measures (MMRM) approach. Model includes baseline HbA1c, baseline log10 (UACR), baseline HbA1c by visit and baseline log10 (UACR) by visit as linear covariates and treatment, visit, visit by treatment interaction as fixed effects.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	The Unstructured covariance structure has been used to fit the mixed model
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	Mean Difference (Final Values) is actually the Adjusted mean difference calculated as Linagliptin 5 mg minus Placebo.

2. Secondary:

The Time Weighted Average of Percentage Change From Baseline in UACR During the Course of 24 Weeks of Treatment [ Time Frame: Baseline and 24 weeks ]

Measure Type	Secondary
Measure Title	The Time Weighted Average of Percentage Change From Baseline in UACR During the Course of 24 Weeks of Treatment
Measure Description	The time weighted average of percentage change from baseline in UACR (mg/g creatinine) during the course of 24 weeks of treatment. The term "baseline" for UACR refers to the geometric mean of UACR values measured at Visits 2 and 3. The number of participants analysed displays the number of participants with available data at the timepoint of interest. The Least Squares Means are adjusted geometric means.
Time Frame	Baseline and 24 weeks

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full Analysis Set (FAS) - including all randomised patients who were treated with at least one dose of study drug, had a baseline HbA1c and a baseline Urinary albumin creatinine ratio (UACR), and at least one on treatment HbA1c or UACR assessment. Last Observation Carried Forward (LOCF).

Reporting Groups

	Description
Placebo	Patients received 1 matching placebo tablet to Linagliptin 5 mg, administered orally, once every day for 24 weeks during the double blind treatment period.
Linagliptin 5 mg	Patients received 1 tablet of Linagliptin 5 mg, administered orally, once every day for 24 weeks during the double blind treatment period.

Measured Values

	Placebo	Linagliptin 5 mg
Participants Analyzed [Units: Participants]	173	178
The Time Weighted Average of Percentage Change From Baseline in UACR During the Course of 24 Weeks of Treatment [Units: Mg/g creatinine] Least Squares Mean (95% Confidence Interval)	0.9487 (0.8857 to 1.0162)	0.8902 (0.8318 to 0.9526)

Statistical Analysis 1 for The Time Weighted Average of Percentage Change From Baseline in UACR During the Course of 24 Weeks of Treatment

Groups ^[1]	All groups
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	ANCOVA
P Value ^[4]	0.1954
Ratio of adjusted geometric means ^[5]	0.94
95% Confidence Interval	0.85 to 1.03

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Superiority of Linagliptin 5 mg vs. placebo: change in UACR is analysed using analysis of covariance model. Model includes baseline HbA1c and baseline log10 (UACR) as linear covariates and treatment as fixed effect.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	Ratio of relative change for Linagliptin 5 mg over placebo is presented.

3. Secondary:

The Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) After 24 Weeks of Treatment [ Time Frame: Baseline and 24 weeks ]

Measure Type	Secondary
Measure Title	The Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) After 24 Weeks of Treatment
Measure Description	The change from baseline in estimated glomerular filtration rate (eGFR) as assessed by chronic kidney disease epidemiology collaboration (CKD-EPI) equation (cystatin C) after 24 weeks of treatment. The term “baseline” refers to the last observation before the start of any randomised trial treatment. The number of participants analysed displays the number of participants with available data at the timepoint of interest. This outcome measure is a secondary safety endpoint.
Time Frame	Baseline and 24 weeks

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Treated Set

Reporting Groups

	Description
Placebo	Patients received 1 matching placebo tablet to Linagliptin 5 mg, administered orally, once every day for 24 weeks during the double blind treatment period.
Linagliptin 5 mg	Patients received 1 tablet of Linagliptin 5 mg, administered orally, once every day for 24 weeks during the double blind treatment period.

Measured Values

	Placebo	Linagliptin 5 mg
Participants Analyzed [Units: Participants]	156	162
The Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) After 24 Weeks of Treatment [Units: Milliliter/minute/1.73 square metre] Least Squares Mean (Standard Error)	-2.35 (1.92)	-4.98 (1.89)

Statistical Analysis 1 for The Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) After 24 Weeks of Treatment

Groups ^[1]	All groups
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	0.3306
Mean Difference (Final Values) ^[5]	-2.63
95% Confidence Interval	-7.95 to 2.68
Standard Error of the mean	(2.70)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Change in eGFR is analysed using mixed model repeated measures (MMRM) approach. Model includes baseline HbA1c, baseline log10 (UACR), baseline eGFR, baseline HbA1c by visit, baseline log10 (UACR) by visit and baseline eGFR by visit as linear covariates and treatment, visit, visit by treatment interaction as fixed effects.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	The Unstructured covariance structure has been used to fit the mixed model
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	Mean Difference (Final Values) is actually the Adjusted mean difference calculated as Linagliptin 5 mg minus Placebo.

Serious Adverse Events

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Other Adverse Events

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Limitations and Caveats

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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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More Information

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Certain Agreements:

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI’s intellectual property rights.

Results Point of Contact:

Name/Title: Boehringer Ingelheim, Call Center
Organization: Boehringer Ingelheim
phone: 1-800-243-0127
e-mail: clintriage.rdg@boehringer-ingelheim.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Groop PH, Cooper ME, Perkovic V, Sharma K, Schernthaner G, Haneda M, Hocher B, Gordat M, Cescutti J, Woerle HJ, von Eynatten M. Dipeptidyl peptidase-4 inhibition with linagliptin and effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: Rationale and design of the MARLINA-T2D™ trial. Diab Vasc Dis Res. 2015 Nov;12(6):455-62. doi: 10.1177/1479164115579002. Epub 2015 Jul 28.

Responsible Party:	Boehringer Ingelheim
ClinicalTrials.gov Identifier:	NCT01792518 History of Changes
Other Study ID Numbers:	1218.89 2012-002603-17 ( EudraCT Number: EudraCT )
Study First Received:	February 14, 2013
Results First Received:	November 8, 2016
Last Updated:	January 13, 2017