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

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01792518
• Collaborator: Eli Lilly and Company (Industry)
• Enrollment: 360
• Locations: 74
• Arms: 2
• Duration (Months): 33.9
• Patients Per Site: 4.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Evaluate linagliptin in terms of glycemic control as defined by HbA1c after 24 weeks of treatment and in terms of renal efficacy as defined by changes in albuminuria (UACR) after 24 weeks of treatment.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2	Drug: Placebo; Drug: Linagliptin 5mg	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 360 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double
• Primary Purpose: Treatment
• Official Title: A Phase IIIb, Multicenter, Multinational, Randomized, Double-blind, Placebo Controlled, Parallel Group Study to Evaluate the Glycemic and Renal Efficacy of Once Daily Administration of Linagliptin 5 mg for 24 Weeks in Type 2 Diabetes Patients, With Micro- or Macroalbuminuria (30-3000mg/g Creatinine) on Top of Current Treatment With Angiotensin ConvEnzyme Inhibitor or Angiotensin Receptor Blocker - MARLINA (Efficacy, Safety & Modification of Albuminuria in Type 2 Diabetes Subjects With Renal Disease With LINAgliptin)
• Study Start Date: Feb 1, 2013
• Actual Primary Completion Date: Nov 1, 2015
• Actual Study Completion Date: Dec 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: linagliptin 5mg linagliptin 5 mg once daily	Drug: Linagliptin 5mg
Placebo Comparator: placebo matching placebo for linagliptin dose once daily	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. HbA1c Change From Baseline After 24 Weeks Double-blind Randomized Treatment [Baseline and 24 weeks]

   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.

Secondary Outcome Measures

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

   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.

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

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Diagnosis of type 2 diabetes mellitus

• Glycosylated Hemoglobin (HbA1c) between 6.5 and 10% (inclusive)

• Current therapy with ACEi or ARB at stable dose for 10 weeks

• Urinary albumin-to-creatinine ratio (UACR): 30-3000 mg/g creatinine documented in the previous 12 months or detected at Screening.

• Estimated Glomerular Filtration Rate (eGFR) greater than 30 ml/min.

• Age between 18 and 80 years.

Exclusion criteria:

• Dual or triple blockade of the Renin Angiotensin System (RAS)

• Uncontrolled hyperglycaemia

• Mean arterial blood pressure > 110 mmHg

• Known hypersensitivity or allergy to the investigational product, or their excipients (including matching placebos).

• Treatment with a glitazone within 6 months prior to informed consent.

• Treatment with a DiPeptidyl-Peptidase 4 (DPP-4) inhibitor, a Glucagon Like Peptide-1 (GLP-1) agonist, a Sodium/Glucose coTransporter 2 (SGLT2) inhibitor, a dopamine-agonist, a bile-acid sequestrant a short acting (prandial) insulin or premixed insulin within 10 weeks prior to informed consent.

• Treatment with anti-obesity drugs 10 weeks prior to informed consent.

• Alcohol or drug abuse within 3 months prior to informed consent that would interfere with trial participation or any ongoing condition leading to a decreased compliance to study procedures or study drug intake in the opinion of the investigator.

• Current treatment with systemic steroids (glucocorticoids) at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent.

• Participation in another trial with an investigational drug within 2 months prior to informed consent.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Boehringer Ingelheim Investigational Site	Birmingham	Alabama	United States
2	Boehringer Ingelheim Investigational Site	Long Beach	California	United States
3	Boehringer Ingelheim Investigational Site	North Hollywood	California	United States
4	Boehringer Ingelheim Investigational Site	Denver	Colorado	United States
5	Boehringer Ingelheim Investigational Site	Miami	Florida	United States
6	Boehringer Ingelheim Investigational Site	Evansville	Indiana	United States
7	Boehringer Ingelheim Investigational Site	Flint	Michigan	United States
8	Boehringer Ingelheim Investigational Site	Jackson	Mississippi	United States
9	Boehringer Ingelheim Investigational Site	Asheboro	North Carolina	United States
10	Boehringer Ingelheim Investigational Site	Charlotte	North Carolina	United States
11	Boehringer Ingelheim Investigational Site	Fargo	North Dakota	United States
12	Boehringer Ingelheim Investigational Site	Columbus	Ohio	United States
13	Boehringer Ingelheim Investigational Site	Oklahoma City	Oklahoma	United States
14	Boehringer Ingelheim Investigational Site	Knoxville	Tennessee	United States
15	Boehringer Ingelheim Investigational Site	Houston	Texas	United States
16	Boehringer Ingelheim Investigational Site	Edmonton	Alberta	Canada
17	Boehringer Ingelheim Investigational Site	Victoria	British Columbia	Canada
18	Boehringer Ingelheim Investigational Site	Mount Pearl	Newfoundland and Labrador	Canada
19	Boehringer Ingelheim Investigational Site	London	Ontario	Canada
20	Boehringer Ingelheim Investigational Site	Mississauga	Ontario	Canada
21	Boehringer Ingelheim Investigational Site	Sarnia	Ontario	Canada
22	Boehringer Ingelheim Investigational Site	Toronto	Ontario	Canada
23	Boehringer Ingelheim Investigational Site	Waterloo	Ontario	Canada
24	Boehringer Ingelheim Investigational Site	Gentofte		Denmark
25	Boehringer Ingelheim Investigational Site	Hillerød		Denmark
26	Boehringer Ingelheim Investigational Site	Silkeborg		Denmark
27	Boehringer Ingelheim Investigational Site	Slagelse		Denmark
28	Boehringer Ingelheim Investigational Site	Kerava		Finland
29	Boehringer Ingelheim Investigational Site	Oulu		Finland
30	Boehringer Ingelheim Investigational Site	Tampere		Finland
31	Boehringer Ingelheim Investigational Site	Turku		Finland
32	Boehringer Ingelheim Investigational Site	Bersée		France
33	Boehringer Ingelheim Investigational Site	Bourg des Comptes		France
34	Boehringer Ingelheim Investigational Site	Grenoble Cedex 09		France
35	Boehringer Ingelheim Investigational Site	Le Creusot		France
36	Boehringer Ingelheim Investigational Site	Marseille cedex		France
37	Boehringer Ingelheim Investigational Site	Saint Mandé cedex		France
38	Boehringer Ingelheim Investigational Site	Vieux Condé		France
39	Boehringer Ingelheim Investigational Site	Vénissieux Cedex		France
40	Boehringer Ingelheim Investigational Site	Aschaffenburg		Germany
41	Boehringer Ingelheim Investigational Site	Asslar		Germany
42	Boehringer Ingelheim Investigational Site	Dresden		Germany
43	Boehringer Ingelheim Investigational Site	Düsseldorf		Germany
44	Boehringer Ingelheim Investigational Site	Flörsheim		Germany
45	Boehringer Ingelheim Investigational Site	Pirna		Germany
46	Boehringer Ingelheim Investigational Site	Schweinfurt		Germany
47	Boehringer Ingelheim Investigational Site	Aoba-ku,Sendai,Miyagi		Japan
48	Boehringer Ingelheim Investigational Site	Chiyoda-ku,Tokyo		Japan
49	Boehringer Ingelheim Investigational Site	Cyuo-ku,Tokyo		Japan
50	Boehringer Ingelheim Investigational Site	Kita-ku, Osaka, Osaka		Japan
51	Boehringer Ingelheim Investigational Site	Shimizu-ku,Shizuoka city,Shizuoka		Japan
52	Boehringer Ingelheim Investigational Site	Suita,Osaka		Japan
53	Boehringer Ingelheim Investigational Site	Teine-ku,Sapporo,Hokkaido		Japan
54	Boehringer Ingelheim Investigational Site	Goyang		Korea, Republic of
55	Boehringer Ingelheim Investigational Site	Jinju		Korea, Republic of
56	Boehringer Ingelheim Investigational Site	Seongnam		Korea, Republic of
57	Boehringer Ingelheim Investigational Site	Seoul		Korea, Republic of
58	Boehringer Ingelheim Investigational Site	Wonju		Korea, Republic of
59	Boehringer Ingelheim Investigational Site	Cebu City, Philippines		Philippines
60	Boehringer Ingelheim Investigational Site	Pasig City, Philippines		Philippines
61	Boehringer Ingelheim Investigational Site	San Juan City, Philippines		Philippines
62	Boehringer Ingelheim Investigational Site	L'Hospitalet de Llobregat		Spain
63	Boehringer Ingelheim Investigational Site	Madrid		Spain
64	Boehringer Ingelheim Investigational Site	Pozuelo de Alarcon		Spain
65	Boehringer Ingelheim Investigational Site	San Sebastian de los Reyes		Spain
66	Boehringer Ingelheim Investigational Site	Valencia		Spain
67	Boehringer Ingelheim Investigational Site	Changhua		Taiwan
68	Boehringer Ingelheim Investigational Site	Kaohsiung		Taiwan
69	Boehringer Ingelheim Investigational Site	New Taipei		Taiwan
70	Boehringer Ingelheim Investigational Site	Taichung		Taiwan
71	Boehringer Ingelheim Investigational Site	Tainan		Taiwan
72	Boehringer Ingelheim Investigational Site	Taipei		Taiwan
73	Boehringer Ingelheim Investigational Site	Hanoi, Vietnam		Vietnam
74	Boehringer Ingelheim Investigational Site	Ho Chi Minh City		Vietnam

Sponsors and Collaborators

• Boehringer Ingelheim
• Eli Lilly and Company

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01792518
• Other Study ID Numbers: 1218.89; 2012-002603-17
• First Posted: Feb 15, 2013
• Last Update Posted: Mar 6, 2017
• Last Verified: Jan 1, 2017

• Additional relevant MeSH terms: Albuminuria; Diabetes Mellitus; Diabetes Mellitus, Type 2; Linagliptin

Study Results

Participant Flow

Recruitment Details	360 patients were randomised and treated (Placebo: 178 patients, Linagliptin: 182 patients.)
Pre-assignment Detail	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

Arm/Group Title	Placebo	Linagliptin 5 mg
Arm/Group Description	Patients received 1 matching placebo tablet to Linagliptin 5 mg, administered orally, once every day for 24 weeks during the double blind treatment period.	Patients received 1 tablet of Linagliptin 5 mg, administered orally, once every day for 24 weeks during the double blind treatment period.
Period Title: Overall Study
STARTED	178	182
COMPLETED	170	175
NOT COMPLETED	8	7

Baseline Characteristics

Arm/Group Title	Placebo	Linagliptin 5 mg	Total
Arm/Group Description	Patients received 1 matching placebo tablet to Linagliptin 5 mg, administered orally, once every day for 24 weeks during the double blind treatment period.	Patients received 1 tablet of Linagliptin 5 mg, administered orally, once every day for 24 weeks during the double blind treatment period.	Total of all reporting groups
Overall Participants	178	182	360
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	60.1 (9.3)	61.0 (10.0)	60.6 (9.6)
Gender (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

1. Primary Outcome

Title	HbA1c Change From Baseline After 24 Weeks Double-blind Randomized Treatment
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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	Linagliptin 5 mg
Arm/Group Description	Patients received 1 matching placebo tablet to Linagliptin 5 mg, administered orally, once every day for 24 weeks during the double blind treatment period.	Patients received 1 tablet of Linagliptin 5 mg, administered orally, once every day for 24 weeks during the double blind treatment period.
Measure Participants	156	161
Least Squares Mean (Standard Error) [Percentage of HbA1c]	-0.03 (0.06)	-0.63 (0.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Linagliptin 5 mg
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	The Unstructured covariance structure has been used to fit the mixed model
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.60
	Confidence Interval	(2-Sided) 95%; -0.78 to -0.43
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.09
	Estimation Comments	Mean Difference (Final Values) is actually the Adjusted mean difference calculated as Linagliptin 5 mg minus Placebo.

2. Secondary Outcome

Title	The Time Weighted Average of Percentage Change From Baseline in UACR During the Course of 24 Weeks of Treatment
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

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	Placebo	Linagliptin 5 mg
Arm/Group Description	Patients received 1 matching placebo tablet to Linagliptin 5 mg, administered orally, once every day for 24 weeks during the double blind treatment period.	Patients received 1 tablet of Linagliptin 5 mg, administered orally, once every day for 24 weeks during the double blind treatment period.
Measure Participants	173	178
Least Squares Mean (95% Confidence Interval) [mg/g creatinine]	0.9487 (0.06)	0.8902 (0.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Linagliptin 5 mg
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1954
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Ratio of adjusted geometric means
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.85 to 1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of relative change for Linagliptin 5 mg over placebo is presented.

3. Secondary Outcome

Title	The Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) After 24 Weeks of Treatment
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

Outcome Measure Data

Analysis Population Description

Treated Set

Arm/Group Title	Placebo	Linagliptin 5 mg
Arm/Group Description	Patients received 1 matching placebo tablet to Linagliptin 5 mg, administered orally, once every day for 24 weeks during the double blind treatment period.	Patients received 1 tablet of Linagliptin 5 mg, administered orally, once every day for 24 weeks during the double blind treatment period.
Measure Participants	156	162
Least Squares Mean (Standard Error) [milliliter/minute/1.73 square metre]	-2.35 (1.92)	-4.98 (1.89)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Linagliptin 5 mg
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3306
	Comments
	Method	Mixed Models Analysis
	Comments	The Unstructured covariance structure has been used to fit the mixed model
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.63
	Confidence Interval	(2-Sided) 95%; -7.95 to 2.68
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.70
	Estimation Comments	Mean Difference (Final Values) is actually the Adjusted mean difference calculated as Linagliptin 5 mg minus Placebo.

Adverse Events

Time Frame	From first drug administration until 28 days after the last drug administration, up to 240 days
Arm/Group Title	Placebo		Linagliptin 5 mg
Arm/Group Description	Patients received 1 matching placebo tablet to Linagliptin 5 mg, administered orally, once every day for 24 weeks during the double blind treatment period.		Patients received 1 tablet of Linagliptin 5 mg, administered orally, once every day for 24 weeks during the double blind treatment period.
All Cause Mortality
	Placebo		Linagliptin 5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Linagliptin 5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/178 (4.5%)		17/182 (9.3%)
Cardiac disorders
Acute myocardial infarction	0/178 (0%)		1/182 (0.5%)
Cardiac failure	0/178 (0%)		1/182 (0.5%)
Cardiac failure congestive	2/178 (1.1%)		0/182 (0%)
Myocardial ischaemia	0/178 (0%)		1/182 (0.5%)
Ear and labyrinth disorders
Sudden hearing loss	1/178 (0.6%)		0/182 (0%)
Vestibular disorder	0/178 (0%)		2/182 (1.1%)
Gastrointestinal disorders
Gastrointestinal fistula	0/178 (0%)		1/182 (0.5%)
Pancreatitis	1/178 (0.6%)		0/182 (0%)
Pancreatitis acute	1/178 (0.6%)		1/182 (0.5%)
General disorders
Pyrexia	1/178 (0.6%)		0/182 (0%)
Infections and infestations
Abscess limb	0/178 (0%)		1/182 (0.5%)
Arteriovenous graft site infection	1/178 (0.6%)		0/182 (0%)
Cellulitis	0/178 (0%)		1/182 (0.5%)
Cystitis	0/178 (0%)		1/182 (0.5%)
Kidney infection	1/178 (0.6%)		0/182 (0%)
Post procedural infection	0/178 (0%)		1/182 (0.5%)
Pyelonephritis	1/178 (0.6%)		0/182 (0%)
Pyelonephritis acute	1/178 (0.6%)		0/182 (0%)
Septic shock	2/178 (1.1%)		0/182 (0%)
Injury, poisoning and procedural complications
Ankle fracture	0/178 (0%)		1/182 (0.5%)
Fall	0/178 (0%)		1/182 (0.5%)
Peripheral nerve injury	0/178 (0%)		1/182 (0.5%)
Postpericardiotomy syndrome	0/178 (0%)		1/182 (0.5%)
Investigations
Lipase increased	1/178 (0.6%)		0/182 (0%)
Musculoskeletal and connective tissue disorders
Myositis	0/178 (0%)		1/182 (0.5%)
Osteoarthritis	0/178 (0%)		1/182 (0.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Gastric cancer	0/178 (0%)		1/182 (0.5%)
Nervous system disorders
Cerebral haemorrhage	0/178 (0%)		1/182 (0.5%)
Seizure	1/178 (0.6%)		0/182 (0%)
Transient ischaemic attack	1/178 (0.6%)		0/182 (0%)
Renal and urinary disorders
Acute kidney injury	1/178 (0.6%)		1/182 (0.5%)
Calculus urinary	0/178 (0%)		1/182 (0.5%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/178 (0%)		1/182 (0.5%)
Vascular disorders
Aortic occlusion	1/178 (0.6%)		0/182 (0%)
Necrosis ischaemic	1/178 (0.6%)		0/182 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Linagliptin 5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/178 (15.2%)		39/182 (21.4%)
Infections and infestations
Nasopharyngitis	10/178 (5.6%)		13/182 (7.1%)
Upper respiratory tract infection	9/178 (5.1%)		4/182 (2.2%)
Metabolism and nutrition disorders
Hypoglycaemia	10/178 (5.6%)		24/182 (13.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.