REducing With MetfOrmin Vascular Adverse Lesions in Type 1 Diabetes (REMOVAL)

• Sponsor: University of Glasgow (Other)
• Overall Status: Completed
• CT.gov ID: NCT01483560
• Collaborator: NHS Greater Glasgow and Clyde (Other), Juvenile Diabetes Research Foundation (Other), Imperial College London (Other), University of Wisconsin, Madison (Other), University of Dundee (Other), Merck Serono S.A., Geneva (Industry), Itamar-Medical, Israel (Industry), University of Western Ontario, Canada (Other), University of Melbourne (Other), Steno Diabetes Center Copenhagen (Other), Maastricht University Medical Center (Other)
• Enrollment: 493
• Locations: 24
• Arms: 2
• Duration (Months): 64.6
• Patients Per Site: 20.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The trial is conducted in the United Kingdom (UK), Australia, Canada, Denmark and the Netherlands. The aim is to test whether 3 years treatment with metformin added to titrated insulin therapy (towards target HbA1c 7.0%/53 mmol/mol) reduces atherosclerosis, as measured by progression of carotid intima-media thickness (cIMT), in adults with confirmed type 1 diabetes aged 40 years and over at increased risk for cardiovascular disease.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 1	Drug: Metformin; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 493 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Phase 3 Study of Metformin in Adults With Type 1 Diabetes
• Study Start Date: Dec 1, 2011
• Actual Primary Completion Date: Mar 19, 2017
• Actual Study Completion Date: Apr 18, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Metformin Oral Metformin (as Glucophage 500mg x 2 bd) titrated from initial 500mg to target 2000mg daily	Drug: Metformin; 3 years treatment duration; Other Names: Glucophage
Placebo Comparator: Placebo	Drug: Placebo; 3 years duration

Outcome Measures

Primary Outcome Measures

1. Change in Averaged Mean Far Wall Common Carotid Artery Intima-media Thickness (cIMT) [0, 12 months, 24 months, 36 months]

   Progression of averaged mean far wall common carotid artery intima media thickness IMT (mean cIMT) measured using B mode ultrasonography with a 7.0 MHz or higher broadband linear array transducer and concurrent recording of 3-lead electrocardiogram (ECG). Longitudinal images of the common carotid artery will be obtained at anterior, lateral and posterior angles at baseline, 12, 24 and 36 months using Meijer's arc to standardize the transducer angle.

Secondary Outcome Measures

1. Change in HbA1c [Baseline, Year 3]

   Measured in accredited local laboratories participating in DCCT-aligned quality control programmes.

2. Change in LDL Cholesterol [Baseline, Year 3]

   mmol/L Centrally assayed at the University of Glasgow

3. Change in Estimated Glomerular Filtration Rate [Baseline, Year 1, Year 2, Year 3]

   Number of participants developing new microalbuminuria; change in absolute concentration Calculated using the MDRD equation1 based on creatinine measured in accredited local laboratories

4. Number of Participants With Retinopathy and at Least a 2 Stage Progression in Retinopathy From Baseline to 36 Months [Baseline, Year 3]

   Two color 45° field retinal photographs (fields 1 and 2) from each eye at 0 and 36 months graded at the University of Wisconsin Ocular Epidemiology Reading Center (OERC) using the modified Airlie House classification scheme and the Early Treatment Diabetic Retinopathy Severity scale.

5. Change in Weight [Baseline, Year 1, Year 2, Year 3]

   Measured at sites using calibrated weighing scales

6. Change in Insulin Dose [Baseline, Year 1, Year 2, Year 3]

   Units/ kg body weight Extracted by study nurses from the Study Diary and reported on the study CRF using dedicated fields

7. Change in Endothelial Function [Baseline, Year 1, Year 3]

   In some centres (Arbitrary units) Reactive Hyperaemia Index using the ENDOPAT device (Itamar, Israel)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Type 1 Diabetes for five years or more*

• Age 40 years or above

• 7.0 =< HbA1c <10.0% (53 - 86 mmol/mol)

AND 3 or more of the following ten CardioVascular Disease (CVD) risk factors:

• BMI >27 kg/m^2

• Current HbA1c >8.0% (64 mmol/mol)

• Known CVD/peripheral vascular disease

• Current smoker

• Estimated glomerular filtration rate (eGFR) <90 ml/min per 1.73 m^3

• Confirmed micro- or macroalbuminuria [according to local assays and reference ranges]

• Hypertension (BP >=140/90 millimeters of mercury (mmHg) or established on antihypertensive treatment)

• Dyslipidaemia [total cholesterol >=5.0 mmol/L (200 mg/dL);OR HDL cholesterol <1.20 mmol/L (46mg/dL) [MEN]; OR <1.30 mmol/L (50 mg/dL) [WOMEN]; or triglycerides >=1.7 mmol/L (150mg/dL); or established on lipid-lowering treatment)]

• Strong family history of CVD (at least one parent, biological aunt/ uncle, or sibling with myocardial infarction or stroke aged <60 years)

• Duration of diabetes > 20 years

Exclusion Criteria:

• eGFR < 45 ml/min/1.73m2

• woman of childbearing age not on effective contraception

• Pregnancy and/or lactation

• Acute coronary syndrome or Stroke/Transient Ischaemic Attack within the last three months

• NYHA stage 3 or 4 heart failure

• Significant hypoglycaemia unawareness

• Impaired cognitive function/ unable to give informed consent

• Previous carotid surgery/ inability to capture adequate carotid images

• Estimated glomerular filtration < 45ml/min/1.73m^2 (MDRD)

• Gastroparesis

• History of lactic acidosis

• Other contraindications to metformin (hepatic impairment, known hypersensitivity to metformin, acute illness such as dehydration, severe infection, shock, acute cardiac failure or suspected tissue hypoxia)

• Any coexistent life threatening condition including prior diagnosis of cancer within two years

• History of alcohol problem or drug abuse

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Royal Melbourne Hospital	Melbourne		Australia
2	St Vincent's Hospital	Melbourne		Australia
3	Royal Prince Albert Hospital	Sydney		Australia
4	St Joseph's Health Care	London	Ontario	Canada
5	Ottawa Hospital Riverside Campus	Ottawa		Canada
6	Steno Diabetes Centre	Gentofte		Denmark
7	Maastricht University Medical Centre	Maastricht		Netherlands
8	Aberdeen Royal Infirmary	Aberdeen		United Kingdom
9	Ayr Hospital	Ayr		United Kingdom	KA6 6DX
10	University Hospitals Bristol	Bristol		United Kingdom	BS2 8HW
11	Diabetes Support Unit, Ninewells Hospital and Medical School	Dundee		United Kingdom
12	University Hospital North Durham	Durham		United Kingdom
13	Edinburgh Royal Infirmary	Edinburgh		United Kingdom
14	Edinburgh Western Infirmary	Edinburgh		United Kingdom
15	Peninsula NIHR Clinical Research Facility, Royal Devon and Exeter NHS Foundation Trust	Exeter		United Kingdom
16	Stobhill Hospital, Diabetes Clinic	Glasgow		United Kingdom
17	Gloucestershire Royal Hospital	Gloucester		United Kingdom	GL1 3NN
18	Michael White Diabetes Centre, Hull Royal Infirmary	Hull		United Kingdom
19	Clinical Sciences Centre, University Hospital	Liverpool		United Kingdom
20	Clinical Investigation Unit, International Centre for Circulatory Health, Imperial College Healthcare NHS Trust	London		United Kingdom
21	Wellcome Trust Clinical Research Facility, Manchester Royal Infirmary	Manchester		United Kingdom
22	Newcastle NIHR Clinical Research Facility, Royal Victoria Hospital	Newcastle		United Kingdom
23	Diabetes Clinical Research Centre, Plymouth	Plymouth		United Kingdom
24	Salford Royal NHS Foundation Trust	Salford		United Kingdom

Sponsors and Collaborators

• University of Glasgow
• NHS Greater Glasgow and Clyde
• Juvenile Diabetes Research Foundation
• Imperial College London
• University of Wisconsin, Madison
• University of Dundee
• Merck Serono S.A., Geneva
• Itamar-Medical, Israel
• University of Western Ontario, Canada
• University of Melbourne
• Steno Diabetes Center Copenhagen
• Maastricht University Medical Center

Investigators

• Principal Investigator: John Petrie, Prof, University of Glasgow
• Study Director: Helen Colhoun, Prof, University of Dundee

Study Documents (Full-Text)

• Study Protocol - Nov 9, 2015
• Statistical Analysis Plan - Apr 7, 2017

More Information

Publications

None provided.

• Responsible Party: Prof John Petrie, Clinical Professor in Diabetic Medicine, University of Glasgow
• ClinicalTrials.gov Identifier: NCT01483560
• Other Study ID Numbers: GN10DI406; 2011-000300-18
• First Posted: Dec 1, 2011
• Last Update Posted: Jun 19, 2019
• Last Verified: Jun 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Prof John Petrie, Clinical Professor in Diabetic Medicine, University of Glasgow: REMOVAL; metformin; carotid IMT; LDL Cholesterol; endothelial function; retinopathy; HbA1c
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Metformin

Study Results

Participant Flow

Pre-assignment Detail	493 participants where enrolled and consented. All participants entered a 3 month Run In phase with placebo. Participants who remained eligible were randomly assigned to receive metformin or placebo for 3 years. 65 participants where ineligible to be randomized.

Arm/Group Title	Metformin	Placebo
Arm/Group Description	Oral Metformin (as Glucophage 500mg x 2 bd) titrated from initial 500mg to target 2000mg daily Metformin: 3 years treatment duration 219 of 428 randomised were assigned to Metformin Group	Placebo: 3 years duration 209 of the 428 randomised were assigned to Placebo
Period Title: Overall Study
STARTED	219	209
COMPLETED	193	194
NOT COMPLETED	26	15

Baseline Characteristics

Arm/Group Title	Metformin	Placebo	Total
Arm/Group Description	Oral Metformin (as Glucophage 500mg x 2 bd) titrated from initial 500mg to target 2000mg daily Metformin: 3 years treatment duration 219 of 428 randomised were assigned to Metformin Group	Placebo: 3 years duration 209 of the 428 randomised were assigned to Placebo	Total of all reporting groups
Overall Participants	219	209	428
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	219 100%	209 100%	428 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.2 (8.5)	55.8 (8.8)	55.5 (8.7)
Sex: Female, Male (Count of Participants)
Female	90 41.1%	85 40.7%	175 40.9%
Male	129 58.9%	124 59.3%	253 59.1%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
Canada	55 25.1%	55 26.3%	110 25.7%
Netherlands	16 7.3%	15 7.2%	31 7.2%
Denmark	4 1.8%	4 1.9%	8 1.9%
United Kingdom	112 51.1%	105 50.2%	217 50.7%
Australia	32 14.6%	30 14.4%	62 14.5%
Diabetes Diagnosis Duration (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	33.4 (11)	34.3 (10.5)	33.85 (10.75)
Existing Cardiovascular Disease (participants) [Number]
Number [participants]	30 13.7%	22 10.5%	52 12.1%
Baseline HbA1c (mmol/mol) [Number]
Number [mmol/mol]	64.8	64.7	64.75
Daily Insulin Dose (units/kg) [Number]
Number [units/kg]	0.63	0.68	0.66
BMI (kg/m2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m2]	28.4 (4.5)	28.5 (4.1)	28.5 (4.3)
Blood Pressure (Systolic BP (mmHg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Systolic BP (mmHg)]	130.5 (15)	128.5 (14.6)	129.5 (14.8)
Total Cholesterol (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	4 (0.88)	4 (0.93)	4 (0.91)
eGFR (ml/min/1.73m2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ml/min/1.73m2]	92.9 (20.9)	91.1 (21.6)	92 (21.3)
Diabetic Retinopathy (participants) [Number]
Number [participants]	51 23.3%	58 27.8%	109 25.5%

Outcome Measures

1. Primary Outcome

Title	Change in Averaged Mean Far Wall Common Carotid Artery Intima-media Thickness (cIMT)
Description	Progression of averaged mean far wall common carotid artery intima media thickness IMT (mean cIMT) measured using B mode ultrasonography with a 7.0 MHz or higher broadband linear array transducer and concurrent recording of 3-lead electrocardiogram (ECG). Longitudinal images of the common carotid artery will be obtained at anterior, lateral and posterior angles at baseline, 12, 24 and 36 months using Meijer's arc to standardize the transducer angle.
Time Frame	0, 12 months, 24 months, 36 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin	Placebo
Arm/Group Description	Oral Metformin (as Glucophage 500mg x 2 bd) titrated from initial 500mg to target 2000mg daily Metformin: 3 years treatment duration 219 of 428 randomised were assigned to Metformin Group	Placebo: 3 years duration 209 of the 428 randomised were assigned to Placebo
Measure Participants	193	194
Baseline	0.773 (0.14)	0.791 (0.183)
12 Months	0.782 (0.147)	0.788 (0.174)
24 Months	0.792 (0.145)	0.823 (0.187)
36 Months	0.793 (0.134)	0.820 (0.177)

2. Secondary Outcome

Title	Change in HbA1c
Description	Measured in accredited local laboratories participating in DCCT-aligned quality control programmes.
Time Frame	Baseline, Year 3

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin	Placebo
Arm/Group Description	Oral Metformin (as Glucophage 500mg x 2 bd) titrated from initial 500mg to target 2000mg daily Metformin: 3 years treatment duration 219 of 428 randomised were assigned to Metformin Group	Placebo: 3 years duration 209 of the 428 randomised were assigned to Placebo
Measure Participants	193	194
Baseline	8.1 (0.9)	8.0 (0.8)
36 Months	8.1 (0.9)	8.1 (0.8)

3. Secondary Outcome

Title	Change in LDL Cholesterol
Description	mmol/L Centrally assayed at the University of Glasgow
Time Frame	Baseline, Year 3

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin	Placebo
Arm/Group Description	Oral Metformin (as Glucophage 500mg x 2 bd) titrated from initial 500mg to target 2000mg daily Metformin: 3 years treatment duration 219 of 428 randomised were assigned to Metformin Group	Placebo: 3 years duration 209 of the 428 randomised were assigned to Placebo
Measure Participants	193	194
Baseline	2.23 (0.7)	2.25 (0.72)
36 Months	2.07 (0.83)	2.21 (0.71)

4. Secondary Outcome

Title	Change in Estimated Glomerular Filtration Rate
Description	Number of participants developing new microalbuminuria; change in absolute concentration Calculated using the MDRD equation1 based on creatinine measured in accredited local laboratories
Time Frame	Baseline, Year 1, Year 2, Year 3

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin	Placebo
Arm/Group Description	Oral Metformin (as Glucophage 500mg x 2 bd) titrated from initial 500mg to target 2000mg daily Metformin: 3 years treatment duration 219 of 428 randomised were assigned to Metformin Group	Placebo: 3 years duration 209 of the 428 randomised were assigned to Placebo
Measure Participants	193	194
Baseline	92.9 (20.9)	91.1 (21.6)
36 Months	92.1 (20.8)	87.2 (19.6)

5. Secondary Outcome

Title	Number of Participants With Retinopathy and at Least a 2 Stage Progression in Retinopathy From Baseline to 36 Months
Description	Two color 45° field retinal photographs (fields 1 and 2) from each eye at 0 and 36 months graded at the University of Wisconsin Ocular Epidemiology Reading Center (OERC) using the modified Airlie House classification scheme and the Early Treatment Diabetic Retinopathy Severity scale.
Time Frame	Baseline, Year 3

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin	Placebo
Arm/Group Description	Oral Metformin (as Glucophage 500mg x 2 bd) titrated from initial 500mg to target 2000mg daily Metformin: 3 years treatment duration 219 of 428 randomised were assigned to Metformin Group	Placebo: 3 years duration 209 of the 428 randomised were assigned to Placebo
Measure Participants	219	209
Baseline	191 87.2%	190 90.9%
36 Months	8 3.7%	10 4.8%

6. Secondary Outcome

Title	Change in Weight
Description	Measured at sites using calibrated weighing scales
Time Frame	Baseline, Year 1, Year 2, Year 3

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin	Placebo
Arm/Group Description	Oral Metformin (as Glucophage 500mg x 2 bd) titrated from initial 500mg to target 2000mg daily Metformin: 3 years treatment duration 219 of 428 randomised were assigned to Metformin Group	Placebo: 3 years duration 209 of the 428 randomised were assigned to Placebo
Measure Participants	193	194
Baseline	83.9 (15.4)	83.5 (13.7)
36 Months	82.0 (15.4)	83.2 (13.8)

7. Secondary Outcome

Title	Change in Insulin Dose
Description	Units/ kg body weight Extracted by study nurses from the Study Diary and reported on the study CRF using dedicated fields
Time Frame	Baseline, Year 1, Year 2, Year 3

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin	Placebo
Arm/Group Description	Oral Metformin (as Glucophage 500mg x 2 bd) titrated from initial 500mg to target 2000mg daily Metformin: 3 years treatment duration 219 of 428 randomised were assigned to Metformin Group	Placebo: 3 years duration 209 of the 428 randomised were assigned to Placebo
Measure Participants	193	194
Baseline	0.36 (0.26)	0.68 (0.30)
36 Months	0.62 (0.26)	0.67 (0.30)

8. Secondary Outcome

Title	Change in Endothelial Function
Description	In some centres (Arbitrary units) Reactive Hyperaemia Index using the ENDOPAT device (Itamar, Israel)
Time Frame	Baseline, Year 1, Year 3

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin	Placebo
Arm/Group Description	Oral Metformin (as Glucophage 500mg x 2 bd) titrated from initial 500mg to target 2000mg daily Metformin: 3 years treatment duration 219 of 428 randomised were assigned to Metformin Group	Placebo: 3 years duration 209 of the 428 randomised were assigned to Placebo
Measure Participants	193	194
Baseline	2.28 (0.74)	2.24 (0.75)
36 Months	2.17 (0.69)	2.24 (0.73)

Adverse Events

Time Frame	Adverse event data collected from the date of consent until 30 days post last IMP dose, an average of 3 years.
Adverse Event Reporting Description	Definition used same as clinical trials.gov
Arm/Group Title	Metformin		Placebo
Arm/Group Description	Oral Metformin (as Glucophage 500mg x 2 bd) titrated from initial 500mg to target 2000mg daily Metformin: 3 years treatment duration 219 of 428 randomised were assigned to Metformin Group		Placebo: 3 years duration 209 of the 428 randomised were assigned to Placebo
All Cause Mortality
	Metformin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/219 (2.3%)		2/209 (1%)
Serious Adverse Events
	Metformin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	34/219 (15.5%)		31/209 (14.8%)
Blood and lymphatic system disorders
Blood and Lymphatic	1/219 (0.5%)	1	0/209 (0%)	0
Cardiac disorders
Cardiac	3/219 (1.4%)	3	6/209 (2.9%)	6
Gastrointestinal disorders
Gastrointestinal	4/219 (1.8%)	4	5/209 (2.4%)	5
General disorders
Sudden Death	1/219 (0.5%)	1	0/209 (0%)	0
Chest Pain	1/219 (0.5%)	1	1/209 (0.5%)	1
Immune system disorders
Immune System Disorder	1/219 (0.5%)	1	0/209 (0%)	0
Infections and infestations
Infections and Infestations	7/219 (3.2%)	7	5/209 (2.4%)	5
Injury, poisoning and procedural complications
Injury	3/219 (1.4%)	3	3/209 (1.4%)	3
Investigations
Angiogram	1/219 (0.5%)	1	0/209 (0%)	0
Blood Glucose Fluctuation	0/219 (0%)	0	1/209 (0.5%)	1
Metabolism and nutrition disorders
Metabolic and nutrition	8/219 (3.7%)	8	5/209 (2.4%)	5
Musculoskeletal and connective tissue disorders
Musculoskeletal	1/219 (0.5%)	1	2/209 (1%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms	6/219 (2.7%)	6	3/209 (1.4%)	3
Nervous system disorders
Cerebral haemorrhage	1/219 (0.5%)	1	0/209 (0%)	0
Cerebrovascular accident	1/219 (0.5%)	1	2/209 (1%)	2
hypoglycaemic coma	1/219 (0.5%)	1	1/209 (0.5%)	1
Transient Ischaemic Attack	2/219 (0.9%)	2	1/209 (0.5%)	1
Headache	0/219 (0%)	0	1/209 (0.5%)	1
Respiratory, thoracic and mediastinal disorders
Respiratory	1/219 (0.5%)	1	5/209 (2.4%)	5
Surgical and medical procedures
Coronary artery bypass graft	1/219 (0.5%)	1	0/209 (0%)	0
lung lobectomy	1/219 (0.5%)	1	1/209 (0.5%)	1
coronary stent insertion	1/219 (0.5%)	1	1/209 (0.5%)	1
Amputation revision	0/219 (0%)	0	1/209 (0.5%)	1
Surgery (unspecified)	0/219 (0%)	0	1/209 (0.5%)	1
Coronary angioplasty	0/219 (0%)	0	1/209 (0.5%)	1
Spinal fusion Surgery	0/219 (0%)	0	1/209 (0.5%)	1
Aortic valve repair	0/219 (0%)	0	1/209 (0.5%)	1
Vascular disorders
Circulatory collapse	1/219 (0.5%)	1	0/209 (0%)	0
Ischaemic Necrosis	0/219 (0%)	0	1/209 (0.5%)	1
Peripheral Ischaemia	0/219 (0%)	0	1/209 (0.5%)	1
Other (Not Including Serious) Adverse Events
	Metformin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	112/219 (51.1%)		52/209 (24.9%)
Cardiac disorders
Cardiovascular	1/219 (0.5%)	1	1/209 (0.5%)	1
Eye disorders
Opthalmic adverse events	18/219 (8.2%)	18	32/209 (15.3%)	32
Gastrointestinal disorders
Gastrointestinal	88/219 (40.2%)	88	18/209 (8.6%)	18
Nervous system disorders
Neurological	0/219 (0%)	0	0/209 (0%)	0
Product Issues
Hypersensitivity to Metformin	5/219 (2.3%)	5	1/209 (0.5%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.