Trial Outcomes & Findings for Simvastatin Therapy for Moderate and Severe COPD (NCT NCT01061671)

NCT ID: NCT01061671

Last Updated: 2018-01-02

Results Overview

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

885 participants

Primary outcome timeframe

up to 37 months

Results posted on

2018-01-02

Participant Flow

Participant milestones

Participant milestones
Measure
Simvastatin
40 mgms of simvastatin daily Simvastatin: 40 mgms of simvastatin daily
Placebo
Matched placebo pill daily Placebo: Matched placebo pill daily
Overall Study
STARTED
433
452
Overall Study
COMPLETED
386
397
Overall Study
NOT COMPLETED
47
55

Reasons for withdrawal

Reasons for withdrawal
Measure
Simvastatin
40 mgms of simvastatin daily Simvastatin: 40 mgms of simvastatin daily
Placebo
Matched placebo pill daily Placebo: Matched placebo pill daily
Overall Study
Withdrawal by Subject
16
20
Overall Study
Lost to Follow-up
3
5
Overall Study
Death
28
30

Baseline Characteristics

Simvastatin Therapy for Moderate and Severe COPD

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure
Simvastatin
n=433 Participants
40 mgms of simvastatin daily Simvastatin: 40 mgms of simvastatin daily
Placebo
n=452 Participants
Matched placebo pill daily Placebo: Matched placebo pill daily
Total
n=885 Participants
Total of all reporting groups
Age, Continuous
62.2 years
STANDARD_DEVIATION 8.5 • n=5 Participants
62.3 years
STANDARD_DEVIATION 8.4 • n=7 Participants
62.2 years
STANDARD_DEVIATION 8.4 • n=5 Participants
Sex: Female, Male
Female
184 Participants
n=5 Participants
203 Participants
n=7 Participants
387 Participants
n=5 Participants
Sex: Female, Male
Male
249 Participants
n=5 Participants
249 Participants
n=7 Participants
498 Participants
n=5 Participants
Ethnicity (NIH/OMB)
Hispanic or Latino
4 Participants
n=5 Participants
7 Participants
n=7 Participants
11 Participants
n=5 Participants
Ethnicity (NIH/OMB)
Not Hispanic or Latino
429 Participants
n=5 Participants
445 Participants
n=7 Participants
874 Participants
n=5 Participants
Ethnicity (NIH/OMB)
Unknown or Not Reported
0 Participants
n=5 Participants
0 Participants
n=7 Participants
0 Participants
n=5 Participants
Race (NIH/OMB)
American Indian or Alaska Native
2 Participants
n=5 Participants
3 Participants
n=7 Participants
5 Participants
n=5 Participants
Race (NIH/OMB)
Asian
2 Participants
n=5 Participants
0 Participants
n=7 Participants
2 Participants
n=5 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
0 Participants
n=5 Participants
1 Participants
n=7 Participants
1 Participants
n=5 Participants
Race (NIH/OMB)
Black or African American
99 Participants
n=5 Participants
91 Participants
n=7 Participants
190 Participants
n=5 Participants
Race (NIH/OMB)
White
328 Participants
n=5 Participants
346 Participants
n=7 Participants
674 Participants
n=5 Participants
Race (NIH/OMB)
More than one race
2 Participants
n=5 Participants
11 Participants
n=7 Participants
13 Participants
n=5 Participants
Race (NIH/OMB)
Unknown or Not Reported
0 Participants
n=5 Participants
0 Participants
n=7 Participants
0 Participants
n=5 Participants
Region of Enrollment
United States
362 participants
n=5 Participants
376 participants
n=7 Participants
738 participants
n=5 Participants
Region of Enrollment
Canada
71 participants
n=5 Participants
76 participants
n=7 Participants
147 participants
n=5 Participants
Smoking History (Pack Years)
50.0 Pack Years
STANDARD_DEVIATION 26.1 • n=5 Participants
51.2 Pack Years
STANDARD_DEVIATION 28.7 • n=7 Participants
50.6 Pack Years
STANDARD_DEVIATION 27.4 • n=5 Participants
Post-bronchodilator FEV1 (forced expiratory volume at one second)
1.19 liters (L)
STANDARD_DEVIATION 0.58 • n=5 Participants
1.19 liters (L)
STANDARD_DEVIATION 0.56 • n=7 Participants
1.19 liters (L)
STANDARD_DEVIATION 0.57 • n=5 Participants
FEV1/FVC (forced expiratory volume at one second/forced vital capacity)
0.44 Ratio
STANDARD_DEVIATION 0.13 • n=5 Participants
0.44 Ratio
STANDARD_DEVIATION 0.13 • n=7 Participants
0.44 Ratio
STANDARD_DEVIATION 0.13 • n=5 Participants
FEV1 (% Predicted)
41.5 percent predicted
STANDARD_DEVIATION 17.8 • n=5 Participants
41.6 percent predicted
STANDARD_DEVIATION 17.6 • n=7 Participants
41.6 percent predicted
STANDARD_DEVIATION 17.7 • n=5 Participants
Acute COPD Exacerbation requiring Hospitalization or ED visit within previous 12 mo
Yes
216 participants
n=5 Participants
238 participants
n=7 Participants
454 participants
n=5 Participants
Acute COPD Exacerbation requiring Hospitalization or ED visit within previous 12 mo
No
217 participants
n=5 Participants
214 participants
n=7 Participants
431 participants
n=5 Participants
Systemic glucocorticoid or antibiotic use within previous 12 mo
Yes
367 participants
n=5 Participants
382 participants
n=7 Participants
749 participants
n=5 Participants
Systemic glucocorticoid or antibiotic use within previous 12 mo
No
66 participants
n=5 Participants
70 participants
n=7 Participants
136 participants
n=5 Participants
Use of supplemental oxygen within previous 12 mo
Yes
198 participants
n=5 Participants
222 participants
n=7 Participants
420 participants
n=5 Participants
Use of supplemental oxygen within previous 12 mo
No
235 participants
n=5 Participants
230 participants
n=7 Participants
465 participants
n=5 Participants

PRIMARY outcome

Timeframe: up to 37 months

Population: Analysis excludes participants without any follow-up data.

Outcome measures

Outcome measures
Measure
Simvastatin
n=430 Participants
40 mgms of simvastatin daily Simvastatin: 40 mgms of simvastatin daily
Placebo
n=447 Participants
Matched placebo pill daily Placebo: Matched placebo pill daily
Rates of COPD Exacerbations
1.36 exacerbations/person-year
Standard Deviation 1.61
1.39 exacerbations/person-year
Standard Deviation 1.73

SECONDARY outcome

Timeframe: up to 37 months

Population: Analysis excludes participants without any follow-up data.

Outcome measures

Outcome measures
Measure
Simvastatin
n=430 Participants
40 mgms of simvastatin daily Simvastatin: 40 mgms of simvastatin daily
Placebo
n=447 Participants
Matched placebo pill daily Placebo: Matched placebo pill daily
Time to First COPD Exacerbation
223 Days to the first exacerbation
Interval 195.0 to 275.0
231 Days to the first exacerbation
Interval 193.0 to 303.0

SECONDARY outcome

Timeframe: Baseline, last measure at up to 37 months

Population: Analysis excludes participants without any follow-up data.

Outcome measures

Outcome measures
Measure
Simvastatin
n=356 Participants
40 mgms of simvastatin daily Simvastatin: 40 mgms of simvastatin daily
Placebo
n=356 Participants
Matched placebo pill daily Placebo: Matched placebo pill daily
Change in FEV1 (% Pred) From Baseline to Last Measure
-0.86 percent predicted
Interval -11.04 to 8.67
-1.81 percent predicted
Interval -10.62 to 7.1

SECONDARY outcome

Timeframe: up to 37 months

Population: Analysis excludes participants without any follow-up data.

Outcome measures

Outcome measures
Measure
Simvastatin
n=430 Participants
40 mgms of simvastatin daily Simvastatin: 40 mgms of simvastatin daily
Placebo
n=447 Participants
Matched placebo pill daily Placebo: Matched placebo pill daily
Acute Exacerbation COPD Hospitalization Rates (Events/Patient Year)
0.31 events per patient year
Interval 0.24 to 0.38
0.31 events per patient year
Interval 0.23 to 0.38

Adverse Events

Simvastatin

Serious events: 178 serious events
Other events: 316 other events
Deaths: 0 deaths

Placebo

Serious events: 190 serious events
Other events: 329 other events
Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure
Simvastatin
n=433 participants at risk
40 mgms of simvastatin daily Simvastatin: 40 mgms of simvastatin daily
Placebo
n=452 participants at risk
Matched placebo pill daily Placebo: Matched placebo pill daily
Infections and infestations
Bacterial Infection
0.00%
0/433 • Up to 37 months
0.22%
1/452 • Number of events 1 • Up to 37 months
Infections and infestations
Viral Infection
0.23%
1/433 • Number of events 1 • Up to 37 months
0.00%
0/452 • Up to 37 months
Infections and infestations
Other Infection
0.00%
0/433 • Up to 37 months
0.22%
1/452 • Number of events 1 • Up to 37 months
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon Cancer
0.00%
0/433 • Up to 37 months
0.22%
1/452 • Number of events 1 • Up to 37 months
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Liver Cancer
0.00%
0/433 • Up to 37 months
0.22%
1/452 • Number of events 2 • Up to 37 months
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Respiratory Cancer
2.1%
9/433 • Number of events 12 • Up to 37 months
2.2%
10/452 • Number of events 14 • Up to 37 months
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bone Neoplasm
0.23%
1/433 • Number of events 1 • Up to 37 months
0.88%
4/452 • Number of events 4 • Up to 37 months
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Genitourinary Neoplasm
0.92%
4/433 • Number of events 5 • Up to 37 months
1.1%
5/452 • Number of events 7 • Up to 37 months
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous Cell Carcinoma
0.00%
0/433 • Up to 37 months
0.22%
1/452 • Number of events 1 • Up to 37 months
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lymphatic Neoplasm
0.00%
0/433 • Up to 37 months
0.22%
1/452 • Number of events 1 • Up to 37 months
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neuroendocrine Neoplasm
0.23%
1/433 • Number of events 1 • Up to 37 months
0.22%
1/452 • Number of events 1 • Up to 37 months
Metabolism and nutrition disorders
Metabolic disorders
1.2%
5/433 • Number of events 6 • Up to 37 months
1.1%
5/452 • Number of events 5 • Up to 37 months
Blood and lymphatic system disorders
Cavernous Hemangioma
0.00%
0/433 • Up to 37 months
0.22%
1/452 • Number of events 2 • Up to 37 months
Psychiatric disorders
Mental Disorder
0.69%
3/433 • Number of events 4 • Up to 37 months
1.1%
5/452 • Number of events 6 • Up to 37 months
Nervous system disorders
Central Nervous System disorders
0.23%
1/433 • Number of events 1 • Up to 37 months
0.00%
0/452 • Up to 37 months
Nervous system disorders
Pain
0.00%
0/433 • Up to 37 months
0.44%
2/452 • Number of events 2 • Up to 37 months
Nervous system disorders
Seizure
0.00%
0/433 • Up to 37 months
0.22%
1/452 • Number of events 1 • Up to 37 months
Eye disorders
Orbital cellulitis
0.00%
0/433 • Up to 37 months
0.22%
1/452 • Number of events 1 • Up to 37 months
Cardiac disorders
Rheumatic Heart Disease
0.23%
1/433 • Number of events 1 • Up to 37 months
0.00%
0/452 • Up to 37 months
Cardiac disorders
Ischemic Heart Disease
0.92%
4/433 • Number of events 4 • Up to 37 months
1.3%
6/452 • Number of events 6 • Up to 37 months
Cardiac disorders
Pulmonary Circulation disorders
0.92%
4/433 • Number of events 5 • Up to 37 months
1.3%
6/452 • Number of events 6 • Up to 37 months
Cardiac disorders
Pericarditis
0.23%
1/433 • Number of events 1 • Up to 37 months
0.00%
0/452 • Up to 37 months
Cardiac disorders
Cardiomyopathy
0.46%
2/433 • Number of events 2 • Up to 37 months
0.00%
0/452 • Up to 37 months
Cardiac disorders
Cardiac Dysrhythmias
1.6%
7/433 • Number of events 7 • Up to 37 months
0.88%
4/452 • Number of events 5 • Up to 37 months
Cardiac disorders
Heart Failure
0.92%
4/433 • Number of events 6 • Up to 37 months
1.1%
5/452 • Number of events 7 • Up to 37 months
Vascular disorders
Cerebrovascular
0.23%
1/433 • Number of events 1 • Up to 37 months
1.3%
6/452 • Number of events 6 • Up to 37 months
Vascular disorders
Artery disorder
0.46%
2/433 • Number of events 2 • Up to 37 months
0.44%
2/452 • Number of events 3 • Up to 37 months
Vascular disorders
Vein disorder
0.92%
4/433 • Number of events 4 • Up to 37 months
0.66%
3/452 • Number of events 4 • Up to 37 months
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Infection
0.23%
1/433 • Number of events 3 • Up to 37 months
0.22%
1/452 • Number of events 1 • Up to 37 months
Respiratory, thoracic and mediastinal disorders
Pneumonia
7.9%
34/433 • Number of events 40 • Up to 37 months
6.0%
27/452 • Number of events 32 • Up to 37 months
Respiratory, thoracic and mediastinal disorders
Influenza
1.2%
5/433 • Number of events 5 • Up to 37 months
1.3%
6/452 • Number of events 9 • Up to 37 months
Respiratory, thoracic and mediastinal disorders
Bronchitis
0.00%
0/433 • Up to 37 months
0.22%
1/452 • Number of events 2 • Up to 37 months
Respiratory, thoracic and mediastinal disorders
Emphysema
0.69%
3/433 • Number of events 3 • Up to 37 months
0.22%
1/452 • Number of events 1 • Up to 37 months
Respiratory, thoracic and mediastinal disorders
Pneumoconioses
0.00%
0/433 • Up to 37 months
0.22%
1/452 • Number of events 1 • Up to 37 months
Respiratory, thoracic and mediastinal disorders
COPD Exacerbation
22.2%
96/433 • Number of events 155 • Up to 37 months
21.5%
97/452 • Number of events 187 • Up to 37 months
Respiratory, thoracic and mediastinal disorders
COPD other
2.1%
9/433 • Number of events 9 • Up to 37 months
2.2%
10/452 • Number of events 15 • Up to 37 months
Respiratory, thoracic and mediastinal disorders
Other Respiratory
2.8%
12/433 • Number of events 14 • Up to 37 months
2.9%
13/452 • Number of events 20 • Up to 37 months
Gastrointestinal disorders
Esophagus and stomach disorders
0.23%
1/433 • Number of events 1 • Up to 37 months
1.1%
5/452 • Number of events 5 • Up to 37 months
Gastrointestinal disorders
Appendicitis
0.23%
1/433 • Number of events 1 • Up to 37 months
0.00%
0/452 • Up to 37 months
Gastrointestinal disorders
Abdominal Hernia
0.46%
2/433 • Number of events 2 • Up to 37 months
0.44%
2/452 • Number of events 2 • Up to 37 months
Gastrointestinal disorders
Enteritis
0.69%
3/433 • Number of events 3 • Up to 37 months
0.00%
0/452 • Up to 37 months
Gastrointestinal disorders
Other Intestinal disorders
1.6%
7/433 • Number of events 9 • Up to 37 months
1.1%
5/452 • Number of events 5 • Up to 37 months
Gastrointestinal disorders
Other Digestive Disorders
2.5%
11/433 • Number of events 14 • Up to 37 months
1.5%
7/452 • Number of events 8 • Up to 37 months
Renal and urinary disorders
Nephrotic disorders
0.46%
2/433 • Number of events 2 • Up to 37 months
0.00%
0/452 • Up to 37 months
Renal and urinary disorders
Other Urinary Disorder
1.2%
5/433 • Number of events 5 • Up to 37 months
1.1%
5/452 • Number of events 5 • Up to 37 months
Renal and urinary disorders
Disorders of the Male Genitourinary System
0.00%
0/433 • Up to 37 months
0.44%
2/452 • Number of events 3 • Up to 37 months
Renal and urinary disorders
Disorders of the Female Genitourinary System
0.23%
1/433 • Number of events 1 • Up to 37 months
0.22%
1/452 • Number of events 1 • Up to 37 months
Skin and subcutaneous tissue disorders
Skin Infection
0.46%
2/433 • Number of events 2 • Up to 37 months
0.66%
3/452 • Number of events 4 • Up to 37 months
Musculoskeletal and connective tissue disorders
Arthropathy
0.23%
1/433 • Number of events 1 • Up to 37 months
1.1%
5/452 • Number of events 6 • Up to 37 months
Musculoskeletal and connective tissue disorders
Dorsopathy
0.92%
4/433 • Number of events 4 • Up to 37 months
0.66%
3/452 • Number of events 3 • Up to 37 months
Musculoskeletal and connective tissue disorders
Rheumatism
0.69%
3/433 • Number of events 3 • Up to 37 months
0.22%
1/452 • Number of events 1 • Up to 37 months
Musculoskeletal and connective tissue disorders
Osteopathy
0.46%
2/433 • Number of events 2 • Up to 37 months
0.22%
1/452 • Number of events 1 • Up to 37 months
Gastrointestinal disorders
Nissen Fundoplication
0.00%
0/433 • Up to 37 months
0.22%
1/452 • Number of events 1 • Up to 37 months
Musculoskeletal and connective tissue disorders
Spondylolisthesis
0.23%
1/433 • Number of events 1 • Up to 37 months
0.00%
0/452 • Up to 37 months
General disorders
Syncope
1.2%
5/433 • Number of events 5 • Up to 37 months
0.22%
1/452 • Number of events 1 • Up to 37 months
General disorders
Dizziness
0.46%
2/433 • Number of events 2 • Up to 37 months
0.00%
0/452 • Up to 37 months
General disorders
Severe Headaches
0.23%
1/433 • Number of events 1 • Up to 37 months
0.00%
0/452 • Up to 37 months
Cardiac disorders
Tachycardia
0.23%
1/433 • Number of events 1 • Up to 37 months
0.00%
0/452 • Up to 37 months
General disorders
Ill defined abdominal pain
0.46%
2/433 • Number of events 2 • Up to 37 months
0.66%
3/452 • Number of events 4 • Up to 37 months
General disorders
Sudden death of unknown cause
0.92%
4/433 • Number of events 4 • Up to 37 months
0.88%
4/452 • Number of events 4 • Up to 37 months
Injury, poisoning and procedural complications
Fractures
1.6%
7/433 • Number of events 7 • Up to 37 months
0.88%
4/452 • Number of events 4 • Up to 37 months
Injury, poisoning and procedural complications
Sprain
0.23%
1/433 • Number of events 1 • Up to 37 months
0.22%
1/452 • Number of events 1 • Up to 37 months
Injury, poisoning and procedural complications
Intracranial injury
0.23%
1/433 • Number of events 1 • Up to 37 months
0.00%
0/452 • Up to 37 months
Injury, poisoning and procedural complications
Internal Injury
0.23%
1/433 • Number of events 2 • Up to 37 months
0.22%
1/452 • Number of events 1 • Up to 37 months
Injury, poisoning and procedural complications
Contusion
0.23%
1/433 • Number of events 1 • Up to 37 months
0.00%
0/452 • Up to 37 months
Injury, poisoning and procedural complications
Trauma from motorcycle accident
0.23%
1/433 • Number of events 1 • Up to 37 months
0.00%
0/452 • Up to 37 months
Injury, poisoning and procedural complications
Poisoning
0.23%
1/433 • Number of events 1 • Up to 37 months
0.22%
1/452 • Number of events 1 • Up to 37 months
General disorders
Complications of surgical and medical care
0.92%
4/433 • Number of events 4 • Up to 37 months
0.44%
2/452 • Number of events 2 • Up to 37 months
General disorders
Respiratory Arrest
0.46%
2/433 • Number of events 2 • Up to 37 months
0.22%
1/452 • Number of events 1 • Up to 37 months
General disorders
Abnormal Gait
0.23%
1/433 • Number of events 1 • Up to 37 months
0.00%
0/452 • Up to 37 months
Skin and subcutaneous tissue disorders
Cellulitis
0.23%
1/433 • Number of events 1 • Up to 37 months
0.00%
0/452 • Up to 37 months
Musculoskeletal and connective tissue disorders
Degenerative Disc Disease
0.23%
1/433 • Number of events 1 • Up to 37 months
0.00%
0/452 • Up to 37 months
General disorders
Epistaxis
0.23%
1/433 • Number of events 1 • Up to 37 months
0.00%
0/452 • Up to 37 months
General disorders
Sepsis
0.23%
1/433 • Number of events 1 • Up to 37 months
0.88%
4/452 • Number of events 4 • Up to 37 months
Respiratory, thoracic and mediastinal disorders
Ill Defined Respiratory events
2.3%
10/433 • Number of events 11 • Up to 37 months
2.9%
13/452 • Number of events 15 • Up to 37 months
Gastrointestinal disorders
Ill defined digestive symptoms
0.23%
1/433 • Number of events 1 • Up to 37 months
0.44%
2/452 • Number of events 2 • Up to 37 months
Respiratory, thoracic and mediastinal disorders
Hypoxemia
0.00%
0/433 • Up to 37 months
0.44%
2/452 • Number of events 2 • Up to 37 months
General disorders
Fatigue
0.00%
0/433 • Up to 37 months
0.22%
1/452 • Number of events 1 • Up to 37 months
Psychiatric disorders
Altered Mental Status
0.00%
0/433 • Up to 37 months
0.22%
1/452 • Number of events 1 • Up to 37 months
Injury, poisoning and procedural complications
Concussion
0.00%
0/433 • Up to 37 months
0.22%
1/452 • Number of events 1 • Up to 37 months

Other adverse events

Other adverse events
Measure
Simvastatin
n=433 participants at risk
40 mgms of simvastatin daily Simvastatin: 40 mgms of simvastatin daily
Placebo
n=452 participants at risk
Matched placebo pill daily Placebo: Matched placebo pill daily
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Infection
25.2%
109/433 • Number of events 159 • Up to 37 months
23.7%
107/452 • Number of events 166 • Up to 37 months
Respiratory, thoracic and mediastinal disorders
Pneumonia
5.1%
22/433 • Number of events 25 • Up to 37 months
3.8%
17/452 • Number of events 19 • Up to 37 months
Respiratory, thoracic and mediastinal disorders
COPD Exacerbation
53.6%
232/433 • Number of events 642 • Up to 37 months
54.0%
244/452 • Number of events 649 • Up to 37 months
Respiratory, thoracic and mediastinal disorders
Other COPD Related Symptoms
9.5%
41/433 • Number of events 79 • Up to 37 months
9.5%
43/452 • Number of events 80 • Up to 37 months
Musculoskeletal and connective tissue disorders
Arthropathies
5.8%
25/433 • Number of events 38 • Up to 37 months
7.1%
32/452 • Number of events 43 • Up to 37 months
Musculoskeletal and connective tissue disorders
Dorsopathies
6.2%
27/433 • Number of events 35 • Up to 37 months
6.0%
27/452 • Number of events 32 • Up to 37 months
Musculoskeletal and connective tissue disorders
Rheumatism
15.5%
67/433 • Number of events 89 • Up to 37 months
11.9%
54/452 • Number of events 73 • Up to 37 months
Renal and urinary disorders
Urinary Infection
6.0%
26/433 • Number of events 56 • Up to 37 months
5.1%
23/452 • Number of events 30 • Up to 37 months
General disorders
Headache
3.7%
16/433 • Number of events 20 • Up to 37 months
5.1%
23/452 • Number of events 27 • Up to 37 months
Respiratory, thoracic and mediastinal disorders
Dyspnea
15.0%
65/433 • Number of events 94 • Up to 37 months
13.1%
59/452 • Number of events 90 • Up to 37 months

Additional Information

Sarah Lindberg

University of Minnesota

Phone: 612-626-9011

Results disclosure agreements

  • Principal investigator is a sponsor employee
  • Publication restrictions are in place