Trial Outcomes & Findings for Nitrates and Bone Turnover; Nitrates and Bone Turnover Bisphosphonate Sub-Study (NCT NCT01387672)
NCT ID: NCT01387672
Last Updated: 2015-05-08
Results Overview
Markers of Bone Formation: * Serum Procollagen type 1 amino- terminal propeptide (P1NP) * Serum Osteocalcin (OC) * Serum Bone-specific alkaline phosphatase (BALP) Markers of Bone Resorption: \- Serum C-telopeptides of collagen cross-links (CTX)
Recruitment status
COMPLETED
Study phase
PHASE3
Target enrollment
265 participants
Primary outcome timeframe
3 months
Results posted on
2015-05-08
Participant Flow
Initial run-in period-subjects received, in random order, each of the 5 nitrate formulations for 2 days with a 2 day wash out period between formulations. There were 265 subjects enrolled in the run-in phase of the study. Out of those, 229 subjects entered the treatment phase of the study, where they were randomized to one of the 6 treatment arms.
Participant milestones
| Measure |
ISMO - Treatment Arm 1
Isosorbide Mononitrate 20mg Oral Tablet
Nitrates (NABT Main trial)
|
Patch (Nitro-Dur) - Treatment Arm 2
Nitroglycerin Extended Release Patch 160mg
Nitrates (NABT Main trial)
|
Ointment (Nitrol) - Treatment Arm 3
Nitroglycerin Ointment 2% USP
Nitrates (NABT Main trial)
|
0.3 Sublingual (Nitrostat 1) - Treatment Arm 4
Nitroglycerin 0.3mg Sublingual Tablet
Nitrates (NABT Main trial)
|
0.6 Sublingual (Nitrostat 2) - Treatment Arm 5
Nitroglycerin 0.6mg Sublingual Tablet
Nitrates (NABT Main trial)
|
Placebo Ointment - Treatment Arm 6
Placebo Ointment
Nitrates (NABT Main trial)
|
|---|---|---|---|---|---|---|
|
Overall Study
STARTED
|
39
|
38
|
38
|
39
|
38
|
37
|
|
Overall Study
COMPLETED
|
32
|
31
|
33
|
35
|
34
|
37
|
|
Overall Study
NOT COMPLETED
|
7
|
7
|
5
|
4
|
4
|
0
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
Nitrates and Bone Turnover; Nitrates and Bone Turnover Bisphosphonate Sub-Study
Baseline characteristics by cohort
| Measure |
ISMO - Treatment Arm 1
n=39 Participants
Isosorbide Mononitrate 20mg Oral Tablet
Nitrates (NABT Main trial)
|
Patch (Nitro-Dur) - Treatment Arm 2
n=38 Participants
Nitroglycerin Extended Release Patch 160mg
Nitrates (NABT Main trial)
|
Ointment (Nitrol) - Treatment Arm 3
n=38 Participants
Nitroglycerin Ointment 2% USP
Nitrates (NABT Main trial)
|
0.3 Sublingual (Nitrostat 1) - Treatment Arm 4
n=39 Participants
Nitroglycerin 0.3mg Sublingual Tablet
Nitrates (NABT Main trial)
|
0.6 Sublingual (Nitrostat 2) - Treatment Arm 5
n=38 Participants
Nitroglycerin 0.6mg Sublingual Tablet
Nitrates (NABT Main trial)
|
Placebo Ointment - Treatment Arm 6
n=37 Participants
Placebo Ointment
Placebo: Placebo ointment Nitrates (NABT Main trial)
|
Total
n=229 Participants
Total of all reporting groups
|
|---|---|---|---|---|---|---|---|
|
Age, Categorical
<=18 years
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
0 Participants
n=4 Participants
|
0 Participants
n=21 Participants
|
0 Participants
n=10 Participants
|
0 Participants
n=115 Participants
|
|
Age, Categorical
Between 18 and 65 years
|
19 Participants
n=5 Participants
|
21 Participants
n=7 Participants
|
20 Participants
n=5 Participants
|
23 Participants
n=4 Participants
|
23 Participants
n=21 Participants
|
20 Participants
n=10 Participants
|
126 Participants
n=115 Participants
|
|
Age, Categorical
>=65 years
|
20 Participants
n=5 Participants
|
17 Participants
n=7 Participants
|
18 Participants
n=5 Participants
|
16 Participants
n=4 Participants
|
15 Participants
n=21 Participants
|
17 Participants
n=10 Participants
|
103 Participants
n=115 Participants
|
|
Sex: Female, Male
Female
|
39 Participants
n=5 Participants
|
38 Participants
n=7 Participants
|
38 Participants
n=5 Participants
|
39 Participants
n=4 Participants
|
38 Participants
n=21 Participants
|
37 Participants
n=10 Participants
|
229 Participants
n=115 Participants
|
|
Sex: Female, Male
Male
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
0 Participants
n=4 Participants
|
0 Participants
n=21 Participants
|
0 Participants
n=10 Participants
|
0 Participants
n=115 Participants
|
|
Region of Enrollment
Canada
|
39 participants
n=5 Participants
|
38 participants
n=7 Participants
|
38 participants
n=5 Participants
|
39 participants
n=4 Participants
|
38 participants
n=21 Participants
|
37 participants
n=10 Participants
|
229 participants
n=115 Participants
|
PRIMARY outcome
Timeframe: 3 monthsPopulation: One subject from the Treatment Arm 3 had outlier bone turnover markers values and was excluded from the analysis. Total number of subjects analyzed in Treatment Arm 3 was therefore 32.
Markers of Bone Formation: * Serum Procollagen type 1 amino- terminal propeptide (P1NP) * Serum Osteocalcin (OC) * Serum Bone-specific alkaline phosphatase (BALP) Markers of Bone Resorption: \- Serum C-telopeptides of collagen cross-links (CTX)
Outcome measures
| Measure |
0.3 Sublingual (Nitrostat 1) - Treatment Arm 4
n=35 Participants
Nitroglycerin 0.3mg Sublingual Tablet
Nitrates (NABT Main trial)
|
0.6 Sublingual (Nitrostat 2) - Treatment Arm 5
n=34 Participants
Nitroglycerin 0.6mg Sublingual Tablet
Nitrates (NABT Main trial)
|
Placebo Ointment - Treatment Arm 6
n=37 Participants
Placebo Ointment
Placebo: Placebo ointment Nitrates (NABT Main trial)
|
Run-in Phase
n=32 Participants
During the run-in phase subjects received, in random order, each of the 5 nitrate formulations for 2 days with a 2 day wash out period between formulations. The severity of headaches was recorded, by subjects, upon awakening, every day during the run in phase using a visual analog scale (VAS).
|
Patch (Nitro-Dur) - Treatment Arm 2
n=31 Participants
Nitroglycerin Extended Release Patch 160mg
Nitrates (NABT Main trial)
|
Ointment (Nitrol) - Treatment Arm 3
n=32 Participants
Nitroglycerin Ointment 2% USP
Nitrates (NABT Main trial)
|
|---|---|---|---|---|---|---|
|
Bone Turnover Markers
BALP
|
-7.000 Percent change from baseline
Standard Deviation 19.011
|
-3.686 Percent change from baseline
Standard Deviation 17.435
|
-1.648 Percent change from baseline
Standard Deviation 21.523
|
-5.023 Percent change from baseline
Standard Deviation 11.824
|
-0.541 Percent change from baseline
Standard Deviation 20.738
|
-7.426 Percent change from baseline
Standard Deviation 11.056
|
|
Bone Turnover Markers
P1NP
|
-6.126 Percent change from baseline
Standard Deviation 16.093
|
2.941 Percent change from baseline
Standard Deviation 36.843
|
-1.635 Percent change from baseline
Standard Deviation 16.749
|
-4.627 Percent change from baseline
Standard Deviation 16.191
|
-0.405 Percent change from baseline
Standard Deviation 20.289
|
-4.297 Percent change from baseline
Standard Deviation 16.236
|
|
Bone Turnover Markers
OC
|
1.046 Percent change from baseline
Standard Deviation 21.818
|
1.033 Percent change from baseline
Standard Deviation 17.931
|
4.247 Percent change from baseline
Standard Deviation 22.088
|
-3.244 Percent change from baseline
Standard Deviation 12.049
|
3.796 Percent change from baseline
Standard Deviation 33.601
|
-4.481 Percent change from baseline
Standard Deviation 14.823
|
|
Bone Turnover Markers
CTX
|
-0.666 Percent change from baseline
Standard Deviation 37.945
|
-1.380 Percent change from baseline
Standard Deviation 52.248
|
-1.783 Percent change from baseline
Standard Deviation 28.063
|
-5.844 Percent change from baseline
Standard Deviation 26.084
|
-1.025 Percent change from baseline
Standard Deviation 32.163
|
-9.699 Percent change from baseline
Standard Deviation 27.299
|
SECONDARY outcome
Timeframe: Run-in phase - 2 daysPopulation: The mean headache score considering all subjects in each of the treatment/formulation group was calculated.
Severity of headaches. Subjects recorded the severity of headaches upon awakening every day during the run-in phase using a visual analogue scale (VAS). The scale is represented by a line (continuum) 10 cm long. Subjects were asked to make a vertical line along the continuum to indicate the severity of their headache each morning upon awakening. The score is recorded in cm from "0" to "10". A vertical line marked at "0" means no headache (score recorded = "0"), a vertical line marked at "10" means a terrible headache (score recorded = "10").
Outcome measures
| Measure |
0.3 Sublingual (Nitrostat 1) - Treatment Arm 4
Nitroglycerin 0.3mg Sublingual Tablet
Nitrates (NABT Main trial)
|
0.6 Sublingual (Nitrostat 2) - Treatment Arm 5
Nitroglycerin 0.6mg Sublingual Tablet
Nitrates (NABT Main trial)
|
Placebo Ointment - Treatment Arm 6
Placebo Ointment
Placebo: Placebo ointment Nitrates (NABT Main trial)
|
Run-in Phase
n=238 Participants
During the run-in phase subjects received, in random order, each of the 5 nitrate formulations for 2 days with a 2 day wash out period between formulations. The severity of headaches was recorded, by subjects, upon awakening, every day during the run in phase using a visual analog scale (VAS).
|
Patch (Nitro-Dur) - Treatment Arm 2
Nitroglycerin Extended Release Patch 160mg
Nitrates (NABT Main trial)
|
Ointment (Nitrol) - Treatment Arm 3
Nitroglycerin Ointment 2% USP
Nitrates (NABT Main trial)
|
|---|---|---|---|---|---|---|
|
Headache
ISMO
|
—
|
—
|
—
|
2.1 score on a scale
Standard Deviation 2.64
|
—
|
—
|
|
Headache
Patch
|
—
|
—
|
—
|
3.1 score on a scale
Standard Deviation 2.98
|
—
|
—
|
|
Headache
Ointment
|
—
|
—
|
—
|
1.5 score on a scale
Standard Deviation 2.12
|
—
|
—
|
|
Headache
0.3 Sublingual
|
—
|
—
|
—
|
0.36 score on a scale
Standard Deviation 1.18
|
—
|
—
|
|
Headache
0.6 Sublingual
|
—
|
—
|
—
|
0.6 score on a scale
Standard Deviation 1.62
|
—
|
—
|
Adverse Events
ISMO - Treatment Arm 1
Serious events: 0 serious events
Other events: 17 other events
Deaths: 0 deaths
Patch (Nitro-Dur) - Treatment Arm 2
Serious events: 0 serious events
Other events: 21 other events
Deaths: 0 deaths
Ointment (Nitrol) - Treatment Arm 3
Serious events: 0 serious events
Other events: 17 other events
Deaths: 0 deaths
0.3 Sublingual (Nitrostat 1) - Treatment Arm 4
Serious events: 1 serious events
Other events: 10 other events
Deaths: 0 deaths
0.6 Sublingual (Nitrostat 2) - Treatment Arm 5
Serious events: 1 serious events
Other events: 12 other events
Deaths: 0 deaths
Placebo Ointment- Treatment Arm 6
Serious events: 0 serious events
Other events: 6 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
ISMO - Treatment Arm 1
n=39 participants at risk
Isosorbide Mononitrate 20mg Oral Tablet
Nitrates (NABT Main trial)
|
Patch (Nitro-Dur) - Treatment Arm 2
n=38 participants at risk
Nitroglycerin Extended Release Patch 160mg
Nitrates (NABT Main trial)
|
Ointment (Nitrol) - Treatment Arm 3
n=38 participants at risk
Nitroglycerin Ointment 2% USP
Nitrates (NABT Main trial)
|
0.3 Sublingual (Nitrostat 1) - Treatment Arm 4
n=39 participants at risk
Nitroglycerin 0.3mg Sublingual Tablet
Nitrates (NABT Main trial)
|
0.6 Sublingual (Nitrostat 2) - Treatment Arm 5
n=38 participants at risk
Nitroglycerin 0.6mg Sublingual Tablet
Nitrates (NABT Main trial)
|
Placebo Ointment- Treatment Arm 6
n=37 participants at risk
Placebo Ointment
Placebo: Placebo ointment Nitrates (NABT Main trial)
|
|---|---|---|---|---|---|---|
|
Nervous system disorders
Transient Global Amnesia
|
0.00%
0/39 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
0.00%
0/38 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
0.00%
0/38 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
0.00%
0/39 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
2.6%
1/38 • Number of events 1 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
0.00%
0/37 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
|
Vascular disorders
Stroke
|
0.00%
0/39 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
0.00%
0/38 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
0.00%
0/38 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
2.6%
1/39 • Number of events 1 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
0.00%
0/38 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
0.00%
0/37 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
Other adverse events
| Measure |
ISMO - Treatment Arm 1
n=39 participants at risk
Isosorbide Mononitrate 20mg Oral Tablet
Nitrates (NABT Main trial)
|
Patch (Nitro-Dur) - Treatment Arm 2
n=38 participants at risk
Nitroglycerin Extended Release Patch 160mg
Nitrates (NABT Main trial)
|
Ointment (Nitrol) - Treatment Arm 3
n=38 participants at risk
Nitroglycerin Ointment 2% USP
Nitrates (NABT Main trial)
|
0.3 Sublingual (Nitrostat 1) - Treatment Arm 4
n=39 participants at risk
Nitroglycerin 0.3mg Sublingual Tablet
Nitrates (NABT Main trial)
|
0.6 Sublingual (Nitrostat 2) - Treatment Arm 5
n=38 participants at risk
Nitroglycerin 0.6mg Sublingual Tablet
Nitrates (NABT Main trial)
|
Placebo Ointment- Treatment Arm 6
n=37 participants at risk
Placebo Ointment
Placebo: Placebo ointment Nitrates (NABT Main trial)
|
|---|---|---|---|---|---|---|
|
Nervous system disorders
Headache
|
43.6%
17/39 • Number of events 17 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
55.3%
21/38 • Number of events 21 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
44.7%
17/38 • Number of events 17 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
25.6%
10/39 • Number of events 10 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
31.6%
12/38 • Number of events 112 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
16.2%
6/37 • Number of events 6 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
|
Nervous system disorders
Dizziness
|
2.6%
1/39 • Number of events 1 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
5.3%
2/38 • Number of events 2 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
2.6%
1/38 • Number of events 1 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
0.00%
0/39 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
5.3%
2/38 • Number of events 2 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
0.00%
0/37 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
|
Gastrointestinal disorders
Nausea
|
2.6%
1/39 • Number of events 1 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
5.3%
2/38 • Number of events 2 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
0.00%
0/38 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
5.1%
2/39 • Number of events 2 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
2.6%
1/38 • Number of events 1 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
0.00%
0/37 • The Adverse Events are reported for the 3 months treatment phase of the study, once the patients were randomized to a specific treatment arm (ISMO - Arm 1; Patch - Arm 2; Ointment - Arm 3; 0.3 Sublingual - Arm 4; 0.6 Sublingual - Arm 5 or Placebo - Arm 6)
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place