Development of 1-Day Rest/Stress Cardiac PET Perfusion Imaging Protocol of BMS747158

• Sponsor: Lantheus Medical Imaging (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00849108
• Collaborator: (none)
• Enrollment: 176
• Locations: 24
• Arms: 2
• Duration (Months): 17
• Patients Per Site: 7.3
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The main purpose of this study is to get more information on using BMS747158 (the study drug),a drug with small amounts of radioactivity to allow for heart imaging, during a PET scan which can then be compared to other images such as SPECT. The safety and quality of images will be studied.

Condition or Disease	Intervention/Treatment	Phase
Ischemia	Drug: BMS747158	Phase 2

Detailed Description

The primary objectives of this study are:

• To acquire data for the development of one-day rest/stress cardiac PET perfusion imaging protocols for BMS747158 with comparable diagnostic image quality to a two-day rest/stress PET protocol

• To assess the safety of multiple doses of BMS747158

The secondary objectives of this study are:

• To assess PET imaging parameters and image quality following administration of BMS747158 at rest and at stress (pharmacologic or exercise) same day (at different time intervals) and 16-48 hours after the rest injection

• To assess feasibility of gated cardiac PET imaging with BMS747158 for left ventricular function assessment

• To assess agreement of one and two day rest/stress PET imaging with BMS747158 in patients with reversible ischemia with rest/stress single photon emission computed tomography (SPECT) imaging

• To perform a preliminary assessment of the diagnostic accuracy of one-day and two-day rest/stress PET perfusion imaging with BMS747158 as compared with invasive coronary angiography or computed tomography angiography (CTA) for detection of

Study Design

• Study Type: Interventional
• Actual Enrollment: 176 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: A Phase 2, Open-Label, Randomized Multicenter Study for the Development of One-Day Rest/Stress Cardiac Positron Emission Tomography (PET) Perfusion Imaging Protocols of BMS747158
• Study Start Date: Jan 1, 2009
• Actual Primary Completion Date: Jun 1, 2010
• Actual Study Completion Date: Jun 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1: dose range and dose interval Patients to receive either 2 or 3 IV bolus injections of BMS747158: 1 at rest and 1 or 2 during pharmacological or exercise stress, over a 1-day or 2-day period.	Drug: BMS747158; dosages at rest and at stress were not to exceed a total of 14 mCi. Cohort 1: Patients received either 2 or 3 IV bolus injections of BMS747158: 1 at rest and 1 or 2 during stress, over a 1-day or 2-day period. Cohort 2: Patients to recieve IV bolus injections of BMS747158: For the Pharmacologic (Adenosine) Stress: Doses at rest were to range between 2.9 and 3.4 mCi. Doses under stress were to be a factor of 2.0 to 2.4 greater than the rest dose, resulting in a range of stress doses between 5.8 and 8.2 mCi. For the Exercise Stress: Doses at rest were to range between 1.7 and 2.0 mCi. Doses under stress were to be a factor of 3.0 to 3.6 greater than the rest dose, resulting in a range between 5.1 and 7.2 mCi.; Other Names: There are no other names
Experimental: Cohort 2: Pharm&exercise stress Efficacy Patients to receive 2 IV bolus injections of BMS747158:1 at rest and 1 at stress For the Pharmacologic (Adenosine) Stress: Doses at rest to range between 2.9 and 3.4 mCi. Doses under stress to be a factor of 2.0 to 2.4 greater than the rest dose, resulting in a range of stress doses between 5.8 and 8.2 mCi. For the Exercise Stress: Doses at rest were to range between 1.7 and 2.0 mCi. Doses under stress were to be a factor of 3.0 to 3.6 greater than the rest dose, resulting in a range between 5.1 and 7.2 mCi.	Drug: BMS747158; dosages at rest and at stress were not to exceed a total of 14 mCi. Cohort 1: Patients received either 2 or 3 IV bolus injections of BMS747158: 1 at rest and 1 or 2 during stress, over a 1-day or 2-day period. Cohort 2: Patients to recieve IV bolus injections of BMS747158: For the Pharmacologic (Adenosine) Stress: Doses at rest were to range between 2.9 and 3.4 mCi. Doses under stress were to be a factor of 2.0 to 2.4 greater than the rest dose, resulting in a range of stress doses between 5.8 and 8.2 mCi. For the Exercise Stress: Doses at rest were to range between 1.7 and 2.0 mCi. Doses under stress were to be a factor of 3.0 to 3.6 greater than the rest dose, resulting in a range between 5.1 and 7.2 mCi.; Other Names: There are no other names

Outcome Measures

Primary Outcome Measures

1. Cohort 1: Determination of Rest Dose: Dose Acquistion Time Product [Dosing visit]

   The rest flurpiridaz dose to be used for subsequent efficacy studies was determined by a modeling method that simulated a range of injected doses using a single fixed injected dose at rest in each subject and a range of acquisition durations. From this, a dose acquisition time product (DATP was determined for each subject that specified the minimal dose for a given acquisition duration that yielded an image in that subject that was negligibly affected by photon counting statistics. Descriptive statistics were used to identify an appropriate rest dose for the population. No other statistical tests were performed

2. Cohort 2: Diagnostic Efficacy of One-day Rest/Stress BMS747158 PET MPI Sensitivity (SN) vs SPECT MPI Sensitivity [Dosing visit]

   Diagnostic efficacy of one-day rest/stress BMS747158 PET MPI is measured by sensitivity as compared to single photon emission computed tomography (SPECT)MPI in the detection of coronary artery disease (CAD)using angiography or three-month cardiac events as the truth standard.

3. Cohort 1: Determination of Ratio of Stress Dose to Rest Dose [Dosing visit]

   The stress flurpiridaz dose for subsequent same-day rest-stress efficacy studies was determined as a multiple of the rest dose by computer modeling. Images derived only from rest flurpiridaz administration were blended using image analysis with images derived only from administration of flurpiridaz following exercise or adenosine stress. The blending fraction that resulted in negligible change in reader interpretation of defect severity was determined for each subject. The minimum value that met this criterion for all subjects was used to calculate the ratio of the stress dose to the rest dose as a function of the delay between administration of the two doses for both adenosine stress and exercise stress separately. No statistical analysis was performed.

4. Cohort 2: Diagnostic Efficacy of One-day Rest/Stress BMS747158 PET MPI Specificity (SP) vs SPECT MPI Specificity [Dosing Visit]

   Diagnostic efficacy of one-day rest/stress BMS747158 PET MPI is measured by specificity as compared to single photon emission computed tomography (SPECT)MPI in the detection of coronary artery disease (CAD)using angiography or three-month cardiac events as the truth standard.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Provide signed IC prior to undergoing any study procedures

• Be male or nonpregnant female, between the ages of 18 to 75 years, inclusive

• Have:A rest/stress SPECT imaging study (either exercise or pharmacologic stress) within 21 days of enrollment, using 99mTc-labeled tracers and showing reversible ischemia

• Female patients must:

• be nonlactating,

• no longer have child-bearing potential, either because they are post-menopausal (defined as amenorrhea ≥ 12 consecutive months, or because they have undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy)

Exclusion Criteria:

• Presence of any condition that may disrupt and/or increase permeability of the BBB, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, acute central nervous system (CNS) infection, CNS tumor, autoimmune disease affecting the CNS, or CNS inflammatory

• Current significant illness, pathology or physical examination or vital signs measurement-findings that could potentiate any adverse pharmacological event associated with a vasodilatory drug or any pathology that, in the opinion of the investigator, might confound the interpretation of the results of the study

• Known hypersensitivity to adenosine, dipyridamole or aminophylline

• Presence of any contraindications to exercise stress testing

• History of New York Heart Association Class III or IV Congestive Heart Failure (CHF)

• Any major surgery within 4 weeks prior to enrollment or planned within 2 weeks following completion of the 2-week telephone follow-up assessment

• Inability to tolerate IV medication.

• History of drug or alcohol abuse within the last year

• Participation in any investigational drug, device, or placebo study within 6 months prior to study enrollment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Silicon Valley Medical Imaging	Fremont	California	United States	94538
2	Scripps Memorial Hospital	La Jolla	California	United States	92037
3	Cedars-Sinai Medical Center	Los Angeles	California	United States	90095
4	UCLA Medical Plaza	Los Angeles	California	United States	90095
5	Radiological Associates of Sacramento	Sacramento	California	United States	95816
6	VA Healthcare System San Diego	San Diego	California	United States	92161
7	Hartford Hospital	Hartford	Connecticut	United States	05102-5037
8	Yale University	New Haven	Connecticut	United States	06520
9	Emory University Hospital	Atlanta	Georgia	United States	30322
10	Primary Care Cardiology Research, Inc	Ayer	Massachusetts	United States	01432
11	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
12	Brigham & Women's Hospital	Boston	Massachusetts	United States	02115
13	University of Michigan	Ann Arbor	Michigan	United States	48109
14	Cardiovascular Consultants	Kansas City	Missouri	United States	64101
15	Saint Louis University	St. Louis	Missouri	United States	63110
16	Washington University School of Medicine	St. Louis	Missouri	United States	63110
17	University of Medicine and Dentistry of New Jersey	Newark	New Jersey	United States	07107
18	Holy Name Hospital	Teaneck	New Jersey	United States	07666
19	Columbia University Medical Center	New York	New York	United States	10032
20	St. Francis Hospital	Roslyn	New York	United States	11576
21	University Hospital Case Medical Center	Cleveland	Ohio	United States	44106
22	Midwest Cardiology Research Foundation	Columbus	Ohio	United States	43214
23	Mountain States Health Alliance	Johnson City	Tennessee	United States	37604
24	East Tennessee Clinical Research Institute	Knoxville	Tennessee	United States	27934

Sponsors and Collaborators

• Lantheus Medical Imaging

Investigators

• Study Director: Cesare Orlandi, MD, Lantheus Medical Imaging

Study Documents (Full-Text)

None provided.

More Information

Publications

• Bateman TM. Cardiac positron emission tomography and the role of adenosine pharmacologic stress. Am J Cardiol. 2004 Jul 22;94(2A):19D-24D; discussion 24D-25D. Review.
• Beller GA, Bergmann SR. Myocardial perfusion imaging agents: SPECT and PET. J Nucl Cardiol. 2004 Jan-Feb;11(1):71-86. Review.
• Beller GA, Zaret BL. Contributions of nuclear cardiology to diagnosis and prognosis of patients with coronary artery disease. Circulation. 2000 Mar 28;101(12):1465-78. Review.
• Beller GA. First annual Mario S. Verani, MD, Memorial lecture: clinical value of myocardial perfusion imaging in coronary artery disease. J Nucl Cardiol. 2003 Sep-Oct;10(5):529-42.
• Cerqueira MD, Verani MS, Schwaiger M, Heo J, Iskandrian AS. Safety profile of adenosine stress perfusion imaging: results from the Adenoscan Multicenter Trial Registry. J Am Coll Cardiol. 1994 Feb;23(2):384-9.
• Glover DK, Gropler RJ. Journey to find the ideal PET flow tracer for clinical use: are we there yet? J Nucl Cardiol. 2007 Nov-Dec;14(6):765-8.
• Guideri F, Ferber D, Galgano G, Isidori S, Blardi P, Pasini FL, Di Perri T. QTc interval prolongation during infusion with dipyridamole or adenosine. Int J Cardiol. 1995 Jan 27;48(1):67-73.
• Henzlova MJ, Cerqueira MD, Mahmarian JJ, Yao SS; Quality Assurance Committee of the American Society of Nuclear Cardiology. Stress protocols and tracers. J Nucl Cardiol. 2006 Nov;13(6):e80-90.
• Miyamoto MI, Vernotico SL, Majmundar H, Thomas GS. Pharmacologic stress myocardial perfusion imaging: a practical approach. J Nucl Cardiol. 2007 Apr;14(2):250-5. Review. Erratum in: J Nucl Cardiol. 2007Jul;14(4):628.

• Responsible Party: Lantheus Medical Imaging
• ClinicalTrials.gov Identifier: NCT00849108
• Other Study ID Numbers: BMS747158-201
• First Posted: Feb 23, 2009
• Last Update Posted: Oct 14, 2015
• Last Verified: Apr 1, 2012

• Keywords provided by Lantheus Medical Imaging: Myocardial Perfusion; PET imaging; SPECT imaging; Coronary artery disease; Subjects that are male and nonpregnant female patients; presenting with reversible ischemia as characterized by a; rest/stress SPECT imaging study using; Technetium(99mTc)-labeled tracers
• Additional relevant MeSH terms: Ischemia

Study Results

Participant Flow

Recruitment Details	Cohort 1 enrolled 33 patients across 3 clinical sites. Dosing for Cohort 1 was initiated January 2009. Cohort 2 enrolled 143 patients across 21 clinical sites. Dosing for Cohort 2 was initiated July 2009
Pre-assignment Detail	Cohort 1: Patients showing a mild to severe reversible perfusion defect on a qualifying SPECT MPI study were considered eligible for the study Cohort 2: Patients with known or suspected cornary artery disease who presented with a broad spectrum of pre-test likelihood of CAD(very low/low, to high likelihood)were considered eligible for the study.

Arm/Group Title	Cohort 1 Dose Ranging and Dose Interval	Cohort 2 Preliminary Efficacy Pharmacologic Stress
Arm/Group Description	Patients received 2 or 3 IV bolus injections of BMS747158: 1 at rest and 1 at pharmacologic/exercise stress, over a 1-day or 2-day period	Patients received 2 injections of BMS747158: 1 at rest and 1 at Pharmacologic stress, over a 1-day period.
Period Title: Cohort 1 Dose Ranging and Dose Interval
STARTED	33	0
COMPLETED	32	0
NOT COMPLETED	1	0
Period Title: Cohort 1 Dose Ranging and Dose Interval
STARTED	0	143
COMPLETED	0	133
NOT COMPLETED	0	10

Baseline Characteristics

Arm/Group Title	Cohort 1 Dose Ranging and Dose Interval	Cohort 2: Pharm Stress	Cohort 2: Efficacy Exercise Stress	Total
Arm/Group Description	Patients received either 2 or 3 IV bolus injhections of BMS747158: 1 at rest and 1 or 2 during stress, over a 1-day or 2-day period	Patient received BMS747158 as a single IV bolus injection at rest and a single bolus injection at pharmacologic stress over a 1-day period. For patients undergoing pharmacologic stress test the dose of BMS747158 were to be a factor of 2.0 to 2.4 greater than the rest dose.	Patient received BMS747158 as a single IV bolus injection at rest and a single bolus injection at exercise stress over a 1-day period. For patients undergoing exercise stress test the dose of BMS747158 were to be a factor of 3.0 to 3.6 greater than the rest dose.	Total of all reporting groups
Overall Participants	33	67	76	176
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	9 27.3%	24 35.8%	52 68.4%	85 48.3%
>=65 years	24 72.7%	43 64.2%	24 31.6%	91 51.7%
Sex: Female, Male (Count of Participants)
Female	9 27.3%	16 23.9%	20 26.3%	45 25.6%
Male	24 72.7%	51 76.1%	56 73.7%	131 74.4%
Region of Enrollment (participants) [Number]
North America	33 100%	67 100%	76 100%	176 100%

Outcome Measures

1. Primary Outcome

Title	Cohort 1: Determination of Rest Dose: Dose Acquistion Time Product
Description	The rest flurpiridaz dose to be used for subsequent efficacy studies was determined by a modeling method that simulated a range of injected doses using a single fixed injected dose at rest in each subject and a range of acquisition durations. From this, a dose acquisition time product (DATP was determined for each subject that specified the minimal dose for a given acquisition duration that yielded an image in that subject that was negligibly affected by photon counting statistics. Descriptive statistics were used to identify an appropriate rest dose for the population. No other statistical tests were performed
Time Frame	Dosing visit

Outcome Measure Data

Analysis Population Description

Intent to treat, received at least one rest dose of BMS 747158

Arm/Group Title	Cohort 1: Dose Acquistion Time Product
Arm/Group Description	Subjects received either 2 or 3 IV bolus injhections of BMS747158: 1 at rest and 1 or 2 during stress, over a 1-day or 2-day period
Measure Participants	33
Mean (Standard Deviation) [MBq X Minutes]	100 (54.7)

2. Primary Outcome

Title	Cohort 2: Diagnostic Efficacy of One-day Rest/Stress BMS747158 PET MPI Sensitivity (SN) vs SPECT MPI Sensitivity
Description	Diagnostic efficacy of one-day rest/stress BMS747158 PET MPI is measured by sensitivity as compared to single photon emission computed tomography (SPECT)MPI in the detection of coronary artery disease (CAD)using angiography or three-month cardiac events as the truth standard.
Time Frame	Dosing visit

Outcome Measure Data

Analysis Population Description

intent to treat, received at least one dose of BMS747158

Arm/Group Title	Cohort 2 Efficacy/Safety
Arm/Group Description	Patient received BMS747158 as a single IV bolus injection at rest and a single bolus injection at stress over a 1-day period. For patients undergoing pharmacologic stress test the dose of BMS747158 were to be a factor of 2.0 to 2.4 greater than the rest dose. For patients undergoing exercise stress test the dose of BMS747158 were to be a factor of 3.0 to 3.6 greater than the rest dose.
Measure Participants	125
PET MPI	0.769
SPECT MPI	0.596

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1: Dose Acquistion Time Product
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments	P-Value for sensitivity comparison of PET MPI for the same reader
	Method	McNemar
	Comments	two-sided McNemar test with 1 degree of freedom.
Method of Estimation	Estimation Parameter	sensitivity
	Estimated Value	0.769
	Confidence Interval	(2-Sided) 95%; 0.655 to 0.884
	Parameter Dispersion	Type: Value:
	Estimation Comments	No standard deviation can be calculated for PET sensitivity

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 1: Dose Acquistion Time Product
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments	p-value for sensitivity comparison for SPECT MPI for the same reader
	Method	McNemar
	Comments
Method of Estimation	Estimation Parameter	Sensitivity
	Estimated Value	0.596
	Confidence Interval	(2-Sided) 95%; 0.463 to 0.730
	Parameter Dispersion	Type: Value:
	Estimation Comments	No standard deviation can be calculated for SPECT sensitivity

3. Primary Outcome

Title	Cohort 1: Determination of Ratio of Stress Dose to Rest Dose
Description	The stress flurpiridaz dose for subsequent same-day rest-stress efficacy studies was determined as a multiple of the rest dose by computer modeling. Images derived only from rest flurpiridaz administration were blended using image analysis with images derived only from administration of flurpiridaz following exercise or adenosine stress. The blending fraction that resulted in negligible change in reader interpretation of defect severity was determined for each subject. The minimum value that met this criterion for all subjects was used to calculate the ratio of the stress dose to the rest dose as a function of the delay between administration of the two doses for both adenosine stress and exercise stress separately. No statistical analysis was performed.
Time Frame	Dosing visit

Outcome Measure Data

Analysis Population Description

Subjects with demonstrated partially or completely reversible defects on prior SPECT who received at least one stress and one rest dose of flurpiridaz F 18, on separate days.

Arm/Group Title	Cohort 1 Dose Ranging and Dose Interval
Arm/Group Description	Subjects received 2 or 3 IV bolus injections of BMS747158: 1 at rest and 1 at pharmacologic/exercise stress, over a 1-day or 2-day period
Measure Participants	26
Number [Fraction of rest added to stress image]	0.228

4. Primary Outcome

Title	Cohort 2: Diagnostic Efficacy of One-day Rest/Stress BMS747158 PET MPI Specificity (SP) vs SPECT MPI Specificity
Description	Diagnostic efficacy of one-day rest/stress BMS747158 PET MPI is measured by specificity as compared to single photon emission computed tomography (SPECT)MPI in the detection of coronary artery disease (CAD)using angiography or three-month cardiac events as the truth standard.
Time Frame	Dosing Visit

Outcome Measure Data

Analysis Population Description

intent to treat, received at least one dose of BMS747158

Arm/Group Title	Cohort 2: Efficacy/Safety
Arm/Group Description	Patient received BMS747158 as a single IV bolus injection at rest and a single bolus injection at stress over a 1-day period. For patients undergoing pharmacologic stress test the dose of BMS747158 were to be a factor of 2.0 to 2.4 greater than the rest dose. For patients undergoing exercise stress test the dose of BMS747158 were to be a factor of 3.0 to 3.6 greater than the rest dose.
Measure Participants	125
PET MPI	0.877
SPECT MPI	0.836

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1: Dose Acquistion Time Product
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.317
	Comments	p-value for comparison of PET specificity for same reader
	Method	McNemar
	Comments
Method of Estimation	Estimation Parameter	PET specificity
	Estimated Value	0.877
	Confidence Interval	(2-Sided) 95%; 0.801 to 0.952
	Parameter Dispersion	Type: Value:
	Estimation Comments	no standard deviation for PET specficity

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 1: Dose Acquistion Time Product
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.317
	Comments	p-value for comparison of SPECT specificity for same reader
	Method	McNemar
	Comments
Method of Estimation	Estimation Parameter	SPECT specificity
	Estimated Value	0.836
	Confidence Interval	(2-Sided) 95%; 0.751 to 0.921
	Parameter Dispersion	Type: Value:
	Estimation Comments	no standard deviation for SPECT specificity

Adverse Events

Time Frame	Cohort 1: Adverse event monitoring was initiated on Study Day 1 at time of rest dose and conitnued through 2-week follow up Cohort 2: Adverse event monitoring was intiatied on Study Day 1 at time of rest dose and continued through 1-week follow up
Adverse Event Reporting Description	Safety data were not combined and are reported by Cohort
Arm/Group Title	Cohort 1: Dose Range and Dose Interval		Cohort 2: Efficacy in Pharm Stress
Arm/Group Description	Patients to receive either 2 or 3 IV bolus injections of BMS747158: 1 at rest and 1 or 2 during pharmacological or exercise stress, over a 1-day or 2-day period. BMS747158: dosages at rest and at stress were not to exceed a total of 14 mCi. Cohort 1: Patients received either 2 or 3 IV bolus injections of BMS747158: 1 at rest and 1 or 2 during stress, over a 1-day or 2-day period.		Patients receive 2 IV injections of BMS747158:at rest and stress For the Pharmacologic (Adenosine) Stress: Doses range at rest between 2.9 and 3.4 mCi. Dose range at stress between 5.8 and 8.2 mCi (factor of 2.0 to 2.4 greater than the rest dose). For the Exercise Stress: Doses at rest were to range between 1.7 and 2.0 mCi. Doses under stress were to be a factor of 3.0 to 3.6 greater than the rest dose, resulting in a range between 5.1 and 7.2 mCi.
All Cause Mortality
	Cohort 1: Dose Range and Dose Interval		Cohort 2: Efficacy in Pharm Stress
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Cohort 1: Dose Range and Dose Interval		Cohort 2: Efficacy in Pharm Stress
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/33 (0%)		2/143 (1.4%)
Musculoskeletal and connective tissue disorders
Joint Effusion	0/33 (0%)	0	1/143 (0.7%)	1
Nervous system disorders
Dizziness	0/33 (0%)	0	1/143 (0.7%)	1
Vascular disorders
Hypertension	0/33 (0%)	0	1/143 (0.7%)	1
Other (Not Including Serious) Adverse Events
	Cohort 1: Dose Range and Dose Interval		Cohort 2: Efficacy in Pharm Stress
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/33 (63.6%)		61/143 (42.7%)
Cardiac disorders
Angina Pectoris	2/33 (6.1%)	2	6/143 (4.2%)	6
Palpitations	1/33 (3%)	1	0/143 (0%)	0
Gastrointestinal disorders
Flatulence	1/33 (3%)	1	0/143 (0%)	0
Nausea	1/33 (3%)	1	6/143 (4.2%)	6
General disorders
Chest Discomfort	2/33 (6.1%)	2	9/143 (6.3%)	9
Fatigue	3/33 (9.1%)	3	0/143 (0%)	0
Feeling Hot	4/33 (12.1%)	4	0/143 (0%)	0
INfluenza Like Illness	1/33 (3%)	1	0/143 (0%)	0
Non Cardiac Chest Pain	1/33 (3%)	1	4/143 (2.8%)	4
Musculoskeletal and connective tissue disorders
Back Pain	1/33 (3%)	1	0/143 (0%)	0
Musculosketetal Pain	1/33 (3%)	1	4/143 (2.8%)	4
Myalgia	1/33 (3%)	1	0/143 (0%)	0
Pain In Extremity	3/33 (9.1%)	3	0/143 (0%)	0
Nervous system disorders
Dizziness	4/33 (12.1%)	4	4/143 (2.8%)	4
Dysgeusia	1/33 (3%)	1	0/143 (0%)	0
Headache	4/33 (12.1%)	4	10/143 (7%)	10
Hypoaesthesia	1/33 (3%)	1	0/143 (0%)	0
Sciatica	1/33 (3%)	1	0/143 (0%)	0
Psychiatric disorders
Anxiety	1/33 (3%)	1	0/143 (0%)	0
Nervousness	1/33 (3%)	1	0/143 (0%)	0
Claustrophobia	0/33 (0%)	0	3/143 (2.1%)	3
Respiratory, thoracic and mediastinal disorders
Cough	1/33 (3%)	1	3/143 (2.1%)	3
Dyspnoea	1/33 (3%)	1	7/143 (4.9%)	7
Skin and subcutaneous tissue disorders
Hyperhidrosis	1/33 (3%)	1	0/143 (0%)	0
Skin Irritation	1/33 (3%)	1	0/143 (0%)	0
Vascular disorders
Flushing	7/33 (21.2%)	7	7/143 (4.9%)	7

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.