Trial Outcomes & Findings for Development of 1-Day Rest/Stress Cardiac PET Perfusion Imaging Protocol of BMS747158 (NCT NCT00849108)

Last Updated: 2015-10-14

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

176 participants

Primary outcome timeframe

Dosing visit

Results posted on

2015-10-14

Participant Flow

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

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.

Participant milestones

Participant milestones
Measure	Cohort 1 Dose Ranging and Dose Interval 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	Cohort 2 Preliminary Efficacy Pharmacologic Stress Patients received 2 injections of BMS747158: 1 at rest and 1 at Pharmacologic stress, over a 1-day period.
Cohort 1 Dose Ranging and Dose Interval STARTED	33	0
Cohort 1 Dose Ranging and Dose Interval COMPLETED	32	0
Cohort 1 Dose Ranging and Dose Interval NOT COMPLETED	1	0
Cohort 2 Efficacy STARTED	0	143
Cohort 2 Efficacy COMPLETED	0	133
Cohort 2 Efficacy NOT COMPLETED	0	10

Reasons for withdrawal

Reasons for withdrawal
Measure	Cohort 1 Dose Ranging and Dose Interval 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	Cohort 2 Preliminary Efficacy Pharmacologic Stress Patients received 2 injections of BMS747158: 1 at rest and 1 at Pharmacologic stress, over a 1-day period.
Cohort 1 Dose Ranging and Dose Interval Withdrawal by Subject	1	0
Cohort 2 Efficacy Adverse Event	0	1
Cohort 2 Efficacy Other	0	9

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1 Dose Ranging and Dose Interval n=33 Participants 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	Cohort 2: Pharm Stress n=67 Participants 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.	Cohort 2: Efficacy Exercise Stress n=76 Participants 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 n=176 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
Age, Categorical Between 18 and 65 years	9 Participants n=5 Participants	24 Participants n=7 Participants	52 Participants n=5 Participants	85 Participants n=4 Participants
Age, Categorical >=65 years	24 Participants n=5 Participants	43 Participants n=7 Participants	24 Participants n=5 Participants	91 Participants n=4 Participants
Sex: Female, Male Female	9 Participants n=5 Participants	16 Participants n=7 Participants	20 Participants n=5 Participants	45 Participants n=4 Participants
Sex: Female, Male Male	24 Participants n=5 Participants	51 Participants n=7 Participants	56 Participants n=5 Participants	131 Participants n=4 Participants
Region of Enrollment North America	33 participants n=5 Participants	67 participants n=7 Participants	76 participants n=5 Participants	176 participants n=4 Participants

PRIMARY outcome

Timeframe: Dosing visit

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

Outcome measures

Outcome measures
Measure	Cohort 1: Dose Acquistion Time Product n=33 Participants 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
Cohort 1: Determination of Rest Dose: Dose Acquistion Time Product	100 MBq X Minutes Standard Deviation 54.7

PRIMARY outcome

Timeframe: Dosing visit

Population: intent to treat, received at least one dose of BMS747158

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.

Outcome measures

Outcome measures
Measure	Cohort 1: Dose Acquistion Time Product n=125 Participants 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
Cohort 2: Diagnostic Efficacy of One-day Rest/Stress BMS747158 PET MPI Sensitivity (SN) vs SPECT MPI Sensitivity PET MPI	0.769 Proportion of True Positive Cases
Cohort 2: Diagnostic Efficacy of One-day Rest/Stress BMS747158 PET MPI Sensitivity (SN) vs SPECT MPI Sensitivity SPECT MPI	0.596 Proportion of True Positive Cases

PRIMARY outcome

Timeframe: Dosing visit

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Cohort 1: Dose Acquistion Time Product n=26 Participants 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
Cohort 1: Determination of Ratio of Stress Dose to Rest Dose	0.228 Fraction of rest added to stress image

PRIMARY outcome

Timeframe: Dosing Visit

Population: intent to treat, received at least one dose of BMS747158

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.

Outcome measures

Outcome measures
Measure	Cohort 1: Dose Acquistion Time Product n=125 Participants 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
Cohort 2: Diagnostic Efficacy of One-day Rest/Stress BMS747158 PET MPI Specificity (SP) vs SPECT MPI Specificity PET MPI	0.877 Proportion of True Negative Cases
Cohort 2: Diagnostic Efficacy of One-day Rest/Stress BMS747158 PET MPI Specificity (SP) vs SPECT MPI Specificity SPECT MPI	0.836 Proportion of True Negative Cases

Adverse Events

Cohort 1: Dose Range and Dose Interval

Serious events: 0 serious events

Other events: 21 other events

Deaths: 0 deaths

Cohort 2: Efficacy in Pharm Stress

Serious events: 2 serious events

Other events: 61 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Cohort 1: Dose Range and Dose Interval n=33 participants at risk 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.	Cohort 2: Efficacy in Pharm Stress n=143 participants at risk 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.
Musculoskeletal and connective tissue disorders Joint Effusion	0.00% 0/33 • 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 Safety data were not combined and are reported by Cohort	0.70% 1/143 • Number of events 1 • 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 Safety data were not combined and are reported by Cohort
Nervous system disorders Dizziness	0.00% 0/33 • 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 Safety data were not combined and are reported by Cohort	0.70% 1/143 • Number of events 1 • 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 Safety data were not combined and are reported by Cohort
Vascular disorders Hypertension	0.00% 0/33 • 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 Safety data were not combined and are reported by Cohort	0.70% 1/143 • Number of events 1 • 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 Safety data were not combined and are reported by Cohort

Other adverse events

Additional Information

Cesare Orlandi, MD, Chief Medical Officer

Lantheus Medical Imaging

Phone: 978-671-8686

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60

Measure	Cohort 1: Dose Range and Dose Interval n=33 participants at risk 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.	Cohort 2: Efficacy in Pharm Stress n=143 participants at risk 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.
Cardiac disorders Angina Pectoris	6.1% 2/33 • Number of events 2 • 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 Safety data were not combined and are reported by Cohort	4.2% 6/143 • Number of events 6 • 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 Safety data were not combined and are reported by Cohort
Cardiac disorders Palpitations	3.0% 1/33 • Number of events 1 • 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 Safety data were not combined and are reported by Cohort	0.00% 0/143 • 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 Safety data were not combined and are reported by Cohort
Gastrointestinal disorders Flatulence	3.0% 1/33 • Number of events 1 • 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 Safety data were not combined and are reported by Cohort	0.00% 0/143 • 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 Safety data were not combined and are reported by Cohort
Gastrointestinal disorders Nausea	3.0% 1/33 • Number of events 1 • 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 Safety data were not combined and are reported by Cohort	4.2% 6/143 • Number of events 6 • 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 Safety data were not combined and are reported by Cohort
General disorders Chest Discomfort	6.1% 2/33 • Number of events 2 • 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 Safety data were not combined and are reported by Cohort	6.3% 9/143 • Number of events 9 • 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 Safety data were not combined and are reported by Cohort
General disorders Fatigue	9.1% 3/33 • Number of events 3 • 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 Safety data were not combined and are reported by Cohort	0.00% 0/143 • 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 Safety data were not combined and are reported by Cohort
General disorders Feeling Hot	12.1% 4/33 • Number of events 4 • 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 Safety data were not combined and are reported by Cohort	0.00% 0/143 • 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 Safety data were not combined and are reported by Cohort
General disorders INfluenza Like Illness	3.0% 1/33 • Number of events 1 • 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 Safety data were not combined and are reported by Cohort	0.00% 0/143 • 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 Safety data were not combined and are reported by Cohort
General disorders Non Cardiac Chest Pain	3.0% 1/33 • Number of events 1 • 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 Safety data were not combined and are reported by Cohort	2.8% 4/143 • Number of events 4 • 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 Safety data were not combined and are reported by Cohort
Musculoskeletal and connective tissue disorders Back Pain	3.0% 1/33 • Number of events 1 • 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 Safety data were not combined and are reported by Cohort	0.00% 0/143 • 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 Safety data were not combined and are reported by Cohort
Musculoskeletal and connective tissue disorders Musculosketetal Pain	3.0% 1/33 • Number of events 1 • 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 Safety data were not combined and are reported by Cohort	2.8% 4/143 • Number of events 4 • 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 Safety data were not combined and are reported by Cohort
Musculoskeletal and connective tissue disorders Myalgia	3.0% 1/33 • Number of events 1 • 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 Safety data were not combined and are reported by Cohort	0.00% 0/143 • 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 Safety data were not combined and are reported by Cohort
Musculoskeletal and connective tissue disorders Pain In Extremity	9.1% 3/33 • Number of events 3 • 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 Safety data were not combined and are reported by Cohort	0.00% 0/143 • 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 Safety data were not combined and are reported by Cohort
Nervous system disorders Dizziness	12.1% 4/33 • Number of events 4 • 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 Safety data were not combined and are reported by Cohort	2.8% 4/143 • Number of events 4 • 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 Safety data were not combined and are reported by Cohort
Nervous system disorders Dysgeusia	3.0% 1/33 • Number of events 1 • 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 Safety data were not combined and are reported by Cohort	0.00% 0/143 • 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 Safety data were not combined and are reported by Cohort
Nervous system disorders Headache	12.1% 4/33 • Number of events 4 • 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 Safety data were not combined and are reported by Cohort	7.0% 10/143 • Number of events 10 • 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 Safety data were not combined and are reported by Cohort
Nervous system disorders Hypoaesthesia	3.0% 1/33 • Number of events 1 • 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 Safety data were not combined and are reported by Cohort	0.00% 0/143 • 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 Safety data were not combined and are reported by Cohort
Nervous system disorders Sciatica	3.0% 1/33 • Number of events 1 • 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 Safety data were not combined and are reported by Cohort	0.00% 0/143 • 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 Safety data were not combined and are reported by Cohort
Psychiatric disorders Anxiety	3.0% 1/33 • Number of events 1 • 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 Safety data were not combined and are reported by Cohort	0.00% 0/143 • 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 Safety data were not combined and are reported by Cohort
Psychiatric disorders Nervousness	3.0% 1/33 • Number of events 1 • 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 Safety data were not combined and are reported by Cohort	0.00% 0/143 • 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 Safety data were not combined and are reported by Cohort
Respiratory, thoracic and mediastinal disorders Cough	3.0% 1/33 • Number of events 1 • 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 Safety data were not combined and are reported by Cohort	2.1% 3/143 • Number of events 3 • 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 Safety data were not combined and are reported by Cohort
Respiratory, thoracic and mediastinal disorders Dyspnoea	3.0% 1/33 • Number of events 1 • 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 Safety data were not combined and are reported by Cohort	4.9% 7/143 • Number of events 7 • 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 Safety data were not combined and are reported by Cohort
Skin and subcutaneous tissue disorders Hyperhidrosis	3.0% 1/33 • Number of events 1 • 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 Safety data were not combined and are reported by Cohort	0.00% 0/143 • 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 Safety data were not combined and are reported by Cohort
Skin and subcutaneous tissue disorders Skin Irritation	3.0% 1/33 • Number of events 1 • 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 Safety data were not combined and are reported by Cohort	0.00% 0/143 • 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 Safety data were not combined and are reported by Cohort
Vascular disorders Flushing	21.2% 7/33 • Number of events 7 • 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 Safety data were not combined and are reported by Cohort	4.9% 7/143 • Number of events 7 • 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 Safety data were not combined and are reported by Cohort
Psychiatric disorders Claustrophobia	0.00% 0/33 • 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 Safety data were not combined and are reported by Cohort	2.1% 3/143 • Number of events 3 • 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 Safety data were not combined and are reported by Cohort