Trial Outcomes & Findings for Safety Study to Assess Opiate Withdrawal Signs and Symptoms in Opioid Dependent Patients (NCT NCT01100437)

Last Updated: 2012-07-13

Results Overview

COWS is an 11 section clinical assessment of withdrawal symptoms, each section is rated from 0 (no symptom) to 4 or 5 (most severe symptom). Total score is classified into a 4 point rating scale (mild 5-12, moderate 13-24, moderately severe 25-36 and severe more than 36 points).

Recruitment status

TERMINATED

Study phase

PHASE4

Target enrollment

14 participants

Primary outcome timeframe

Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 24 hours (hr) post-dose and unscheduled assessment (UA)

Results posted on

2012-07-13

Participant Flow

Participant milestones

Participant milestones
Measure	EMBEDA Capsule Then EMBEDA Solution EMBEDA (morphine sulfate plus naltrexone hydrochloride) Extended Release (ER) capsule(s) were administered orally once or twice a day (20 milligrams \[mg\] to 120 mg). During the open label titration and stabilization phase EMBEDA was administered and titrated to a dose that adequately managed the participants pain up to 35 days. In the open label Maintenance Phase the participant was administered the established stable dose for a minimum of 7 days up to 28 days. The participant was then randomized to one of two double-blind treatment sequences for the Treatment Phase. During the Treatment Phase the participant was administered whole EMBEDA capsules orally at participant's stable dose along with a matched placebo solution in the first intervention period. In the second intervention period the participant received crushed EMBEDA capsules that were mixed in solution and administered orally at participant's stable dose along with matched placebo capsules.	EMBEDA Solution Then EMBEDA Capsule EMBEDA (morphine sulfate plus naltrexone hydrochloride) ER capsule(s) were administered orally once or twice a day (20 mg to 120 mg). During the open label titration and stabilization phase EMBEDA was administered and titrated to a dose that adequately managed the participants pain up to 35 days. In the open label Maintenance Phase the participants were administered the established stable dose for a minimum of 7 days up to 28 days. The participant was then randomized to one of two double-blind treatment sequences for the Treatment Phase. During the Treatment Phase the participant was administered crushed EMBEDA capsules orally at participants stable dose mixed in solution along with matched placebo capsules in the first intervention period. In the second intervention period the participant received whole EMBEDA capsules administered orally at participant's stable dose along with matched placebo solution.	EMBEDA Capsule EMBEDA (morphine sulfate plus naltrexone hydrochloride) ER capsule(s) were administered orally once or twice a day (20 mg to 120 mg). During the titration and stabilization phase EMBEDA was administrated and titrated to a dose that adequately managed the participants pain for up to 35 days. In the Maintenance Phase the participant's were administered the established stable dose for a minimum of 7 days up to 28 days. Participants were not randomized to treatment phase.
Screening STARTED	4	2	8
Screening COMPLETED	4	2	8
Screening NOT COMPLETED	0	0	0
Titration/Stabilization STARTED	4	2	8
Titration/Stabilization COMPLETED	4	2	2
Titration/Stabilization NOT COMPLETED	0	0	6
Maintenance STARTED	4	2	2
Maintenance COMPLETED	4	2	0
Maintenance NOT COMPLETED	0	0	2
Treatment 1 STARTED	4	2	0
Treatment 1 COMPLETED	4	2	0
Treatment 1 NOT COMPLETED	0	0	0
Washout (4 Days) STARTED	4	2	0
Washout (4 Days) COMPLETED	4	2	0
Washout (4 Days) NOT COMPLETED	0	0	0
Treatment 2 STARTED	4	2	0
Treatment 2 COMPLETED	4	2	0
Treatment 2 NOT COMPLETED	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	EMBEDA Capsule Then EMBEDA Solution EMBEDA (morphine sulfate plus naltrexone hydrochloride) Extended Release (ER) capsule(s) were administered orally once or twice a day (20 milligrams \[mg\] to 120 mg). During the open label titration and stabilization phase EMBEDA was administered and titrated to a dose that adequately managed the participants pain up to 35 days. In the open label Maintenance Phase the participant was administered the established stable dose for a minimum of 7 days up to 28 days. The participant was then randomized to one of two double-blind treatment sequences for the Treatment Phase. During the Treatment Phase the participant was administered whole EMBEDA capsules orally at participant's stable dose along with a matched placebo solution in the first intervention period. In the second intervention period the participant received crushed EMBEDA capsules that were mixed in solution and administered orally at participant's stable dose along with matched placebo capsules.	EMBEDA Solution Then EMBEDA Capsule EMBEDA (morphine sulfate plus naltrexone hydrochloride) ER capsule(s) were administered orally once or twice a day (20 mg to 120 mg). During the open label titration and stabilization phase EMBEDA was administered and titrated to a dose that adequately managed the participants pain up to 35 days. In the open label Maintenance Phase the participants were administered the established stable dose for a minimum of 7 days up to 28 days. The participant was then randomized to one of two double-blind treatment sequences for the Treatment Phase. During the Treatment Phase the participant was administered crushed EMBEDA capsules orally at participants stable dose mixed in solution along with matched placebo capsules in the first intervention period. In the second intervention period the participant received whole EMBEDA capsules administered orally at participant's stable dose along with matched placebo solution.	EMBEDA Capsule EMBEDA (morphine sulfate plus naltrexone hydrochloride) ER capsule(s) were administered orally once or twice a day (20 mg to 120 mg). During the titration and stabilization phase EMBEDA was administrated and titrated to a dose that adequately managed the participants pain for up to 35 days. In the Maintenance Phase the participant's were administered the established stable dose for a minimum of 7 days up to 28 days. Participants were not randomized to treatment phase.
Titration/Stabilization Adverse Event	0	0	4
Titration/Stabilization Non-compliance	0	0	1
Titration/Stabilization Sponsor canceled study	0	0	1
Maintenance Withdrawal by Subject	0	0	1
Maintenance Sponsor termination of study	0	0	1

Baseline Characteristics

Safety Study to Assess Opiate Withdrawal Signs and Symptoms in Opioid Dependent Patients

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Entire Study Population n=14 Participants EMBEDA (morphine sulfate plus naltrexone hydrochloride) ER capsule(s) were administered orally once or twice a day (20 mg to 120 mg). During the titration and stabilization phase EMBEDA was administered and titrated to a dose that adequately managed the participant's pain up to 35 days. The participants then started the Maintenance Phase and were administered the established stable dose of EMBEDA for a minimum of 7 days up to 28 days. Eligible participants were randomized into the 2 treatment groups.
Age Continuous	45.2 years n=93 Participants
Sex: Female, Male Female	8 Participants n=93 Participants
Sex: Female, Male Male	6 Participants n=93 Participants

PRIMARY outcome

Timeframe: Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 24 hours (hr) post-dose and unscheduled assessment (UA)

Population: Intent-to-treat population (ITT): all randomized participants who received at least one dose of double-blind treatment in the Treatment Phase and had at least one post-dose pharmacodynamic assessment completed in the Treatment Phase.

Outcome measures

Outcome measures
Measure	EMBEDA Whole Capsules n=6 Participants EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA Crushed in Solution n=6 Participants EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Number of Participants With Clinical Opiate Withdrawal Scale (COWS) Score Greater Than or Equal to (≥) 13 in the Treatment Phase	1 participants	3 participants

SECONDARY outcome

Timeframe: Baseline up to Day 63

Population: ITT; N=number of participants with evaluable data; n=number of participants evaluated at the specific time point

Average pain scores in the previous 24 hours using an 11 point NPRS ranging from no pain (0) to worst pain (10).

Outcome measures

Outcome measures
Measure	EMBEDA Whole Capsules n=6 Participants EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA Crushed in Solution EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Average Numeric Pain Rating Scale (NPRS) in Titration/Stabilization and Maintenance Phases Titration/Stabilization-Baseline (n=6)	5.5 units on a scale Standard Deviation 1.05	—
Average Numeric Pain Rating Scale (NPRS) in Titration/Stabilization and Maintenance Phases Titration/Stabilization-Visit 2b (n=6)	5.2 units on a scale Standard Deviation 2.23	—
Average Numeric Pain Rating Scale (NPRS) in Titration/Stabilization and Maintenance Phases Titration/Stabilization-Visit 2c (n=2)	5.5 units on a scale Standard Deviation 3.54	—
Average Numeric Pain Rating Scale (NPRS) in Titration/Stabilization and Maintenance Phases Titration/Stabilization-Visit 2d (n=1)	3.0 units on a scale Standard Deviation NA Not applicable (NA). One participant with analyzable data, no standard deviation calculated.	—
Average Numeric Pain Rating Scale (NPRS) in Titration/Stabilization and Maintenance Phases Maintenance (n=6)	4.2 units on a scale Standard Deviation 1.94	—

SECONDARY outcome

Timeframe: Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose

Population: Pharmacokinetic (PK) population: all randomized participants who received at least one dose of EMBEDA (whole or crushed) in the Treatment Phase and had at least one PK assessment completed in the Treatment Phase; n=number of participants with evaluable data for the specific category

Average Tmax for Morphine, Naltrexone and 6-β-Naltrexol

Outcome measures

Outcome measures
Measure	EMBEDA Whole Capsules n=6 Participants EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA Crushed in Solution n=6 Participants EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Time to Reach Maximum Observed Plasma Concentration (Tmax) During the Treatment Phase Morphine (n=6,6)	5.67 hours (h) Standard Deviation 2.658	1.29 hours (h) Standard Deviation 0.813
Time to Reach Maximum Observed Plasma Concentration (Tmax) During the Treatment Phase Naltrexone (n=0,6)	NA hours (h) Standard Deviation NA No participants with evaluable data	1.46 hours (h) Standard Deviation 0.697
Time to Reach Maximum Observed Plasma Concentration (Tmax) During the Treatment Phase 6-β-Naltrexol (n=4,6)	6.13 hours (h) Standard Deviation 11.919	1.63 hours (h) Standard Deviation 0.787

SECONDARY outcome

Timeframe: Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose

Population: PK population; n=number of participants with evaluable data for specific category

Average Cmax for Morphine, Naltrexone and 6-β-Naltrexol

Outcome measures

Outcome measures
Measure	EMBEDA Whole Capsules n=6 Participants EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA Crushed in Solution n=6 Participants EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Maximum Observed Plasma Concentration (Cmax) During the Treatment Phase Morphine (n=6,6)	27.5 nanogram per milliliter (ng/mL) Standard Deviation 14.14	70.4 nanogram per milliliter (ng/mL) Standard Deviation 47.88
Maximum Observed Plasma Concentration (Cmax) During the Treatment Phase Naltrexone (n=0,6)	NA nanogram per milliliter (ng/mL) Standard Deviation NA No participants with evaluable data	321.1 nanogram per milliliter (ng/mL) Standard Deviation 225.05
Maximum Observed Plasma Concentration (Cmax) During the Treatment Phase 6-β-Naltrexol (n=4,6)	24.4 nanogram per milliliter (ng/mL) Standard Deviation 15.40	3398.3 nanogram per milliliter (ng/mL) Standard Deviation 1327.97

SECONDARY outcome

Timeframe: Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose

Population: PK population; n=number of participants with evaluable data for specific category

Average Cmin for Morphine, Naltrexone and 6-β-Naltrexol

Outcome measures

Outcome measures
Measure	EMBEDA Whole Capsules n=6 Participants EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA Crushed in Solution n=6 Participants EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Minimum Observed Plasma Concentration (Cmin) During the Treatment Phase Morphine (n=6,6)	13.8 ng/mL Standard Deviation 6.89	11.2 ng/mL Standard Deviation 8.86
Minimum Observed Plasma Concentration (Cmin) During the Treatment Phase Naltrexone (n=0,6)	NA ng/mL Standard Deviation NA No participants with evaluable data	6.9 ng/mL Standard Deviation 1.17
Minimum Observed Plasma Concentration (Cmin) During the Treatment Phase 6-β-Naltrexol (n=4,6)	15.9 ng/mL Standard Deviation 9.29	42.7 ng/mL Standard Deviation 66.93

SECONDARY outcome

Timeframe: Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose

Population: PK population; N=number of participants with evaluable data; n=number of participants with evaluable data for the specific category

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

Outcome measures

Outcome measures
Measure	EMBEDA Whole Capsules n=3 Participants EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA Crushed in Solution n=6 Participants EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Apparent Oral Clearance (CL/F) During the Treatment Phase Morphine (n=2,6)	37.6 liters/hour (L/h) Standard Deviation 11.53	77.2 liters/hour (L/h) Standard Deviation 25.36
Apparent Oral Clearance (CL/F) During the Treatment Phase Naltrexone (n=0,6)	NA liters/hour (L/h) Standard Deviation NA No participants with evaluable data	75151.0 liters/hour (L/h) Standard Deviation 51706.48
Apparent Oral Clearance (CL/F) During the Treatment Phase 6-β-Naltrexol (n=3,6)	45143.6 liters/hour (L/h) Standard Deviation 14157.49	1758.0 liters/hour (L/h) Standard Deviation 381.67

SECONDARY outcome

Timeframe: Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose

Population: PK population; N=number of participants with evaluable data; n=number of participants with evaluable date for the specific category

Average Vd/F for Morphine, Naltrexone and 6-β-Naltrexol

Outcome measures

Outcome measures
Measure	EMBEDA Whole Capsules n=3 Participants EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA Crushed in Solution n=6 Participants EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Volume of Distribution (Vd/F)During the Treatment Phase Morphine (n=2,6)	3173.1 liter (L) Standard Deviation 1724.61	1668.2 liter (L) Standard Deviation 830.08
Volume of Distribution (Vd/F)During the Treatment Phase Naltrexone (n=0,6)	NA liter (L) Standard Deviation NA No participants with evaluable data.	304171.8 liter (L) Standard Deviation 206998.86
Volume of Distribution (Vd/F)During the Treatment Phase 6-β-Naltrexol (n=3,6)	3447244.4 liter (L) Standard Deviation 1868128.43	26304.5 liter (L) Standard Deviation 10730.59

SECONDARY outcome

Timeframe: Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose

Population: PK population; N=number of participants with evaluable data; n=number of participants with evaluable data for the specific category

Average plasma decay half-life of morphine, naltrexone and 6-β-Naltrexol. Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.

Outcome measures

Outcome measures
Measure	EMBEDA Whole Capsules n=3 Participants EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA Crushed in Solution n=6 Participants EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Plasma Decay Half-Life (t1/2) During the Treatment Phase Morphine (n=2,6)	56.2 h Standard Deviation 14.55	17.0 h Standard Deviation 10.99
Plasma Decay Half-Life (t1/2) During the Treatment Phase Naltrexone (n=0,6)	NA h Standard Deviation NA No participants with evaluable data	3.0 h Standard Deviation 1.10
Plasma Decay Half-Life (t1/2) During the Treatment Phase 6-β-Naltrexol (n=3,6)	50.9 h Standard Deviation 11.77	10.1 h Standard Deviation 2.43

SECONDARY outcome

Timeframe: Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose

Population: PK population; n=number of participants with evaluable data for the specific category

Average AUC0-τ for Morphine, Naltrexone and 6-β-Naltrexol reported. τ=24 hours

Outcome measures

Outcome measures
Measure	EMBEDA Whole Capsules n=6 Participants EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA Crushed in Solution n=6 Participants EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Area Under the Curve From Time Zero to End of Dosing Interval (AUC0-τ) During the Treatment Phase Morphine (n=6,6)	513.4 ng times h divided by mL (ng*h/mL) Standard Deviation 310.87	542.6 ng times h divided by mL (ng*h/mL) Standard Deviation 366.62
Area Under the Curve From Time Zero to End of Dosing Interval (AUC0-τ) During the Treatment Phase Naltrexone (n=0,6)	NA ng times h divided by mL (ng*h/mL) Standard Deviation NA No participants with evaluable data	1314.7 ng times h divided by mL (ng*h/mL) Standard Deviation 1119.25
Area Under the Curve From Time Zero to End of Dosing Interval (AUC0-τ) During the Treatment Phase 6-β-Naltrexol (n=4,6)	463.5 ng times h divided by mL (ng*h/mL) Standard Deviation 290.94	28891.2 ng times h divided by mL (ng*h/mL) Standard Deviation 14871.70

SECONDARY outcome

Timeframe: Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose

Population: PK population; n=number of participants with evaluable data for the specific category

Average AUC0-last for Morphine, Naltrexone and 6-β-Naltrexol. Area under the plasma concentration time-curve from time zero to the last measured concentration.

Outcome measures

Outcome measures
Measure	EMBEDA Whole Capsules n=6 Participants EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA Crushed in Solution n=6 Participants EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Area Under the Curve From Time Zero to the Time of Last Measurable Concentration (AUC0-last) During the Treatment Phase Morphine (n=6,6)	513.4 ng*h/mL Standard Deviation 310.87	542.6 ng*h/mL Standard Deviation 366.62
Area Under the Curve From Time Zero to the Time of Last Measurable Concentration (AUC0-last) During the Treatment Phase Naltrexone (n=0,6)	NA ng*h/mL Standard Deviation NA No participants with evaluable data	1300.0 ng*h/mL Standard Deviation 1131.24
Area Under the Curve From Time Zero to the Time of Last Measurable Concentration (AUC0-last) During the Treatment Phase 6-β-Naltrexol (n=4,6)	450.3 ng*h/mL Standard Deviation 312.56	28891.2 ng*h/mL Standard Deviation 14871.69

SECONDARY outcome

Timeframe: Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose

Population: PK population; N=number of participants with evaluable data; n=number of participants with evaluable data for the specific category

AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞). Average AUC 0-∞ for Morphine, Naltrexone and 6-β-Naltrexol reported.

Outcome measures

Outcome measures
Measure	EMBEDA Whole Capsules n=3 Participants EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA Crushed in Solution n=6 Participants EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] During the Treatment Phase Morphine (n=2,6)	2023.5 ng*h/mL Standard Deviation 1935.01	887.7 ng*h/mL Standard Deviation 583.83
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] During the Treatment Phase Naltrexone (n=0,6)	NA ng*h/mL Standard Deviation NA No participants with evaluable data	1330.7 ng*h/mL Standard Deviation 1141.75
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] During the Treatment Phase 6-β-Naltrexol (n=3,6)	1469.5 ng*h/mL Standard Deviation 955.52	35297.8 ng*h/mL Standard Deviation 18407.20

OTHER_PRE_SPECIFIED outcome

Timeframe: Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 24 hr post-dose and UA

Population: ITT; Subset of participants with COWS \>= 13

Average time to first occurrence of a COWS score ≥ 13

Outcome measures

Outcome measures
Measure	EMBEDA Whole Capsules n=1 Participants EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA Crushed in Solution n=3 Participants EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Time to First Occurrence of a COWS Score ≥ 13 for Each Treatment During the Treatment Phase	2.5 h Standard Error NA One participant with analyzable data, no standard error calculated.	0.7 h Standard Error 0.02

OTHER_PRE_SPECIFIED outcome

Timeframe: Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose

Population: ITT; Subset of participants with COWS ≥ 13

Outcome measures

Outcome measures
Measure	EMBEDA Whole Capsules n=1 Participants EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA Crushed in Solution n=3 Participants EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Morphine Plasma Concentration at First COWS ≥ 13 in the Treatment Phase	16.00 ng/mL Standard Deviation NA One participant with analyzable data, no standard deviation calculated.	86.30 ng/mL Standard Deviation 53.316

OTHER_PRE_SPECIFIED outcome

Timeframe: Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose

Population: ITT; Subset of participants with COWS ≥ 13

Outcome measures

Outcome measures
Measure	EMBEDA Whole Capsules n=1 Participants EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA Crushed in Solution n=3 Participants EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Naltrexone Plasma Concentration at First COWS ≥ 13 in the Treatment Phase	NA picogram/milliliter (pg/mL) Standard Deviation NA No participants with evaluable data.	350.50 picogram/milliliter (pg/mL) Standard Deviation 195.869

OTHER_PRE_SPECIFIED outcome

Timeframe: Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose

Population: ITT; Subset of all participants with COWS ≥ 13

Outcome measures

Outcome measures
Measure	EMBEDA Whole Capsules n=1 Participants EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA Crushed in Solution n=3 Participants EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
6-β-Naltrexone Plasma Concentration at First COWS ≥ 13 in Treatment Phase	NA pg/mL Standard Deviation NA No participants with evaluable data	3375.00 pg/mL Standard Deviation 827.315

OTHER_PRE_SPECIFIED outcome

Timeframe: Between 0.5 and 24 hours post-dose

Population: ITT

Outcome measures

Outcome measures
Measure	EMBEDA Whole Capsules n=6 Participants EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA Crushed in Solution n=6 Participants EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Maximum Post-dose COWS in the Treatment Phase	3.7 units on a scale Standard Deviation 4.63	10.7 units on a scale Standard Deviation 6.83

Adverse Events

EMBEDA Whole Capsule Treatment Period

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

EMBEDA Crushed in Solution Treatment Period

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

EMBEDA Capsule Titration/Stabilization Period

Serious events: 0 serious events

Other events: 12 other events

Deaths: 0 deaths

EMBEDA Capsules Maintenance Period

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Pfizer ClinicalTrials.gov Call Center

Pfizer, Inc.

Phone: 1-800-718-1021

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
Publication restrictions are in place

Restriction type: OTHER

Other adverse events
Measure	EMBEDA Whole Capsule Treatment Period n=6 participants at risk EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA Crushed in Solution Treatment Period n=6 participants at risk EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo whole capsules in any treatment period .	EMBEDA Capsule Titration/Stabilization Period n=14 participants at risk EMBEDA capsule(s) administered orally once or twice a day (20 mg go 120 mg) to adequately manage the participants pain.	EMBEDA Capsules Maintenance Period n=8 participants at risk EMBEDA capsule(s) administered orally once or twice a day dose (20 mg go 120 mg) at the participants stable dose for 7 days minimum.
Nervous system disorders Headache	50.0% 3/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	50.0% 3/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Tremor	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	66.7% 4/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	14.3% 2/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Dizziness	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	7.1% 1/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Restless legs syndrome	0.00% 0/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Psychiatric disorders Anxiety	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	100.0% 6/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	42.9% 6/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Psychiatric disorders Restlessness	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	50.0% 3/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	14.3% 2/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Nausea	50.0% 3/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	66.7% 4/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	28.6% 4/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Abdominal pain	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	50.0% 3/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	14.3% 2/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Abdominal pain upper	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	33.3% 2/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Diarrhoea	0.00% 0/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	50.0% 3/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	7.1% 1/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Flatulence	0.00% 0/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	33.3% 2/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Dry mouth	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Haematochezia	0.00% 0/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Retching	0.00% 0/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Yawning	33.3% 2/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	66.7% 4/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	33.3% 2/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	7.1% 1/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Dysphonia	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Nasal congestion	0.00% 0/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	7.1% 1/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Irritability	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Chest discomfort	0.00% 0/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Chills	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	7.1% 1/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Fatigue	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Pain	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	21.4% 3/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	33.3% 2/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	7.1% 1/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	21.4% 3/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Bone pain	0.00% 0/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Muscle twitching	0.00% 0/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Musculoskeletal stiffness	0.00% 0/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Myalgia	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Vascular disorders Flushing	33.3% 2/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	50.0% 3/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	7.1% 1/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Eye disorders Lacrimation increased	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	33.3% 2/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	7.1% 1/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Eye disorders Mydriasis	0.00% 0/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	33.3% 2/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Hyperhidrosis	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	33.3% 2/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	7.1% 1/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Tachycardia	0.00% 0/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Sinusitis	0.00% 0/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Investigations Oxygen saturation decreased	0.00% 0/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	16.7% 1/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Gastrooesophageal reflux disease	0.00% 0/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	12.5% 1/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Constipation	0.00% 0/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/6 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	21.4% 3/14 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/8 • Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2. The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.