Chronic Pain
Conditions
Keywords
opioid, morphine, naltrexone, withdrawal signs, withdrawal symptoms
Brief summary
This study will evaluate whether crushed EMBEDA capsules induce clinical opiate withdrawal signs and symptoms in opioid-dependent patients with chronic non-cancer pain who are stabilized on EMBEDA.
Detailed description
The decision to terminate the trial was due to a lack of study drug supply. Decision was not based on any safety concerns. The date of the notification of termination letter was March 11, 2011.
Interventions
DRUGEMBEDA™ (morphine sulfate/naltrexone hydrochloride) crush
Placebo capsules plus EMBEDA capsules crushed and mixed in solution administered orally at each patient's stable dose, given either once daily or twice daily
DRUGEMBEDA™ (morphine sulfate/naltrexone hydrochloride) whole
EMBEDA capsules, administered orally and intact at each patient's stable dose, given either once daily or twice daily with 150mL placebo solution
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Chronic moderate to severe non-cancer pain that has been treated with opioid analgesics for at least three months (with stabilized pain control and stabilized dose for 28 days prior to enrollment). * Receiving an opioid dose equivalent to 20 mg - 120 mg morphine once or twice daily. * Patient displays signs and symptoms of withdrawal (i.e., COWS score ≥5) following naloxone administration during the Naloxone Challenge. If female and able to become pregnant, must use an approved method of birth control. * Excluding the chronic moderate to severe non-cancer pain, the patient is judged by the Investigator to be in generally good health at screening based upon the results of a medical history, physical examination, laboratory profile, and 12 lead electrocardiogram (ECG).
Exclusion criteria
* Female who is pregnant or breastfeeding. * Patient has a known allergy or history of significant adverse reaction to morphine, other opioids, naltrexone, acetaminophen, or related compounds. * Patient is receiving systemic chemotherapy, has an active malignancy of any type, or has been diagnosed with cancer within the 5 years prior to screening (excluding squamous or basal cell carcinoma of the skin). * History of, or ongoing, alcohol or drug abuse. * Patient has made a donation of blood or has had a significant blood loss within 30 days prior to screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical Opiate Withdrawal Scale (COWS) Score Greater Than or Equal to (≥) 13 in the Treatment Phase | 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) | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Minimum Observed Plasma Concentration (Cmin) During the Treatment Phase | 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 | Average Cmin for Morphine, Naltrexone and 6-β-Naltrexol |
| Volume of Distribution (Vd/F)During the Treatment Phase | 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 | Average Vd/F for Morphine, Naltrexone and 6-β-Naltrexol |
| Plasma Decay Half-Life (t1/2) During the Treatment Phase | 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 | 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. |
| Area Under the Curve From Time Zero to End of Dosing Interval (AUC0-τ) During the Treatment Phase | 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 | Average AUC0-τ for Morphine, Naltrexone and 6-β-Naltrexol reported. τ=24 hours |
| Area Under the Curve From Time Zero to the Time of Last Measurable Concentration (AUC0-last) During the Treatment Phase | 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 | 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. |
| Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] During the Treatment Phase | 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 | 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. |
| Average Numeric Pain Rating Scale (NPRS) in Titration/Stabilization and Maintenance Phases | Baseline up to Day 63 | Average pain scores in the previous 24 hours using an 11 point NPRS ranging from no pain (0) to worst pain (10). |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) During the Treatment Phase | 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 | Average Tmax for Morphine, Naltrexone and 6-β-Naltrexol |
| Maximum Observed Plasma Concentration (Cmax) During the Treatment Phase | 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 | Average Cmax for Morphine, Naltrexone and 6-β-Naltrexol |
| Apparent Oral Clearance (CL/F) During the Treatment Phase | 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 | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Naltrexone Plasma Concentration at First COWS ≥ 13 in the Treatment Phase | 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 | — |
| 6-β-Naltrexone Plasma Concentration at First COWS ≥ 13 in Treatment Phase | 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 | — |
| Maximum Post-dose COWS in the Treatment Phase | Between 0.5 and 24 hours post-dose | 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). |
| Morphine Plasma Concentration at First COWS ≥ 13 in the Treatment Phase | 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 | — |
| Time to First Occurrence of a COWS Score ≥ 13 for Each Treatment During the Treatment Phase | 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 | Average time to first occurrence of a COWS score ≥ 13 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population 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. | 14 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Maintenance | Sponsor termination of study | 0 | 0 | 1 |
| Maintenance | Withdrawal by Subject | 0 | 0 | 1 |
| Titration/Stabilization | Adverse Event | 0 | 0 | 4 |
| Titration/Stabilization | Non-compliance | 0 | 0 | 1 |
| Titration/Stabilization | Sponsor canceled study | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age Continuous | 45.2 years |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 6 | 6 / 6 | 12 / 14 | 1 / 8 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 14 | 0 / 8 |
Outcome results
Primary
Number of Participants With Clinical Opiate Withdrawal Scale (COWS) Score Greater Than or Equal to (≥) 13 in the Treatment Phase
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).
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EMBEDA Whole Capsules | Number of Participants With Clinical Opiate Withdrawal Scale (COWS) Score Greater Than or Equal to (≥) 13 in the Treatment Phase | 1 participants |
| EMBEDA Crushed in Solution | Number of Participants With Clinical Opiate Withdrawal Scale (COWS) Score Greater Than or Equal to (≥) 13 in the Treatment Phase | 3 participants |
Secondary
Apparent Oral Clearance (CL/F) During the Treatment Phase
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.
Time frame: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EMBEDA Whole Capsules | Apparent Oral Clearance (CL/F) During the Treatment Phase | Morphine (n=2,6) | 37.6 liters/hour (L/h) | Standard Deviation 11.53 |
| EMBEDA Whole Capsules | Apparent Oral Clearance (CL/F) During the Treatment Phase | Naltrexone (n=0,6) | NA liters/hour (L/h) | — |
| EMBEDA Whole Capsules | 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 |
| EMBEDA Crushed in Solution | Apparent Oral Clearance (CL/F) During the Treatment Phase | Morphine (n=2,6) | 77.2 liters/hour (L/h) | Standard Deviation 25.36 |
| EMBEDA Crushed in Solution | Apparent Oral Clearance (CL/F) During the Treatment Phase | Naltrexone (n=0,6) | 75151.0 liters/hour (L/h) | Standard Deviation 51706.48 |
| EMBEDA Crushed in Solution | Apparent Oral Clearance (CL/F) During the Treatment Phase | 6-β-Naltrexol (n=3,6) | 1758.0 liters/hour (L/h) | Standard Deviation 381.67 |
Secondary
Area Under the Curve From Time Zero to End of Dosing Interval (AUC0-τ) During the Treatment Phase
Average AUC0-τ for Morphine, Naltrexone and 6-β-Naltrexol reported. τ=24 hours
Time frame: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EMBEDA Whole Capsules | 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 |
| EMBEDA Whole Capsules | 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) | — |
| EMBEDA Whole Capsules | 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 |
| EMBEDA Crushed in Solution | Area Under the Curve From Time Zero to End of Dosing Interval (AUC0-τ) During the Treatment Phase | Morphine (n=6,6) | 542.6 ng times h divided by mL (ng*h/mL) | Standard Deviation 366.62 |
| EMBEDA Crushed in Solution | Area Under the Curve From Time Zero to End of Dosing Interval (AUC0-τ) During the Treatment Phase | Naltrexone (n=0,6) | 1314.7 ng times h divided by mL (ng*h/mL) | Standard Deviation 1119.25 |
| EMBEDA Crushed in Solution | Area Under the Curve From Time Zero to End of Dosing Interval (AUC0-τ) During the Treatment Phase | 6-β-Naltrexol (n=4,6) | 28891.2 ng times h divided by mL (ng*h/mL) | Standard Deviation 14871.7 |
Secondary
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] During the Treatment Phase
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.
Time frame: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EMBEDA Whole Capsules | 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 |
| EMBEDA Whole Capsules | 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 | — |
| EMBEDA Whole Capsules | 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 |
| EMBEDA Crushed in Solution | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] During the Treatment Phase | Morphine (n=2,6) | 887.7 ng*h/mL | Standard Deviation 583.83 |
| EMBEDA Crushed in Solution | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] During the Treatment Phase | Naltrexone (n=0,6) | 1330.7 ng*h/mL | Standard Deviation 1141.75 |
| EMBEDA Crushed in Solution | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] During the Treatment Phase | 6-β-Naltrexol (n=3,6) | 35297.8 ng*h/mL | Standard Deviation 18407.2 |
Secondary
Area Under the Curve From Time Zero to the Time of Last Measurable Concentration (AUC0-last) During the Treatment Phase
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.
Time frame: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EMBEDA Whole Capsules | 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 |
| EMBEDA Whole Capsules | 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 | — |
| EMBEDA Whole Capsules | 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 |
| EMBEDA Crushed in Solution | Area Under the Curve From Time Zero to the Time of Last Measurable Concentration (AUC0-last) During the Treatment Phase | Morphine (n=6,6) | 542.6 ng*h/mL | Standard Deviation 366.62 |
| EMBEDA Crushed in Solution | Area Under the Curve From Time Zero to the Time of Last Measurable Concentration (AUC0-last) During the Treatment Phase | Naltrexone (n=0,6) | 1300.0 ng*h/mL | Standard Deviation 1131.24 |
| EMBEDA Crushed in Solution | 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) | 28891.2 ng*h/mL | Standard Deviation 14871.69 |
Secondary
Average Numeric Pain Rating Scale (NPRS) in Titration/Stabilization and Maintenance Phases
Average pain scores in the previous 24 hours using an 11 point NPRS ranging from no pain (0) to worst pain (10).
Time frame: Baseline up to Day 63
Population: ITT; N=number of participants with evaluable data; n=number of participants evaluated at the specific time point
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EMBEDA Whole Capsules | 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 |
| EMBEDA Whole Capsules | 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 |
| EMBEDA Whole Capsules | 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 |
| EMBEDA Whole Capsules | Average Numeric Pain Rating Scale (NPRS) in Titration/Stabilization and Maintenance Phases | Titration/Stabilization-Visit 2d (n=1) | 3.0 units on a scale | — |
| EMBEDA Whole Capsules | 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
Maximum Observed Plasma Concentration (Cmax) During the Treatment Phase
Average Cmax for Morphine, Naltrexone and 6-β-Naltrexol
Time frame: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EMBEDA Whole Capsules | Maximum Observed Plasma Concentration (Cmax) During the Treatment Phase | Morphine (n=6,6) | 27.5 nanogram per milliliter (ng/mL) | Standard Deviation 14.14 |
| EMBEDA Whole Capsules | Maximum Observed Plasma Concentration (Cmax) During the Treatment Phase | Naltrexone (n=0,6) | NA nanogram per milliliter (ng/mL) | — |
| EMBEDA Whole Capsules | Maximum Observed Plasma Concentration (Cmax) During the Treatment Phase | 6-β-Naltrexol (n=4,6) | 24.4 nanogram per milliliter (ng/mL) | Standard Deviation 15.4 |
| EMBEDA Crushed in Solution | Maximum Observed Plasma Concentration (Cmax) During the Treatment Phase | Morphine (n=6,6) | 70.4 nanogram per milliliter (ng/mL) | Standard Deviation 47.88 |
| EMBEDA Crushed in Solution | Maximum Observed Plasma Concentration (Cmax) During the Treatment Phase | Naltrexone (n=0,6) | 321.1 nanogram per milliliter (ng/mL) | Standard Deviation 225.05 |
| EMBEDA Crushed in Solution | Maximum Observed Plasma Concentration (Cmax) During the Treatment Phase | 6-β-Naltrexol (n=4,6) | 3398.3 nanogram per milliliter (ng/mL) | Standard Deviation 1327.97 |
Secondary
Minimum Observed Plasma Concentration (Cmin) During the Treatment Phase
Average Cmin for Morphine, Naltrexone and 6-β-Naltrexol
Time frame: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EMBEDA Whole Capsules | Minimum Observed Plasma Concentration (Cmin) During the Treatment Phase | Morphine (n=6,6) | 13.8 ng/mL | Standard Deviation 6.89 |
| EMBEDA Whole Capsules | Minimum Observed Plasma Concentration (Cmin) During the Treatment Phase | Naltrexone (n=0,6) | NA ng/mL | — |
| EMBEDA Whole Capsules | Minimum Observed Plasma Concentration (Cmin) During the Treatment Phase | 6-β-Naltrexol (n=4,6) | 15.9 ng/mL | Standard Deviation 9.29 |
| EMBEDA Crushed in Solution | Minimum Observed Plasma Concentration (Cmin) During the Treatment Phase | Morphine (n=6,6) | 11.2 ng/mL | Standard Deviation 8.86 |
| EMBEDA Crushed in Solution | Minimum Observed Plasma Concentration (Cmin) During the Treatment Phase | Naltrexone (n=0,6) | 6.9 ng/mL | Standard Deviation 1.17 |
| EMBEDA Crushed in Solution | Minimum Observed Plasma Concentration (Cmin) During the Treatment Phase | 6-β-Naltrexol (n=4,6) | 42.7 ng/mL | Standard Deviation 66.93 |
Secondary
Plasma Decay Half-Life (t1/2) During the Treatment Phase
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.
Time frame: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EMBEDA Whole Capsules | Plasma Decay Half-Life (t1/2) During the Treatment Phase | Morphine (n=2,6) | 56.2 h | Standard Deviation 14.55 |
| EMBEDA Whole Capsules | Plasma Decay Half-Life (t1/2) During the Treatment Phase | Naltrexone (n=0,6) | NA h | — |
| EMBEDA Whole Capsules | Plasma Decay Half-Life (t1/2) During the Treatment Phase | 6-β-Naltrexol (n=3,6) | 50.9 h | Standard Deviation 11.77 |
| EMBEDA Crushed in Solution | Plasma Decay Half-Life (t1/2) During the Treatment Phase | Naltrexone (n=0,6) | 3.0 h | Standard Deviation 1.1 |
| EMBEDA Crushed in Solution | Plasma Decay Half-Life (t1/2) During the Treatment Phase | Morphine (n=2,6) | 17.0 h | Standard Deviation 10.99 |
| EMBEDA Crushed in Solution | Plasma Decay Half-Life (t1/2) During the Treatment Phase | 6-β-Naltrexol (n=3,6) | 10.1 h | Standard Deviation 2.43 |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) During the Treatment Phase
Average Tmax for Morphine, Naltrexone and 6-β-Naltrexol
Time frame: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EMBEDA Whole Capsules | Time to Reach Maximum Observed Plasma Concentration (Tmax) During the Treatment Phase | Morphine (n=6,6) | 5.67 hours (h) | Standard Deviation 2.658 |
| EMBEDA Whole Capsules | Time to Reach Maximum Observed Plasma Concentration (Tmax) During the Treatment Phase | Naltrexone (n=0,6) | NA hours (h) | — |
| EMBEDA Whole Capsules | 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 |
| EMBEDA Crushed in Solution | Time to Reach Maximum Observed Plasma Concentration (Tmax) During the Treatment Phase | Morphine (n=6,6) | 1.29 hours (h) | Standard Deviation 0.813 |
| EMBEDA Crushed in Solution | Time to Reach Maximum Observed Plasma Concentration (Tmax) During the Treatment Phase | Naltrexone (n=0,6) | 1.46 hours (h) | Standard Deviation 0.697 |
| EMBEDA Crushed in Solution | Time to Reach Maximum Observed Plasma Concentration (Tmax) During the Treatment Phase | 6-β-Naltrexol (n=4,6) | 1.63 hours (h) | Standard Deviation 0.787 |
Secondary
Volume of Distribution (Vd/F)During the Treatment Phase
Average Vd/F for Morphine, Naltrexone and 6-β-Naltrexol
Time frame: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EMBEDA Whole Capsules | Volume of Distribution (Vd/F)During the Treatment Phase | Morphine (n=2,6) | 3173.1 liter (L) | Standard Deviation 1724.61 |
| EMBEDA Whole Capsules | Volume of Distribution (Vd/F)During the Treatment Phase | Naltrexone (n=0,6) | NA liter (L) | — |
| EMBEDA Whole Capsules | Volume of Distribution (Vd/F)During the Treatment Phase | 6-β-Naltrexol (n=3,6) | 3447244.4 liter (L) | Standard Deviation 1868128.43 |
| EMBEDA Crushed in Solution | Volume of Distribution (Vd/F)During the Treatment Phase | Morphine (n=2,6) | 1668.2 liter (L) | Standard Deviation 830.08 |
| EMBEDA Crushed in Solution | Volume of Distribution (Vd/F)During the Treatment Phase | Naltrexone (n=0,6) | 304171.8 liter (L) | Standard Deviation 206998.86 |
| EMBEDA Crushed in Solution | Volume of Distribution (Vd/F)During the Treatment Phase | 6-β-Naltrexol (n=3,6) | 26304.5 liter (L) | Standard Deviation 10730.59 |
Other Pre-specified
6-β-Naltrexone Plasma Concentration at First COWS ≥ 13 in Treatment Phase
Time frame: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EMBEDA Whole Capsules | 6-β-Naltrexone Plasma Concentration at First COWS ≥ 13 in Treatment Phase | NA pg/mL | — |
| EMBEDA Crushed in Solution | 6-β-Naltrexone Plasma Concentration at First COWS ≥ 13 in Treatment Phase | 3375.00 pg/mL | Standard Deviation 827.315 |
Other Pre-specified
Maximum Post-dose COWS in the Treatment Phase
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).
Time frame: Between 0.5 and 24 hours post-dose
Population: ITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EMBEDA Whole Capsules | Maximum Post-dose COWS in the Treatment Phase | 3.7 units on a scale | Standard Deviation 4.63 |
| EMBEDA Crushed in Solution | Maximum Post-dose COWS in the Treatment Phase | 10.7 units on a scale | Standard Deviation 6.83 |
Other Pre-specified
Morphine Plasma Concentration at First COWS ≥ 13 in the Treatment Phase
Time frame: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EMBEDA Whole Capsules | Morphine Plasma Concentration at First COWS ≥ 13 in the Treatment Phase | 16.00 ng/mL | — |
| EMBEDA Crushed in Solution | Morphine Plasma Concentration at First COWS ≥ 13 in the Treatment Phase | 86.30 ng/mL | Standard Deviation 53.316 |
Other Pre-specified
Naltrexone Plasma Concentration at First COWS ≥ 13 in the Treatment Phase
Time frame: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EMBEDA Whole Capsules | Naltrexone Plasma Concentration at First COWS ≥ 13 in the Treatment Phase | NA picogram/milliliter (pg/mL) | — |
| EMBEDA Crushed in Solution | Naltrexone Plasma Concentration at First COWS ≥ 13 in the Treatment Phase | 350.50 picogram/milliliter (pg/mL) | Standard Deviation 195.869 |
Other Pre-specified
Time to First Occurrence of a COWS Score ≥ 13 for Each Treatment During the Treatment Phase
Average time to first occurrence of a COWS score ≥ 13
Time frame: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EMBEDA Whole Capsules | Time to First Occurrence of a COWS Score ≥ 13 for Each Treatment During the Treatment Phase | 2.5 h | — |
| EMBEDA Crushed in Solution | Time to First Occurrence of a COWS Score ≥ 13 for Each Treatment During the Treatment Phase | 0.7 h | Standard Error 0.02 |