Analgesia Disorder, Pain
Conditions
Keywords
Analgesic, Opioids, Pain relief after surgery, Dinalbuphine, Sebacoyl Dinalbuphine Ester, SDE, SDN, LT1001
Brief summary
This is a randomized, double blind, placebo-controlled, single dose study to assess the safety and efficacy of intramuscular sebacoyl dinalbuphine ester (SDE) for post-hemorrhoidectomy pain management.
Detailed description
This study was a multicenter, double-blind, randomized, placebo-controlled, parallel, pretreatment study, sponsored by Lumosa therapeutics Co., Ltd (Taiwan). All subjects received training of visual analog scores (VAS) before surgery using the 10-mm horizontal version. VAS was taken by study subjects themselves before the first dose of PCA ketorolac, and at 1, 2, 3, 4, 8, 12, 16, 24, 28, 32, 36, 40, 44, 48 hours after surgery. After discharge, VAS was taken, also by the study subjects, twice a day, in the morning and evening of Dayday 3 through Dayday 7. Subjects were asked to complete a short form questionnaire, Brief Pain Inventory, on day 1, day 2, and final visit (day 7-10) after surgery. Patient satisfaction of postsurgical analgesia was assessed at the final visit using a 5-grade categorical scale. The primary objective of the study was to evaluate the efficacy and safety of single intramuscular injection of SDE in an extended-release formulation, against placebo control, administrated pre-operatively in subjects scheduled to undergo elective hemorrhoidectomies.
Interventions
Intramuscular injection 2mL/vial (75mg/mL)
DRUGPlacebo
Sebacoyl Dinalbuphine Ester injection placebo, 2mL/vial
Sponsors
Lumosa Therapeutics Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female \>= 20 years of age at Screening * Scheduled to electively undergo 2 or 3-column excisional hemorrhoidectomy * American Society of Anesthesiology Physical Class 1 - 3 * Adequate clinical lab values (values of potential clinical concern are detailed in Appendix) or, if abnormal, deemed not clinically significant per the Investigator. * Ability and willingness to provide informed consent, adhere to the study visit schedule and complete all study assessments and language specific questionnaires
Exclusion criteria
* Body weight less than 40 kg. * Concurrent fissurectomy. * Subject is pregnant or breastfeeding. Women of childbearing potential must have a negative urine pregnancy test at Baseline. * Women of childbearing potential disagree to use an acceptable method of contraception (e.g., hormonal contraceptives, IUD, barrier device or abstinence) throughout the study. * History of hypersensitivity or allergy to amide-type local anesthetics, opioid, or any ingredient of the medications administered in this study. * Subject has a resting respiratory rate less than 8 per minute and blood oxygen saturation less than 90 mmHg. * Use of any NSAIDs, selective COX-2 inhibitors, opioid, acetaminophen, selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants (TCA), gabapentin, or pregabalin within three days of surgery. * Chronic use of opioid medications for more than 14 days in the last 3 months, or non-opioid pain medications more than 5 times per week before screening visit. * Use of any long-acting opioid medication within 3 days of surgery or any opioid medication within 24 hours of surgery. * Current painful physical condition or concurrent surgery requires analgesic treatment in the postoperative period. * Contraindication to epinephrine or any of the pain-control agents planned for postoperative use. * Administration of an investigational drug within the longer of 30 days or 5 elimination half-lives of such investigational drug prior to study drug administration. * Any psychiatric disorder, psychological, medical, or laboratory condition that may interfere with study assessments or compliance. * Significant medical conditions or laboratory results that may indicate an increased vulnerability to study drugs and procedures, and thus expose the subject to an unreasonable risk as a result of participating in this clinical trial. * Any clinically significant event or condition may be uncovered during surgery. * History of abuse illicit drugs, prescription medicines or alcohol within the past 2 years. * Known history of anti-HIV antibody positive * Failure to pass drug and alcohol screen.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pain Assessment Calculated as the Area Under the Curve of VAS Pain Intensity Scores Through 48 Hours After Surgery | 1±0.1, 2±0.1, 3±0.1, 4±0.25, 8±0.5, 12±0.5, 16±0.5, 20±0.5, 24±1, 28±1, 32±2, 36±2, 40±2, 44±2, 48±2 h after the surgery | The primary outcome measure of this study is pain assessment (time-specific pain intensity) calculated as the area under the curve (AUC) of VAS pain intensity scores through 48 hours after surgery (AUC0-48). Pain intensity was measured with visual analog scale (VAS) and the assessment began right before the first use of analgesics, and at 1±0.1, 2±0.1, 3±0.1, 4±0.25, 8±0.5, 12±0.5, 16±0.5, 20±0.5, 24±1, 28±1, 32±2, 36±2, 40±2, 44±2, 48±2 hours after the operation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pain Assessment Measured With VAS During Day 3-7 in the Morning and Evening, as Well as During Special Events Such as Bowel Movements. | Day 3-7 | Pain intensity was assessed using a Visual Analog Scale (VAS). The scale ranged from 0 (no pain) to 10 (worst pain imaginable), reported as units on a scale. Higher values indicate worse pain. Pain intensity were measured with VAS scores in the morning and evening during Day 3-7. It should be noted that the VAS scores during Day 3-7 were not adjusted by rescue medications used for pain relief. |
| Time From the End of Operation to the First PCA Ketorolac Dose | From the end of operation until the first PCA ketorolac dose used, assessed up to 48 hrs | — |
| Consumption of Ketorolac Via Intravenous Patient- Controlled Analgesia (IV PCA) | Day 1-2 | Consumption of ketorolac via intravenous Patient- Controlled Analgesia (IV PCA) was calculated through 48 hrs after surgery (study day1-2) |
| Consumption of Oral Ketorolac (Day 3-7) | Day 3-7 | Patients discharged on Day 2. The total amount of oral Ketorolac, as supplemental analgesics after discharge, was used to evaluate the efficacy of extended-release SDE compared with the placebo group. |
| Subject Satisfaction With Post-Surgical Analgesic Between Treatment Groups | Day 7 | Subject will be asked to classify themselves as either: 'highly satisfied', 'satisfied', 'uncertain', 'dissatisfied' or 'very dissatisfied' at final visit, and a Cochran-Mantel-Haenszel test was used in comparison of subjects' satisfaction with post-surgical analgesic between treatment groups. |
| Brief Pain Inventory (BPI) | Day 1, 2 and Day 7 | Pain severity was assessed using the Brief Pain Inventory (BPI). The BPI pain severity score is based on a numeric rating scale ranging from 0 to 10 units on a scale, where 0 indicates no pain and 10 indicates pain as bad as you can imagine. Higher scores represent worse pain outcomes. Assessments were conducted on Day 1, Day 2, and Day 7. |
Countries
Taiwan
Participant flow
Recruitment details
This study enrolled hemorrhoid subjects from 6 sites in Taiwan between 29th December 2012 and 14th April 2015.
Pre-assignment details
A total of 221 subjects (109 subjects in SDE group; 112 subjects in placebo group) were enrolled into the study and randomized to receive either SDE or placebo treatment.There were 12 of the 221 subjects excluded from the original ITT population since they were protocol violation; therefore, 209 subjects comprised the mITT population.
Participants by arm
| Arm | Count |
|---|---|
| SDE 150mg Single dose, intramuscular, Sebacoyl Dinalbuphine Ester injection 150 mg (2 ml)
Sebacoyl Dinalbuphine Ester: Intramuscular injection 2mL/vial (75mg/mL) | 103 |
| Placebo Single dose, intramuscular , Sebacoyl Dinalbuphine Ester placebo injection (2mL)
Placebo: Sebacoyl Dinalbuphine Ester injection placebo, 2mL/vial | 106 |
| Total | 209 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 6 | 6 |
Baseline characteristics
| Characteristic | Placebo | SDE 150mg | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 104 Participants | 101 Participants | 205 Participants |
| Age, Continuous | 44.5 years STANDARD_DEVIATION 11.4 | 43.2 years STANDARD_DEVIATION 12.1 | 43.8 years STANDARD_DEVIATION 11.7 |
| Region of Enrollment Taiwan | 106 participants | 103 participants | 209 participants |
| Sex: Female, Male Female | 59 Participants | 52 Participants | 111 Participants |
| Sex: Female, Male Male | 47 Participants | 51 Participants | 98 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 76 / 109 | 62 / 112 |
| serious Total, serious adverse events | 8 / 109 | 2 / 112 |
Outcome results
Primary
Pain Assessment Calculated as the Area Under the Curve of VAS Pain Intensity Scores Through 48 Hours After Surgery
The primary outcome measure of this study is pain assessment (time-specific pain intensity) calculated as the area under the curve (AUC) of VAS pain intensity scores through 48 hours after surgery (AUC0-48). Pain intensity was measured with visual analog scale (VAS) and the assessment began right before the first use of analgesics, and at 1±0.1, 2±0.1, 3±0.1, 4±0.25, 8±0.5, 12±0.5, 16±0.5, 20±0.5, 24±1, 28±1, 32±2, 36±2, 40±2, 44±2, 48±2 hours after the operation.
Time frame: 1±0.1, 2±0.1, 3±0.1, 4±0.25, 8±0.5, 12±0.5, 16±0.5, 20±0.5, 24±1, 28±1, 32±2, 36±2, 40±2, 44±2, 48±2 h after the surgery
Population: The analysis included all patients in the modified Intent-to-Treat (mITT) population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SDE 150mg | Pain Assessment Calculated as the Area Under the Curve of VAS Pain Intensity Scores Through 48 Hours After Surgery | 209.93 VAS score*hour | Standard Deviation 111.26 |
| Placebo | Pain Assessment Calculated as the Area Under the Curve of VAS Pain Intensity Scores Through 48 Hours After Surgery | 253.53 VAS score*hour | Standard Deviation 108.49 |
p-value: <0.0195% CI: [-71.68, -12.71]ANOVA
Secondary
Brief Pain Inventory (BPI)
Pain severity was assessed using the Brief Pain Inventory (BPI). The BPI pain severity score is based on a numeric rating scale ranging from 0 to 10 units on a scale, where 0 indicates no pain and 10 indicates pain as bad as you can imagine. Higher scores represent worse pain outcomes. Assessments were conducted on Day 1, Day 2, and Day 7.
Time frame: Day 1, 2 and Day 7
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SDE 150mg | Brief Pain Inventory (BPI) | Day7 | 2.94 units on a scale | Standard Deviation 2.1 |
| SDE 150mg | Brief Pain Inventory (BPI) | Day1 | 3.50 units on a scale | Standard Deviation 2.54 |
| SDE 150mg | Brief Pain Inventory (BPI) | Day2 | 3.14 units on a scale | Standard Deviation 2.34 |
| Placebo | Brief Pain Inventory (BPI) | Day7 | 3.19 units on a scale | Standard Deviation 2.2 |
| Placebo | Brief Pain Inventory (BPI) | Day1 | 3.60 units on a scale | Standard Deviation 2.24 |
| Placebo | Brief Pain Inventory (BPI) | Day2 | 3.20 units on a scale | Standard Deviation 2.07 |
Comparison: ANOVA with Treatment, Center effect (and Treatment\*Center effect if p-value ≤ 0.1 in non-reduced model)p-value: <0.05ANOVA
Secondary
Consumption of Ketorolac Via Intravenous Patient- Controlled Analgesia (IV PCA)
Consumption of ketorolac via intravenous Patient- Controlled Analgesia (IV PCA) was calculated through 48 hrs after surgery (study day1-2)
Time frame: Day 1-2
Population: The analysis included all patients in the modified Intent-to-Treat (mITT) population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SDE 150mg | Consumption of Ketorolac Via Intravenous Patient- Controlled Analgesia (IV PCA) | 50.06 mg | Standard Deviation 45.72 |
| Placebo | Consumption of Ketorolac Via Intravenous Patient- Controlled Analgesia (IV PCA) | 82.33 mg | Standard Deviation 66.44 |
p-value: <0.01ANOVA
Secondary
Consumption of Oral Ketorolac (Day 3-7)
Patients discharged on Day 2. The total amount of oral Ketorolac, as supplemental analgesics after discharge, was used to evaluate the efficacy of extended-release SDE compared with the placebo group.
Time frame: Day 3-7
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SDE 150mg | Consumption of Oral Ketorolac (Day 3-7) | 3.86 mg | Standard Deviation 0.81 |
| Placebo | Consumption of Oral Ketorolac (Day 3-7) | 4.29 mg | Standard Deviation 0.69 |
p-value: <0.01ANOVA
Secondary
Pain Assessment Measured With VAS During Day 3-7 in the Morning and Evening, as Well as During Special Events Such as Bowel Movements.
Pain intensity was assessed using a Visual Analog Scale (VAS). The scale ranged from 0 (no pain) to 10 (worst pain imaginable), reported as units on a scale. Higher values indicate worse pain. Pain intensity were measured with VAS scores in the morning and evening during Day 3-7. It should be noted that the VAS scores during Day 3-7 were not adjusted by rescue medications used for pain relief.
Time frame: Day 3-7
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SDE 150mg | Pain Assessment Measured With VAS During Day 3-7 in the Morning and Evening, as Well as During Special Events Such as Bowel Movements. | Day3 Evening | 3.51 units on a scale | Standard Deviation 2.8 |
| SDE 150mg | Pain Assessment Measured With VAS During Day 3-7 in the Morning and Evening, as Well as During Special Events Such as Bowel Movements. | Day5 Evening | 3.20 units on a scale | Standard Deviation 2.72 |
| SDE 150mg | Pain Assessment Measured With VAS During Day 3-7 in the Morning and Evening, as Well as During Special Events Such as Bowel Movements. | Day4 Evening | 3.27 units on a scale | Standard Deviation 2.69 |
| SDE 150mg | Pain Assessment Measured With VAS During Day 3-7 in the Morning and Evening, as Well as During Special Events Such as Bowel Movements. | Day6 Morning | 2.88 units on a scale | Standard Deviation 2.51 |
| SDE 150mg | Pain Assessment Measured With VAS During Day 3-7 in the Morning and Evening, as Well as During Special Events Such as Bowel Movements. | Day4 Morning | 3.30 units on a scale | Standard Deviation 2.46 |
| SDE 150mg | Pain Assessment Measured With VAS During Day 3-7 in the Morning and Evening, as Well as During Special Events Such as Bowel Movements. | Day6 Evening | 2.67 units on a scale | Standard Deviation 2.36 |
| SDE 150mg | Pain Assessment Measured With VAS During Day 3-7 in the Morning and Evening, as Well as During Special Events Such as Bowel Movements. | Day5 Morning | 3.05 units on a scale | Standard Deviation 2.54 |
| SDE 150mg | Pain Assessment Measured With VAS During Day 3-7 in the Morning and Evening, as Well as During Special Events Such as Bowel Movements. | Day7 Morning | 2.50 units on a scale | Standard Deviation 2.33 |
| SDE 150mg | Pain Assessment Measured With VAS During Day 3-7 in the Morning and Evening, as Well as During Special Events Such as Bowel Movements. | Day3 Morning | 2.75 units on a scale | Standard Deviation 2.3 |
| Placebo | Pain Assessment Measured With VAS During Day 3-7 in the Morning and Evening, as Well as During Special Events Such as Bowel Movements. | Day7 Morning | 2.98 units on a scale | Standard Deviation 2.6 |
| Placebo | Pain Assessment Measured With VAS During Day 3-7 in the Morning and Evening, as Well as During Special Events Such as Bowel Movements. | Day3 Morning | 2.79 units on a scale | Standard Deviation 2.28 |
| Placebo | Pain Assessment Measured With VAS During Day 3-7 in the Morning and Evening, as Well as During Special Events Such as Bowel Movements. | Day3 Evening | 3.39 units on a scale | Standard Deviation 2.75 |
| Placebo | Pain Assessment Measured With VAS During Day 3-7 in the Morning and Evening, as Well as During Special Events Such as Bowel Movements. | Day4 Morning | 3.78 units on a scale | Standard Deviation 2.73 |
| Placebo | Pain Assessment Measured With VAS During Day 3-7 in the Morning and Evening, as Well as During Special Events Such as Bowel Movements. | Day4 Evening | 3.56 units on a scale | Standard Deviation 2.67 |
| Placebo | Pain Assessment Measured With VAS During Day 3-7 in the Morning and Evening, as Well as During Special Events Such as Bowel Movements. | Day5 Morning | 3.46 units on a scale | Standard Deviation 2.51 |
| Placebo | Pain Assessment Measured With VAS During Day 3-7 in the Morning and Evening, as Well as During Special Events Such as Bowel Movements. | Day5 Evening | 3.38 units on a scale | Standard Deviation 2.6 |
| Placebo | Pain Assessment Measured With VAS During Day 3-7 in the Morning and Evening, as Well as During Special Events Such as Bowel Movements. | Day6 Morning | 3.20 units on a scale | Standard Deviation 2.66 |
| Placebo | Pain Assessment Measured With VAS During Day 3-7 in the Morning and Evening, as Well as During Special Events Such as Bowel Movements. | Day6 Evening | 3.08 units on a scale | Standard Deviation 2.63 |
p-value: >0.05ANOVA
Secondary
Subject Satisfaction With Post-Surgical Analgesic Between Treatment Groups
Subject will be asked to classify themselves as either: 'highly satisfied', 'satisfied', 'uncertain', 'dissatisfied' or 'very dissatisfied' at final visit, and a Cochran-Mantel-Haenszel test was used in comparison of subjects' satisfaction with post-surgical analgesic between treatment groups.
Time frame: Day 7
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| SDE 150mg | Subject Satisfaction With Post-Surgical Analgesic Between Treatment Groups | Satisfied | 68 participants |
| SDE 150mg | Subject Satisfaction With Post-Surgical Analgesic Between Treatment Groups | Dissatisfied | 3 participants |
| SDE 150mg | Subject Satisfaction With Post-Surgical Analgesic Between Treatment Groups | Uncertain | 13 participants |
| SDE 150mg | Subject Satisfaction With Post-Surgical Analgesic Between Treatment Groups | Very dissatisfied | 0 participants |
| SDE 150mg | Subject Satisfaction With Post-Surgical Analgesic Between Treatment Groups | Highly satisfied | 18 participants |
| Placebo | Subject Satisfaction With Post-Surgical Analgesic Between Treatment Groups | Very dissatisfied | 1 participants |
| Placebo | Subject Satisfaction With Post-Surgical Analgesic Between Treatment Groups | Highly satisfied | 20 participants |
| Placebo | Subject Satisfaction With Post-Surgical Analgesic Between Treatment Groups | Satisfied | 69 participants |
| Placebo | Subject Satisfaction With Post-Surgical Analgesic Between Treatment Groups | Uncertain | 10 participants |
| Placebo | Subject Satisfaction With Post-Surgical Analgesic Between Treatment Groups | Dissatisfied | 6 participants |
Comparison: At the final visit, each subject was asked the questions for evaluation of satisfaction and a Cochran-Mantel-Haenszel test was used in comparison of subjects' satisfaction with post-surgical analgesic between treatment groups.p-value: >0.05Cochran-Mantel-Haenszel
Secondary
Time From the End of Operation to the First PCA Ketorolac Dose
Time frame: From the end of operation until the first PCA ketorolac dose used, assessed up to 48 hrs
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| SDE 150mg | Time From the End of Operation to the First PCA Ketorolac Dose | 4.67 hours |
| Placebo | Time From the End of Operation to the First PCA Ketorolac Dose | 4.32 hours |
p-value: <0.05Log-rank tests
Post Hoc
Post-hoc Analysis of Secondary Outcome Measures (Pain Assessment During Day 3-7)
Pain assessment during Day 3-7 was not corrected for the use of rescue medication in the initial secondary endpoint analysis as that was done for the primary end point, where the VAS scores for the measurement of pain intensity from 0 to 48 hours post-surgery were calculated as the area under the curve (AUC0-48). And for the calculation of AUC, data were imputed with the use of the windowed worst observation carried forward plus last observation carried forward method.For subjects who used rescue medication for pain relief, their VAS scores recorded within the window of ketorolac medication (6 hours, which is one half-life of ketorolac) was replaced by the worst observation (i.e., the highest score before taking ketorolac). For the post hoc analysis, the same principle was applied, i.e. the VAS scores AUC0-final (Time zero post-surgery to final visit) were analyzed following the same methodology used for AUC0-48
Time frame: Day 3-7
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SDE 150mg | Post-hoc Analysis of Secondary Outcome Measures (Pain Assessment During Day 3-7) | 630.79 VAS score*hour | Standard Deviation 350.9 |
| Placebo | Post-hoc Analysis of Secondary Outcome Measures (Pain Assessment During Day 3-7) | 749.94 VAS score*hour | Standard Deviation 353.72 |
p-value: <0.0595% CI: [-209.153, -21.26]ANOVA