Buprenorphine Sublingual Spray for the Treatment of Moderate to Severe Pain
Study Details
Study Description
Brief Summary
This is a phase 3, multicenter, randomized, double-blind, multiple-dose, parallel-group, placebo-controlled study to evaluate the safety and efficacy of up to 3 dosing regimens of Buprenorphine Sublingual (under the tongue) Spray and/or matching placebo in participants with moderate to severe postoperative pain after bunionectomy. The study will comprise 4 periods: the Screening Period, the Surgical Period, the Treatment Period, and the Follow-up Period.
Participants will be admitted to the study site on the morning of the scheduled surgery, will remain at the study site until postoperative Day 3 (a total of 3 nights at the study site), and will return for the Follow-up Visit 5 to 9 days after surgery.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Buprenorphine 0.5 mg TID Participants received buprenorphine 0.5 mg sublingual spray three times daily (TID) and placebo-matching buprenorphine sublingual spray once daily (QD) for two days. |
Drug: Buprenorphine Sublingual Spray
Buprenorphine sublingual spray delivered via single 100 μL spray
Drug: Placebo
Placebo-matching buprenorphine sublingual spray delivered via single 100 μL spray
|
| Experimental: Buprenorphine 1.0 mg BID Participants received buprenorphine 1.0 mg sublingual spray twice daily (BID) and placebo-matching buprenorphine sublingual spray BID for two days. |
Drug: Buprenorphine Sublingual Spray
Buprenorphine sublingual spray delivered via single 100 μL spray
Drug: Placebo
Placebo-matching buprenorphine sublingual spray delivered via single 100 μL spray
|
| Experimental: Buprenorphine 1.0 mg TID Participants received buprenorphine 1.0 mg sublingual spray TID and placebo-matching buprenorphine sublingual spray QD for two days. |
Drug: Buprenorphine Sublingual Spray
Buprenorphine sublingual spray delivered via single 100 μL spray
Drug: Placebo
Placebo-matching buprenorphine sublingual spray delivered via single 100 μL spray
|
| Placebo Comparator: Placebo Participants received placebo-matching buprenorphine sublingual spray four times daily for two days. |
Drug: Placebo
Placebo-matching buprenorphine sublingual spray delivered via single 100 μL spray
|
Outcome Measures
Primary Outcome Measures
- Numeric Rating Scale (NRS) Summed Pain Intensity Difference (SPID) Over 0 to 48 Hours After Time 0 (NRS SPID-48) [Baseline and 0 to 48 hours after Time 0]
Pain intensity was assessed by the participant using an 11-point NRS from 0=no pain to 10=worst possible pain. Pain intensity scores were collected at Baseline (prior to study drug) and at multiple time points up to 48 hours after Time 0 (administration of first dose of study drug). Pain intensity difference is calculated by subtracting the pain intensity at each time point from the pain intensity at Time 0. The SPID scores are the sum of the differences at each time point multiplied by the duration in hours since the previous time point. Positive numbers indicate a reduction in pain [maximum (max)=10 at each time point] and negative numbers indicate an increase in pain [minimum (min)=-10 at each time point]. The overall min and max are -10 and 10 times the number of hours specified; SPID-48 range is -480 to 480. The NRS SPID-48 was analyzed using an analysis of covariance (ANCOVA) model, which included treatment and site as main effects and Baseline pain intensity as the covariate.
Secondary Outcome Measures
- NRS Mean Pain Intensity Difference (PID) at 4, 8, 24 and 48 Hours After Time 0 [Baseline and 4, 8, 24 and 48 hours after Time 0]
Pain intensity was assessed by the participant using an 11-point NRS from 0=no pain to 10=worst possible pain. Pain intensity scores were collected at Baseline (prior to study drug administration) and at multiple time points up to 48 hours after Time 0 (time of administration of the first dose of study drug). NRS PID is defined as the difference in pain at each scheduled timepoint relative to Baseline (PID=pain intensity at baseline - pain intensity at time point). A higher value of NRS PID score indicates a higher decrease in pain from Baseline.
- NRS Mean Pain Intensity Score at 4, 8, 24 and 48 Hours After Time 0 [4, 8, 24 and 48 hours after Time 0]
Pain intensity was assessed by the participant using an 11-point NRS from 0=no pain to 10=worst possible pain. Pain intensity scores were collected at Baseline (prior to study drug administration) and at multiple time points up to 48 hours after Time 0 (time of administration of the first dose of study drug). A lower value indicates improvement in pain.
- NRS SPID Over 0 to 4 Hours After Time 0 (NRS SPID-4) [Baseline and 0 to 4 hours after Time 0]
Pain intensity was assessed by the participant using an 11-point NRS from 0=no pain to 10=worst possible pain. Pain intensity scores were collected at Baseline (prior to study drug) and at multiple time points up to 4 hours after Time 0 (administration of first dose of study drug). Pain intensity difference is calculated by subtracting the pain intensity at each time point from the pain intensity at Time 0. The SPID scores are the sum of the differences at each time point multiplied by the duration in hours since the previous time point. Positive numbers indicate a reduction in pain [maximum (max)=10 at each time point] and negative numbers indicate an increase in pain [minimum (min)=-10 at each time point]. The overall min and max are -10 and 10 times the number of hours specified; SPID-4 range is -40 to 40. The NRS SPID-4 was analyzed using an analysis of covariance (ANCOVA) model, which included treatment and site as main effects and Baseline pain intensity as the covariate.
- NRS SPID Over 0 to 8 Hours After Time 0 (NRS SPID-8) [Baseline and 0 to 8 hours after Time 0]
Pain intensity was assessed by the participant using an 11-point NRS from 0=no pain to 10=worst possible pain. Pain intensity scores were collected at Baseline (prior to study drug) and at multiple time points up to 8 hours after Time 0 (administration of first dose of study drug). Pain intensity difference is calculated by subtracting the pain intensity at each time point from the pain intensity at Time 0. The SPID scores are the sum of the differences at each time point multiplied by the duration in hours since the previous time point. Positive numbers indicate a reduction in pain [maximum (max)=10 at each time point] and negative numbers indicate an increase in pain [minimum (min)=-10 at each time point]. The overall min and max are -10 and 10 times the number of hours specified; SPID-8 range is -80 to 80. The NRS SPID-8 was analyzed using an analysis of covariance (ANCOVA) model, which included treatment and site as main effects and Baseline pain intensity as the covariate.
- NRS SPID Over 0 to 24 Hours After Time 0 (NRS SPID-24) [Baseline and 0 to 24 hours after Time 0]
Pain intensity was assessed by the participant using an 11-point NRS from 0=no pain to 10=worst possible pain. Pain intensity scores were collected at Baseline (prior to study drug) and at multiple time points up to 24 hours after Time 0 (administration of first dose of study drug). Pain intensity difference is calculated by subtracting the pain intensity at each time point from the pain intensity at Time 0. The SPID scores are the sum of the differences at each time point multiplied by the duration in hours since the previous time point. Positive numbers indicate a reduction in pain [maximum (max)=10 at each time point] and negative numbers indicate an increase in pain [minimum (min)=-10 at each time point]. The overall min and max are -10 and 10 times the number of hours specified; SPID-24 range is -240 to 240. The NRS SPID-24 was analyzed using an analysis of covariance (ANCOVA) model, which included treatment and site as main effects and Baseline pain intensity as the covariate.
- Percentage of Participants Who Used Rescue Medication for Pain [From Time 0 (first dose of study drug) up to Day 9]
The percentage of participants who needed to take an alternate medication for pain relief during the study.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Meets protocol-specified criteria for qualification and contraception
-
Is able to speak and understand the language in which the study is being conducted, is able to understand the procedures and study requirements and has voluntarily signed and dated an informed consent form approved by the Institutional Review Board before the conduct of any study procedure
-
Is willing and able to comply with study requirements (including diet, alcohol, and smoking restrictions), complete the pain evaluations, remain at the study site for three days, and return for follow up between 7 and 9 days after surgery.
Exclusion Criteria:
-
History or current use of over-the-counter medications, dietary supplements, or drugs (including nicotine and alcohol) outside protocol-specified parameters
-
Signs, symptoms or history of any condition that, per protocol or in the opinion of the investigator, might compromise:
-
the safety or well-being of the participant or study staff
-
the safety or well-being of the participant's offspring (such as through pregnancy or breast-feeding)
-
the analysis of results
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Phoenix | Arizona | United States | 85027 | |
| 2 | Pasadena | Maryland | United States | 21122 | |
| 3 | Austin | Texas | United States | 78728 |
Sponsors and Collaborators
- INSYS Therapeutics Inc
Investigators
- Study Director: Giovanni DeCastro, INSYS Therapeutics Inc
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- INS-14-026
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Buprenorphine 0.5 mg TID | Buprenorphine 1.0 mg BID | Buprenorphine 1.0 mg TID | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Participants received buprenorphine 0.5 mg sublingual (under the tongue) spray three times daily (TID) and placebo-matching buprenorphine sublingual spray once daily (QD) for two days. | Participants received buprenorphine 1.0 mg sublingual spray twice daily (BID) and placebo-matching buprenorphine sublingual spray BID for two days. | Participants received buprenorphine 1.0 mg sublingual spray TID and placebo-matching buprenorphine sublingual spray QD for two days. | Participants received placebo-matching buprenorphine sublingual spray four times daily for two days. |
| Period Title: Overall Study | ||||
| STARTED | 9 | 11 | 10 | 10 |
| COMPLETED | 6 | 9 | 9 | 9 |
| NOT COMPLETED | 3 | 2 | 1 | 1 |
Baseline Characteristics
| Arm/Group Title | Buprenorphine 0.5 mg TID | Buprenorphine 1.0 mg BID | Buprenorphine 1.0 mg TID | Placebo | Total |
|---|---|---|---|---|---|
| Arm/Group Description | Participants received buprenorphine 0.5 mg sublingual spray three times daily (TID) and placebo-matching buprenorphine sublingual spray once daily (QD) for two days. | Participants received buprenorphine 1.0 mg sublingual spray twice daily (BID) and placebo-matching buprenorphine sublingual spray BID for two days. | Participants received buprenorphine 1.0 mg sublingual spray TID and placebo-matching buprenorphine sublingual spray QD for two days. | Participants received placebo-matching buprenorphine sublingual spray four times daily for two days. | Total of all reporting groups |
| Overall Participants | 9 | 11 | 10 | 10 | 40 |
| Age (years) [Mean (Full Range) ] | |||||
| Mean (Full Range) [years] |
48.0
|
43.5
|
40.8
|
40.5
|
43.2
|
| Sex: Female, Male (Count of Participants) | |||||
| Female |
7
77.8%
|
9
81.8%
|
7
70%
|
9
90%
|
32
80%
|
| Male |
2
22.2%
|
2
18.2%
|
3
30%
|
1
10%
|
8
20%
|
Outcome Measures
| Title | Numeric Rating Scale (NRS) Summed Pain Intensity Difference (SPID) Over 0 to 48 Hours After Time 0 (NRS SPID-48) |
|---|---|
| Description | Pain intensity was assessed by the participant using an 11-point NRS from 0=no pain to 10=worst possible pain. Pain intensity scores were collected at Baseline (prior to study drug) and at multiple time points up to 48 hours after Time 0 (administration of first dose of study drug). Pain intensity difference is calculated by subtracting the pain intensity at each time point from the pain intensity at Time 0. The SPID scores are the sum of the differences at each time point multiplied by the duration in hours since the previous time point. Positive numbers indicate a reduction in pain [maximum (max)=10 at each time point] and negative numbers indicate an increase in pain [minimum (min)=-10 at each time point]. The overall min and max are -10 and 10 times the number of hours specified; SPID-48 range is -480 to 480. The NRS SPID-48 was analyzed using an analysis of covariance (ANCOVA) model, which included treatment and site as main effects and Baseline pain intensity as the covariate. |
| Time Frame | Baseline and 0 to 48 hours after Time 0 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants from the Intent-to-Treat (ITT) Population. |
| Arm/Group Title | Buprenorphine 0.5 mg TID | Buprenorphine 1.0 mg BID | Buprenorphine 1.0 mg TID | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Participants received buprenorphine 0.5 mg sublingual spray three times daily (TID) and placebo-matching buprenorphine sublingual spray once daily (QD) for two days. | Participants received buprenorphine 1.0 mg sublingual spray twice daily (BID) and placebo-matching buprenorphine sublingual spray BID for two days. | Participants received buprenorphine 1.0 mg sublingual spray TID and placebo-matching buprenorphine sublingual spray QD for two days. | Participants received placebo-matching buprenorphine sublingual spray four times daily for two days. |
| Measure Participants | 9 | 11 | 10 | 10 |
| Least Squares Mean (Standard Error) [units on a scale] |
169.621
(29.9942)
|
150.964
(27.5418)
|
129.133
(29.3429)
|
64.648
(29.0597)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Buprenorphine 0.5 mg TID, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.012 |
| Comments | ||
| Method | ANCOVA | |
| Comments | The analysis included treatment and site as main effects and Baseline pain intensity as the covariate. | |
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | 104.973 | |
| Confidence Interval |
(2-Sided) 95% 25.13 to 184.81 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 39.2433 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Buprenorphine 1.0 mg BID, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.028 |
| Comments | ||
| Method | ANCOVA | |
| Comments | The analysis included treatment and site as main effects and Baseline pain intensity as the covariate. | |
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | 86.316 | |
| Confidence Interval |
(2-Sided) 95% 9.94 to 162.69 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 37.5385 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Buprenorphine 1.0 mg TID, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.110 |
| Comments | ||
| Method | ANCOVA | |
| Comments | The analysis included treatment and site as main effects and Baseline pain intensity as the covariate. | |
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | 64.485 | |
| Confidence Interval |
(2-Sided) 95% -15.36 to 144.33 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 39.2459 |
|
| Estimation Comments | ||
| Title | NRS Mean Pain Intensity Difference (PID) at 4, 8, 24 and 48 Hours After Time 0 |
|---|---|
| Description | Pain intensity was assessed by the participant using an 11-point NRS from 0=no pain to 10=worst possible pain. Pain intensity scores were collected at Baseline (prior to study drug administration) and at multiple time points up to 48 hours after Time 0 (time of administration of the first dose of study drug). NRS PID is defined as the difference in pain at each scheduled timepoint relative to Baseline (PID=pain intensity at baseline - pain intensity at time point). A higher value of NRS PID score indicates a higher decrease in pain from Baseline. |
| Time Frame | Baseline and 4, 8, 24 and 48 hours after Time 0 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants from the ITT Population with data available at each timepoint. |
| Arm/Group Title | Buprenorphine 0.5 mg TID | Buprenorphine 1.0 mg BID | Buprenorphine 1.0 mg TID | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Participants received buprenorphine 0.5 mg sublingual spray three times daily (TID) and placebo-matching buprenorphine sublingual spray once daily (QD) for two days. | Participants received buprenorphine 1.0 mg sublingual spray twice daily (BID) and placebo-matching buprenorphine sublingual spray BID for two days. | Participants received buprenorphine 1.0 mg sublingual spray TID and placebo-matching buprenorphine sublingual spray QD for two days. | Participants received placebo-matching buprenorphine sublingual spray four times daily for two days. |
| Measure Participants | 9 | 11 | 10 | 10 |
| 4 Hours |
4.7
(1.73)
|
3.4
(3.01)
|
3.8
(2.94)
|
1.6
(1.33)
|
| 8 Hours |
3.4
(1.41)
|
4.0
(2.97)
|
3.9
(2.28)
|
1.2
(1.99)
|
| 24 Hours |
5.5
(1.76)
|
3.0
(3.16)
|
3.4
(1.81)
|
2.6
(1.94)
|
| 48 Hours |
6.3
(1.03)
|
4.2
(2.39)
|
4.1
(2.80)
|
3.2
(2.64)
|
| Title | NRS Mean Pain Intensity Score at 4, 8, 24 and 48 Hours After Time 0 |
|---|---|
| Description | Pain intensity was assessed by the participant using an 11-point NRS from 0=no pain to 10=worst possible pain. Pain intensity scores were collected at Baseline (prior to study drug administration) and at multiple time points up to 48 hours after Time 0 (time of administration of the first dose of study drug). A lower value indicates improvement in pain. |
| Time Frame | 4, 8, 24 and 48 hours after Time 0 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants from the ITT Population with data available at each timepoint. |
| Arm/Group Title | Buprenorphine 0.5 mg TID | Buprenorphine 1.0 mg BID | Buprenorphine 1.0 mg TID | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Participants received buprenorphine 0.5 mg sublingual spray three times daily (TID) and placebo-matching buprenorphine sublingual spray once daily (QD) for two days. | Participants received buprenorphine 1.0 mg sublingual spray twice daily (BID) and placebo-matching buprenorphine sublingual spray BID for two days. | Participants received buprenorphine 1.0 mg sublingual spray TID and placebo-matching buprenorphine sublingual spray QD for two days. | Participants received placebo-matching buprenorphine sublingual spray four times daily for two days. |
| Measure Participants | 9 | 11 | 10 | 10 |
| 4 Hours |
2.2
(2.49)
|
2.9
(3.08)
|
4.0
(2.87)
|
4.9
(3.14)
|
| 8 Hours |
3.5
(2.14)
|
2.3
(3.00)
|
3.9
(2.42)
|
5.2
(2.64)
|
| 24 Hours |
1.8
(1.47)
|
3.3
(2.55)
|
4.6
(2.07)
|
3.9
(2.80)
|
| 48 Hours |
1.0
(0.89)
|
2.1
(1.76)
|
3.9
(2.42)
|
3.2
(2.11)
|
| Title | NRS SPID Over 0 to 4 Hours After Time 0 (NRS SPID-4) |
|---|---|
| Description | Pain intensity was assessed by the participant using an 11-point NRS from 0=no pain to 10=worst possible pain. Pain intensity scores were collected at Baseline (prior to study drug) and at multiple time points up to 4 hours after Time 0 (administration of first dose of study drug). Pain intensity difference is calculated by subtracting the pain intensity at each time point from the pain intensity at Time 0. The SPID scores are the sum of the differences at each time point multiplied by the duration in hours since the previous time point. Positive numbers indicate a reduction in pain [maximum (max)=10 at each time point] and negative numbers indicate an increase in pain [minimum (min)=-10 at each time point]. The overall min and max are -10 and 10 times the number of hours specified; SPID-4 range is -40 to 40. The NRS SPID-4 was analyzed using an analysis of covariance (ANCOVA) model, which included treatment and site as main effects and Baseline pain intensity as the covariate. |
| Time Frame | Baseline and 0 to 4 hours after Time 0 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT Population included all participants who were randomized. |
| Arm/Group Title | Buprenorphine 0.5 mg TID | Buprenorphine 1.0 mg BID | Buprenorphine 1.0 mg TID | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Participants received buprenorphine 0.5 mg sublingual spray three times daily (TID) and placebo-matching buprenorphine sublingual spray once daily (QD) for two days. | Participants received buprenorphine 1.0 mg sublingual spray twice daily (BID) and placebo-matching buprenorphine sublingual spray BID for two days. | Participants received buprenorphine 1.0 mg sublingual spray TID and placebo-matching buprenorphine sublingual spray QD for two days. | Participants received placebo-matching buprenorphine sublingual spray four times daily for two days. |
| Measure Participants | 9 | 11 | 10 | 10 |
| Least Squares Mean (Standard Error) [units on a scale] |
11.430
(3.6221)
|
5.088
(3.3259)
|
7.095
(3.5434)
|
-2.968
(3.5092)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Buprenorphine 0.5 mg TID, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.005 |
| Comments | ||
| Method | ANCOVA | |
| Comments | The analysis included treatment and site as main effects and Baseline pain intensity as the covariate. | |
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | 14.398 | |
| Confidence Interval |
(2-Sided) 95% 4.76 to 24.04 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 4.7390 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Buprenorphine 1.0 mg BID, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.085 |
| Comments | ||
| Method | ANCOVA | |
| Comments | The analysis included treatment and site as main effects and Baseline pain intensity as the covariate. | |
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | 8.056 | |
| Confidence Interval |
(2-Sided) 95% -1.17 to 17.28 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 4.5331 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Buprenorphine 1.0 mg TID, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.041 |
| Comments | ||
| Method | ANCOVA | |
| Comments | The analysis included treatment and site as main effects and Baseline pain intensity as the covariate. | |
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | 10.063 | |
| Confidence Interval |
(2-Sided) 95% 0.42 to 19.70 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 4.7393 |
|
| Estimation Comments | ||
| Title | NRS SPID Over 0 to 8 Hours After Time 0 (NRS SPID-8) |
|---|---|
| Description | Pain intensity was assessed by the participant using an 11-point NRS from 0=no pain to 10=worst possible pain. Pain intensity scores were collected at Baseline (prior to study drug) and at multiple time points up to 8 hours after Time 0 (administration of first dose of study drug). Pain intensity difference is calculated by subtracting the pain intensity at each time point from the pain intensity at Time 0. The SPID scores are the sum of the differences at each time point multiplied by the duration in hours since the previous time point. Positive numbers indicate a reduction in pain [maximum (max)=10 at each time point] and negative numbers indicate an increase in pain [minimum (min)=-10 at each time point]. The overall min and max are -10 and 10 times the number of hours specified; SPID-8 range is -80 to 80. The NRS SPID-8 was analyzed using an analysis of covariance (ANCOVA) model, which included treatment and site as main effects and Baseline pain intensity as the covariate. |
| Time Frame | Baseline and 0 to 8 hours after Time 0 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT Population included all randomized participants. |
| Arm/Group Title | Buprenorphine 0.5 mg TID | Buprenorphine 1.0 mg BID | Buprenorphine 1.0 mg TID | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Participants received buprenorphine 0.5 mg sublingual spray three times daily (TID) and placebo-matching buprenorphine sublingual spray once daily (QD) for two days. | Participants received buprenorphine 1.0 mg sublingual spray twice daily (BID) and placebo-matching buprenorphine sublingual spray BID for two days. | Participants received buprenorphine 1.0 mg sublingual spray TID and placebo-matching buprenorphine sublingual spray QD for two days. | Participants received placebo-matching buprenorphine sublingual spray four times daily for two days. |
| Measure Participants | 9 | 11 | 10 | 10 |
| Least Squares Mean (Standard Error) [units on a scale] |
24.283
(6.2667)
|
19.223
(5.7543)
|
19.761
(6.1306)
|
-2.382
(6.0715)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Buprenorphine 0.5 mg TID, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0003 |
| Comments | ||
| Method | ANCOVA | |
| Comments | The analysis included treatment and site as main effects and Baseline pain intensity as the covariate. | |
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | 26.665 | |
| Confidence Interval |
(2-Sided) 95% 9.98 to 43.35 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 8.1991 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Buprenorphine 1.0 mg BID, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.009 |
| Comments | ||
| Method | ANCOVA | |
| Comments | The analysis included treatment and site as main effects and Baseline pain intensity as the covariate. | |
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | 21.605 | |
| Confidence Interval |
(2-Sided) 95% 5.65 to 37.56 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 7.8429 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Buprenorphine 1.0 mg TID, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.011 |
| Comments | ||
| Method | ANCOVA | |
| Comments | The analysis included treatment and site as main effects and Baseline pain intensity as the covariate. | |
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | 22.143 | |
| Confidence Interval |
(2-Sided) 95% 5.46 to 38.83 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 8.1997 |
|
| Estimation Comments | ||
| Title | NRS SPID Over 0 to 24 Hours After Time 0 (NRS SPID-24) |
|---|---|
| Description | Pain intensity was assessed by the participant using an 11-point NRS from 0=no pain to 10=worst possible pain. Pain intensity scores were collected at Baseline (prior to study drug) and at multiple time points up to 24 hours after Time 0 (administration of first dose of study drug). Pain intensity difference is calculated by subtracting the pain intensity at each time point from the pain intensity at Time 0. The SPID scores are the sum of the differences at each time point multiplied by the duration in hours since the previous time point. Positive numbers indicate a reduction in pain [maximum (max)=10 at each time point] and negative numbers indicate an increase in pain [minimum (min)=-10 at each time point]. The overall min and max are -10 and 10 times the number of hours specified; SPID-24 range is -240 to 240. The NRS SPID-24 was analyzed using an analysis of covariance (ANCOVA) model, which included treatment and site as main effects and Baseline pain intensity as the covariate. |
| Time Frame | Baseline and 0 to 24 hours after Time 0 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT Population included all participants who were randomized. |
| Arm/Group Title | Buprenorphine 0.5 mg TID | Buprenorphine 1.0 mg BID | Buprenorphine 1.0 mg TID | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Participants received buprenorphine 0.5 mg sublingual spray three times daily (TID) and placebo-matching buprenorphine sublingual spray once daily (QD) for two days. | Participants received buprenorphine 1.0 mg sublingual spray twice daily (BID) and placebo-matching buprenorphine sublingual spray BID for two days. | Participants received buprenorphine 1.0 mg sublingual spray TID and placebo-matching buprenorphine sublingual spray QD for two days. | Participants received placebo-matching buprenorphine sublingual spray four times daily for two days. |
| Measure Participants | 9 | 11 | 10 | 10 |
| Least Squares Mean (Standard Error) [units on a scale] |
83.668
(14.0612)
|
70.071
(12.9115)
|
76.666
(13.7558)
|
19.787
(13.6231)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Buprenorphine 0.5 mg TID, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.001 |
| Comments | ||
| Method | ANCOVA | |
| Comments | The analysis included treatment and site as main effects and Baseline pain intensity as the covariate. | |
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | 63.881 | |
| Confidence Interval |
(2-Sided) 95% 26.45 to 101.31 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 18.3971 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Buprenorphine 1.0 mg BID, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.007 |
| Comments | ||
| Method | ANCOVA | |
| Comments | The analysis included treatment and site as main effects and Baseline pain intensity as the covariate. | |
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | 50.284 | |
| Confidence Interval |
(2-Sided) 95% 14.48 to 86.09 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 17.5979 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Buprenorphine 1.0 mg TID, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.004 |
| Comments | ||
| Method | ANCOVA | |
| Comments | The analysis included treatment and site as main effects and Baseline pain intensity as the covariate. | |
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | 56.879 | |
| Confidence Interval |
(2-Sided) 95% 19.45 to 94.31 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 18.3984 |
|
| Estimation Comments | ||
| Title | Percentage of Participants Who Used Rescue Medication for Pain |
|---|---|
| Description | The percentage of participants who needed to take an alternate medication for pain relief during the study. |
| Time Frame | From Time 0 (first dose of study drug) up to Day 9 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT Population included all participants who were randomized. |
| Arm/Group Title | Buprenorphine 0.5 mg TID | Buprenorphine 1.0 mg BID | Buprenorphine 1.0 mg TID | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Participants received buprenorphine 0.5 mg sublingual spray three times daily (TID) and placebo-matching buprenorphine sublingual spray once daily (QD) for two days. | Participants received buprenorphine 1.0 mg sublingual spray twice daily (BID) and placebo-matching buprenorphine sublingual spray BID for two days. | Participants received buprenorphine 1.0 mg sublingual spray TID and placebo-matching buprenorphine sublingual spray QD for two days. | Participants received placebo-matching buprenorphine sublingual spray four times daily for two days. |
| Measure Participants | 9 | 11 | 10 | 10 |
| Number [percentage of participants] |
44.4
493.3%
|
54.5
495.5%
|
60.0
600%
|
100
1000%
|
Adverse Events
| Time Frame | Serious Adverse Events: from signing of informed consent to the Follow-up visit (up to 9 days). Non-serious Adverse Events: from the first dose of study drug to the Follow-up visit (up to 9 days). | |||||||
|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||||
| Arm/Group Title | Buprenorphine 0.5 mg TID | Buprenorphine 1.0 mg BID | Buprenorphine 1.0 mg TID | Placebo | ||||
| Arm/Group Description | Participants received buprenorphine 0.5 mg sublingual spray three times daily (TID) and placebo-matching buprenorphine sublingual spray once daily (QD) for two days. | Participants received buprenorphine 1.0 mg sublingual spray twice daily (BID) and placebo-matching buprenorphine sublingual spray BID for two days. | Participants received buprenorphine 1.0 mg sublingual spray TID and placebo-matching buprenorphine sublingual spray QD for two days. | Participants received placebo-matching buprenorphine sublingual spray four times daily for two days. | ||||
All Cause Mortality |
||||||||
| Buprenorphine 0.5 mg TID | Buprenorphine 1.0 mg BID | Buprenorphine 1.0 mg TID | Placebo | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | / (NaN) | ||||
Serious Adverse Events |
||||||||
| Buprenorphine 0.5 mg TID | Buprenorphine 1.0 mg BID | Buprenorphine 1.0 mg TID | Placebo | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/9 (11.1%) | 0/11 (0%) | 0/10 (0%) | 0/10 (0%) | ||||
| Cardiac disorders | ||||||||
| Atrial fibrillation | 1/9 (11.1%) | 0/11 (0%) | 0/10 (0%) | 0/10 (0%) | ||||
Other (Not Including Serious) Adverse Events |
||||||||
| Buprenorphine 0.5 mg TID | Buprenorphine 1.0 mg BID | Buprenorphine 1.0 mg TID | Placebo | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 9/9 (100%) | 11/11 (100%) | 9/10 (90%) | 7/10 (70%) | ||||
| Eye disorders | ||||||||
| Visual disturbance | 0/9 (0%) | 1/11 (9.1%) | 0/10 (0%) | 0/10 (0%) | ||||
| Gastrointestinal disorders | ||||||||
| Burning mouth | 0/9 (0%) | 1/11 (9.1%) | 0/10 (0%) | 0/10 (0%) | ||||
| Constipation | 0/9 (0%) | 3/11 (27.3%) | 2/10 (20%) | 0/10 (0%) | ||||
| Diarrhea | 0/9 (0%) | 0/11 (0%) | 0/10 (0%) | 1/10 (10%) | ||||
| Dry mouth | 1/9 (11.1%) | 0/11 (0%) | 1/10 (10%) | 0/10 (0%) | ||||
| Dysphagia | 1/9 (11.1%) | 1/11 (9.1%) | 0/10 (0%) | 0/10 (0%) | ||||
| Emesis | 4/9 (44.4%) | 5/11 (45.5%) | 5/10 (50%) | 0/10 (0%) | ||||
| Heartburn | 1/9 (11.1%) | 0/11 (0%) | 0/10 (0%) | 0/10 (0%) | ||||
| Loose stools | 0/9 (0%) | 0/11 (0%) | 0/10 (0%) | 1/10 (10%) | ||||
| Nausea | 7/9 (77.8%) | 10/11 (90.9%) | 7/10 (70%) | 3/10 (30%) | ||||
| Numbness mouth | 0/9 (0%) | 1/11 (9.1%) | 0/10 (0%) | 0/10 (0%) | ||||
| Sore mouth | 0/9 (0%) | 1/11 (9.1%) | 0/10 (0%) | 0/10 (0%) | ||||
| Tingling lips | 1/9 (11.1%) | 0/11 (0%) | 0/10 (0%) | 0/10 (0%) | ||||
| Tingling tongue | 0/9 (0%) | 1/11 (9.1%) | 0/10 (0%) | 0/10 (0%) | ||||
| Vomiting | 2/9 (22.2%) | 3/11 (27.3%) | 3/10 (30%) | 0/10 (0%) | ||||
| Xerostomia | 0/9 (0%) | 2/11 (18.2%) | 0/10 (0%) | 0/10 (0%) | ||||
| General disorders | ||||||||
| Feeling hot | 1/9 (11.1%) | 0/11 (0%) | 0/10 (0%) | 0/10 (0%) | ||||
| Shivering | 1/9 (11.1%) | 0/11 (0%) | 0/10 (0%) | 0/10 (0%) | ||||
| Infections and infestations | ||||||||
| Cellulitis | 0/9 (0%) | 1/11 (9.1%) | 0/10 (0%) | 0/10 (0%) | ||||
| Post procedural cellulitis | 0/9 (0%) | 0/11 (0%) | 1/10 (10%) | 0/10 (0%) | ||||
| Injury, poisoning and procedural complications | ||||||||
| Incision site erythema | 0/9 (0%) | 0/11 (0%) | 2/10 (20%) | 0/10 (0%) | ||||
| Investigations | ||||||||
| Oxygen saturation decreased | 1/9 (11.1%) | 0/11 (0%) | 0/10 (0%) | 0/10 (0%) | ||||
| Respiratory rate decreased | 0/9 (0%) | 0/11 (0%) | 1/10 (10%) | 0/10 (0%) | ||||
| Temperature elevation | 1/9 (11.1%) | 0/11 (0%) | 0/10 (0%) | 0/10 (0%) | ||||
| Metabolism and nutrition disorders | ||||||||
| Anorexia | 1/9 (11.1%) | 0/11 (0%) | 0/10 (0%) | 0/10 (0%) | ||||
| Dehydration | 0/9 (0%) | 1/11 (9.1%) | 0/10 (0%) | 0/10 (0%) | ||||
| Musculoskeletal and connective tissue disorders | ||||||||
| Cramps in leg | 1/9 (11.1%) | 0/11 (0%) | 0/10 (0%) | 0/10 (0%) | ||||
| Low back pain | 0/9 (0%) | 1/11 (9.1%) | 0/10 (0%) | 0/10 (0%) | ||||
| Nervous system disorders | ||||||||
| Dizziness | 5/9 (55.6%) | 4/11 (36.4%) | 4/10 (40%) | 0/10 (0%) | ||||
| Dizzy | 0/9 (0%) | 1/11 (9.1%) | 0/10 (0%) | 0/10 (0%) | ||||
| Drowsiness | 4/9 (44.4%) | 3/11 (27.3%) | 4/10 (40%) | 0/10 (0%) | ||||
| Dysgeusia | 0/9 (0%) | 0/11 (0%) | 1/10 (10%) | 0/10 (0%) | ||||
| Headache | 1/9 (11.1%) | 4/11 (36.4%) | 1/10 (10%) | 2/10 (20%) | ||||
| Intermittent headache | 0/9 (0%) | 0/11 (0%) | 0/10 (0%) | 2/10 (20%) | ||||
| Lightheadedness | 2/9 (22.2%) | 1/11 (9.1%) | 1/10 (10%) | 0/10 (0%) | ||||
| Paresthesia of fingers | 1/9 (11.1%) | 0/11 (0%) | 0/10 (0%) | 0/10 (0%) | ||||
| Shakiness | 0/9 (0%) | 0/11 (0%) | 1/10 (10%) | 0/10 (0%) | ||||
| Trembling | 0/9 (0%) | 1/11 (9.1%) | 0/10 (0%) | 0/10 (0%) | ||||
| Psychiatric disorders | ||||||||
| Confusion | 1/9 (11.1%) | 0/11 (0%) | 0/10 (0%) | 0/10 (0%) | ||||
| Euphoria | 0/9 (0%) | 1/11 (9.1%) | 0/10 (0%) | 0/10 (0%) | ||||
| Vivid dreams | 0/9 (0%) | 1/11 (9.1%) | 0/10 (0%) | 0/10 (0%) | ||||
| Renal and urinary disorders | ||||||||
| Urinary retention | 0/9 (0%) | 0/11 (0%) | 1/10 (10%) | 0/10 (0%) | ||||
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Cough | 0/9 (0%) | 0/11 (0%) | 0/10 (0%) | 1/10 (10%) | ||||
| Hiccups | 0/9 (0%) | 1/11 (9.1%) | 0/10 (0%) | 0/10 (0%) | ||||
| Singultus | 1/9 (11.1%) | 0/11 (0%) | 0/10 (0%) | 0/10 (0%) | ||||
| Skin and subcutaneous tissue disorders | ||||||||
| Adhesive tape allergy | 0/9 (0%) | 0/11 (0%) | 0/10 (0%) | 1/10 (10%) | ||||
| Diaphoresis | 2/9 (22.2%) | 2/11 (18.2%) | 1/10 (10%) | 0/10 (0%) | ||||
| Itching | 1/9 (11.1%) | 1/11 (9.1%) | 0/10 (0%) | 0/10 (0%) | ||||
| Localised rash | 0/9 (0%) | 0/11 (0%) | 1/10 (10%) | 1/10 (10%) | ||||
| Pruritus | 1/9 (11.1%) | 1/11 (9.1%) | 1/10 (10%) | 0/10 (0%) | ||||
| Pruritus facial | 1/9 (11.1%) | 1/11 (9.1%) | 0/10 (0%) | 0/10 (0%) | ||||
| Wheals | 0/9 (0%) | 1/11 (9.1%) | 0/10 (0%) | 0/10 (0%) | ||||
| Vascular disorders | ||||||||
| Flushing | 0/9 (0%) | 1/11 (9.1%) | 0/10 (0%) | 0/10 (0%) | ||||
| Hot flush | 1/9 (11.1%) | 2/11 (18.2%) | 0/10 (0%) | 0/10 (0%) | ||||
| Hypertension | 0/9 (0%) | 0/11 (0%) | 0/10 (0%) | 1/10 (10%) | ||||
| Pallor | 1/9 (11.1%) | 0/11 (0%) | 0/10 (0%) | 0/10 (0%) | ||||
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Director, Clinical Development |
|---|---|
| Organization | Insys Therapeutics, Inc. |
| Phone | 480-500-3105 |
| gdecastro@insysrx.com |
- INS-14-026