Low Back Pain, Pain
Conditions
Keywords
buccal soluble film, enriched enrollment, randomized withdrawal
Brief summary
The purpose of this study is to determine whether buprenorphine hydrochloride (HCl) buccal film is effective and safe in the treatment of chronic low back pain (CLBP).
Detailed description
This is an enriched enrollment, randomized withdrawal study with an open label, dose-titration period followed by a randomized, double-blind, placebo-controlled treatment period of 12 weeks. During the double-blind treatment period, this study will evaluate the effectiveness of buprenorphine HCl buccal film versus placebo buccal film in treating CLBP in subjects. Buprenorphine HCl buccal film is an oral transmucosal form of the opioid analgesic, buprenorphine hydrochloride, intended for application to the buccal mucosa. Buprenorphine is a synthetic opioid that is classified as a partial µ-receptor agonist and a Schedule III controlled substance in the United States.
Interventions
DRUGBuprenorphine
buccal soluble film; applied to the buccal mucosa twice daily
DRUGPlacebo
buccal soluble film; applied to the buccal mucosa twice daily
Sponsors
BioDelivery Sciences International
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or non-pregnant and non-nursing female aged 18 or older * History of moderate to severe chronic low back pain for ≥3 months with a pain intensity ≥5 \[11 point numerical rating scale\] reported at the open-label titration period Day 0/1 visit following a washout period (opioids, nonsteroidal anti-inflammatory drugs \[NSAIDs\], and muscle relaxants) of approximately 12 to 24 hours * Currently taking ≤60 mg oral morphine/day or equianalgesic dose of another opioid (including opioid naïve) for 1 week or longer * Stable health, as determined by the Investigator, on the basis of medical history, physical examination, and screening laboratory results so as to comply with all study procedures * Female subjects of childbearing potential must be using a recognized effective method of birth control * Written informed consent obtained at Screening, prior to any procedure being performed
Exclusion criteria
* Reflex sympathetic dystrophy or causalgia (complex regional pain syndrome), acute spinal cord compression, cauda equina compression, acute nerve root compression, meningitis, and discitis * Surgical procedure for back pain within 2 months prior to screening or nerve/plexus block within 4 weeks of screening * Hypokalemia or clinically unstable cardiac disease, including: unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, or active myocardial ischemia * Corrected QT (QTc) interval of \>450 milliseconds on the 12-lead electrocardiogram (ECG) * History of long QT syndrome, or an immediate family member with this condition * Diagnosis of moderate to severe hepatic impairment. * History of severe emesis with opioids * Clinically significant sleep apnea
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Pain Intensity From Baseline to Week 12 | Baseline, Week 12 | Change in pain intensity = average of daily pain scores from the last 7 days prior to week 12 visit - average of daily pain scores for the last 7 days prior to randomization. Average pain intensity over the last 24 hours was rated on an 11-point numeric rating scale (NRS) ranging from 0 (no pain) to 10 (worst pain imaginable). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Response to Treatment as Assessed by an NRS Scale | Week 12 | Responses are defined as the relative improvement in pain score at week 12 from baseline, calculated from ratings of average pain intensity over the last 24 hours on an 11-point numeric rating scale (NRS) ranging from 0 (no pain) to 10 (worst pain imaginable). |
| Percentage of Participants With Treatment Failure in the Double-blind Treatment Phase (up to 12 Weeks) | Baseline to treatment failure or end of double-blind treatment phase (up to 12 weeks) | Treatment failure is defined as study discontinuation due to lack of efficacy or due to adverse event in the double-blind treatment phase. |
| Subject Impression of Change in Pain Intensity From Baseline to Week 12 Using PGIC Scale | Baseline, Week 12 | Subjects assessed changes in activity, limitations, symptoms, and overall quality of life related to their painful condition since beginning treatment using the Patient Global Impression of Change (PGIC), a balanced 7-point scale from 1 (no change or condition got worse) to 7 (a great deal better and considerable improvement that has made all the difference). |
| Change From Baseline to Week 12 in Treatment Satisfaction Using TSQM | Baseline, Week 12 | The Treatment Satisfaction Questionnaire for Medication (TSQM) is a 14-item instrument used to assess the subject's satisfaction with the ability of the study medication to prevent or treat the condition of chronic low back pain (CLBP) for effectiveness, side effects, convenience, and global satisfaction. Scores range from 0 to 100, where a higher score indicates less dissatisfaction (ie, greater satisfaction). |
| Change From Baseline in Pain Intensity Over Time Using NRS Scale | Baseline; Day 14, Day 28, Day 42, Day 56, Day 70, and Day 84 | Change in pain intensity = average of daily pain scores from the last 7 days prior to each visit - average of daily pain scores for the last 7 days prior to randomization. Average pain intensity over the last 24 hours was rated on an 11-point numeric rating scale (NRS) ranging from 0 (no pain) to 10 (worst pain imaginable). |
| Change From Baseline to Week 12 in Subject's Overall Satisfaction With Study Drug | Baseline, Week 12 | Subjects were asked to rate their overall satisfaction with their study drug on a 5-point scale ranging from 1 (poor) to 5 (excellent). |
| Change From Baseline to Week 12 in Investigator's Overall Satisfaction With Study Drug | Baseline, Week 12 | Investigators rated their overall satisfaction with the study drug administered to a given subject on a 5-point scale ranging from 1 (poor) to 5 (excellent). |
| Use of Rescue Medication | Day 7, 14, 28, 42, 56, 70, 84, and 91 within double-blind treatment phase | Calculated from the use of rescue medication recorded in subject diary as the sum of all rescue medication tablets used in the last 7 days previous to the derived visit, divided by the number of days in this duration where the amount was reported. |
| Change From Baseline to Week 12 in Roland Morris Disability Questionnaire | Baseline, Week 12 | Subjects assess disability due to back pain using the Roland Morris Disability Questionnaire (RMDQ) consisting of 24 statements of disability. The score of the RMDQ is the total number of items checked, ranging from 0 to 24 with higher scores indicating greater disability. |
Countries
United States
Participant flow
Pre-assignment details
Of 334 subjects who were enrolled in the open-label (OL) titration phase; a total of 235 completed the open-label titration phase and were randomized in the double-blind (DB) treatment phase.
Participants by arm
| Arm | Count |
|---|---|
| DB Buprenorphine HCl Buccal Film Buprenorphine HCl buccal film, 60, 120, 180, or 240 µg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period | 117 |
| DB Placebo Film Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period | 118 |
| Total | 235 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-blind Treatment | Adverse Event | 0 | 8 | 6 |
| Double-blind Treatment | Lack of analgesic effect | 0 | 5 | 6 |
| Double-blind Treatment | Lost to Follow-up | 0 | 1 | 7 |
| Double-blind Treatment | Non-compliance | 0 | 5 | 4 |
| Double-blind Treatment | Opioid withdrawal symptoms | 0 | 0 | 1 |
| Double-blind Treatment | Other | 0 | 9 | 12 |
| Double-blind Treatment | Withdrawal by Subject | 0 | 0 | 1 |
| Open-label Titration | Adverse Event | 39 | 0 | 0 |
| Open-label Titration | Lack of analgesic effect | 30 | 0 | 0 |
| Open-label Titration | Lost to Follow-up | 7 | 0 | 0 |
| Open-label Titration | Non-compliance | 9 | 0 | 0 |
| Open-label Titration | Other | 13 | 0 | 0 |
| Open-label Titration | Screen failure | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | DB Placebo Film | DB Buprenorphine HCl Buccal Film | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 18 Participants | 17 Participants | 35 Participants |
| Age, Categorical Between 18 and 65 years | 100 Participants | 100 Participants | 200 Participants |
| Age, Continuous | 51.5 years | 52.0 years | 52.0 years |
| Gender Female | 66 Participants | 62 Participants | 128 Participants |
| Gender Male | 52 Participants | 55 Participants | 107 Participants |
| Region of Enrollment United States | 118 participants | 117 participants | 235 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 163 / 330 | 36 / 117 | 28 / 118 |
| serious Total, serious adverse events | 1 / 330 | 1 / 117 | 0 / 118 |
Outcome results
Primary
Change in Pain Intensity From Baseline to Week 12
Change in pain intensity = average of daily pain scores from the last 7 days prior to week 12 visit - average of daily pain scores for the last 7 days prior to randomization. Average pain intensity over the last 24 hours was rated on an 11-point numeric rating scale (NRS) ranging from 0 (no pain) to 10 (worst pain imaginable).
Time frame: Baseline, Week 12
Population: Analysis based on Intent-to-Treat (ITT) population; all randomized subjects who received at least 1 dose of double-blind study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DB Buprenorphine HCl Buccal Film | Change in Pain Intensity From Baseline to Week 12 | 0.33 units on a scale | Standard Deviation 1.944 |
| DB Placebo Film | Change in Pain Intensity From Baseline to Week 12 | 0.46 units on a scale | Standard Deviation 2.093 |
p-value: 0.58795% CI: [-0.646, 0.366]ANCOVA
Secondary
Change From Baseline in Pain Intensity Over Time Using NRS Scale
Change in pain intensity = average of daily pain scores from the last 7 days prior to each visit - average of daily pain scores for the last 7 days prior to randomization. Average pain intensity over the last 24 hours was rated on an 11-point numeric rating scale (NRS) ranging from 0 (no pain) to 10 (worst pain imaginable).
Time frame: Baseline; Day 14, Day 28, Day 42, Day 56, Day 70, and Day 84
Population: Analysis based on ITT population; all randomized subjects who received at least 1 dose of double-blind study medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DB Buprenorphine HCl Buccal Film | Change From Baseline in Pain Intensity Over Time Using NRS Scale | Day 14 | 0.21 units on a scale | Standard Deviation 1.469 |
| DB Buprenorphine HCl Buccal Film | Change From Baseline in Pain Intensity Over Time Using NRS Scale | Day 28 | 0.20 units on a scale | Standard Deviation 1.539 |
| DB Buprenorphine HCl Buccal Film | Change From Baseline in Pain Intensity Over Time Using NRS Scale | Day 42 | 0.13 units on a scale | Standard Deviation 1.535 |
| DB Buprenorphine HCl Buccal Film | Change From Baseline in Pain Intensity Over Time Using NRS Scale | Day 56 | 0.21 units on a scale | Standard Deviation 1.709 |
| DB Buprenorphine HCl Buccal Film | Change From Baseline in Pain Intensity Over Time Using NRS Scale | Day 70 | 0.15 units on a scale | Standard Deviation 1.783 |
| DB Buprenorphine HCl Buccal Film | Change From Baseline in Pain Intensity Over Time Using NRS Scale | Day 84 | 0.29 units on a scale | Standard Deviation 1.984 |
| DB Placebo Film | Change From Baseline in Pain Intensity Over Time Using NRS Scale | Day 70 | 0.35 units on a scale | Standard Deviation 2.056 |
| DB Placebo Film | Change From Baseline in Pain Intensity Over Time Using NRS Scale | Day 14 | 0.25 units on a scale | Standard Deviation 1.624 |
| DB Placebo Film | Change From Baseline in Pain Intensity Over Time Using NRS Scale | Day 56 | 0.23 units on a scale | Standard Deviation 1.926 |
| DB Placebo Film | Change From Baseline in Pain Intensity Over Time Using NRS Scale | Day 28 | 0.29 units on a scale | Standard Deviation 1.877 |
| DB Placebo Film | Change From Baseline in Pain Intensity Over Time Using NRS Scale | Day 84 | 0.38 units on a scale | Standard Deviation 2.058 |
| DB Placebo Film | Change From Baseline in Pain Intensity Over Time Using NRS Scale | Day 42 | 0.25 units on a scale | Standard Deviation 1.84 |
Secondary
Change From Baseline to Week 12 in Investigator's Overall Satisfaction With Study Drug
Investigators rated their overall satisfaction with the study drug administered to a given subject on a 5-point scale ranging from 1 (poor) to 5 (excellent).
Time frame: Baseline, Week 12
Population: Analysis based on ITT population; all randomized subjects who received at least 1 dose of double-blind study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DB Buprenorphine HCl Buccal Film | Change From Baseline to Week 12 in Investigator's Overall Satisfaction With Study Drug | -0.27 units on a scale | Standard Deviation 1.312 |
| DB Placebo Film | Change From Baseline to Week 12 in Investigator's Overall Satisfaction With Study Drug | -0.37 units on a scale | Standard Deviation 1.369 |
Secondary
Change From Baseline to Week 12 in Roland Morris Disability Questionnaire
Subjects assess disability due to back pain using the Roland Morris Disability Questionnaire (RMDQ) consisting of 24 statements of disability. The score of the RMDQ is the total number of items checked, ranging from 0 to 24 with higher scores indicating greater disability.
Time frame: Baseline, Week 12
Population: Analysis based on ITT population; all randomized subjects who received at least 1 dose of double-blind study medication
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DB Buprenorphine HCl Buccal Film | Change From Baseline to Week 12 in Roland Morris Disability Questionnaire | 0.09 units on a scale | Standard Deviation 5.606 |
| DB Placebo Film | Change From Baseline to Week 12 in Roland Morris Disability Questionnaire | 1.00 units on a scale | Standard Deviation 4.319 |
Secondary
Change From Baseline to Week 12 in Subject's Overall Satisfaction With Study Drug
Subjects were asked to rate their overall satisfaction with their study drug on a 5-point scale ranging from 1 (poor) to 5 (excellent).
Time frame: Baseline, Week 12
Population: Analysis based on ITT population; all randomized subjects who received at least 1 dose of double-blind study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DB Buprenorphine HCl Buccal Film | Change From Baseline to Week 12 in Subject's Overall Satisfaction With Study Drug | -0.30 units on a scale | Standard Deviation 1.409 |
| DB Placebo Film | Change From Baseline to Week 12 in Subject's Overall Satisfaction With Study Drug | -0.48 units on a scale | Standard Deviation 1.329 |
Secondary
Change From Baseline to Week 12 in Treatment Satisfaction Using TSQM
The Treatment Satisfaction Questionnaire for Medication (TSQM) is a 14-item instrument used to assess the subject's satisfaction with the ability of the study medication to prevent or treat the condition of chronic low back pain (CLBP) for effectiveness, side effects, convenience, and global satisfaction. Scores range from 0 to 100, where a higher score indicates less dissatisfaction (ie, greater satisfaction).
Time frame: Baseline, Week 12
Population: Analysis based on ITT population; all randomized subjects who received at least 1 dose of double-blind study medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DB Buprenorphine HCl Buccal Film | Change From Baseline to Week 12 in Treatment Satisfaction Using TSQM | Effectiveness | -2.06 units on a scale | Standard Deviation 25.172 |
| DB Buprenorphine HCl Buccal Film | Change From Baseline to Week 12 in Treatment Satisfaction Using TSQM | Side effects | 3.09 units on a scale | Standard Deviation 14.137 |
| DB Buprenorphine HCl Buccal Film | Change From Baseline to Week 12 in Treatment Satisfaction Using TSQM | Convenience | -3.12 units on a scale | Standard Deviation 13.294 |
| DB Buprenorphine HCl Buccal Film | Change From Baseline to Week 12 in Treatment Satisfaction Using TSQM | Global satisfaction | -8.19 units on a scale | Standard Deviation 26.146 |
| DB Placebo Film | Change From Baseline to Week 12 in Treatment Satisfaction Using TSQM | Global satisfaction | -11.73 units on a scale | Standard Deviation 26.829 |
| DB Placebo Film | Change From Baseline to Week 12 in Treatment Satisfaction Using TSQM | Effectiveness | -9.03 units on a scale | Standard Deviation 27.804 |
| DB Placebo Film | Change From Baseline to Week 12 in Treatment Satisfaction Using TSQM | Convenience | -0.00 units on a scale | Standard Deviation 14.081 |
| DB Placebo Film | Change From Baseline to Week 12 in Treatment Satisfaction Using TSQM | Side effects | 10.88 units on a scale | Standard Deviation 18.243 |
Secondary
Number of Participants With Response to Treatment as Assessed by an NRS Scale
Responses are defined as the relative improvement in pain score at week 12 from baseline, calculated from ratings of average pain intensity over the last 24 hours on an 11-point numeric rating scale (NRS) ranging from 0 (no pain) to 10 (worst pain imaginable).
Time frame: Week 12
Population: Analysis based on ITT population; all randomized subjects who received at least 1 dose of double-blind study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| DB Buprenorphine HCl Buccal Film | Number of Participants With Response to Treatment as Assessed by an NRS Scale | ≥30% Response | 28 participants |
| DB Buprenorphine HCl Buccal Film | Number of Participants With Response to Treatment as Assessed by an NRS Scale | ≥60% Response | 11 participants |
| DB Buprenorphine HCl Buccal Film | Number of Participants With Response to Treatment as Assessed by an NRS Scale | ≥20% Response | 37 participants |
| DB Buprenorphine HCl Buccal Film | Number of Participants With Response to Treatment as Assessed by an NRS Scale | ≥70% Response | 8 participants |
| DB Buprenorphine HCl Buccal Film | Number of Participants With Response to Treatment as Assessed by an NRS Scale | ≥40% Response | 19 participants |
| DB Buprenorphine HCl Buccal Film | Number of Participants With Response to Treatment as Assessed by an NRS Scale | ≥80% Response | 5 participants |
| DB Buprenorphine HCl Buccal Film | Number of Participants With Response to Treatment as Assessed by an NRS Scale | ≥10% Response | 48 participants |
| DB Buprenorphine HCl Buccal Film | Number of Participants With Response to Treatment as Assessed by an NRS Scale | ≥90% Response | 5 participants |
| DB Buprenorphine HCl Buccal Film | Number of Participants With Response to Treatment as Assessed by an NRS Scale | ≥50% Response | 13 participants |
| DB Buprenorphine HCl Buccal Film | Number of Participants With Response to Treatment as Assessed by an NRS Scale | ≥100% Response | 3 participants |
| DB Buprenorphine HCl Buccal Film | Number of Participants With Response to Treatment as Assessed by an NRS Scale | ≥0% Response | 117 participants |
| DB Placebo Film | Number of Participants With Response to Treatment as Assessed by an NRS Scale | ≥100% Response | 6 participants |
| DB Placebo Film | Number of Participants With Response to Treatment as Assessed by an NRS Scale | ≥0% Response | 118 participants |
| DB Placebo Film | Number of Participants With Response to Treatment as Assessed by an NRS Scale | ≥10% Response | 32 participants |
| DB Placebo Film | Number of Participants With Response to Treatment as Assessed by an NRS Scale | ≥20% Response | 30 participants |
| DB Placebo Film | Number of Participants With Response to Treatment as Assessed by an NRS Scale | ≥30% Response | 27 participants |
| DB Placebo Film | Number of Participants With Response to Treatment as Assessed by an NRS Scale | ≥40% Response | 23 participants |
| DB Placebo Film | Number of Participants With Response to Treatment as Assessed by an NRS Scale | ≥50% Response | 20 participants |
| DB Placebo Film | Number of Participants With Response to Treatment as Assessed by an NRS Scale | ≥60% Response | 16 participants |
| DB Placebo Film | Number of Participants With Response to Treatment as Assessed by an NRS Scale | ≥70% Response | 13 participants |
| DB Placebo Film | Number of Participants With Response to Treatment as Assessed by an NRS Scale | ≥80% Response | 9 participants |
| DB Placebo Film | Number of Participants With Response to Treatment as Assessed by an NRS Scale | ≥90% Response | 7 participants |
Secondary
Percentage of Participants With Treatment Failure in the Double-blind Treatment Phase (up to 12 Weeks)
Treatment failure is defined as study discontinuation due to lack of efficacy or due to adverse event in the double-blind treatment phase.
Time frame: Baseline to treatment failure or end of double-blind treatment phase (up to 12 weeks)
Population: Analysis based on ITT population; all randomized subjects who received at least 1 dose of double-blind study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DB Buprenorphine HCl Buccal Film | Percentage of Participants With Treatment Failure in the Double-blind Treatment Phase (up to 12 Weeks) | 9.4 percentage of participants |
| DB Placebo Film | Percentage of Participants With Treatment Failure in the Double-blind Treatment Phase (up to 12 Weeks) | 11.9 percentage of participants |
Secondary
Subject Impression of Change in Pain Intensity From Baseline to Week 12 Using PGIC Scale
Subjects assessed changes in activity, limitations, symptoms, and overall quality of life related to their painful condition since beginning treatment using the Patient Global Impression of Change (PGIC), a balanced 7-point scale from 1 (no change or condition got worse) to 7 (a great deal better and considerable improvement that has made all the difference).
Time frame: Baseline, Week 12
Population: Analysis based on ITT population; all randomized subjects who received at least 1 dose of double-blind study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DB Buprenorphine HCl Buccal Film | Subject Impression of Change in Pain Intensity From Baseline to Week 12 Using PGIC Scale | -0.32 units on a scale | Standard Deviation 2.091 |
| DB Placebo Film | Subject Impression of Change in Pain Intensity From Baseline to Week 12 Using PGIC Scale | -0.92 units on a scale | Standard Deviation 2.11 |
Secondary
Use of Rescue Medication
Calculated from the use of rescue medication recorded in subject diary as the sum of all rescue medication tablets used in the last 7 days previous to the derived visit, divided by the number of days in this duration where the amount was reported.
Time frame: Day 7, 14, 28, 42, 56, 70, 84, and 91 within double-blind treatment phase
Population: Analysis based on ITT population; all randomized subjects who received at least 1 dose of double-blind study medication
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DB Buprenorphine HCl Buccal Film | Use of Rescue Medication | Day 7 | 0.87 Tablets per day | Standard Deviation 1.143 |
| DB Buprenorphine HCl Buccal Film | Use of Rescue Medication | Day 28 | 0.93 Tablets per day | Standard Deviation 1.239 |
| DB Buprenorphine HCl Buccal Film | Use of Rescue Medication | Day 70 | 0.83 Tablets per day | Standard Deviation 1.197 |
| DB Buprenorphine HCl Buccal Film | Use of Rescue Medication | Day 14 | 0.93 Tablets per day | Standard Deviation 1.135 |
| DB Buprenorphine HCl Buccal Film | Use of Rescue Medication | Day 84 | 0.97 Tablets per day | Standard Deviation 1.277 |
| DB Buprenorphine HCl Buccal Film | Use of Rescue Medication | Day 42 | 0.97 Tablets per day | Standard Deviation 1.25 |
| DB Buprenorphine HCl Buccal Film | Use of Rescue Medication | Follow-up Day 91 | 0.79 Tablets per day | Standard Deviation 1.143 |
| DB Buprenorphine HCl Buccal Film | Use of Rescue Medication | Day 56 | 0.89 Tablets per day | Standard Deviation 1.245 |
| DB Placebo Film | Use of Rescue Medication | Follow-up Day 91 | 1.07 Tablets per day | Standard Deviation 1.37 |
| DB Placebo Film | Use of Rescue Medication | Day 7 | 0.82 Tablets per day | Standard Deviation 1.103 |
| DB Placebo Film | Use of Rescue Medication | Day 14 | 1.03 Tablets per day | Standard Deviation 1.289 |
| DB Placebo Film | Use of Rescue Medication | Day 28 | 1.02 Tablets per day | Standard Deviation 1.325 |
| DB Placebo Film | Use of Rescue Medication | Day 42 | 1.04 Tablets per day | Standard Deviation 1.358 |
| DB Placebo Film | Use of Rescue Medication | Day 56 | 0.99 Tablets per day | Standard Deviation 1.364 |
| DB Placebo Film | Use of Rescue Medication | Day 70 | 0.98 Tablets per day | Standard Deviation 1.611 |
| DB Placebo Film | Use of Rescue Medication | Day 84 | 0.91 Tablets per day | Standard Deviation 1.276 |