Bone Neoplasms, Cancer, Pain, Intractable
Conditions
Brief summary
The purpose of this study is to assess the analgesic efficacy of flexibly-dosed pregabalin in the adjunctive treatment of subjects with cancer-induced bone pain.
Detailed description
Pfizer decided to discontinue additional enrollment into the study effective Sept 5 2010 after assessing the feasibility of completing this study in a realistic timeframe.The study was not stopped for any safety concerns.
Interventions
DRUGPregabalin
Capsule, Flexible-dosing, Double-blind. Treatment duration is 28 days at 100-600 mg/day administered BID+ taper (6 days).
DRUGPlacebo
Placebo
Sponsors
Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient must have a malignant, solid tumor that has been diagnosed as having metastasized to bone, and must have moderate to severe pain secondary to the bone metastasis at an identifiable reference site.
Exclusion criteria
* The patient who has undergone diagnostic or therapeutic invasive interventions (angiography, biopsy, surgery) less than 15 days prior to study start that would impact their assessment of pain at the reference pain site or area, in the opinion of the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Duration Adjusted Average Change (DAAC) From Baseline in Daily Worst Pain, Fixed Dosing Date to Day 28 | Baseline, Fixed Dosing Date to Day 28 or Early Termination (ET) | DAAC from baseline based on Numeric Rating Scale (NRS) score for Worst Pain at Reference site from the last day dose adjustment was needed (fixed dosing date) to day 28. DAAC defined as area under the curve (AUC) of change in worst pain divided by pain measurement duration. Pain rated on an 11 point scale ranged from 0 (no pain) to 10 (worst possible pain). Change was week x minus baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| DAAC From Baseline in Daily Worst Pain, Day 1 to End of Dose Adjustment | Baseline, Day 1 to End of Dose Adjustment or ET | DAAC from baseline in the daily worst pain based on the NRS Worst Pain at Reference Site score collected from participant's daily diary. Pain rated on an 11 point scale ranged from 0 (no pain) to 10 (worst possible pain). DAAC defined as AUC of daily worst pain score divided by pain measurement duration. Change was week x minus baseline. |
| DAAC From Baseline in Daily Worst Pain 14 Days After Fixed Dosing Date Up to Day 28 | Baseline, 14 Days After Fixed Dosing Date up to Day 28 or ET | DAAC from baseline in the daily worst pain based on the NRS Worst Pain at Reference Site score collected from participant's daily diary 14 days after dosing stabilized (fixed dosing date) up to Day 28. Pain rated on an 11 point scale ranged from 0 (no pain) to 10 (worst possible pain). DAAC defined as AUC of daily worst pain score divided by pain measurement duration. Change was week x minus baseline. |
| Change From Baseline in Modified Brief Pain Inventory (mBPI-sf) Pain Severity Index Score at Week 4 | Baseline, Week 4 or ET | m-BPI-sf: participant rated 11-point Likert rating scale ranging from 0 (no pain) to 10 (worst pain possible). Pain severity index was the mean of item scores 1, 2, 3, and 4 (worst, least, average and current pain scores). Change was scores at observation minus scores at baseline. |
| Change From Baseline in mBPI-sf Interference Index Score at Week 4 | Baseline, Week 4 or ET | m-BPI-sf: participant-rated 11 point Likert rating scale ranging from 0 (does not interfere) to 10 (completely intereres) with functional activities (general activity, mood, walking ability, relations with other people, sleep, normal work, and enjoyment of life) in past 24 hours. Change was score at each observation minus baseline score. |
| Change From Baseline in Average Pain Scores at Weeks 1, 2, 3 and 4 | Baseline, Weeks 1, 2, 3 and 4 or ET | Change from baseline in daily average pain score NRS 0 (no pain) to 10 (pain as bad as you can imagine) for pain intensity over past 24 hours recorded every evening before bedtime. Change was week x average minus baseline average. |
| DAAC From Baseline in Daily Worst Pain, Days 1 Through 28 | Baseline, Days 1 through 28 or ET | DAAC from baseline in the daily worst pain based on the NRS Worst Pain at Reference Site score collected from participant's daily diary. Pain rated on an 11 point scale ranged from 0 (no pain) to 10 (worst possible pain). DAAC defined as AUC of daily worst pain score divided by pain measurement duration. Change was week x minus baseline. |
| Change From Pre-Baseline in Total Daily Dose of Morphine Equivalents Day 0 Through Day 28 | Baseline, Day 0 through Day 28 or ET | IR and SR formulations separately and combined. Change was day x minus baseline. |
| Change From Baseline in Hospital Anxiety and Depression Scale (HADS) at Week 4 | Baseline, Week 4 or ET | HADS: participant rated questionnaire with 2 subscales. HADS-Anxiety assessed generalized anxiety (anxious mood/ restlessness/ anxious thoughts/panic attacks); HADS-Depression assessed lost interest/diminished pleasure response (lowering of hedonic tone). Each subscale has 7 items which ranged from 0 (no presence of anxiety or depression) to 3 (severe feeling anxiety/depression). Total 0-21 for each subscale; higher score indicates greater severity of anxiety and depression symptoms. Change was week x minus baseline. |
| Patient Global Impression of Change (PGIC) | Weeks 2 and 4 or ET | PGIC: participant rated instrument to measure participant's change in overall status on a 7-point scale; range from 1 (very much improved) to 7 (very much worse). |
| Change From Baseline in Opioid-Related Symptoms Distress Scale (OR-SDS) at Day 14 and Day 28 | Baseline, Day 14, Day 28 or ET | OR-SDS included OR-SDS individual items by dimension of frequency (rarely to almost constantly), severity (slight to very severe), and degree of bother (not at all to very much), number of episodes of retching/vomiting, OR-SDS dimension composite and overall composite scores. Change was scores at occurance minus score at baseline. |
| Change From Baseline in Eastern Cooperative Oncology Group Performance (ECOG) Status Scale at Day 28 | Baseline, Day 28 or ET | ECOG - assessed disease progression and how disease affected the daily living abilities of the participant and determined appropriate treatment and prognosis. Graded 0 (fully active able to carry on all pre-disease performance without restrictions) to 5 (dead). Change was day 28 minus baseline. |
| Change From Baseline in Total Daily Dose of Opioids Day 0 Through Day 28 | Baseline, Day 0 through Day 28 or ET | Change from baseline in total daily dose of opioids immediate release (IR), sustained release (SR) formulations separately and combined. |
Countries
Canada, Czechia, Egypt, Finland, France, Hungary, Italy, Mexico, Peru, Philippines, Poland, Russia, South Korea, Spain, Sweden, Taiwan, Thailand, United States, Venezuela
Participant flow
Recruitment details
A0081128 terminated on 01-SEP-2010 due to slow enrollment, analysis at 50 percent (%) enrollment determined that increasing the sample size would require significant extension of enrollment period.
Participants by arm
| Arm | Count |
|---|---|
| Pregabalin Pregabalin Flexible Dose 50 to 300 milligrams (mg) capsules orally twice per day (100 to 600 mg/day) for 28 days. Dose adjustments from Day 2 up to Day 14 as needed, followed by fixed dosing through Day 28, followed by dose tapering to Day 34 | 72 |
| Placebo Matching placebo capsules orally twice per day | 80 |
| Total | 152 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 7 |
| Overall Study | Death | 3 | 4 |
| Overall Study | Lack of Efficacy | 2 | 4 |
| Overall Study | Other | 2 | 2 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | Pregabalin | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 22 Participants | 26 Participants | 48 Participants |
| Age, Categorical Between 18 and 65 years | 50 Participants | 54 Participants | 104 Participants |
| Sex: Female, Male Female | 36 Participants | 41 Participants | 77 Participants |
| Sex: Female, Male Male | 36 Participants | 39 Participants | 75 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 38 / 72 | 31 / 80 |
| serious Total, serious adverse events | 12 / 72 | 12 / 80 |
Outcome results
Primary
Duration Adjusted Average Change (DAAC) From Baseline in Daily Worst Pain, Fixed Dosing Date to Day 28
DAAC from baseline based on Numeric Rating Scale (NRS) score for Worst Pain at Reference site from the last day dose adjustment was needed (fixed dosing date) to day 28. DAAC defined as area under the curve (AUC) of change in worst pain divided by pain measurement duration. Pain rated on an 11 point scale ranged from 0 (no pain) to 10 (worst possible pain). Change was week x minus baseline.
Time frame: Baseline, Fixed Dosing Date to Day 28 or Early Termination (ET)
Population: Intent-To-Treat population (ITT): all randomized participants for whom at least one post-baseline efficacy evaluation was obtained; N= the number of participants with evaluable data analyzed; n= number of participants with evaluable data at the specific time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pregabalin | Duration Adjusted Average Change (DAAC) From Baseline in Daily Worst Pain, Fixed Dosing Date to Day 28 | Baseline (n=72, 79) | 6.28 Units on a scale | Standard Deviation 1.68 |
| Pregabalin | Duration Adjusted Average Change (DAAC) From Baseline in Daily Worst Pain, Fixed Dosing Date to Day 28 | Change at Day 28 (n=72, 77) | -1.53 Units on a scale | Standard Deviation 1.81 |
| Placebo | Duration Adjusted Average Change (DAAC) From Baseline in Daily Worst Pain, Fixed Dosing Date to Day 28 | Baseline (n=72, 79) | 6.47 Units on a scale | Standard Deviation 1.59 |
| Placebo | Duration Adjusted Average Change (DAAC) From Baseline in Daily Worst Pain, Fixed Dosing Date to Day 28 | Change at Day 28 (n=72, 77) | -1.23 Units on a scale | Standard Deviation 1.74 |
Secondary
Change From Baseline in Average Pain Scores at Weeks 1, 2, 3 and 4
Change from baseline in daily average pain score NRS 0 (no pain) to 10 (pain as bad as you can imagine) for pain intensity over past 24 hours recorded every evening before bedtime. Change was week x average minus baseline average.
Time frame: Baseline, Weeks 1, 2, 3 and 4 or ET
Population: Data not analyzed due to early study termination.
Secondary
Change From Baseline in Eastern Cooperative Oncology Group Performance (ECOG) Status Scale at Day 28
ECOG - assessed disease progression and how disease affected the daily living abilities of the participant and determined appropriate treatment and prognosis. Graded 0 (fully active able to carry on all pre-disease performance without restrictions) to 5 (dead). Change was day 28 minus baseline.
Time frame: Baseline, Day 28 or ET
Population: Data not analyzed due to early study termination.
Secondary
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) at Week 4
HADS: participant rated questionnaire with 2 subscales. HADS-Anxiety assessed generalized anxiety (anxious mood/ restlessness/ anxious thoughts/panic attacks); HADS-Depression assessed lost interest/diminished pleasure response (lowering of hedonic tone). Each subscale has 7 items which ranged from 0 (no presence of anxiety or depression) to 3 (severe feeling anxiety/depression). Total 0-21 for each subscale; higher score indicates greater severity of anxiety and depression symptoms. Change was week x minus baseline.
Time frame: Baseline, Week 4 or ET
Population: ITT; LOCF; n= number of evaluable participants analyzed at each time point; N= number of participants with evaluable data analyzed; individual symptoms not analyzed
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pregabalin | Change From Baseline in Hospital Anxiety and Depression Scale (HADS) at Week 4 | Anxiety Baseline (n= 72, 78) | 11.61 Units on a scale | Standard Deviation 2.94 |
| Pregabalin | Change From Baseline in Hospital Anxiety and Depression Scale (HADS) at Week 4 | Anxiety Change at Week 4 (n= 60, 60) | 0.98 Units on a scale | Standard Deviation 3.31 |
| Pregabalin | Change From Baseline in Hospital Anxiety and Depression Scale (HADS) at Week 4 | Anxiety Change at Week 4/LOCF (n=64, 65) | 0.80 Units on a scale | Standard Deviation 3.37 |
| Pregabalin | Change From Baseline in Hospital Anxiety and Depression Scale (HADS) at Week 4 | Depression Baseline (n= 72, 78) | 9.33 Units on a scale | Standard Deviation 2.18 |
| Pregabalin | Change From Baseline in Hospital Anxiety and Depression Scale (HADS) at Week 4 | Depression Change at Week 4 (n= 60, 60) | 0.20 Units on a scale | Standard Deviation 2.77 |
| Pregabalin | Change From Baseline in Hospital Anxiety and Depression Scale (HADS) at Week 4 | Depression Change at Week 4/LOCF (n=64, 65) | 0.22 Units on a scale | Standard Deviation 2.73 |
| Placebo | Change From Baseline in Hospital Anxiety and Depression Scale (HADS) at Week 4 | Depression Change at Week 4 (n= 60, 60) | -0.57 Units on a scale | Standard Deviation 2.13 |
| Placebo | Change From Baseline in Hospital Anxiety and Depression Scale (HADS) at Week 4 | Anxiety Baseline (n= 72, 78) | 11.60 Units on a scale | Standard Deviation 2.74 |
| Placebo | Change From Baseline in Hospital Anxiety and Depression Scale (HADS) at Week 4 | Depression Baseline (n= 72, 78) | 10.15 Units on a scale | Standard Deviation 2.59 |
| Placebo | Change From Baseline in Hospital Anxiety and Depression Scale (HADS) at Week 4 | Anxiety Change at Week 4 (n= 60, 60) | 0.80 Units on a scale | Standard Deviation 2.29 |
| Placebo | Change From Baseline in Hospital Anxiety and Depression Scale (HADS) at Week 4 | Depression Change at Week 4/LOCF (n=64, 65) | -0.57 Units on a scale | Standard Deviation 2.81 |
| Placebo | Change From Baseline in Hospital Anxiety and Depression Scale (HADS) at Week 4 | Anxiety Change at Week 4/LOCF (n=64, 65) | 0.71 Units on a scale | Standard Deviation 2.42 |
Secondary
Change From Baseline in mBPI-sf Interference Index Score at Week 4
m-BPI-sf: participant-rated 11 point Likert rating scale ranging from 0 (does not interfere) to 10 (completely intereres) with functional activities (general activity, mood, walking ability, relations with other people, sleep, normal work, and enjoyment of life) in past 24 hours. Change was score at each observation minus baseline score.
Time frame: Baseline, Week 4 or ET
Population: ITT; LOCF; n= number of evaluable participants analyzed at each time point; N= number of participants with evaluable data analyzed
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pregabalin | Change From Baseline in mBPI-sf Interference Index Score at Week 4 | Baseline (n=71, 76) | 4.92 Units on a scale | Standard Deviation 2.22 |
| Pregabalin | Change From Baseline in mBPI-sf Interference Index Score at Week 4 | Change at Week 4 (n=59, 58) | -1.83 Units on a scale | Standard Deviation 2.47 |
| Pregabalin | Change From Baseline in mBPI-sf Interference Index Score at Week 4 | Change at Week 4/LOCF(n=64, 62) | -1.66 Units on a scale | Standard Deviation 2.57 |
| Placebo | Change From Baseline in mBPI-sf Interference Index Score at Week 4 | Baseline (n=71, 76) | 5.27 Units on a scale | Standard Deviation 2.14 |
| Placebo | Change From Baseline in mBPI-sf Interference Index Score at Week 4 | Change at Week 4 (n=59, 58) | -1.50 Units on a scale | Standard Deviation 2.44 |
| Placebo | Change From Baseline in mBPI-sf Interference Index Score at Week 4 | Change at Week 4/LOCF(n=64, 62) | -1.48 Units on a scale | Standard Deviation 2.56 |
Secondary
Change From Baseline in Modified Brief Pain Inventory (mBPI-sf) Pain Severity Index Score at Week 4
m-BPI-sf: participant rated 11-point Likert rating scale ranging from 0 (no pain) to 10 (worst pain possible). Pain severity index was the mean of item scores 1, 2, 3, and 4 (worst, least, average and current pain scores). Change was scores at observation minus scores at baseline.
Time frame: Baseline, Week 4 or ET
Population: ITT; LOCF= Last observation carried forward; n= number of evaluable participants analyzed at each time point; N= number of participants with evaluable data analyzed
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pregabalin | Change From Baseline in Modified Brief Pain Inventory (mBPI-sf) Pain Severity Index Score at Week 4 | Baseline (n=71, 77) | 5.18 Units on a scale | Standard Deviation 1.8 |
| Pregabalin | Change From Baseline in Modified Brief Pain Inventory (mBPI-sf) Pain Severity Index Score at Week 4 | Change at Week 4 (n=59, 59) | -2.06 Units on a scale | Standard Deviation 1.75 |
| Pregabalin | Change From Baseline in Modified Brief Pain Inventory (mBPI-sf) Pain Severity Index Score at Week 4 | Change at Week 4/LOCF (n=64, 63) | -1.94 Units on a scale | Standard Deviation 1.88 |
| Placebo | Change From Baseline in Modified Brief Pain Inventory (mBPI-sf) Pain Severity Index Score at Week 4 | Baseline (n=71, 77) | 5.03 Units on a scale | Standard Deviation 1.72 |
| Placebo | Change From Baseline in Modified Brief Pain Inventory (mBPI-sf) Pain Severity Index Score at Week 4 | Change at Week 4 (n=59, 59) | -1.41 Units on a scale | Standard Deviation 2.51 |
| Placebo | Change From Baseline in Modified Brief Pain Inventory (mBPI-sf) Pain Severity Index Score at Week 4 | Change at Week 4/LOCF (n=64, 63) | -1.35 Units on a scale | Standard Deviation 2.54 |
Secondary
Change From Baseline in Opioid-Related Symptoms Distress Scale (OR-SDS) at Day 14 and Day 28
OR-SDS included OR-SDS individual items by dimension of frequency (rarely to almost constantly), severity (slight to very severe), and degree of bother (not at all to very much), number of episodes of retching/vomiting, OR-SDS dimension composite and overall composite scores. Change was scores at occurance minus score at baseline.
Time frame: Baseline, Day 14, Day 28 or ET
Population: Data not analyzed due to early study termination.
Secondary
Change From Baseline in Total Daily Dose of Opioids Day 0 Through Day 28
Change from baseline in total daily dose of opioids immediate release (IR), sustained release (SR) formulations separately and combined.
Time frame: Baseline, Day 0 through Day 28 or ET
Population: Data no analyzed due to early study termination.
Secondary
Change From Pre-Baseline in Total Daily Dose of Morphine Equivalents Day 0 Through Day 28
IR and SR formulations separately and combined. Change was day x minus baseline.
Time frame: Baseline, Day 0 through Day 28 or ET
Population: Data not analyzed due to early study termination.
Secondary
DAAC From Baseline in Daily Worst Pain 14 Days After Fixed Dosing Date Up to Day 28
DAAC from baseline in the daily worst pain based on the NRS Worst Pain at Reference Site score collected from participant's daily diary 14 days after dosing stabilized (fixed dosing date) up to Day 28. Pain rated on an 11 point scale ranged from 0 (no pain) to 10 (worst possible pain). DAAC defined as AUC of daily worst pain score divided by pain measurement duration. Change was week x minus baseline.
Time frame: Baseline, 14 Days After Fixed Dosing Date up to Day 28 or ET
Population: ITT; N= number of participants with evaluable data analyzed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | DAAC From Baseline in Daily Worst Pain 14 Days After Fixed Dosing Date Up to Day 28 | -1.47 Units on a scale | Standard Deviation 1.79 |
| Placebo | DAAC From Baseline in Daily Worst Pain 14 Days After Fixed Dosing Date Up to Day 28 | -1.15 Units on a scale | Standard Deviation 1.72 |
Secondary
DAAC From Baseline in Daily Worst Pain, Day 1 to End of Dose Adjustment
DAAC from baseline in the daily worst pain based on the NRS Worst Pain at Reference Site score collected from participant's daily diary. Pain rated on an 11 point scale ranged from 0 (no pain) to 10 (worst possible pain). DAAC defined as AUC of daily worst pain score divided by pain measurement duration. Change was week x minus baseline.
Time frame: Baseline, Day 1 to End of Dose Adjustment or ET
Population: ITT; N= number of participants with evaluable data analyzed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | DAAC From Baseline in Daily Worst Pain, Day 1 to End of Dose Adjustment | -0.72 Units on a scale | Standard Deviation 1.11 |
| Placebo | DAAC From Baseline in Daily Worst Pain, Day 1 to End of Dose Adjustment | -0.53 Units on a scale | Standard Deviation 1.01 |
Secondary
DAAC From Baseline in Daily Worst Pain, Days 1 Through 28
DAAC from baseline in the daily worst pain based on the NRS Worst Pain at Reference Site score collected from participant's daily diary. Pain rated on an 11 point scale ranged from 0 (no pain) to 10 (worst possible pain). DAAC defined as AUC of daily worst pain score divided by pain measurement duration. Change was week x minus baseline.
Time frame: Baseline, Days 1 through 28 or ET
Population: ITT; N= number of participants with evaluable data analyzed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | DAAC From Baseline in Daily Worst Pain, Days 1 Through 28 | -1.27 Units on a scale | Standard Deviation 1.45 |
| Placebo | DAAC From Baseline in Daily Worst Pain, Days 1 Through 28 | -1.03 Units on a scale | Standard Deviation 1.37 |
Secondary
Patient Global Impression of Change (PGIC)
PGIC: participant rated instrument to measure participant's change in overall status on a 7-point scale; range from 1 (very much improved) to 7 (very much worse).
Time frame: Weeks 2 and 4 or ET
Population: ITT; LOCF; n=number of evaluable participants analyzed at each time point; N= the number of participants with evaluable data analyzed
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pregabalin | Patient Global Impression of Change (PGIC) | Week 2 (n=66,68) | 2.97 Units on a scale | Standard Deviation 1.36 |
| Pregabalin | Patient Global Impression of Change (PGIC) | Week 4 (n=59, 60) | 2.73 Units on a scale | Standard Deviation 1.39 |
| Pregabalin | Patient Global Impression of Change (PGIC) | LOCF/ET (n=69, 74) | 2.88 Units on a scale | Standard Deviation 1.46 |
| Placebo | Patient Global Impression of Change (PGIC) | Week 2 (n=66,68) | 3.09 Units on a scale | Standard Deviation 1.19 |
| Placebo | Patient Global Impression of Change (PGIC) | Week 4 (n=59, 60) | 2.87 Units on a scale | Standard Deviation 1.46 |
| Placebo | Patient Global Impression of Change (PGIC) | LOCF/ET (n=69, 74) | 2.99 Units on a scale | Standard Deviation 1.45 |