Neurotoxicity, Pain, Peripheral Neuropathy, Unspecified Adult Solid Tumor, Protocol Specific
Conditions
Keywords
unspecified adult solid tumor, protocol specific, neurotoxicity, pain, peripheral neuropathy
Brief summary
RATIONALE: Duloxetine may lessen peripheral neuropathy caused by chemotherapy. It is not yet known whether duloxetine is more effective than a placebo in treating peripheral neuropathy caused by chemotherapy. PURPOSE: This randomized phase III trial is studying duloxetine to see how well it works compared with a placebo in treating peripheral neuropathy caused by chemotherapy in patients with cancer.
Detailed description
OBJECTIVES: Primary * Determine the efficacy of duloxetine hydrochloride in cancer patients with painful chemotherapy-induced (taxane or platinum agent) peripheral neuropathy. Secondary * Determine the influence of this drug on peripheral neuropathy-related functional status and quality of life of these patients. * Describe the differences in duloxetine hydrochloride efficacy when used to treat pain caused by chemotherapy-induced peripheral neuropathy based on the neurotoxic drug and class. OUTLINE: This is a randomized, double-blind, placebo-controlled, crossover study. Patients are stratified according to prior neurotoxic agent (paclitaxel vs oxaliplatin vs other taxane agents without paclitaxel vs platinum agents \[cisplatin\] without oxaliplatin) and high risk for developing painful chemotherapy-induced peripheral neuropathy (no vs yes). Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients receive oral duloxetine hydrochloride once or twice daily in weeks 1-6. After a 1-week rest period, patients cross over to receive an oral placebo once or twice daily in weeks 8-13. * Arm II: Patients receive an oral placebo once or twice daily in weeks 1-6. After a 1-week rest period, patients cross over to receive oral duloxetine hydrochloride once or twice daily in weeks 8-13. Patients complete pain and quality of life questionnaires, including the BPI-SF once weekly and FACT/GOG-NTX and EORTC QLQ-C30 questionnaires, in weeks 1, 6, 8, and 13. After completion of study treatment, patients are followed for 2 weeks.
Interventions
DRUGduloxetine hydrochloride
Given orally
OTHERplacebo
Given orally
Sponsors
National Cancer Institute (NCI)
Alliance for Clinical Trials in Oncology
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
SUPPORTIVE_CARE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
25 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Diagnosis of cancer * CNS malignancy allowed with the exception of leptomeningeal carcinomatosis * Must have painful sensory chemotherapy-induced peripheral neuropathy (CIPN) resulting from prior treatment with single-agent taxane or platinum agents (paclitaxel, docetaxel, nab-paclitaxel, oxaliplatin, cisplatin) (may not have received drugs from both classes) * CIPN \> grade 1 as measured by NCI-CTCAE v 4.0 * Average neuropathic pain score ≥ 4 * Patients with the following illnesses known to cause peripheral neuropathy are eligible, provided they have no evidence of neuropathy from these illnesses: * Diabetes mellitus * Peripheral vascular disease * HIV infection * Significant degenerative or familial neurologic disorder known to cause peripheral neuropathy * No clinical or subclinical neuropathy from nerve compression injuries (i.e., carpal tunnel syndrome, brachial plexopathy, spinal stenosis, or spinal nerve root compression) PATIENT CHARACTERISTICS: * AST ≤ 3 times upper limit of normal * Total bilirubin ≤ normal * Creatinine clearance \> 30 mL/min * Not pregnant or nursing * Able to take oral or enteral medication * No history of seizure disorder * No diagnosis of ethanol addiction or dependence within the past 10 years * No history of narrow-angle glaucoma * None of the following: * History of suicidal thoughts * Symptoms of or history of schizophrenia, bipolar disease, or a major depression * Serious eating disorder such as bulimia or anorexia where electrolyte imbalance is likely PRIOR CONCURRENT THERAPY: * At least 3 months since prior and no concurrent taxane or platinum agent * At least 14 days since prior and no concurrent monoamine oxidase inhibitors or other antidepressants * No other prior or concurrent neurotoxic drugs (e.g., vincristine, vinblastine, cytarabine, thalidomide, bortezomib, carboplatin, or procarbazine) * No concurrent anticonvulsants * No concurrent B or E vitamin supplementation in doses greater than the recommended daily allowance (RDA) * Centrum (standard formula) and One-A-Day essential formula which contain 100% RDA for vitamins B6, E, and B12 allowed * Other multivitamins allowed provided they contain no more than 100% RDA of B vitamins and vitamin E * No concurrent treatment (pharmacologic) for depression
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Average Pain From Week 1 to Week 5, as Measured by the BPI-SF Average Pain Severity Item | Day 1 of Week 1 to Day 1 of Week 6 | Change in average pain from Week 1 to Week 5, measured on day 1 of Weeks 1 and 6 by the Brief Pain Inventory Short Form (BPI-SF) was calculated as value at Day 1 of Week 1 minus value at Day 1 of Week 6 to yield positive improvement values. The BPI-SF contains 4 items assessing average, worst, least, and intermediate pain severity in the last 24 hours. Pain severity items are scored using an 11-point numeric rating scale (0, no pain; 10, pain as bad as you can imagine). Average pain severity was chosen as the primary outcome based on recommendations from the Initiative on Methods, Measurements, and Pain Assessment in Clinical Trials (IMMPACT). Patients completed the BPI-SF when thinking only about pain from peripheral neuropathy. The Cronbach's alpha reliability for the BPI ranges between 0.77 and 0.91. The comparison of interest was the difference between the 2 treatment groups in pain change during the initial treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Pain-related Functional Interference Score From Week 1 to Week 5, as Measured by the BPI-SF Interference Score | Day 1 of Week 1 to Day 1 to Week 6 | Change in pain-related functional interference score during the initial treatment period (Week 1 to Week 5), as measured by the BPI-SF interference score: Using an accepted method for accessing the influence of pain on function, 7 BPI-SF items were used to quantify the degree to which pain interfered with daily activities or function (0, does not interfere; 10 completely interferes). The 7 items were summed to obtain a total interference score, which ranged from 0 to 70, with lower scores meaning less interference. The mean change in pain-related functional interference score during the initial treatment period are reported below for each treatment arm and was calculated as value at Day 1 of Week 1 minus value at Day 1 of Week 6 to yield positive improvement values. |
| Change in the Total Score of the FACT/COG-NTX From Week 1 to Week 5 | Day 1 of Week 1 to Day 1 of Week 6 | Patient-reported QOL was assessed using the Functional Assessment of Cancer Treatment, Gynecologic Oncology Group Neurotoxicity (FACT/GOG-Ntx) subscale on day 1 of weeks 1, 6, 8, and 13. The instrument contains 11 questions, assessing numbness, tingling, and discomfort in the hands or feet; difficulty hearing; tinnitus; joint pain or muscle cramps; weakness; or trouble walking, buttoning buttons, or feeling small shapes when placed in the hand. Items are scored from 0 to 4 (o, not at all; 4, very much) and summed (total score range, 0-44, with higher scores indicating a worse outcome). A 2- to 3-point change is defined as a clinically meaningful improvement in QOL per published recommendations specific to similar measures. The Mean Change During Initial Treatment Period in the FACT/GOG-Ntx total score are reported for each treatment arm and was calculated as value at Day 1 of Week 1 minus value at Day 1 of Week 6 to yield positive improvement values. |
| Change in Average Pain From Week 8 to Week 12, as Measured by the BPI-SF Average Pain Severity Item | Day 1 of Week 8 to Day 1 of Week 13 | Change in average pain from Week 8 to Week 12, measured on day 1 of Weeks 8 and 13 by the Brief Pain Inventory Short Form (BPI-SF) was calculated as value at Day 1 of Week 8 minus value at Day 1 of Week 13 to yield positive improvement values. The BPI-SF contains 4 items assessing average, worst, least, and intermediate pain severity in the last 24 hours. Pain severity items are scored using an 11-point numeric rating scale (0, no pain; 10, pain as bad as you can imagine). Average pain severity was chosen as the primary outcome based on recommendations from the Initiative on Methods, Measurements, and Pain Assessment in Clinical Trials (IMMPACT). Patients completed the BPI-SF when thinking only about pain from peripheral neuropathy. The Cronbach's alpha reliability for the BPI ranges between 0.77 and 0.91. The comparison of interest was the difference between the 2 treatment groups in pain change during the crossover treatment period. |
Countries
United States
Participant flow
Pre-assignment details
The number of screened and the number offered participation but declined was not captured.
Participants by arm
| Arm | Count |
|---|---|
| Arm I/Group A (Duloxetine Then Placebo) Patients will take one capsule of 30 mg duloxetine orally daily for 7 days (week 1), and then increase to two capsules of duloxetine (60 mg duloxetine) orally daily for 28 days (weeks 2-5). Duloxetine will be tapered during week 6 (one capsule daily for 7 days), and will be discontinued during week 7 (no capsules for 7 days). Patients will then cross over to receive the alternative treatment (placebo), and the sequence will be repeated. Patients will take one capsule of placebo daily for 7 days (week 8), two capsules of placebo daily for 28 days (weeks 9-12), one capsule of placebo daily for 7 days (week 13), and then no capsules for 7 days (week 14). | 109 |
| Arm II/Group B (Placebo Then Duloxetine) Patients will take one capsule of placebo orally daily for 7 days (week 1), and then increase to two capsules of placebo orally daily for 28 days (weeks 2-5). Placebo will be tapered during week 6 (one capsule daily for 7 days), and will be discontinued during week 7 (no capsules for 7 days). Patients will then cross over to receive the alternative treatment (duloxetine), and the sequence will be repeated. Patients will take one capsule of duloxetine daily for 7 days (week 8), two capsules of duloxetine daily for 28 days (weeks 9-12), one capsule of duloxetine daily for 7 days (week 13), and then no capsules for 7 days (week 14). | 111 |
| Total | 220 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Crossover Treatment Period (Weeks 8-12) | Discontinued intervention early | 11 | 12 |
| Crossover Treatment Period (Weeks 8-12) | Incomplete data | 7 | 7 |
| Initial Treatment Period (Weeks 1-5) | Discontinued study drug early | 21 | 12 |
| Initial Treatment Period (Weeks 1-5) | Incomplete data | 1 | 5 |
| Initial Treatment Period (Weeks 1-5) | Withdrew consent prior to intervention | 6 | 5 |
Baseline characteristics
| Characteristic | Arm I/Group A (Duloxetine Then Placebo) | Arm II/Group B (Placebo Then Duloxetine) | Total |
|---|---|---|---|
| Age, Continuous | 60.0 years STANDARD_DEVIATION 10.4 | 59.0 years STANDARD_DEVIATION 10.6 | 59.0 years STANDARD_DEVIATION 10.5 |
| Region of Enrollment United States | 109 participants | 111 participants | 220 participants |
| Sex: Female, Male Female | 71 Participants | 67 Participants | 138 Participants |
| Sex: Female, Male Male | 38 Participants | 44 Participants | 82 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 93 / 108 | 91 / 107 |
| serious Total, serious adverse events | 1 / 108 | 3 / 107 |
Outcome results
Primary
Change in Average Pain From Week 1 to Week 5, as Measured by the BPI-SF Average Pain Severity Item
Change in average pain from Week 1 to Week 5, measured on day 1 of Weeks 1 and 6 by the Brief Pain Inventory Short Form (BPI-SF) was calculated as value at Day 1 of Week 1 minus value at Day 1 of Week 6 to yield positive improvement values. The BPI-SF contains 4 items assessing average, worst, least, and intermediate pain severity in the last 24 hours. Pain severity items are scored using an 11-point numeric rating scale (0, no pain; 10, pain as bad as you can imagine). Average pain severity was chosen as the primary outcome based on recommendations from the Initiative on Methods, Measurements, and Pain Assessment in Clinical Trials (IMMPACT). Patients completed the BPI-SF when thinking only about pain from peripheral neuropathy. The Cronbach's alpha reliability for the BPI ranges between 0.77 and 0.91. The comparison of interest was the difference between the 2 treatment groups in pain change during the initial treatment period.
Time frame: Day 1 of Week 1 to Day 1 of Week 6
Population: Patients who completed initial intervention (prior to crossing over to receive alternate study drug duloxetine or placebo) and had complete data were included in the primary analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm I/Group A (Duloxetine Then Placebo) | Change in Average Pain From Week 1 to Week 5, as Measured by the BPI-SF Average Pain Severity Item | 1.06 units on a scale |
| Arm II/Group B (Placebo Then Duloxetine) | Change in Average Pain From Week 1 to Week 5, as Measured by the BPI-SF Average Pain Severity Item | 0.34 units on a scale |
p-value: 0.00395% CI: [0.26, 1.2]Wilcoxon (Mann-Whitney)
Secondary
Change in Average Pain From Week 8 to Week 12, as Measured by the BPI-SF Average Pain Severity Item
Change in average pain from Week 8 to Week 12, measured on day 1 of Weeks 8 and 13 by the Brief Pain Inventory Short Form (BPI-SF) was calculated as value at Day 1 of Week 8 minus value at Day 1 of Week 13 to yield positive improvement values. The BPI-SF contains 4 items assessing average, worst, least, and intermediate pain severity in the last 24 hours. Pain severity items are scored using an 11-point numeric rating scale (0, no pain; 10, pain as bad as you can imagine). Average pain severity was chosen as the primary outcome based on recommendations from the Initiative on Methods, Measurements, and Pain Assessment in Clinical Trials (IMMPACT). Patients completed the BPI-SF when thinking only about pain from peripheral neuropathy. The Cronbach's alpha reliability for the BPI ranges between 0.77 and 0.91. The comparison of interest was the difference between the 2 treatment groups in pain change during the crossover treatment period.
Time frame: Day 1 of Week 8 to Day 1 of Week 13
Population: Patients who completed crossover intervention and had complete data were included in the analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm I/Group A (Duloxetine Then Placebo) | Change in Average Pain From Week 8 to Week 12, as Measured by the BPI-SF Average Pain Severity Item | 0.41 units on a scale |
| Arm II/Group B (Placebo Then Duloxetine) | Change in Average Pain From Week 8 to Week 12, as Measured by the BPI-SF Average Pain Severity Item | 1.42 units on a scale |
95% CI: [0.36, 1.65]
Secondary
Change in Pain-related Functional Interference Score From Week 1 to Week 5, as Measured by the BPI-SF Interference Score
Change in pain-related functional interference score during the initial treatment period (Week 1 to Week 5), as measured by the BPI-SF interference score: Using an accepted method for accessing the influence of pain on function, 7 BPI-SF items were used to quantify the degree to which pain interfered with daily activities or function (0, does not interfere; 10 completely interferes). The 7 items were summed to obtain a total interference score, which ranged from 0 to 70, with lower scores meaning less interference. The mean change in pain-related functional interference score during the initial treatment period are reported below for each treatment arm and was calculated as value at Day 1 of Week 1 minus value at Day 1 of Week 6 to yield positive improvement values.
Time frame: Day 1 of Week 1 to Day 1 to Week 6
Population: Patients who completed initial intervention (prior to crossing over to receive alternate study drug duloxetine or placebo) and had complete data were included in the primary analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm I/Group A (Duloxetine Then Placebo) | Change in Pain-related Functional Interference Score From Week 1 to Week 5, as Measured by the BPI-SF Interference Score | 7.9 units on a scale |
| Arm II/Group B (Placebo Then Duloxetine) | Change in Pain-related Functional Interference Score From Week 1 to Week 5, as Measured by the BPI-SF Interference Score | 3.5 units on a scale |
95% CI: [0.93, 7.88]
Secondary
Change in the Total Score of the FACT/COG-NTX From Week 1 to Week 5
Patient-reported QOL was assessed using the Functional Assessment of Cancer Treatment, Gynecologic Oncology Group Neurotoxicity (FACT/GOG-Ntx) subscale on day 1 of weeks 1, 6, 8, and 13. The instrument contains 11 questions, assessing numbness, tingling, and discomfort in the hands or feet; difficulty hearing; tinnitus; joint pain or muscle cramps; weakness; or trouble walking, buttoning buttons, or feeling small shapes when placed in the hand. Items are scored from 0 to 4 (o, not at all; 4, very much) and summed (total score range, 0-44, with higher scores indicating a worse outcome). A 2- to 3-point change is defined as a clinically meaningful improvement in QOL per published recommendations specific to similar measures. The Mean Change During Initial Treatment Period in the FACT/GOG-Ntx total score are reported for each treatment arm and was calculated as value at Day 1 of Week 1 minus value at Day 1 of Week 6 to yield positive improvement values.
Time frame: Day 1 of Week 1 to Day 1 of Week 6
Population: Patients who completed initial intervention (prior to crossing over to receive alternate study drug duloxetine or placebo) and had complete data were included in the primary analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm I/Group A (Duloxetine Then Placebo) | Change in the Total Score of the FACT/COG-NTX From Week 1 to Week 5 | 2.44 units on a scale |
| Arm II/Group B (Placebo Then Duloxetine) | Change in the Total Score of the FACT/COG-NTX From Week 1 to Week 5 | 0.87 units on a scale |
p-value: 0.0395% CI: [0.15, 3]Wilcoxon (Mann-Whitney)