Duloxetine to Prevent Oxaliplatin-Induced Chemotherapy-Induced Peripheral Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Phase II to Phase III Study
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 220
- 试验地点
- 793
- 主要终点
- Prevention of sensory oxaliplatin-induced peripheral neuropathy (OIPN) response (Phase II)
研究概览
简要总结
This phase II/III trial studies the best dose of duloxetine and how well it works in preventing pain, tingling, and numbness (peripheral neuropathy) caused by treatment with oxaliplatin in patients with stage II-III colorectal cancer. Duloxetine increases the amount of certain chemicals in the brain that help relieve depression and pain. Giving duloxetine in patients undergoing treatment with oxaliplatin for colorectal cancer may help prevent peripheral neuropathy.
详细描述
The primary and secondary objectives of the study:
PRIMARY OBJECTIVES:
I. To determine the dosage of duloxetine hydrochloride (duloxetine) (30 mg or 60 mg daily) that appears most promising in preventing oxaliplatin-induced peripheral neuropathy (OIPN). (Phase II)
II. To demonstrate that the most promising dosage of duloxetine identified in the Phase II component is more effective than placebo at preventing OIPN sensory symptoms. (Phase III)
III. To demonstrate that the most promising dosage of duloxetine identified in the Phase II component is more effective than placebo at preventing oxaliplatin-induced chronic neuropathic pain. (Phase III)
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Supportive Care
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 25 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Stage II-III colorectal cancer patients scheduled to receive oxaliplatin 510 mg/m^2 (cumulative dose) over 12 weeks as a component of adjuvant leucovorin calcium (calcium folinate), 5-fluorouracil and oxaliplatin (FOLFOX) treatment, in which patients are scheduled to receive oxaliplatin 85 mg/m^2 every 2 weeks for 12 weeks (i.e., 6 cycles), or adjuvant capecitabine and oxaliplatin (CAPOX) treatment, in which patients are scheduled to receive oxaliplatin 135 mg/m^2 every 3 weeks for 12 weeks (i.e., 4 cycles)
- •No prior neurotoxic chemotherapy
- •No pre-existing clinical or pre-clinical peripheral neuropathy from any cause.
- •No history of seizure disorder,
- •No history of narrow-angle glaucoma.
- •No symptoms of or history of schizophrenia, bipolar disease, suicidal thoughts and/or a major depression.
- •No serious eating disorder such as bulimia or anorexia.
- •No known diagnosis of ethanol (ETOH) addiction/dependence within the past 10 years.
- •Concomitant medications:
- •No concomitant use of other adjuvant pharmacologic interventions (e.g., gabapentin, pregabalin, venlafaxine) with known or hypothesized efficacy for peripheral neuropathy. Must be discontinued at least 7 days prior to start of protocol treatment
- •No anticipated or concurrent use of any antidepressant or serotonin-altering agent known to interact with duloxetine, due to concern regarding cumulative toxicity and potential drug interactions.
- •Use of a monoamine oxidase inhibitor (MAOI) or other antidepressants must be discontinued at least 14 days prior to start of protocol treatment.
- •No concomitant treatment with strong CYP1A2 and CYP2D6 inhibitors.
- •Chronic concomitant treatment with drugs that are extensively metabolized by CYP2D6 and that have a narrow therapeutic index, including certain antidepressants, phenothiazines, and Type 1C antiarrhythmics should be approached with caution. Concomitant administration of duloxetine and thioridazine should be avoided.
- •No use of warfarin or heparin products.
- •Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential, a negative pregnancy test done =< 7 days prior to registration is required
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- •In order to complete the mandatory patient-completed measure, patients must be able to speak and read English
- •Calculated creatinine clearance > 30 mL/min
- •Aspartate aminotransferases (AST)/serum glutamic-oxaloacetic transaminase (SGOT) =< 3 x upper limit of normal (ULN)
排除标准
- 未提供
研究组 & 干预措施
Phase II, Arm I (duloxetine hydrochloride, placebo)
Patients in Phase II receive duloxetine hydrochloride 30 mg (1 duloxetine capsule) orally (PO) once daily (QD) during week 1, duloxetine hydrochloride 30 mg (1 duloxetine capsule) PO QD and placebo (1 placebo capsule) PO QD during weeks 2-16, followed by duloxetine hydrochloride 30 mg (1 duloxetine capsule) PO QD during week 17 in the absence of unacceptable toxicity.
干预措施: Oxaliplatin (Drug)
Phase II, Arm I (duloxetine hydrochloride, placebo)
Patients in Phase II receive duloxetine hydrochloride 30 mg (1 duloxetine capsule) orally (PO) once daily (QD) during week 1, duloxetine hydrochloride 30 mg (1 duloxetine capsule) PO QD and placebo (1 placebo capsule) PO QD during weeks 2-16, followed by duloxetine hydrochloride 30 mg (1 duloxetine capsule) PO QD during week 17 in the absence of unacceptable toxicity.
干预措施: Duloxetine Hydrochloride (Drug)
Phase II, Arm I (duloxetine hydrochloride, placebo)
Patients in Phase II receive duloxetine hydrochloride 30 mg (1 duloxetine capsule) orally (PO) once daily (QD) during week 1, duloxetine hydrochloride 30 mg (1 duloxetine capsule) PO QD and placebo (1 placebo capsule) PO QD during weeks 2-16, followed by duloxetine hydrochloride 30 mg (1 duloxetine capsule) PO QD during week 17 in the absence of unacceptable toxicity.
干预措施: Duloxetine (Drug)
Phase II, Arm I (duloxetine hydrochloride, placebo)
Patients in Phase II receive duloxetine hydrochloride 30 mg (1 duloxetine capsule) orally (PO) once daily (QD) during week 1, duloxetine hydrochloride 30 mg (1 duloxetine capsule) PO QD and placebo (1 placebo capsule) PO QD during weeks 2-16, followed by duloxetine hydrochloride 30 mg (1 duloxetine capsule) PO QD during week 17 in the absence of unacceptable toxicity.
干预措施: Quality-of-Life Assessment (Other)
Phase II, Arm I (duloxetine hydrochloride, placebo)
Patients in Phase II receive duloxetine hydrochloride 30 mg (1 duloxetine capsule) orally (PO) once daily (QD) during week 1, duloxetine hydrochloride 30 mg (1 duloxetine capsule) PO QD and placebo (1 placebo capsule) PO QD during weeks 2-16, followed by duloxetine hydrochloride 30 mg (1 duloxetine capsule) PO QD during week 17 in the absence of unacceptable toxicity.
干预措施: Questionnaire Administration (Other)
Phase II, Arm I (duloxetine hydrochloride, placebo)
Patients in Phase II receive duloxetine hydrochloride 30 mg (1 duloxetine capsule) orally (PO) once daily (QD) during week 1, duloxetine hydrochloride 30 mg (1 duloxetine capsule) PO QD and placebo (1 placebo capsule) PO QD during weeks 2-16, followed by duloxetine hydrochloride 30 mg (1 duloxetine capsule) PO QD during week 17 in the absence of unacceptable toxicity.
干预措施: Placebo (Other)
Phase II, Arm II (duloxetine hydrochloride)
Patients in Phase II receive duloxetine hydrochloride 30 mg (1 duloxetine capsule) orally (PO) once daily (QD) during week 1, duloxetine hydrochloride 60 mg (2 duloxetine capsules) PO QD during weeks 2-16, followed by duloxetine hydrochloride 30 mg (1 duloxetine capsule) PO QD during week 17 in the absence of unacceptable toxicity.
干预措施: Oxaliplatin (Drug)
Phase II, Arm II (duloxetine hydrochloride)
Patients in Phase II receive duloxetine hydrochloride 30 mg (1 duloxetine capsule) orally (PO) once daily (QD) during week 1, duloxetine hydrochloride 60 mg (2 duloxetine capsules) PO QD during weeks 2-16, followed by duloxetine hydrochloride 30 mg (1 duloxetine capsule) PO QD during week 17 in the absence of unacceptable toxicity.
干预措施: Duloxetine Hydrochloride (Drug)
Phase II, Arm II (duloxetine hydrochloride)
Patients in Phase II receive duloxetine hydrochloride 30 mg (1 duloxetine capsule) orally (PO) once daily (QD) during week 1, duloxetine hydrochloride 60 mg (2 duloxetine capsules) PO QD during weeks 2-16, followed by duloxetine hydrochloride 30 mg (1 duloxetine capsule) PO QD during week 17 in the absence of unacceptable toxicity.
干预措施: Duloxetine (Drug)
Phase II, Arm II (duloxetine hydrochloride)
Patients in Phase II receive duloxetine hydrochloride 30 mg (1 duloxetine capsule) orally (PO) once daily (QD) during week 1, duloxetine hydrochloride 60 mg (2 duloxetine capsules) PO QD during weeks 2-16, followed by duloxetine hydrochloride 30 mg (1 duloxetine capsule) PO QD during week 17 in the absence of unacceptable toxicity.
干预措施: Quality-of-Life Assessment (Other)
Phase II, Arm II (duloxetine hydrochloride)
Patients in Phase II receive duloxetine hydrochloride 30 mg (1 duloxetine capsule) orally (PO) once daily (QD) during week 1, duloxetine hydrochloride 60 mg (2 duloxetine capsules) PO QD during weeks 2-16, followed by duloxetine hydrochloride 30 mg (1 duloxetine capsule) PO QD during week 17 in the absence of unacceptable toxicity.
干预措施: Questionnaire Administration (Other)
Phase II, Arm III (placebo)
Patients in Phase II receive placebo (1 placebo capsule) orally (PO) once daily (QD) during week 1, placebo (2 placebo capsules) PO QD weeks 2-16, followed by placebo (1 placebo capsule) PO QD during week 17 in the absence of unacceptable toxicity.
干预措施: Oxaliplatin (Drug)
Phase II, Arm III (placebo)
Patients in Phase II receive placebo (1 placebo capsule) orally (PO) once daily (QD) during week 1, placebo (2 placebo capsules) PO QD weeks 2-16, followed by placebo (1 placebo capsule) PO QD during week 17 in the absence of unacceptable toxicity.
干预措施: Quality-of-Life Assessment (Other)
Phase II, Arm III (placebo)
Patients in Phase II receive placebo (1 placebo capsule) orally (PO) once daily (QD) during week 1, placebo (2 placebo capsules) PO QD weeks 2-16, followed by placebo (1 placebo capsule) PO QD during week 17 in the absence of unacceptable toxicity.
干预措施: Questionnaire Administration (Other)
Phase II, Arm III (placebo)
Patients in Phase II receive placebo (1 placebo capsule) orally (PO) once daily (QD) during week 1, placebo (2 placebo capsules) PO QD weeks 2-16, followed by placebo (1 placebo capsule) PO QD during week 17 in the absence of unacceptable toxicity.
干预措施: Placebo (Other)
Phase III, Arm I (duloxetine hydrochloride)
Patients in Phase III receive most promising dose of duloxetine hydrochloride from Phase II PO QD in the absence of unacceptable toxicity.
干预措施: Oxaliplatin (Drug)
Phase III, Arm I (duloxetine hydrochloride)
Patients in Phase III receive most promising dose of duloxetine hydrochloride from Phase II PO QD in the absence of unacceptable toxicity.
干预措施: Duloxetine Hydrochloride (Drug)
Phase III, Arm I (duloxetine hydrochloride)
Patients in Phase III receive most promising dose of duloxetine hydrochloride from Phase II PO QD in the absence of unacceptable toxicity.
干预措施: Duloxetine (Drug)
Phase III, Arm I (duloxetine hydrochloride)
Patients in Phase III receive most promising dose of duloxetine hydrochloride from Phase II PO QD in the absence of unacceptable toxicity.
干预措施: Quality-of-Life Assessment (Other)
Phase III, Arm I (duloxetine hydrochloride)
Patients in Phase III receive most promising dose of duloxetine hydrochloride from Phase II PO QD in the absence of unacceptable toxicity.
干预措施: Questionnaire Administration (Other)
Phase III, Arm II (placebo)
Patients in Phase III receive placebo PO QD in the absence of unacceptable toxicity.
干预措施: Oxaliplatin (Drug)
Phase III, Arm II (placebo)
Patients in Phase III receive placebo PO QD in the absence of unacceptable toxicity.
干预措施: Quality-of-Life Assessment (Other)
Phase III, Arm II (placebo)
Patients in Phase III receive placebo PO QD in the absence of unacceptable toxicity.
干预措施: Questionnaire Administration (Other)
Phase III, Arm II (placebo)
Patients in Phase III receive placebo PO QD in the absence of unacceptable toxicity.
干预措施: Placebo (Other)
结局指标
主要结局
Prevention of sensory oxaliplatin-induced peripheral neuropathy (OIPN) response (Phase II)
时间窗: Up to 1 month post-oxaliplatin treatment
Will be measured using 6 individual Quality of Life Questionnaire - Chemotherapy-Induced Peripheral Neuropathy 20 (QLQ-CIPN20) questions that quantify numbness, tingling, and pain in the fingers (or hands) and toes (or feet). For each of the 6 individual questions, patients are asked to select 1 of 4 choices regarding how each of the sensory symptoms had affected them during the preceding week: 1 = Not at all, 2 = A little, 3 = Quite a bit, and 4 = Very much. Response will be defined as a patient reporting a highest score of ≤ 2 at any time during oxaliplatin exposure, including 1 month post-oxaliplatin treatment without discontinuing the study due to sensory oxaliplatin-induced peripheral neuropathy. The proportion of responders within each arm will be estimated by the number of responders divided by the total number of evaluable patients. Two-sided 90% exact confidence intervals for the true response proportion will be calculated according to the approach of Clopper and Pearson.
Prevention of sensory oxaliplatin-induced peripheral neuropathy (OIPN) response (Phase III)
时间窗: Up to 1 month post-oxaliplatin treatment
Will be measured using 6 individual Quality of Life Questionnaire - Chemotherapy-Induced Peripheral Neuropathy 20 (QLQ-CIPN20) questions that quantify numbness, tingling, and pain in the distal extremities. For each of the 6 questions, patients are asked to select 1 of 4 choices regarding how each of the sensory symptoms had affected them during the preceding week: 1=Not at all, 2=A little, 3=Quite a bit, and 4=Very much. Response will be defined as a patient reporting a highest score of ≤ 2 at any time during oxaliplatin exposure, including 1 month post-oxaliplatin treatment without discontinuing the study due to sensory OIPN. The analysis population is defined as all randomized patients who received at least 1 dose of oxaliplatin and have completed the 6 QLQCIPN20 sensory symptom items on at least 1 occasion during oxaliplatin treatment, including 1 month post-oxaliplatin treatment. The Fisher exact test will be used for a between-arm comparison of the proportion of responders.
Chronic neuropathic pain response (Phase III)
时间窗: Up to 1 month after oxaliplatin treatment
Response will be defined as a 7-day average of chronic neuropathic pain (on the average) ≤ 3 on a 0 (no pain) to 10 (pain as bad as you can imagine) scale 1 month after oxaliplatin treatment, which is obtained from the 7-day chronic neuropathy pain diary. The analysis population is defined as all randomized patients who received at least 1 dose of oxaliplatin and have completed the 7-day chronic neuropathy pain diary on at least 3 of the 7 days 1 month after the last oxaliplatin dose. The Fisher exact test will be used for a between-arm comparison of the proportion of responders.
次要结局
- Incidence of adverse events, including duloxetine side effects of nausea, dry mouth, dizziness, somnolence, fatigue, and insomnia (Phase II)(Up to 1 month post-oxaliplatin treatment)
- Serially measured total sensory neuropathy scores (Phase III)(Up to 1 month post-oxaliplatin treatment)
- Serially measured patient reported on the average pain scores (Phase III)(Up to 1 month post-oxaliplatin treatment)
- Incidence of adverse events, including duloxetine side effects of nausea, dry mouth, dizziness, somnolence, fatigue, and insomnia (Phase III)(Up to 1 month post-oxaliplatin treatment)