Olanzapine for the Prevention and Treatment of Nausea and Vomiting Induced by Chemotherapy of Lung Cancer

Study Overview
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Brief Summary
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Chemotherapy induced nausea and vomiting (CINV) is a common adverse effect in treatment of cancer, which influences the quality of life and adherence to treatment of patients and leads to dehydration, malnutrition and even death. Prevention and relieving the CINV is an important step to ensure the conduction of chemotherapy. Mechanism of CINV remains to be obscure, while most studies showed that it is mainly related to the following respects: ⑴ Chemotherapeutic agents stimulate gastrointestinal tract, which induces the release of neurotransmitters by chromaffin cells. Neurotransmitters bind to corresponding receptors, and then results in vomiting by stimulating the vomiting center; ⑵ Chemotherapeutic agents and the metabolites of them activate chemoreceptors directly, which causes vomiting. ⑶ Feeling and mental factors irritate cerebral cortex pathway directly. There are studies suggested that 5- hydroxytryptamine (5-HT) was related to acute nausea and vomiting induced by chemotherapy, which means 5-HT receptor antagonist would be a effective medicine for acute CINV. In addition, there are researches proclaimed that neurokinin-1 (NK-1) receptor antagonist, aprepitant, is a potent agent to relieve CINV. Thus, correlative guidelines recommend regimens with 5-HT receptor antagonist, NK-1 receptor antagonist and glucocorticoid as the standard treatment for strongly emetic chemotherapy regimens. But the prevention of moderately emetic chemotherapy regimens remains to be a problem in clinical practice. Besides, there is no study to demonstrate differences of mechanisms between acute CINV and delayed CINV. Olanzapine inhibits kinds of neurotransmitters which cause CINV, it is why this medicine is effective in both acute and delayed CINV. It can also alleviate anxiety, improve sleep quality and relieve pain in patients with cancer. The most common adverse effects of olanzapine are lethargy, body mass increase, fatigue, dry mouth, constipation, hyperlipidemia and hyperglycemia. Among them, the most common one is lethargy, which can oppose insomnia and excitation caused by dexamethasone. In a word, olanzapine is an agent with mild adverse effects, it is worth to be generalized. But there are still problems to be resolved in the application of olanzapine in CINV: ⑴ Aprepitant is expensive and not covered in medical care in China, which limits the application in patients. ⑵There is no large clinical trial to confirm the efficacy and safety of olanzapine in Chinese populations. To explore these issues better, investigators intend to compare the regimen with olanzapine, dexamethasone and 5-HT receptor antagonists with the regimen with placebo, dexamethasone and 5-HT receptor antagonists about the efficacy and adverse events in treatment of CINV. Investigators aim to provide an available therapeutic options for CINV, improve the quality of life and prolong the survival of patients with lung cancer.

Official Title
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Olanzapine as First Line Treatment for Prevention of Nausea and Vomiting Induced by Chemotherapy of Lung Cancer: a Multicenter, Double-blind and Randomized Trial

Conditions
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Chemotherapy-induced Nausea and Vomiting, Lung Cancer

Intervention / Treatment
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* Drug: Olanzapine
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) Performance Status≤2 or Karnofsky performance statu (KPS) scores≥60. Patients with cytologically or histologically confirmed lung cancer. Patients who are willing to receive chemotherapy and can tolerate at least 2 cycles chemotherapy. Chemotherapy regimens accord with standard regimens recommended by clinical practice guidelines (National Comprehensive Cancer Network guidelines and Chinese Society of Clinical Oncology guidelines of lung cancer). There is at least one kind of high emetic risk chemotherapy agent, mainly including regimens contain cisplatin or carboplatin (AUC≥4). Adequate organ function including the following: Adequate bone marrow reserve: white blood cell (WBC) count superior or equal to 2.0×10^9/L , absolute neutrophil count (ANC) superior or equal to 1.5×10^9/L, platelets superior or equal to 80×10^9/L, and hemoglobin superior or equal to 90g/L; Hepatic: bilirubin <1.5 times the upper limit of normal (ULN), aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5×ULN (or <5×ULN with liver metastases); Renal: Serum creatinine≤1×ULN, calculated creatinine clearance (CrCl) superior or equal to 50 milliliter/min based on the standard Cockcroft and Gault formula. At least 3 weeks after the end of the last chemotherapy. Women of reproductive years are willing to contracept in appropriate methods in the period of trial and in the 8 weeks after the last administration. Doing pregnancy test before the beginning of this trial when necessary, and results of which need to be negative. Exclusion Criteria: Women who are pregnant or breastfeeding Need to undergo radiotherapy during this trial. Patients with alimentary tract obstruction. Patients with severe heart disease, renal and liver disease and metabolic abnormalities. Patients with epilepsy or who are using antipsychotics. Patients who have been administrated with antiemetic in 24 hours or who have suffered vomiting before chemotherapy. Patients with brain metastases. Patients with contraindications of chemotherapy. Patients who are attending another clinical trial or will attend in 2 weeks. Patients who are considered unsuitable to be included by treating physicians.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebos group<br>Patients will be administered with dexamethasone plus tropisetron from D1 to D3. Patients will also be administrated with placebos from D1-D4 | Drug: Placebos<br>* Dexamethasone (10mg/d) (Days1-3) Tropisetron (4mg or 4.48mg or 5mg /d) (Days1-3) Placebos (Days1-4)<br>|
| Experimental: Experimental group<br>Patients will receive a regimen with dexamethasone plus tropisetron from D1-D3. Patients will also be administrated with olanzapine from D1-D4. | Drug: Olanzapine<br>* Dexamethasone (10mg/d) (Days1-3) Tropisetron (4mg or 4.48mg or 5mg /d) (Days1-3) Olanzapine (10mg/d) (Days1-4)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence rate of no delayed nausea and vomiting | Number of participants with nausea and vomiting occuring within 24 hours after chemotherapy in all participants. | 1 week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response of acute nausea and vomiting | Number of participants with no nausea and vomiting occuring within 24 hours after chemotherapy as assessed by CTCAE v4.0. | 1 week | 
| Complete response of delayed nausea and vomiting | Number of participants with no nausea and vomiting occuring in 24 hours to 120 hours after chemotherapy as assessed by CTCAE v4.0. | 1 week | 
| Disease control rate | Number of participants who reach complete response or partial response. | 1 week | 
| Quality of life of participants by The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer 13 scale | Quality of life of participants is measured with The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Lung Cancer 13(QLQ-LC13) scale which is filled by participants themselves. The questionnaire is consist of several symptoms measured by scores range from 1 to 7, the higher the symptoms are scored, the worse the quality of life is. | 1 week | 
| Quality of life of participants by The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer 30 scale | Quality of life of participants is measured with EORTC QLQ-LC30 scale which is filled by participants themselves. The questionnaire is consist of several symptoms measured by scores range from 1 to 7, the higher the symptoms are scored, the worse the quality of life is. | 1 week | 
| Quality of life of participants by Functional Assessment of Cancer Therapy-Lung cancer scale | Quality of life of participants is measured with Functional Assessment of Cancer Therapy-Lung cancer (FACT-L) scale which is filled by participants themselves. The FACT-L, version 4, is a combination of the 27-item FACT-General (FACT-G) and the 9-item Lung Cancer Subscale (LCS) which measures multidimensional quality of life. The FACT-L score ranges from 0 to 136. The higher the score obtained by each patient in question, the greater the final score of the subscale and the better the quality of life. | 1 weeks |