Efficacy and Safety Analyses of Mirtazapine in NSCLC Patients With Depression

Efficacy and Safety Analyses of Mirtazapine in the Treatment of Malignant Tumor Related Depression: A Phase II, Placebo-controlled, Randomized, Double-blinded Clinical Trial in Advanced Non-small Cell Lung Cancer Patients

This is a phase II, placebo-controlled, randomized, double-blinded clinical trial. Study objective is to assess the efficacy and safety of mirtazapine in advanced NSCLC patients with malignant tumor related depression. Study hypothesis is that advanced NSCLC diagnosed with depression undertaking palliative chemotherapy with mirtazapine treatment for 8 weeks will have remarkable improvement in depression compared to baseline. Eligible advanced NSCLC Patients with PHQ-9 score ≥ 8, and undertaking palliative chemotherapy will be enrolled into this study. patients will be stratified (gender, age, Numerical Rating Scale score for cancer pain 0-3/4-6/7-10) randomized (1:1) into mirtazapine or placebo treatment. Patients in mirtazapine arm will be orally administered with mirtazapine 15mg, QD, consecutive medication for 8 weeks; along with palliative chemotherapy regimen decided by investigators. Patients in placebo arm will be orally administered with placebo 15mg, QD, consecutive medication for 8 weeks; along with palliative chemotherapy regimen decided by investigators. During the treatment, Patient health questionnaire (PHQ-9), Hamilton Depression Scale (HAMD-17) and European Organization for Research on Treatment of Cancer (EORTC) quality of life questionnaire-C30 (QLQ-C30) questionnaires will be collected at baseline, 3 weeks (d22) and 8 weeks (d57), or treatment discontinuation date due to depression deteriorated or suicidal tendency and behavior. Follow-up will last up to 4 weeks after treatment end with depression assessment (questionnaires every 2 weeks). Study endpoints: primary endpoint is the anti-depression efficacy (response rate). Response defined as the PHQ-9 or HAMD-17 questionnaire score decrease ≥ 50% compared with baseline level.

Major depression prevail in patients with malignant tumor with an incident rate of 20% - 40%, 2-3 times more than the prevalence of population, especially high in patients with advanced solid tumor patients as 40% - 50.6%. National Comprehensive Cancer Network (NCCN) palliative care guideline recommended PHQ-9 as the diagnosis tool for depression, total scores ≥ 8 was considered the standard of malignant tumor related depression. Major depression had been proved related with malignant tumors, mirtazapine is the currently effective drug in anti-depression clinical therapy, have better tolerance and equal effect compared to Tricyclic antidepressants (TCAs) and 5-hydroxytryptamine (5-HT) or noradrenaline serotonin-norepinephrine reuptake inhibitors (NE-SNRIs). This is a phase II, placebo-controlled, randomized, double-blinded clinical trial. Study objective is to assess the efficacy and safety of mirtazapine in advanced NSCLC patients with malignant tumor related depression. Study hypothesis is that advanced NSCLC diagnosed with depression undertaking palliative chemotherapy with mirtazapine treatment for 8 weeks will have remarkable improvement in depression compared to baseline. Palliative chemotherapy and mirtazapine have better efficacy, recovery rate, response duration, tolerance and quality of life improvement than palliative chemotherapy and placebo. Moreover, mirtazapine could improve patients' anxiety and chemotherapy related nausea and vomit. Eligible advanced NSCLC Patients with PHQ-9 score ≥ 8, and undertaking palliative chemotherapy will be enrolled into this study. After baseline assessment (PHQ-9, HAMD-17 and EORTC QLQ-C30 questionnaires), 236 patients will be stratified (gender, age, NRS score for cancer pain 0-3/4-6/7-10) randomized (1:1) into mirtazapine or placebo treatment. Patients in mirtazapine arm will be orally administered with mirtazapine 15mg, QD, consecutive medication for 8 weeks; along with palliative chemotherapy regimen decided by investigators. Patients in placebo arm will be orally administered with placebo 15mg, QD, consecutive medication for 8 weeks; along with palliative chemotherapy regimen decided by investigators. During the treatment, PHQ-9, HAMD-17 and EORTC QLQ-C30 questionnaires will be collected at 3 weeks (d22) and 8 weeks (d57), or treatment discontinuation date due to depression deteriorated or suicidal tendency and behavior. Follow-up will last up to 4 weeks after treatment end with depression assessment (questionnaires every 2 weeks). If anti-depression therapy is not effective after 8 weeks treatment or treatment discontinuation, patients will be unblinded and receive other treatment according to investigators. Treatment end at 8 weeks. Study endpoints: primary endpoint is the anti-depression efficacy (response rate). Response defined as the PHQ-9 or HAMD-17 questionnaire score decrease ≥ 50% compared with baseline level. Secondary endpoints included: 1.recovery rate, recovery defined as the PHQ-9 score less than 8 points. 2. Response duration, defined as the time period from treatment response to regression recurrence (PHQ-9 score ascending above baseline level). 3. Quality of life improvement, define as the best quality of life score minus baseline level. 4. Compliance to anti-depression therapy, defined as the medication count at each follow-up time points.

Mirtazapine arm will be orally administered with mirtazapine 15mg, QD, consecutive medication for 8 weeks; along with palliative chemotherapy regimen decided by investigators.

Placebo arm will be orally administered with placebo 15mg, QD, consecutive medication for 8 weeks; along with palliative chemotherapy regimen decided by investigators.

Patients in mirtazapine arm will be orally administered mirtazapine as an anti-depression therapy; along with palliative chemotherapy.

Using PHQ-9 or HAMD-17 questionnaire to assess the change of depression scores at the time points above. The measure unit is questionnaire score point, remain the same at every time points. And to calculate response number of patients (patients had 50% percent of depression questionnaire score points reduction compared to baseline after treatment initiation) and recovery number of patients (patients had PHQ-9 score less than 8 points PHQ-9 score less than 8 points during the treatment).

From date of randomization until the date of first documented regression recurrence, assessed up to 12 weeks"

Using EORTC QLQ-C30 (V3.0) to assess the quality of life change at the time points above. The measure unit is questionnaire score point, remain the same at every time points. And to calculate improved number of patients (patients had quality of life questionnaire score points gained compared to baseline after treatment initiation)

Inclusion Criteria: Pathology confirmed non-small cell lung cancer, undertaking palliative chemotherapy Age above 18 years old PHQ-9 score ≥ 8 points at baseline assessment Eastern Cooperative Oncology Group (ECOG) performance score 0 -2 Orally administration of drugs without difficulties Eligible bone marrow function, liver and kidney function for chemotherapy Pregnancy test negative in 7 days for women of child-bearing age; willing to take contraception measures. Signed Informed consent form (ICF) Exclusion Criteria: Clinical diagnosis of depression before advanced NSCLC confirmed Suicide tendency or behavior Mania in past medical history Received surgery or radiation therapy in 4 weeks Central nervous system (CNS) metastasis or spinal compression; except no symptoms and with no cortical hormonotherapy in 4 weeks. Systemically treatment with psychotropic medications, antihistamines drugs, antibiotics, cortical hormone therapy, antiepileptic drugs, immunosuppressive agents or other drugs might affect treatment in 4 weeks; or locally used of these drug in 2 weeks. AST or ALT ≥ 2.5 ULN without liver metastasis; or ≥ 5 ULN with liver metastasis. Serum creatinine ≥ 2 mg/dl Residual toxicity event ≥ CTCAE grade 2, except peripheral neurotoxicities. Any severe or uncontrolled systemic diseases judged by investigators. Any contraindication of mirtazapine. Exclusion Criteria: Invalid subject after randomization Major protocol violations judged by investigators. Poor compliance Intolerable adverse events Subject withdraw ICF Any pregnancy events No clinical benefits due to clinical adverse events, laboratory abnormalities or other medical conditions Other reasons of treatment discontinuation judged by investigators.

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