Efficacy and Safety Analyses of Mirtazapine in NSCLC Patients With Depression

Overview

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.

Full Title of Study: “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”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Double (Participant, Investigator)
  • Study Primary Completion Date: June 2018

Detailed Description

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.

Interventions

  • Drug: Mirtazapine
    • Patients in mirtazapine arm will be orally administered mirtazapine as an anti-depression therapy; along with palliative chemotherapy.
  • Drug: Placebo
    • Patients in placebo arm will be orally administered placebo; along with palliative chemotherapy.

Arms, Groups and Cohorts

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

Clinical Trial Outcome Measures

Primary Measures

  • Number of participants responded to treatment.
    • Time Frame: baseline, and 3 weeks (d22), and 8 weeks (d57), and follow-up (d71, d85)
    • 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).

Secondary Measures

  • Response duration
    • Time Frame: From date of randomization until the date of first documented regression recurrence, assessed up to 12 weeks”
    • Regression recurrence defined as PHQ-9 score ascending above baseline level.
  • Number of participants had quality of life improvement
    • Time Frame: baseline, and 3 weeks (d22), and 8 weeks (d57), and follow-up (d71, d85)
    • 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)

Participating in This Clinical Trial

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.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Sun Yat-sen University
  • Provider of Information About this Clinical Study
    • Principal Investigator: Li Zhang, M.D. and Professor – Sun Yat-sen University
  • Overall Official(s)
    • Li Zhang, professor, Principal Investigator, Sun Yat-sen University

References

Reddy MS. Depression: the disorder and the burden. Indian J Psychol Med. 2010 Jan;32(1):1-2. doi: 10.4103/0253-7176.70510.

Sharpe M, Walker J, Holm Hansen C, Martin P, Symeonides S, Gourley C, Wall L, Weller D, Murray G; SMaRT (Symptom Management Research Trials) Oncology-2 Team. Integrated collaborative care for comorbid major depression in patients with cancer (SMaRT Oncology-2): a multicentre randomised controlled effectiveness trial. Lancet. 2014 Sep 20;384(9948):1099-108. doi: 10.1016/S0140-6736(14)61231-9. Epub 2014 Aug 27.

Stafford L, Judd F, Gibson P, Komiti A, Mann GB, Quinn M. Anxiety and depression symptoms in the 2 years following diagnosis of breast or gynaecologic cancer: prevalence, course and determinants of outcome. Support Care Cancer. 2015 Aug;23(8):2215-24. doi: 10.1007/s00520-014-2571-y. Epub 2015 Jan 6.

Walker J, Hansen CH, Martin P, Symeonides S, Gourley C, Wall L, Weller D, Murray G, Sharpe M; SMaRT (Symptom Management Research Trials) Oncology-3 Team. Integrated collaborative care for major depression comorbid with a poor prognosis cancer (SMaRT Oncology-3): a multicentre randomised controlled trial in patients with lung cancer. Lancet Oncol. 2014 Sep;15(10):1168-76. doi: 10.1016/S1470-2045(14)70343-2. Epub 2014 Aug 27.

Rodin G. Effective treatment for depression in patients with cancer. Lancet. 2014 Sep 20;384(9948):1076-8. doi: 10.1016/S0140-6736(14)61342-8. Epub 2014 Aug 28.

Andersen BL, Rowland JH, Somerfield MR. Screening, assessment, and care of anxiety and depressive symptoms in adults with cancer: an american society of clinical oncology guideline adaptation. J Oncol Pract. 2015 Mar;11(2):133-4. doi: 10.1200/JOP.2014.002311. Epub 2014 Dec 16.

Amini H, Aghayan S, Jalili SA, Akhondzadeh S, Yahyazadeh O, Pakravan-Nejad M. Comparison of mirtazapine and fluoxetine in the treatment of major depressive disorder: a double-blind, randomized trial. J Clin Pharm Ther. 2005 Apr;30(2):133-8.

HAMILTON M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960 Feb;23:56-62.

Spiegel D. Minding the body: psychotherapy and cancer survival. Br J Health Psychol. 2014 Sep;19(3):465-85. doi: 10.1111/bjhp.12061. Epub 2013 Aug 26. Review.

Massie MJ. Prevalence of depression in patients with cancer. J Natl Cancer Inst Monogr. 2004;(32):57-71. Review.

Hopwood P, Stephens RJ. Depression in patients with lung cancer: prevalence and risk factors derived from quality-of-life data. J Clin Oncol. 2000 Feb;18(4):893-903.

Arrieta O, Angulo LP, Núñez-Valencia C, Dorantes-Gallareta Y, Macedo EO, Martínez-López D, Alvarado S, Corona-Cruz JF, Oñate-Ocaña LF. Association of depression and anxiety on quality of life, treatment adherence, and prognosis in patients with advanced non-small cell lung cancer. Ann Surg Oncol. 2013 Jun;20(6):1941-8. doi: 10.1245/s10434-012-2793-5. Epub 2012 Dec 22.

Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, Dahlin CM, Blinderman CD, Jacobsen J, Pirl WF, Billings JA, Lynch TJ. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010 Aug 19;363(8):733-42. doi: 10.1056/NEJMoa1000678.

de Souza BF, de Moraes JA, Inocenti A, dos Santos MA, Silva AE, Miasso AI. Women with breast cancer taking chemotherapy: depression symptoms and treatment adherence. Rev Lat Am Enfermagem. 2014 Oct;22(5):866-73. English, Portuguese, Spanish.

Badr H, Shen MJ. Pain catastrophizing, pain intensity, and dyadic adjustment influence patient and partner depression in metastatic breast cancer. Clin J Pain. 2014 Nov;30(11):923-33. doi: 10.1097/AJP.0000000000000058.

Lee Y, Lin PY, Chien CY, Fang FM. Prevalence and risk factors of depressive disorder in caregivers of patients with head and neck cancer. Psychooncology. 2015 Feb;24(2):155-61. doi: 10.1002/pon.3619. Epub 2014 Jul 10.

Theobald DE, Kirsh KL, Holtsclaw E, Donaghy K, Passik SD. An open-label, crossover trial of mirtazapine (15 and 30 mg) in cancer patients with pain and other distressing symptoms. J Pain Symptom Manage. 2002 May;23(5):442-7.

Burrows GD, Kremer CM. Mirtazapine: clinical advantages in the treatment of depression. J Clin Psychopharmacol. 1997 Apr;17 Suppl 1:34S-39S. Review.

Anttila SA, Leinonen EV. A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev. 2001 Fall;7(3):249-64. Review.

Ito T, Okubo Y, Roth A. [Efficacy of mirtazapine for appetite loss and nausea of the cancer patient--from clinical experience in Memorial Sloan-Kettering Cancer Center]. Gan To Kagaku Ryoho. 2009 Apr;36(4):623-6. Japanese. Retraction in: Ito T, Sato H. Gan To Kagaku Ryoho. 2009 Oct;36(10):1779.

Puzantian T. Mirtazapine, an antidepressant. Am J Health Syst Pharm. 1998 Jan 1;55(1):44-9. Review.

Sanacora G, Treccani G, Popoli M. Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology. 2012 Jan;62(1):63-77. doi: 10.1016/j.neuropharm.2011.07.036. Epub 2011 Aug 3. Review.

Popoli M, Yan Z, McEwen BS, Sanacora G. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci. 2011 Nov 30;13(1):22-37. doi: 10.1038/nrn3138. Review.

Huntzinger E, Izaurralde E. Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet. 2011 Feb;12(2):99-110. doi: 10.1038/nrg2936. Review.

Zeng LH, Rensing NR, Wong M. Developing Antiepileptogenic Drugs for Acquired Epilepsy: Targeting the Mammalian Target of Rapamycin (mTOR) Pathway. Mol Cell Pharmacol. 2009 Jan 1;1(3):124-129.

Smalheiser NR, Lugli G, Rizavi HS, Torvik VI, Turecki G, Dwivedi Y. MicroRNA expression is down-regulated and reorganized in prefrontal cortex of depressed suicide subjects. PLoS One. 2012;7(3):e33201. doi: 10.1371/journal.pone.0033201. Epub 2012 Mar 9.

Baudry A, Mouillet-Richard S, Schneider B, Launay JM, Kellermann O. miR-16 targets the serotonin transporter: a new facet for adaptive responses to antidepressants. Science. 2010 Sep 17;329(5998):1537-41. doi: 10.1126/science.1193692.

Issler O, Haramati S, Paul ED, Maeno H, Navon I, Zwang R, Gil S, Mayberg HS, Dunlop BW, Menke A, Awatramani R, Binder EB, Deneris ES, Lowry CA, Chen A. MicroRNA 135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity. Neuron. 2014 Jul 16;83(2):344-360. doi: 10.1016/j.neuron.2014.05.042. Epub 2014 Jun 19.

Bocchio-Chiavetto L, Maffioletti E, Bettinsoli P, Giovannini C, Bignotti S, Tardito D, Corrada D, Milanesi L, Gennarelli M. Blood microRNA changes in depressed patients during antidepressant treatment. Eur Neuropsychopharmacol. 2013 Jul;23(7):602-11. doi: 10.1016/j.euroneuro.2012.06.013. Epub 2012 Aug 25.

Lotrich FE. Inflammatory cytokine-associated depression. Brain Res. 2015 Aug 18;1617:113-25. doi: 10.1016/j.brainres.2014.06.032. Epub 2014 Jul 5. Review.

Clinical trials entries are delivered from the US National Institutes of Health and are not reviewed separately by this site. Please see the identifier information above for retrieving further details from the government database.

At TrialBulletin.com, we keep tabs on over 200,000 clinical trials in the US and abroad, using medical data supplied directly by the US National Institutes of Health. Please see the About and Contact page for details.