Comparison Between Mirtazapine and Megestrol for the Control of Anorexia-cachexia in Cancer Patients in Palliative Care.

Randomized, Double-blind Clinical Trial of the Use of Mirtazapine Versus Megestrol for the Control of Anorexia-cachexia in Cancer Patients in Palliative Care.

Cancer-associated anorexia-cachexia is an insidious syndrome that has a major impact on the patient's quality of life, but is also associated with a significant reduction in survival. Despite its clinical importance, it remains a widely underestimated and untreated condition. Considering the scarcity of pharmacological measures, it is necessary to invest in studies that may contribute to the rational and effective treatment of this clinical condition. Mirtazapine has a special therapeutic potential because it is a well-tolerated drug with few adverse effects and with well-known orexigenic action in clinical practice.The objective of this study is to evaluate the effect of mirtazapine as a pharmacological measure in the management of cancer-related anorexia-cachexia in patients in palliative care. A randomized, double-blind clinical trial involving 52 cancer patients with anorexia-cachexia in palliative care will be conducted. Patients will be randomized to receive mirtazapine or megestrol and will be evaluated longitudinally for a period of 8 weeks. The primary endpoint will be to assess the effect of mirtazapine on anorexia and weight gain and secondary outcomes will be to assess the tolerability and safety of mirtazapine and the effect of mirtazapine on body composition, quality of life, and functional capacity of patients.

Study Overview

• Status: Completed
• Conditions: Anorexia; Cachexia; Cancer
• Intervention / Treatment: Drug: Mirtazapine; Drug: Megestrol

Detailed Description

Cancer-associated anorexia-cachexia is an insidious syndrome that has a major impact on the patient's quality of life, but is also associated with a significant reduction in survival. Unintentional weight loss can predict a poor prognosis in cancer patients which is most likely due to decreased doses of treatment. Despite its clinical importance, it remains a widely underestimated and untreated condition. Considering the scarcity of pharmacological measures, it is necessary to invest in studies that may contribute to the rational and effective treatment of this clinical condition. Mirtazapine has a special therapeutic potential because it is a well-tolerated drug with few adverse effects and with well-known orexigenic action in clinical practice. It has been shown to have side effects of increased appetite and weight gain in cancer subjects with depression and nausea, as well as in non-depressed cancer patients, but there are not, as yet, randomized controlled trials showing its effect on cancer-associated anorexia-cachexia. The objective of this study is to evaluate the effect of mirtazapine as a pharmacological measure in the management of cancer-related anorexia-cachexia in patients in palliative care. A randomized, double-blind clinical trial involving 52 cancer patients with anorexia-cachexia in palliative care will be conducted. Patients will be randomized to receive mirtazapine or megestrol and will be evaluated longitudinally for a period of 8 weeks. After the initial evaluation and randomization, patients will be reassessed after 4 and 8 weeks at an outpatient clinic where they will be evaluated for the following variables: (1) General and demographic characteristics; (2) Usual food intake; (3) Anthropometric evaluation; (4) Presence and degree of symptoms using the Edmonton Symptom Assessment System; (4) Status performance using the Karnofsky performance status; (5) Quality of life using the QLQ-C30 Questionnaire; (6) Depression using the Hospital Anxiety and Depression Scale; (7) Prognosis using the Palliative Prognostic Score; (8) Evaluation of functional capacity using hand grip strength and gait speed; (9) Body composition using electrical bioimpedance and dual energy x-ray absorptiometry; (10) Physical Activity Behaviour using a tri-axial accelerometer. Patients will also be contacted via telephone calls at weeks 1, 2, 3, 5 and 6 for information regarding adverse events and drug compliance. The questioning about the occurrence of adverse events will also be performed at the outpatient clinic. Self-report of ingestion of tablets and counting of tablets on return of packages at the end of the study will be used to determine patient compliance. It is expect that use of mirtazapine can bring benefits increasing appetite and the body weight in cancer patientes in palliative care compared to the use of megestrol.

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • São Paulo
    • Ribeirão Preto, São Paulo, Brazil, 14048900
      • Clinics Hospital, Ribeirão Preto Medical School, University of São Paulo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients aged ≥ 50 years.
• Patients with confirmed diagnosis of cancer by histopathological examination, including those not yet submitted to any therapy because they are in the therapeutic definition phase and those whose therapies have already been suspended because they are ineffective.
• Patients with cancer progression, with either local or distant metastases, documented by radiological or histopathological methods.
• Patients complaining of anorexia graded by the patient as ≥ 5 by the Edmonton Sympton Assessement Scale.
• Patients with weight loss ≥ 2% in the last 2 months or weight loss ≥ 5% in the last 6 months, referred by the patient or documented in electronic medical records, compared to the stable weight before diagnosis.
• Patients with a life expectancy of ≥ 2 months by the Palliative Prognostic Score.
• Patients with performance status greater than or equal to 60% using the Karnofsky Performance Status scale.

Exclusion Criteria:

• Patients diagnosed with depression or using antidepressant therapy with a score ≥ 12 in the depression items of the Hospital Anxiety and Depression Scale.
• Patients with unstable doses of corticosteroids.
• Patients with moderate renal and/or hepatic dysfunction (total bilirubin ≥ 1.5x the upper limit of normal, AST and ALT ≥ 5x upper limit of normal or creatinine ≥1.5x upper limit of normal).
• Patients with Central Nervous System metastases.
• Patients with inability to take oral medications.
• Patients with mechanical obstruction of the gastrointestinal tract.
• Patients with clinically bulky ascites and generalized edema.
• Patients with reports of allergy to the medications studied.
• Patients with hypothyroidism with TSH levels greater than or equal to 5 μU/mL and free T4 less than 0.7 ng/dL.
• Patients with uncorrected hydroelectrolytic disturbances, with altered serum sodium, potassium and/ or ionic calcium.
• Patients with persistent and uncontrolled nausea and/or vomiting associated with gastrointestinal tract neoplasia and/or chemotherapeutic or radiotherapeutic treatment.
• Patients with pacemakers.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Mirtazapine; Tablets of 15mg mirtazapine will be used according to randomization. At the first visit, patients will be instructed to take one tablet at night for better tolerability. From the second week, if there is good tolerance, they will take two tablets at night until the end of the study.	Drug: Mirtazapine; Tablets of 15mg mirtazapine will be used according to randomization. At the first visit, patients will be instructed to take one tablet at night for better tolerability. From the second week, if there is good tolerance, they will take two tablets at night until the end of the study.; Other Names: Remeron
Active Comparator: Megestrol; Tablets of 160mg megestrol will be used according to randomization. At the first visit, patients will be instructed to take one tablet at night for better tolerability. From the second week, if there is good tolerance, they will take two tablets at night until the end of the study.	Drug: Megestrol; Tablets of 160mg megestrol will be used according to randomization. At the first visit, patients will be instructed to take one tablet at night for better tolerability. From the second week, if there is good tolerance, they will take two tablets at night until the end of the study.; Other Names: megestrol acetate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in appetite	Assessed by Edmonton Symptom Assessment Scale. This evaluation will be collected at baseline and after 8 weeks of follow-up. Changes in appetite will be divided into 3 categories according to the following definitions: appetite improvement will be a decrease ≥ 2 points in Edmonton Symptom Assessment Scale, maintenance of appetite as an improvement or worsening of 1 point and worsening of appetite as deterioration ≥ 2 points.	8 weeks
Change in body weight	Assessed by body weight. This evaluation will be collected at baseline and after 8 weeks of follow-up. The weight changes will be divided into 3 categories according to the following definitions: weight improvement will be a gain ≥ 1 kg, weight maintenance will be a loss < 500g or a gain < 1kg and weight loss will be a loss ≥ 500g.	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in body lean and fat mass	Assessed by body bioelectrical impedance and dual energy x-ray absorptiometry. They will be performed at baseline and after 8 weeks of follow-up. The body bioelectrical impedance will be performed using the ImpediMed DF50 mono-frequency system (ImpediMed Limited, Australia). The dual energy x-ray absorptiometry will be performed on the measuring table using the equipment-specific software.	8 weeks
Change in Quality of life	The European Organization for Research and Treatment of Cancer (EORTC) instrument QLQ-C30 Questionnaire will be used to assess quality of life at baseline and after 8 weeks of follow-up.	8 weeks
Assessment of muscle strength	Assessed by hand grip strenght measured by the use of a manual hydraulic dynamometer (Saehan, model SH 5.001, Koreia). It will be performed at baseline and after 8 weeks of follow-up.	8 weeks
Assessment of gait speed	The gait speed will be measured at 4 meters on usual speed. It will be performed at baseline and after 8 weeks of follow-up. The results will be expressed in m/s.	8 weeks
Physical Activity behaviour	Assessed by a tri-axial accelerometer to measure profile of spontaneous physical activity. It will be performed at first week and the last week of follow-up.	8 weeks
Incidence of treatment-related Adverse Events	Assessed by contact via telephone calls at weeks 1, 2, 3, 5 and 6 for information regarding treatment-related adverse events. The questioning about the occurrence of treatment-related adverse events will also be performed at the outpatient clinic at baseline and weeks 4 and 8 during the follow-up.	8 weeks

Collaborators and Investigators

• Sponsor: University of Sao Paulo
• Investigators: Principal Investigator: Nereida KC Lima, MD, PhD, University of Sao Paulo

Publications and helpful links

General Publications

• Riechelmann RP, Burman D, Tannock IF, Rodin G, Zimmermann C. Phase II trial of mirtazapine for cancer-related cachexia and anorexia. Am J Hosp Palliat Care. 2010 Mar;27(2):106-10. doi: 10.1177/1049909109345685. Epub 2009 Sep 23.
• 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. doi: 10.1016/s0885-3924(02)00381-0.
• Tomiska M, Tomiskova M, Salajka F, Adam Z, Vorlicek J. Palliative treatment of cancer anorexia with oral suspension of megestrol acetate. Neoplasma. 2003;50(3):227-33.
• Wen HS, Li X, Cao YZ, Zhang CC, Yang F, Shi YM, Peng LM. Clinical studies on the treatment of cancer cachexia with megestrol acetate plus thalidomide. Chemotherapy. 2012;58(6):461-7. doi: 10.1159/000346446. Epub 2013 Feb 7.

Helpful Links

• webpage of the Ribeirão Preto Medical School

Study record dates

Study Major Dates

• Study Start (Actual): March 26, 2019
• Primary Completion (Actual): February 2, 2022
• Study Completion (Actual): February 2, 2022

Study Registration Dates

• First Submitted: September 10, 2017
• First Submitted That Met QC Criteria: September 12, 2017
• First Posted (Actual): September 14, 2017

Study Record Updates

• Last Update Posted (Actual): July 7, 2023
• Last Update Submitted That Met QC Criteria: July 5, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: palliative care; mirtazapine; cachexia; anorexia; megestrol
• Additional Relevant MeSH Terms: Metabolic Diseases; Signs and Symptoms, Digestive; Nutrition Disorders; Body Weight; Body Weight Changes; Weight Loss; Thinness; Anorexia; Wasting Syndrome; Cachexia; Physiological Effects of Drugs; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Antidepressive Agents; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Anti-Anxiety Agents; Serotonin 5-HT3 Receptor Antagonists; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Contraceptives, Oral, Hormonal; Central Nervous System Stimulants; Adrenergic alpha-Antagonists; Adrenergic alpha-2 Receptor Antagonists; Appetite Stimulants; Mirtazapine; Megestrol; Megestrol Acetate
• Other Study ID Numbers: Mirtazapine_Cachexia

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD to be made available after the end of the study protocol.
• IPD Sharing Time Frame: after the publication of the results of study.
• IPD Sharing Access Criteria: researchers after the review and approval of protocol by the principal investigator
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No