Effect of Mirtazapine Versus Placebo in Patients With Non-small Cell Lung Cancer and Anorexia

Study Overview
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Brief Summary
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The realization of this project will generate an important advance in knowledge regarding one of the most important comorbidities in cancer patients: malnutrition. Currently, comprehensive treatments of cancer patients recognize the importance of the assessment of nutritional status, and the impact it has on the prognosis, quality of life and toxicity generated by cancer treatment. Due to this, it is imperative to offer diagnostic tools that identify patients in a timely manner and, in addition to this, offer therapeutic strategies for the improvement of nutritional status, in an adjuvant manner to their oncological treatment. It is widely recognized that the cachexia-anorexia syndrome (CACS) is present in 30 to 80% of cases in cancer patients and this proportion increases as the disease progresses, with weight loss being a powerful predictor of shorter survival. Unfortunately, current therapies available to treat anorexia and / or cancer-associated cachexia offer only partial results, mainly because the intervention is late and the development of an earlier and more effective intervention is still sought. Mirtazapine has recently gained attention not only because of its antidepressant effect, but also because of its potential benefit in patients with anorexia and weight loss, recently reported in a phase II study. Therefore, it is important to continue its evaluation through a randomized, double-blind clinical trial in which the effect of mirtazapine is compared and it is determined if it is superior compared to placebo to increase appetite in patients with NSCLC who present with anorexia. This type of strategy is a relevant therapeutic option in those patients in whom nutritional counseling by itself is not sufficient to counteract the damage caused by anorexia and to cope with or prevent the development of cachexia.

Detailed Description
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Lung cancer is the leading cause of cancer death in Mexico and the world. One of the comorbidities most commonly associated with this type of malignancy is malnutrition, which occurs in approximately 40-50% of newly diagnosed cases. In addition to its high incidence, malnutrition in patients with cancer is of great relevance due to the negative effect that this entails on the quality of life and the prognosis of patients, as well as the increase in toxicity associated with oncological treatment. Malnutrition is a pathological state in which the deficiency in the adequate contribution of energy contributes to its development, producing a systemic catabolic state; Its etiology is variable, however, in most patients malnutrition is associated with a lack of appetite, which is called anorexia. Mirtazapine is a tetracyclic antidepressant which has been widely used for the treatment of depression. Several clinical studies have proven its efficacy in this indication, with more than 5000 patients endorsing its clinical effect compared to placebo, other tetracyclic antidepressants and trazodone. In addition to its effect on mood, it has been observed that mirtazapine, used in standard doses, induces weight gain, increasing appetite and food consumption compared to patients receiving placebo. The increase in appetite with consequent weight gain and increased food intake may be due to the blocking of 5HT1b, 5-HT2, 5-HT3, H1 receptors, involved in the regulation of appetite. A pilot study of 2 doses of mirtazapine (15 or 30 mg per day) in ambulatory cancer patients with pain and other discomforts suggests that it provides a significant improvement in quality of life, particularly in weight and energy intake. Recently, another phase II study observed that 57% of oncology patients, ambulatory, non-depressed, increased their appetite and body weight when treated with mirtazapine for 4 weeks. Despite these encouraging data, the study included a small sample of patients, so it is not possible to generate robust conclusions from these data. The objective of this protocol is to conduct a prospective, randomized, double-blind clinical trial to evaluate the effect of Mirtazapine on appetite, nutritional status and quality of life in patients with anorexia associated with lung cancer. The sample would include 86 patients, 43 patients with Mirtazapine and 43 sith placebo for 8 weeks, with an inducing dose of 15 mg to a máximum of 30 mg. The methodology for conducting this study consists of recruiting patients diagnosed with anorexia according to the anorexia-cachexia (ACS) scale, which has a cut-off point specifically validated for lung cáncer. Once the patient is selected, they are invited to participate in the study and an informed consent is requested. Subsequently a subjective global evaluation is performed, a 24-hour reminder of energy consumption, evaluation of anthropometric measures (weight, height,% weight loss, body mass index), evaluation of body composition (% fat, fat-free mass and phase angle), common gastrointestinal adverse effects of chemotherapy according to CTCAE, an evaluation of anxiety and depression (HADS) , as well as determination of quality of life through the questionnaire The European organization for research and treatment of cancer quality of life questionnaire (QLQ) -C30 and (QLQ) LC-13, validated for Mexican population. All determinations will be made at baseline, at 4 and at 8 weeks. All the variables are going to be evaluated inside each groups and between groups. It´s going to be considered significant p ≤ 0.05.

Official Title
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Effect of Mirtazapine Versus Placebo on Appetite, Nutritional Status and Quality of Life in Non-small Cell Lung cáncer Patients With Anorexia; Randomized Double-blind Clinical Trial.

Conditions
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Anorexia, Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: Mirtazapine
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Outpatients over 18 years of age who are receiving care in INCan with histopathological diagnosis of advanced stage non-small cell lung cancer (IIIB or IV). A score ≤ 32 on the cachexia anorexia scale or ≥ 5% weight loss in the last month. Good performance status (ECOG 0-2) That they are receiving chemotherapy as standard treatment or tyrosine kinase inhibitors or immunotherapy. Have a life expectancy> 8 weeks. Accept and sign informed consent letter. Exclusion Criteria: Known allergy to mirtazapine Patients who are treated with antidepressants Patients who are under treatment with megestrol acetate Patients with moderate hepatic and / or renal dysfunction (bilirubin level ≥ 1.5 x above normal limits (UNL), AST and ALT ≥ 5 x UNL, or creatinine ≥5 x UNL). Those unable to take medication orally. Patients with mechanical obstruction of the gastrointestinal tract, ascites or generalized edema. Patients with a history of phenylketonuria (preparation contains phenylalanine). Patients with delirium.

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: Randomized, double-blind clinical trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intervention group<br>arm to receive 15 to 30 mg of Mirtazapine for a period of 8 weeks. | Drug: Mirtazapine<br>* arm to receive 15 to 30 mg of Mirtazapine for a period of 8 weeks.<br>|
| Placebo Comparator: Placebo group<br>arm to receive 15 to 30 mg of placebo for a period of 8 weeks. | Drug: Placebo Oral Tablet<br>* arm to receive 15 to 30 mg of Placebo for a period of 8 weeks.<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with Anorexia | The primary endpoint will assess the percentage of patients who continue to present anorexia after 4 and 8 weeks of treatment with placebo or mirtazapine. Anorexia will be defined as the lack of desire to eat, lack of appetite, as measured using the validated version of the Anorexia / Cachexia Scale from the Functional Assessment of Anorexia Cachexia Therapy (FAACT). A score of less than or equal to 24 will be considered diagnostic for anorexia. | From the baseline assessment to 4 and 8 weeks | 
| Energy Consumption | Total kilocalories consumed on average per day by a subject | From the baseline assessment to 4 and 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weight | Sum of all the components of the organism and represents the total body mass. | From the baseline assessment to 8 weeks | 
| Body Mass Index | It is an index of the weight of a person in relation to his height BMI = Weight (Kg.) / [height (m) * height) (m)] | From the baseline assessment to 8 weeks | 
| Subjetive Global Assessment | Practical, quick and lower cost method used to make a nutritional evaluation, which consists of 3 parts: Anamnesis, physical examination and qualification. A: Patients with an adequate nutritional status B: Suspected malnutrition or moderate malnutrition C: Patients with severe malnutrition | From the baseline assessment to 8 weeks | 
| Protein consumption | Grams of protein consumed on average per day by a subject | From the baseline assessment to 8 weeks | 
| Lipids consumption | Grams of lipids consumed on average per day by a subject | From the baseline assessment to 8 weeks | 
| Carbohydrates consumption | Grams of carbohydrates consumed on average per day by a subject | From the baseline assessment to 8 weeks | 
| Body fat | Body fat | From the baseline assessment to 8 weeks | 
| Fat free mass | skeletal muscle, visceral protein, plasma proteins, extracellular water, skin and skeleton. | From the baseline assessment to 8 weeks | 
| phase angle | Angular transformation of the ratio of reactance to resistance | From the baseline assessment to 8 weeks | 
| Quality of life - Global status | Physical, physiological and social factors in the life of a patient. The Global status of Quality of Life evaluation will be evaluated using the validated Mexican-Spanish version of the European Organization for the Research and Treatment of Cancer (EORTC) Quality of life questionnaires specific for cancer with the items 29 and 30 (QLQ-C30 version 3.0) and complemented with the quality of life questionnaire for lung cancer (QLQ-LC13). Scores range from 0-100, with higher scores representing better quality of life. The items included in each scale are calculated a raw count (average = s score) and the corresponding formula is applied to obtain the final count (Score). | From the baseline assessment to 8 weeks | 
| Quality of life - physical functioning | The physical functioning will be evaluated using the validated Mexican-Spanish version of the European Organization for the Research and Treatment of Cancer (EORTC) Quality of life questionnaires specific for cancer using the physical functioning scale (from QLQ-C30 version 3.0). Scores range from 0-100, with higher scores representing better physical functioning. The items included in each scale are calculated a raw count (average = s score) and the corresponding formula is applied to obtain the final count (Score). | From the baseline assessment to 8 weeks | 
| Quality of life -Role functioning | The role functioning will be evaluated using the validated Mexican-Spanish version of the European Organization for the Research and Treatment of Cancer (EORTC) Quality of life questionnaires specific for cancer using the role functioning scale (from QLQ-C30 version 3.0). Scores range from 0-100, with higher scores representing better role functioning. The items included in each scale are calculated a raw count (average = s score) and the corresponding formula is applied to obtain the final count (Score). | From the baseline assessment to 8 weeks | 
| Quality of life - Emotional functioning | The emotional functioning will be evaluated using the validated Mexican-Spanish version of the European Organization for the Research and Treatment of Cancer (EORTC) Quality of life questionnaires specific for cancer using the emotional functioning scale (from QLQ-C30 version 3.0). Scores range from 0-100, with higher scores representing better emotional functioning. The items included in each scale are calculated a raw count (average = s score) and the corresponding formula is applied to obtain the final count (Score). | From the baseline assessment to 8 weeks | 
| Quality of life - Cognitive functioning | The cognitive functioning will be evaluated using the validated Mexican-Spanish version of the European Organization for the Research and Treatment of Cancer (EORTC) Quality of life questionnaires specific for cancer using the cognitive functioning scale (from QLQ-C30 version 3.0). Scores range from 0-100, with higher scores representing better cognitive functioning. The items included in each scale are calculated a raw count (average = s score) and the corresponding formula is applied to obtain the final count (Score). | From the baseline assessment to 8 weeks | 
| Quality of life - Social functioning | The social functioning will be evaluated using the validated Mexican-Spanish version of the European Organization for the Research and Treatment of Cancer (EORTC) Quality of life questionnaires specific for cancer using the social functioning scale (from QLQ-C30 version 3.0). Scores range from 0-100, with higher scores representing better social functioning. The items included in each scale are calculated a raw count (average = s score) and the corresponding formula is applied to obtain the final count (Score). | From the baseline assessment to 8 weeks | 
| Quality of life - Fatigue | Fatigue will be evaluated using the validated Mexican-Spanish version of the European Organization for the Research and Treatment of Cancer (EORTC) Quality of life questionnaires specific for cancer using the fatigue symptom scale (from QLQ-C30 version 3.0). Scores range from 0-100, with higher scores representing worse fatigue. The items included in each scale are calculated a raw count (average = s score) and the corresponding formula is applied to obtain the final count (Score). | From the baseline assessment to 8 weeks | 
| Quality of life - Nausea and vomiting | Nausea and vomiting will be evaluated using the validated Mexican-Spanish version of the European Organization for the Research and Treatment of Cancer (EORTC) Quality of life questionnaires specific for cancer using the nausea and vomiting symptom scale (from QLQ-C30 version 3.0). Scores range from 0-100, with higher scores representing worse nausea and vomiting. The items included in each scale are calculated a raw count (average = s score) and the corresponding formula is applied to obtain the final count (Score). | From the baseline assessment to 8 weeks | 
| Quality of life - loss of appetite | Loss of appetite will be evaluated using the validated Mexican-Spanish version of the European Organization for the Research and Treatment of Cancer (EORTC) Quality of life questionnaires specific for cancer using the loss of appetite single item (from QLQ-C30 version 3.0). Scores range from 0-100, with higher scores representing worse loss of appetite. The items included in each scale are calculated a raw count (average = s score) and the corresponding formula is applied to obtain the final count (Score). | From the baseline assessment to 8 weeks | 
| Anxiety | Mental state characterized by great restlessness, intense excitement and extreme insecurity. Anxiety will be evaluated using the Mexican version of the Hospital Anxiety and Depression Scale (HADS) which was validated by Galindo Vázquez et al. (2015) is comprised of a scale which includes 14 items, which have four options as answers (ranging from 0-3). Scores range from 0-21. Highest scores denote higher anxiety. | From the baseline assessment to 8 weeks | 
| Depression | Illness or mental disorder that is characterized by a deep sadness, mood decay, low self-esteem, loss of interest in everything and decrease in psychic functions. Depression will be evaluated using the Mexican version of the Hospital Anxiety and Depression Scale (HADS) which was validated by Galindo Vázquez et al. (2015) is comprised of a scale which includes 14 items, which have four options as answers (ranging from 0-3). Scores range from 0-21. Highest scores denote higher depression. | From the baseline assessment to 8 weeks |