Nabilone Effect on the Attenuation of Anorexia, Nutritional Status and Quality of Life in Lung Cancer Patients

Study Overview
=================
Brief Summary
-----------------
Anorexia is common symptom in cancer patients and is associated with increased morbidity and mortality. However timely detection with objective tools is necessary to establish the diagnosis of anorexia and to assess the magnitude of change over time. The anorexia pathophysiology is not clearly understood and treatment options are limited. Anecdotal historical benefits of smoking marijuana on nausea, pain and anorexia led to studies with marijuana and synthetic cannabinoids from Δ-9-tetrahydrocannabinol, the main active agent in marijuana. The endogenous cannabinoid system with its receptors CB1 and CB2 regulate appetite in four functional levels: (1) limbic system (hedonistic quality), (2) hypothalamus (appetite stimulant), (3) intestinal, and (4) tissue adipose. Nabilone, a synthetic analogue of THC approved in Mexico for nausea and vomiting induced by chemotherapy is also used in palliative care units for clinical improvement in increased appetite patients in terminal stages, however, there are no clinical trials demonstrating this benefit.

Detailed Description
-----------------
Background: Lung cancer is the leading cause of cancer death in Mexico and the world. Malnutrition is often associated with this type of cancer appearing in about 40-50% of patients the diagnosis made, affecting the quality of life and prognosis, as well as increased toxicity to cancer treatment. Cancer anorexia is characterized by loss of appetite and is the main cause of reduced food consumption in lung cancer patients. Anorexia occurs in up to 25% of cases. Unfortunately, current therapies available to treat anorexia and / or cachexia associated with cancer provide only partial results, mainly because the intervention is delayed and the development of an early and effective intervention is still looking. In most patients, malnutrition is associated with a hyporexia secondary to the production of pro-inflammatory cytokines such as tumor necrosis factor (TNF), leading to an increase in metabolism and appetite loss. Nabilone is a synthetic cannabinoid derivative that is widely used in oncology for its antiemetic and adjuvant effect of pain. Although widely used for the treatment of anorexia in palliative care, no randomized clinical trials demonstrating an effect on cancer-associated anorexia, however, in animal models, stimulation of cannabinoid receptors, mainly through CB1 receptor can modulate hypothalamic circuits in the brain stem, which in turn regulate food intake and satiety. Moreover cannabinoids are able to block the effects of TNF in the nervous system, which is associated with appetite changes in cancer patients. Additionally, agonists of cannabinoid receptors attenuated weight loss in murine models of anorexia. Additionally, to diagnosis anorexia The Anorexia-Cachexia scale (A/CS-12) from The Functional Assessment of Anorexia-Cachexia therapy (FAACT) questionnaire relates differences in symptoms and severity, assigning a value of 0-4 for each of 12 items. A 2010 consensus of special interest group of CACS from ESPEN (The European Society for Clinical Nutrition and Metabolism) in order to unify criteria, proposed that a score ≤24 of the A/CS-12 would be enough to establish a diagnosis of anorexia. The administration of Nabilone in patients with anorexia associated with Non-Small Cell Lung Cancer (NSCLC) is expected to increase appetite, nutritional status and quality of life. Methods: randomized double-blind clinical trial assessing Nabilone effect in non-small cell lung cancer (NSCLC) patients with unresectable stage III/IV NSCLC, ECOG performance status (ECOG PS) 1-2 and anorexia (main criteria: score of Anorexia Cachexia scale (AC/S-12) from Functional Assessment of Anorexia Cachexia Therapy ≤24). Patients are randomized to Nabilone at 0.5mg to 1mg, or placebo, given daily orally for 8 weeks. Changes are evaluated from baseline to week 2, 4, and 8. Time Assessment Dose T0 Baseline 0.5mg T1 2 weeks 1 mg T2 4 weeks 1 mg T3 8 weeks 1 mg Sample size: To determine the sample size is considered the effect of cannabinoid (dronabinol, 2.5 mg / 22 days) in appetite in cancer patients by a difference in proportions of 34% more than placebo, requiring 32 patients per group plus 20% of loss gives us a total of 39 patients per group, with a power of 90% and an α of 0.05

Official Title
-----------------
Nabilone Effect on the Attenuation of Anorexia, Nutritional Status and Quality of Life in Patients With Anorexia Associated With Advanced Lung Cancer: Randomized Double Blind Clinical Trial

Conditions
-----------------
Non-Small Cell Lung Cancer, Anorexia, Cachexia, Weight Lose

Intervention / Treatment
-----------------
* Drug: Nabilone
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Non-small cell lung cancer (NSCLC) patients with unresectable stage IIIB/IV ECOG performance status ≤2 Life expectancy of > 4 months at time of screening If woman of childbearing potential or a fertile man, he/she must agree to use an effective form of contraception during the study and for 30 days following the last dose of study drug (an effective form of contraception is abstinence, a hormonal contraceptive, or a double-barrier method) Must be willing and able to give signed informed consent and, in the opinion of the Investigator, to comply with the protocol tests and procedures Exclusion Criteria: Known allergy to some derivative of marijuana, there is a dependency or who have previously been treated with cannabinoids. Consumption of dietary supplements at baseline. Currently taking prescription medications intended to increase appetite or treat weight loss; these include, but are not limited to, testosterone, androgenic compounds, megestrol acetate, methylphenidate, and Anamorelin.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nabilone<br>Patients start receiving a dose of 0.5 mg daily oral nabilone the first 2 weeks and then 1 mg to complete 8 weeks. | Drug: Nabilone<br>* Patients going to take 0.5 mg capsules of nabilone (CESAMET) the first 2 weeks and then increased to 1 mg to complete 8 weeks.<br>* Other names: cesamet;|
| Placebo Comparator: placebo<br>Patients start receiving a dose of 0.5 mg daily oral placebo the first 2 weeks and then 1 mg to complete 8 weeks. | Drug: Placebo<br>* Patients going to take capsules of placebo until complete 8 weeks.<br>* Other names: placebo nabilona;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| anorexia | Lack of desire to eat food. Will be obtained through a questionnaire Anorexia / Cachexia scale from Functional Assessment of Anorexia Cachexia Therapy (FAACT) (score ≤24 diagnosis of anorexia) | from the start of consumption until 8 weeks. | 
| percentage weight loss | percentage weight loss in the last month | from the start of consumption until 8 weeks. | 
| Body Mass Index | It is an index of a person's weight in relation to height | from the start of consumption until 8 weeks. | 
| Subjective Global Assessment | convenient, fast and cheaper method used to make a nutritional assessment, consisting of 3 parts: anamnesis, physical examination and qualification. | from the start of consumption until 8 weeks. | 
| energy consumption | Total calories consumed on average per day for a subject | from the start of consumption until 8 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| protein consumption | Total protein grams consumed on average per day for a subject | from the start of consumption until 8 weeks. | 
| lipids consumption | Total lipids grams consumed on average per day for a subject | from the start of consumption until 8 weeks. | 
| carbohydrate consumption | Total carbohydrate grams consumed on average per day for a subject | from the start of consumption until 8 weeks. | 
| nausea | adverse effect from Common terminology criteria for adverse event | from the start of consumption until 8 weeks. | 
| vomiting | adverse effect from Common terminology criteria for adverse event | from the start of consumption until 8 weeks. | 
| constipation | adverse effect from Common terminology criteria for adverse event | from the start of consumption until 8 weeks. | 
| Diarrhea | adverse effect from Common terminology criteria for adverse event | from the start of consumption until 8 weeks. | 
| Dysgeusia | adverse effect from Common terminology criteria for adverse event | from the start of consumption until 8 weeks. | 
| Global Status of Quality of Life | The Global status of Quality of Life evaluation is evaluated using the validated Mexican-Spanish version of the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaires specific for cancer with the items 29 and 30. | from the start of consumption until 8 weeks. | 
| Physical functioning | The Physical functioning evaluation is evaluated from the validated Mexican-Spanish version of the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaires specific for cancer | from the start of consumption until 8 weeks. | 
| Role Functioning | The Role functioning evaluation is evaluated from the validated Mexican-Spanish version of the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaires specific for cancer | from the start of consumption until 8 weeks. | 
| Emotional Functioning | The Emotional Functioning evaluation is evaluated from the validated Mexican-Spanish version of the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaires specific for cancer | from the start of consumption until 8 weeks. | 
| Social Functioning | The Social Functioning evaluation is evaluated from the validated Mexican-Spanish version of the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaires specific for cancer | from the start of consumption until 8 weeks. | 
| Nausea/Vomiting | The Nausea/Vomiting evaluation is evaluated from the validated Mexican-Spanish version of the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaires specific for cancer | from the start of consumption until 8 weeks. | 
| Fatigue | The Fatigue evaluation is evaluated from the validated Mexican-Spanish version of the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaires specific for cancer | from the start of consumption until 8 weeks. | 
| appetite loss | The appetite loss evaluation is evaluated from the validated Mexican-Spanish version of the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaires specific for cancer | from the start of consumption until 8 weeks. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
nabilone, anorexia, Non-Small Cell Lung Cancer