MIR-P: Mirtazapine in Cancer-related Poly-symptomatology

Sponsor

Hospices Civils de Lyon (Other)

Overall Status

Recruiting

CT.gov ID

NCT04763135

Collaborator

(none)

418

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

1.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Multicenter, prospective, randomized, controlled trial based on a mixed-method methodology using parallel groups, of oral mirtazapine (intervention) compared with oral escitalopram (control), with a 56 days follow-up. Improvement of the Global health Status (issued from the EORTC-QLQ-C30 (Quality of Life Questionnaire)) will be used as the primary outcome on day 56. Semi-structures interviews will be performed on a purposive sample for qualitative analysis. The 418 participants will be followed-up at day 7, 14, 28 and 56 for a 56 days period. A sub-group of participants will be invited to take part into qualitative interviews at baseline and day 56. Recruitment of participants to the qualitative part will be based on a purposive sampling.

Condition or Disease	Intervention/Treatment	Phase
Cancer Neoplasms Neoplasm Metastasis	Drug: Mirtazapine Drug: Escitalopram	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

418 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

What is the Effectiveness and Safety of Mirtazapine Versus Escitalopram in Alleviating Cancer-associated Poly-symptomatology (MIR-P)? A Mixed-method Randomized Controlled Trial Protocol

Actual Study Start Date :

Dec 15, 2021

Anticipated Primary Completion Date :

Feb 15, 2024

Anticipated Study Completion Date :

Feb 15, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Oral mirtazapine Arm 1 patients will be treated using a daily mirtazapine treatment. Treatment will be taken on the evening. Treatment will be initiated at 15 mg daily and gradually increased depending on symptom control and side effects. Treatment doses will be adapted for old patients and those with liver failure.	Drug: Mirtazapine Orally disintegrating tablets of mirtazapine introduced at the dose of 15 mg and increased up to 45 mg per day during 56 days. Doses escalation: based on symptom management and side effect assessment.
Active Comparator: Oral escitalopram Arm 2 patients will be treated using a daily escitalopram treatment. Treatment will be taken in the morning. Treatment will be initiated at 10 mg daily and gradually increased depending on symptom control and side effects. Treatment doses will be adapted for 5 mg for old patients.	Drug: Escitalopram Orally disintegrating tablets of escitalopram introduced at the dose of 10 mg (or 5 mg for patients older than 65) and increased up to 20 mg per day during 56 days. Doses escalation: based on symptom management and side effect assessment.

Arm

Intervention/Treatment

Experimental: Oral mirtazapine

Arm 1 patients will be treated using a daily mirtazapine treatment. Treatment will be taken on the evening. Treatment will be initiated at 15 mg daily and gradually increased depending on symptom control and side effects. Treatment doses will be adapted for old patients and those with liver failure.

Drug: Mirtazapine

Orally disintegrating tablets of mirtazapine introduced at the dose of 15 mg and increased up to 45 mg per day during 56 days. Doses escalation: based on symptom management and side effect assessment.

Active Comparator: Oral escitalopram

Arm 2 patients will be treated using a daily escitalopram treatment. Treatment will be taken in the morning. Treatment will be initiated at 10 mg daily and gradually increased depending on symptom control and side effects. Treatment doses will be adapted for 5 mg for old patients.

Drug: Escitalopram

Orally disintegrating tablets of escitalopram introduced at the dose of 10 mg (or 5 mg for patients older than 65) and increased up to 20 mg per day during 56 days. Doses escalation: based on symptom management and side effect assessment.

Outcome Measures

Primary Outcome Measures

Global health status score [At baseline and day 56]
The Global Health Status will be calculated from the specific subscale included in the EORTC-QLQ-C30 scale. The difference between baseline and the end-point (day 56) will be the primary judgment criteria. A 4 to 8 points difference between baseline and endpoint will be considered as a mild difference, and a difference over 8 points will be considered as a moderate difference.

Secondary Outcome Measures

The subjective experience associated with symptoms burden. [At baseline and day 56.]
Qualitative analysis of compared semi-structured interviews undertaken at baseline and day 56 on a convenience sample.
Proportion of mitigated symptoms. [Day 28]
The Edmonton Symptom Assessment Scale 12F will be used to assess each symptoms intensities for the following symptoms: pain, nausea, vomiting, lack of appetite, breathlessness, depression, anxiety, sleep disorders and wellness. For each symptom, the difference between baseline and the assessment time will be calculated. A difference equal or over one point will be regarded as mitigation. The judgment criteria will be the proportion of symptoms that were rated over three at baseline and that were mitigated at the assessment time.
Proportion of mitigated symptoms. [Day 56]
The Edmonton Symptom Assessment Scale 12F will be used to assess each symptoms intensities for the following symptoms: pain, nausea, vomiting, lack of appetite, breathlessness, depression, anxiety, sleep disorders and wellness. For each symptom, the difference between baseline and the assessment time will be calculated. A difference equal or over one point will be regarded as mitigation. The judgment criteria will be the proportion of symptoms that were rated over three at baseline and that were mitigated at the assessment time.
Auto-assessment depression score. [Day 28]
The Hospital Anxiety and Depression Scale-D auto-assessment score will be used to assess the auto-assessment depression score. The judgment criteria will be the difference between baseline and the assessment time. A difference over 1.5 points will be regarded as clinically significant.
Auto-assessment depression score. [Day 56]
The Hospital Anxiety and Depression Scale-D auto-assessment score will be used to assess the auto-assessment depression score. The judgment criteria will be the difference between baseline and the assessment time. A difference over 1.5 points will be regarded as clinically significant.
Hetero-assessment-based depression score. [Day 28]
The Montgomery-Asberg Depression Rating Scale hetero-assessment score will be used to assess the hetero-assessment depression score. The judgment criteria will be the difference between baseline and the assessment time. A difference over 1.9 points will be regarded as clinically significant.
Hetero-assessment-based depression score. [Day 56]
The Montgomery-Asberg Depression Rating Scale hetero-assessment score will be used to assess the hetero-assessment depression score. The judgment criteria will be the difference between baseline and the assessment time. A difference over 1.9 points will be regarded as clinically significant.
Proportion of improvement in functioning sub-scales. [Day 28]
The cognitive functioning, physical functioning, emotional functioning, and role functioning sub-scales issued from the EORTC-QLQ-C30 will be used. For the cognitive functioning sub-scale, a difference over 3 points will be considered as clinically significant. For the physical functioning subscale, a difference over 2 points will be considered as clinically significant. For the emotional functioning subscale, a difference over 6 points will be considered as clinically significant. For the social functioning subscale, a difference over 6 points will be considered as clinically significant. The judgment criteria will be the proportion of patients that improved their functioning score. The judgment criteria will be assessed for each subscale independently.
Proportion of improvement in functioning sub-scales. [Day 56]
The cognitive functioning, physical functioning, emotional functioning, and role functioning sub-scales issued from the EORTC-QLQ-C30 will be used. For the cognitive functioning sub-scale, a difference over 3 points will be considered as clinically significant. For the physical functioning subscale, a difference over 2 points will be considered as clinically significant. For the emotional functioning subscale, a difference over 6 points will be considered as clinically significant. For the social functioning subscale, a difference over 6 points will be considered as clinically significant. The judgment criteria will be the proportion of patients that improved their functioning score. The judgment criteria will be assessed for each subscale independently.
Weight control [Day 28]
Weight control will be defined as a difference under 500g between the weight at baseline minus the weight at the assessment time. The judgment criteria will be the proportion of patients with weight control at assessment time.
Weight control [Day 56]
Weight control will be defined as a difference under 500g between the weight at baseline minus the weight at the assessment time. The judgment criteria will be the proportion of patients with weight control at assessment time.
Weight improvement. [Day 28]
Weight improvement will be defined as a difference over 500g between the weight at the assessment time minus the weight at baseline. The judgment criteria will be the proportion of patients with weight improvement at assessment time.
Weight improvement. [Day 56]
Weight improvement will be defined as a difference over 500g between the weight at the assessment time minus the weight at baseline. The judgment criteria will be the proportion of patients with weight improvement at assessment time.
Stability in oral morphine milligram equivalents. [Day 28]
The stability in oral morphine milligrams equivalent will be defined as a decrease or stability in the daily doses of opioid pain killers measured using oral morphine milligram equivalents. The judgment criteria will be the proportion of patients with stability in oral morphine milligram equivalents.
Stability in oral morphine milligram equivalents. [Day 56]
The stability in oral morphine milligrams equivalent will be defined as a decrease or stability in the daily doses of opioid pain killers measured using oral morphine milligram equivalents. The judgment criteria will be the proportion of patients with stability in oral morphine milligram equivalents.
Escalation in symptom control treatment doses [Day 28]
Escalation in symptom control treatment doses will be defined as any escalation in the dose of a treatment existing at baseline or any new treatment introduced to control one of the following symptoms: pain, nausea, vomiting, lack of appetite, breathlessness, depression, anxiety, sleep disorders and wellness. The judgment criteria will be the proportion of patients with an escalation in symptom control treatment doses.
Escalation in symptom control treatment doses [Day 56]
Escalation in symptom control treatment doses will be defined as any escalation in the dose of a treatment existing at baseline or any new treatment introduced to control one of the following symptoms: pain, nausea, vomiting, lack of appetite, breathlessness, depression, anxiety, sleep disorders and wellness. The judgment criteria will be the proportion of patients with an escalation in symptom control treatment doses.
Number of side effects. [Day 7]
The number of side effects will be used to assess the security of use. It will be assessed using the Antidepressant Side Effect Checklist and side effects will be considered if rated moderate or severe.
Number of side effects. [Day 14]
The number of side effects will be used to assess the security of use. It will be assessed using the Antidepressant Side Effect Checklist and side effects will be considered if rated moderate or severe.
Number of side effects. [Day 28]
The number of side effects will be used to assess the security of use. It will be assessed using the Antidepressant Side Effect Checklist and side effects will be considered if rated moderate or severe.
Number of side effects. [Day 56]
The number of side effects will be used to assess the security of use. It will be assessed using the Antidepressant Side Effect Checklist and side effects will be considered if rated moderate or severe.
Medication adherence. [Day 56]
The medication adherence will be assessed using the Medication Adherence Rating Scale score at day 56 and the Proportion of Days Covered all along the follow-up period.
Symptoms' intensities auto-assessment on the following symptoms: pain, nausea, vomiting, lack of appetite, breathlessness, depression, anxiety, sleep disorders and wellness. [Day 28]
The Edmonton Symptom Assessment Scale 12F will be used to assess each symptoms intensities for the following symptoms: pain, nausea, vomiting, lack of appetite, breathlessness, depression, anxiety, sleep disorders and wellness. For each symptom, the difference between baseline and the assessment time will be used as the judgment criteria. A difference equal or over one point will be regarded as clinically significant.
Symptoms' intensities auto-assessment on the following symptoms: pain, nausea, vomiting, lack of appetite, breathlessness, depression, anxiety, sleep disorders and wellness. [Day 56]
The Edmonton Symptom Assessment Scale 12F will be used to assess each symptoms intensities for the following symptoms: pain, nausea, vomiting, lack of appetite, breathlessness, depression, anxiety, sleep disorders and wellness. For each symptom, the difference between baseline and the assessment time will be used as the judgment criteria. A difference equal or over one point will be regarded as clinically significant.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Being over 18 years old
Suffering from advanced cancer
Having a clinically estimated life expectancy over 3 months.
Being diagnosed from having a depressive syndrome by a Hospital Anxiety and Depression Scale-D over 11.
Being in need of an antidepressant treatment.
Suffering from at least one under-controlled symptom (defined as a score over 3 on the Edmonton Symptom Assessment Scale) among: pain, nausea, vomiting, breathlessness, lack of appetite, sleep disorders, anxiety or impaired wellbeing.
Having or not a cancer treatment.
Being able to understand the information related to the study, and to sign informed consent.
Having agreed to take part to the study.
Being able to fill Patient Reported Outcomes questionnaires.
Being available to be call on days 7 and 14.
Having a social security affiliation.

Exclusion Criteria:

Being treated by an antidepressive agent during the four weeks before inclusion.
Having had a hypersensitivity event to mirtazapine, escitalopram of any excipient.
Having had a prior inefficient treatment by mirtazapine or escitalopram.
Having postural hypotension or arterial systolic hypotension inferior to 90 mmHg measured following the guidelines of the European Society of Cardiology
Having a QT interval over 420 ms.
Having uncontrolled hearth rhythm disorder or uncontrolled conduction disorder.
Having had or having bipolar disorder.
Having uncontrolled seizure or epilepsy (relative non-inclusion criteria needing a neurology specialist opinion)
Having or having history of closed-angle glaucoma.
Having bone marrow aplasia.
Practicing breast-feeding or being pregnant.
Women of childbearing age with no contraception method.
Having a treatment with:
Monoamine oxidase inhibitors (Selegiline, Moclobemide, Isocarboxazid, Nialamide, Phenelzine, Tranylcypromine, Iproniazid, Iproclozide, Toloxatone, Linezolid, Safinamide, Rasagiline)
One of the following antiarrhythmic drugs: Flecainide, Propafenone, any class IA and III antiarrhythmic drug (amiodarone, disopyramide, hydroquinidine, quinidine, procainamide, sparteine, ajmaline, prajmaline, lorajmine, bretylium tosilate, bunaftine, dofetilide, ibutilide, tedisamil, dronedarone).
Antipsychotic drugs (phenothiazine antipsychotics, pimozide, haloperidol)
Linezolid, sparfloxacin, moxifloxacin, macrolides (IV erythromycin, josamycin, clarithromycin, telithromycin), pentamidin, halofantrine, HIV protease inhibitors (ritonavir, nelfinavir, amprenavir, indinavir), azolic antifungal agents (ketoconazole, itraconazole, miconazole, fluconazole, voriconazole)
Mizolastine and Cimetidine
Ticlopidine
Metoprolol
Methadone
Ketamine
Triptan drugs
Dapoxetine
St. John's wort
Antidepressant drug
Any other medication known to cause prolonged QT intervals.
Having genetic galactose intolerance or glucose-galactose malabsorption.
Having one of the following electrolyte disorders not corrected at the time of inclusion: hyponatremia, hyperkalemia, hypokalemia, hypermagnesemia, and hypomagnesemia.
Having end-stage renal disease with a creatinine clearance inferior to 15 ml/min calculated using the Cockroft's formula.
Having hepatic failure.
Having legal incapacity

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Centre Hospitalier Universitaire de Clermont-Ferrand	Cébazat	France	63118
2	Centre Hospitalier Universitaire de Grenoble	La Tronche	France	38700
3	Hôpital Edouard Herriot	Lyon	France	69003
4	Hôpital de la Croix-Rousse	Lyon	France	69004
5	Centre Médico-Chirurgical de Réadaptation des Massues Croix-Rouge française	Lyon	France	69005
6	Centre Léon Bérard	Lyon	France	69008
7	Institut Curie	Paris	France	75005
8	Centre Hospitalier Lyon Sud	Pierre-Bénite	France	69495
9	Centre Hospitalier Universitaire de Saint-Etienne	Saint-Étienne	France	42100
10	Hôpitaux universitaires de Strasbourg	Strasbourg	France	67098
11	Centre Hospitalier de Valence	Valence	France	26000