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Cost-utility Analysis of Maintenance rTMS for Treatment-resistant Depression (ACOUSTIM)

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ClinicalTrials.gov Identifier: NCT03701724
Recruitment Status : Recruiting
First Posted : October 10, 2018
Last Update Posted : February 26, 2019
Sponsor:
Information provided by (Responsible Party):
Nantes University Hospital

Brief Summary:
Treatment resistant depression (TRD) is a frequent, debilitating condition mostly treated by antidepressants. Repeated magnetic transcranial stimulation (rTMS) has proven adjuvant efficacy in TRD in the acute phase of treatment with a very good tolerance and acceptability. Maintenance rTMS (mTMS) is a strategy consisting in adding regular single TMS sessions after response to an acute course in order to keep the benefit of initial treatment over several month or years. Demonstrating that rTMS is efficient to improve long-term prognosis and decrease economic burden would have a tremendous impact in clinical practice in psychiatry. Thus the investigator's aim is to analyze the long term impact of mTMS treatment on costs, but also quality of life and clinical issues.

Condition or disease Intervention/treatment Phase
Treatment-resistant Depression Device: Systematic maintenance rTMS Device: rTMS course in case of relapse Device: sham rTMS Not Applicable

Detailed Description:
TRD is associated with enormous social, economic, and personal costs. In literature, psychosocial and pharmacological interventions showed limited one year long-term efficacy in terms of relapse (only 10% of sustained remission at one-year follow-up actually) and quality of life due to refractoriness, observance and adverse effects. In the recent years the field of non-invasive brain stimulation became more mature with an increasing level of evidence reaching Level 1 for rTMS as curative treatment for depression in international guidelines. It is a safe and well tolerated treatment but with still high relapse rate at 6 month and one year (comparable to those former described for ECT). mTMS is a promising tool (as it was proven for ECT) to achieve sustained response several month after treatment in a significant proportion of patients. Little is known about its long-term economic and social benefit which is a crucial question given its time consuming nature. To date there is no large Randomized Clinical Trial (RCT) assessing the long-term health economic interest or adjuvant mTMS compared to treatment as usual (TAU) alone in unipolar TRD . This study is a double-blind randomized controlled trial aiming at determining a 12 month cost-utility analysis, according to collective perspective, of two different modalities of rTMS (systematic mTMS or curative rTMS in case of relapse) for TRD compared to TAU alone. The secondary aims are to describe 24 month cost-utility, longitudinal clinical issues in terms of mood and quality of life, prognosis factors, as well as TAU actual strategies in that population.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 318 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description: Sham rTMS will be used for the arm "without rTMS"
Primary Purpose: Other
Official Title: Cost-utility Analysis of Maintenance rTMS for Treatment-resistant Depression
Actual Study Start Date : November 5, 2018
Estimated Primary Completion Date : October 15, 2021
Estimated Study Completion Date : October 30, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Systematic maintenance rTMS (arm A)
Active rTMS treatment followed, for responders, by systematic maintenance rTMS Depression usual medical treatment (psychosocial approach and/or pharmacotherapy and/or, ECT…)
Device: Systematic maintenance rTMS
Same parameters as the initial course (session of 8,5 minutes, at 1 Hz, on the right dorsolateral prefrontal cortex (DLPFC) targeting with either neuronavigation or the Beam). The frequency is : 2 sessions / week during 1 month, then 1 session / week during 2 months and finally 1 session every 2 weeks during 8 months.

Experimental: rTMS course in case of relapse (arm B)
Active rTMS treatment followed, for responders, by additional rTMS courses, in case of relapse Depression usual medical treatment (psychosocial approach and/or pharmacotherapy and/or, ECT…)
Device: rTMS course in case of relapse
Same parameters as the initial course. The frequency is the same as the initial course: one daily session on 5 consecutive working days from Monday to Friday for at least 20 to 30 sessions over 4 to 6 weeks.

Sham Comparator: Sham rTMS (arm C)
sham rTMS followed, for responders, by either systematic sham mTMS (50%) or additional sham rTMS course in case of relapse(50%) Depression usual medical treatment (psychosocial approach and/or pharmacotherapy and/or, ECT…)
Device: sham rTMS
The sham stimulation consists of the identical rTMS procedure at the identical location using a commercial figure-eight sham coil. However, it does not produce the identical tactile sensation. A local electrical stimulation will be delivered with two disposable Electromyogram (EMG) electrodes using a transcutaneous electrical nerve stimulation (TENS) Stimulator.




Primary Outcome Measures :
  1. Cost-utility ratio, according to collective perspective of rTMS use in TRD compared to conventional therapeutic approaches without active rTMS. [ Time Frame: 12 months ]

    The utility will be measured by :

    Quality Adjusted Life Year (QALYs) as estimated from responses to the Euroqol-5 Dimensions (EQ-5D) health-related quality of life questionnaire. The questionnaire focuses on 5 dimensions: mobility, personal autonomy, current activities, pain/discomfort and anxiety/depression. For each of these dimensions, 3 answers are possible.

    The costs will be measured by the addition of the following costs:

    Drugs dispensing via Health insurance database "National system of information of the French health insurance" (SNIIRAM), hospitalizations, work stoppages and care consumption collected in a declarative patient questionnaire.



Secondary Outcome Measures :
  1. Cost-utility ratio, according to collective perspective of rTMS use in TRD compared to conventional therapeutic approaches without active rTMS. [ Time Frame: 24 months ]

    Quality Adjusted Life Year (QALYs) as estimated from responses to the Euroqol-5 Dimensions (EQ-5D) health-related quality of life questionnaire

    The costs will be measured by the additional of the following costs:

    Drugs dispensing via Health insurance database SNIIRAM, hospitalizations, work stoppages and care consumption collected in a declarative patient questionnaire


  2. Budget impact analysis of spreading the most efficient strategy for using rTMS (systematic mTMS or rTMS course in case of relapse). [ Time Frame: 5 years ]
    Comparison of intervention costs on the study sample and projection of these costs over 5 years, from the health insurance and hospital perspectives

  3. Major depressive disorder history [ Time Frame: Baseline ]
    This outcome will be assessed by patient interview, with the following data (not exhaustive): date of initial symptoms, length of the current episode, family antecedents of mood disorders.

  4. Level of depression treatment-resistance [ Time Frame: Baseline ]
    Maudsley Staging model score: a multidimensional tool to quantify treatment resistance in depression. It evaluates 5 dimensions: 1) length of the current depressive episode, 2) symptomatic intensity, 3) failure of the antidepressant drugs, 4) Increase treatment 5) use of Electro-convulsive therapy. The total score ranges from 3 to 15. 15 being the highest level of treatment resistance.

  5. professional status [ Time Frame: Baseline,12 months and 24 months ]
    patient's professional status (active, unemployed, retired...)

  6. marital status [ Time Frame: Baseline,12 months and 24 months ]
    patient's marital status (married, widow, single...)

  7. Response rate [ Time Frame: 12 months and 24 months ]
    Response is defined as follows: decrease of the MADRS score by at least 50% compared to baseline score. MADRS stands for Montgomery-Asberg Depression Rating Scale. It is used to measure the severity of depressive episodes in patients with mood disorders. The questionnaire includes questions on the following symptoms 1. Apparent sadness 2. Reported sadness 3. Inner tension 4. Reduced sleep 5. Reduced appetite 6. Concentration difficulties 7. Lassitude 8. Inability to feel 9. Pessimistic thoughts 10. Suicidal thoughts and each item yields a score of 0 to 6. The overall score ranges from 0 to 60. A score from 0 to 6 being normal/symptom absent and a score >34 being severe depression.

  8. Remission rate [ Time Frame: 12 months and 24 months ]
    Remission is defined as follows: MADRS score ≤ 10 (see detailed description of MADRS in outcome 8)

  9. Relapse-free survival [ Time Frame: 12 months and 24 months ]
    Number of patients with no relapse. Relapse is defined as follows: MADRS ≥ 20 (see detailed description of MADRS in outcome 8)

  10. MADRS score [ Time Frame: Baseline, 2 months, 6 months , 9 months, 12 months, 18 months, 24 months ]
    MADRS score (see detailed description of MADRS in outcome 8)

  11. Beck Depression Inventory (BDI) score [ Time Frame: Baseline, 2 months, 6 months , 9 months, 12 months, 18 months, 24 months ]
    The BDI is 13-item multiple-choice self-report inventory, for measuring the severity of depression. The global score is an addition of each item's score and ranges from 0 (minimal depression) to 39 (severe depression).

  12. Clinical Global Impression (CGI) score [ Time Frame: Baseline, 2 months, 6 months , 9 months, 12 months, 18 months, 24 months ]
    The Clinical Global Impression (CGI) rating scales are measures of symptom severity, treatment response and the efficacy of treatments in treatment studies of patients with mental disorders. Each scale is rated from 0 to 7. 0 being the best level and 7 the worst level.

  13. Adverse events linked to the medical treatment for depression [ Time Frame: 24 months ]
    Number and types of adverse events linked to the medical treatment for depression

  14. Declarative drug compliance via the MARS (Medication Adherence Report Scale) [ Time Frame: baseline, 12 months and 24 months ]
    MARS is the Medication Adherence Report Scale, including 10 questions, the global score ranges from 0 to 10, 0 corresponds to the worst drug compliance and 10 to an excellent drug compliance

  15. Declarative drug compliance via the CRS (Clinician Rating Scale) [ Time Frame: baseline, 12 months and 24 months ]
    CRS is the Clinician Rating Scale , including 7 questions, the global score ranges from 1 to 7, 7 being the worst level of drug compliance.

  16. Treatment(s) switch(es) [ Time Frame: Baseline, 2 months, 6 months , 9 months, 12 months, 18 months, 24 months ]
    Number of treatment switches per patient

  17. Treatment(s) dose increase [ Time Frame: Baseline, 2 months, 6 months , 9 months, 12 months, 18 months, 24 months ]
    Number of drug(s) dose(s) increases prescribed to the patient

  18. Treatments combination(s) [ Time Frame: Baseline, 2 months, 6 months , 9 months, 12 months, 18 months, 24 months ]
    List of drugs (name) prescribed to the patient

  19. Rate of suicide attempts and suicides [ Time Frame: 12 months and 24 months ]
    number of suicide attempts and suicides per patient

  20. Patient's quality of life [ Time Frame: baseline,12 months and 24 months ]
    Short-Form 36 (SF 36) questionnaire: instrument used to assess multidimensional health-related quality of life, which measures 8 health related parameters: physical function, social function, physical role, emotional role, mental health, energy, pain, general health perceptions

  21. Response rate at the end of rTMS courses [ Time Frame: 1 month after each rTMS treatments ]
    Response is defined as follows: decrease of the MADRS score by at least 50% compared to baseline score (see detailed description of MADRS in outcome 8)

  22. Remission rate at the end of rTMS courses [ Time Frame: 1 month after each rTMS treatments ]
    Remission is defined as follows: MADRS score ≤ 10 (see detailed description of MADRS in outcome 8)

  23. Number of days between the successive rTMS courses [ Time Frame: 24 months ]
    Number of days between end of rTMS course X and beginning of course X+1, for each patient

  24. Total number of rTMS sessions [ Time Frame: 24 months ]
    total number of rTMS sessions per patient

  25. Time between relapses [ Time Frame: 24 months ]
    Number of days between relapses, per patient

  26. Compliance with rTMS [ Time Frame: 24 months ]
    number of missed sessions over the number of planned sessions, per patient

  27. Patient acceptability of the rTMS technique: Analog Visual Scale [ Time Frame: 24 months ]
    Analog Visual Scale of acceptability of the rTMS completed by the patient, ranging from 0 to 10. 0 being "not acceptable" and 10 being "totally acceptable"



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Major depressive disorder according to Diagnostic and Statistical Manual of Mental Disorders (DSM) 5 MADRS >19
  • Episode duration: 12 weeks to 3 years.
  • 2 to 4 unsuccessful treatment lines (including antidepressants, and potentialization agents lithium and quetiapine) despite adequate dosage and duration (6 weeks stable posology)
  • Ability to consent and express informed consent, to answer questionnaires and to go to follow-up visits.
  • Affiliation to social security

Exclusion Criteria:

  • Bipolar disorder
  • Schizophrenia and other psychotic disorders
  • Mental retardation or developmental disorder
  • Substance abuse or dependence
  • Depression symptoms better explained by medical conditions
  • Neurologic conditions (e.g.,previous epilepsy or unexplained seizures, stroke, trauma, infection, metabolic disease, severe migraines, multiple sclerosis, brain tumor)
  • Presence of at least one contra-indication to rTMS
  • Pregnancy/breast-feeding
  • Patient who previously received 5 lines or more pharmacological treatment for the current episode (excluding symptomatic psychotropic drugs, e.g. benzodiazepines and hypnotics)
  • Former use of electroconvulsive therapy or rTMS within the current episode.
  • Previous failure of adequate ECT (at least 12 well conducted sessions) or rTMS course (at least 20 well conducted sessions) in the medical history.
  • History of at least two courses of ECT, previous need for maintenance ECT.
  • Protection measure : maintenance of justice, tutelage, legal guardianship
  • Woman of childbearing age without effective contraception
  • Liberty deprivation (e.g. incarceration, therapeutic injunction)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03701724


Contacts
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Contact: Samuel Bulteau, MD +33 2 40 08 47 95 samuel.bulteau@chu-nantes.fr
Contact: Cécile DERT +33 2 53 48 28 52 cecile.dert@chu-nantes.fr

Locations
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France
CHU d'Angers Recruiting
Angers, France, 49100
Contact: Bénédicte GOHIER, Phd    +332 41 35 36 37    BeGohier@chu-angers.fr   
CHRU de Besançon Recruiting
Besançon, France, 25000
Contact: Emmanuel HAFFEN, Phd    +333 81 66 81 66    emmanuel.haffen@univ-fcomte.fr   
CH le Vinatier Lyon Recruiting
Bron, France
Contact: Filipe GALVÃO, Md    +334 37 91 52 58    filipe.galvao@ch-le-vinatier.fr   
CHU de Caen Recruiting
Caen, France
Contact: Clément NATHOU, Md    +332 31 06 50 18    nathou-c@chu-caen.fr   
CHU de Clermont-Ferrand Recruiting
Clermont-Ferrand, France
Contact: Isabelle JALENQUES, Phd         
Contact    +334 73 75 21 14    ijalenques@chu-clermontferrand.fr   
CHU de Dijon Recruiting
Dijon, France
Contact: Benoit TROJAK, Phd    +333 80 29 30 31    benoit.trojak@chu-dijon.fr   
CHU de Grenoble Recruiting
Grenoble, France
Contact: Gaelle DALL'IGNA, Md    +334 76 76 75 75    GDalligna@chu-grenoble.fr   
EPSM de Lille Recruiting
Lille, France
Contact: Maxime BUBROVSZKY, Md    +333 20 63 76 08    maxime.bubrovszky@epsm-al.fr   
CH Esquirol - Limoges Recruiting
Limoges, France
Contact: Benjamin CALVET, Md    +335 55 43 11 02    benjamin.calvet@orange.fr   
CHU de Montpellier Recruiting
Montpellier, France
Contact: Jerome ATTAL, Phd    +334 67 33 97 18    j-attal@chu-montpellier.fr   
Nantes University Hospital Recruiting
Nantes, France, 44000
Contact: Samuel Bulteau, MD    +33 2 40 08 47 95    samuel.bulteau@chu-nantes.fr   
EPS de Ville-Evrard Recruiting
Neuilly-sur-Marne, France
Contact: Dominique JANUEL, Md    +331 43 00 43 33    urcve1@gmail.com   
CH Henri Laborit (Poitiers) Recruiting
Poitiers, France, 86000
Contact: Nematollah JAAFARI, Phd    +335 49 44 57 57    nemat.jaafari@ch-poitiers.fr   
Centre hospitalier Guillaume Regnier Rennes Recruiting
Rennes, France, 35000
Contact: Dominique DRAPIER, Phd    332 99 33 39 00    d.drapier@ch-guillaumeregnier.fr   
CH du Rouvray - Rouen Recruiting
Rouen, France
Contact: Maud ROTHARMEL, Md    +332 32 95 12 34    maud.rotharmel@ch-lerouvray.fr   
CHU de Toulouse Recruiting
Toulouse, France
Contact: Antoine YRONDI, Md    +335 34 55 75 23    yrondi.a@chu-toulouse.fr   
CHU de Tours / CHRU de Tours Recruiting
Tours, France, 37540
Contact: WISSAM EL HAGE, Phd    332 47 47 47 47    W.ELHAGE@chu-tours.fr   
Sponsors and Collaborators
Nantes University Hospital
Investigators
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Principal Investigator: Samuel Bulteau, MD Nantes University Hospital

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Responsible Party: Nantes University Hospital
ClinicalTrials.gov Identifier: NCT03701724     History of Changes
Other Study ID Numbers: RC17_0494
First Posted: October 10, 2018    Key Record Dates
Last Update Posted: February 26, 2019
Last Verified: February 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Nantes University Hospital:
Major Depressive Disorder
Unipolar depression
Chronic depression
Recurrent depression
Depressive disorder
Magnetic stimulation
Non-invasive brain stimulation
1 Hertz (Hz) rTMS
Maintenance rTMS
Cost-utility
Efficiency
Medico-economic
Antidepressants
Additional relevant MeSH terms:
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Depression
Depressive Disorder
Depressive Disorder, Treatment-Resistant
Behavioral Symptoms
Mood Disorders
Mental Disorders