Intranasal Esketamine Against Depression. A real world clinical treatment Cohort-Study in the Netherlands (INESKAD)

Study type

• Study topic:
  Disease /health condition

  Human medicinal product
• Study topic, other:
  Treatment Resistant Depression
• Study type:
  Non-interventional study
• Scope of the study:
  Assessment of risk minimisation measure implementation or effectiveness

  Drug utilisation

  Effectiveness study (incl. comparative)

  Evaluation of patient-reported outcomes

  Other

  Safety study (incl. comparative)
• If ‘other’, further details on the scope of the study:
  Prestratification
• Data collection methods:
  Primary data collection

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Study drug International non-proprietary name (INN) or common name:
  ESKETAMINE
• Anatomical Therapeutic Chemical (ATC) code:
  (N06AX27) esketamine

  esketamine
• Medical condition to be studied:
  Depression
• Additional medical condition(s):
  Treatment Resistant Depression

Population studied

• Short description of the study population:
  In order to be eligible to participate in this study, a subject must meet the following ; Inclusion criteria:; - Clinical diagnosis of primary MDD, preferably confirmed by a structured clinical interview (MINI/SCID-I); - Treatment Resistant Depression, defined as non-response to at least two antidepressants used at adequate dosages for a minimum of 6 weeks; - Age >18 years old (no maximum age); - Current use of (and compliance to) an antidepressant (non-SSRI/SNRI is allowed); ; Exclusion criteria:; - Current psychotic illness; - Bipolar disorder; - Severe suicidal/homicidal risk (to be determined by psychiatrist); - Insufficient understanding of Dutch to fill-out questionnaires and/or understand information; - Unable to self-administer esketamine nasal spray; - History of moderate-severe substance abuse or dependence meeting DSM-5 criteria; - Pregnancy or wish to become pregnant; - No form of adequate anti-conception (both genders); - Instable epileptic disease/seizures in previous 6 months; - Unstable hypertension (>140/90 mmHg) or recent cardiovascular event (cerebrovascular, myocardial, aneurysmal vascular disease, angina-pectoris, . hemodynamically significant valvular heart disease, NYHA Class III-IV heart failure); - Hypo-thyroidism, liver-failure/cirrhosis ; - Any anatomical or medical condition that may impede delivery or absorption of intranasal esketamine; - Other unstable somatic/medical illness; - Previous non-response to esketamine (intranasal) or ketamine in current MDD episode; - Known allergies, hypersensitivity, intolerance, or contraindications to esketamine/ketamine and/or its excipients;
• Age groups:
  • Adult and elderly population (≥18 years)

    • Adults (18 to < 65 years)

      • Adults (18 to < 46 years)
      • Adults (46 to < 65 years)
    • Elderly (≥ 65 years)

      • Adults (65 to < 75 years)
      • Adults (75 to < 85 years)
      • Adults (85 years and over)
• Special population of interest, other:
  Treatment Resistant Depression
• Estimated number of subjects:
  10000

Study design details

• Study design:
  This is a cohort study of patients who are treated with intranasal esketamine (open label). For the objectives of this study, no other routines will be applied apart from the necessary measurements in clinical medical records of the patients, who will provide informed consent for the data-collection
• Main study objective:
  Primary Objective: To collect short- and long-term effectiveness and acceptability data for the treatment with intranasal esketamine in treatment resistant depressed patients treated in collaborating esketamine treatment centres.; Secondary Objective(s): ; To pool pseudoanonymised data of effectiveness and acceptability of esketamine intranasal from based on clinical registrations in patient’s real-world health records. ; To use predicted treatment response based on pooled clinical and behavioural data as pre-selection tool.;
• Setting:
  Primarily outpatients treated in day-care facilities due to EMA-regulatons, sometimes inpatients if disease severity requires hospitalisation.
• Comparators:
  None
• Outcomes:
  Primary endpoint is the change (relative to baseline) in clinician-rated MADRS score (Montgomery 1979) at 4 and 8 weeks of treatment.; Secondary endpoints are: ; - The change (relative to baseline) in clinician-rated MADRS score (Montgomery 1979) over time measured in 4 weeks intervals after week 8.; - The change (relative to baseline) in self-rated IDS-SR score (Rush 1996; Trivedi 2004) at 4 weeks and over time measured in 4 week intervals thereafter.; - Quality of Life measurement (EQ-5D-5L) at 4 weeks and over time measured in 4 week intervals thereafter (relative to baseline); - Level of functioning at 4 weeks (WHODAS-2.0) and over time measured in 4 week intervals thereafter (relative to baseline); - Cost-effectiveness (modified TiC-P) at 4 and 8 weeks and 3 monthly intervals thereafter (relative to baseline); - The change in mood (before-after) esketamine intranasal spray per session as measured by a visual analogue scale before administration and after completion of the session (before leaving).; - Occurrence of adverse effects including dissociative symptoms at T=40 min after administration (or as close as possible) and at the end of the session as measured with the K-SET per session ; - Discontinuation rates: due to adverse effects of the treatment or other reasons. ; - Changes in blood-pressure during esketamine intranasal sessions (baseline, 10, 40, 90 minutes per session); - Follow-up 3 months after discontinuation of intranasal esketamine treatment.; - With the PIT, we apply a test that quantifies affect-driven avoidance and approach behaviors, with great potential in predicting the effect of intranasal esketamine on TRD (baseline, 4 wekes of treatment).; ; Before the treatment is initiated we will assess the level of treatment resistance with the DM-TRD
• Data analysis plan:
  For the continuous MADRS-scores differences relative to baseline will be expressed over time. This will initially be done for the full sample. Subsequently we will investigate the association of the primary outcome with the level of treatment resistance and specific aspects thereof (e.g. ECT-non-responders) with linear mixed models (to accommodate repeated follow-up measurements and unavoidable missing data over time). We will pool this data across different treatment centres in order to increase power and obtain more quantitative information about possible characteristics of responders vs non-responders.; For secondary outcome study parameters (IDS-SR, QoL and level of functioning) we will use a comparable approach as for the primary study outcome. Discontinuation rates will be described over time, also in relation with level of TRD. The DM-TRD will be used as a continuous variable in regression and mixed model analyses. For illustrative purposes the scores of this scale can be split into tertiles (low and high levels of TRD).; Occurrence of dissociative symptoms and blood-pressure per session will be examined for stability over time. Moreover, the severity of these adverse effects and the variation thereof between patients will be described descriptively. ; ; For each separate analysis done in this consortium, we will pre-register an analysis plan at the Open Science Framework (https://osf.io/); ;
• Summary results:
  To be expected