This study has been transitioned to CTIS with ID 2024-517485-42-00 check the CTIS register for the current data. To investigate whether oral esketamine is non-inferior to ECT in achieving treatment response on depression severity in NTRD.
ID
Source
Brief title
Condition
- Mood disorders and disturbances NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Phase 1
The primary objective in phase 1 is to investigate whether oral esketamine
treatment is non-inferior to ECT in terms of response rates. The main study
parameter comprises the percentage of patients with a treatment response,
defined as a >=30% reduction (i.e., MICD) on the MADRS, in the esketamine
relative to the ECT condition after eight weeks of treatment.
Phase 2
The primary objective in phase 2 is to compare the efficacy of maintenance
treatment with either oral esketamine or ECT in preventing relapse (i.e., loss
of response) in patients who responded to the acute treatment (phase 1). The
main study parameter comprises the percentage of patients with a depression
relapse (i.e., loss of response), defined as a <30% reduction on the MADRS, in
the esketamine relative to the ECT condition after 12 months of maintenance
treatment.
Secondary outcome
Secondary objectives and respective study parameters include:
1. To investigate whether oral esketamine is non-inferior to ECT in patients
with NTRD on the short-term in with regard to depression symptom severity,
suicidality, clinical impression, functioning, and quality of life, measured by:
a) Response rates, more strictly defined as a >=50% reduction on the MADRS.
b) Change in self-rated depressive symptom severity, defined as a reduction in
IDS-SR total score between baseline and 8-weeks of treatment.
c) Change in suicidal ideation, defined as a reduction in Columbia Suicide
Severity Rating Scale (C-SSRS) scores between baseline and 8-weeks of treatment.
d) Change in general clinical impression, defined as a reduction in the
Clinical Global Impression (CGI) score, the Clinical Global Impression Severity
scale (CGI-S) score, and an increase in the Clinical Global Impression
Improvement scale (CGI-I) score between baseline and 8-weeks of treatment.
e) Change in functioning, defined as a reduction in the WHO Disability
Assessment Schedule (WHODAS) total score between baseline and 8-weeks of
treatment.
f) Change in health-related quality of life, defined as a reduction in the
5-level Euroqol-5D (EQ-5D-5L) total score between baseline and 8-weeks of
treatment.
2. To explore long-term effectiveness of oral esketamine treatment compared to
ECT treatment in participants who respond to initial treatment on variables
other than loss of response, as measured by:
a) Remission rates, defined as MADRS total score <= 9 at the follow-up visits,
and including both sustained remission (remission achieved <= 8-weeks of
treatment and sustained during follow-up), and delayed remission (remission
achieved > 8 weeks of treatment and sustained during 1-year follow-up);
b) Relapse in terms of loss of remission (within 6 months of remission) and
recurrence (after 6 months of remission) rates, defined as:
• Meeting the MADRS criteria for depressive disorder (total score >= 19) for at
least two consecutive measurements, OR;
• Worsening of symptoms requiring treatment policy change, OR;
• Readmission to hospital, OR;
• Suicide attempt.
c) Comparing the differences in course of depression during the 52 weeks of
follow-up between the two conditions, based upon the monthly MADRS and IDS-SR
total scores.
d) Change in self-rated depressive symptom severity, defined as a reduction in
IDS-SR total score between 8-weeks of treatment and 1-year-follow-up.
e) Change in suicidal ideation, defined as a reduction or preservation of
initial reduction in C-SSRS scores between 8-weeks of treatment and
1-year-follow-up.
f) Change in general clinical impression, defined as a reduction or
preservation of initial reduction in the CGI score, CGI-S score, and
improvement as measured with the CGI-I between 8-weeks of treatment and 1-year
follow-up.
g) Change in functioning, defined as a reduction or preservation of initial
reduction in the WHODAS total score between 8-weeks of treatment and 1-year
follow-up.
h) Change in health-related quality of life, defined as a reduction or
preservation of initial reduction in the EQ-5D-5L total score between 8-weeks
of treatment and 1-year follow-up.
i) The comparable or more narrow profile of additional treatments received
during follow-up, derived from the Treatment Inventory of Costs in Psychiatric
Patients (TIC-P) questionnaire.
3. To investigate whether oral esketamine is more patient friendly than ECT
with respect to treatment burden, side effects, and tolerability during
treatment and at follow-up, as measured by:
a) Systematic Assessment for Treatment Emergent Events (SAFTEE);
b) Cognitive tests: Dutch Adult Reading Test (DART); Dutch Rey Auditory Verbal
Learning Test (D-RAVLT); Montreal Cognitive Assessment (MoCA); Trail making
Test A and B; Subjective Assessment of Memory Impairment (SAMI); Columbia
Autobiographical Memory Interview (CUAMI);
c) Body weight, blood pressure, heart rate, kidney function and liver enzyme
levels.
d) Exploring participants* treatment experiences by:
o Interviewing a subset of participants who received either ECT or esketamine
(optional in informed consent).
o Questionnaires to assess psychedelic experiences (esketamine condition only):
Ketamine Side Effect Tool (K-SET); 5-Dimensional Altered States of
Consciousness Rating Scale (5D-ASC).
4. To investigate whether oral esketamine treatment is more cost-effective
compared to ECT, as expressed by incremental costs per Quality Adjusted Life
Year (QALY) gained. Costs will be measured from a societal perspective,
including productivity costs using the TIC-P. QALYs will be assessed with
utility scores derived from the EQ-5D-5L using the validated Dutch tariff. A
Budget Impact Analysis (BIA) will be conducted to inform decision-makers about
the financial consequences of the adoption and diffusion of oral esketamine
treatment for NTRD in the Dutch healthcare system.
5. To investigate predictors and working mechanisms of successful oral
esketamine and ECT treatment, by:
a) Assessing demographical, clinical staging, and profiling characteristics,
including: gender, age, depression subtypes (as assessed by the MINI-plus at
screening), level of treatment resistance (as assessed by the Dutch Method for
Staging TRD (DM-TRD)), previous depressive treatments (including ECT and IN
esketamine), treatment expectancy (as assessed by the Credibility and
Expectancy Questionnaire (CEQ)), personality traits (as assessed by the
Standardized Assessment of Personality - Abbreviated Scale (SAPAS)), and
childhood trauma (as assessed by the Jeugd Trauma Vragenlijst (JTV), a Dutch
version of the Childhood Trauma Questionnaire (CTQ)).In addition, the degree of
dissociative and mystical experience (as assessed by the 5D-ASC) will be
explored as a predictor in participants who received oral esketamine treatment.
b) Assessing neurobiological markers covering major pathophysiological
mechanisms involved in mood disorders to evaluate *predictors* of treatment
responses (i.e., baseline values) and *targets* of treatment (i.e., change in
baseline value at follow-up) in the ECT and esketamine condition.
Neurobiological markers include (optional in informed consent):
a. blood biomarkers;
b. gene expression patterns in white blood cells;
And only in participants randomised to oral esketamine treatment:
c) Assessing the detailed pharmacokinetic profile of oral esketamine in a
subsample of patients (n = 20), by measuring fluctuations (three measurements)
in plasma levels of esketamine and its metabolites, and explore the
relationship between plasma levels of esketamine and its metabolites (single
measurement) and the primary outcome in all patients in the esketamine
condition (n = 78).
d) Exploring potential pharmacodynamic characteristics of oral esketamine, by
exploring the relationship between the pharmacokinetic profile of oral
esketamine and:
a. Body Mass Index (BMI);
b. The concurrent use of antidepressants and benzodiazepines;
c. Ethnic origin.
6. To explore participants* subjective experiences with treatment with oral
esketamine or ECT, as measured by a Dutch individual semi-structured interview
questioning a subset of participants derived from both treatment arms about
their personal experiences of the treatment and procedures. Also, the interview
will address how participants relate to their illness and their personal
circumstances. Asking permission to participate will be asked at inclusion, the
semi-structured interview will be conducted at the end of phase 1.
Background summary
Depression is one of the most impactful medical conditions worldwide, a leading
cause of disability, and a major contributor to the overall global burden of
disease. Unfortunately, response to treatment is rather unpredictable, slow in
onset, and incomplete in success rate. Stepwise protocolled treatment with
different antidepressants and psychotherapies fails to achieve a clinically
meaningful response in approximately 30% of patients.
Professional guidelines advise electroconvulsive therapy (ECT) as the final
treatment step for patients with Treatment Resistant Depression (TRD), but ECT
entails certain disadvantages: the procedure requires repeated anesthesia and
clinical admission, there is a risk of persistent and significant cognitive
side effects, and 40% of patients relapse within 6 months. Hence, there is a
pressing need for efficacious alternatives for patients with TRD. This is even
more so in patients with Non-psychotic Treatment Resistant Depression (NTRD),
for whom ECT is overall less effective than in patients who have depression
with psychotic features. A novel intervention that has shown rapid and robust
antidepressant effects is ketamine treatment, either as intraveneus (IV),
intranasal (IN) or oral formulation, all of which were shown to be effective in
patients with NTRD. IV esketamine appears to have the most robust immediate
results on the reduction of depressive symptoms, but direct comparisons between
the different applications have not been done, and at 4 to 8 weeks the
differences in effects between the different forms of applications appear to be
very limited. Furthermore, not much is known about how to sustain the
antidepressant effect after successful initial esketamine treatment. Looking at
patiënt burden, IV clearly is the most invasive variant, followed by IN dosing
that needs to be applied in the clinic at every dose and oral esketamine that
may safely be used for longer periods of time, including at home. These
advantages make generic oral esketamine a patient-friendly treatment compared
to the other formulations. Furthermore, oral esketamine is much cheaper than IN
esketamine and also less costly than ECT. Given its promising effects and
presumed advantages, an important question is whether oral esketamine or a
combination of oral and IV esketamine, may serve as effective and acceptable
alternatives to ECT for NTRD patients.
This study is funded by a grant Zorg Instituut Nederland (ZINL) under the
program 'Veelbelovende Zorg*. If outcomes are positive, ZINL will facilitate
subsequent implementation and reimbursement of low-cost generic oral esketamine
for the treatment of patients with NTRD in the Netherlands. This could lead to
an additional, affordable, reimbursed esketamine variant on the market.
Study objective
This study has been transitioned to CTIS with ID 2024-517485-42-00 check the CTIS register for the current data.
To investigate whether oral esketamine is non-inferior to ECT in achieving
treatment response on depression severity in NTRD.
Study design
This study comprises a multicentre, randomized clinical non-inferiority trial
with long-term follow-up, with two parallel 1:1 treatment arms: oral esketamine
versus ECT. Phase 1 comprises the randomized non-inferiority part of the trial
in which the efficacy of the two treatments is compared. In phase 1
participants will be assigned to one of the two treatment arms, and will
receive either oral esketamine or ECT twice a week for eight weeks, titrating
the dosages. Phase 2 comprises the long-term follow-up of both study
conditions, for one year in total. This phase is more naturalistic and
describes whether the two conditions are successful in maintaining initial
response. In phase 2, both conditions will be tapered down on individual
basis.
Intervention
Participants will be provided either oral esketamine or ECT twice a week. Both
conditions are individually tailored for optimal effectiveness. The
esketamine arm will start with an initial dose of 0.5 mg/kg oral esketamine.
Dosages are then titrated, based on individual tolerability and clinical
effect, to a maximum dose of 3.0 mg/kg.
ECT is also performed twice a week, according to Standard care consistent with
the Dutch national ECT guideline. ECT is individually tailored, as seizure
threshold levels are determined for each patiënt to choose the amount of charge
(dosage) of the stimulus offered.
If results are suboptimal after 6 weeks, ECT is switched from right unilateral
to (potentially more potent) bilateral treatemtn.
All participants who have shown a Minimally Clinically Important Difference
(MCID), MCID is established as a 30% reduction on MADRS total score, at 8 weeks
of treatment (phase 1) are offered continuation of treatment in phase 2.
Frequency is tapered depending on clinical outcome following a fixed protocol,
aiming to keep responders stable and prevent depression relapse or recurrence.
In both conditions, participants will also use regular antidepressant
medication, in order to further reduce the chance of relapse. This is the
Standard procedure for both ECT and oral esketamine follow-up treatments.
Study burden and risks
The study is intended to benefit participants directly, because the treatments
are specifically aimed at reducing depressive symptoms. Since blinding is
impossible to achieve in the comparison between ECT and esketamine, and
withholding treatment in this severely ill patiënt group is unethical, there is
no placebo arm and all participants receive an active treatment. Participation
in this trial implies that participants contribute to the development of
medical knowledge that may also be of benefit for future patients. The health
risks attached to participation will be limited. There is ample experience with
esketamine as an anaesthetic and analgesic agent, that is used in a wide range
of medical settings and indications, including NTRD. In addition, recent
studies have also demonstrated safety of esketamine for NTRD patients. Known
side effects of esketamine are usually mild and self-limiting. Side effects
will be closely monitored during and after treatment sessions. Actual risks,
for example increase in blood pressure, will be identified swiftly and
appropriately acted upon. The health risks and treatment burden in the ECT arm
are not different from regular ECT treatment, which is Standard guideline-based
practica in psychiatry. Participants will be asked to answer or fill out
questionnaires at several moments during the study. This Routine Outcome
Monitoring is broadly implemented in mental healthcare, and Standard practice
in clinical psychiatry for all forms of depression treatment. However, for
study purposes additional questionnaires are added. Completing questionnaires
take time and could sometimes be experienced as boring and/or annoying. The
interviews could also distress participants to some degree, considering the
personal and emotional content. However, we have found in earlier studies that
patients often appreciate this as careful attention that is paid to their
burdensome situation. Venipuncture is associated with negligible risks, and
negligible to mild burden. Physical examination is associated with negligible
to mild burden. Participants are allowed to object to any or part of the
assessments or investigations during study participation. Given the limited
additional patiënt burden in the current trial compared to routine treatment,
and the possible positive outcome for participants themselves as well as for
future patients, we believe that offering study participation to patients that
fit the inclusion criteria is well justified.
Hanzeplein 1
Groningen 9713GZ
NL
Hanzeplein 1
Groningen 9713GZ
NL
Listed location countries
Age
Inclusion criteria
- 18 years or older of age at screening;
- Sufficiënt level of spoken and written Dutch;
- Ability to freely provide written informed consent prior to study
participation;
- Current DSM-5 diagnosis of MDD without psychotic symptoms, ascertained by the
Mini International Neuropsychiatry Interview (MINI-plus);
- At least moderate to severe depression, defined by a MADRS total score >= 20;
- Indication for ECT treatment for the treatment of the current depressive
episode.
- Treatment Resistant Depression, defined as non-response to (or established
non-tolerability of) treatment with at least two different antidepressants plus
an augmentation step such as lithium, mirtazapine or quetiapine during
lifetime, all prescribed in an adequate dose (i.e. defined daily dose) for at
least four weeks;
- Patients agree with initial clinical admission and subsequent
daycare/outpatient treatment.
Exclusion criteria
• Prior or current bipolar disorder, schizophrenia spectrum, other psychotic
disorders, current MDD with psychotic features (previous MDD with psychotic
features is allowed if the current episode is non-psychotic). All diagnoses
according to DSM-5, assessed with MINI-plus interview at screening;
• The presence of current moderate or severe dependence of alcohol or drugs 6
months within screening according to the DSM-5, not including tobacco-related
and caffeine-related disorders, ascertained by the MINI-plus interview at
screening;
• Current use of a MAOI in excess of a daily dose of 60 mg;
• Recent (within the last four weeks of screening) or current use of cannabis
or any other non-prescribed psychoactive compounds, including Saint John*s
wort, assessed at screening;
• Relevant neurological disorders, such as dementia or epilepsy;
• Recent (within the last four weeks of screening) change of treatment with
antidepressants;
• Planned changes in antidepressant treatment during phase 1 of the study, not
being part of the standard practice of ECT treatment like change in lithium or
anti-epileptics;
• Active suicidal plans, defined by a score higher than 5 (explicit plans for
suicide when there is an opportunity or active preparations for suicide) on the
MADRS*s item for suicidal ideation;
• (Suspected) pregnancy, lactation, or insufficient contraception. In fertile
women, a urine pregnancy test will be performed prior to Phase 1 (screening)
and prior to Phase 2 (month 1) of the study. Current use of benzodiazepine and
benzodiazepine-like agents (zolpidem, zopiclone) in excess of 3 mg lorazepam or
an equivalent per day;
• Recent (within the last four weeks of screening) start or change in the use
of somatic medication that commonly affects mood, like corticosteroids;
• Previous treatment with ECT or esketamine during the current depressive
episode;
• Presence of any absolute contra-indication for esketamine use (according to
the Summaries of Product Characteristics) or ECT (according to Dutch ECT
guidelines, Appendix A), namely pheochromocytoma, increased intracranial
pressure, intracranial surgery (< 6 months), a recent cerebrovascular accident
/ cerebral trauma, glaucoma, recent myocardial infarction (<6 months), unstable
angina pectoris or myocardial disease (New York Heart Association (NYHA) class
IV), aneurysmal vascular disease, severe hypertension, severe hyperthyroidism,
severe liver problems (Child-Pugh class C), severe kidney problems, acute
intermittent porphyria, severe upper airway infection, the use of medication
that esketamine interacts with on a major level, such as xanthine derivates
(aminophylline, theophylline) or previous hypersensitivity to esketamine or its
components;
• Presence of any of the following relative contra-indications for esketamine
use (according to the Summaries of Product Characteristics) or ECT (according
to Dutch ECT guidelines, Appendix A), namely stable angina pectoris,
hypertension, myocardial infarction (> 6 months ago), intracranial process,
unstable cervical spine, carcinoid, severe COPD, severe obesity,
pseudocholinesterase deficiency, malignant hyperthermia and congenital muscle
diseases. Cardiovascular relative contra-indications will lead to consultation
with a colleague from the cardiology department. This will be performed after
screening by the researcher who screened the patient. After cardiological
clearance it may still be possible to enrol. Presence of an intracranial
process will be discussed after screening with a colleague from neurosurgery
department and an anaesthesiologist. Remaining relative contra-indications will
lead to discussion with the anaesthesiology department. This will be performed
after screening by the researcher who screened the patient. After
anaesthesiologic clearance it may still be possible to enrol.
• Mental incompetence to fully understand the informed consent of this study,
based on the judgment of the general practitioner or treating psychiatrist of
the participant;
• Inability to understand or comply with study requirements, as judged by the
investigator(s);
• Use of other investigational drugs within 4 weeks of screening.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-517485-42-00 |
| EudraCT | EUCTR2022-000383-21-NL |
| CCMO | NL80517.042.22 |