Phase 1:The primary objective of this trial is to investigate whether oral esketamine is non-inferior to ECT after eight weeks of individually optimized treatment, in participants with NTRD.Phase 2:To compare the efficacy of maintenance oral…
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Source
Brief title
Condition
- Mood disorders and disturbances NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To investigate whether oral esketamine is non-inferior to ECT, the short term
effectiveness is measured by the percentage of patients with response to
treatment at change from baseline in MADRS total score (defined as >=30%
reduction or MCID) to 8 weeks of treatment, in patients with NTRD.
Secondary outcome
Secondary objectives and endpoints include:
1. To investigate whether oral esketamine is non-inferior to ECT in patients
with NTRD on the short term in depression symptom severity, suicidality,
clinical impression, functioning, and quality of life, measured by:
a) Change in depressive symptom severity, defined as a reduction in IDS-SR
total score between baseline and 8-weeks of treatment.
b) Change in suicidal ideation, defined as a reduction in Columbia Suicide
Severity Rating Scale (C-SSRS) scores between baseline and 8-weeks of treatment.
c) 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.
d) Change in functioning, defined as a reduction in the WHO Disability
Assessment Schedule (WHODAS) total score between baseline and 8-weeks of
treatment.
e) 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, 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 (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 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 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, tolerability and risk of abuse
during treatment and at follow-up, as measured by:
a) Systematic Assessment for Treatment Emergent Events (SAFTEE);
b) Ketamine Side Effect Tool (K-SET);
c) 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC);
d) 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);
e) Body weight, blood pressure, heart rate, kidney function and liver enzyme
levels.
f) Exploring participants* experiences with treatment with oral esketamine or
ECT, by interviewing a subset of participants (optional in informed consent).
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 (especially ECT and IN
esketamine), dissociative experiences (as assessed by the 5D-ASC), 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)).
b) Assessing neurobiological markers covering major pathophysiological
mechanisms involved in mood disorders (optional in informed consent):
a. blood and urine biomarkers;
b. gene expression patterns in white blood cells;
c) Assessing the pharmacokinetic profile of oral esketamine, by measuring
plasma levels of esketamine and its metabolites, and by exploring the
relationship between these and our primary outcome.
d) Exploring potential pharmacodynamic characteristics of oral esketamine, by
exploring the relationship between the pharmacokinetic profile of oral
esketamine and:
a. The genotype of the CYP enzyme(s) involved in the metabolism of oral
esketamine (in a subgroup of 12 participants);
b. Body Mass Index (BMI);
c. The concurrent use of antidepressants and benzodiazepines;
d. 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 devired 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 intravenous (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 patient 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 from ZonMw together with 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
Phase 1:
The primary objective of this trial is to investigate whether oral esketamine
is non-inferior to ECT after eight weeks of individually optimized treatment,
in participants with NTRD.
Phase 2:
To compare the efficacy of maintenance oral esketamine treatment versus ECT to
prevent relapse, during one year follow-up, in participants who responded to
initial treatment in phase 1.
Secondary objectives include: 1) To investigate whether oral esketamine is
non-inferior to ECT in patients with NTRD on the short term including
depressive symptom severity, suicidal ideation, clinical impression,
functionality, and quality of life; 2) To explore long-term effectiveness of
oral esketamine treatment compared to ECT treatment in participants who respond
to initial treatment; 3) To investigate whether oral esketamine is more patient
friendly than ECT with respect to treatment burden, side effects, tolerability
and risk of abuse; 4) To investigate whether oral esketamine is more
cost-effective compared to ECT; 5) To explore predictors and working mechanisms
of successful oral esketamine and ECT treatment; 6) To explore participants*
subjective experiences with treatment with oral esketamine or ECT.
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 patient 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 application.
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 oral esketamine, and
withholding treatment in this severely ill patient 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 oral 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 practice 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 patient 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;
• Sufficient 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.
• TRD, 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;
• Current use of a MAOI in excess of a daily dose of 60 mg;
• The presence of current moderate or severe dependence of alcohol or drugs at
screening according to the DSM-5, not including tobacco-related and
caffeine-related disorders, ascertained by the MINI-plus;
• 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. If there is
any doubt, a pregnancy test is performed;
• 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 contra-indication for esketamine use, such as increased
intracranial pressure, cerebrovascular accident, cerebral trauma, glaucoma,
recent myocardial infarction (<6 months), or other relevant cardiac problems
like unstable angina pectoris or myocardial disease, aneurysmal vascular
disease, severe hypertension, severe hyperthyroidism, severe liver problems,
severe kidney problems, the use of medication that esketamine interacts with on
a major level, such as monoamine oxidase inhibitors and xanthine derivates
(aminophylline, theophylline) or previous hypersensitivity to esketamine or its
components; While not exclusion criteria, enrolling a potential participant who
meets any of the relative contra-indications for esketamine use according to
the Summary of Product Characteristics (SPC), like clinically significant
respiratory conditions, will be decided based on a per patient assessment of
potential risk;
• Presence of any contra-indication for ECT according to the Dutch Richtlijn
Electroconvulsietherapie (2010) (appendix A). While not exclusion criteria,
enrolling a potential participant who meets any of the relative
contra-indications for ECT according to the Richtlijn Electroconvulsietherapie
will be decided based on a perpatient assessment of potential risk;
• 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 |
|---|---|
| EudraCT | EUCTR2021-001326-21-NL |
| CCMO | NL80223.042.22 |