Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05973851 |
| Other study ID # |
2023-506617-21-00 (EU CT#) |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
May 31, 2024 |
| Est. completion date |
June 30, 2026 |
Study information
| Verified date |
May 2024 |
| Source |
UMC Utrecht |
| Contact |
Inge Winter, Dr. |
| Phone |
+31875553227 |
| Email |
i.winter[@]umcutrecht.nl |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Over 28 million people suffer from current depressive disorder in the European Union. Major
depressive disorder (MDD) is one of the most common psychiatric illnesses. The symptoms cause
clinically significant distress or impairment in social, occupational, and other important
areas of functioning. To treat MDD, there are several antidepressants available and
prescribing medication is a process of trial-and-error. Guidelines do not explicitly advise
on the order in which antidepressant medication should be prescribed. The choice of
antidepressant should be tailored to the patient, while involving the patient in the
decision-making process. In general, the choice for the first- and second-line treatment will
be a second-generation antidepressant. Recently, esketamine nasal spray (intranasal (IN)
administration) was approved for patients with treatment-resistant MDD (TRD). A patient is
diagnosed with TRD when having used two antidepressants in sufficient duration and adequate
dose without sufficient effect. TRD is associated with a negative impact on quality of life,
higher risk for hospitalisations and suicide, comorbidities, poorer social and occupational
functioning and a high carer burden. The efficacy of intranasal use of esketamine has been
demonstrated in MDD subjects with treatment-resistant symptoms but also in subjects with
non-treatment resistant depression, and is approved by the FDA and EMA as a third-line
treatment. Besides the registered esketamine nasal spray, which is not available in all
countries to all patients because of the high costs, off-label utilization of (es)ketamine
infusions (IV) is growing extensively over time to treat TRD. Research conducted so far
indicates an unequivocal initial substantial response to (es)ketamine IV in MDD populations,
regardless of whether or not patients suffer from treatment resistant MDD. However, until
now, there has not been a study investigating this in a sufficiently large population. This
may be a unique opportunity to potentially prevent patients progressing into a treatment
resistant illness stage. The potential implications of the results of the current study are
the prevention of unnecessary trials of ineffective treatments, reducing subject burden
substantially, as well as a reduction of healthcare and societal costs.
Description:
Rationale Over 28 million people suffer from current depressive disorder in the European
Union. Major depressive disorder (MDD) is one of the most common psychiatric illnesses. The
symptoms cause clinically significant distress or impairment in social, occupational, and
other important areas of functioning. To treat MDD, there are several antidepressants
available and prescribing medication is a process of trial-and-error. Guidelines do not
explicitly advise on the order in which antidepressant medication should be prescribed. The
choice of antidepressant should be tailored to the patient, while involving the patient in
the decision-making process. In general, the choice for the first- and second-line treatment
will be a second-generation antidepressant. Recently, esketamine nasal spray (intranasal (IN)
administration) was approved for patients with treatment-resistant MDD (TRD). A patient is
diagnosed with TRD when having used two antidepressants in sufficient duration and adequate
dose without sufficient effect. TRD is associated with a negative impact on quality of life,
higher risk for hospitalisations and suicide, comorbidities, poorer social and occupational
functioning and a high carer burden. The efficacy of intranasal use of esketamine has been
demonstrated in MDD subjects with treatment-resistant symptoms but also in subjects with
non-treatment resistant depression, and is approved by the FDA and EMA as a third-line
treatment. Besides the registered esketamine nasal spray, which is not available in all
countries to all patients because of the high costs, off-label utilization of (es)ketamine
infusions (IV) is growing extensively over time to treat TRD. Research conducted so far
indicates an unequivocal initial substantial response to (es)ketamine IV in MDD populations,
regardless of whether or not patients suffer from treatment resistant MDD. However, until
now, there has not been a study investigating this in a sufficiently large population. This
may be a unique opportunity to potentially prevent patients progressing into a treatment
resistant illness stage. The potential implications of the results of the current study are
the prevention of unnecessary trials of ineffective treatments, reducing subject burden
substantially, as well as a reduction of healthcare and societal costs.
Objective The primary objective is to compare the treatment response (baseline; visit 2 vs.
end of treatment; visit 4), expressed as symptom severity at six weeks and changes in symptom
severity from baseline, as measured through the Montgomery-Åsberg Depression Rating Scale
(MADRS) under an early-intensified pharmacological treatment to that under treatment as
usual, in subjects who had a first-time treatment failure of first-line treatment during the
current episode of MDD.
Main trial endpoints Change in symptom severity total score from baseline (visit 2) to end of
treatment (visit 4). This is measured using MADRS.
Secondary trial endpoints
1. To compare changes in severity and improvement in global functioning assessed by the
Clinical Global Impression Scale (CGI) between the two treatment arms.
2. To compare changes in the levels of depression and anxiety between treatment arms.
3. To compare changes in quality of life and functioning measures between treatment arms.
4. To compare changes in cognitive performance between treatment arms.
5. To compare the proportion of participants (EIPT vs. TAU) that is in symptomatic
remission at visit 4.
6. To compare presence of side effects between treatment arms.
7. To compare use of concomitant medication between treatment arms.
8. To compare premature discontinuation (timing and reason) between treatment arms.
9. To compare changes in suicidal ideation between treatment arms.
Trial design The clinical study is an international, multicenter controlled, randomised, open
label trial (with blinded raters), with a treatment duration of four weeks.
Trial population The aim is to recruit 418 subjects with major depressive disorder, without
psychotic features. Male and female subjects, in- and out-patients, within the age range of
18 to 65 years old are eligible for participation. The main exclusion criteria are defined to
protect the wellbeing of subjects, e.g. being pregnant or breastfeeding, subjects with
previous failure on (es)ketamine, meeting any contraindications, or participants with a known
intolerance to (es)ketamine.
Interventions
Subjects are randomised to treatment as usual (second-line treatment) or to the
early-intensified pharmacological treatment (third-line treatment). Treatment per can be
found in the table below:
Table 1. Overview of treatment randomisation per study sample. MDD sample Treatment as Usual
(TAU) Switch to second-line antidepressant Early-Intensified Pharmacological Treatment (EIPT)
Oral antidepressant plus esketamine nasal spray or esketamine IV or ketamine IV
Ethical considerations relating to the clinical trial including the expected benefit to the
individual subject or group of subjects represented by the trial subjects as well as the
nature and extent of burden and risks In the current study, clinical practice is mimicked as
much as possible to maximize generalizability and for feasibility purposes. To this end,
Summaries of Product Characteristics (SmPCs) are followed with regards to contraindications
(implemented as exclusion criterion), safety measures and allowed combinations with other
medications. Site visits and assessments are kept to a minimum to keep subject burden at an
acceptable level, while meeting the objectives of the study. Blood samples for biomarker
analyses are only collected when subjects provide consent; safety measures are performed as
part of clinical routine.
Use of both EIPT and TAU medications implies that there is a risk of side effects. For TAU,
these side effects are well-known, and would be no different from regular clinical practice.
For EIPT, there are acute psychotropic effects of (es)ketamine which are considered side
effects for this study, such as anxiety, delusional thoughts, dissociation and hallucinations
(see IMPDs). In addition, increased blood pressure and heart rate, as well as dizziness and
nausea are reported. These acute effect are transient and after 2 hours completely
dissipated. Therefore, an observation period of 2 hours after every administration is
implemented to monitor this closely. The potential side effects of all treatments are
well-known and will be monitored during the study with a standardized side-effect scale
(GASE), spontaneous reporting and the local standard procedure regarding other measures such
as laboratory tests, physical examinations, ECGs. The results will be captured (as data) and
reviewed for tolerability. Most of the tests that will be done as part of standard clinical
care (lab tests, ECG, physical examination) for EIPT are also part of TAU.
A benefit of the study is that while ensuring that the tolerability and additional burden
remains acceptable, the investigators expect that the larger effect in reducing symptom
severity will justify the increase in burden relative to the TAU group. When participants are
treated with the intense treatment in earlier stage of the illness (less trial and error
before moving on to this treatment option), this is expected to result in a reduced burden of
disease for subjects, expressed as less relapses, lower all-cause mortality, hospitalisations
and job losses and improved quality of life, in addition to lower societal and healthcare
costs as well as preventing patients from turning into a treatment-resistant treatment phase.
Last, an advantage of participation could be that subjects will be more thoroughly followed
and examined, and that therefore effects and side effects are measured and managed better.
IMPORTANT: the study was submitted to the European authorities before (see NCT05603104) and
they requested to split this study into 3 studies (1 for each diagnostic category). The
investigators have done this and created 3 new ClinicalTrials.gov studies as well, from which
this is one for major depressive disorder. The ClinicalTrial.gov numbers for the other
studies are NCT05958875 for INTENSIFY SZ and NCT05973786 for INTENSIFY BD. The site in the UK
(London) followed the advice and will submit 3 separate protocols and are therefore included
in the current record. However, Israel already submitted this as one protocol. Therefore, the
investigators keep the old clinicaltrials.gov number for Israel (NCT05603104).
