Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05973786 |
| Other study ID # |
2023-506605-19-00 (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
Bipolar disorders affect approximately 4.5 million people across the European Union (EU) and
are associated with high annual healthcare and societal costs. Bipolar disorder I and II
represent disorders that cause extreme fluctuation in a person's mood, energy, and ability to
function, in which symptoms of (hypo)mania and depression alternate. The depressive episodes
of bipolar disorders are often referred to as bipolar depression (BD). In other words: it is
a phase/state of the disorder. For many patients with BD, the depressive polarity is often
more pervasive and more debilitating than manic states, with estimates that depressed mood
accounts for up to two-thirds of the time spent unwell, even with treatment. The burden of
not received an effective treatment for BD is high: more severe psychopathology, higher rates
of unemployment, more hospitalisations, lower quality of life, lower cognitive functioning,
risk of suicide, comorbidities and poorer social and occupational functioning and thus more
carer burden. For BD, the treatment guidelines are very heterogeneous, amongst other reasons
because the disease is heterogeneous and treatments should be tailored to the patients. There
is no clear treatment algorithm and it cannot yet be predicted which treatment will be
effective. Especially the place of adjunctive antidepressants is under debate. Usually, for
psychiatric disorders (including bipolar disorder), a patient is considered to be
treatment-resistant is two medicinal treatments have been tried (in sufficient duration and
dosage) without sufficient success. For BD, there is no consensus on when to consider a
patient as treatment-resistant, but the most common definition is after one prior treatment
failure. This raises the research question whether adjunctive antidepressants to treat BD
should be introduced earlier in the treatment. Additionally, The INTENSIFY trial is part of
the larger Horizon 2021 project, with the central goal of paving the way for a shift towards
a treatment decision-making process tailored for the individual at risk for treatment
resistance. To that end, we aim to establish evidence-based criteria to make decisions of
early intense treatment in individuals at risk for treatment resistance across the major
psychiatric disorders of schizophrenia, bipolar disorder and major depression.
Description:
Rationale Bipolar disorders affect approximately 4.5 million people across the European Union
(EU) and are associated with high annual healthcare and societal costs. Bipolar disorder I
and II represent disorders that cause extreme fluctuation in a person's mood, energy, and
ability to function, in which symptoms of (hypo)mania and depression alternate. The
depressive episodes of bipolar disorders are often referred to as bipolar depression (BD). In
other words: it is a phase/state of the disorder. For many patients with BD, the depressive
polarity is often more pervasive and more debilitating than manic states, with estimates that
depressed mood accounts for up to two-thirds of the time spent unwell, even with treatment.
The burden of not received an effective treatment for BD is high: more severe
psychopathology, higher rates of unemployment, more hospitalisations, lower quality of life,
lower cognitive functioning, risk of suicide, comorbidities and poorer social and
occupational functioning and thus more carer burden. For BD, the treatment guidelines are
very heterogeneous, amongst other reasons because the disease is heterogeneous and treatments
should be tailored to the patients. There is no clear treatment algorithm and it cannot yet
be predicted which treatment will be effective. Especially the place of adjunctive
antidepressants is under debate. Usually, for psychiatric disorders (including bipolar
disorder), a patient is considered to be treatment-resistant is two medicinal treatments have
been tried (in sufficient duration and dosage) without sufficient success. For BD, there is
no consensus on when to consider a patient as treatment-resistant, but the most common
definition is after one prior treatment failure. This raises the research question whether
adjunctive antidepressants to treat BD should be introduced earlier in the treatment.
Additionally, The INTENSIFY trial is part of the larger Horizon 2021 project, with the
central goal of paving the way for a shift towards a treatment decision-making process
tailored for the individual at risk for treatment resistance. To that end, we aim to
establish evidence-based criteria to make decisions of early intense treatment in individuals
at risk for treatment resistance across the major psychiatric disorders of schizophrenia,
bipolar disorder and major depression.
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 on their first-line treatment.
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.
10. To compare occurrence of (hypo)manic episode during the study between the treatment
arms.
Trial design The clinical study is an international, multicenter controlled, randomised, open
label trial (with blinded raters), with a treatment duration of six weeks.
Trial population The aim is to recruit 418 subjects with bipolar disorder type I or II,
currently in a depressive episode. Male and female subjects, in- and out-patients, with the
age of at least 18 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 quetiapine, meeting any contraindications, or participants with a
known intolerance to quetiapine.
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.
Treatment as Usual (TAU) Switch to quetiapine plus lithium or valproate acid
Early-Intensified Pharmacological Treatment (EIPT) Switch to
1. one of the following: escitalopram, sertraline, duloxetine, bupropion or venlafaxine
plus
2. two of the following: lithium, valproate acid or quetiapine
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 All medications studied in the current trial are widely
used (alone or in combination) in clinical practice and the risks for side effects are well
established. In the current study, clinical practice is mimicked as much as possible to
maximize generalisability 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.
Overall, the risks are similar to daily clinical practice; the only difference relative to
clinical practice is the application of three pharmacological treatments (EIPT) versus two
(TAU) earlier in the illness. Still, these additional treatment options are also commonly
prescribed by clinicians. There are no indications in existing literature or clinical
practice that the earlier introduction of these medications poses a safety risk when used in
an earlier illness phase than indicated in the SmPC.
A benefit of the study is that if it indeed turns out that the early-intensified treatment is
associated with more symptom improvement compared to treatment as usual, future patients have
to go through less trial and error, which results in a reduced burden (higher quality of
life, less unemployment, less hospitalisations) for patients and carers as well as lower
societal and healthcare costs.
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). We have
done this and created 3 new ClinicalTrials.gov studies as well, from which this is one for
bipolar depression. The ClinicalTrials.gov numbers of the related trials are NCT05958875 for
the INTENSIFY SZ trial and NCT05973851 for the INTENSIFY MDD trial. 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, we
keep the old clinicaltrials.gov number for Israel (NCT05603104).
