A Randomised, Controlled Trial to Investigate the... — Clinical Trial Details

The aim of this study is to test if third-line treatments for depression (MDD), should be prescribed earlier in the illness course, after a first-line treatment fails. This study is testing the idea (hypothesis) that medications that are usually only used third-line ( called Early Intensified Pharmacological Treatment - EIPT in this study) are more effective than the medications that currently get used second-line (Treatment As Usual - TAU).
This study has a six-week duration and participants are randomised into either the EIPT or TAU group. Participants must have a regular treating doctor (GP or psychiatrist) who is willing to be contacted by the study team, and who will prescribe and manage the medication for all TAU participants, The study doctors will prescribe and dispense medication for EIPT participants in MDD.
There are optional "opt-in' biodata, blood and stool samples that participants may choose to give; these are to help researchers identify predictors for treatment-resistance and treatment response.

To be eligible to participate in this study, a participant must meet ALL of the following criteria:
1.. In- or outpatient, 18-65 years old. (18-50 if the person identifies as an Aboriginal or Torres Strait Islander person).
2. Being willing and able to provide written informed consent. Having a legal guardian to co-sign is allowed. Informed consent will be signed at visit 1, before any study procedure.
3. Female participants of childbearing potential must use effective contraception during the trial and as per the requirements of the applicable PIs. WOCBP must also have a negative pregnancy test at visit 1 and visit 2.
4. According to the DSM-5-TR, meeting diagnostic criteria for a primary diagnosis of: major depressive disorder (without psychotic features) r type I and II currently in a depressive episode). The primary diagnosis will be confirmed by the Mini International Neuropsychiatric Interview (MINI v7.0.2).
5. Participant currently experiences their first treatment failure due to lack of efficacy; this treatment is a first-line pharmacotherapeutic agent for the primary DSM-5-TR diagnosis,and was prescribed for at least 4 weeks within the dose range as specified in the Product Information (PI).
6. Participant has failed on current psychopharmacological treatment of current episode of MDD as confirmed by a CGI-I equal to 3.
7. Participant and treating clinician intend to change pharmacotherapeutic treatment
8. A minimum symptom severity threshold needs to be present (moderate level; see below) and participant needs to experience functional impairment.
The minimum symptom severity threshold for: MDD is a score of greater than 20 on the Montgomery Åsberg Depression Rating Scale (MADRS)
Functional impairment is defined as a score of 5 or higher on any of the three scales of the Sheehan Disability Scale (SDS) for MDD participants.
Further information:
If participants have already stopped the previous pharmacological treatment, the stopped treatment should still be the first treatment failure on a first line pharmacotherapeutic agent prescribed for at least 4 weeks within the dose range as specified in the PI. If the participant used more than one pharmacological treatment in the past, the reason for discontinuing these previous treatments should not be recorded as non-efficacy; in total there should be one treatment failure (now or in the past).
Preferably, the CGI-I is obtained from the (previous) treating doctor or clinical team, who decided that there is a treatment failure. If this is not possible, it is acceptable for the study team to obtain this information from the participant.
Change is considered a full change (tapering off previous treatment (if not already stopped) and initiating the new treatment as indicated by the randomisation arm) or the addition of medications as indicated by the randomisation arm.

Exclusion Criteria
1. Being pregnant or breastfeeding.
2. Participant has participated in another clinical trial in which the participant received an experimental or investigational drug or agent within 30 days prior to visit 1.
3. Participant experiences any other significant disease or disorder which, in the opinion of the study doctor, may either put the participant at risk because of participation in the trial, or may influence the results of the trial, or the participants ability to participate in the trial.
4. Participants with active suicidal ideation with some intent to act, without specific plan (“Yes” to question 4 of the Columbia-Suicide Severity Rating Scale (C-SSRS)) or active suicidal ideation with specific plan and intent (“Yes” to question 5 of the C-SSRS), followed by an assessment by the treating clinician who determines it is not safe for the participant to continue in the study )
5. Participant meets criteria for current substance abuse disorder, as confirmed by Module I (Alcohol use disorder) and J (Substance use disorder (non-alcohol) of the (MINI v7.0.2). Nicotine dependence is allowed as is mild and moderate alcohol and/or cannabis use disorder as defined by MINI v7.0.2. Severe alcohol and/or cannabis use disorder is not allowed.
6. Participant has been committed to an institution by virtue of an order from a legal authority such as a tribunal, magistrate, or office of the Chief Psychiatrist
7. Participants personally affiliated with the sponsor, investigators or trial site must be excluded from participation in advance.
The decision to include the participant is at the clinician’s discretion. If the score on the C-SSRS does not exceed the threshold, but the clinician still considers the risk of a suicide attempt too high, it still can be decided to exclude the participant. If the score on suicidal ideation is 4 or 5, there will follow a clinical judgement that should be documented in the source. Participants personally affiliated with the sponsor, investigators or trial site must be excluded from participation in advance.
8.Participant has used (es) ketamine in the past.
9. Participant has a known intolerance to ketamine or to all TAU medication options.
10. Participant meets any of the contraindications for ketamine or to all TAU medication options, as specified within the applicable PI, supported by clinically significant abnormal values on local laboratory tests, electrocardiogram (ECG) or physical examination.
Participant has a known intolerance to all TAU medication options.
For clarity, if the participant is currently on a first-line treatment that is not efficacious and will be switched within the study, this medication does not count for this criterion. This criterion focuses on other psychotropic concomitant medication (not on the primary diagnosis). Last, “more” means that the participant requires a higher dose than the maximum for the allowed benzodiazepines/antipsychotics throughout the study.
The decision to include the participant is at the study doctor’s discretion. If the score on Module B (Suicidality) of the MINI v7.0.2 is lower than 9, but the study doctor still considers the risk of a suicide attempt too high, it can still be decided to exclude the participant.
Significant diseases, disorders or conditions preventing use of ketamine are: hypersensitivity to benzethonium chloride or other excipients, conditions where increasing blood pressure or intercranial pressure would lead to a serious hazard, severe coronary or myocardial disease. We refer to the PIs for significant conditions that prevent use of oral antidepressant medication.
Some Product Information Sheets specify precautions. These are not considered as contraindications in this trial or in clinical practice. If investigators take precautionary measures, participants can still be initiated on the medication, as this is in line with clinical practice and the Product Information

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A Randomised, Controlled Trial to Investigate the Effect of a six-week Intensified Pharmacological Treatment for Major Depressive Disorder, compared to Treatment as Usual in Participants Who Had a First-time Treatment Failure on Their First-line Treatment for -Major Depressive Disorder Cohort.

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