Intensified Pharmacological Treatment for Schizophrenia, Major Depressive Disorder and Bipolar Depression After a First-time Treatment Failure

Study Overview
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Brief Summary
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Schizophrenia, bipolar and major depressive disorders collectively affect over 10 million people across the EU and are associated with annual healthcare and societal costs in excess of 100 billion Euros. When diagnosed with one of these disorders, patients are prescribed psychotropic medication such as antidepressants, mood stabilisers or antipsychotics. It is unknown whether this first-line treatment will be successful. After this first-line treatment fails, usually a second-line treatment is initiated, and when this is not successful either a third-line treatment is initiated. Third-line treatments are quite successful, especially when compared to second-line treatments. The research question is whether the third-line treatments (early-intensified treatments) would be more efficacious than the current second-line treatments (treatment as usual) for schizophrenia, bipolar and major depressive disorders. If this is indeed the case, this could lead to the prevention of unnecessary trials of ineffective treatments and adaptations of worldwide guidelines as well as a reduction of healthcare and societal costs.

Detailed Description
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Rationale Schizophrenia (SZ), bipolar depression (BD) and major depressive disorders (MDD) collectively affect over 10 million people across the European Union (EU) and are associated with annual healthcare and societal costs in excess of 100 billion Euros. When diagnosed with one of these disorders, patients are prescribed psychotropic medication such as antidepressants, mood stabilisers and/or antipsychotics. The effectiveness of these treatments for individual patients cannot be predicted. After this first-line treatment fails, usually a second-line treatment is initiated; when this is not effective either, a third-line treatment is initiated. Third-line treatments are quite effective, for people not responding to the first two treatments lines. However, clear evidence from direct comparisons of treatment algorithms is lacking. The research question is whether the third-line treatments would be more efficacious than the current second-line treatments (treatment as usual) for schizophrenia, bipolar and major depressive disorders. Third-line treatment can then be regarded as 'early-intensified'. If this is indeed the case, this could lead to the prevention of unnecessary trials of ineffective treatments and recommendations for adaptations of worldwide guidelines as well as a reduction of healthcare and societal costs. 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, expressed as mean change in symptom severity as measured through the Positive And Negative Syndrome Scale (PANSS; SZ sample), and the Montgomery-Åsberg Depression Rating Scale (MADRS; MDD/BD samples) 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). For SZ, this is measured using PANSS. For MDD and BD, MADRS is applied. Secondary trial endpoints All study samples: to compare changes in the severity and improvement sub-scores of the Clinical Global Impression Scale (CGI 1) between the two treatment arms over the four (MDD)/ six (SZ/BD) week treatment period (visit 2 versus visit 4). All study samples: to compare changes in the levels of depression and anxiety as assessed with the Hospital Anxiety and Depression Scale (HADS 2) between the two treatment arms over the four (MDD)/six (SZ/BD) week treatment period (visit 2 versus visit 4). All study samples: to compare changes in cognitive performance as measured through the Trail Making Test 3, Digit Symbol Substitution Test 4, Rey Auditory Verbal Learning Test 5 as well as the Perceived Deficits Questionnaire 6 between the two treatment arms over the four (MDD)/six (SZ/BD) week treatment period (visit 2 versus visit 4). All study samples: to compare changes in quality of life and functioning measures (Q-LES-Q-SF 7, LAPS 8, QLS-100 9 and SDS 10 between the two treatment arms over the four (MDD) six (SZ/BD) week treatment period (visit 2 versus visit 4). All study samples: to compare presence of side effects as measured through General Assessment of Side Effects Scale (GASE) and reported spontaneously between the two treatment arms over the four (MDD)/six (SZ/BD) week treatment period (visit 2 versus visit 4). All study samples: to compare use of concomitant medication between the two treatment arms over the four (MDD)/six (SZ/BD) week treatment period (visit 2 versus visit 4). All study samples: to compare premature discontinuation (timing and reason) between the two treatment arms over the four (MDD)/six (SZ/BD) week treatment period (visit 2 versus visit 4). All study samples: comparison of the proportion of participants (EIPT vs. TAU) that is remission at visit 4. For SZ, remission is defined as meeting the PANSS modified Andreasen criteria (Low scores (≤3) P1. Delusions; P3. Hallucinatory behavior; P2. Conceptual disorganization; N1. Blunted affect; N4. Passive/apathetic social withdrawal; N6. Lack of spontaneity and flow of conversation; G5. Mannerisms/posturing; G9. Unusual thought content. For MDD/BD, remission is defined as a MADRS score ≤ 12, All study samples: to compare long-term effects of the treatment between the two study arms (comparison visit 2, 4 and 5). SZ sample: to compare changes in PANSS subscale scores between the two treatment arms over the six-week treatment period (visit 2 versus visit 4). Trial design The clinical study is an international, multicenter controlled, randomised, open label trial, with a treatment duration of 4-6 weeks. Trial population The aim is to recruit 418 subjects into each of the study samples, leading to a total sample size of 1254 subjects. The study samples are: schizophrenia (schizophrenia, schizoaffective disorder or schizophreniform disorder), major depressive disorder and bipolar depressive disorder (bipolar I or II disorder currently in a depressive episode). Male and female subjects, in- and out-patients, within the age range of 18 to 70 years old are eligible for participation. The main exclusion criteria to protect the subjects are subjects being pregnant or breastfeeding, subjects with previous failure on the early-intensified pharmacological treatments, known intolerance to any of the treatments or meeting any contraindications for the early-intensified pharmacological treatments. Interventions Per study sample (SZ, MDD, BD), subjects are randomised to treatment as usual (second-line treatment) or to the early-intensified pharmacological treatment (third-line treatment). Treatment per group per study sample can be found below: SZ sample: Treatment as Usual (TAU): Switch to second line antipsychotic Early-Intensified Pharmacological Treatment (EIPT): Switch to clozapine 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 BD sample: Treatment as Usual (TAU): Switch to quetiapine plus lithium or valproate acid or lamotrigine Early-Intensified Pharmacological Treatment (EIPT): Switch to: one of the following: escitalopram, sertraline, duloxetine, bupropion or venlafaxine plus two of the following: lithium, lamotrigine, 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 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 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 early-intensified pharmacological treatment earlier in the illness. However, these intense treatment options are also commonly prescribed by clinicians. There are no indications in existing literature that the earlier introduction of these medications poses a safety risk. A benefit of the study is that if it indeed turns out that the early-intensified pharmacological treatment is associated with more symptom improvement compared to treatment as usual, treatment guidelines may be changed accordingly and early-intensified pharmacological treatment becomes available earlier in the illness course, as second-line treatment. This would mean that future subjects have to go through less trial and error, which results in a reduced burden for subjects as well as lower societal and healthcare costs. IMPORTANT: the study was submitted to the European suthorities 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. Once we have received the NCT numbers we will add them here. The site in the UK (London) followed the advice and will submit 3 separate protocols. However, Israel already submitted this as one protocol. Therefore, we keep this clinicaltrials.gov number for Israel.

Official Title
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A Randomised, Controlled Trial to Investigate the Effect of an Intensified Pharmacological Treatment for Schizophrenia, Major Depressive Disorder and Bipolar Depression in Subjects Who Had a First-time Treatment Failure on Their First-line Treatment.

Conditions
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Schizophrenia and Related Disorders, Major Depressive Disorder, Bipolar Depression

Intervention / Treatment
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* Drug: Clozapine
* Drug: Esketamine Nasal Product
* Drug: Escitalopram
* Drug: Sertraline
* Drug: Duloxetine
* Drug: Venlafaxine
* Drug: Lithium
* Drug: Lamotrigine
* Drug: Valproate acid
* Drug: Quetiapine
* Drug: Second-line Antidepressants
* Drug: Second-line Antipsychotics
* Drug: Ketamine Hydrochloride
* Drug: Esketamine hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In- or out patients, at least 18 years of age up until 70. Being willing and able to provide written informed consent. If unable, having a legal guardian to provide written informed consent is allowed (subject's opinion will also be considered in these cases). Female subjects of child bearing potential must be willing to ensure that they use effective contraception during the trial and as per the requirements in the protocol (section 8.2). Meeting diagnostic criteria for a primary diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder, major depressive disorder (without psychotic features) or bipolar depression (bipolar disorder type I and II currently in a depressive episode), according to DSM-5. The primary diagnosis will be confirmed by the Mini International Neuropsychiatric Interview (MINI v7.0.2). Subject currently experiences his/her first treatment failure due to lack of efficacy; this treatment is a first-line pharmacotherapeutic agent for the primary DSM-5 diagnosis, and was prescribed for at least 4 weeks within the dose range as specified in the Summary of Product Characteristics (SmPCs). Subject has failed on current psychopharmacological treatment of current episode of SZ/MDD/BD, as confirmed by a CGI-I ≥3. Subject and clinician intend to change pharmacotherapeutic treatment. A minimum symptom severity threshold needs to be present (moderate level; see below) and subject needs to experience functional impairment. The minimum symptom severity threshold for SZ subjects is at least 2 PANSS positive or negative items with a score of 4, or at least one PANSS positive or negative item with a score of 5. The minimum symptom severity threshold for MDD is a score of ≥ 20 on the Montgomery Åsberg Depression Rating Scale (MADRS) The minimum symptom severity threshold for BD is a score of ≥20 on the Montgomery Åsberg Depression Rating Scale (MADRS) For all study samples: Functional impairment is defined as a score of 5 or higher on any of the three scales of the Sheehan Disability Scale (SDS). Exclusion criteria: Being pregnant or breastfeeding. Subject has failed previously on the EIPT study medication (i.e. SZ: clozapine; MDD: esketamine intranasal/(es)ketamine IV) or the TAU treatment for BD (quetiapine) due to inefficacy. Treatment duration as ≥ 4 weeks within an efficacious dose range according to the SmPC. Subject has a known intolerance to clozapine (SZ only), esketamine intranasal/ (es)ketamine IV (MDD only) or quetiapine (BD only) or to all medication options for a study sample. (related to the TAU treatment arms). Meeting any of the contraindications of clozapine (SZ only), esketamine intranasal/ (es)ketamine IV (MDD only) or quetiapine (BD only), or to all medication options for a study sample (related to the TAU treatment arms)., as specified within the applicable SmPC. Subject has participated in another clinical trial in which the subject received an experimental or investigational drug or agent within 30 days before visit 1. Subject currently uses more than the allowed psychotropic concomitant medication and needs to stay on this medication during the study. Subject experiences any other significant disease or disorder which, in the opinion of the investigator, may either put the subjects at risk because of participation in the trial, or may influence the result of the trial, or the subject's ability to participate in the trial. Current active suicidal ideation within the last 2 weeks, defined as a score of 1 or higher on CDSS question 8, followed by an assessment by the treating clinician who determines it is not safe for the subject to participate in the study. For MDD/BD study samples: Subject meets criteria for current alcohol and/or drugs substance use disorderdependency, as confirmed by the Mini International Neuropsychiatric Interview (MINI v7.0.2). For all study samples: Nnicotine dependency is allowed, as well as mild alcohol and/or cannabis use disorder (as defined by MINI v7.0.2). Moderate and severe alcohol and/or cannabis use disorder are not allowed. Subjects who are admitted in the (psychiatric) clinic due to a court or administrative order are not allowed to participate in the study. For the SZ sample only: schizophrenia subjects cannot meet the modified Andreasen criteria for remission. For the BD sample only: a score of 8 or higher on the Young Mania Rating Scale (YMRS) in order to exclude subjects with predominant manic symptoms or mixed symptoms.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel randomization to the treatment as usual (TAU) or early-intensified pharmacological treatment (EIPT) group for each of the study groups (schizophrenia, major depressive disorder, bipolar depression) leading to 6 arms.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Schizophrenia EIPT: Switch to clozapine<br>Schizophrenia randomized to EIPT: Switch to clozapine. Brand, dosage, frequency and duration up to the investigator's discretion | Drug: Clozapine<br>* See arm description<br>* Other names: ATC code: N05AH02;|
| Active Comparator: Schizophrenia TAU: second-line antispychotic<br>Schizophrenia randomized to TAU: switch to second-line antispychotic. Compound, brand, dosage, frequency and duration up to the investigator's discretion (in accordance with SmPC) | Drug: Second-line Antipsychotics<br>* See arm description<br>|
| Experimental: Major Depressive Disorder EIPT: second-line antidepressant + esketamine nasal spray<br>Major depressive disorder randomized to EIPT: Switch to second-line antidepressant + esketamine nasal spray or (es)ketamine infusion. Antidepressant: Compound, brand, dosage, frequency and duration up to the investigator's discretion (in accordance with SmPC). Esketamine nasal spray: 2 times per week for 4 weeks. Initial dose 28 mg, after that increases can be made with 28 mg per increase (up to 84 mg per week). This decision is up to the investigator's discretion (in accordance with SmPC). (Es)ketamine infusion: performed twice weekly for 4 weeks. Compound, brand up to the investigator's discretion (in accordance with SmPC). | Drug: Esketamine Nasal Product<br>* See arm description<br>* Other names: ATC code: N06AB10;Drug: Second-line Antidepressants<br>* See arm description<br>Drug: Ketamine Hydrochloride<br>* See arm description<br>* Other names: N01AX03;Drug: Esketamine hydrochloride<br>* See arm description<br>* Other names: N015X14;|
| Active Comparator: Major Depressive Disorder TAU: second-line antidepressant<br>Major depressive disorder randomized to TAU: Switch to second-line antidepressant + esketamine nasal spray or ketamine IV or esketamine IV . Antidepressant: Compound, brand, dosage, frequency and duration up to the investigator's discretion (in accordance with SmPC). | Drug: Second-line Antidepressants<br>* See arm description<br>|
| Experimental: Bipolar Depression EIPT: Switch to one of the following combinations:<br>Bipolar Depression randomized to EIPT: Switch to 1. one of the following: escitalopram, sertraline, duloxetine or venlafaxine plus 2. two of the following: lithium, lamotrigine, valproate acid or quetiapine | Drug: Escitalopram<br>* See arm description<br>* Other names: ATC code: N06AB10;Drug: Sertraline<br>* See arm description<br>* Other names: ATC code: N06AB06;Drug: Duloxetine<br>* See arm description<br>* Other names: ATC code: N06AX21;Drug: Venlafaxine<br>* See arm description<br>* Other names: ATC code: N06AX16;Drug: Lithium<br>* See arm description<br>* Other names: ATC code: N05AN01;Drug: Lamotrigine<br>* See arm description<br>* Other names: ATC code: N03AX09.;Drug: Valproate acid<br>* See arm description<br>* Other names: ATC code: N03AG01;Drug: Quetiapine<br>* See arm description<br>* Other names: ATC code: N05AH04;|
| Active Comparator: Bipolar Depression TAU: Switch to quetiapine plus lithium or valproate acid or lamotrigine<br>Bipolar Depression randomized to TAU: Switch to quetiapine plus lithium or valproate acid or lamotrigine Compound, brand, dosage, frequency and duration up to the investigator's discretion (in accordance with SmPC). | Drug: Lithium<br>* See arm description<br>* Other names: ATC code: N05AN01;Drug: Lamotrigine<br>* See arm description<br>* Other names: ATC code: N03AX09.;Drug: Valproate acid<br>* See arm description<br>* Other names: ATC code: N03AG01;Drug: Quetiapine<br>* See arm description<br>* Other names: ATC code: N05AH04;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in symptom severity | Change in symptom severity total score from baseline (visit 2) to end of treatment (visit 4). For Schizophrenia, this is measured using the Positive And Negative Syndrome Scale. For Major Depressive Disorder and Bipolar Depression, Montgomery Åsberg Depression Rating Scale is applied. | 4-6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All study samples: to compare changes in the severity and improvement | All study samples: to compare changes in the severity and improvement sub-scores of the Clinical Global Impression Scale between the two treatment arms over the four weeks (Major Depressive Disorder Group)/six weeks (Schizophrenia/Bipolar Depression groups) treatment period (visit 2 versus visit 4). | 4-6 weeks | 
| All study samples: to compare changes in the levels of depression and anxiety | All study samples: to compare changes in the levels of depression and anxiety as assessed with the Hospital Anxiety and Depression Scale between the two treatment arms over the four weeks (Major Depressive Disorder Group)/six weeks (Schizophrenia/Bipolar Depression groups) (visit 2 versus visit 4). | 4-6 weeks | 
| All study samples: to compare changes in cognitive performance #1 | All study samples: to compare changes in cognitive performance as measured through the Trail Making Test between the two treatment arms over four weeks (Major Depressive Disorder Group)/six weeks (Schizophrenia/Bipolar Depression groups) treatment period (visit 2 versus visit 4). | 4-6 weeks | 
| All study samples: to compare changes in cognitive performance #2 | All study samples: to compare changes in cognitive performance as measured through the Digit Symbol Substitution Test between the two treatment arms over four weeks (Major Depressive Disorder Group)/six weeks (Schizophrenia/Bipolar Depression groups) treatment period (visit 2 versus visit 4). | 4-6 weeks | 
| All study samples: to compare changes in cognitive performance #3 | All study samples: to compare changes in cognitive performance as measured through the Rey Auditory Verbal Learning Test between the two treatment arms over four weeks (Major Depressive Disorder Group)/six weeks (Schizophrenia/Bipolar Depression groups) treatment period (visit 2 versus visit 4). | 4-6 weeks | 
| All study samples: to compare changes in cognitive performance #4 | All study samples: to compare changes in cognitive performance as measured through the Perceived Deficits Questionnaire between the two treatment arms over four weeks (Major Depressive Disorder Group)/six weeks (Schizophrenia/Bipolar Depression groups) treatment period (visit 2 versus visit 4). | 4-6 weeks | 
| All study samples: to compare changes in functioning measure #1 | All study samples: to compare changes in functioning measure (Leuven Afective and Pleasure Scale) between the two treatment arms over the four weeks (Major Depressive Disorder Group)/six weeks (Schizophrenia/Bipolar Depression groups) treatment period (visit 2 versus visit 4). | 4-6 weeks | 
| All study samples: to compare changes in functioning measure #2 | All study samples: to compare changes in functioning measure (Sheehan Disability Scale) between the two treatment arms over the four weeks (Major Depressive Disorder Group)/six weeks (Schizophrenia/Bipolar Depression groups) treatment period (visit 2 versus visit 4). | 4-6 weeks | 
| All study samples: to compare changes in quality of life #1 | All study samples: to compare changes in quality of life (Quality of Life Enjoyment and Satisfaction Questionnaire Short Form) between the two treatment arms over the four weeks (Major Depressive Disorder Group)/six weeks (Schizophrenia/Bipolar Depression groups) treatment period (visit 2 versus visit 4). | 4-6 weeks | 
| All study samples: to compare changes in quality of life #2 | All study samples: to compare changes in quality of life and functioning measures (Quality of Life Scale -100, subscale inner tension) between the two treatment arms over the four weeks (Major Depressive Disorder Group)/six weeks (Schizophrenia/Bipolar Depression groups) treatment period (visit 2 versus visit 4). | 4-6 weeks | 
| All study samples: to compare presence of side effects | All study samples: to compare presence of side effects as measured through General Assessment of Side Effect Scale between the two treatment arms over the two treatment arms over the four weeks (Major Depressive Disorder Group)/six weeks (Schizophrenia/Bipolar Depression groups) treatment period (visit 2 versus visit 4). | 4-6 weeks | 
| All study samples: to compare use of concomitant medication | All study samples: to compare use of concomitant medication between the two treatment arms over the two treatment arms over the four weeks (Major Depressive Disorder Group)/six weeks (Schizophrenia/Bipolar Depression groups) treatment period (visit 2 versus visit 4). | 4-6 weeks | 
| All study samples: to compare premature discontinuation | All study samples: to compare premature discontinuation (timing and reason) between the two treatment arms over the two treatment arms over the four weeks (Major Depressive Disorder Group)/six weeks (Schizophrenia/Bipolar Depression groups) treatment period (visit 2 versus visit 4). | 4-6 weeks | 
| All study samples: to compare long-term effects of the treatment | All study samples: to compare long-term effects of the treatment between the two study arms (comparison Positive And Negative Syndrome Scale for Schizoprenia and comparison Montgomery Asberg Depression rating Scale for Major Depressive Disorder on visits 2, 4 and 5). | 4-6 weeks | 
| Schizophrenia sample: to compare changes in Positive and Negative syndrome subscale scores | Schizophrenia sample: to compare changes in Positive and Negative syndrome subscale scores between the two treatment arms over the six week treatment period (visit 2 versus visit 4). | 4-6 weeks | 
| All study samples: comparison of the proportion of participants (EIPT vs. TAU) that is remission at visit 4. | For SZ, remission is defined as meeting the PANSS modified Andreasen criteria (Low scores (≤3) P1. Delusions; P3. Hallucinatory behavior; P2. Conceptual disorganization; N1. Blunted affect; N4. Passive/apathetic social withdrawal; N6. Lack of spontaneity and flow of conversation; G5. Mannerisms/posturing; G9. Unusual thought content. For MDD/BD, remission is defined as a MADRS score ≤ 12, | 4-6 weeks |