xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT06037993</url>
    </required_header>
    <id_info>
      <org_study_id>IRB-DAME 93/2023</org_study_id>
      <nct_id>NCT06037993</nct_id>
    </id_info>
    <brief_title>Endocannabinoid Activity Remodulation for Psychosis Liability in Youth</brief_title>
    <acronym>EARLY</acronym>
    <official_title>Endocannabinoid Activity Remodulation for Psychosis Liability in Youth (EARLY)</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>University of Udine</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>National Research Council (CNR), Institute of Biomolecular Chemistry (ICB), Italy</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>University of Udine</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
      <is_us_export>No</is_us_export>
    </oversight_info>
    <brief_summary>
      <textblock>
        The condition of Clinical High-Risk (CHR) for Psychosis is characterized by the occurrence of&#xD;
        unusual stressful experiences (attenuated psychotic symptoms, APS), anxious symptoms and&#xD;
        psychological distress, and substantial impairment of the subject's daily functioning.&#xD;
  &#xD;
        It is estimated to be associated with up to 30-35% risk of evolution to frank psychotic&#xD;
        disorder within 2-2.5 years. Currently, no psychotherapeutic or pharmacological approaches&#xD;
        have shown therapeutic evidence in this group of patients, leading to the increasingly&#xD;
        diligent search for new treatment agents by the scientific community.&#xD;
  &#xD;
        Therefore, the aim of this study is to provide a response to an unmet clinical need in this&#xD;
        framework of psychic vulnerability by initiating oral therapy with palmitoylethanolamide&#xD;
        (PEA), a nutraceutical/food supplement with proven anti-inflammatory and neuroprotective&#xD;
        properties.&#xD;
  &#xD;
        Indeed, many conditions of psychological distress are thought to be underpinned by systemic&#xD;
        inflammatory and/or neuroinflammatory processes, on which PEA has shown remarkable efficacy,&#xD;
        including through modulation of the immune response and the interaction between the&#xD;
        endocannabinoid system and the gut-microbiota-brain axis.&#xD;
  &#xD;
        The trial we are proposing is a 12-week open-label phase 2 study involving the daily intake&#xD;
        of PEA 600 mg, at a dosage of 1 tablet/day.&#xD;
  &#xD;
        This study will be conducted at the Unit of Psychiatry of Santa Maria della Misericordia&#xD;
        Udine University Hospital.&#xD;
  &#xD;
        Through this study, we wish to evaluate: the ability of PEA to alleviate attenuated psychotic&#xD;
        symptoms, anxiety symptomatology, and psychic distress condition in CHR-APS patients; the&#xD;
        safety and tolerability of sustained intake of PEA in CHR-APS patients; and the biological&#xD;
        basis of PEA functioning.&#xD;
  &#xD;
        - What does participation in this study entail? The study involves taking PEA orally once&#xD;
        daily (600 mg daily) at the same time as a meal during the initial 12-week phase. Upon&#xD;
        completion of the initial phase, you will be offered to enter an extension phase of the trial&#xD;
        of an additional 24 weeks to assess treatment stability, with the possibility of titration of&#xD;
        PEA to 1200 mg daily based on observed clinical compensation. Each participant will be on PEA&#xD;
        treatment for up to 36 weeks.&#xD;
  &#xD;
        During the course of the study, periodic clinical re-evaluations will be conducted at our&#xD;
        Day-Hospital setting.&#xD;
  &#xD;
        The trial will unfold through one screening visit, one baseline visit, and two follow-up&#xD;
        visits (FUP, 4 weeks and 12 weeks apart). The patient will be administered standardized&#xD;
        interviews by a qualified investigating physician; clinical objective examination, collection&#xD;
        of blood and urine samples for standard hematochemical investigations, collection of blood&#xD;
        and stool samples for analysis of some biological markers of interest, monitoring of&#xD;
        adherence to therapy intake, side effects, and adverse effects will also be performed during&#xD;
        the follow-up visits. The nutraceutical PEA will be dispensed by the clinical investigators&#xD;
        at each follow-up visit.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        1. STATE OF THE ART Among subjects at clinical high-risk (CHR) for psychosis, 30-35 % will&#xD;
             develop a full-blown disorder after 2-2.5 years, although to date there are no proper&#xD;
             tools to predict whoever will evolve this way. At the same time, the scientific debate&#xD;
             is not unanimous in decreeing any psychotherapeutic or pharmacological intervention of&#xD;
             first choice to prevent the risk of progression at 6-12 months, highlighting the&#xD;
             importance of responding to this unmet clinical need by further exploring novel&#xD;
             therapeutic agents. As such, growing evidence strengthen the therapeutic potential of&#xD;
             the endocannabinoid (eCB) system modulation. Indeed, the eCB system has not only been&#xD;
             widely recognised as a mediator of the dopaminergic and glutamatergic systems via the&#xD;
             cannabinoid receptor 1 (CB1) in the central nervous system (CNS), but also as early&#xD;
             altered in psychosis. To this end, cannabidiol (CBD) has shown promising results as a&#xD;
             treatment for both psychosis and CHR, especially by regulating eCBs levels via the&#xD;
             peroxisome proliferator activated receptors (PPARs). Moreover, recent research has&#xD;
             focused on the role of eCB-like compounds interacting with non-CB receptors, in order to&#xD;
             identify novel putative pharmacological targets. Similarly, the gut microbiome&#xD;
             modulation has been emphasised as a possible therapeutic candidate in the context of&#xD;
             several mental disorders, such as schizophrenia itself, whose symptom severity seems to&#xD;
             be correlated to the diversity of the microbiome and gut-brain axis metabolic&#xD;
             alterations. Intriguingly, the enlarged eCB system, conceived as endocannabinome&#xD;
             (eCBome), and the intestinal microbiome seem to be strictly intertwined with each other:&#xD;
             for instance, altered eCB-like compound palmitoylethanolamide (PEA) signaling has been&#xD;
             shown to be responsible for the link between microbiota diversity and&#xD;
             anhedonia/amotivation.&#xD;
  &#xD;
             Oral PEA supplementation has recently been shown to produce beneficial effects over&#xD;
             common mental health dimensional constructs as anhedonia/amotivation, which are commonly&#xD;
             experienced by 15-20% of the general population, as well as promising therapeutic&#xD;
             results as an adjunctive treatment for patients with schizophrenia negative symptoms and&#xD;
             acute mania. Interestingly, PEA and other endocannabinoids(eCBs)/acylethanolamines(AEs)&#xD;
             peripheral blood levels have been proven to be elevated in individuals at CHR for&#xD;
             psychosis and schizophrenia patients, being modulated further in those with a personal&#xD;
             history of child maltreatment or substance misuse. Oral PEA has shown well-documented&#xD;
             safety and tolerability in numerous clinical trials with over 1000 individuals with&#xD;
             doses 300-1200 mg per day both in healthy and sick populations. Acute oral PEA toxicity&#xD;
             studies have shown LD50 &gt; 2000 mg/Kg of body weight, while 14- and 90-day repeat dose&#xD;
             toxicity studies reported its No Observed Adverse Effect Level to be &gt; 1000 mg/Kg of&#xD;
             weight per day.&#xD;
  &#xD;
             Its nature as an endogenous autacoid and essential human diet compound renders PEA&#xD;
             nearly devoid of known or potential adverse effects.&#xD;
  &#xD;
          2. DETAILED DESCRIPTION OF THE PROJECT 2.1. RATIONALE FOR CURRENT STUDY&#xD;
  &#xD;
             The main purpose of the present study is to address the absence of an effective&#xD;
             treatment for subjects at risk for the development of psychosis (clinical high-risk&#xD;
             (CHR) for psychosis patients), which can be considered a major unmet clinical need for&#xD;
             this group of patients. We will thus perform an investigator-initiated proof-of-concept&#xD;
             study (Phase-2 Pilot Study), with the purpose to examine:&#xD;
  &#xD;
             (i) Palmitoylethanolamide (PEA) ability to alleviate subtle psychotic and anxiety&#xD;
             symptoms in CHR patients; (ii) PEA safety and tolerability; (iii) The biological basis&#xD;
             of PEA effect.&#xD;
  &#xD;
             2.2. TRIAL OBJECTIVES&#xD;
  &#xD;
             To evaluate:&#xD;
  &#xD;
             (i) The viability of identifying and consenting CHR patients into a trial with PEA; (ii)&#xD;
             The efficacy of PEA in providing relief to attenuated psychotic symptoms (APS) in CHR&#xD;
             patients; (iii) Whether sustained PEA treatment is well tolerated by CHR patients over a&#xD;
             period of at least 12 weeks; (iv) The biological mechanisms underpinning PEA beneficial&#xD;
             effects in CHR patients (e.g., modulation of the endocannabinoid (eCB) system,&#xD;
             immunological response, metabolic fingerprinting, gut microbiome composition).&#xD;
  &#xD;
             - Objective (i)&#xD;
  &#xD;
             Feasibility questions:&#xD;
  &#xD;
             Over the first 12 months from first patient recruited we will assess whether:&#xD;
  &#xD;
             (i) A minimum of 20 eligible patients have consented to be enrolled into the study; (ii)&#xD;
             At least 80% of recruited patients have completed the 12-week follow-up;&#xD;
  &#xD;
             Feasibility endpoints:&#xD;
  &#xD;
             (i) Number of subjects giving consent; (ii) Proportion of participants completing the&#xD;
             12-week follow-up.&#xD;
  &#xD;
             - Objective (ii)&#xD;
  &#xD;
             Research Questions:&#xD;
  &#xD;
             Our primary clinical research question is whether PEA added to treatment as usual in CHR&#xD;
             patients:&#xD;
  &#xD;
             (i) Improves APS;&#xD;
  &#xD;
             Our secondary clinical research questions are whether PEA added to treatment as usual&#xD;
             (TAU) in CHR patients:&#xD;
  &#xD;
             (ii) Improves APS to the extent that patients no longer satisfy the diagnostic criteria&#xD;
             for the CHR state; (iii) Relieves the distress associated with psychotic symptoms; (iv)&#xD;
             Improves anxiety symptoms; (v) Ameliorates social and role functioning.&#xD;
  &#xD;
             Primary endpoints:&#xD;
  &#xD;
             Severity of psychotic symptoms as measured using the Comprehensive Assessment of At-Risk&#xD;
             Mental State (CAARMS).&#xD;
  &#xD;
             Secondary endpoints:&#xD;
  &#xD;
             (i) Distress associated with psychotic symptoms as measured using the CAARMS; (ii)&#xD;
             Severity of anxiety symptoms assessed using the Hospital Anxiety and Depression Scale&#xD;
             (HADS); (iii) The level of impaired global functioning assessed using the Social and&#xD;
             Role functioning Scale; (iv) Clinical remission, defined as no longer meeting the APS&#xD;
             criteria; (v) Total CAARMS score. All the study endpoints for the 12-week clinical trial&#xD;
             will be assessed by comparing follow-up (FUP) visits and baseline. For those&#xD;
             participants continuing in the 24-week extension phase, change (FUP visit minus&#xD;
             baseline) in the severity of psychotic symptoms as measured using the CAARMS will be&#xD;
             compared with the group of those willing to discontinue PEA and continue with TAU.&#xD;
  &#xD;
             - Objective (iii)&#xD;
  &#xD;
             Safety questions:&#xD;
  &#xD;
             We will evaluate if sustained PEA treatment is well tolerated, with minimal&#xD;
             side-effects.&#xD;
  &#xD;
             Safety endpoints:&#xD;
  &#xD;
             Incidence of adverse effects during the study period, as measured using the UKU&#xD;
             side-effect rating scale.&#xD;
  &#xD;
             2.3. PARTICIPANTS&#xD;
  &#xD;
             - Selection of participants: The proposed single-centre study will involve a university&#xD;
             clinical research facility in Italy. Participants will be enrolled into the internal&#xD;
             pilot, that will progress to the open-label trial. Patients who express an interest in&#xD;
             the study and are identified as having CHR with APS by their clinical teams will be&#xD;
             approached by study researchers and given a patient information sheet. Those who agree&#xD;
             to take part in the study will be invited for a screening visit.&#xD;
  &#xD;
             - Heterogeneity in CHR: CHR patients are an heterogeneous group, including three&#xD;
             sub-groups of patients engaged using standardized and internationally recognized CAARMS&#xD;
             criteria into: (i) APS individuals, (ii) individuals with 'brief limited intermittent&#xD;
             psychotic symptoms' (BLIPS), and (iii) individuals included in the Vulnerability&#xD;
             subgroup. Being the present study primarily designed to assess the effect of PEA over&#xD;
             the symptoms of CHR state and to support clinical homogeneity, we will focus on the&#xD;
             CHR-APS sub-group of patients, who are the most severely symptomatic, excluding the&#xD;
             other two groups at the screening stage. CHR-APS patients represent the greatest&#xD;
             majority (at least 80%) of CHR patients treated by mental health services.&#xD;
  &#xD;
             2.4. INTERVENTION&#xD;
  &#xD;
             - Trial Medication: Oral Palmitoylethanolamide (PEA; 600 mg per day) in tablet form. PEA&#xD;
             will be obtained by a pharmaceutical company operating under good manufacturing practice&#xD;
             conditions with appropriate certification. The information presented on the labels for&#xD;
             PEA will comply with applicable national and local regulations.&#xD;
  &#xD;
             - Dosing Regimen: PEA is to be taken orally once a day (600 mg per day) around mealtime&#xD;
             during the 12-week initial phase of the study. During the 24-week extension phase of the&#xD;
             study, the trial medication is to be taken from once a day up to twice a day (600-1200&#xD;
             mg per day), based on clinical judgment of the improvement obtained so far, around&#xD;
             mealtime. Each participant will undergo PEA treatment for a maximum of 36 weeks. The&#xD;
             information presented on the labels for the PEA will comply with applicable national and&#xD;
             local regulations.&#xD;
  &#xD;
             - Medication Risks: Being a food supplement/nutraceutical, PEA can be purchased at&#xD;
             pharmacies without a medical prescription. While unknown risks cannot be excluded,&#xD;
             serious adverse events including overdose have not been documented.&#xD;
  &#xD;
             - Drug Accountability: Study specific prescriptions can be used for dispensing the study&#xD;
             product. The study medication can only be prescribed by qualified physicians clearly&#xD;
             given this role on the study delegation log. Only people designated by the Principal&#xD;
             Investigator (PI) can collect medication. Only PEA supplied for this study can be&#xD;
             dispensed against the study specific prescription. Full accountability records will be&#xD;
             completed including recording the batch, expiry date, people dispensing/checking the&#xD;
             prescription, quantity and date of drug returns, empty packaging. Nothing is destroyed&#xD;
             without the authorization from the PI.&#xD;
  &#xD;
             - Storage of study medication: PEA will be stored at room temperature (&lt; 25 °C) and not&#xD;
             kept in a refrigerator, in compliance with local regulations. It will be stored in a&#xD;
             secure area away from other treatments and clearly marked for this study.&#xD;
  &#xD;
             - Removal of study medication outside of expiry date/at trial conclusion and&#xD;
             destruction: The expiry date will always be reported on the study medication. Study&#xD;
             medication outside of the expiry date will not be dispensed and will be destroyed,&#xD;
             subject to authorization, on an ongoing basis.&#xD;
  &#xD;
             - Withdrawal of Subjects: According to Declaration of Helsinki, all participants will&#xD;
             have the right to withdraw from the study at any time without giving any reason, without&#xD;
             any prejudice to their future medical care, and will be informed as such before consent.&#xD;
             A participant's withdrawal will be discussed in terms of only discontinuing the study&#xD;
             treatment and continuing follow-up visits. Should the patient request to completely&#xD;
             withdraw from the study, the decision will be respected. All reasonable efforts will be&#xD;
             made to ascertain the reason for discontinuation, even though patients will be not&#xD;
             obliged to give any explanations. Already collected data will be kept and included in&#xD;
             the final analysis. The investigator themselves may also withdraw participants for&#xD;
             various reasons, including but not limited to the following: protocol violations,&#xD;
             inter-current illness, adverse events, serious adverse events, suspected unexpected&#xD;
             serious adverse reactions, administrative reasons, participation in the trial affecting&#xD;
             their ongoing care, symptomatic worsening. In the latter case, patients will be followed&#xD;
             up with the same schedule of research assessments as those who continue in the study,&#xD;
             till they complete the 12-week follow-up period or till they progress to frank psychosis&#xD;
             (whichever is earlier). In case of CHR patients experiencing progression to a first&#xD;
             episode of psychosis (frank psychosis), they will exit from the study intervention, be&#xD;
             deemed as treatment failure, and will only be assessed for safety outcomes until they&#xD;
             complete the 12-week follow-up period.&#xD;
  &#xD;
             - Subject Compliance: Pill-counts will be performed at FUP visits 1, 2, 3, and 4, in&#xD;
             order to assess compliance with PEA treatment. Patients will be defined as complying in&#xD;
             the presence of a pill count greater than 50% the expected number taken. Patients who&#xD;
             are defined as non-complying with the medication will be coded as protocol deviators.&#xD;
  &#xD;
             - Concomitant Medication: Based on participants' clinical history, concomitant&#xD;
             requirement of psychotropic medication is an exclusion criterion for the study, with the&#xD;
             exception of patients undergoing Selective Serotonin Reuptake Inhibitor (SSRI) stable&#xD;
             monotherapy (at least 8 months). Patients requiring continued treatment with other&#xD;
             classes of psychotropic medications during the treatment phase may be withdrawn from the&#xD;
             study by the PI. Very short-term treatment with rescue medications that have a&#xD;
             well-established sedative or calming effect (e.g., Benzodiazepines) during the study may&#xD;
             be allowed. Throughout the study, any other concomitant medications or treatments deemed&#xD;
             necessary to provide adequate supportive care may be prescribed by investigators. A&#xD;
             record will be kept to list all concomitant medications received during the treatment&#xD;
             phase.&#xD;
  &#xD;
             2.5. VISIT ASSESSMENTS&#xD;
  &#xD;
             The following visit assessments will be performed:&#xD;
  &#xD;
             - First Screening Visit: This will take place approximately one week prior to the Second&#xD;
             Screening Visit and two to three weeks prior to the Baseline Visit. First, informed&#xD;
             consent will be obtained from those who wish to take part to the study. Consenting&#xD;
             patients will then be screened against the study inclusion and exclusion criteria using&#xD;
             the CAARMS and collecting information on their medical history and substance use&#xD;
             information. Individuals satisfying the criteria will be recruited by employed or&#xD;
             delegated investigators. Also, consent will be obtained on all participants screened to&#xD;
             collect plasma/serum/urine/fecal samples for routine biochemistry and haematology,&#xD;
             endocannabinoid, immune, metabolic, and gut microbiome analysis. Consent will be sought&#xD;
             to analyse screening data as well as regarding long-term follow-up beyond the outcomes&#xD;
             of the trial and to link participants' data to routinely collected data sources such as&#xD;
             Hospital Episode Statistics and General Practitioner records.&#xD;
  &#xD;
             - Second Screening Visit: This will take place one to two weeks prior to Baseline Visit.&#xD;
             Safety blood and urine samples (for routine biochemistry and haematology) will be&#xD;
             obtained, physical examination and vital signs will be recorded.&#xD;
  &#xD;
             - Baseline Visit (day 0): Following satisfactory completion of screening, baseline&#xD;
             measures (CAARMS, HADS, Global Functioning), physical examination, blood, and fecal&#xD;
             samples for endocannabinome (eCBome), immune, metabolic, and gut microbiota analyses&#xD;
             will be acquired. Patients will be prescribed PEA and the medication will be dispensed.&#xD;
             Side effects will also be assessed, by using the UKU side-effect rating scale.&#xD;
  &#xD;
             - FUP Visit 1 (Week 4 ± 7 days, approximately day 28): This visit will be carried out at&#xD;
             Month 1 and involve clinical assessments (CAARMS, HADS, Global Functioning), blood, and&#xD;
             fecal sampling for eCBome, immune, metabolic, and gut microbiota analyses, monitoring of&#xD;
             compliance, side effects, adverse events, and dispensing of study drugs.&#xD;
  &#xD;
             - FUP Visit 2 (Week 12 ± 14 days, approximately Day 84): This visit will be carried out&#xD;
             at Month 3 and involve clinical measures (CAARMS, HADS, Global Functioning), physical&#xD;
             examination, safety blood and urine samples, blood and fecal sampling for eCBome,&#xD;
             immune, metabolic, and gut microbiota analyses, monitoring of compliance, side effects,&#xD;
             adverse events, and dispensing of study drugs.&#xD;
  &#xD;
             - FUP Visit 3 (Week 24 ± 14 days, approximately Day 168): This visit will be carried out&#xD;
             at Month 6 on those enrolled in the extension phase and involve clinical assessments&#xD;
             (CAARMS, HADS, Global Functioning), blood and fecal sampling for eCBome, immune,&#xD;
             metabolic, and gut microbiota analyses, monitoring of compliance, side effects, adverse&#xD;
             events, and dispensing of study drugs.&#xD;
  &#xD;
             - FUP Visit 4 (Week 36 ± 14 days, at approximately Day 252): This visit will be carried&#xD;
             out at Month 9 on those enrolled in the extension phase and involve clinical measures&#xD;
             (CAARMS, HADS, Global Functioning), physical examination, safety blood and urine&#xD;
             samples, blood and fecal sampling for eCBome, immune, metabolic, and gut microbiota&#xD;
             analyses, monitoring of compliance, side effects, adverse events, and dispensing of&#xD;
             study drugs.&#xD;
  &#xD;
             - Laboratory Tests: Clinical Laboratory measures: blood tests for haematology (Full&#xD;
             blood count and Haemoglobin), biochemistry (Urea &amp; Electrolytes, liver function test,&#xD;
             lipid profile), and immune profile characterization will be carried out at the clinical&#xD;
             research recruitment hub as per their standard procedure. Blood results will be printed&#xD;
             and filed as source in the patient folder. Serum samples for performing metabolic&#xD;
             fingerprinting by Raman Spectroscopy, as well as blood and fecal samples for measurement&#xD;
             of the levels of eCBome mediators and determination of the microbial composition in&#xD;
             feces by Next Generation Sequencing (NGS) of 16SRNA and shotgun metagenomics&#xD;
             methodologies, will be shipped to counseling specialized centers where they will be&#xD;
             stored and analysed.&#xD;
  &#xD;
             2.6. SAMPLE SIZE&#xD;
  &#xD;
             - Proposed sample size: We aim at enrolling 20 patients within 12 months from the start&#xD;
             of recruitment.&#xD;
  &#xD;
             - Sample size justification: The number is coherent with suggested sample sizes for&#xD;
             pilot studies and is deemed sufficient to evaluate feasibility outcomes. No powered&#xD;
             sample size calculation was implemented for the pilot study.&#xD;
  &#xD;
             2.7. METHODS - Data collection, management and archiving: Assessment and collection of&#xD;
             baseline, outcome and other trial data will be performed according to Visit assessments&#xD;
             flow-chart. In case of trial intervention discontinuation, follow-up data will be&#xD;
             collected anyway, unless a participant expresses the wish to be completely withdrawn&#xD;
             from the study. All data source will be held on as a paper source data worksheet (SDW).&#xD;
             These will be managed locally under the care of the recruiting and consenting site PI.&#xD;
             Collected data will be held on paper SDW which will be thereafter recorded by allowed&#xD;
             study team members on a 24-hour-accessible electronic-based data entry system hosted by&#xD;
             the clinical research recruitment hub at ASUFC and University of Udine, consenting data&#xD;
             entry to run in parallel with participant enrolment and visits. At the conclusion of the&#xD;
             trial the study team will have resolved the data queries and request to remove user&#xD;
             access to ensure that the final dataset cannot be changed. SDWs, electronic-based data,&#xD;
             and the final statistical report will be archived. Systems will be in place to secure&#xD;
             the data collection system against permanent loss and allow the recovery and restoration&#xD;
             in the event of such a loss occurring.&#xD;
  &#xD;
             - Data verification, statistical monitoring and analysis: At the study start, a&#xD;
             structured data verification plan will be agreed and developed by the Head Statistician&#xD;
             of the research team. Data will be checked for consistency across paper- and&#xD;
             electronic-based entry systems. Statistical monitoring will include patient severity&#xD;
             level, eventual withdrawals, baseline data, FUP visits data, and AEs. The research team&#xD;
             will approve a Statistical Analysis Plan within the early stages of the study, and&#xD;
             before the Head Statistician summarizes any data. Proportions will be presented for each&#xD;
             feasibility outcome. Interim analyses are not planned. The Head Statistician will both&#xD;
             carry out and interpret statistical analysis. Our primary analysis will involve a&#xD;
             generalized linear model with CAARMS psychotic symptom severity as the dependent measure&#xD;
             and time as a repeated measure within subject. We are interested in whether there is a&#xD;
             significant benefit over time with PEA treatment. CAARMS distress and total score as&#xD;
             well as HADS ratings will be analysed in a similar manner. We will also conduct paired t&#xD;
             tests based on baseline and endpoint assessments to examine measures of CAARMS severity&#xD;
             and secondary measures. Rates of side effects will be reported, as well as reasons for&#xD;
             dropouts from the trial.&#xD;
  &#xD;
             - Missing Data: We expect withdrawn patients to be missing at random, and very few&#xD;
             participants withdrawing consent. All patients having at least one post-baseline outcome&#xD;
             measure, would be included in each analysis. Nonetheless, patterns of missing data will&#xD;
             be explored to investigate any evidence against missing at random, whose impact on the&#xD;
             analysis will be considered by introducing imputation methods.&#xD;
  &#xD;
             2.8. ETHICS&#xD;
  &#xD;
             - Ethics &amp; Regulatory Approvals: The trial will be conducted in accordance with the&#xD;
             principles of the Declaration of Helsinki (1996), the principles of Good Clinical&#xD;
             Practice (GCP), and with all applicable regulatory requirements. This protocol and&#xD;
             related documents will be submitted for review to the local Research Ethics Committee&#xD;
             (REC).&#xD;
  &#xD;
             - Consent Prior to Screening: Those expressing interest into the study will be referred&#xD;
             to the clinical research recruitment hub by their consultants. At screening,&#xD;
             investigators will introduce the trial and provide the patients with exhaustive Patient&#xD;
             Information Sheets (PIS). Allowed qualified physicians will discuss the trial with&#xD;
             patients in light of the information provided in the PIS and give appropriate time for&#xD;
             the participants to understand the information provided, before asking written informed&#xD;
             consent from those willing to take part to the trial.&#xD;
  &#xD;
             - Biological Samples: The collection of routine blood samples, urine samples, fecal&#xD;
             samples, and genotyping will be specifically addressed through the collection of ad hoc&#xD;
             consent for biological materials. After collection at the research recruitment hub,&#xD;
             obtained blood samples for haematology, biochemistry, and Immune profile&#xD;
             characterization will be delivered by the study research team to the local laboratory&#xD;
             for analysis. Blood and fecal samples collected to perform metabolic fingerprinting,&#xD;
             measurement of the levels of eCBome mediators, and determination of the microbial&#xD;
             composition, will be stored in local facilities under adequate conditions (-80°C) and&#xD;
             then shipped to counseling specialized centers for subsequent analysis.&#xD;
  &#xD;
             2.9. CONFIDENTIALITY All study-related information will be stored securely at the study&#xD;
             site. All participant information will be stored in locked file cabinets in areas with&#xD;
             limited access. All laboratory specimens, reports, data collection, process, and&#xD;
             administrative forms will be identified by a coded identification (ID) number only to&#xD;
             maintain participant confidentiality. All records that contain names or other personal&#xD;
             identifiers, such as locator forms and informed consent forms, will be stored separately&#xD;
             from study records identified by code number. All local databases will be secured with&#xD;
             password-protected access systems. Forms, lists, logbooks, appointment books, and any&#xD;
             other listings that link participant ID numbers to other identifying information will be&#xD;
             stored in a separate, locked file in an area with limited access. Participants' study&#xD;
             information will not be released outside of the study without the written permission of&#xD;
             the participant.&#xD;
  &#xD;
          3. INTEREST FOR THE ADVANCEMENT OF KNOWLEDGE AND RISK/BENEFIT CONSIDERATIONS It is not&#xD;
             unusual in clinical practice that patients feel that their current treatments, either&#xD;
             psychological or pharmacological, result in suboptimal improvements. They also express&#xD;
             growing interest in trying nutraceutical or alternative treatments. In recent times,&#xD;
             growing interest has been aroused regarding the therapeutic potential of&#xD;
             endocannabinoid-like compounds. This is particularly relevant for Clinical High-Risk&#xD;
             (CHR) for psychosis patients where no established treatment is available. Thus,&#xD;
             identifying novel safe and tolerable treatments is recognised as a key priority to&#xD;
             relieve these patients' and their families' sufferings, even more so if compared to&#xD;
             traditional psychotropic therapies often not devoid of unpleasant side effects. Besides,&#xD;
             the involvement of youths who manifest sub-threshold symptoms not reaching criteria for&#xD;
             the diagnosis of a full-blown psychotic disorder, raises concerns about the use of&#xD;
             conventional anti-psychotics, from both a forensic and an ethical perspective. The trial&#xD;
             objective will be pursued with minimal risks for study participants, considering that&#xD;
             Palmitoylethanolamide (PEA) is a well-established nutraceutical for sustained medical&#xD;
             treatment in humans, and serious adverse events have not been documented. No invasive&#xD;
             assessment techniques will be implemented throughout the whole study.&#xD;
  &#xD;
          4. DISSEMINATION POLICY The results of the study are intended to be reported and&#xD;
             disseminated at national/international conferences and in peer-reviewed scientific&#xD;
             journals. Our objective is to submit for publication the main results of the trial&#xD;
             within two years of last patient recruitment.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">November 1, 2022</start_date>
    <completion_date type="Anticipated">November 2025</completion_date>
    <primary_completion_date type="Anticipated">November 2024</primary_completion_date>
    <phase>N/A</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>N/A</allocation>
      <intervention_model>Single Group Assignment</intervention_model>
      <intervention_model_description>We will evaluate the study viability through an internal pilot that will assess the ability of the study to identify, consent, and follow up CHR patients experiencing APS in the study. We propose a 12-week, open-label, investigator-initiated proof of concept study (Phase-2 Pilot Study) of PEA (600 mg/day) for the treatment of APS in CHR patients. We plan to enrol 20 CHR young adults. Those completing the 12-week initial phase, will be proposed to enter a 24-week extension phase to evaluate the clinical stability of treatment, with the possibility of PEA titration to 1200 mg/day based on clinical improvement obtained so far.</intervention_model_description>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Severity of attenuated psychotic symptoms (APS) as measured using the Comprehensive Assessment of At-Risk Mental State (CAARMS)</measure>
      <time_frame>12 weeks for the initial phase, further 24 weeks for the extension phase</time_frame>
    </primary_outcome>
    <secondary_outcome>
      <measure>Distress associated with psychotic symptoms as measured using the CAARMS</measure>
      <time_frame>12 weeks for the initial phase, further 24 weeks for the extension phase</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Severity of anxiety symptoms assessed using the Hospital Anxiety and Depression Scale (HADS)</measure>
      <time_frame>12 weeks for the initial phase, further 24 weeks for the extension phase</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>The level of impaired global functioning assessed using the Social and Role functioning Scale</measure>
      <time_frame>12 weeks for the initial phase, further 24 weeks for the extension phase</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Clinical remission, defined as no longer meeting the APS criteria</measure>
      <time_frame>12 weeks for the initial phase, further 24 weeks for the extension phase</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Total CAARMS score</measure>
      <time_frame>12 weeks for the initial phase, further 24 weeks for the extension phase</time_frame>
    </secondary_outcome>
    <other_outcome>
      <measure>Safety endpoints: Incidence of adverse effects during the study period, as measured using the UKU side-effect rating scale</measure>
      <time_frame>12 weeks for initial phase, further 24 weeks for extension phase</time_frame>
    </other_outcome>
    <number_of_arms>1</number_of_arms>
    <enrollment type="Anticipated">20</enrollment>
    <condition>Clinical High Risk for Psychosis</condition>
    <condition>Ultra High Risk for Psychosis</condition>
    <condition>Attenuated Psychotic Symptoms</condition>
    <arm_group>
      <arm_group_label>Single arm: palmitoylethanolamide (PEA)-treated patients</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
    </arm_group>
    <intervention>
      <intervention_type>Dietary Supplement</intervention_type>
      <intervention_name>Ultra-micronized Palmitoylethanolamide (PEA)</intervention_name>
      <description>Palmitoylethanolamide (PEA) is an N-acylethanolamine (AE), produced &quot;on demand&quot; by different cell types as a response to actual or potential damage, proven to down-regulate central and peripheral activity of mast cells and non-neuronal cells (e.g., astrocytes, microglia) and to exert protective functions against glutamate neuro-toxicity, accounting for its naturally-occurring anti-inflammatory, analgesic, and anticonvulsant properties. Due to the shared pharmacodynamic properties, PEA is considered as the endogenous equivalent of Cannabidiol (CBD). A growing body of literature has confirmed the role of PEA in most neurobiological mechanisms underpinning several neuropsychiatric conditions both in clinical and preclinical settings. The effect of PEA over neuroinflammation and glutamate signaling may represent a promising biobehavioral mechanism underlying the clinical utility of its oral supplementation in CHR state.</description>
      <arm_group_label>Single arm: palmitoylethanolamide (PEA)-treated patients</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria&#xD;
  &#xD;
            -  Individuals diagnosed with CHR-APS, as defined using CAARMS criteria;&#xD;
  &#xD;
            -  Aged 18-35 years;&#xD;
  &#xD;
            -  To be able to understand and communicate in Italian;&#xD;
  &#xD;
            -  To be able to give informed consent.&#xD;
  &#xD;
          Exclusion Criteria&#xD;
  &#xD;
            -  Lifetime history of a psychotic or manic episode lasting 7 days or longer;&#xD;
  &#xD;
            -  Active suicidal ideation indicating significant current risk or history of serious&#xD;
               suicide attempt in the opinion of the PI, as evaluated at the screening stage;&#xD;
  &#xD;
            -  Lifetime neurological disorders (e.g., epilepsy, except febrile convulsions) or severe&#xD;
               intercurrent physical illness;&#xD;
  &#xD;
            -  Current treatment with psychotropic medication, with the exception of Selective&#xD;
               Serotonin Reuptake Inhibitor (SSRI) stable monotherapy (at least 8 months);&#xD;
  &#xD;
            -  Lifetime treatment with antipsychotic medication for more than 7 days;&#xD;
  &#xD;
            -  IQ &lt; 70;&#xD;
  &#xD;
            -  Female patients who are pregnant, lactating or not using an acceptable effective form&#xD;
               contraception if they are at risk of falling pregnant;&#xD;
  &#xD;
            -  Taking part in another pharmacological trial.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>35 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_contact>
      <last_name>Marco Colizzi, MD, PhD</last_name>
      <phone>+390432559155</phone>
      <email>marco.colizzi@uniud.it</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Riccardo Bortoletto, MD</last_name>
      <phone>+393484739255</phone>
      <email>bortoletto.riccardo@spes.uniud.it</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Unit of Psychiatry, University Hospital of Udine</name>
        <address>
          <city>Udine</city>
          <state>UD</state>
          <zip>33100</zip>
          <country>Italy</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Marco Colizzi, MD, PhD</last_name>
        <phone>+390432559155</phone>
        <email>marco.colizzi@uniud.it</email>
      </contact>
      <contact_backup>
        <last_name>Riccardo Bortoletto, MD</last_name>
        <phone>+393484739255</phone>
        <email>bortoletto.riccardo@spes.uniud.it</email>
      </contact_backup>
      <investigator>
        <last_name>Marco Colizzi, MD, PhD</last_name>
        <role>Principal Investigator</role>
      </investigator>
      <investigator>
        <last_name>Riccardo Bortoletto, MD</last_name>
        <role>Sub-Investigator</role>
      </investigator>
    </location>
    <location>
      <facility>
        <name>Unit of Psychiatry, University Hospital of Udine</name>
        <address>
          <city>Udine</city>
          <zip>33100</zip>
          <country>Italy</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Marco Colizzi, MD, PhD</last_name>
        <phone>+390432559155</phone>
        <email>marco.colizzi@uniud.it</email>
      </contact>
    </location>
    <location_countries>
      <country>Italy</country>
    </location_countries>
    <link>
      <url>https://www.frontiersin.org/articles/10.3389/fpsyt.2023.1231710/full</url>
      <description>Questioning the role of palmitoylethanolamide in psychosis: a systematic review of clinical and preclinical evidence</description>
    </link>
    <link>
      <url>https://www.frontiersin.org/articles/10.3389/fpsyt.2022.1038122/full</url>
      <description>Therapeutic effect of palmitoylethanolamide in cognitive decline: A systematic review and preliminary meta-analysis of preclinical and clinical evidence</description>
    </link>
    <link>
      <url>https://www.mdpi.com/2076-3425/12/1/101</url>
      <description>Is It Time to Test the Antiseizure Potential of Palmitoylethanolamide in Human Studies? A Systematic Review of Preclinical Evidence</description>
    </link>
    <link>
      <url>https://www.mdpi.com/2072-6643/13/4/1346</url>
      <description>Palmitoylethanolamide and Its Biobehavioral Correlates in Autism Spectrum Disorder: A Systematic Review of Human and Animal Evidence</description>
    </link>
    <link>
      <url>https://www.nature.com/articles/tp201215</url>
      <description>Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia</description>
    </link>
    <link>
      <url>https://www.cambridge.org/core/journals/psychological-medicine/article/abs/childhood-trauma-and-being-atrisk-for-psychosis-are-associated-with-higher-peripheral-endocannabinoids/BFFDA252EF2250C2F2B45786CC152CDC</url>
      <description>Childhood trauma and being at-risk for psychosis are associated with higher peripheral endocannabinoids</description>
    </link>
    <verification_date>September 2023</verification_date>
    <study_first_submitted>September 7, 2023</study_first_submitted>
    <study_first_submitted_qc>September 7, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 14, 2023</study_first_posted>
    <last_update_submitted>September 7, 2023</last_update_submitted>
    <last_update_submitted_qc>September 7, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 14, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>At-Risk Mental State</keyword>
    <keyword>Schizophrenia</keyword>
    <keyword>Endocannabinoid System</keyword>
    <keyword>Gut-Brain Axis</keyword>
    <keyword>Palmitoylethanolamide</keyword>
    <keyword>Nutraceuticals</keyword>
    <keyword>Prevention</keyword>
    <keyword>Early Intervention</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Psychotic Disorders</mesh_term>
      <mesh_term>Mental Disorders</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Palmidrol</mesh_term>
    </intervention_browse>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT06037993
  org study id: IRB-DAME 93/2023
  nct id: NCT06037993
  lead sponsor: 
  collaborator: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  is us export: No
  The condition of Clinical High-Risk (CHR) for Psychosis is characterized by the occurrence of
        unusual stressful experiences (attenuated psychotic symptoms, APS), anxious symptoms and
        psychological distress, and substantial impairment of the subject's daily functioning.
  
        It is estimated to be associated with up to 30-35% risk of evolution to frank psychotic
        disorder within 2-2.5 years. Currently, no psychotherapeutic or pharmacological approaches
        have shown therapeutic evidence in this group of patients, leading to the increasingly
        diligent search for new treatment agents by the scientific community.
  
        Therefore, the aim of this study is to provide a response to an unmet clinical need in this
        framework of psychic vulnerability by initiating oral therapy with palmitoylethanolamide
        (PEA), a nutraceutical/food supplement with proven anti-inflammatory and neuroprotective
        properties.
  
        Indeed, many conditions of psychological distress are thought to be underpinned by systemic
        inflammatory and/or neuroinflammatory processes, on which PEA has shown remarkable efficacy,
        including through modulation of the immune response and the interaction between the
        endocannabinoid system and the gut-microbiota-brain axis.
  
        The trial we are proposing is a 12-week open-label phase 2 study involving the daily intake
        of PEA 600 mg, at a dosage of 1 tablet/day.
  
        This study will be conducted at the Unit of Psychiatry of Santa Maria della Misericordia
        Udine University Hospital.
  
        Through this study, we wish to evaluate: the ability of PEA to alleviate attenuated psychotic
        symptoms, anxiety symptomatology, and psychic distress condition in CHR-APS patients; the
        safety and tolerability of sustained intake of PEA in CHR-APS patients; and the biological
        basis of PEA functioning.
  
        - What does participation in this study entail? The study involves taking PEA orally once
        daily (600 mg daily) at the same time as a meal during the initial 12-week phase. Upon
        completion of the initial phase, you will be offered to enter an extension phase of the trial
        of an additional 24 weeks to assess treatment stability, with the possibility of titration of
        PEA to 1200 mg daily based on observed clinical compensation. Each participant will be on PEA
        treatment for up to 36 weeks.
  
        During the course of the study, periodic clinical re-evaluations will be conducted at our
        Day-Hospital setting.
  
        The trial will unfold through one screening visit, one baseline visit, and two follow-up
        visits (FUP, 4 weeks and 12 weeks apart). The patient will be administered standardized
        interviews by a qualified investigating physician; clinical objective examination, collection
        of blood and urine samples for standard hematochemical investigations, collection of blood
        and stool samples for analysis of some biological markers of interest, monitoring of
        adherence to therapy intake, side effects, and adverse effects will also be performed during
        the follow-up visits. The nutraceutical PEA will be dispensed by the clinical investigators
        at each follow-up visit.
  1. STATE OF THE ART Among subjects at clinical high-risk (CHR) for psychosis, 30-35 % will
             develop a full-blown disorder after 2-2.5 years, although to date there are no proper
             tools to predict whoever will evolve this way. At the same time, the scientific debate
             is not unanimous in decreeing any psychotherapeutic or pharmacological intervention of
             first choice to prevent the risk of progression at 6-12 months, highlighting the
             importance of responding to this unmet clinical need by further exploring novel
             therapeutic agents. As such, growing evidence strengthen the therapeutic potential of
             the endocannabinoid (eCB) system modulation. Indeed, the eCB system has not only been
             widely recognised as a mediator of the dopaminergic and glutamatergic systems via the
             cannabinoid receptor 1 (CB1) in the central nervous system (CNS), but also as early
             altered in psychosis. To this end, cannabidiol (CBD) has shown promising results as a
             treatment for both psychosis and CHR, especially by regulating eCBs levels via the
             peroxisome proliferator activated receptors (PPARs). Moreover, recent research has
             focused on the role of eCB-like compounds interacting with non-CB receptors, in order to
             identify novel putative pharmacological targets. Similarly, the gut microbiome
             modulation has been emphasised as a possible therapeutic candidate in the context of
             several mental disorders, such as schizophrenia itself, whose symptom severity seems to
             be correlated to the diversity of the microbiome and gut-brain axis metabolic
             alterations. Intriguingly, the enlarged eCB system, conceived as endocannabinome
             (eCBome), and the intestinal microbiome seem to be strictly intertwined with each other:
             for instance, altered eCB-like compound palmitoylethanolamide (PEA) signaling has been
             shown to be responsible for the link between microbiota diversity and
             anhedonia/amotivation.
  
             Oral PEA supplementation has recently been shown to produce beneficial effects over
             common mental health dimensional constructs as anhedonia/amotivation, which are commonly
             experienced by 15-20% of the general population, as well as promising therapeutic
             results as an adjunctive treatment for patients with schizophrenia negative symptoms and
             acute mania. Interestingly, PEA and other endocannabinoids(eCBs)/acylethanolamines(AEs)
             peripheral blood levels have been proven to be elevated in individuals at CHR for
             psychosis and schizophrenia patients, being modulated further in those with a personal
             history of child maltreatment or substance misuse. Oral PEA has shown well-documented
             safety and tolerability in numerous clinical trials with over 1000 individuals with
             doses 300-1200 mg per day both in healthy and sick populations. Acute oral PEA toxicity
             studies have shown LD50 > 2000 mg/Kg of body weight, while 14- and 90-day repeat dose
             toxicity studies reported its No Observed Adverse Effect Level to be > 1000 mg/Kg of
             weight per day.
  
             Its nature as an endogenous autacoid and essential human diet compound renders PEA
             nearly devoid of known or potential adverse effects.
  
          2. DETAILED DESCRIPTION OF THE PROJECT 2.1. RATIONALE FOR CURRENT STUDY
  
             The main purpose of the present study is to address the absence of an effective
             treatment for subjects at risk for the development of psychosis (clinical high-risk
             (CHR) for psychosis patients), which can be considered a major unmet clinical need for
             this group of patients. We will thus perform an investigator-initiated proof-of-concept
             study (Phase-2 Pilot Study), with the purpose to examine:
  
             (i) Palmitoylethanolamide (PEA) ability to alleviate subtle psychotic and anxiety
             symptoms in CHR patients; (ii) PEA safety and tolerability; (iii) The biological basis
             of PEA effect.
  
             2.2. TRIAL OBJECTIVES
  
             To evaluate:
  
             (i) The viability of identifying and consenting CHR patients into a trial with PEA; (ii)
             The efficacy of PEA in providing relief to attenuated psychotic symptoms (APS) in CHR
             patients; (iii) Whether sustained PEA treatment is well tolerated by CHR patients over a
             period of at least 12 weeks; (iv) The biological mechanisms underpinning PEA beneficial
             effects in CHR patients (e.g., modulation of the endocannabinoid (eCB) system,
             immunological response, metabolic fingerprinting, gut microbiome composition).
  
             - Objective (i)
  
             Feasibility questions:
  
             Over the first 12 months from first patient recruited we will assess whether:
  
             (i) A minimum of 20 eligible patients have consented to be enrolled into the study; (ii)
             At least 80% of recruited patients have completed the 12-week follow-up;
  
             Feasibility endpoints:
  
             (i) Number of subjects giving consent; (ii) Proportion of participants completing the
             12-week follow-up.
  
             - Objective (ii)
  
             Research Questions:
  
             Our primary clinical research question is whether PEA added to treatment as usual in CHR
             patients:
  
             (i) Improves APS;
  
             Our secondary clinical research questions are whether PEA added to treatment as usual
             (TAU) in CHR patients:
  
             (ii) Improves APS to the extent that patients no longer satisfy the diagnostic criteria
             for the CHR state; (iii) Relieves the distress associated with psychotic symptoms; (iv)
             Improves anxiety symptoms; (v) Ameliorates social and role functioning.
  
             Primary endpoints:
  
             Severity of psychotic symptoms as measured using the Comprehensive Assessment of At-Risk
             Mental State (CAARMS).
  
             Secondary endpoints:
  
             (i) Distress associated with psychotic symptoms as measured using the CAARMS; (ii)
             Severity of anxiety symptoms assessed using the Hospital Anxiety and Depression Scale
             (HADS); (iii) The level of impaired global functioning assessed using the Social and
             Role functioning Scale; (iv) Clinical remission, defined as no longer meeting the APS
             criteria; (v) Total CAARMS score. All the study endpoints for the 12-week clinical trial
             will be assessed by comparing follow-up (FUP) visits and baseline. For those
             participants continuing in the 24-week extension phase, change (FUP visit minus
             baseline) in the severity of psychotic symptoms as measured using the CAARMS will be
             compared with the group of those willing to discontinue PEA and continue with TAU.
  
             - Objective (iii)
  
             Safety questions:
  
             We will evaluate if sustained PEA treatment is well tolerated, with minimal
             side-effects.
  
             Safety endpoints:
  
             Incidence of adverse effects during the study period, as measured using the UKU
             side-effect rating scale.
  
             2.3. PARTICIPANTS
  
             - Selection of participants: The proposed single-centre study will involve a university
             clinical research facility in Italy. Participants will be enrolled into the internal
             pilot, that will progress to the open-label trial. Patients who express an interest in
             the study and are identified as having CHR with APS by their clinical teams will be
             approached by study researchers and given a patient information sheet. Those who agree
             to take part in the study will be invited for a screening visit.
  
             - Heterogeneity in CHR: CHR patients are an heterogeneous group, including three
             sub-groups of patients engaged using standardized and internationally recognized CAARMS
             criteria into: (i) APS individuals, (ii) individuals with 'brief limited intermittent
             psychotic symptoms' (BLIPS), and (iii) individuals included in the Vulnerability
             subgroup. Being the present study primarily designed to assess the effect of PEA over
             the symptoms of CHR state and to support clinical homogeneity, we will focus on the
             CHR-APS sub-group of patients, who are the most severely symptomatic, excluding the
             other two groups at the screening stage. CHR-APS patients represent the greatest
             majority (at least 80%) of CHR patients treated by mental health services.
  
             2.4. INTERVENTION
  
             - Trial Medication: Oral Palmitoylethanolamide (PEA; 600 mg per day) in tablet form. PEA
             will be obtained by a pharmaceutical company operating under good manufacturing practice
             conditions with appropriate certification. The information presented on the labels for
             PEA will comply with applicable national and local regulations.
  
             - Dosing Regimen: PEA is to be taken orally once a day (600 mg per day) around mealtime
             during the 12-week initial phase of the study. During the 24-week extension phase of the
             study, the trial medication is to be taken from once a day up to twice a day (600-1200
             mg per day), based on clinical judgment of the improvement obtained so far, around
             mealtime. Each participant will undergo PEA treatment for a maximum of 36 weeks. The
             information presented on the labels for the PEA will comply with applicable national and
             local regulations.
  
             - Medication Risks: Being a food supplement/nutraceutical, PEA can be purchased at
             pharmacies without a medical prescription. While unknown risks cannot be excluded,
             serious adverse events including overdose have not been documented.
  
             - Drug Accountability: Study specific prescriptions can be used for dispensing the study
             product. The study medication can only be prescribed by qualified physicians clearly
             given this role on the study delegation log. Only people designated by the Principal
             Investigator (PI) can collect medication. Only PEA supplied for this study can be
             dispensed against the study specific prescription. Full accountability records will be
             completed including recording the batch, expiry date, people dispensing/checking the
             prescription, quantity and date of drug returns, empty packaging. Nothing is destroyed
             without the authorization from the PI.
  
             - Storage of study medication: PEA will be stored at room temperature (< 25 °C) and not
             kept in a refrigerator, in compliance with local regulations. It will be stored in a
             secure area away from other treatments and clearly marked for this study.
  
             - Removal of study medication outside of expiry date/at trial conclusion and
             destruction: The expiry date will always be reported on the study medication. Study
             medication outside of the expiry date will not be dispensed and will be destroyed,
             subject to authorization, on an ongoing basis.
  
             - Withdrawal of Subjects: According to Declaration of Helsinki, all participants will
             have the right to withdraw from the study at any time without giving any reason, without
             any prejudice to their future medical care, and will be informed as such before consent.
             A participant's withdrawal will be discussed in terms of only discontinuing the study
             treatment and continuing follow-up visits. Should the patient request to completely
             withdraw from the study, the decision will be respected. All reasonable efforts will be
             made to ascertain the reason for discontinuation, even though patients will be not
             obliged to give any explanations. Already collected data will be kept and included in
             the final analysis. The investigator themselves may also withdraw participants for
             various reasons, including but not limited to the following: protocol violations,
             inter-current illness, adverse events, serious adverse events, suspected unexpected
             serious adverse reactions, administrative reasons, participation in the trial affecting
             their ongoing care, symptomatic worsening. In the latter case, patients will be followed
             up with the same schedule of research assessments as those who continue in the study,
             till they complete the 12-week follow-up period or till they progress to frank psychosis
             (whichever is earlier). In case of CHR patients experiencing progression to a first
             episode of psychosis (frank psychosis), they will exit from the study intervention, be
             deemed as treatment failure, and will only be assessed for safety outcomes until they
             complete the 12-week follow-up period.
  
             - Subject Compliance: Pill-counts will be performed at FUP visits 1, 2, 3, and 4, in
             order to assess compliance with PEA treatment. Patients will be defined as complying in
             the presence of a pill count greater than 50% the expected number taken. Patients who
             are defined as non-complying with the medication will be coded as protocol deviators.
  
             - Concomitant Medication: Based on participants' clinical history, concomitant
             requirement of psychotropic medication is an exclusion criterion for the study, with the
             exception of patients undergoing Selective Serotonin Reuptake Inhibitor (SSRI) stable
             monotherapy (at least 8 months). Patients requiring continued treatment with other
             classes of psychotropic medications during the treatment phase may be withdrawn from the
             study by the PI. Very short-term treatment with rescue medications that have a
             well-established sedative or calming effect (e.g., Benzodiazepines) during the study may
             be allowed. Throughout the study, any other concomitant medications or treatments deemed
             necessary to provide adequate supportive care may be prescribed by investigators. A
             record will be kept to list all concomitant medications received during the treatment
             phase.
  
             2.5. VISIT ASSESSMENTS
  
             The following visit assessments will be performed:
  
             - First Screening Visit: This will take place approximately one week prior to the Second
             Screening Visit and two to three weeks prior to the Baseline Visit. First, informed
             consent will be obtained from those who wish to take part to the study. Consenting
             patients will then be screened against the study inclusion and exclusion criteria using
             the CAARMS and collecting information on their medical history and substance use
             information. Individuals satisfying the criteria will be recruited by employed or
             delegated investigators. Also, consent will be obtained on all participants screened to
             collect plasma/serum/urine/fecal samples for routine biochemistry and haematology,
             endocannabinoid, immune, metabolic, and gut microbiome analysis. Consent will be sought
             to analyse screening data as well as regarding long-term follow-up beyond the outcomes
             of the trial and to link participants' data to routinely collected data sources such as
             Hospital Episode Statistics and General Practitioner records.
  
             - Second Screening Visit: This will take place one to two weeks prior to Baseline Visit.
             Safety blood and urine samples (for routine biochemistry and haematology) will be
             obtained, physical examination and vital signs will be recorded.
  
             - Baseline Visit (day 0): Following satisfactory completion of screening, baseline
             measures (CAARMS, HADS, Global Functioning), physical examination, blood, and fecal
             samples for endocannabinome (eCBome), immune, metabolic, and gut microbiota analyses
             will be acquired. Patients will be prescribed PEA and the medication will be dispensed.
             Side effects will also be assessed, by using the UKU side-effect rating scale.
  
             - FUP Visit 1 (Week 4 ± 7 days, approximately day 28): This visit will be carried out at
             Month 1 and involve clinical assessments (CAARMS, HADS, Global Functioning), blood, and
             fecal sampling for eCBome, immune, metabolic, and gut microbiota analyses, monitoring of
             compliance, side effects, adverse events, and dispensing of study drugs.
  
             - FUP Visit 2 (Week 12 ± 14 days, approximately Day 84): This visit will be carried out
             at Month 3 and involve clinical measures (CAARMS, HADS, Global Functioning), physical
             examination, safety blood and urine samples, blood and fecal sampling for eCBome,
             immune, metabolic, and gut microbiota analyses, monitoring of compliance, side effects,
             adverse events, and dispensing of study drugs.
  
             - FUP Visit 3 (Week 24 ± 14 days, approximately Day 168): This visit will be carried out
             at Month 6 on those enrolled in the extension phase and involve clinical assessments
             (CAARMS, HADS, Global Functioning), blood and fecal sampling for eCBome, immune,
             metabolic, and gut microbiota analyses, monitoring of compliance, side effects, adverse
             events, and dispensing of study drugs.
  
             - FUP Visit 4 (Week 36 ± 14 days, at approximately Day 252): This visit will be carried
             out at Month 9 on those enrolled in the extension phase and involve clinical measures
             (CAARMS, HADS, Global Functioning), physical examination, safety blood and urine
             samples, blood and fecal sampling for eCBome, immune, metabolic, and gut microbiota
             analyses, monitoring of compliance, side effects, adverse events, and dispensing of
             study drugs.
  
             - Laboratory Tests: Clinical Laboratory measures: blood tests for haematology (Full
             blood count and Haemoglobin), biochemistry (Urea & Electrolytes, liver function test,
             lipid profile), and immune profile characterization will be carried out at the clinical
             research recruitment hub as per their standard procedure. Blood results will be printed
             and filed as source in the patient folder. Serum samples for performing metabolic
             fingerprinting by Raman Spectroscopy, as well as blood and fecal samples for measurement
             of the levels of eCBome mediators and determination of the microbial composition in
             feces by Next Generation Sequencing (NGS) of 16SRNA and shotgun metagenomics
             methodologies, will be shipped to counseling specialized centers where they will be
             stored and analysed.
  
             2.6. SAMPLE SIZE
  
             - Proposed sample size: We aim at enrolling 20 patients within 12 months from the start
             of recruitment.
  
             - Sample size justification: The number is coherent with suggested sample sizes for
             pilot studies and is deemed sufficient to evaluate feasibility outcomes. No powered
             sample size calculation was implemented for the pilot study.
  
             2.7. METHODS - Data collection, management and archiving: Assessment and collection of
             baseline, outcome and other trial data will be performed according to Visit assessments
             flow-chart. In case of trial intervention discontinuation, follow-up data will be
             collected anyway, unless a participant expresses the wish to be completely withdrawn
             from the study. All data source will be held on as a paper source data worksheet (SDW).
             These will be managed locally under the care of the recruiting and consenting site PI.
             Collected data will be held on paper SDW which will be thereafter recorded by allowed
             study team members on a 24-hour-accessible electronic-based data entry system hosted by
             the clinical research recruitment hub at ASUFC and University of Udine, consenting data
             entry to run in parallel with participant enrolment and visits. At the conclusion of the
             trial the study team will have resolved the data queries and request to remove user
             access to ensure that the final dataset cannot be changed. SDWs, electronic-based data,
             and the final statistical report will be archived. Systems will be in place to secure
             the data collection system against permanent loss and allow the recovery and restoration
             in the event of such a loss occurring.
  
             - Data verification, statistical monitoring and analysis: At the study start, a
             structured data verification plan will be agreed and developed by the Head Statistician
             of the research team. Data will be checked for consistency across paper- and
             electronic-based entry systems. Statistical monitoring will include patient severity
             level, eventual withdrawals, baseline data, FUP visits data, and AEs. The research team
             will approve a Statistical Analysis Plan within the early stages of the study, and
             before the Head Statistician summarizes any data. Proportions will be presented for each
             feasibility outcome. Interim analyses are not planned. The Head Statistician will both
             carry out and interpret statistical analysis. Our primary analysis will involve a
             generalized linear model with CAARMS psychotic symptom severity as the dependent measure
             and time as a repeated measure within subject. We are interested in whether there is a
             significant benefit over time with PEA treatment. CAARMS distress and total score as
             well as HADS ratings will be analysed in a similar manner. We will also conduct paired t
             tests based on baseline and endpoint assessments to examine measures of CAARMS severity
             and secondary measures. Rates of side effects will be reported, as well as reasons for
             dropouts from the trial.
  
             - Missing Data: We expect withdrawn patients to be missing at random, and very few
             participants withdrawing consent. All patients having at least one post-baseline outcome
             measure, would be included in each analysis. Nonetheless, patterns of missing data will
             be explored to investigate any evidence against missing at random, whose impact on the
             analysis will be considered by introducing imputation methods.
  
             2.8. ETHICS
  
             - Ethics & Regulatory Approvals: The trial will be conducted in accordance with the
             principles of the Declaration of Helsinki (1996), the principles of Good Clinical
             Practice (GCP), and with all applicable regulatory requirements. This protocol and
             related documents will be submitted for review to the local Research Ethics Committee
             (REC).
  
             - Consent Prior to Screening: Those expressing interest into the study will be referred
             to the clinical research recruitment hub by their consultants. At screening,
             investigators will introduce the trial and provide the patients with exhaustive Patient
             Information Sheets (PIS). Allowed qualified physicians will discuss the trial with
             patients in light of the information provided in the PIS and give appropriate time for
             the participants to understand the information provided, before asking written informed
             consent from those willing to take part to the trial.
  
             - Biological Samples: The collection of routine blood samples, urine samples, fecal
             samples, and genotyping will be specifically addressed through the collection of ad hoc
             consent for biological materials. After collection at the research recruitment hub,
             obtained blood samples for haematology, biochemistry, and Immune profile
             characterization will be delivered by the study research team to the local laboratory
             for analysis. Blood and fecal samples collected to perform metabolic fingerprinting,
             measurement of the levels of eCBome mediators, and determination of the microbial
             composition, will be stored in local facilities under adequate conditions (-80°C) and
             then shipped to counseling specialized centers for subsequent analysis.
  
             2.9. CONFIDENTIALITY All study-related information will be stored securely at the study
             site. All participant information will be stored in locked file cabinets in areas with
             limited access. All laboratory specimens, reports, data collection, process, and
             administrative forms will be identified by a coded identification (ID) number only to
             maintain participant confidentiality. All records that contain names or other personal
             identifiers, such as locator forms and informed consent forms, will be stored separately
             from study records identified by code number. All local databases will be secured with
             password-protected access systems. Forms, lists, logbooks, appointment books, and any
             other listings that link participant ID numbers to other identifying information will be
             stored in a separate, locked file in an area with limited access. Participants' study
             information will not be released outside of the study without the written permission of
             the participant.
  
          3. INTEREST FOR THE ADVANCEMENT OF KNOWLEDGE AND RISK/BENEFIT CONSIDERATIONS It is not
             unusual in clinical practice that patients feel that their current treatments, either
             psychological or pharmacological, result in suboptimal improvements. They also express
             growing interest in trying nutraceutical or alternative treatments. In recent times,
             growing interest has been aroused regarding the therapeutic potential of
             endocannabinoid-like compounds. This is particularly relevant for Clinical High-Risk
             (CHR) for psychosis patients where no established treatment is available. Thus,
             identifying novel safe and tolerable treatments is recognised as a key priority to
             relieve these patients' and their families' sufferings, even more so if compared to
             traditional psychotropic therapies often not devoid of unpleasant side effects. Besides,
             the involvement of youths who manifest sub-threshold symptoms not reaching criteria for
             the diagnosis of a full-blown psychotic disorder, raises concerns about the use of
             conventional anti-psychotics, from both a forensic and an ethical perspective. The trial
             objective will be pursued with minimal risks for study participants, considering that
             Palmitoylethanolamide (PEA) is a well-established nutraceutical for sustained medical
             treatment in humans, and serious adverse events have not been documented. No invasive
             assessment techniques will be implemented throughout the whole study.
  
          4. DISSEMINATION POLICY The results of the study are intended to be reported and
             disseminated at national/international conferences and in peer-reviewed scientific
             journals. Our objective is to submit for publication the main results of the trial
             within two years of last patient recruitment.
  allocation: N/A
  intervention model: Single Group Assignment
  intervention model description: We will evaluate the study viability through an internal pilot that will assess the ability of the study to identify, consent, and follow up CHR patients experiencing APS in the study. We propose a 12-week, open-label, investigator-initiated proof of concept study (Phase-2 Pilot Study) of PEA (600 mg/day) for the treatment of APS in CHR patients. We plan to enrol 20 CHR young adults. Those completing the 12-week initial phase, will be proposed to enter a 24-week extension phase to evaluate the clinical stability of treatment, with the possibility of PEA titration to 1200 mg/day based on clinical improvement obtained so far.
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Severity of attenuated psychotic symptoms (APS) as measured using the Comprehensive Assessment of At-Risk Mental State (CAARMS)
  time frame: 12 weeks for the initial phase, further 24 weeks for the extension phase
  measure: Distress associated with psychotic symptoms as measured using the CAARMS
  time frame: 12 weeks for the initial phase, further 24 weeks for the extension phase
  measure: Severity of anxiety symptoms assessed using the Hospital Anxiety and Depression Scale (HADS)
  time frame: 12 weeks for the initial phase, further 24 weeks for the extension phase
  measure: The level of impaired global functioning assessed using the Social and Role functioning Scale
  time frame: 12 weeks for the initial phase, further 24 weeks for the extension phase
  measure: Clinical remission, defined as no longer meeting the APS criteria
  time frame: 12 weeks for the initial phase, further 24 weeks for the extension phase
  measure: Total CAARMS score
  time frame: 12 weeks for the initial phase, further 24 weeks for the extension phase
  measure: Safety endpoints: Incidence of adverse effects during the study period, as measured using the UKU side-effect rating scale
  time frame: 12 weeks for initial phase, further 24 weeks for extension phase
  arm group label: Single arm: palmitoylethanolamide (PEA)-treated patients
  arm group type: Experimental
  intervention type: Dietary Supplement
  intervention name: Ultra-micronized Palmitoylethanolamide (PEA)
  description: Palmitoylethanolamide (PEA) is an N-acylethanolamine (AE), produced "on demand" by different cell types as a response to actual or potential damage, proven to down-regulate central and peripheral activity of mast cells and non-neuronal cells (e.g., astrocytes, microglia) and to exert protective functions against glutamate neuro-toxicity, accounting for its naturally-occurring anti-inflammatory, analgesic, and anticonvulsant properties. Due to the shared pharmacodynamic properties, PEA is considered as the endogenous equivalent of Cannabidiol (CBD). A growing body of literature has confirmed the role of PEA in most neurobiological mechanisms underpinning several neuropsychiatric conditions both in clinical and preclinical settings. The effect of PEA over neuroinflammation and glutamate signaling may represent a promising biobehavioral mechanism underlying the clinical utility of its oral supplementation in CHR state.
  arm group label: Single arm: palmitoylethanolamide (PEA)-treated patients
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 35 Years
  healthy volunteers: No
  last name: Marco Colizzi, MD, PhD
  phone: +390432559155
  email: marco.colizzi@uniud.it
  last name: Riccardo Bortoletto, MD
  phone: +393484739255
  email: bortoletto.riccardo@spes.uniud.it
  facility: 
  status: Recruiting
  contact: 
  contact backup: 
  investigator: 
  investigator: 
  facility: 
  status: Recruiting
  contact: 
  country: Italy
  url: https://www.frontiersin.org/articles/10.3389/fpsyt.2023.1231710/full
  description: Questioning the role of palmitoylethanolamide in psychosis: a systematic review of clinical and preclinical evidence
  url: https://www.frontiersin.org/articles/10.3389/fpsyt.2022.1038122/full
  description: Therapeutic effect of palmitoylethanolamide in cognitive decline: A systematic review and preliminary meta-analysis of preclinical and clinical evidence
  url: https://www.mdpi.com/2076-3425/12/1/101
  description: Is It Time to Test the Antiseizure Potential of Palmitoylethanolamide in Human Studies? A Systematic Review of Preclinical Evidence
  url: https://www.mdpi.com/2072-6643/13/4/1346
  description: Palmitoylethanolamide and Its Biobehavioral Correlates in Autism Spectrum Disorder: A Systematic Review of Human and Animal Evidence
  url: https://www.nature.com/articles/tp201215
  description: Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia
  url: https://www.cambridge.org/core/journals/psychological-medicine/article/abs/childhood-trauma-and-being-atrisk-for-psychosis-are-associated-with-higher-peripheral-endocannabinoids/BFFDA252EF2250C2F2B45786CC152CDC
  description: Childhood trauma and being at-risk for psychosis are associated with higher peripheral endocannabinoids
  responsible party type: Sponsor
  mesh term: Psychotic Disorders
  mesh term: Mental Disorders
  mesh term: Palmidrol