Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT06037993 |
| Other study ID # |
IRB-DAME 93/2023 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
November 1, 2022 |
| Est. completion date |
November 2025 |
Study information
| Verified date |
September 2023 |
| Source |
University of Udine |
| Contact |
Marco Colizzi, MD, PhD |
| Phone |
+390432559155 |
| Email |
marco.colizzi[@]uniud.it |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Clinical High-Risk (CHR) for Psychosis is characterized by the occurrence of unusual
stressful experiences (attenuated psychotic symptoms, APS), anxious symptoms, 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. To date, no psychotherapeutic or pharmacological approaches have
shown therapeutic evidence in this group of patients.
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 APS, anxiety, and
psychic distress in CHR-APS individuals; the safety and tolerability of sustained intake of
PEA in CHR-APS individuals; and the biological basis of PEA functioning.
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, subjects 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.
Description:
1. STATE OF THE ART Among clinical high-risk (CHR) for psychosis individuals, 30-35 % will
develop a full-blown disorder after 2-2.5 years. To date there are no proper tools to
predict whoever will evolve to full-blown psychosis nor first-choice interventions to
prevent the risk of progression at 6-12 months. The endocannabinoid (eCB) system stands
as a mediator of the dopaminergic and glutamatergic systems via the cannabinoid receptor
1 (CB1) in the central nervous system (CNS) and seems to be early altered in psychosis.
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). Recent research has focused on the role of eCB-like compounds interacting with
non-CB receptors, to identify novel putative pharmacological targets. To this extent,
oral palmitoylethanolamide (PEA) supplementation has shown promising therapeutic effects
as an adjunctive treatment for patients with schizophrenia negative symptoms and acute
mania. Interestingly, PEA peripheral blood levels are elevated in CHR individuals and
schizophrenia patients. Oral PEA has shown well-documented safety and tolerability in
numerous clinical trials with doses 300-1200 mg per day both in healthy and sick
populations. 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 CHR individuals. We will perform an investigator-initiated
proof-of-concept study (Phase-2 Pilot Study), with the purpose to examine:
(i) 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 CHR; (iii) Relieves the distress associated with APS; (iv) Improves anxiety
symptoms; (v) Improves social and role functioning. 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
Comprehensive Assessment of At-Risk Mental State (CAARMS) will be compared with the
group of those willing to discontinue PEA.
- Objective (iii) Safety questions: We will evaluate if sustained PEA treatment is
well tolerated, with minimal side-effects.
2.3. PARTICIPANTS
- Selection of participants: The proposed 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: 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 will be prescribed by qualified physicians 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. 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, 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, 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, except
for 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 listing all concomitant medications received during the treatment phase.
2.5. VISIT ASSESSMENTS
The following visit assessments will be performed:
- First Screening Visit: Approximately one week prior to the Second Screening Visit
and two to three weeks prior to the Baseline Visit. 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
hematology, endocannabinoid, immune, metabolic, and gut microbiome analysis.
Consent will be sought to analyze 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: One to two weeks prior to Baseline Visit. Safety blood and
urine samples (for routine biochemistry and hematology) 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): 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: Blood tests for hematology (Full blood count and Hemoglobin),
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 analyzed.
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. 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.
