Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT06187090 |
| Other study ID # |
IRB-DAME 188/2023 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
September 1, 2023 |
| Est. completion date |
November 2026 |
Study information
| Verified date |
December 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
In addition to the "core" symptoms of ASD (i.e., impaired communication, impaired reciprocal
social interaction and restricted, repetitive and stereotyped patterns of behaviors or
interests), it is estimated that up to 70% of autistic people present at least one comorbid
psychiatric disorder, leading to a deterioration in quality of life, a greater demand for
support and worse prognosis and outcome. Anxiety and depressive symptoms would seem to be
more present in individuals with Level 1 ASD, requiring their prioritisation against core
symptoms. To date, the first-line treatment for autistic patients with comorbid depressive
and/or anxiety symptoms is still debated and it is not always clear whether they may or may
not benefit from psychotherapeutic and conventional psychopharmacological approaches. As
such, growing evidence strengthens the therapeutic potential of the endocannabinoid (eCB)
system modulation and of eCB-like compounds.
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 symptoms of psychic
distress (i.e., anxiety and/or depression) in Level 1 autistic adults; the safety and
tolerability of sustained intake of PEA in Level 1 autistic adults; 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. RATIONALE FOR CURRENT STUDY
The main purpose of the present study is to address a major unmet clinical need for
Level 1 autistic individuals with comorbid anxiety and/or depressive symptoms, with
respect to a condition of psychic vulnerability not responding to conventional
psychopharmacological approaches. 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 symptoms of psychic distress (i.e.,
anxiety and/or depression) in Level 1 autistic individuals; (ii) PEA safety and
tolerability; (iii) The biological basis of PEA effect.
2. TRIAL OBJECTIVES
To evaluate:
(i) The viability of identifying and consenting Level 1 autistic volunteers into a trial
with PEA; (ii) The efficacy of PEA in providing relief to anxiety and/or depressive
symptoms in Level 1 autistic individuals; (iii) Whether sustained PEA treatment is well
tolerated by Level 1 autistic individuals over a period of at least 12 weeks; (iv) The
biological mechanisms underpinning PEA beneficial effects in Level 1 autistic
individuals (e.g., modulation of the endocannabinoid (eCB) system, immunological
response, metabolic fingerprinting, gut microbiome composition).
2.1. Objective (i) Feasibility questions
Over the first 12 months from first patient recruited we will assess whether:
(i) A minimum of 20 eligible volunteers 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.
2.2. Objective (ii) Research Questions
Our primary clinical research question is whether PEA added to treatment as usual (TAU)
in Level 1 autistic individuals:
(i) Improves psychic distress (i.e., anxiety and depressive symptoms) to the extent of
impacting on levels of self-sufficiency;
Our secondary clinical research questions are whether PEA added to TAU in Level 1
autistic individuals:
(ii) Reduces the intensity of anxiety and/or depressive symptoms, with particular
regards to the subdomains of somatisation, anxiety and depression; (iii) Improves
interpersonal and neurocognitive functioning. Primary endpoints Assessing the global
improvement in symptom intensity and psychological distress associated with autism
through the Global Score Index (GSI) of the SCL-90-R.
Secondary endpoints (i) Impact on levels of personal autonomy as measured through the
WHODAS 2.0 total score.
(ii) Severity of anxiety symptoms as assessed using the Hospital Anxiety and Depression
Scale (HADS) and the somatisation, anxiety and depression subscales of the SCL-90-R;
(iii) Severity of neurocognitive and interpersonal functioning as assessed using the
subdomains 1 'cognitive activities' and 4 'interpersonal relationships' of the WHODAS
2.0.
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 symptom intensity and
psychological distress associated with autism as measured through the GSI of the
SCL-90-R and the impact on levels of personal autonomy measured through the WHODAS 2.0
total score will be compared with the group of those willing to discontinue PEA and
continue with TAU.
2.3. 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.
3. TRIAL DESIGN We will evaluate the study viability through an internal pilot that will
assess the ability of the study to identify, consent, and follow up Level 1 autistic
volunteers experiencing anxiety and/or depressive symptoms 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 psychic distress (i.e., sub-threshold anxiety
and/or depressive symptoms) in Level 1 autistic individuals. We plan to enrol 20 young
adults diagnosed with Autism Spectrum Disorder (ASD). 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.
4. PARTICIPANTS 4.1. 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. Volunteers who
express an interest in the study and are identified as having Level 1 autistic
individuals with comorbid anxiety and/or depressive symptoms 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.
4.2. Heterogeneity in autism spectrum disorder ASD comprises three subgroups of patients
based on the severity of symptoms whose classification is based on impairment of social
communication and restricted, repetitive behaviour patterns: (i) Level 1 'Support is
needed', (ii) Level 2 "Significant support is needed", (iii) Level 3 "Very significant
support is needed very significant support'. As the present study was designed to assess
the effect of PEA on mentally fragile conditions with interference in the global
functioning of autistic individuals, we will focus on subjects with severity level 1,
more affected by depressive and anxious symptoms than autistic subjects with higher
levels of impairment, requiring a prioritisation of these manifestations compared to
core symptoms. Symptoms of psychological distress in ASD individuals, below the
threshold of clinical criteria for the diagnosis of a full-blown psychiatric disorder
and not requiring the introduction of conventional psychotropic medications, are
nevertheless often deserving of an intervention to support their well-being.
5. INTERVENTION 5.1. 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.
5.2. 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.
5.3. 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.
5.4. 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.
5.5. 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
5.6. 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.
5.7. 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 participants 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, participants 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
psychiatric disturbance (whichever is earlier). In case of autistic individuals
experiencing progression to a full-blown psychiatric disorder, 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.
5.8. Subject Compliance Pill-counts will be performed at FUP visits 1, 2, 3, and 4, in
order to assess compliance with PEA treatment. Participants will be defined as complying
in the presence of a pill count greater than 50% the expected number taken. Participants
who are defined as non-complying with the medication will be coded as protocol
deviators.
5.9. 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.
6. VISIT ASSESSMENTS
The following visit assessments will be performed:
6.1. 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 and collecting information on their medical history. 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.
6.2. 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.
6.3. Baseline Visit (day 0) Following satisfactory completion of screening, baseline
measures (SCL-90-R, HADS, WHODAS-2.0), physical examination, blood, and fecal samples
for endocannabinome (eCBome), immune, metabolic, and gut microbiota analyses will be
acquired. Participants will be prescribed PEA and the medication will be dispensed. Side
effects will also be assessed, by using the UKU side-effect rating scale.
6.4. FUP Visit 1 (Week 4 ± 7 days, approximately day 28) This visit will be carried out
at Month 1 and involve blood and fecal sampling for eCBome, immune, metabolic, and gut
microbiota analyses, monitoring of compliance, side effects [39], adverse events, and
dispensing of study medication.
6.5. FUP Visit 2 (Week 12 ± 14 days, approximately Day 84) This visit will be carried
out at Month 3 and involve clinical measures (SCL-90-R, HADS, WHODAS-2.0), 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 medication.
6.6. 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, blood and fecal
sampling for eCBome, immune, metabolic, and gut microbiota analyses, monitoring of
compliance, side effects [39], adverse events, and dispensing of study medication.
6.7. 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 (SCL-90-R, HADS, WHODAS-2.0), 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 medication.
6.8. 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 (e.g., Institute of
Biomolecular Chemistry, Department of Chemical Sciences and Materials Technologies,
National Research Council (CNR) Pozzuoli, Italy) where they will be stored and analysed.
7. SAMPLE SIZE 7.1. Proposed sample size We aim at enrolling 20 volunteers 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.
8. METHODS 8.1. 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.
8.2. 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 the subject's
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 SCL-90-R 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. WHODAS-2.0 and 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 SCL-90-R severity and
secondary measures. Rates of side effects will be reported, as well as reasons for
dropouts from the trial.
8.3. Missing Data We expect withdrawn participants to be missing at random, and very few
participants withdrawing consent. All participants 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.
9. ETHICS 9.1. Ethics & Regulatory Approvals The trial will be conducted in accordance with
the principles of the Declaration of Helsinki (1996) [48, 49], the principles of Good
Clinical Practice (GCP) [50], and with all applicable regulatory requirements. This
protocol and related documents will be submitted for review to the local Research Ethics
Committee (REC).
9.2. 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.
9.3. 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 (e.g., Institute of Biomolecular
Chemistry, Department of Chemical Sciences and Materials Technologies, National Research
Council (CNR) Pozzuoli, Italy) for subsequent analysis.
10. 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.
11. INSURANCE POLICY INFORMATION We did not deem it necessary to arrange a specific
insurance policy for the present study. Any allergic reactions to PEA or unexpected
adverse effects will be monitored when PEA is first administered at the Day Hospital
service, which provides insurance coverage for patients admitted and undergoing
non-invasive procedures as part of clinical routine.
12. 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.
