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PEA vs. Placebo for Major Depression (PEA-01)

Primary Purpose

Bipolar Depression, Major Depressive Disorder

Status
Recruiting
Phase
Phase 2
Locations
Moldova, Republic of
Study Type
Interventional
Intervention
Palmitoylethanolamide
Sponsored by
The Israeli Medical Center for Alzheimer's
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Bipolar Depression

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Meet DSM V criteria for a Major Depressive Episode, with or without a diagnosis of Bipolar I or Bipolar II disorder. Between 18-65 years of age, male or female subjects of any race. Able to provide informed consent. All participant patients must have signed an informed consent document indicating they understand the purpose of the study and are willing to complying with the study procedures and restrictions. Have a MADRS above 20 and an YMRS < 12. Inpatients or outpatients at the discretion of the investigator. Live with a caregiver or have a relative/close friend who is in contact with them at least twice a week via phone. Exclusion Criteria: Diagnosis of schizophrenia or schizoaffective disorder Women of child-bearing potential who do not practice contraception. Women who are pregnant or breast-feeding. Psychotic symptoms during the 2 weeks preceding the baseline day. Failure of three or more antidepressant treatment trials. Unstable medical disease (malignancy, poorly controlled diabetes, or cardiomyopathy, serious pulmonary disease, kidney disease, impaired liver functioning. Particular attention should be given to exclude patients with ischemic heart disease). Has a clinically significant abnormal 12-lead electrocardiogram (ECG) at the Screening Visit, as determined by the Investigator. At significant risk of committing suicide, or in the opinion of the Investigator, currently is at imminent risk of suicide or harming others. Patients with a current DSM-V substance or alcohol dependence. Concurrent delirium, mental retardation, drug-induced psychosis.

Sites / Locations

  • State University of Medicine and Pharmacy " Nicolae Testemitsanu"Recruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Palmitoylethanolamide 1200 mg

Matching placebo

Arm Description

Dose: PEA 1200 mg given in 300 mg capsules (2 capsules twice daily) Route of administration: oral Duration and frequency: study medication will be provided to patients in bottles every two weeks for the duration of the study (three dispensations). Formulation: PEA Dosing scheme: Patients will be instructed to take two capsules twice daily for the 42 days of the study.

2 capsules twice daily identical to study arm. Route of administration: oral Duration and frequency: pills will be provided to patients in bottles every two weeks for the duration of the study (three dispensations). Formulation: placebo in identical capsules. Dosing scheme: Patients will be instructed to take two capsules twice daily for the 42 days of the study.

Outcomes

Primary Outcome Measures

Hamilton Depression Rating Scale (HAM-D)
Depression Scale

Secondary Outcome Measures

Clinical Global Impressions-Severity-Bipolar Scale or Clinical Global Impressions-Severity-Depression
Scale for Overall Bipolar Depression and Unipolar Depression severity
Hamilton Anxiety Rating Scale (HAM-A)
Anxiety Scake
Plasma measures including Allo and pregnanolone, their isomers, the sulfated congeners (pregnanolone sulphate and Allo sulphate)
neurosteroids
DHEA
measured with the state-of-the-art methodology gas chromatography mass spectrometry (GC-MS).
BDNF
Brain-derived neurotrophic factor
CRP
C-Reactive Protein
TLR-4
Toll-like Receptor 4
Cytokines
Inflammatory markers

Full Information

First Posted
March 23, 2023
Last Updated
September 26, 2023
Sponsor
The Israeli Medical Center for Alzheimer's
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1. Study Identification

Unique Protocol Identification Number
NCT06063369
Brief Title
PEA vs. Placebo for Major Depression
Acronym
PEA-01
Official Title
Palmitoylethanolamide (PEA) vs Placebo for Major Depression: a Phase II Exploratory Study
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 21, 2022 (Actual)
Primary Completion Date
December 21, 2023 (Anticipated)
Study Completion Date
December 21, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
The Israeli Medical Center for Alzheimer's

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Major Depression is often resistant to treatment, and all of the currently marketed anti-depressants can cause significant side effects and may precipitate mania. The aim of this proposal is to perform a proof-of-concept RCT testing Palmitoylethanolamide (PEA) as a treatment for unipolar or bipolar depression, randomizing 100 patients to 6-week treatment with PEA 1200 mg/d or matching placebo. There are several rationales for this study: (A) PEA acts at the peroxisome proliferator-activated receptor-alpha (PPAR-α), stimulating Allo biosynthesis. Allo is an endogenous, positive allosteric modulator of GABA-A receptors in glutamatergic neurons, including cortical and hippocampal pyramidal glutamatergic neurons and may be one of the endogenous regulators of depression and anxiety. (B) Sage Therapeutics has developed Allo which is FDA approved to treat post-partum depression, and is testing a molecular modification which can be administered orally for post-partum depression and unipolar depression, with mixed efficacy results. Pregnenolone, a precursor of neurosteroids, has also been reported to improve bipolar depression. Based on animal models, PEA increases Allo synthesis in areas of the brain thought to be involved in anxiety and depression. It may also favor the biosynthesis of sulfated forms of Allo and congeners that inhibit tonic rather than phasic NMDA-mediated excitatory neurotransmission. Showing that PEA-induced selective inhibition of tonic NMDA neurotransmission improves depression might enable development of steroid-based NMDA-inhibitor therapeutics. In addition, PEA-induced Allo upregulation potentiates GABA-A receptor-mediated inhibition. The NMDA and the GABAergic mechanisms may act in concert to improve behavioral outcomes. Since PEA increases Allo in the brain where it is endogenously formed, it might be more effective compared with exogenous administration, which is not site specific. There is evidence of a role of inflammation in depression; PEA has potent immunoregulatory and anti-inflammatory effects by directly activating PPAR-α, which has a protective role against neuroinflammation by inhibiting the signaling mediated by toll-like receptor 4.There is one published study which shows that PEA has an antidepressant effect in unipolar depression, 58 patients were randomized to receive 1200 mg/d of PEA or placebo added-on to citalopram, showing clinical improvements in patients receiving PEA.
Detailed Description
This is a multi-center, 6-week, randomized, double blind, placebo-controlled clinical trial of PEA vs. placebo in patients with unipolar or bipolar disorder who are currently in a Major Depressive Episode (MDE). PEA or placebo will be administered as monotherapy and any antidepressant, mood stabilizer or antipsychotic medication will be tapered down starting from the randomization day. The tapering process will be of one week, except for fluoxetine which will be tapered for a duration of two weeks. At the screening visit, after signing the informed consent form, patients will be assessed using the MINI. MADRS and YMRS will be assessed for inclusion/exclusion criteria. Demographic information will be collected, psychiatric and medical history obtained, physical examination including height and weight, blood pressure and pulse rate will be performed. Blood samples for biochemistry analyses and CBC, and urine samples for urinalysis will be taken. Females of child-bearing potential will be tested for pregnancy. An ECG will be performed. Blood for neurosteroids and other biomarkers will be taken, processed to separate plasma from PBMC and stored, to be sent later to the laboratory of Dr. Pinna. The baseline visit will be performed up to 7 days after screening. MADRS, CGI-BP/CGI-D, HAM-A and HAM-D will be collected. The use of concomitant medications as well as Adverse Events will be recorded throughout the study. Patients will be randomized to start study medication. The clinical questionnaires will be administered 2, 4 and 6 (End-of study, EOS) weeks after baseline. Biomarker analyses, including plasma neurosteroid and BDNF levels will be measured at baseline, and at the week 6 (EOS) visit. Concomitant medications and adverse events, as well as any other clinical change will be monitored through phone visits which will take place twice weekly on weeks 1, 3 and 5. Study medication will be manufactured by Innexus Nutraceuticals in the Netherlands according to GMP, and will then be sent to Micronisierungs-Kontor Oberrot GmbH in Germany for micronization. The micronized compound will then be sent to PharmaMed Inc. in Pennsylvania, USA for packaging and labelling. Study medication will be randomized according to a computerized list supplied by the investigators to Innexus Nutraceuticals and PharmaMed Inc. Randomization of patients will be sequential. Kits will be kept in one central site, and after randomization patients from other site will be supplied with the kits. Concomitant medication: After the screening visit, patients will start a tapering process for all antidepressant/antipsychotic/mood stabilizer. The tapering process will be of one week, except for fluoxetine which will be tapered for a duration of two weeks. Rescue Medication: Up to 3 mg/day of lorazepam will be allowed as rescue medication in case of clinical deterioration, based on clinician's judgment. Laboratory: Quantification of Allo and congeners, and PEA will performed by the state-of-the-art technology, GC-MS. The methodology to determine neurosteroid levels is a technique developed in Dr Pinna's lab (HPLC combined with GC-MS quantification), which allows the simultaneous determination of various neurosteroids from a single sample due to molar sensitivity and unsurpassed structural specificity.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bipolar Depression, Major Depressive Disorder

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Phase II - Randomized, double blind, placebo-controlled, parallel group clinical trial.
Masking
ParticipantInvestigator
Masking Description
Double-Blind
Allocation
Randomized
Enrollment
100 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Palmitoylethanolamide 1200 mg
Arm Type
Experimental
Arm Description
Dose: PEA 1200 mg given in 300 mg capsules (2 capsules twice daily) Route of administration: oral Duration and frequency: study medication will be provided to patients in bottles every two weeks for the duration of the study (three dispensations). Formulation: PEA Dosing scheme: Patients will be instructed to take two capsules twice daily for the 42 days of the study.
Arm Title
Matching placebo
Arm Type
Placebo Comparator
Arm Description
2 capsules twice daily identical to study arm. Route of administration: oral Duration and frequency: pills will be provided to patients in bottles every two weeks for the duration of the study (three dispensations). Formulation: placebo in identical capsules. Dosing scheme: Patients will be instructed to take two capsules twice daily for the 42 days of the study.
Intervention Type
Drug
Intervention Name(s)
Palmitoylethanolamide
Other Intervention Name(s)
PEA
Intervention Description
Dose: PEA 1200 mg given in 400 mg capsules (3 capsules per day) or Placebo Route of administration: oral Duration and frequency: study medication will be provided to patients in bottles every two weeks for the duration of the study (three dispensations). Formulation: PEA and placebo in identical capsules. Dosing scheme: Patients will be instructed to take two capsules twice daily for the 42 days of the study.
Primary Outcome Measure Information:
Title
Hamilton Depression Rating Scale (HAM-D)
Description
Depression Scale
Time Frame
6 weeks trial
Secondary Outcome Measure Information:
Title
Clinical Global Impressions-Severity-Bipolar Scale or Clinical Global Impressions-Severity-Depression
Description
Scale for Overall Bipolar Depression and Unipolar Depression severity
Time Frame
6 weeks trial
Title
Hamilton Anxiety Rating Scale (HAM-A)
Description
Anxiety Scake
Time Frame
6 weeks trial
Title
Plasma measures including Allo and pregnanolone, their isomers, the sulfated congeners (pregnanolone sulphate and Allo sulphate)
Description
neurosteroids
Time Frame
6 weeks trial
Title
DHEA
Description
measured with the state-of-the-art methodology gas chromatography mass spectrometry (GC-MS).
Time Frame
6 weeks trial
Title
BDNF
Description
Brain-derived neurotrophic factor
Time Frame
6 weeks trial
Title
CRP
Description
C-Reactive Protein
Time Frame
6 weeks trial
Title
TLR-4
Description
Toll-like Receptor 4
Time Frame
6 weeks trial
Title
Cytokines
Description
Inflammatory markers
Time Frame
6 weeks trial

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Meet DSM V criteria for a Major Depressive Episode, with or without a diagnosis of Bipolar I or Bipolar II disorder. Between 18-65 years of age, male or female subjects of any race. Able to provide informed consent. All participant patients must have signed an informed consent document indicating they understand the purpose of the study and are willing to complying with the study procedures and restrictions. Have a MADRS above 20 and an YMRS < 12. Inpatients or outpatients at the discretion of the investigator. Live with a caregiver or have a relative/close friend who is in contact with them at least twice a week via phone. Exclusion Criteria: Diagnosis of schizophrenia or schizoaffective disorder Women of child-bearing potential who do not practice contraception. Women who are pregnant or breast-feeding. Psychotic symptoms during the 2 weeks preceding the baseline day. Failure of three or more antidepressant treatment trials. Unstable medical disease (malignancy, poorly controlled diabetes, or cardiomyopathy, serious pulmonary disease, kidney disease, impaired liver functioning. Particular attention should be given to exclude patients with ischemic heart disease). Has a clinically significant abnormal 12-lead electrocardiogram (ECG) at the Screening Visit, as determined by the Investigator. At significant risk of committing suicide, or in the opinion of the Investigator, currently is at imminent risk of suicide or harming others. Patients with a current DSM-V substance or alcohol dependence. Concurrent delirium, mental retardation, drug-induced psychosis.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Igor Nastas, Dr
Phone
+37367133770
Email
igornastas@yahoo.com
First Name & Middle Initial & Last Name or Official Title & Degree
Mark Prof Weiser, Professor
Phone
972-526666570
Email
Mark.weiser@sheba.health.gov.il
Facility Information:
Facility Name
State University of Medicine and Pharmacy " Nicolae Testemitsanu"
City
Chișinău
Country
Moldova, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Igor Nastas, Dr
Phone
+37367133770
Email
igornastas@yahoo.com
First Name & Middle Initial & Last Name & Degree
Mark Weiser, Professsor
First Name & Middle Initial & Last Name & Degree
Igor Nastas, Doctor

12. IPD Sharing Statement

Plan to Share IPD
No

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PEA vs. Placebo for Major Depression

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