Bipolar DepressionPhase 2PEA-01NCT06063369
PEA vs. Placebo for Major Depression
A Phase 2 study testing Palmitoylethanolamide in people with Bipolar Depression and Major Depressive Disorder, run by The Israeli Medical Center for Alzheimer's at 1 site in Moldova.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Bipolar Depression, Major Depressive Disorder
- What is being tested?
- Palmitoylethanolamide
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 100 participants
- Where
- 1 siteMoldova
- Study dates
- 21 Dec 2022to 21 Dec 2024
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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).
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- 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.
Trial locations and contacts
1 site in 1 country.
Moldova1 site, 1 recruiting
- Recruiting
State University of Medicine and Pharmacy " Nicolae Testemitsanu"
Chisinau
Igor Nastas, Dr, +37367133770, igornastas@yahoo.com
Mark Weiser, Professsor
About this study
Official title: Palmitoylethanolamide (PEA) vs Placebo for Major Depression: a Phase II Exploratory Study
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.
Read the 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.
- Conditions
- Bipolar Depression, Major Depressive Disorder
- Being tested
- Palmitoylethanolamide
- Medical subject headings
- Bipolar Disorder, Depressive Disorder, Major
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PalmitoylethanolamideDrug
Also called PEA
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.
| Study group | Role | What they receive |
|---|---|---|
| Palmitoylethanolamide 1200 mg | Experimental | 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. Receives: Drug: Palmitoylethanolamide |
| Matching placebo | Placebo comparator | 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. Receives: Drug: Palmitoylethanolamide |
What is being measured
The primary outcome is the main question the study is designed to answer.
Hamilton Depression Rating Scale (HAM-D)
Depression Scale
Measured: 6 weeks trial
Secondary outcomes (8)
Clinical Global Impressions-Severity-Bipolar Scale or Clinical Global Impressions-Severity-Depression
Scale for Overall Bipolar Depression and Unipolar Depression severity
Measured: 6 weeks trial
Hamilton Anxiety Rating Scale (HAM-A)
Anxiety Scake
Measured: 6 weeks trial
Plasma measures including Allo and pregnanolone, their isomers, the sulfated congeners (pregnanolone sulphate and Allo sulphate)
neurosteroids
Measured: 6 weeks trial
DHEA
measured with the state-of-the-art methodology gas chromatography mass spectrometry (GC-MS).
Measured: 6 weeks trial
BDNF
Brain-derived neurotrophic factor
Measured: 6 weeks trial
CRP
C-Reactive Protein
Measured: 6 weeks trial
TLR-4
Toll-like Receptor 4
Measured: 6 weeks trial
Cytokines
Inflammatory markers
Measured: 6 weeks trial
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Oct 2023
- Study start21 Dec 2022
- Primary completion21 Dec 2023 (estimated)
- Study completion21 Dec 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Bipolar DepressionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Phase II - Randomized, double blind, placebo-controlled, parallel group clinical trial.
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 100 participants (estimated)
Sponsor and investigators
- Lead sponsor
- The Israeli Medical Center for Alzheimer's
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Prof Mark Weiser, The Israeli Medical Center for Alzheimer's
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06063369
- Sponsor's protocol ID
- PEA-01
- Acronym
- PEA-01
- Status last verified
- Sep 2023
- First submitted
- 23 Mar 2023
- Last updated
- 2 Oct 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 2 Oct 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Palmitoylethanolamide (PEA) vs Placebo for Major Depression: a Phase II Exploratory Study
- ClinicalTrials.gov ID
- NCT06063369
- Acronym / sponsor ID
- PEA-01 / PEA-01
- Conditions
- Bipolar Depression, Major Depressive Disorder
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 100 participants (estimated)
- Lead sponsor
- The Israeli Medical Center for Alzheimer'sUniversity, hospital or other
- Study start
- 21 Dec 2022 (actual)
- Primary completion
- 21 Dec 2023 (estimated)
- Study completion
- 21 Dec 2024 (estimated)
- First posted
- 2 Oct 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
- Model description
- Phase II - Randomized, double blind, placebo-controlled, parallel group clinical trial.
| Arm | Type | Receives |
|---|---|---|
| Palmitoylethanolamide 1200 mg | Experimental | Drug: PalmitoylethanolamideDose: 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. |
| Matching placebo | Placebo comparator | Drug: Palmitoylethanolamide2 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. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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.
Key exclusion criteria (10 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PalmitoylethanolamideAlso: PEADose: 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. | Drug | Matching placebo, Palmitoylethanolamide 1200 mg |
Primary outcome
Hamilton Depression Rating Scale (HAM-D)
Time frame: 6 weeks trial
Depression Scale
8 secondary outcomes
Clinical Global Impressions-Severity-Bipolar Scale or Clinical Global Impressions-Severity-Depression
Time frame: 6 weeks trial
Hamilton Anxiety Rating Scale (HAM-A)
Time frame: 6 weeks trial
Plasma measures including Allo and pregnanolone, their isomers, the sulfated congeners (pregnanolone sulphate and Allo sulphate)
Time frame: 6 weeks trial
DHEA
Time frame: 6 weeks trial
BDNF
Time frame: 6 weeks trial
CRP
Time frame: 6 weeks trial
TLR-4
Time frame: 6 weeks trial
Cytokines
Time frame: 6 weeks trial
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Oct 2023.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Palmitoylethanolamide in people with Bipolar Depression and Major Depressive Disorder, run by The Israeli Medical Center for Alzheimer's at 1 site in Moldova.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 2 Oct 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Moldova. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Igor Nastas, Dr (+37367133770, igornastas@yahoo.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Hamilton Depression Rating Scale (HAM-D) (time frame: 6 weeks trial). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Oct 2023.