UMIN-CTR Clinical Trial

Public title

Effects of Plasmalogens on Psychological Symptoms in Healthy Men

Acronym

Effects of Plasmalogens on Psychological Symptoms in Healthy Men

Scientific Title

Effects of Plasmalogens on Psychological Symptoms in Healthy Men

Scientific Title:Acronym

Effects of Plasmalogens on Psychological Symptoms in Healthy Men

Region

Japan

Condition

Healthy

Classification by specialty

Adult

Classification by malignancy

Others

Genomic information

NO

Narrative objectives1

We aim to evaluate the possible effects on depressed mood, anxiety, sleep, and cognitive functions in healthy men by administering a 1 mg daily dose of plasmalogens for three months.

Basic objectives2

Efficacy

Basic objectives -Others

Trial characteristics_1

Confirmatory

Trial characteristics_2

Explanatory

Developmental phase

Primary outcomes

Amelioration of depressed mood as evaluated by Beck Depression Inventory-Second Edition (BDI-II) at six weeks and three months after the start of plasmalogen administration

Key secondary outcomes

We aim to assess the following factors at six weeks and three months after the start of the plasmalogen administration.

1. Amelioration of anxiety, sleep, and cognitive functions
2. Changes in plasmalogen levels in blood plasma, serum, and erythrocyte membranes
3. Changes in other biochemical parameters in the blood
4. Changes in salivary cortisol and immunoglobulin A levels

Study type

Interventional

Basic design

Parallel

Randomization

Randomized

Randomization unit

Individual

Blinding

Double blind -all involved are blinded

Control

Placebo

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

No. of arms

2

Purpose of intervention

Treatment

Type of intervention

Food

Interventions/Control_1

Two plasmalogen capsules will be administered daily (0.5 mg plasmalogens x 2) for three months

Interventions/Control_2

Two placebo capsules will be administered daily for three months

Interventions/Control_3

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

20

years-old

<=

Age-upper limit

70

years-old

>=

Gender

Male

Key inclusion criteria

1) Subjects who did not see a psychiatric doctor, did not receive psychological treatments, and did not take any psychotropic drugs within the past three months
2) Subjects whose body mass index (BMI) ranges from 18.5 to 29.9
3) Subjects who do not participate in any other clinical studies

Key exclusion criteria

1) Subjects with a history of drug or alcohol abuse
2) Subjects with a history of severe head injuries
3) Subjects with a history of severe internal diseases or severe injuries within the past three months
4) Subjects with a history of severe life events occuring within the past three months
5) Subjects with a shell food allergy
6) The lead researcher or collaborative researcher will determine those who are not eligible for this trial

Target sample size

72

Name of lead principal investigator

1st name	Hiroshi
Middle name
Last name	Kunugi

Organization

National Center of Neurology and Psychiatry

Division name

Department of Mental Disorder Research

Zip code

187-8502

Address

4-1-1 Ogawa-Higashi, Kodaira, Tokyo, Japan

TEL

042-341-2711

Email

hkunugi@ncnp.go.jp

Name of contact person

1st name	Shintaro
Middle name
Last name	Ogawa

Organization

National Center of Neurology and Psychiatry

Division name

Department of Mental Disorder Research

Zip code

187-8502

Address

4-1-1 Ogawa-Higashi, Kodaira, Tokyo, Japan

TEL

042-341-2711

Homepage URL

Email

sogawa@ncnp.go.jp

Institute

National Center of Neurology and Psychiatry

Institute

Department

Personal name

Organization

The Japanese Plasmalogen Society

Organization

Division

Category of Funding Organization

Other

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

National Center of Neurology and Psychiatry Institutional Review Board

Address

4-1-1 Ogawa-Higashi, Kodaira, Tokyo, Japan

Tel

042-341-2711

Email

rinri-jimu@ncnp.go.jp

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

Date of disclosure of the study information

2018

Year

05

Month

16

Day

URL releasing protocol

https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000034269

Publication of results

Unpublished

URL related to results and publications

https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000034269

Number of participants that the trial has enrolled

72

Results

No significant differences were observed between the groups at 1.5 months and 3 months in the primary endpoint, which is the change in depression (BDI-II) scores. However, the analysis of interaction terms showed that in the plasmalogen group, compared to the placebo group, subjects with higher baseline scores experienced a significantly greater reduction in scores. This suggests that plasmalogen intake may have a potential improvement effect on individuals with stronger initial depressive symptoms.

Results date posted

2024

Year

11

Month

18

Day

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

- Number of subjects (gender): 72 (male: 72)
- Age: 40.5 +/- 15.6
- Years of education: 15.1 +/- 2.0
- BMI: 22.7 +/- 2.5

Other baseline information (limited to those among the study subjects who have at least one analyzable follow-up data point in addition to baseline information) is as follows. Although random allocation was conducted in this study, the baseline data for psychological scale scores and blood phospholipid levels showed significantly higher scores for the BDI-II (Beck Depression Inventory 2nd edition) and the "Depression" scores on the HSCL (Hopkins Symptom Checklist) in the placebo group.

Furthermore, although random allocation was conducted for the baseline data of cognitive function tests and biochemical parameters in blood and saliva, the placebo group showed significantly higher values of aspartic acid, beta-aminoisobutyric acid, and lysine in plasma. For the subsequent results analysis, all effects of plasmalogen intake were examined using analytical methods that controlled for initial values (repeated measures mixed-effects models, general linear models, multiple regression analysis).

Participant flow

Regarding this research project, it initially began as a clinical study based on the "Ethical Guidelines for Medical and Health Research Involving Human Subjects" (former medical guidelines), but with the enforcement of the Clinical Trials Act, the study was continued under the framework of a specified clinical trial. Approval as a specified clinical trial was granted on March 8, 2019, and the initial public release on jRCT (Japan Registry of Clinical Trials) was on March 18, 2019.

[Research Implementation Period and Course of Study]
- Research Implementation Period: From September 26, 2017 (approval date of the research plan under the former medical guidelines) to September 30, 2024 (Initially, the research period was planned to be until March 31, 2021, after switching to a specified clinical trial, but an application for an extension of the research period was made, resulting in an extension of 3.5 years).
- Case Registration and Observation Period: March 29, 2018 -- November 29, 2019
- Data Analysis and Participant Follow-up Period: November 30, 2019 -- September 30, 2024

This study conducted a randomized individual assignment intervention trial in a double-blind placebo-controlled comparative design to exploratively examine the effects of daily intake of 1 mg plasmalogen for three months on depression, anxiety symptoms, sleep, and cognitive function in healthy males. Therefore, participants were assigned to take either capsules of "Plasmalogen S", which is already approved and commercially available as a functional food, or placebo capsules with a similar appearance. The timing of visits included the initial visit at baseline, a mid-visit at 1.5 months after taking the test capsules, and a final visit at 3 months after taking the test capsules.

The first case registration date for this study was March 29, 2018. The number of consented participants was 76 (one of whom only gave verbal consent and did not participate in the trial), and 72 proceeded to registration and assignment, starting the trial. At the initial visit, 72 subjects participated, but one person refused blood sampling, resulting in missing blood parameters. At the 1.5-month visit, 70 subjects were examined, but one person discontinued participation on-site, thus 69 completed the 1.5-month visit. At the 3-month visit, 66 subjects were examined, but one case had significant outlier values in self-administered test items, and it was declared to exclude this case from analysis before data locking. Therefore, 7 of the 72 subjects dropped out or were excluded, with 65 subjects ultimately completing the study.

The following describes instances of non-compliance that occurred in this study. In March 2019, the study's framework was switched from a clinical study to a specified clinical study under the Clinical Trials Act, and the explanatory documents were also changed. However, for 16 subjects who continued to participate or newly participated during this period, the main changes in the study were not re-explained and re-consented using the new explanatory documents. Of these 16 subjects, 2 eventually expressed their intention to discontinue participation, and 1 was excluded by the researcher's judgment due to communication loss. Among the remaining 13 subjects, 12 confirmed receipt of the latest research plan sent via email attachment, and one was sent the latest explanatory document and a document explaining the main changes by mail to their home, requesting the return of a consent withdrawal form within three months if the participant did not agree to the explanation, and confirmed no response. This matter has been already reported to the Ethics Committee as a "Non-compliance Report" on March 27, 2020.

The end date of the participant observation period was November 29, 2019. From this point, data cleaning and verification were conducted, data was locked on April 3, 2021, and the key was opened on April 21, 2021. Analysis was conducted until July 29, 2024. The original study end date was March 31, 2021, but additional time was required, so applications for an extension of the research period were made annually from FY2020 to FY2023, resulting in a final study implementation period until September 30, 2024.

Adverse events

The occurrence of adverse events, including diseases, throughout the entire research period is shown. Adverse events in the study were aggregated, analyzed, and examined according to the definition of the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (US Department of Health and Human Services. Common Terminology Criteria for Adverse Events version 5.0., https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_8.5x11.pdf) from the initial visit to the 3-month visit. As a result, no significant differences in the frequency of occurrences were observed between the groups for blood parameters, serum biochemical parameters, and serum electrolyte parameters.

In addition, adverse events not defined by the CTCAE were also analyzed and examined. The criteria used were cases where the baseline values were within the normal range but fell outside the normal range at the 3-month visit, or cases where the baseline values were abnormal and showed further deterioration. Since it is not possible to evaluate these cases using the GRADE system, we summarized instances where values fell outside the upper or lower limits of the normal range from baseline or showed further deterioration from the abnormal baseline values. As a result, no significant differences in the frequency of occurrences were observed between the groups for blood parameters and serum biochemical parameters.

Outcome measures

The results of the analysis for the primary and secondary endpoints are shown below. First, regarding the change in the depression score (BDI-II: Beck Depression Inventory-II), the primary endpoint, there were no significant differences between the groups at both 1.5 months and 3 months. For the secondary endpoints, the results of changes in psychological scales and blood phospholipid parameters at 1.5 and 3 months showed that the value of phosphatidylserine on the erythrocyte membrane significantly decreased in the plasmalogen group compared to the placebo group at 1.5 months. However, there was no difference between the groups at 3 months for the same parameter. The value of choline plasmalogen in plasma was significantly lower in the placebo group compared to the plasmalogen group at 3 months.

Next, regarding changes in cognitive function and blood biochemical parameters, the score of "verbal memory" in the BACS (Brief Assessment of Cognition in Schizophrenia) at 3 months significantly increased in the placebo group compared to the plasmalogen group. Also, the value of salivary immunoglobulin A at 3 months significantly decreased in the plasmalogen group compared to the placebo group. Furthermore, the values of asparagine, glycine, methionine, and lysine in plasma significantly increased in the plasmalogen group compared to the placebo group at 3 months.

Additionally, the analysis results using the interaction terms of initial values and group (placebo vs. plasmalogen) are shown. For the BDI-II score, subjects with higher initial values had a greater decrease in scores at subsequent visits in both groups, but this decrease was significantly stronger in the plasmalogen group compared to the placebo group. Similar results were also observed in the total score, "Interpersonal sensitivity," and "Anxiety" scores in the HSCL. On the other hand, for the "State anxiety" score of the STAI (State-Trait Anxiety Inventory), higher baseline scores in the placebo group led to a decrease, but this decrease was significantly suppressed in the plasmalogen group. Similarly, for ethanolamine plasmalogen on the erythrocyte membrane, those with higher baseline values in the placebo group showed a decrease, but this decrease was significantly suppressed in the plasmalogen group.

Continuing with the interaction term analysis, the "digit sequencing" score of the BACS significantly decreased in those with higher baseline scores in the placebo group, but this decrease was significantly suppressed in the plasmalogen group. For plasma amino acid-related molecules, the values of threonine, citrulline, cystine, methionine, phenylalanine, tryptophan, and ethanolamine generally showed a significant decrease in the plasmalogen group compared to the placebo group for those with higher baseline values. Moreover, the value of high-sensitivity CRP in serum significantly decreased in the plasmalogen group compared to the placebo group for those with higher baseline values.

Plan to share IPD

IPD sharing Plan description

Recruitment status

Completed

Date of protocol fixation

2018

Year

03

Month

22

Day

Date of IRB

2018

Year

03

Month

14

Day

Anticipated trial start date

2018

Year

03

Month

29

Day

Last follow-up date

2019

Year

11

Month

29

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

Other related information

Registered date

2018

Year

05

Month

15

Day

Last modified on

2024

Year

11

Month

18

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034269