Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620001311943
Ethics application status
Approved
Date submitted
21/08/2020
Date registered
7/12/2020
Date last updated
14/10/2022
Date data sharing statement initially provided
7/12/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Palmitoylethanolamide and polydatin effect on pain and dysmenorrhea in women scheduled for laparoscopic treatment of possible endometriosis: a double blind randomised controlled trial.
Scientific title
Palmitoylethanolamide and polydatin effect on pain and dysmenorrhea in women scheduled for laparoscopic treatment of possible endometriosis: a double blind randomised controlled trial.
Secondary ID [1] 301986 0
MRFF9911715
Universal Trial Number (UTN)
U1111-1256-6265
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Endometriosis 318545 0
Persistent pelvic pain 318551 0
Condition category
Condition code
Anaesthesiology 316559 316559 0 0
Pain management
Reproductive Health and Childbirth 316560 316560 0 0
Menstruation and menopause

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Palmitoylethanolamide/polydatin (PEA/PLD), 400 mg/40 mg, oral capsule, taken twice daily for a duration of 8 weeks. Course to be completed within two weeks of previously planned laparoscopic surgery for treatment of endometriosis.

Compliance is assessed via the questionnaire the participants receive at the end of the medical treatment ( before surgery) on which there is a question: "1. At the end of the 8 weeks treatment, how many tablets were left in your jar?"
Intervention code [1] 318272 0
Treatment: Drugs
Comparator / control treatment
Placebo will contain micro-crystalline cellulose in a ‘OO’ size capsule which is the same as the active capsule. There will be no other ingredients.
Mode of administration is oral.
Taken twice daily for a duration of 8 weeks. Course to be completed within two weeks of previously planned laparoscopic surgery for treatment of endometriosis.

Compliance is assessed via the questionnaire the participants receive at the end of the medical treatment ( before surgery) on which there is a question: "1. At the end of the 8 weeks treatment, how many tablets were left in your jar?"
Control group
Placebo

Outcomes
Primary outcome [1] 324680 0
To compare the change in dysmenorrhoea visual analogue scale (VAS) score between PEA/PLD and placebo treatment in patients with endometriosis prior to laparoscopic surgical treatment.
Timepoint [1] 324680 0
After 8 weeks of post commencement of intervention (pre surgery)
Primary outcome [2] 324681 0
To compare the change in dyspareunia VAS score between PEA/PLD and placebo treatment in patients with endometriosis prior to laparoscopic surgical treatment.
Timepoint [2] 324681 0
After 8 weeks of post commencement of intervention (pre surgery)
Primary outcome [3] 325303 0
To compare the change in dyschezia VAS score between PEA/PLD and placebo treatment in patients with endometriosis prior to laparoscopic surgical treatment.
Timepoint [3] 325303 0
After 8 weeks of post commencement of intervention (pre surgery)
Secondary outcome [1] 385390 0
PRIMARY OUTCOME
To compare the change in persistent pelvic pain visual analogue scale (VAS) score between PEA/PLD and placebo treatment in patients with endometriosis prior to laparoscopic surgical treatment.
Timepoint [1] 385390 0
After 8 weeks of post commencement of intervention (pre surgery)
Secondary outcome [2] 385391 0
To compare the change in dysmenorrhoea VAS score between PEA/PLD and placebo treatment at baseline and 4 months after laparoscopic surgery for endometriosis.
Timepoint [2] 385391 0
At recruitment, and 6 months post commencement of intervention (4 months after surgery)
Secondary outcome [3] 385392 0
To compare the change in dyspareunia VAS score between PEA/PLD and placebo treatment at baseline and 4 months after laparoscopic surgery for endometriosis.
Timepoint [3] 385392 0
At recruitment, and 6 months post commencement of intervention (4 months after surgery)
Secondary outcome [4] 385393 0
To compare the change in dyschezia VAS score between PEA/PLD and placebo treatment at baseline and 4 months after laparoscopic surgery for endometriosis.
Timepoint [4] 385393 0
At recruitment, and 6 months post commencement of intervention ( 4 months after surgery)
Secondary outcome [5] 385394 0
To compare the change in persistent pelvic pain VAS score between PEA/PLD and placebo treatment at baseline and 4 months after laparoscopic surgery for endometriosis.
Timepoint [5] 385394 0
At recruitment, and 6 months post commencement of intervention ( 4 months after surgery)
Secondary outcome [6] 385395 0
To compare the change in dysmenorrhoea VAS score between PEA/PLD and placebo in patients without surgical evidence of endometriosis.
Timepoint [6] 385395 0
At recruitment, at 8 weeks post commencement of intervention (time of surgery), and 6 months post commencement of intervention ( 4 months after surgery)
Secondary outcome [7] 385398 0
To compare the change in dyspareunia VAS score between PEA/PLD and placebo in patients without surgical evidence of endometriosis.
Timepoint [7] 385398 0
At recruitment, at 8 weeks post commencement of intervention (time of surgery), and 6 months post commencement of intervention ( 4 months after surgery)
Secondary outcome [8] 387459 0
To compare the change in dyschezia VAS score between PEA/PLD and placebo in patients without surgical evidence of endometriosis.
Timepoint [8] 387459 0
At recruitment, at 8 weeks post commencement of intervention (time of surgery), and 6 months post commencement of intervention ( 4 months after surgery)
Secondary outcome [9] 387908 0
To compare the change in persistent pelvic pain VAS score between PEA/PLD and placebo in patients without surgical evidence of endometriosis.
Timepoint [9] 387908 0
At recruitment, at 8 weeks post commencement of intervention (time of surgery), and 6 months post commencement of intervention ( 4 months after surgery)
Secondary outcome [10] 387909 0
To compare the change of quality of life between PEA/PLD and placebo treatment in women with surgical evidence of endometriosis.
Timepoint [10] 387909 0
QOL questionnaire called Endometriosis Health Profile (EHP-30) and EQ-5D 5L at recruitment, and at 6 months post commencement of intervention (4 months after surgery)
Secondary outcome [11] 387910 0
To compare changes in cellular and molecular markers from endometriotic lesions between patients treated by PEA/PLD and placebo.
Timepoint [11] 387910 0
At time of surgery.
There are several cellular and molecular markers that will be assessed based upon the compounds used and their current known targets.  These include inflammation (CD45, ICAM, P-selectin, nitrotyrosine, PARP), mast cells (CD117, CD63), cytokine expression (TNFa, NFkB, IL1ß) as well as PEA direct targets (PPARa, GPR55), PEA indirect targets (CB1, CB2, TRPV1), PEA degrading enzyme (FAAH) and proposed regulator of PEA degradation (VEZT).   Other markers investigated will be determined by the NGS findings from the lesions and endometrial tissue .
Secondary outcome [12] 387911 0
To compare changes in cellular and molecular markers from blood samples between patients treated by PEA/PLD and placebo.
Timepoint [12] 387911 0
At time of surgery.
There are several cellular and molecular markers that will be assessed based upon the compounds used and their current known targets.  These include inflammation (CD45, ICAM, P-selectin, nitrotyrosine, PARP), mast cells (CD117, CD63), cytokine expression (TNFa, NFkB, IL1ß) as well as PEA direct targets (PPARa, GPR55), PEA indirect targets (CB1, CB2, TRPV1), PEA degrading enzyme (FAAH) and proposed regulator of PEA degradation (VEZT).   Other markers investigated will be determined by the NGS findings from the lesions and endometrial tissue .
Secondary outcome [13] 387912 0
To compare changes in cellular and molecular markers from peritoneal fluid samples between patients treated by PEA/PLD and placebo.
Timepoint [13] 387912 0
At time of surgery.
There are several cellular and molecular markers that will be assessed based upon the compounds used and their current known targets.  These include inflammation (CD45, ICAM, P-selectin, nitrotyrosine, PARP), mast cells (CD117, CD63), cytokine expression (TNFa, NFkB, IL1ß) as well as PEA direct targets (PPARa, GPR55), PEA indirect targets (CB1, CB2, TRPV1), PEA degrading enzyme (FAAH) and proposed regulator of PEA degradation (VEZT).   Other markers investigated will be determined by the NGS findings from the lesions and endometrial tissue .
Secondary outcome [14] 387913 0
To compare changes in cellular and molecular markers from endometrium samples between patients treated by PEA/PLD and placebo.
Timepoint [14] 387913 0
At time of surgery.
There are several cellular and molecular markers that will be assessed based upon the compounds used and their current known targets.  These include inflammation (CD45, ICAM, P-selectin, nitrotyrosine, PARP), mast cells (CD117, CD63), cytokine expression (TNFa, NFkB, IL1ß) as well as PEA direct targets (PPARa, GPR55), PEA indirect targets (CB1, CB2, TRPV1), PEA degrading enzyme (FAAH) and proposed regulator of PEA degradation (VEZT).   Other markers investigated will be determined by the NGS findings from the lesions and endometrial tissue .
Secondary outcome [15] 387914 0
To assess for any side effects of PEA/PLD. (For example, gastrointestinal upset, drowsiness, heart palpitations.)
Timepoint [15] 387914 0
Treatment adverse reactions will be tracked by questionnaire at 8 weeks post commencement of intervention.

In case of any adverse reaction, patient can stop treatment at any time and seek advice with the allocated contact person for complaints in each hospital or 24 hours a day at the emergency department of each hospital for severe reactions.

Eligibility
Key inclusion criteria
- Women aged 18 – 45 with pelvic pain scheduled for laparoscopic treatment of possible endometriosis. Both women with and without previous evidence of endometriosis on ultrasound or previous surgery are eligible
- Women who agree to use any type of contraception and avoid conceiving during the 8-week treatment phase.
- English speakers
Minimum age
18 Years
Maximum age
45 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Pregnancy or actively trying to conceive
Breastfeeding
Previous hysterectomy
Suspected malignancy
Inability to provide informed consent

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by computer. Randomisation will be stratified based on recruitment site (Royal Women’s Hospital, Mercy Hospital for Women and Private Setting), with lists produced for each site. These will be held by the dispensing compounding pharmacy that will provide the PEA/PLD or placebo in identical containers directly to the patients. The subject and medical staff will be blinded to each subject's treatment.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Block randomization will be performed using the statistical software “R”, directing subjects to treatment with 400mg/40mg PEA/PLD twice daily or placebo of identical appearance. Blocks will consist of 4 subjects who consecutively enter the trial.  Randomization will be stratified based on recruitment site (Royal Women’s Hospital, Mercy Hospital for Women and Private Setting), with lists produced for each site.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
STATISTICAL METHODS
Continuous variables will be explored with summary statistics (mean, standard deviation, quartiles, range) and graphs (box plots, dot plots). Comparisons between the PEA/PLD treatment and placebo will be performed using t-tests, or Mann-Whitney U tests if appropriate.
The impact of the treatment on continuous pain measures will be assessed using linear models adjusting for the effect of covariates, including pre-treatment pain measures.
Categorical variables will be summarised as proportions and cross tabulated frequencies, and associations examined using chi-squared and Fisher’s exact tests. A modified intention to treat approach to analysis will be undertaken.

SAMPLE SIZE
The sample size required for a one point difference on the numerical pain scale between PEA/PLD treatment and placebo in the change of each type of pain measured VAS score before (at recruitment) and at 4 months after surgery, and SD of 2 (based on a previous study performed by our team), was calculated to be 128 (64 in each group), based on an alpha of 0.05, power of 0.8 and two sided p-value. Allowing for a drop-out rate of 30%, and assuming that 30% of patients will not be found to have endometriosis on surgery, a total sample size required is 130 in each group (N=260).
If the participant withdraws prior to completing 6 weeks of medical treatment, she will be removed from the study.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/04/2021
Actual
12/07/2021
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
260
Accrual to date
41
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 17214 0
The Royal Women's Hospital - Parkville
Recruitment hospital [2] 17215 0
Mercy Hospital for Women - Heidelberg
Recruitment hospital [3] 17216 0
Frances Perry House - Parkville
Recruitment hospital [4] 17217 0
Epworth Richmond - Richmond
Recruitment hospital [5] 17219 0
Epworth Freemasons (Victoria Parade) - East Melbourne
Recruitment hospital [6] 17220 0
Cabrini Hospital - Malvern - Malvern
Recruitment hospital [7] 17221 0
Warringal Private Hospital - Heidelberg
Recruitment hospital [8] 17222 0
St Vincents & Mercy Private Hospital - Mercy campus - East Melbourne
Recruitment hospital [9] 17223 0
Sunshine Hospital - St Albans
Recruitment hospital [10] 17224 0
The Women’s at Sandringham - Sandringham
Recruitment hospital [11] 17282 0
Holmesglen Private Hospital - Moorabbin
Recruitment postcode(s) [1] 30923 0
3052 - Parkville
Recruitment postcode(s) [2] 30924 0
3084 - Heidelberg
Recruitment postcode(s) [3] 30925 0
3121 - Richmond
Recruitment postcode(s) [4] 30927 0
3002 - East Melbourne
Recruitment postcode(s) [5] 30928 0
3144 - Malvern
Recruitment postcode(s) [6] 30929 0
3021 - St Albans
Recruitment postcode(s) [7] 30930 0
3189 - Moorabbin
Recruitment postcode(s) [8] 30932 0
3191 - Sandringham

Funding & Sponsors
Funding source category [1] 306407 0
Government body
Name [1] 306407 0
Department of Health
Country [1] 306407 0
Australia
Primary sponsor type
University
Name
The University of Melbourne
Address
Department of Obstetrics and Gynaecology
Level 7
Royal Womens Hospital
20 Flemington Rd
Parkville,
Victoria, 3052
Country
Australia
Secondary sponsor category [1] 306915 0
None
Name [1] 306915 0
Address [1] 306915 0
Country [1] 306915 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306605 0
Austin Health Human Reserch Ethics Committee (HREC)
Ethics committee address [1] 306605 0
Austin Hospital
145 Studley Road
PO Box 5555
Heidelberg Victoria 3084
Ethics committee country [1] 306605 0
Australia
Date submitted for ethics approval [1] 306605 0
08/07/2020
Approval date [1] 306605 0
05/11/2020
Ethics approval number [1] 306605 0

Summary
Brief summary
Effective medical therapies for the treatment of endometriosis related pelvic pain are limited and are often associated with side-effects.
Palmitoylethanolamide (PEA) is a food supplement that has been shown to have anti-inflammatory action.
Polydatin (PLD) is also a food supplement that has antioxidant and pain inhibiting activities.

There have been some small studies performed to assess if the combination of PEA/PLD is helpful for persistent pain associated with endometriosis. The results suggest it might have benefit, but further studies are required.

Multiple studies that assessed PEA/PLD for pain relief in various other pain conditions have not reported any significant side effects.

The aim of this study is to determine if treatment with PEA/PLD improves endometriosis associated pain.

Women who are booked for surgical treatment of possible endometriosis will be offered participation in this study. Participation will not change their surgeon’s care plan. The participants will be randomised to either receive 8 weeks of PEA/PLD treatment or placebo prior to their surgery. The endometriosis will then be confirmed or excluded during the surgery. Lesions of endometriosis, endometrium, pelvic fluid and blood will be collected where possible to assess inflammatory markers.

Participants will also complete a survey including pain and quality of life assessments. This survey will be completed at recruitment, after 8 weeks of treatment (pre surgery) and at 6 months (4 months after surgery).

We will assess the change in pain scores and quality of life scores between the 2 groups to see if PEA/PLD is beneficial.
Trial website
Trial related presentations / publications
Public notes
The tolerability of the drug was viewed in a meta-analysis of all randomized, controlled trials involving the effect of PEA on pain score of different chronic pain conditions. Adverse events reported with PEA treatment in 786 patients included gastrointestinal upset (2), drowsiness (1), and heart palpitations (1). No significant adverse side effects were reported in other studies. Moreover, treatment was given to patients seeking fertility, after surgical diagnosis of endometriosis while trying to conceive with no concern of teratogenicity.Worldwide, more than 800,000 patients have been treated with PEA, most of them in Italy and Spain, with some in The Netherlands, Germany, UK, Canada and the US, and no serious side effects have been reported.

Contacts
Principal investigator
Name 104438 0
Dr Michal Amir
Address 104438 0
The Royal Women's Hospital
20 Flemington Rd
Parkville
VIC 3052
Country 104438 0
Australia
Phone 104438 0
+61 403274870
Fax 104438 0
Email 104438 0
[email protected]
Contact person for public queries
Name 104439 0
Dr Michal Amir
Address 104439 0
The Royal Women's Hospital
20 Flemington Rd
Parkville
VIC 3052
Country 104439 0
Australia
Phone 104439 0
+61 403274870
Fax 104439 0
Email 104439 0
[email protected]
Contact person for scientific queries
Name 104440 0
Dr Michal Amir
Address 104440 0
The Royal Women's Hospital
20 Flemington Rd
Parkville
VIC 3052
Country 104440 0
Australia
Phone 104440 0
+61 403274870
Fax 104440 0
Email 104440 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?




Results publications and other study-related documents

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