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Trial registered on ANZCTR


Registration number
ACTRN12621001269820
Ethics application status
Approved
Date submitted
4/08/2021
Date registered
20/09/2021
Date last updated
20/09/2021
Date data sharing statement initially provided
20/09/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
(S)-S-adenosylmethionine (SAMe) in the treatment of pre-menstrual spectrum disorders in adult women: An open-label pilot study
Scientific title
(S)-S-adenosylmethionine (SAMe) in the treatment of pre-menstrual spectrum disorders in adult women: An open-label pilot study
Secondary ID [1] 304935 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Premenstrual Dysphoric Disorder 323085 0
Premenstrual Syndrome 323086 0
Condition category
Condition code
Mental Health 320660 320660 0 0
Other mental health disorders
Reproductive Health and Childbirth 320875 320875 0 0
Menstruation and menopause

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention is the complementary medicine (S)-S-adenosylmethionine disulfate tosylate (SAMe), as SAMe 400 Complex. This study will involve the use of 1200mg of oral SAMe, self-administered by participants as 400mg oral SAMe 400 Complex three times daily, during the luteal phase (the 14 days leading up to menstruation), in two consecutive menstrual cycles. The intervention will be self-administered by participants, with clear instructions, during two “treatment” menstrual cycles, with one control cycle (no SAMe administration) at the start of the study and one control cycle at the end of the study. Ovulation will be confirmed using a urine ovulation test, which will be completed by participants 21 days after their last menstrual period until returning a positive result, every menstrual cycle. As a safety precaution, participants will also complete a urine pregnancy test the day before commencing SAMe treatment on both treatment cycles, and only commence treatment if they return a negative result. SAMe is available over-the-counter in Australia. Participants will be mailed 82 tablets of 400mg oral SAMe with clear instructions for self-administration. Adherence will be confirmed using self-report measures in the structured adverse events questionnaire, during the study conclusion interview and through a tablet return system at the end of the trial. SAMe is a physiological co-substrate involved in various biochemical reactions such DNA modification, epigenetic methylation and cellular metabolism. There is a growing body of evidence demonstrating the efficacy of SAMe in the treatment of depression.
Intervention code [1] 321330 0
Treatment: Other
Comparator / control treatment
Open label pilot study, all participants will receive treatment. Participants will undergo two control menstrual cycles without treatment for baseline measurements and two cycles involving intervention (SAMe 400 Complex oral three times daily for 14 days).

The study will run for a total of 16 weeks, made up for four cycles. Cycle one (week 1-4) is a baseline cycle, in which participants will receive no active treatment. Cycle two (week 5-8) consists of 14 days of SAMe treatment starting on day one of menstruation (approximately week 8-12). Cycle three (week 9-12) will be the second treatment cycle as described for cycle two. The final cycle, cycle four (week 13-16), will be a washout cycle with no active SAMe treatment, this cycle is the same as cycle one (baseline cycle).
Control group
Uncontrolled

Outcomes
Primary outcome [1] 328506 0
Change in overall severity of premenstrual spectrum disorder symptoms as measured by the mean Daily Record of Severity of Problems (DRSP) questionnaire score in the luteal phase of the SAMe treatment cycles (treatment cycle one and two) compared to untreated cycles (baseline and washout).
Timepoint [1] 328506 0
The primary outcome measure will be the mean DRSP total score over 14-days during the luteal phase of the menstrual cycle. This will include the sum of the 21 items including items assessing mood and physical symptoms, alongside social impacts of these symptoms.

The Daily Record of Severity of Problems (DRSP) will be recorded daily, and the mean DRSP across the 14 day luteal phase of each treatment cycle will be compared to the mean score across the 14 day luteal phase of the control menstrual cycles (baseline and washout cycles).
Secondary outcome [1] 399242 0
Change in severity of depression and anxiety symptoms of Pre-Menstrual Spectrum Disorders as measured by the 21-item Depression Anxiety Stress Scale (DASS-21) in the luteal phase of the SAMe treatment cycles (treatment cycle one and two) compared to untreated cycles (baseline and washout). This will be assessed as a composite outcome.
Timepoint [1] 399242 0
The DASS-21 will be measured on the first day of menstruation during each treatment (treatment cycle one and two) and control menstrual cycle (baseline and washout cycle).

Eligibility
Key inclusion criteria
1. Women aged between 18-45 with regular menstrual cycles (regular onset, duration and cycle).
2. Fulfill the diagnostic criteria for a premenstrual spectrum disorder, either PMS or PMDD as per the Diagnostic and Statistical Manual Version Five (DSM-V) criteria as screened during recruitment.
3. Proficient in both reading and writing in English.
4. Stabilise in current psychotherapy, if applicable, for at least eight weeks prior to study commencement.
Minimum age
18 Years
Maximum age
45 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Pregnant or lactating women.
2. Women less than one-year post-partum.
2. Women with irregular menstrual cycles, including perimenopausal and menopausal women and women diagnosed with polycystic ovarian syndrome.
3. Taking hormone replacement therapy and hormonally based contraceptives, including the Combined Oral Contraceptive Pill (COCP), etonogestrel implant (Implanon), intrauterine levonogestral devices (Mirena), transdermal oestradiol patches or depot progesterone injections.
4. Taking psychotropic medications such as serotonergic agents, monoamine oxidase inhibitors or other forms of antidepressants, including atypical antidepressants such as agomelatine.
5. Clinically significant renal or hepatic impairment, haematological, oncological or cardiovascular disease.
6. Consumption of alcohol beyond the National Health and Medical Research Council (NHMRC) guidelines for safer alcohol use. That is, no more than 10 standard drinks a week and no more than four standard drinks in any single occasion.
7. Substance misuse or dependence requiring intervention or rehabilitation in the last three months.
8. Woman taking other complimentary alternative medicines, including cannabinoid containing agents such as cannabidiol (CBD) products.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
N/A
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
For this pilot study, a sample size of 30 participants will be utilised in the primary assessment of the feasibility of the study protocol and to assess preliminary effects of SAMe 400 Complex in pre-menstrual spectrum disorders. Over a three-month period, it is assumed that 30 participants will be able to be recruited to participate in this study. The sample size has been selected according to the literature which suggests that 30 participants is frequently large enough to determine the feasibility of procedures and methods (Hertzog, 2008). In terms of determining treatment effect size, this study is likely to only detect preliminary effect sizes, which will inevitably require further analysis in a larger double blinded placebo control trial. Due to the small sample size, a Bonferroni correction will be applied to correct for type I error during statistical analysis.

Primary outcome;
The primary outcome measure will be the mean DRSP total score over 14-days during the luteal phase of the menstrual cycle. This will include the sum of the 21 items including items assessing mood and physical symptoms, alongside social impacts of these symptoms.

Statistical analysis will involve a comparison of the mean total DRSP score over 14 days during the baseline cycle (capturing the luteal phase), compared to the DRSP score over 14 days during treatment cycle one and two. This will involve conducting two repeated measures, one sample t-tests. The first will compare the mean DRSP score for the previous two weeks ending at the end of the baseline cycle (day one treatment cycle one, end of week 4) to the mean DRSP score for the past two weeks recorded at the end of the first treatment cycle (day one, treatment cycle two, end of week eight).
The second will compare the mean DRSP score collected for the previous two weeks ending on day one cycle 2 (end of week four) to the mean DRSP score for the past two weeks ending on day one cycle four (end of week twelve). No statistical analysis will be performed on data collected from the washout cycle. However, this cycle will assist in determining the feasibility of this protocol for future trials.

The secondary outcome measure will include the total DASS-21 score, will be used as a measure of mood symptoms, including depression, anxiety and stress, and assess participants experience of mood symptoms over the past 14-days.
Statistical analysis will involve a comparison of the total DASS-21 score recorded at the end of the baseline cycle, compared to the total DASS-21 score at the end of treatment cycles one and two. This will involve conducting two repeated measures, one sample t-tests. The first will compare the total DASS-21 score recorded at the end of the baseline cycle (day one treatment cycle one, end of week 4), compared to the total DASS-21 score recorded at the end of treatment cycle one (day one, treatment cycle two, end of eight). The second will compare the total DASS-21 score recorded at the end of the baseline cycle (day one treatment cycle one, end of week 4), compared to the total DASS-21 score recorded at the end of treatment cycle two (day one, treatment cycle three, end of twelve).

References;
Hertzog, M. A. (2008). Considerations in determining sample size for pilot studies. Res. Nurs. Health, 31(2), 180-191. doi:10.1002/nur.20247

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
27/09/2021
Actual
Date of last participant enrolment
Anticipated
27/09/2021
Actual
Date of last data collection
Anticipated
1/04/2022
Actual
Sample size
Target
30
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 20135 0
Monash Alfred Psychiatry Research Centre - Melbourne
Recruitment postcode(s) [1] 34856 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 309315 0
Other Collaborative groups
Name [1] 309315 0
Monash Alfred Psychiatry Research Centre
Country [1] 309315 0
Australia
Primary sponsor type
Hospital
Name
Alfred Health
Address
55 Commercial Rd, Melbourne VIC 3004
Country
Australia
Secondary sponsor category [1] 310288 0
None
Name [1] 310288 0
Address [1] 310288 0
Country [1] 310288 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309143 0
Alfred Human Research Ethics Committee
Ethics committee address [1] 309143 0
Ethics committee country [1] 309143 0
Australia
Date submitted for ethics approval [1] 309143 0
04/08/2021
Approval date [1] 309143 0
30/08/2021
Ethics approval number [1] 309143 0
HREC/78215/Alfred-2021

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 113138 0
Prof Jayashri Kulkarni
Address 113138 0
Monash Alfred Psychiatry Research Centre, Level 4/607 St Kilda Rd, Melbourne VIC 3004
Country 113138 0
Australia
Phone 113138 0
+61390766924
Fax 113138 0
Email 113138 0
jayashri.kulkarni@monash.edu
Contact person for public queries
Name 113139 0
Brendan Stevenson
Address 113139 0
Monash Alfred Psychiatry Research Centre, Level 4/607 St Kilda Rd, Melbourne VIC 3004
Country 113139 0
Australia
Phone 113139 0
+61390766564
Fax 113139 0
Email 113139 0
brendan.stevenson@monash.edu
Contact person for scientific queries
Name 113140 0
Brendan Stevenson
Address 113140 0
Monash Alfred Psychiatry Research Centre, Level 4/607 St Kilda Rd, Melbourne VIC 3004
Country 113140 0
Australia
Phone 113140 0
+61 3 9076 6564
Fax 113140 0
Email 113140 0
brendan.stevenson@monash.edu

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?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.