Clinical trial NCT01464697
Conditions: Hot Flushes Night Sweats
Keywords: hot flushes/hot flashes night sweats sleep problems negative mood anxiety perimenopause progesterone vasomotor symptoms depression women's perceived change perimenopause interference questionnaire
Sponsor: University of British Columbia
Start date: 2011-10-01; Completion date: 2018-06-01
Enrollment: 249 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to test whether a oral micronized progesterone reduces the Vasomotor Symptom Score comprised of the number and severity of hot flushes and night sweats in perimenopausal women. Oral micronized progesterone is molecularly identical to human progesterone, a steroid hormone. It is sold by prescription for use to prevent endometrial cancer in women taking estrogen in menopause. This research study will test whether progesterone reduces perimenopausal hot flushes and night sweats. It will also test whether progesterone improves sleep disturbances and anxiety.

Detailed description:
This is a randomized, double-blind placebo-controlled trial of oral micronized progesterone (300 mg daily at bedtime) for perimenopausal women living anywhere in Canada. Using the self-reported maximum menstrual cycle length in the previous year, women will be stratified as in Early Perimenopause (\<60 days) or Late Perimenopause (\>=60 days). The design includes a 28-day baseline run-in followed by 12 weeks of randomized therapy.

Arms: arm 1: Oral micronized progesterone is Prometrium 300 mg at bedtime daily arm 2: Placebo
Interventions: intervention 1: Oral micronized progesterone intervention 2: placebo
Intervention descriptions: intervention 1: 300 mg as 3-100 mg capsules taken orally at bedtime daily for 12 weeks intervention 2: placebo comparator, taken as 3 round capsules at bedtime daily for 12 weeks

Protocol documents:
Prot_SAP_000.pdf: 
Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms 
 
 
NCT01464697 
 
 
Study Protocol: June 12, 2014 
Clinical Research Ethics Board explanation of Amendments: November 18, 2018 
Amendments to Study Protocol: November 9, 2018 
 
 


	

	





Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms Study 
Protocol - Version 7.0; 12 June 2014 
 
Page 1 of 26 
 
CeMCOR Protocol:  Peri-P-236267-01 
Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms Study 
 
Investigators: 
 
Principal Investigator 
Jerilynn C. Prior BA MD FRCPC 
Scientific Director, Centre for Menstrual Cycle 
and Ovulation Research (CeMCOR); 
Professor of Endocrinology, University of 
British Columbia (UBC) 
Co-Investigator 
Andrea Cameron, RN BScN 
Research Coordinator 
Co-Investigator 
Michelle Fung MD MHSc  FRCPC 
Clinical Assistant Professor, UBC 
Co-Investigator 
Christine L. Hitchcock PhD 
Co-Investigator 
Shirin Kalyan PhD 
Co-Investigator 
Sandra Sirrs MD FRCPC 
Clinical Associate Professor, UBC; 
Medical Director, Adult Metabolic Diseases 
Clinic 
Co-Investigator 
Patricia Janssen PhD 
Professor, UBC School of Population & Public 
Health (SPPH) 
Co-Investigator 
Joel Singer PhD 
Professor, UBC School of Population & Public 
Health 
Collaborator 
Elana Brief PhD 
Research Associate, UBC 
Collaborator 
Caroline Ferris MD  
Family Physician 
 
Funding: 
CIHR Operating Grant “Oral Micronized Progesterone for Perimenopausal Vasomotor 
Symptoms”, March 2010 competition, funded for 4 years (CIHR # 221598). 
Drug and placebo to be provided by Besins Healthcare—see attached letter of collaboration. 
The University of British Columbia and CeMCOR will provide research space and facilities to 
conduct the trial; the investigators have a well-developed network of contacts for efficient 
recruitment. 
Pharmacists at a research pharmacy will dispense drugs according to web-based random therapy 
allocations. 
 
Summary 
This is a randomized, double-masked, placebo-controlled trial of oral micronized progesterone 
(300 mg at bedtime daily) for hot flushes and night sweats (collectively vasomotor symptoms, 
VMS) in women stratified to be in Early or Late Perimenopause. We have recently completed a 
similar trial showing that oral micronized progesterone provides effective therapy for healthy 


	

	





Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms Study 
Protocol - Version 7.0; 12 June 2014 
 
Page 2 of 26 
 
postmenopausal women with VMS. Currently there is no effective, evidence based treatment for 
perimenopausal VMS.  
 
Background 
1.1 Problem to be addressed 
Perimenopausal women urgently need effective therapy to treat VMS. The post-war generation is 
passing through perimenopause, and evidence-based therapies are lacking. Existing therapies 
have been developed for and tested on postmenopausal women; none have been performed, thus 
none are proven effective in perimenopause, a life phase during which estradiol levels average at 
least normal or higher and are highly variable, yet progesterone levels are lower than in 
premenopausal women. VMS occur in 80% of perimenopausal women—9% of these experience 
moderate to severe VMS 1. Oral micronized progesterone (OMP, Prometrium) is an effective 
therapy for VMS in healthy women 1-11 years since the final menstrual period. Furthermore, it 
is effective for frequent and moderate-severe VMS . This is a trial of similar design using oral 
micronized progesterone for women experiencing perimenopausal VMS. 
 
There is increasing recognition that VMS are a feature of midlife rather than of old age and 
are predominantly experienced by women in the years leading up to and the year immediately 
following the final menstrual period (perimenopause). A recent meta-analysis of prospective, 
longitudinal studies estimated VMS to last a median of four years in symptomatic women 2. 
Although prospective population-based studies suggest a VMS duration of 5.5 year3 recently a 
single cohort study starting earlier in perimenopause indicates those with the earliest onset may 
have VMS continuing for over 12 years4. Most women do recover. VMS symptoms, however, 
can begin at a much younger age than many people realize; in a Swedish population-based 
survey, 38% of those aged 46 at the time of the survey reported VMS 5; 25% of “premenopausal” 
women (so defined because they were still regularly menstruating) in a cohort aged 35-65, also 
reported having VMS 6. 
 
In addition to VMS, perimenopausal women often also have issues with mid-sleep wakening, 
interrupted and non-refreshing sleep 5;7-11 and increased anxiety 8;10;12, although the causal 
relationships need clarification 11;13. OMP has been shown to be effective for postmenopausal 
insomnia 14;15 and to improve sleep in men 16. Clinical observations suggest it will also help 
perimenopausal sleep problems. Anxiety is also a common problem for symptomatic 
perimenopausal women 12;17. OMP has anxiolytic effects 18 acting through neurotransmitters 19. 
In this study we will assess sleep and anxiety (as part of a composite measure of mood) as 
secondary outcomes, to assess whether they are also improved by the therapeutic use of OMP.  
 
The diagnosis of the “menopausal transition” is divided into early and late based on elevated 
follicle stimulating hormone (FSH) levels and patterns of menstrual flow. Both major attempts at 
classification of midlife women’s stages, STRAW 20 and ReSTAGE 21, use patterns of menstrual 
bleeding to delineate late reproductive age (normal FSH levels and no period changes), early 
menopausal transition increased FSH plus “irregular” cycles) and late menopausal transition (a 
skipped period, or cycle >60 d.). These definitions of perimenopause/menopausal transition 
include only those women whose cycles have become irregular. 
  


	

	





Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms Study 
Protocol - Version 7.0; 12 June 2014 
 
Page 3 of 26 
 
Perimenopause extends one year beyond the final menstrual flow 20 and thus differs from the 
menopausal transition which ends at the final flow. Based on the known hormonal changes and 
new experiences reported by regularly menstruating midlife women, our research centre extends 
the bleeding-based definition of perimenopause to also include women ages 35 or older who 
experience ≥ 3 of the following unexplained changes: (i) new onset of heavy and/or longer flow; 
(ii) shorter menstrual cycles (< 25 days); (iii) new sore, swollen or lumpy breasts; (iv) new mid-
sleep wakening; (v) increased cramps; (vi) onset of night sweats, in particular premenstrually; 
(vii) new or markedly increased migraine headaches; (viii) new or increased premenstrual mood 
swings; (ix) weight gain without changes in exercise or eating 22. Thus, the distinction between 
Early Perimenopause and Late Perimenopause is based on menstrual cycle patterns; Late 
Perimenopause begins when a woman first goes ≥60 days between spontaneous menstrual 
bleeding episodesall other midlife women with VMS are considered to be in Early 
Perimenopause. 
 
Although VMS are experienced by menstruating women in perimenopause and by 
postmenopausal women who no longer menstruate, there are important physiological differences 
between these two groups 23;24. Therapies that work in postmenopause may or may not work 
in perimenopause and need to be specifically tested in this population. In perimenopause, 
hormonal feedback pathways are impaired as part of ovarian aging 24;25. It is a common 
misconception that estrogen levels gradually decline across perimenopause. In fact, 
perimenopausal estrogen levels are higher, on average, than those in younger, premenopausal 
women 23, because the feedback mechanisms that normally suppress FSH with rising levels of 
estrogen are disrupted. By contrast, in postmenopause, estrogen levels are low.  
 
Perimenopausal women menstruate, but they have a high rate of anovulatory cycles, and cycles 
with delayed ovulation and shortened luteal phases 24;26-28 thus the balance between estrogen and 
progesterone is shifted towards estrogen 27. Clinically, high estrogen levels present as heavy 
menstrual flow 29, tender and swollen breasts or increased migraine headaches. Perimenopause 
may also be a window of risk for endometrial cancer 30. Exogenous estrogen given as therapy 
may not suppress a woman’s own high perimenopausal estrogen levels 23;25. Therefore, those 
estrogen treatments that are effective for VMS in postmenopause may not be as effective in 
perimenopause, may increase the already elevated endogenous estrogen levels and could cause 
harm. By contrast with estrogen, progesterone levels are lower in perimenopause than in 
premenopause. 
   
Although the terms “progestin” and “progesterone” are sometimes used interchangeably, it is 
important to note that progestins and progesterone are not the same. Progestins are, by 
definition, not normally found in the body, but have two classical uterine progestational effects 
on the uterus: conversion of the endometrium of an immature rabbit to a secretory state 
following estrogen priming, and support of rat pregnancy following removal of the ovaries 31. 
Other than these two uterine effects, there is no requirement that other actions of a progestin be 
similar to those of progesterone. Some progestins are derived from androgens, some have 
androgenic effects, some have anti-androgenic effects, and many differ significantly in structure 
from progesterone itself. All progestins share the uterine effects of progesterone; the effects 
on other sites and systems are diverse. 
 


	

	





Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms Study 
Protocol - Version 7.0; 12 June 2014 
 
Page 4 of 26 
 
There is more research and more clinical experience with the use of estrogens, and more 
with progestins than with progesterone itself, in part because of an accident of history and of 
biology. Following their discoveries in the 1920s and 30s, and unlike estrogen, progesterone was 
not active when taken by mouth—the quickly synthesized progestins were. Micronization, a 
comparatively recent innovation, allows progesterone, the same molecule as that secreted by the 
ovaries, to be used as an oral therapy. Oral micronized progesterone (OMP) was first launched in 
France in 1980. In Canada, OMP (Prometrium) was first approved for use in 1995 with 
USA FDA approval in 1998.  
 
Progestins were added to estrogen therapy in postmenopause to counter the increased 
endometrial cancer rates of the previously popular estrogen-only therapy; the most commonly 
used progestin, and the one tested in the Women’s Health Initiative, was medroxyprogesterone 
acetate (MPA). Most clinicians in North America draw their clinical experience from the 
addition of MPA to postmenopausal estrogen therapy, not from the use of MPA or OMP 
(progesterone) as independent therapy.  
 
Widespread clinical confidence in the cardioprotective and youth-sustaining benefits of estrogen 
therapy for healthy postmenopausal women was shaken by the results of the large, randomized, 
placebo-controlled trials of estrogen (for women with a hysterectomy)32 and Estrogen+Progestin 
(for women with an intact uterus) of the Women’s Health Initiative 33.  Although there is 
ongoing debate, and a controversial attempt to construct a timing hypothesis to support the 
benefits of estrogen when used sufficiently early in the sequence of reproductive ageing, it is 
clear that lifelong use of estrogen therapy for healthy postmenopausal women is no longer 
recommended. Estrogen therapies are now clearly recommended for the treatment of symptoms, 
not for prevention. Women are advised to use estrogen for VMS but at the lowest possible dose 
for the shortest possible time, and that the benefits of therapy must be weighed against the 
potential risks. 
 
Therapeutic recommendations are also drawn from the widespread use of combined hormonal 
contraceptives for therapy. All oral contraceptives (OC) use progestins, not progesterone (and all 
available combined OC use ethinyl estradiol, not the molecularly identical, 17 βestradiol). Safety 
profile differences among the progestins in OC remain a controversial and contested area of 
research. The recent EURAS trial, a large, European, post-marketing surveillance study of the 
venous thrombosis (VT) risks of OC in premenopausal women confirmed that current 
formulations cause an approximately three-fold increased risk compared to non-users 34. The risk 
of VT also increases with age, body weight (which is notably higher in North America than in 
Europe), and smoking. Moreover, VMS themselves have been associated with increased 
cardiovascular risk 35.  
 
The role of progesterone and progestins in perimenopausal and postmenopausal therapy 
Both progesterone and progestins have a well-recognized and effective role in the treatment of 
heavy bleeding 36. Two older studies 37;38 and a more recent randomized controlled trial 39 from 
our own group have shown MPA to be an effective therapy for VMS in postmenopausal women. 
The overwhelming majority of clinical research on the role of progesterone and progestins in 
perimenopausal and menopausal therapy considers only their protective role against the 
endometrial cancer that is caused by unopposed estrogen therapy used by a postmenopausal 
woman with a uterus. A thorough systematic review 40 completed in 2005 (that also found only 


	

	





Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms Study 
Protocol - Version 7.0; 12 June 2014 
 
Page 5 of 26 
 
the progestin or progesterone studies we describe in this proposal ), concluded that “trials of 
progestin indicate mixed results for the treatment of vasomotor symptoms.” The technical report 
and the NIH consensus statement it informed both called for more research specifically for 
symptoms in perimenopause, and specifically for more research on progesterone and progestins 
as therapies 41.  
 
Clinical trials of progestin or progesterone therapy in postmenopause 
We have recently (Oct 2009) completed a randomized, masked, placebo-controlled trial of OMP 
for VMS in healthy postmenopausal women42. This is the only trial of OMP for VMS of which 
we are aware. We found significantly more improvement in those randomized to OMP 
(Prometrium, 300 mg at bedtime daily) therapy than to placebo: (52% vs. 22%) improvement 
in VMS Score, and greater decreases in daily VMS frequency (44% vs. 17%) and severity (38% 
vs. 19%). Significant therapy by baseline interactions indicated that those who had more 
frequent/intense VMS at baseline showed greater treatment benefits from progesterone compared 
with placebo, for both VMS Score and VMS Frequency. This analysis considered all randomized 
women for whom we had daily diary records of VMS (n=127); for 13 of these, we used last 
observation carried forward to impute the final score.  
 
Considerable RCT evidence is available showing the effectiveness of medroxyprogesterone 
(MPA), the most biochemically similar progestin to OMP, either orally 37;38;43;44 or as a depo-
injection 43;45 for the treatment of VMS. Furthermore, a parallel double-masked 1-yr trial (begun 
in the 1980s when these were the dominant hormonal therapies) of conjugated equine estrogen 
(Premarin, 0.6 mg/d) compared with MPA (Provera, 10 mg/d) found equivalently effective 
control of the expected increase in VMS following bilateral ovariectomy in premenopausal 
women 39. The three published trials of transdermal progesterone cream (Pcream) for VMS in 
menopausal women showed contradictory results—one with 20 mg/d over one year showed 
significant improvement 46 while a 12-week trial of 32 mg/d Pcream showed no significant effect 
47, and a dose-response trial tended to show benefit at the highest dose 48. 
 
Neither our searches nor those of others recently reviewing the literature 40 have uncovered any 
further controlled clinical trials investigating progestins or progesterone as therapy for 
postmenopausal VMS. 
 
Clinical trials of progestin or progesterone therapy for VMS in perimenopause 
We have been unable to find any such trials. 
 
Clinical trials of other therapies for VMS in perimenopause 
The most common recommendations for perimenopausal symptoms are to use the estrogen-
based therapies that are the gold standard for postmenopausal women, or to use OC 49. Neither 
recommendation is supported by evidence from clinical trials with perimenopausal women. The 
only clinical trial of OC (Minestrin, 20 mcg ethinyl estradiol with 1 mg norethindrone acetate) 
for perimenopausal symptoms 50 enrolled 134 women aged 40-55 who were menstruating 
(details not provided), with FSH levels <40 mIU/ml, who were “experiencing perimenopausal 
signs and symptoms” and without contraindications to combined OC. Women were randomized 
to take OC or identical placebo for 6 28-day cycles (168 days) with a standard 21/7 pattern of 
active and placebo pills. The study had multiple endpoints, one of which was VMS; 65% of the 
women had one or more hot flush during the study and were included in that analysis. For a 


	

	





Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms Study 
Protocol - Version 7.0; 12 June 2014 
 
Page 6 of 26 
 
VMS therapy study, the rate of hot flushes was very low. The average daily count was 0.45 for 
placebo and 0.24 for active therapy, and the range was from 0.1 to 2.1 hot flushes per day. The 
difference between placebo and active therapy was not statistically significant, nor was the 
magnitude decrease observed (0.2, or roughly one fewer hot flush per 5 days) likely to be 
perceptible to the women or clinically relevant 50. The other trial of OC in perimenopause 
provided incomplete description of the methods and its methodological flaws limit data 
interpretation 51. While it is possible that hot flushes can be effectively treated with oral 
contraceptives, this has yet to be established in a clinical trial. 
 
Recently a clinical trial of a rhubarb-like herb (ERr-731) with 110 perimenopausal women found 
significantly better treatment of VMS than with placebo 52. This formulation, however, is not 
currently available in Canada and the study methodology was importantly lacking 53. 
 
In summary, progesterone is a likely candidate therapy for VMS in perimenopausal women 
because: 
1. It is an effective therapy for VMS in healthy postmenopausal women within 10 years of 
their final menstrual flow 54; 
2. It counters the known endometrial risks of elevated and unopposed endogenous estrogen, 
and is effective therapy for abnormal and heavy bleeding which is common in 
perimenopause; and 
3. The sedative effects of OMP, when taken at bedtime, have additional benefits for 
improving sleep 14, and may reduce anxiety 18, both of which are frequent problems for 
symptomatic women in perimenopause. 
This study will be the first to specifically address the treatment of VMS in perimenopausal 
women, and, if successful, will improve clinical care. The availability of effective therapy will 
ease the burden on health care utilization, improve the health and lives of perimenopausal 
women who are symptomatic because of VMS, and may also improve their associated 
perimenopausal bone loss 55 and increased cardiovascular risks 35. 
 
1.2 Principal research question 
Research Question:  Is progesterone (OMP) an effective treatment for night sweats and hot 
flushes in perimenopausal women?  
1. Is daily OMP therapy (300 mg, taken before sleep) an effective therapy for hot flushes 
and night sweats (vasomotor symptoms, VMS) in Early and Late Perimenopause? 
2. Does OMP therapy improve other perimenopausal symptoms, specifically sleep 
disturbances and anxiety?   
 
1.3 Why a trial is needed now 
In addition to the reasons given for the relevance of this trial (section 1.1), clinical trial data from 
the Women’s Health Initiative 32;33 have created great interest in alternatives to estrogen 
treatment. The post-war “baby boom” generation is now passing through their perimenopausal 
years and thus there is a large demographic (22% of all Canadian women) and approximately 
20% of these will be sufficiently symptomatic to seek medical treatment.  
 
We have recently completed a trial of OMP for postmenopausal VMS 42;54, showing that 
significantly greater improvement in those randomized to progesterone than placebo. This trial 
provides proof of principle that OMP is effective VMS therapy. However, OMP remains to be 


	

	





Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms Study 
Protocol - Version 7.0; 12 June 2014 
 
Page 7 of 26 
 
tested in perimenopausal women. Further, the investigators have the expertise for this new VMS 
trial in perimenopause. For all of these reasons, this is an ideal time for this important trial.  
 
1.4 Systematic reviews of treatment of VMS 
A meta-analysis of randomized controlled trials of estrogen or estrogen and progestin for VMS 
was unable to find any trials that studied VMS only in perimenopausal women 56. Clinical trials 
for VMS in perimenopause are few. Recently a rhubarb extract was shown to be more effective 
than placebo, but this has not been standardized and is unavailable in North America. There are 
two trials of OC in perimenopause. In one case OC was not better than placebo 50, and in the 
other case incomplete description of the methods and methodological flaws limit data 
interpretation 51. Medroxyprogesterone, which is a progestin that is most biochemically similar to 
progesterone of any other available in North America, has repeatedly been shown to be effective 
for VMS 37;38 and equally effective as estrogen 39. The results of three trials of transdermal 
progesterone cream were inconsistent, with one showing efficacy and the others not 46-48. 
 
There is an extensive systematic review of the literature on hormonal therapies in 
postmenopausal and perimenopausal women 40 that was prepared following the Women’s Health 
Initiative clinical trial results to support a 2005 NIH Consensus conference 41. This review and 
the summary documents from the consensus statement summarize the same few studies on 
progestins and progesterone that we have found, and call for more research in this area. 
Systematic searches of the clinical trial registries and of PubMed have not found any further 
relevant research. 
 
1.5 Use of trial results  
The trial results will be published in peer-reviewed journals, and in articles reviewing the options 
for perimenopausal VMS in general medical journals specifically for family practice physicians. 
A variety of media will be used to communicate our trial results such that these results will be 
readily accessible and available to the medical and also the women’s health communities. In 
addition, our results will be presented on the Centre for Menstrual Cycle and Ovulation Research 
(CeMCOR) website (www.cemcor.ubc.ca) to provide information on treatment options for 
treating severe VMS. Our efforts to inform women will use the CeMCOR website, print and 
other media, and free public lectures as well other women’s health on-line resources (BC Centres 
of Excellence for Women and Health, Women’s Health Research Institute, Society for Menstrual 
Cycle Research blog, etc.). 
 
1.6 Potential risks to the safety of participants involved in the trial. 
We do not believe that there are significant risks to participants involved in this trial. There were 
no serious adverse events related to OMP in our recently completed trial with 127 
postmenopausal women 54. In studies of combined therapy, it is common to describe estrogen 
positively and ascribe negative side effects to progestins or progesterone 57;58. There are 
remarkably few placebo-controlled trials on the safety of OMP alone; those that are available 
show positive rather than negative effects 14;18. Both progesterone and synthetic progestins are 
predominantly used to prevent endometrial cancer in postmenopausal women treated with 
estrogen therapy, and drug prescription databases list the same adverse effects for progesterone 
as they do for estrogen therapy. It is worth noting that progestin-only OC carry a clear disclaimer 
that combined estrogen-progestin OC side effects (especially thromboembolic disease) do not 


	

	





Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms Study 
Protocol - Version 7.0; 12 June 2014 
 
Page 8 of 26 
 
apply to progestin-only formulations; this distinction appears to not have been sought for 
progestins or OMP prescribed for non-contraceptive purposes.  
 
No convincing evidence suggests that OMP alone (without estrogen) causes thromboembolism, 
breast cancer, heart disease, migraine headaches, fluid retention or depression, although large, 
long-term safety studies are not available. This is a short-term (3 month) therapy trial and we 
will carefully document adverse events, particularly those that have been attributed to 
progesterone.  
 
Women assessed as having high risk for breast cancer (ie first degree relative with breast cancer 
or known/suspected history of breast cancer) will be required to have a normal screening 
mammogram and clinical breast examination within 12 months of study enrollment. 
 
Women who are breastfeeding will be excluded. 
 
Although fertility is reduced in perimenopause, unplanned conception remains a possibility. 
There are no teratogenic effects of progesterone during pregnancy, however 59. Sexually active 
women wanting to conceive will be excluded; those not planning pregnancy will be strongly 
advised to use appropriate methods of non-hormonal birth control (barrier methods such as 
condoms/diaphragm + vaginal spermicide) for the duration of the study. 
 
The proposed therapy differs slightly from that used in clinical practice. When progesterone is 
prescribed for symptomatic Early Perimenopausal women, the PI typically recommends it be 
taken cyclically (days 14-27 of the regular menstrual cycle or 14 days on and 14 off for those 
with irregular cycles). Clinical practice for women in Late Perimenopause is to prescribe 
progesterone daily because periods are not expected to be regular. Because this trial is treating 
women in both Early and Late Perimenopause, and cyclic OMP would likely be ineffective in 
Late Perimenopause, we will use daily OMP. Because of the disturbed perimenopausal 
hypothalamic-pituitary-ovarian feedback loops, daily OMP should reduce but not eliminate flow, 
and will be unlikely to suppress endogenous estradiol levels in those in Early Perimenopause 
whose flow has been regular or slightly irregular.  
 
Late Perimenopausal bone loss is almost universal (almost 2% loss a year by meta-analysis of 
spine dual energy X-ray absorptiometry 23;60), therefore we will provide all participants with the 
“ABC’s of Midlife Osteoporosis Prevention” handout (from www.cemcor.ubc.ca) and advise 
they follow its instructions.  
 
The dose of OMP, 300 mg/day, is one that, although larger than the typical 100-mg 
postmenopausal dose, keeps the blood level of progesterone above the luteal phase threshold for 
24 hours, given that, because of drowsiness effects, it must be dosed only at bedtime 61. 
 
OMP causes drowsiness in some women, and so should be taken just before bed. This timing is 
predominantly so that the soporific effects of OMP occur during sleep, which has two benefits: 
(i) drowsiness happens during sleep and does not interfere with daytime functioning; (ii) it can 
decrease sleep latency, increase early REM sleep and decrease sleep fragmentation 14, all of 
which are benefits in this population. The precise timing is not important, and usual variability in 
bedtimes will not be an issue. 
 


	

	





Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms Study 
Protocol - Version 7.0; 12 June 2014 
 
Page 9 of 26 
 
2. The Trial 
2.1 Trial design  
This is a double-masked, placebo-controlled 28-day (4-week) baseline, 84-day (12-week) 
experimental trial, enrolling 175 women and stratifying random therapy assignment by Early or 
Late Perimenopause. 
 
2.2 Trial interventions  
The proposed trial intervention is OMP, 300 mg/day (Experimental) or matching placebo 
(Control), each taken as three capsules daily before sleep. This is important because OMP should 
not be taken during waking hours because of its soporific effects 14. The dose of 300 mg of OMP 
is a physiological one that maintains the serum progesterone at or above the luteal (normal post-
ovulatory) threshold for 24 hours 61.  
 
Placebo-control of trials are required for VMS therapy because of the well-known response to 
placebo treatment, estimated by meta-analysis of RCT studies as 50.8% improvement (95% CI 
41.7-58.5) 56. Postmenopausal women randomized to placebo in our randomized trial showed a 
22% reduction in VMS Score (daytime VMS number X intensity plus nighttime VMS number X 
intensity) from baseline 54. Also, there are no effective therapies to use for an active comparison. 
There is an additional reason to include a placebo control for a VMS trial with perimenopausal 
women, because the natural history is for hot flushes to be variable and to increase over time to a 
maximum during the final year without flow 3;9.  
 
2.3 Allocation of participants within the trial  
Random allocation will be stratified by phase of perimenopause (Early, <60 days cycle length, 
versus Late, having had at least one >60 day long menstrual cycle). Two lists of random numbers 
will be computer-generated by a statistician not associated directly with the study. Permuted 
blocks of size 10 will be used. A research pharmacist will access appropriate (Early or Late 
Perimenopause) lists from this computer webpage to determine whether to dispense 
Experimental or Control therapy.   
 
2.4 Protecting against bias  
Neither participants nor research staff (including the research coordinator, and anyone directly 
related to the trial) will know who received Experimental or Control therapies. The only person 
directly interacting with participants who will know the therapy assignment will be the research 
pharmacist. Progesterone and placebo will be provided as white coloured, round capsules, 
identical except for the active ingredient. Investigators will remain masked until all participants 
have completed the study and the data have been entered, cleaned and checked.  
 
As each participant completes her participation, the research pharmacist will provide her with a 
letter disclosing her therapy assignment, with instructions to not disclose it to the researchers. 
(Although therapy assignment is conventionally withheld from participants until study 
completion, we feel that participants need this information to make informed choices about 
active therapy following their participation and before the end of the study. By providing women 
with copies of their own diary data and their therapy group assignment, we allow them, in a 
timely manner, to directly benefit from study participation. We have found this an additional 
incentive for study participation.) 
 


	

	





Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms Study 
Protocol - Version 7.0; 12 June 2014 
 
Page 10 of 26 
 
Besins Healthcare, providers of drug and placebo, will have no role in the design, conduct, 
analysis or publication of the study. 
 
2.5 Inclusion/exclusion criteria 
To make the study as widely generalizable as possible, the study inclusions are broad and there 
are minimal exclusions:  
 
Inclusion: 
 
• >35 to <58 years of age 
• At least4 VMS per day on average, for at least two weeks of every four-weeks, or at 
least 56 over a four-week period. In addition, women should report having VMS that 
of moderate or severe rather than of mild intensity. Women reporting fewer VMS 
than this, but who report night sweats that awaken them from sleep on two or more 
nights per week will also be included, because we believe that VMS that disturb sleep 
are clinically important.  
• Perimenopausal status either based on irregularity of menstrual periods, or by onset of 
new perimenopausal symptoms in women with regular periods 22  (as described 
earlier). 
• At least one menstrual period within 12 months of study enrollment 
• Ability and willingness to complete the Daily Perimenopausal Hot Flush Calendar 
recording instrument.  
• Ability to understand, speak, read and write English. 
• Women who are at high risk for breast cancer (ie first degree relative with breast 
cancer, known/suspected history of breast cancer) will be required to have a normal 
mammogram and clinical breast examination within 12 months of study enrollment. 
 
 
Exclusion: 
• VMS without perimenopausal etiology 
• Women who have had a  hysterectomy, ± ovariectomy 
• Peanut allergy (because peanut oil is used in the progesterone formulation) 
• Current or recent (within 6-mo of study enrollment) use of hormonal therapies (estrogen, 
progesterone, hormonal contraceptives, hormonal fertility treatments), or plans to initiate 
use during the study period.  Two exceptions will be made.  The first is women using a 
progestin-releasing intrauterine device (IUD) will not be excluded as it is felt that the 
level of hormone released will not have an effect on VMS.  The second is women taking 
very low-dose transdermal progesterone therapies who have VMS and meet inclusion 
criteria will be considered for inclusion on a case-by-case basis.  If enrolled, they will be 
required to continue and document use of this very low-dose hormone therapy throughout 
the entire trial. 
• Planned pregnancy or fertility treatment during the study period 
• Women who are breastfeeding 
• Participants with a score of > 15 on the Personal Health Questionnaire (PHQ-9) will be 
assessed on a case-by-case basis.  Women assessed as needing further investigation 
and/or treatment for depression will be excluded. 
 


	

	





Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms Study 
Protocol - Version 7.0; 12 June 2014 
 
Page 11 of 26 
 
2.6 Duration of the experimental period 
The treatment period is 12-weeks (84 days). This is conventional for VMS treatment trials, and is 
recommended by the FDA for VMS studies for postmenopausal women 62. 
 
2.7 Frequency and duration of participant follow up 
 
Screening Study enquirers will be screened initially by telephone.  
 
Subsequent study visits will occur in-person or through remote participation; this differentiation 
will be recorded in the study database.  Procedures are identical for both types of participation 
except that communication for remote participation will be through web-conference (Skype), 
telephone, email or mail. Participants returning study documents and medication via mail will be 
provided with postage-paid envelopes.  Faxes will be received into confidential fax machines. 
 
Initial Visit  
Women will review the consent form sent by email, fax or mail.  Eligible women who remain 
interested will be seen in person, sign informed consent, receive a fully executed copy of the 
consent, complete questionnaires and be taught to keep the Daily Perimenopause Hot Flush 
Calendar (‘the Calendar.’) Instructions for completing the Calendar will be included on the 
Calendar form. With remote participation, verbal consent will be obtained,  the participant will 
email, fax, mail the signed consent. As measures of good health practice, breast self-examination 
will be taught, women will be encouraged to perform this monthly and women will be provided 
with a handout on osteoporosis prevention.  
 
Randomization Visit (one month after initial visit)  
The Calendar data will be assessed for completeness and clarity. Participants will complete some 
health questionnaires. Based on self-report of maximum menstrual cycle length during the 
previous year, women will be stratified to Early (<60 days) versus Late Perimenopause (>60 
days). This information will be provided with a prescription to the study pharmacy so they can 
be randomized to Experimental or Control therapy. With remote participation the research 
coordinator will obtain study medication on the participant’s behalf and send it to the participant 
via courier. 
 
Monthly follow-up while on study treatment  
During study treatment period, women will be contacted by telephone or e-mail monthly to 
assess their progress, monitor for safety and to answer any of their questions.  
 
Final Visit  
Women will return completed Calendar forms, complete questionnaires, return any remaining 
study  medication. Returned pills will be counted and/or Calendar recording will be reviewed, to 
assess adherence and ensure drug accountability.  The final questionnaire may be 
emailed/faxed/mailed to the participant for completion the day following last dose of study 
treatment, in the event the final visit cannot be scheduled for this date. 
 
2.8 Primary and secondary outcome measures 
The primary outcome will be assessed from prospective records using the Daily Perimenopause 
Hot Flush Calendar. The Calendar is a one-page chart with a vertical column for each day of the 
month that includes flow, sleep problems and anxiety as well as VMS (attached). Items are rated 


	

	





Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms Study 
Protocol - Version 7.0; 12 June 2014 
 
Page 12 of 26 
 
on 5-point scales or as counts, as appropriate. Daily VMS frequency and severity are recorded 
separately for hot flushes during the individual’s waking or work day and night sweats that occur 
during sleep. Uniformity of training will be addressed through standardized verbal and written 
instructions.   
 
PRIMARY OUTCOMES  
1. Vasomotor Symptoms (VMS) – VMS Score, computed from prospective daily Calendar 
ratings of night sweat frequency and severity and hot flush frequency and severity as 64: 
Daily VMS Score = (# night sweats) x (severity) + (# hot flushes) x (severity) and 
summarized as a daily average during the final 28 days of therapy with average run-in 
scores as a covariate. This composite score has the advantage that it includes both 
number and intensity during the waking day and during sleep. However, this score 
assumes that two moderate episodes are equivalent to a single very intense episode, 
which may or may not be the case.  
Subgroup analysis for those with frequent and severe VMS: To complement this analysis, 
we will do a subgroup analysis of the number and VMS Score for those with more 
frequent (≥7/d and moderate to severe episodes of intensity >2) at baseline. 
     2.    Frequency and Severity (0-4) of VMS, evaluated from prospective daily Calendar  
            ratings as a daily average during the final 28 days of therapy with average run-in scores  
            as covariates.  
SECONDARY OUTCOME: 
3. Daily prospective ratings of Sleep Problems (0-4) and Anxiety (0-4) evaluated from 
prospective Calendar ratings as a daily average during the final 28 days of therapy with 
average run-in scores as covariates. 
 
As additional assessments of health, participants will complete the following questionnaires: 
 
Personal Health Questionnaire – 9 (PHQ-9) is a standardized questionnaire administered as a 
screening tool for depression 66.  A score of 15 or higher represents moderately severe depression 
and is the point at which treatment is recommended.  Women with PHQ-9 scores > 15 will be 
assessed on a case-by-case basis. Women will be excluded if assessed as needing treatment 
and/or further investigation for depression.  Also,  region-specific contact information for mental 
health resources will be provided. Women suspected of being suicidal will be advised to go to 
the nearest emergency department and emergency services will be deployed as appropriate.  The 
PHQ-9 will be completed at the randomization and final visits.  
 
CeMCOR Perimenopause Interference Questionnaire (attached). 
We have recently developed and validated this two-item, self-administered visual analog scale to 
assess the extent to which the body and mood changes of perimenopause interfere with a 
woman’s usual activities. The two items are averaged to provide a single 100-point score. In a 
recent validation study (Hitchcock & Prior, unpublished MS), we showed fair test-retest 
repeatability over a 1-2 month period (R=0.51, n=42), as well as a good correlation with the 
Vitality Scale of the SF-36 HRQoL instrument (R=0.59, n=62). Using the interpersonal 
comparison method of Redelmeier 69, we estimate that the minimal important difference in the 
CeMCOR-PIQ is 17. The CeMCOR-PIQ will be completed at the initial, randomization and final 
visits.   
   


	

	





Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms Study 
Protocol - Version 7.0; 12 June 2014 
 
Page 13 of 26 
 
2.9 Measurement of outcome measures at follow up 
The study timeline for each subject is shown on the following page. Women will complete the 
Diary or Calendar throughout the study. Questionnaires will be completed at the initial, 
randomization and final visits.   
 
2.10 Relevance to health care service  
No formal health economic analysis is planned. The costs of the proposed intervention are 
modest (as compared with, e.g., surgery) and a complete health economic analysis would require 
data collection well beyond the scope of the study.  
 
2.11 Sample size  
The proposed sample size is 175 women, to be stratified into Early and Late Perimenopause 
and randomized equally to active therapy or placebo. Previous analysis of similar VMS Score 
data from menopausal breast cancer therapy studies 64 concluded that a VMS Score difference of 
3 is clinically important, which supports our recent estimate of 2.7 for the minimal important 
difference in perimenopausal women using the interpersonal assessment methods of Redelmeier 
69 (Hitchcock & Prior, unpublished MS). This corresponds to an effect size of 0.58 64. We 
anticipate more VMS variability in perimenopause than in postmenopause, and thus a smaller 
effect size. The sample size of 175 reflects an anticipated discontinuation rate of 20% (as in our 
past progesterone trial for VMS in postmenopausal women), and an effect size of 0.48 (revised 
to allow for 20% greater SD in perimenopausal women above that in postmenopause), an alpha 
of 0.05 using a two-tailed test and having a power of 0.80 to detect a significant difference 
between two groups (calculations using GPower3)73. 
 
2.12 Recruitment—rate, organization, evidence it is achievable 
Given our previous recruitment success, we anticipate that many perimenopausal women will be 
interested in participating. Each woman’s participation will take 112 days (timeline below).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


	

	





Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms Study 
Protocol - Version 7.0; 12 June 2014 
 
Page 14 of 26 
 
 
Figure 3: Flow of Participants through the Trial.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Meets inclusion criteria (phone) 
Baseline Data collection x 4 weeks 
Final Clinic Visit (in-person or remote)_ 
 
• 
Questionnaires, pill count 
 
Initial Clinic Visit (in-person or remote) 
Questionnaires & Calendar teaching 
Randomization Clinic Visit (in-person or remote) 
 
• Check Calendar Quality—if ok 
• Questionnaires 
• Stratified Randomization to Active or Placebo, 
within Perimenopausal Phase (Early or Late) 
Continuous Active or Placebo Therapy x 12 weeks 
• 
Daily Perimenopause Hot Flush Calendar 
daily 
• 
Monthly contact (phone/e-mail) to monitor 


	

	





Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms Study 
Protocol - Version 7.0; 12 June 2014 
 
Page 15 of 26 
 
We plan a three-year continuous recruitment period, with a gradual increase in recruitment 
during this time as word-of-mouth increases (see Gantt chart in appendices). We will allow 
extension of this recruitment period if enrollment targets are not met and funds allow.  We 
project enrollments of 20, 60, 75 and 20 women during the four years of the study (Year 1 
includes 6 months of recruitment; Year 4 includes two months of recruitment and 4 months to 
allow completion of the study by the last participants) with an anticipated six women enquiring 
about participation for each eligible and enrolled participant (based on our pilot research 
experience).  
 
Our past recruitment experience has shown that broadcast emails at a local health authority, 
posting notices on library and community boards, advertising on the CeMCOR web page and 
newsletter, and free public lectures on perimenopause will all be effective. We will, of necessity, 
include more internet and social media-based as well as cross-Canada women’s health and 
perimenopausal contacts to aid recruitment.  For our recently completed randomized trial for 
postmenopausal women, we enrolled 178 postmenopausal women with VMS, using more 
stringent screening conditions (e.g., non-smoking, normal body weight, no history of heart 
disease, normal measured fasting glucose and lipids and ECG). Many were perimenopausal who 
sought information but were ineligible for that study, further illustrating the demand for a 
perimenopausal VMS study.  
 
CeMCOR has a history of excellent recruitment: 120 women contacted us the first day of a study 
needing 100 women; 610 premenopausal women not on OC were enrolled and studied for one 
menstrual cycle within a 16-month time period; and 114 women with PCOS enrolled and were 
studied within 8 months. Thus, recruitment of the required 175 women is feasible given the 
geographical and women’s media reach of investigators and collaborators and use of internet and 
social media recruitment strategies.   
 
Approximately 22% of all women in the Metro Vancouver region are in perimenopause and, 
based on a recent large epidemiological survey, approximately 9% of this population will have 
severe VMS 1. Remote participation will offer the opportunity for women living outside the 
Metro Vancouver area to participate as well.  There is a large population of women looking for 
answers and likely to enroll. CeMCOR and the PI have a history of excellent study recruitment 
rates, supported by a popular website for laywomen (www.cemcor.ubc.ca) and the publication of 
several books, including an award-winning book about perimenopause, Estrogen’s Storm 
Season—stories of perimenopause 10.  
 
2.13 Compliance/Adherence 
The research coordinator will be systematically making contact with and ensuring the well being 
of each participant monthly during the experimental phase. If adherence or record-keeping 
problems were anticipated, this should decrease those risks.  
 
A review of adherence in our progesterone for postmenopausal VMS study showed that 98.8% 
of women used 80% or more of their pills, and the average was 96%. The single individual with 
poor adherence (42%) discussed her difficulty with the coordinator. Part of our research practice 
is to reassure women that we all occasionally miss pills, and to record this. This limits the 
perception that we expect perfect adherence, decreases participant anxiety, and leads to openness 
about pill taking. Serum progesterone levels could, potentially, be used to confirm adherence. 


	

	





Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms Study 
Protocol - Version 7.0; 12 June 2014 
 
Page 16 of 26 
 
However, in perimenopause this measurement would be confounded by menstrual cycle timing 
and progesterone production following ovulation. It is a greater burden to participants and 
research staff than warranted to obtain a timed progesterone blood sample (at a particular phase 
of the menstrual cycle) in perimenopause, a life phase characterized by unpredictable and 
sometimes very long menstrual cycles. 
 
Recent reports of the unreliability of paper-based daily diary methods have come from studies 
funded by companies who market hand-held electronic record systems 74. Electronic diary 
systems are expensive and carry their own issues of training and usability.  However, we will be 
open to developing one should the opportunity arise and funds allow. Our experience over more 
than 25 years of using daily diary instruments in clinical and research practice is that women are 
motivated to keep accurate diaries. They often report that the diary-keeping provides valuable 
insights and helps them understand their new and confusing experiences. The information 
women gain about their own experience through keeping the Diary or Calendar is, itself, 
rewarding and encourages study continuation. Our study coordinator emphasizes that the 
Calendar is important as our primary tool for measuring VMS, and suggests that the woman use 
it to understand and learn more about herself. 
 
A routine Calendar check after the baseline month and before randomization further ensures data 
quality. Should there be a problem with diary quality, the research coordinator will individually 
review items, offer supportive corrective feedback and  will ask that the participant keep her 
record for a further baseline month. All of these strategies are likely to lead to excellent Diary or 
Calendar quality.  
 
2.14 Likely rate of loss to follow up  
We anticipate that 20-25% of women will discontinue the study following randomization. This 
figure is based on our experience of those who did not complete our progesterone for 
postmenopausal VMS study (not including secondary exclusions for abnormal lipids or ECG) in 
our similar-length trial. The higher figure was for drop-outs during a more demanding (one cycle 
of daily urinary hormone collection) pilot observational study of perimenopausal VMS. 
 
2.15 How many centres will be involved? 
This is a single-centre study by CeMCOR at Vancouver Coastal Health Research Institute. Given 
the required sample size, broad inclusion criteria and lack of need for in-person visits, it is 
feasible to complete this study as a single centre trial; the methodologies and quality assurance 
measures are all in place. However, given our unexpected recruitment shortfall we have 
converted it to a single centre Canada-wide trial with remote or in-person options even for 
locally residing participants.  
 
2.16 Statistical analysis  
The analysis will use analysis of covariance (ANCOVA) of the final outcome variable by 
therapy assignment, phase of perimenopause (Early/Late) and the interaction of therapy with 
phase, with baseline outcome variable as a covariate 75. The interaction term will assess the 
possibility that the response to therapy differs between those in Early and Late Perimenopause.             
For Daily Perimenopause Diary or Calendar VMS data, two 28-day (4-week) averages will be 
compared: immediately prior to therapy assignment and the final 4-weeks of the treatment phase. 
For questionnaires, the scores from pre-randomization and final visits will be used. The 


	

	





Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms Study 
Protocol - Version 7.0; 12 June 2014 
 
Page 17 of 26 
 
assumptions of parametric analysis will be checked, and data will be either transformed prior to 
analysis or analyzed non-parametrically as required. 
 
The primary analysis will be intent to treat including all women randomized and taking at least 
one dose of the experimental/placebo therapies with data carried forward. For practical reasons, 
only those with at least 14 days of Daily Perimenopause Diary or Calendar data will be included 
in any diary-based outcome measures (one week of baseline and one week of therapy).  
 
2.17 Frequency of analyses 
There will be a single primary analysis when all data are entered into a database and checked for 
completeness and accuracy. However, our sample size calculations were based on the 
assumption that the SD for within-woman change during perimenopause will be 20% greater 
than that in menopause. Through the Data Safety and Monitoring Committee, an interim analysis 
when we have sufficient data for comprehensive assessment, will confirm whether this 
assumption was accurate; if necessary, we will increase our enrollment target to ensure we have 
80% power.  
 
2.18 Subgroup analysis 
We plan to do a sensitivity analysis of the results for those women whose pill counts show at 
least 80% adherence for at least 60 days of experimental treatment. 
 
We will also perform a subgroup analysis for those women who meet the FDA recommended 
(postmenopausal) threshold for frequent, moderate-severe VMS (>50 VMS/wk of >2 intensity).  
 
Should our enrollment of women identifying as non-white/non-Caucasian allow it, we will assess 
the role of ethnicity in the effectiveness of progesterone therapy for VMS. 
 
Participants in clinical trials may become unmasked to therapy assignment as a result of their 
experiences. Because, in our previous trial, women used lack of drowsiness or improved sleep to 
decide they were on placebo, we have explicitly stated in the consent that not all women on 
progesterone experience sleep changes. To address the role of expectation on the outcomes, at 
the final visit we will ask women whether they believe that they were randomized to the 
Experimental or Control therapy. This information will be used to examine the potential role of 
expectation on the VMS outcome. 
 
2.19 Pilot data 
The experimental design is exactly parallel to a recently completed study. In that study, we 
enrolled 178 healthy VMS treatment-seeking postmenopausal women (1-10 years beyond their 
last menstrual period) into a randomized, double blind, placebo-controlled trial of daily OMP 
(300 mg). Secondary cardiovascular exclusions do not apply to the proposed perimenopausal 
study, therefore we have incorporated the observed rate of women discontinuing after 
randomization (20%) into our power analysis.  
 
We also have studied 27 menstruating early perimenopausal women aged 35-50 with regular 
menstrual cycles and night sweats in a four-cycle observational study to pilot and validate some 
new questionnaires and to confirm our sample size calculations. Of these, 20 completed the 
entire trial (including a 1.5 cycle daily first morning urine collection). Based on this experience, 
we anticipate that we will enroll one woman out of each six contacts, and that 20% of enrolled 


	

	





Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms Study 
Protocol - Version 7.0; 12 June 2014 
 
Page 18 of 26 
 
women will discontinue before study completion. Women appear most likely to discontinue prior 
to randomization. 
 
3. Trial Management 
3.1 Arrangements for day-to-day management of the trial 
A research coordinator for the study will handle the day-to-day tasks of responding to potential 
participants who enquire, assessing eligibility, teaching them how to complete the Calendar and 
interviewing them. The research coordinator will be under the direct supervision of the principal 
investigator and will meet with her regularly at no less than two week intervals. 
 
When participants have completed the baseline assessment and their symptoms meet 
randomization criteria, they will be given a prescription for masked study medication which also 
has information on their Early or Late Perimenopause status. The pharmacist will access the 
web-based treatment allocation programme to obtain the next randomly selected allocation (see 
section 2.3 for details), and dispense either OMP or placebo to the participant.   For remote 
participants, the research coordinator will go the study pharmacy on the participant’s behalf and 
send the medication by courier.   
       
Should there be a medical need to determine the therapy assignment for a participant during the 
study, Dr. Michelle Fung, who is not directly involved with participants, will address any 
relevant clinical concerns.  Dr. Caroline Ferris or Dr. Sandra Sirrs who are also not directly 
involved with participants, will act as back-up in the event Dr. Fung is unavailable.   
 
3.2 What is the role of each principal investigator and co-investigator? 
Jerilynn C. Prior BA MD FRCPC: Principal Investigator. Dr. Prior has over 30 years of clinical 
research experience, including designing and conducting four previously published RCT, and is a 
full time UBC Professor of Endocrinology. Dr. Prior is responsible for the conception, 
justification, design, conduct and publication/communication/translation of trial results as well as 
direct supervision of the research coordinator and all other personnel. 
 
Andrea Cameron RN BScN:  Co-Investigator.  Ms. Cameron will be the research coordinator 
for the trial and contribute to decisions regarding trial design, management and conduct as well 
as being involved in the interpretation and publication of results. 
 
Michelle Fung MHSc MD FRCPC: Co-Investigator. Dr. Fung is a Clinical Assistant Professor 
of Endocrinology with previous research design and implementation training and is active in islet 
cell transplantation research at VCHRI. Dr. Fung works at the Osteoporosis Clinic and has her 
own practice from which she can inform potential participants of the study. She will not be 
directly involved in participant management and thus could handle unexpected adverse events, 
including breaking the code, if necessary. 
 
Christine L. Hitchcock MA, PhD: Co-Investigator. Dr. Hitchcock has clinical research 
experience and has worked with Dr. Prior for over 12 years. She has contributed importantly to 
experimental design and development of study materials. Since she is no longer in the region, 
depending on her continued input she will participate in the final analysis and interpretation/ 
publication of the data or not.   
 


	

	





Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms Study 
Protocol - Version 7.0; 12 June 2014 
 
Page 19 of 26 
 
Shirin Kalyan PhD: Co-Investigator. Dr. Kalyan is a UBC Research Associate after a three-year 
post-doctoral clinical research fellowship with Drs. Prior and Hitchcock. Dr. Kalyan, now a 
Junior Research Fellow in the prestigious von Humboldt programme in Germany but is expected 
to return to a UBC position in 2014. She will assist in later trial management, and preparation of 
final manuscripts and knowledge translation. 
 
Sandra Sirrs MD FRCPC: Co-Investigator.  Dr. Sirrs is a seasoned endocrinology clinician who 
will provide support and advice in the conduct of the trial, act as back-up physician for breaking 
the code and assist with the interpretation and dissemination of the results. 
 
Patricia Janssen PhD: Co-Investigator. Dr. Janssen, a Professor in SPPH at UBC with a clinical 
background in nursing and midwifery, has designed, funded and conducted practical clinical 
trials in women’s health and worked with Dr. Prior for >6 yr. Dr. Janssen will review the 
experimental design, and assist in research interpretation and publication. 
 
Joel Singer, PhD: Co-Investigator.  Dr. Singer is a professor in the SPPH at UBC.  He will be 
involved with important decisions regarding study management, interpretation and analysis of 
data and publication of results. 
 
Caroline Ferris MD: Collaborator.  Dr. Ferris is a family practitioner and founder of the 
Morgan Creek Women’s Health Clinic in a southeastern suburb of Vancouver.  She is also 
working with the Fraser Health Authority, has previously worked with Dr. Prior and will be a 
primary/family physician consultant for the study, contact for the family physician community, 
and will be active in recruitment and knowledge translation. She is also a back-up physician for 
breaking the code.    
 
Elana Brief PhD: Collaborator.  Dr. Brief is a UBC Research Associate in Physics, and active in 
promoting women’s health research in BC through several leadership roles. She will also be 
assisting with recruitment and knowledge translation.  
 
3.3 Trial Steering Committee and Data Safety and Monitoring Committees 
All co-investigators will form the Trial Steering Committee—this group will meet as needed 
during and following the trial until the results are published and disseminated. 
 
A Data Safety Monitoring Committee (DSMC) will consist of three members including a 
methodologist/statistician (Chair—Dr. Hubert Wong, Professor SPPH at UBC) and two 
clinician-scientists with clinical trials experience and expertise in perimenopause and VMS (Drs. 
Nanette Santoro, Chair of Obstetrics and Gynecology at University of Colorado in Denver and 
Leora Swartzman, Associate Professor of Psychology at University of Western Ontario in 
London, Ontario). The DSMC will meet every six months during the trial. 
 
4.  Assessment of Safety 
 
An Adverse Event will be defined as follows:   
Any untoward medical occurrence in a participant administered a pharmaceutical product and 
which does not necessarily have to have a causal relationship with this treatment.   
 
A Serious Adverse Event will be defined as follows:   
A serious adverse event (experience) or reaction is any untoward medical 


	

	





Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms Study 
Protocol - Version 7.0; 12 June 2014 
 
Page 20 of 26 
 
occurrence that at any dose: 
 results in death, 
 is life-threatening, 
 requires inpatient hospitalization or prolongation of existing hospitalization, 
 results in persistent or significant disability/incapacity, or 
 is a congenital anomaly/birth defect .  
 
Adverse events will be assessed throughout study participation through direct questioning of 
study participants, by specific study-end questionnaires and will all be followed to resolution. 
 
All serious adverse events will be assessed by the principal investigator, reported to the DSMC 
and the local research ethics board, and be followed to resolution.  Adverse Drug Reactions will 
be reported to Health Canada per applicable regulatory guidelines.  For study data purposes, 
period of capture for serious adverse events and adverse drug reactions will be from first, up to 
and including last day of study treatment. 
 
 
Reference List 
 
 
(1)  Williams RE, Kalilani L, DiBenedetti DB et al. Frequency and severity of vasomotor 
symptoms among peri- and postmenopausal women in the United States. Climacteric 
2008;11:32-43. 
 
(2)  Politi MC, Schleinitz MD, Col NF. Revisiting the duration of vasomotor symptoms of 
menopause: a meta-analysis. J Gen Intern Med 2008;23:1507-1513. 
 
(3)  Col NF, Guthrie JR, Politi M, Dennerstein L. Duration of vasomotor symptoms in 
middle-aged women: a longitudinal study. Menopause 2009;16:453-457. 
 
(4)  Freeman EW, Sammel MD, Lin H, Liu Z, Gracia CR. Duration of menopausal hot 
flushes and associated risk factors. Obstet Gynecol 2011;117:1095-1104. 
 
(5)  Thunell L, Stadberg E, Milsom I, Mattsson LA. A longitudinal population study of 
climacteric symptoms and their treatment in a random sample of Swedish women. 
Climacteric 2004;7:357-365. 
 
(6)  Bardel A, Wallander MA, Svardsudd K. Hormone replacement therapy and symptom 
reporting in menopausal women: a population-based study of 35-65-year-old women in 
mid-Sweden. Maturitas 2002;41:7-15. 
 
(7)  Kravitz HM, Ganz PA, Bromberger J, Powell LH, Sutton-Tyrrell K, Meyer PM. Sleep 
difficulty in women at midlife: a community survey of sleep and the menopausal 
transition. Menopause 2003;10:19-28. 
 
(8)  Shaver JL, Paulsen VM. Sleep, psychological distress and somatic symptoms in 
perimenopausal women. Fam Pract Res J 1993;13:373-384. 


	

	





Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms Study 
Protocol - Version 7.0; 12 June 2014 
 
Page 21 of 26 
 
 
(9)  Dennerstein L, Dudley EC, Hopper JL, Guthrie JR, Burger HG. A prospective 
population-based study of menopausal symptoms. Obstet Gynecol 2000;96:351-358. 
 
(10)  Prior JC. Estrogen's Storm Season- Stories of Perimenopause. reprinted 2007 ed. 
Vancouver, BC: CeMCOR, 2005. 
 
(11)  Vaari T, Engblom J, Helenius H, Erkkola R, Polo-Kantola P. Survey of sleep problems 
in 3421 women aged 41-55 years. Menopause Int 2008;14:78-82. 
 
(12)  Prior JC. Perimenopause lost - reframing the end of menstruation. Journal of 
Reproductive and Infant Psychology 2006;24:323-335. 
 
(13)  Hale GE, Hitchcock CL, Williams LA, Vigna YM, Prior JC. Cyclicity of breast 
tenderness and night-time vasomotor symptoms in mid-life women: information 
collected using the Daily Perimenopause Diary. Climacteric 2003;6:128-139. 
 
(14)  Schussler P, Kluge M, Yassouridis A et al. Progesterone reduces wakefulness in sleep 
EEG and has no effect on cognition in healthy postmenopausal women. 
Psychoneuroendocr 2008;33:1124-1131. 
 
(15)  Montplaisir J, Lorrain J, Denesle R, Petit D. Sleep in menopause: differential effects of 
two forms of hormone replacement therapy. Menopause 2001;8:10-16. 
 
(16)  Friess E, Tagaya H, Trachsel L, Holsboer F, Rupprecht R. Progesterone-induced 
changes in sleep in male subjects. Am J Physiol 1997;272:E885-E891. 
 
(17)  Prior JC, Hitchcock C, Sathi P, Tighe M. Walking the Talk: Doing Science with 
Perimenopausal Women and their Health Care Providers. Journal of Interdisciplinary 
Feminist Thought 2007;2:43-57. 
 
(18)  Dennerstein L, Spencer-Gardner C, Gotts G, Brown JB, Smith MA. Progesterone and 
the premenstrual syndrome: a double blind crossover trial. Br Med J 1985;290:1617-
1621. 
 
(19)  Gibson CL, Coomber B, Rathbone J. Is progesterone a candidate neuroprotective factor 
for treatment following ischemic stroke? Neuroscientist 2009;15:324-332. 
 
(20)  Soules MR, Sherman S, Parrott E et al. Executive summary: stages of reproductive 
aging workshop (STRAW). Fertil Steril 2001;76:874-878. 
 
(21)  Harlow SD, Cain K, Crawford S et al. Evaluation of four proposed bleeding criteria for 
the onset of late menopausal transition. J Clin Endocrinol Metab 2006;91:3432-3438. 
 
(22)  Prior JC. Clearing confusion about perimenopause. BC Med J 2005;47:534-538. 
 
(23)  Prior JC. Perimenopause: The complex endocrinology of the menopausal transition. 
Endocr Rev 1998;19:397-428. 


	

	





Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms Study 
Protocol - Version 7.0; 12 June 2014 
 
Page 22 of 26 
 
 
(24)  Hale GE, Zhao X, Hughes CL, Burger HG, Robertson DM, Fraser IS. Endocrine 
features of menstrual cycles in middle and late reproductive age and the menopausal 
transition classified according to the Staging of Reproductive Aging Workshop 
(STRAW) staging system. J Clin Endocrinol Metab 2007;92:3060-3067. 
 
(25)  Prior JC. Ovarian aging and the perimenopausal transition: the paradox of endogenous 
ovarian hyperstimulation. Endocrine 2005;26:297-300. 
 
(26)  Santoro N, Rosenberg J, Adel T, Skurnick JH. Characterization  of reproductive 
hormonal dynamics in the perimenopause. J Clin Endocrinol Metab 1996;81:4,1495-
1501. 
 
(27)  O'Connor KA, Ferrell RJ, Brindle E et al. Total and Unopposed Estrogen Exposure 
across Stages of the Transition to Menopause. Cancer Epidemiol Biomarkers Prev 
2009;18:828-836. 
 
(28)  Weiss G, Skurnick JH, Goldsmith LT, Santoro NF, Park SJ. Menopause and 
hypothalamic-pituitary sensitivity to estrogen. JAMA 2004;292:2991-2996. 
 
(29)  Moen MH, Kahn H, Bjerve KS, Halvorsen TB. Menometrorrhagia in the 
perimenopause is associated with increased serum estradiol. Maturitas 2004;47:151-
155. 
 
(30)  Hale GE, Hughes CL, Cline JM. Endometrial cancer: hormonal factors, the 
perimenopausal "window of risk", and isoflavones. J Clin Endocrinol Metab 
2002;87:3-15. 
 
(31)  Sitruk-Ware R. Pharmacological profile of progestins. Maturitas 2004;47:277-283. 
 
(32)  Anderson GL, Limacher M, Assaf AR et al. Effects of conjugated equine estrogen in 
postmenopausal women with hysterectomy: the Women's Health Initiative randomized 
controlled trial. JAMA 2004;291:1701-1712. 
 
(33)  Writing Group for the Women's Health Initiative Investigators. Risks and benefits of 
estrogen plus progestin in health postmenopausal women: prinicpal results from the 
Women's Health Initiative Randomized Control trial. JAMA 2002;288:321-333. 
 
(34)  Dinger JC, Heinemann LA, Kuhl-Habich D. The safety of a drospirenone-containing 
oral contraceptive: final results from the European Active Surveillance Study on oral 
contraceptives based on 142,475 women-years of observation. Contraception 
2007;75:344-354. 
 
(35)  Pinkerton JV, Stovall DW. Is there an association between vasomotor symptoms and 
both low bone density and cardiovascular risk? Menopause 2009;16:219-223. 
 
(36)  Lethaby A, Farquhar C. Treatments for heavy menstrual bleeding. BMJ 2003;327:1243-
1244. 


	

	





Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms Study 
Protocol - Version 7.0; 12 June 2014 
 
Page 23 of 26 
 
 
(37)  Schiff I, Tulchinsky D, Cramer D, Ryan KJ. Oral medroxyprogesterone in the treatment 
of postmenopausal symptoms. Journal of the American Medical Association 
1980;244:1443-1445. 
 
(38)  Albrecht BH, Schiff I, Tulchinsky D, Ryan KJ. Objective evidence that placebo and 
oral medroxyprogesterone acetate therapy diminish menopausal vasomotor flushes. Am 
J Obstet Gynecol 1981;139:631-635. 
 
(39)  Prior JC, Nielsen JD, Hitchcock CL, Williams LA, Vigna YM, Dean CB. 
Medroxyprogesterone and conjugated oestrogen are equivalent for hot flushes: a 1-year 
randomized double-blind trial following premenopausal ovariectomy. Clin Sci (Lond) 
2007;112:517-525. 
 
(40)  Nelson HD, Haney E, Humphrey L, Miller J, Nedrow A, Nicolaidis C et al. 
Management of menopause-related symptoms. 120, 2-6. 2005.  Oregon evidence-based 
practice center. Evidence report/Technology Assessment.  
Ref Type: Report 
 
(41)  National Institutes of Health State-of-the-Science Conference statement: management 
of menopause-related symptoms. Ann Intern Med 2005;142:1003-1013. 
 
(42)  Hitchcock CL, Prior JC. Oral Micronized Progesterone for Vasomotor Symptoms in 
Healthy Postmenopausal Women—-a placebo-controlled randomized trial. Menopause 
2012;19:886-893. 
 
(43)  Morrison JC, Martin DC, Blair RA et al. The use of medroxyprogesterone acetate for 
relief of climacteric symptoms. Am J Obstet Gynecol 1980;138:99-104. 
 
(44)  Makarainen L, Ronnberg L, Kauppila A. Medroxyprogesterone acetate 
supplementation diminishes the hypoestrogenic side effects of gonadotropin-releasing 
hormone agonist without changing its efficacy in endometriosis. Fertil Steril 
1996;65:29-34. 
 
(45)  Lobo RA, McCormick W, Singer F, Roy S. Depo-medroxyprogesterone acetate 
compared with conjugated estrogens for the treatment of postmenopausal women. 
Obstet Gynecol 1984;63:1-5. 
 
(46)  Leonetti HB, Longo S, Anasti JN. Transdermal progesterone cream for vasomotor 
symptoms and postmenopausal bone loss. Obstet Gynecol 1999;94:225-228. 
 
(47)  Wren BG, Champion SM, Willetts K, Manga RZ, Eden JA. Transdermal progesterone 
and its effect on vasomotor symptoms, blood lipid levels, bone metabolic markers, 
moods, and quality of life for postmenopausal women. Menopause 2003;10:13-18. 
 
(48)  Benster B, Carey A, Wadsworth F, Vashisht A, Domoney C, Studd J. A double-blind 
placebo-controlled study to evaluate the effect of progestelle progesterone cream on 
postmenopausal women. Menopause Int 2009;15:63-69. 


	

	





Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms Study 
Protocol - Version 7.0; 12 June 2014 
 
Page 24 of 26 
 
 
(49)  Estrogen and progestogen use in peri- and postmenopausal women: March 2007 
position statement of The North American Menopause Society. Menopause 
2007;14:168-182. 
 
(50)  Casper RF, Dodin S, Reid RL, Study Investigators. The effect of 20 ug ethinyl 
estradiol/1 mg norethindrone acetate (MinestrinTM), a low-dose oral contraceptive, on 
vaginal bleeding patterns, hot flashes, and quality of life in symptomatic 
perimenopausal women. Menopause 1997;4:139-147. 
 
(51)  Shargil AA. Hormone replacement therapy in perimenopausal women with a triphasic 
contraceptive compound: a three-year prospective study. Int J Fertil 1985;30:15-28. 
 
(52)  Heger M, Ventskovskiy BM, Borzenko I et al. Efficacy and safety of a special extract 
of Rheum rhaponticum (ERr 731) in perimenopausal women with climacteric 
complaints: a 12-week randomized, double-blind, placebo-controlled trial. Menopause 
2006;13:744-759. 
 
(53)  Prior JC, Seifert-Klauss V, Kalyan S, Pride S. Effectiveness of ERr 731 in the 
management of symptomatic perimenopause: clinical significance. Menopause 14[2], 
1-2. 2007.  
Ref Type: Map 
 
(54)  Prior JC, Hitchcock CL. Progesterone for vasomotor symptoms: A 12-week 
randomized, masked placebo-controlled trial in healthy, normal-weight women 1-10 
years since final menstrual flow [abstract]Prior JC, Hitchcock CL. Endocr Rev 
2010;31:S51 
 
(55)  Pinto MM, Prior JC, Tomlinson G, Cheung AM. Are night sweats related to bone 
change? A prospective population-based study in women 40-60 from the Canadian 
Multicentre Osteoporosis Study [abstract]Pinto MM, Prior JC, Tomlinson G, Cheung 
AM. Endocrine Society Abstracts 2007;P2-143 
 
(56)  MacLennan A, Lester S, Moore V. Oral estrogen replacement therapy versus placebo 
for hot flushes: a systematic review. Climacteric 2001;4:58-74. 
 
(57)  MacDonald PC, Dombroski RA, Casey ML. Recurrent secretion of progesterone in 
large amounts: an endocrine/metabolic disorder unique to young women? Endocr Rev 
1991;12:372-401. 
 
(58)  Baxter S, Prior JC. The Estrogen Errors: Why Progesterone is Better For Women's 
Health. Westport: Praeger Publishers, 2009. 
 
(59)  Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH. Progesterone and the risk of 
preterm birth among women with a short cervix. N Engl J Med 2007;357:462-469. 


	

	





Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms Study 
Protocol - Version 7.0; 12 June 2014 
 
Page 25 of 26 
 
 
(60)  Seifert-Klauss V, link TM, heumann C et al. Influence of pattern on menopausal 
transition on the amount of trabecular bone loss. Results from a 6-year prospective 
longitudinal study. Maturitas 2006;55:317-324. 
 
(61)  Simon JA, Shangold MM, Andrews MC, Buster JC, Hodgen GD. Micronized 
progesterone therapy: the importance of route of administration and pharmacokinetics 
on clinical outcome. J Contracept Fertil Sex 1992;20:13-18. 
 
(62)  Food and Drug Administration. Draft guidance for industry on estrogen and 
estrogen/progestin drug products to treat vasomotor symptoms and vulvar and vaginal 
atrophy symptoms - recommendations for clinical evaluation. Federal Register 
2003;69:5025-5026. 
 
(63)  Prior JC. "The Puzzle of Perimenopause - Using the Daily Perimenopause Diary" 
  .  1999.  
Ref Type: Online Source 
 
(64)  Sloan JA, Loprinzi CL, Novotny PJ, Barton DL, LaVasseur BI, Windschitl H. 
Methodologic lessons learned from hot flash studies. J Clin Oncol 2001;19:4280-4290. 
 
(65)  Hopman WM, Towheed T, Anastassiades T et al. Canadian normative data for the SF-
36 health survey. CMAJ 2000;163:265-271. 
 
(66)  Kroenke K, Spitzer RL, Williams JB. The PHQ-15: validity of a new measure for 
evaluating the severity of somatic symptoms. Psychosom Med 2002;64:258-266. 
 
(67)  Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. J Health 
Soc Behav 1983;24:385-396. 
 
(68)  Swartzman LC, Edelberg R, Kemmann E. Impact of stress on objectively recorded 
menopausal hot flushes and on flush report bias. Health Psychology 1990;9:529-545. 
 
(69)  Redelmeier DA, Guyatt GH, Goldstein RS. Assessing the minimal important difference 
in symptoms: a comparison of two techniques. J Clin Epidemiol 1996;49:1215-1219. 
 
(70)  Schneider HP, Heinemann LA, Rosemeier HP, Potthoff P, Behre HM. The Menopause 
Rating Scale (MRS): reliability of scores of menopausal complaints. Climacteric 
2000;3:59-64. 
 
(71)  Bastien CH, Vallieres A, Morin CM. Validation of the Insomnia Severity Index as an 
outcome measure for insomnia research. Sleep Med 2001;2:297-307. 
 
(72)  Brazier J, Roberts J, Deverill M. The estimation of a preference-based measure of 
health from the SF-36. J Health Econ 2002;21:271-292. 
 
(73)  Erdfelder E, Faul F, Buchner A. GPower: a general power analysis program. Behavior 
Research Methods, Instruments, & Computers 1998;28:1-11. 
 
(74)  Stone AA, Shiffman S, Schwartz JE, Broderick JE, Hufford MR. Patient compliance 
with paper and electronic diaries. Control Clin Trials 2003;24:182-199. 


	

	





Oral Micronized Progesterone for Perimenopausal Vasomotor Symptoms Study 
Protocol - Version 7.0; 12 June 2014 
 
Page 26 of 26 
 
 
(75)  Vickers AJ, Altman DG. Statistics notes: Analysing controlled trials with baseline and 
follow up measurements. BMJ 2001;323:1123-1124. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
18 November 2018 
 
To whom it may concern: 
 
Re: Randomized Controlled Trial of Progesterone for Perimenopausal Vasomotor Symptoms 
 
As Chair of the Clinical Research Ethics Board (CREB) at the University of British Columbia (UBC) that has 
overseen and approved the Canadian Institutes for Health Research-funded Randomized Controlled Trial 
of Progesterone for Perimenopausal Vasomotor Symptoms (VMS) since it began in 2011, I have 
reviewed the posted protocol, which was the latest one approved by CREB and the evidence that it has 
some inadvertent clerical omissions. I have also reviewed the proposed Amendments to this protocol.   
 
The protocol omissions include this study’s Data Safety and Monitoring Committee decision (and details 
about the blinded analysis leading to it) that led to the official increase in sample size. Another was that 
the DSMC mandated addition of the Personal Health Questionnaire-9 (PHQ-9) to screen for depression. 
The investigators then decided (and CREB approved) administration of the PHQ-9 also at the study end. 
However, the analysis of PHQ-9 was inadvertently not listed as a secondary outcome. And finally other 
instruments were included in the study initially for administration at the randomization and the final 
study visits, were approved by CREB, were partially described in the protocol but not were listed as 
secondary outcomes including: a likert-type assessment of “Women’s Perception of Change” (related to 
daytime hot flushes and night sweats, flow and sleep) and the CeMCOR Perimenopause Interference 
Questionnaire (CeMCOR PIQ).  
 
Although it is unusual to amend a RCT protocol once the database has been locked and statistical 
analysis has occurred, these amendments to the protocol are important, and they will allow the 
outcomes of approved, collected instruments to contribute to the scientific literature. To collect data 
that, for inadvertent clerical reasons cannot be evaluated and reported, would be unethical given the 
overall “contract” that participants make with investigators and institutions. Participants expect that 
what they have contributed will add to Knowledge with an expectation of providing benefit for Society 
or Science. 
 
For these reasons, I approve uploading of Amendments dated November 9, 2018 to the 2014 posted 
protocol. 
 
All the best, 
 
 
Stephen 
 
Stephen A Hoption Cann PhD 
Clinical Professor, School of Population & Public Health 
Chair, Clinical Research Ethics Board  
Faculty of Medicine | University of British Columbia 
261-2206 East Mall | Vancouver BC | V6T 1Z3 Canada  
Office  604-822-5688 | Cell  778-928-8383 
hoption.cann@ubc.ca  


Amendments to Protocol—Progesterone for Perimenopausal VMS 
 
Progesterone for perimenopausal VMS RCT 09 November 2018 
Page 1 
 
These amendments are to the Progesterone for Perimenopausal VMS Protocol version 7; 12 June 
2014; 09 November 2018 
Amendment #1 (2.1 Trial Design):  
This enrolment goal was changed to 245 women based on the blinded, pre‐planned interim assessment 
of the “effective SD” during the final month (adjusted by correlation with baseline given that they were 
on experimental or control therapy)  after 68 women had completed the trial.  (see also Amendment 6) 
Amendment #2 (2.4 Protecting against bias) 
When it became clear that the enrolment goal had to be changed (Amendment # 1), a further year of 
recruitment was allowed by the Data Safety and Monitoring Committee.  However, CIHR funding was 
not sufficient to cover this. The PI applied to Besins Healthcare International who, through the 
University of British Columbia and UILO agreed to and provided $40,306.00 to fund the extension of this 
trial with a continued commitment to have no role in the design, conduct, analysis or publication of the 
study. 
Amendment #3 (2.8 Primary and secondary outcome measures)  
The Final Questionnaire (as in the previous progesterone for menopausal RCT43) included an unnamed 
instrument that asked several questions about overall three‐month changes (decreased by up to 5 
points [0 to ‐5] or increased by up to 5 point [0 to +5]) in VMS and in quality of sleep and characteristics 
of flow. This instrument is now named “Women’s Perceived Changes Questionnaire” and has become a 
secondary outcome. 
We have also included at baseline and the final visit the CeMCOR Perimenopausal Interference 
Questionnaire (CeMCOR PIQ) as used in the Perimenopause Experiences Project. The within‐woman 
body and mood changes in interference with usual activities of these two likert‐type measures by 
therapy assignment are also a secondary outcome and will further be analyzed together as a single 
score.  
Finally, the DSMC, partially into the RCT, recommended that we add the Personal Health Questionnaire‐
9 (PHQ‐9) to screen out potential participants who might be depressed or suicidal. We followed their 
instructions but also elected to include the PHQ‐9 at the Final Visit and to assess within‐woman changes 
in the PHQ‐9 score as a secondary outcome.     
Amendment #4 (PRIMARY OUTCOME) 
We will also do subgroup analyses of VMS Score by Early Perimenopause (no skipped period or <60 day 
cycle length) and by Late Perimenopause (those with skipped or ≥60 day cycle lengths). 
Amendment #5 (SECONDARY OUTCOMES) 
1. Women’s Perceived Changes Questionnaire of changes (from ‐5 to 0 to +5) in Daytime Hot 
Flushes and Nighttime Night Sweats and Hot Flushes (both number and severity) as recorded on 
the Final Questionnaire and by subgroup for Early and Late Perimenopause.  
2. Women’s Perceived Changes Questionnaire of changes (from ‐5 to 0 to +5) in the quality of 
sleep over the three months of the trial as assessed by the Final Questionnaire based on their 
random assignment to the progesterone or placebo arms of this RCT and by Early/Late 


Amendments to Protocol—Progesterone for Perimenopausal VMS 
 
Progesterone for perimenopausal VMS RCT 09 November 2018 
Page 2 
 
perimenopause. (This is in addition to the listed secondary outcome:  “sleep problems” from the 
Daily Perimenopause Diary/Perimenopause Hot Flush and Night Sweat Calendar.)   
3. Within‐woman changes in baseline and end‐of‐trial perceptions of interference of 
perimenopausal body changes and mood changes with usual activities (as recorded by the 
CeMCOR Perimenopause Interference Questionnaire [CeMCOR PIQ] at baseline and final) and in 
the within‐woman mean of the two assessments (body and mood) scored together in women 
randomized to the progesterone versus to placebo and by Early/Late Perimenopause. 
4. Vaginal flow (see separate Flow Study protocol) related to progesterone therapy in 
perimenopause will be assessed based on Women’s Perceived Changes Questionnaire of 
changes in the experience of menstrual flow/vaginal bleeding (‐5/+5) from the Final 
Questionnaire, and/or change in their Diary/Calendar recorded use of sanitary products or 
volume of flow recorded by use of a menstrual cup compared with the same experiences in 
women randomized to placebo.  
5. Depression related to progesterone therapy in perimenopause will be assessed based on the 
Personal Health Questionnaire‐9 (PHQ‐9) score changes within‐woman from baseline to the 
end‐of‐trial compared with the women randomized to placebo. 
 
Amendment #6 (2.11 Sample size)  
A pre‐planned evaluation of sample size was undertaken after 68 women had completed the study. This 
involved evaluation of the SD of the VMS Score in the final month without regard to random study group 
assignment. An effective standard deviation (SD) of ~ 9 in the Vasomotor Symptom Score SD over the 
last 4 weeks of experimental therapy was discovered after adjustment for the fact that the final and the 
run‐in SD values correlated with an r of 0.56.  This interim assessment was blinded and without 
knowledge of the therapy. The original estimated SD of 6.25 was used in our application to CIHR. This re‐
evaluation of sample size led to an increased enrolment of goal of 245.