Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05937360 |
| Other study ID # |
CREC-SA.1723/08/2022 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
January 1, 2023 |
| Est. completion date |
December 30, 2023 |
Study information
| Verified date |
August 2023 |
| Source |
The University of The West Indies |
| Contact |
Stephanie Dr Mohammed, Ph.D. |
| Phone |
18687955950 |
| Email |
stephanie.mohammed[@]sta.uwi.edu |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
According to World Health Organization (WHO), in 2010, Polycystic Ovarian Syndrome (PCOS)
affected approximately 116 million women worldwide (3.4% of the population). It has been
considered one of the most common causes of female infertility and the most common endocrine
disorder. The standard diagnosis for the syndrome dates back to international conferences
organized by the National Institutes of Health (NIH) in 1990 and the Rotterdam European
Society of Human Reproduction and Embryology/ American Society for Reproductive Medicine
(ESHRE/ASRM) sponsored PCOS consensus workshop group in 2003 and 2004. Clinical
manifestations of the disease may include menstrual irregularities, amenorrhea,
ovulation-related infertility, polycystic ovaries, and signs of androgen excess such as acne
and hirsutism. This condition may also lead to chronic diseases such as obesity, type 2
diabetes (T2D), dyslipidaemia, and cardiovascular events. Despite the increasing knowledge
concerning PCOS, the global picture of the disorder is deficient in a number of geographic
regions. Understanding the global prevalence will help to better assess the public health and
economic implications of PCOS in Trinidad, allow for improved screening methods, help
elucidate the underlying factors and foster improved understanding of the molecular
mechanisms in improving the evolutionary process.
Description:
Background According to World Health Organization (WHO), in 2010, Polycystic Ovarian Syndrome
(PCOS) affected approximately 116 million women worldwide (3.4% of the population). This
condition caused symptoms in about 5-10% of women of reproductive age (12 - 45 years). It has
been considered one of the most common causes of female infertility and the most common
endocrine disorder. The standard diagnosis for the syndrome dates back to international
conferences organized by the National Institutes of Health (NIH) in 1990 and the Rotterdam
European Society of Human Reproduction and Embryology/ American Society for Reproductive
Medicine (ESHRE/ASRM) sponsored PCOS consensus workshop group in 2003 and 2004 (Rotterdam
ESHER/ASRM-sponsored PCOS consensus workshop group 2004). Clinical manifestations of the
disease may include menstrual irregularities, amenorrhea, ovulation-related infertility,
polycystic ovaries, and signs of androgen excess such as acne and hirsutism. This condition
may also lead to chronic diseases such as obesity, type 2 diabetes (T2D), dyslipidemia, and
cardiovascular events.
Statement of Problem
Despite the increasing knowledge concerning PCOS, the global picture of the disorder is
deficient in a number of geographic regions. Understanding the global prevalence and
phenotypic presentation of any common disorder, including PCOS, allows for:
1. A determination of the prevalence and associated morbidities of the disorder, to better
assess the public health and economic implications of PCOS in this region.
2. A determination of the phenotype of PCOS in this region, allowing for improved screening
methods.
3. The elucidation of underlying environmental or ethnic factors that may affect the
prevalence, severity or complications of the disorder, via comparison of data between
countries.
4. The elucidation of genetic variants underlying the disorder in this region, fostering
and improved understanding of the molecular mechanisms underlying the disorder and a
better understanding of the evolutionary selection processes that have paradoxically
resulted in the current high prevalence of the disorder in the face of obvious
reproductive deficits.
Benefit These data would not only lead to an improved understanding of the public health
implications of the disorder in Trinidad but also potentially highlight novel etiologic
avenues and therapeutic targets.
Aims and objectives
Primary:
1. To determine the prevalence of PCOS among women of reproductive age (a selected
population (18 to 45)) in Trinidad.
Secondary
2. To determine the distribution of phenotypes among women diagnosed with PCOS in the above
objective overall and by ethnicity. PCOS sub-phenotypes are as follows: Phenotype A -
clinical and/or biochemical hyperandrogenism (HA) and oligi-/anovulation (OA), and
polycystic ovarian morphology (PCOM); B - HA and OA; C - HA and PCOM; and D - OA and
PCOM;
3. To determine the risks for, metabolic syndrome, depression, obstructive sleep apnea
symptoms, fibroids, and general health issues for PCOS women versus women without PCOS
in the age groups 18 - 45 years.
4. To determine the genotype of PCOS in Trinidad. Outcome measures and variables Outcome
measures (dependent variables) c) Primary outcome ii) Prevalence of PCOS and its
symptoms d) Secondary outcome iv) Phenotype of PCOS v) Genotype of PCOS vi) Prevalence
and prevalence rationale for PCOS subphenotypes in Trinidad, odds ratio for metabolic
syndrome, depression, obstructive sleep apnea symptoms, fibroids, and general patient
health issues, adjusted for age, ethnicity, BMI, treatment (OCP), and socioeconomic
parameters.
Covariates (independent variables)
1. Socio-demographic variables
2. Baseline characteristics
Methodology Study design This is a prospective, cross-sectional study. The study will be
conducted among females in Trinidad from different geographical locations.
Study population Based on a review of nine studies conducted in the general population,
a conservative prevalence estimate for PCOS, using the Rotterdam 2003 definition, is
13.4%. Based on this formula, a sample size of 495 untreated individuals will be
required to determine the prevalence with an absolute error of 3%. Assuming a 50%
enrollment rate, 990 women would need to be approached for study inclusion. The study
population will be females of reproductive age from Trinidad.
Strategies for Sampling, Recruitment and Retention Participants will be samples
proportionally from all 8 zones in Trinidad. Approximately 124 women in the reproductive
age (18 - 45 years old) will be randomly sampled from each zone. Houses will be numbered
and random numbers of these houses will be generated using a random number calculator.
In each sampled house, females would be prescreened and those that satisfy our inclusion
criteria would be selected.
Telephone numbers of participants will be obtained and follow-up calls made.
Sampling units are defined as individual unselected women between the ages of 18 and 45
years, identified in the community. The investigators target power analysis on women who
do not use hormonal contraception. The investigators assume a conservative response rate
of 50% of sampled women. This response rate includes the following parameters: use of
hormone/contraceptive use (15%), excluded due to hysterectomy or ovariectomy (3%),
excluded due to pregnancy (2%), refusal to participate (20%), and study drop-out/lost to
follow-up (10%).
A conservative prevalence estimate for PCOS based on a review of nine studies conducted
in the general population using the Rotterdam 2003 definition is 13.4%. Using the above
formula, a sample size of 495 individuals will be required to determine the prevalence
with an absolute error of ±3%. Assuming a 50% enrollment rate, 990 women would need to
be approached for study inclusion.
Selection criteria Inclusion criteria
1. Female, ages 18 to 45 years., all ethnic backgrounds.
2. The participants must have at least one of the following two features:
i) Dermatological signs or complaints of clinical hyperandrogenism such as unwanted
facial or body hair, loss of scalp hair (alopecia) or persistent acne (pimple).
ii) Signs or complaints of ovulatory dysfunction such as irregular menses
(oligomenorrhoea, amenorrhea or polymenorrhoea), history of anovulation or
ultrasonographic findings of polycystic ovarian morphology.
Exclusion criteria
1. Women less than 18 years or older than 45 years
2. Women who are pregnant at the time of evaluation
3. Postmenopausal women
4. Women who had undergone hysterectomy and/or bilateral oophorectomy
5. Anything that would place the individual at increased risk or preclude the
individuals' compliance with or completion of the study.
6. Unwillingness to participate or difficulty understanding the consent process or the
study objectives and requirements.
Sampling technique A consecutive sampling technique will be used for each phase of
the study. Consecutive study participants, who meet the selection criteria and give
informed written consent, will be recruited for the study. A unique serial
identification number will be given to each study participant until the intended
sample is attained.
Study procedure Potential study participants from selected geographical locations
will be invited to participate in the study. A confidential study register
containing details of potential study participants (name, age, height, weight,
blood pressure and contact phone number) will be kept. Potential study participants
will be counseled on the objectives of the study and the study protocol. If the
potential participant refuses to participate, no further contact will be made with
the participant. Inform consent (see attached) will be obtained from each eligible
study participant before recruitment for the study. A subject tracking log for
longitudinal observation study will be used to track eligible subjects.
After an informed consent, data will be collected from each study participant using
a standard format in a clinical report form (CRF) for uniform data collection from
all participants. Each CRF will contain a unique serial identification number. The
CRF will be filled by a suitably trained researcher (including the PI,
co-investigators and medically trained research assistants). All CRF will be
checked for missing data within 24 hours of completion, and any missing data will
be detected and collected immediately.
Each participant will undergo anthropometric measurements (weight, height, waist,
circumference and hip circumference) and physical examination for hirsutism, acne,
alopecia, and acanthosis nigricans. Participants with an initial hirsutism (mFG)
score of 3 or more will be re-assessed by a physician.
Laboratory investigations will be scheduled during the morning hours (08:00 to
10:00 hours), for blood collection.
After overnight fasting (of 8 hours or more), 10 ml of venous blood sample will be
collected from each study participant. About half (5 ml) of the venous blood will
be collected in an EDTA- containing tube for plasma/DNA and the remaining in a
plain tube for serum.
All blood samples will be stored and transported to the laboratory in cooler boxes
containing ice packs immediately after collection. At the laboratory, the sample
will be separated into serum, plasma and whole blood by centrifugation for 20
minutes at 3000 rpm. The biological specimens will be stored, in small aliquots (of
0.5 ml), in 1.5 to 2.0 ml plastic containers (about 12 cryovials) able to withstand
temperatures of -80 degrees.
Samples for hormonal assay and initial evaluation will be batched at regular
intervals for analysis to provide study participants with timely results, allow
classification of participants, and minimize the impact of inter-assay variability.
At the end of the study, a repeat analysis of biological samples for androgen
levels and insulin estimation will be performed at a reference laboratory (Eric
William Medical Science Complex).
Each subject will also complete the following standardized data instruments or
forms as appropriate: FG Score self-assessment, SF-12, and Beck depression
inventory assessment (see attached).
The genetic analysis will be performed at the Laboratory at the Department of
Pre-clinical Sciences. The initial evaluation and classification of study
participants will be done using the flow chart/diagnostic tree by Prof. Azzizz one
of the investigators on this project.
Related or mimicking disorders will be excluded using history, physical
examination, and serum TSH, prolactin and 17-OH progesterone. Participants with
hypothyroidism on thyroxine replacement therapy will not be recruited for the study
until TSH level is normal. Study participants with elevated 17-OH progesterone
2ng/dl (or 200 ng/dl) will have non-classical congenital adrenal hyperplasia
(NCAH).
Data collection instrument:
The methods of collecting data for the assessment of study objectives include the
use of standardized interview-based medical forms; surveys; physical examinations.
The CRF developed for this study includes; a clinical and anthropometric section
and a laboratory result section. The questionnaire section will seek information on
socio-demographic variables, reproductive history with an emphasis on menstrual
cycle (dating and regularity) and gynecological history, hirsutism, acne,
medications, and family history. The anthropometry and clinical section will
document the physical findings such as hirsutism, acne, alopecia, and acanthosis
nigricans. Subjects will also complete the following standardized data instruments
or forms as appropriate: FG Score self-assessment, SF-12, Beck depression
inventory, and Epworth sleepiness scale.
A summary of initial and follow-up procedures.
1. Physical Exam
A physical exam will include:
- Baseline medical examination and
- Study specific procedures as outlined above.
2. Baseline medical examination will include • Waist-to-circumference ratio
- Height measurement
- Weight measurement
- Hirsutism assessment
- Acne assessment
- Alopecia assessment
- Acanthosis nigricans assessment
- Waist and hip circumferences measurement The following measures will
be obtained with the subject standing: a) the waist circumference,
measured as the circumferential measurement encompassing the lower
borders of the 10th rib at the mid-axillary lines; and b) the iliac
crest (hip) circumference, measured as the circumferential
measurement obtained at the height of the iliac crests, with the
tape maintained parallel to the floor. The waist and hip
circumferences will be recorded to the nearest 0.1 cm. The waist
divided by the iliac crest (hip) circumference will be used to
calculate the waist-hip ratio
- Hirsutism assessment Hirsutism assessment will be performed using
the modified Ferriman-Gallwey (mFG) visual hirsutism score scale, by
trained study personnel. Inter-reviewer variation will be assessed
between study investigators. Photographic examples of each grade
will be provided to investigators, as well as training to study
personnel.
mFG scoring will be performed as follows: • Nine body areas are assessed, including
the upper lip, chin, chest, upper back, lower back, upper arm, upper and lower
abdomen, and thighs.
- A score of 0 to 4 is assigned to each area examined, based on the density of
terminal hairs. A score of 0 represents the absence of terminal hairs, a score
of 1 minimal terminal hair growth, a score of 2 mild terminal hair growth, a
score of 3 moderate hair growth, and a score of 4 severe terminal hair growth
(i.e., like that of a hairy man).
o Terminal hairs represent hairs that if not cut or trimmed would grow >5 mm
in length, are usually pigmented, and are coarser and harder than the softer
surrounding vellus hairs, as they have a compact medulla (core) of melanocytes
within.
- Each body area on the mFG form is circled accordingly, leaving those areas
with a score of zero blank.
The scores are summed up to for the 'Total modified FG score'. If patients use
permanent/long term epilation or shave hairs, that fact will be recorded on the mFG
score sheet.
• In addition, all subjects will self-score their body and facial hair growth,
marking on the mFG score sheet. The subjects will be provided the same mFG score
sheet that is used by medical personnel, and will be instructed by trained
personnel to circle on the sheet their own body areas they perceive to be affected
by excess hair growth. Before they do so the trained personnel will provide them
with a short instructional - covering how mFG is performed, what the scores 0
through 4 mean, what terminal hair growth means, and what each body area covers.
- Acne assessment Assessment of acne will be made by trained personnel; using a
standard acne lesion assessment.
• Acne is scored according to whether it is grade 1 (mild), 2 (moderate), or 3
(severe). Mild acne is characterized by the presence of few to several papules and
pustules, but no nodules.
• Moderate acne by the presence of several to many papules and pustules, along with
a few to several nodules.
• Severe acne by the presence of numerous or extensive papules and pustules, as
well as many nodules.
- Alopecia assessment The Ludwig Scale will be used to diagnose the severity of
female hair loss. From left to right in the image below, these Types include
Class I, Class II, and Class III: (Attached)
- Acanthosis nigricans assessment
- All areas demonstrating acanthosis nigricans should be checked and
indicated (see attached).
- No score is used to denote severity.
3. Screening blood samples for evaluation PCOS Inclusion/Exclusion labs
- TSH**
- PRL**
- 17-OHP***
- P4++
- oGTT** * To be determined in the local clinical lab (MDS Biochemistry Laboratory) in
UWI, Trinidad.
- All subjects. *** For subjects with oligomenorrhea and/or hirsutism and/or PCOM
only, who do not use Hormonal Contraception (HC).
- For subjects with hirsutism and/or PCOM, who have apparently regular menstrual
bleeding a day 22-24 progesterone (P4) level will be obtained.
FUNCTIONAL TESTING Adrenocorticotropic Hormone (ACTH) Stimulation Test
An acute ACTH stimulation test is a clinical test performed to exclude 21-hydroxylase
deficient nonclassic congenital adrenal hyperplasia (NC-CAH), if the screening (basal)
17-hydroxyprogesterone (17-HP) level is 2 ng/mL (200 ng/dL) or 6.0 nmol/L. This test may also
be performed on included subjects, such as controls, for further phenotyping. For androgen
excess and/or PCOS patients, an ACTH stimulation test may be part of their standard clinical
evaluation if basal 17-HP levels are elevated. The test will be performed as follows:
- The subject will come in between 7-10 am in the morning.
- A small indwelling catheter will be placed in a vein in an arm and a blood sample is
drawn through the intravenous catheter (0 min sample).
- 250 mcg of 1-24 ACTH (Cortrosyn®) is then injected through the catheter. The injection
is performed over 60 seconds by a physician.
- Sixty minutes after the injection, a second blood sample (60 min, sample) is drawn. •
The total amount of blood drawn is 60 ml.
Laboratory evaluations and sample storage in research. Research lab
- SHBG
- Total and Free Testosterone
- DHEAS
- Blood for DNA extraction for later genetic analysis • Extra blood for repository
DNA Core Facility The investigators will obtain blood for DNA extraction since all subjects
will undergo standard phenotyping. Blood (in EDTA tubes) will be sent to the Biochemistry
Laboratory at Preclinical Sciences, UWI where DNA will be extracted and stored for future
analyses. The primary purpose is to serve as a repository to participate in genome wide
association studies. In both cases, there will be no release of personal identifiers, and we
the investigaotrs will obtain a Certificate of Confidentiality, as done in prior studies.
This will be a part of the initial protocol, though subjects will have the option to opt out
of this segment of the study or limit the use of their specimen on the consent form. This
resource may also prove useful for genome wide association studies or other studies of the
genetics of PCOS, oligomenorrhea, and hyperandrogenism.
At this time no genetic analyses are proposed as the number of subjects being collected are
insufficient for any significant genetic study. However, as it is the investigators hope that
this study will serve as the anchor for subsequent investigations of women's health and PCOS
in Trinidad, the investigators intend to isolate and store DNA in the subjects examined in
the study. The samples will be stored at The University of the West Indies. If in the future
a decision is made to study the DNA samples accumulated, perhaps along with other samples
collected, then we the investigators will apply for an amendment for genetic analysis.
Definitions
Ovulatory dysfunction is defined by:
1. Menstrual dysfunction (MD)
1. Oligi/amenorrhoea: menstrual interval > 35 days or < 10 cycles per year
2. Polymenorrhoea: menstrual interval < 26 days
3. Irregular cycle: menstrual interval > 4 days variation
2. Luteal phase (day 21-24) progesterone
a. Oligi-ovulation: progesterone level < 4ng/ml
3. Polycystic ovarian morphology (PCOM)
1. Antral follicular count (AFC) of 12 or more follicles measuring 2-9 mm in at least
one ovary.
2. Ovarian volume 0 cm3 in at least one ovary Clinical hyperandrogenism will be
diagnosed using hirsutism defined by modified Ferriman-Gallwey (mFG) score of 6
regardless of the presence or absence or acne and alopecia.
Hyperandrogenemia will be defined as a total testosterone, and/or free testosterone, and
androstenedione, and/or DHEAS level above the upper 95th percentile of 100 healthy,
non-hirsute eumenorrheic women.
Hyperinsulinemia will be defined as a fasting insulin level above the upper 95th percentile
of 100 healthy, non-obese women with normal glucose tolerance and no diabetic history or
medication use.
Classifications/Phenotypes:
1. Phenotyping: For further evaluation, participants will be divided by presenting
phenotype:
1. Phenotype 'NOT PCOS' i. On medical history a. Long-term predictable regular monthly
menstrual bleeding and b. No chronic endocrine disorder or untreated thyroid
disorder; and ii. On physical exam: no evidence of hirsutism (i.e. mFG < 3) iii. On
transvaginal ultrasonography (TV-U/S): no evidence of ovarian abnormality and no
other clinical abnormality.
2. POSSIBLE PCOS: subdivide into 7 clinical phenotypes i. Phenotype 'POSS. PCOS-MD
only':
1. On medical history: menstrual dysfunction (MD);
2. On physical exam: no evidence of hirsutism (HIR: i.e. mFG 3); and
3. On TV-U/S: no PCOM. ii. Phenotype 'POSS. PCOS-MD + PCOM':
1. On medical history: menstrual dysfunction (MD);
2. On physical exam: no evidence of hirsutism (HIR: i.e. mFG 3); and
3. On TV-U/S: has PCOM. iii. Phenotype ' POSS. PCOS-HIR only':
1. On medical history: long-term predictable regular monthly menstrual bleeding;
2. On physical exam: evidence of hirsutism (HIR: i.e. mFG 3); and
3. On TV-U/S: no PCOM. iv. Phenotype 'POSS. PCOS-PCOM only':
1. On medical history: long-term predictable regular monthly menstrual bleeding;
2. On physical exam: no evidence of hirsutism (HIR: i.e. mFG 3); and
3. On TV-U/S: has PCOM.
v. Phenotype 'POSS. PCOS-MD+HR':
1. On medical history: menstrual dysfunction (MD);
2. On physical exam: evidence of hirsutism (HIR: i.e. mFG 3); and
3. On TV-U/S: no PCOM. vi. Phenotype 'POSS. PCOS - MD+HIR+PCOM':
1. On medical history: menstrual dysfunction (MD);
2. On physical exam: evidence of hirsutism (HIR: i.e. mFG 3); and
3. On TV-U/S: has PCOM. vii. Phenotype 'POSS. PCOS - HIR+PCOM':
1. On medical history: long-term predictable regular monthly menstrual bleeding;
2. On physical exam: evidence of hirsutism (HIR: i.e. mFG 3); and
3. On TV-U/S: has PCOM.
2. Biochemical Phenotyping: For final evaluation, participants will be divided into 3 major
phenotypes:
1. Hyperandrogenic hyperinsulinemia
2. Hyperandrogenic, non-hyperinsulinemia, and
3. Non-hyperandrogenic, non-hyperinsulinemia.
Study Specific Biospecimens
The study staff will store the specimens with the following specifications:
- According to the temperature requirements
- Maintain a written and electronic log of sample receipt
- Maintain an electronic log of sample location
- Maintain a written and electronic log of equipment temperatures (temperatures or
conditions will be measured daily at the same time)
- Ensure that the freezers or refrigerators have adequate temperature controls
- Ensure quality assurance of equipment, which includes records of regular maintenance and
quality evaluations
- Place the sample in a clearly identified location in the freezer or refrigerator (i.e.,
bar coded container) • Log the sample/s into a database with the location of sample for
easy retrieval.
Reporting Procedures The current study provides minimum to modest additional patient risk
than standard of care. All SAEs throughout study participation from the start of the study
will be reported within 24 hours (or 1 business day) of learning of the event to the local
IRB. Reporting will be accomplished by completing the Serious Adverse Event Report. Only
study number will identify subject and no other identifying information will be included on
the form. The investigators will include the following information when reporting an adverse
event, or any other incident, experience, or outcome as an unanticipated problem to the IRB.
Statistical analysis will be done using SPSS.
Data management and Statistical analysis:
Data entry, data processing, and statistical analysis will be done using IBM Statistical
Software for Social Sciences (SPSS, Inc., Chicago, IL) version 20.0. Continuous variables
(such as age, anthropometric measurements, laboratory values of assay) will be checked for
normality using one-sample Kolmogorov-Smirnoff test, and expressed as means ± standard
deviation or median ± interquartile range (for data that are not normally distributed).
Categorical variables (such as race, and socioeconomic characteristics) will be expressed as
frequencies with accompanying percentages. Differences between groups will be compared using
Pearson's Chi-square test or Fisher's exact test for categorical variables. Odds ratio and
the corresponding 95% confidence intervals (CI) will be presented. The student t test and
ANOVA will be used to compare differences between groups for normally distributed continuous
variables. Comparison of continuous variables that were not normally distributed will be done
using a non-parametric (Mann-Whitney U test or Kruskal-Wallis test) inferential statistical
test.
Linear and logistic regression analysis (univariate and multivariate) will be performed to
evaluate the relationship between dependent and independent variables. Test of statistical
significance will be set at a p-value less than 0.05.
Ethical considerations:
This study will be conducted according to the ethical guidelines and principles of The
International Declaration of Helsinki, the Guidelines for Good Clinical Practice and the
National Code of Health Research Ethics (NCHRE). The Ethical Committee for The University of
the West Indies will issue approval. All researchers involved in this research project have
received training in the Responsible Conduct of Research.
No participant recruitment will commence until approval is received. Written informed consent
will be obtained from all participants before recruitment.
Confidentiality of data:
All information about the participants will be obtained using anonymous questionnaires and
shall be kept strictly confidential. The participants will be assured that their identity
will be kept in confidence by the investigators and that the results obtained will be
presented in aggregate manner.
Beneficence to participants:
No participant in this study will be made to pay for any of the procedures. All study
participants with abnormal findings will be notified of the results of their evaluation, and
those with abnormal physical, historical, or biochemical findings will be encouraged to
undergo further investigation or treatment.
Non-Maleficence to the participants:
All precautions will be taken to reduce the discomfort that may result from the venipuncture.
