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“ "Bernard W. Somers1, Betsy Singh2, Laura J. Camacho Choza3, Pablo F. Gonzalez Limon3, Alejandro Avendano3, Nadina Jose4
1Department of Medicinal Chemistry, Rutgers University New Brunswick, NJ, 2BRCG Medical Research Group, Midlothian, VA, 3PanAmerican Clinical Research Group, Mexico, 4Department of Health Informatics, Rutgers University Newark, NJ
Menopausal symptoms are commonly experienced by women as they age. A prospective, open-label dietary supplement clinical study was approved by 2 Ethics Committees in Mexico to study oral Crila® herbal supplements (containing Crinum latifolium L var. crilae Tram & Khanh) in 61 women with menopausal symtpoms. Crila® capsules were taken orally for 90 days. Every 30 days symptom severity was quantified using the validated MENQOL Survey to determine the benefits of Crila®. 61 women completed the study at the height of the COVID-19 pandemic. A decentralized design was key to the study completion. 93% of women showed improvement in their menopausal symptoms after study completion while significant improvement was observed from Day 0 to each subsequent visit, from Day 30 to Day 60 (p = 0.019), and from Day 30 to Day 90 (p < 0.001). In addition, all four domains of menopausal symptoms (vasomotor, psychosocial, physical, and sexual) on the MENQOL survey showed significant improvement ( p < 0.001) from Baseline Visit 1 to each of the subsequent 3 visits.
Menopausal symptoms are commonly experienced by women of all races as they age1, 2. The onset of menopause typically occurs from 42-53 years2. Vasomotor symptoms of hot flashes (or flush-es) and night sweats are primary menopausal manifestations that may also be associated with sleep, mood and cognitive disturbances with consequent quality of life impairment. In some women, vasomotor symptoms may last for over 10 years. The most effective approved treatment for vasomotor symptoms is sex hormone therapy, which may have numerous side effects3. Women often prefer natural remedies for menopuase treatment, these may include: black cohosh (Actaea racemosa), chaste tree berry (Vitex agnus), licorice (Glycyrrhiza glabra) and soy (Glycine max)4. An ex-perimental drug, fezolinetant, recently completed Phase 3 clinical trial in N = 527 women and was efficacious for the treatment of moderate-to-severe vasomotor symptoms associated with meno-pause , with no major safety concerns5. The genus Crinum, including C. latifolium, has been used as a traditional medicinal herb in Asia and around the world and was shown to be a non-estrogenic botanical6. There is no prior research examing the effect of Crila® on menopausal symtoms. However, in 2007 a 3 month study was conducted at 3 hospitals in Vietnam on N = 195 women examining the effect of Crila® on the size of uterine fibroids (leiomyoma) and their associated symptoms7. A beneficial result informed us to examine the effects of Crila® on menopausal symptoms.
This study is a two-center, prospective, open-label study in women with vasomotor symptoms who received 4 to 10 capsules (depending on body weight) of C. latifolium extract (Crila®) for 3 months (Table 1, Table 2). This study was conducted in 2 university affiliated centers in Guadalajara and Querétaro, Mexico. The study’s primary endpoint was designed to evaluate the impact of oral Crila® capsules on menopausal symptom severity as assessed by the MENQOL (Figure 1). Subjects were asked how bothered they were by the problems in the past month, on a scale from 0 to 6. 0 being not bothered at all and 6 being extremely bothered (Figure 1). Subjects who met all inclusion and none of the exclusion criteria (see below) were evaluated throughout the study. 61 subjects completed the study. Subjects completed procedures as detailed in Table 1. A subject’s total study duration comprised up to 90 days from screening (Day 0) through conclusion of the Final Visit (Day 90).
Female subjects at least 45 years of age; BMI < 30; Experiencing at least 35 vasomotor symptoms (hot flashes and/or night sweats) per week (average of 5 per day) for the previous 3 months; Able and willing to return to
the clinic for all study procedures; Able and willing to provide informed consent; Willing to use 2 forms of acceptable birth control (condom and/or diaphragm in addition to spermicidal gel) when sexually active; Meeting
at least one of the following 3 sub-criteria:
1) No menses or menses of irregular length in the last 6 months. 2) Mood swings with onset or worsening in the last year. 3) Sleep problems with onset or worsening in the last year.
BMI > 30; Previous oophorectomy; Fewer than 35 vasomotor symptoms per week; Women who are pregnant, plan to become pregnant in the next 3 months, or lactating females; Previous history of endometrial hyperplasia/ neoplasia; Previous history of cancers of the breast or reproductive tract; History or presence of myocardial infarction or stroke; Abnormal vaginal bleeding of undetermined cause; Blood pressure > 165 diastolic or > 95 systolic; Clinically significant pulmonary, cardiac, gastroenterologic, neurologic, renal, musculoskeletal, rheumatologic, metabolic, neoplastic, or endocrine disease or any clinically significant abnormalities on physical examination, medical history, or vital signs as judged by the Investigator; Concurrent administration of hormone replacement therapy, estrogen, progestin, SERM (selective estrogen receptor modulators), St. John’s wort (Hypericum perforatum), black cohosh, maca (Lepidium meyennii), red clover (Trifolium pratense), phytoestrogen formula, aromatase inhibitors, or SSRIs for previous 3 months; History of deep vein thrombosis, thrombophlebitis or thromboembolic disorder; Subjects with a significant acute condition, or any other condition that, in the opinion of the Investigator, might interfere with the evaluation of the study objectives; Currently taking any of the following medications: corticosteroids (oral replacement of ≤ 5 mg/day prednisolone, inhaled and topical corticosteroids are allowed), immunomodulatory treatments, or any prescription that, in the opinion of the Investigator, might interfere with the evaluation of the study objectives; Current alcohol or substance abuse that, in the opinion of the investigator, would interfere with adherence to study requirements; Participation in any clinical study with an experimental medication where the last dose was within 5 half-lives or 30 days (whichever is longer) of enrollment in the current study, or participation in any study with an experimental device within 30 days of enrollment in the current study; Uncontrolled diabetes in the Investigator’s opinion; Dementia or significant signs of compromised cognitive ability.
The mean total score for each of the 4 visits for N = 61 subjects who completed the study is illustrated in Figure 2 and listed in Table 3. When compared to the Baseline Visit 1, subsequent visits had a significantly lower total score on MENQOL survey (p < 0.001, Figure 2, Table 4) suggesting Crila® continually reduced Menopausal symptoms over the entire course of the regimen. We also observe a significant reduction in menopausal symptoms when comparing the total score p-value of Visit 2 to Visit 3 (p = 0.019), but we do not observe a significant reduction in menopausal symptoms when comparing Visit 3 to Visit 4 (p = 0.222, Table 3, Table 4). This may indicate the most therapeutic benefit is realized within the first 60 days of treatment. All four domains of menopausal symptoms (vasomotor, psychosocial, physical, and sexual) on the MENQOL survey showed significant improvement (p < 0.001) from Baseline Visit 1 to each of the subsequent 3 visits (Figure 3).
Crila® herbal supplement is a clinically effective botanical product in reducing
menopausal symptoms of female subjects. According to the data, symptoms
are continually reduced over the entire course of the 90-day regimen and the
extent to which they reduce increases with time.
A recommendation for a longer duration study of 6-12 months would indicate if
symptoms continue to improve over a longer course of time and if/when a
symptom plateau is observed. This longer duration study will provide information
to inform an initial dosing schedule and a maintenance dosing schedule in
females with menopausal symptoms.
1Sussman, Matthew et al. “Prevalence of menopausal symptoms among mid-life women: findings from electronic medical records.” BMC Women's
Health Volume 15 58. 13 Aug. 2015.
2Palacios, S., et al. "Age of menopause and impact of climacteric symptoms by geographical region." Climacteric 13.5 (2010): 419-428.
3Meeta, Meeta, et al. "Clinical practice guidelines on menopause:* An executive summary and recommendations: Indian menopause society
2019–2020." Journal of Mid-life Health 11.2 (2020): 55.
4Mayo, Joseph L. "A natural approach to menopause." Applied Nutritional Science Reports 5.7 (1999): 1-8.
5Lederman, Samuel, et al. "Phase 3 Study of Fezolinetant for Treatment of Moderate-to-Severe Vasomotor Symptoms Associated With Menopause
[A132]." Obstetrics & Gynecology 139.1 (2022): 39S-39S.
6Burton, Tristesse C., Yongchao Li, and Richard B. van Breemen. "Examining the Estrogenicity of Crinum latifolium L. var. crilae Tram & Khanh,
var n.(Amaryllidaceae) Using Cell-based and Receptor-based Assays." MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE
SOCIETY. Vol. 21. No. 12. 2014.
7Hoa, V. T., To Evaluate the Effect and Possibility of Accepting of Crila in Uterus Fibroid Tumor Treatment. Vietnam Ministry of Health 2007.
Crila Health
EPIC CRO
CliniOps Inc.
BRCG Medical Research
PanAmerican Clinical Research
Rutgers, The State University of New Jersey
This research is supported by Crila Health Pte. Ltd., and, in part, by a directed donation from the Avis LaGrone Charitable Fund.
Bernard W. Somers: bernard.somers@rutgers.edu
Nadina Jose MD: ncj26@rutgers.edu