madman
Super Moderator
Safety and acceptability of intravaginal rings releasing estradiol and progesterone (2023)
M. L. Hull, B. Stuckey, K. Hartman, N. Zack, A. Thurman & D. R. Friend
ABSTRACT
Objective: This study aimed to evaluate the safety and acceptability of two fixed-dose 28-day vaginal ring formulations of 17p-estradiol (E2) and progesterone (P4) to treat vasomotor symptoms (VMS) and the genitourinary syndrome of menopause.
Design: DARE HRT1-001 was the first-in-woman study of 28-day exposure to two 28-day intravaginal rings (IVRs) designed to release 80 ug/day E2-+4mg/day P4 (IVR1) or 160pg/day E2+8mg/day P4 (IVR2) compared with oral E2 1mg/day + oral P4 100 mg/day. To assess safety, participants completed a daily diary to record treatment-emergent adverse events (TEAEs). To determine acceptability, at the end of treatment, IVR users completed a questionnaire assessing tolerability and usability.
Results: Enrolled women (n = 34) were randomized to use IVR1 (n=10), IVR2 (n=12), or oral (n=12). Thirty-one participants (IVR1 =10, IVR2= 10, oral = 11) completed the study. The TEAE profile of those in the IVR groups was similar to the referent oral regimen. TEAEs related to the study product were more common with IVR2 use. Endometrial biopsies were not performed unless endometrial thickness was >4mm or for clinically significant postmenopausal bleeding. One IVR1 participant had an endometrial stripe increase from 4mm at the screening to 8 mm at the end of treatment. The biopsy indicated no evidence of plasma cells or endometritis and no evidence of atypia, hyperplasia, or malignancy. Two other endometrial biopsies were performed for postmenopausal bleeding with similar findings. There were no clinically meaningful laboratory or vital sign abnormalities or trends identified in observed values or changes from baseline. Pelvic speculum examination identified no clinically significant abnormalities in any participant at any visit. Tolerability and usability data demonstrated that both IVRs were generally highly acceptable.
Conclusions: Both IVR1 and IVR2 were safe and well tolerated in healthy postmenopausal women. TEAE profiles were comparable to the referent oral regimen.
Introduction
The advent of menopause is associated with many symptoms, the most common of which are vasomotor symptoms (VMS) such as hot flashes and night sweats. Other significant symptoms include vaginal dryness, dyspareunia, sleep disturbance, and arthralgia [1]. Menopause is associated with a reduction in estrogen levels. Lower levels of estrogen cause thinning of the vaginal epithelium, reduced vaginal elasticity, and an increase in connective tissue with eventual fibrotic changes. Decreased estrogen levels are also associated with a reduction in vaginal blood flow and lubrication [2]. These physiological changes can lead to vulvovaginal atrophy (VVA) and symptoms of vaginal dryness, vaginal and/or vulvar irritation/itching, dysuria, vaginal pain associated with sexual activity, and vaginal bleeding associated with sexual activity.
Hormone therapy (local and systemic) is accepted as an effective treatment for the management of both VMS and symptomatic VVA. The use of estrogen for the treatment of symptoms of menopause is advocated by several professional medical organizations [3,4].
Although estrogen is the most effective treatment for VMS, unopposed treatment (estrogen alone without a progestogen) is associated with an increased risk of endometrial hyperplasia and carcinoma in women with an intact uterus. A meta-analysis of 30 studies showed a relative risk of cancer of 2.3 (95% confidence interval 2.1-2.5) among women using estrogen without a progestogen [5]. This risk is reduced by the addition of progestogens, with the incidence of endometrial cancer under combined treatment being no different from that in untreated women [6]. Furthermore, a Cochrane Review noted a greater effect on reducing hot flash severity following treatment with estrogen and progestogens than with estrogen alone [7].
DARE-HRT1 is an ethylene vinyl acetate (EVA) copolymer intravaginal ring (IVR) designed to release bioidentical 17festradiol (E2) and progesterone (P4) over 28 days of use and is being developed for the following indications: treatment of moderate-to-severe VMS associated with menopause in women with an intact uterus; and reduction in the incidence of symptomatic VVA in women requiring treatment for VMS due to menopause.
*To understand the safety, tolerability, and usability of these IVRs, a phase 1 clinical study (DARE-HRT1-001) was conducted in Australia. The primary objectives of the study were to describe the pharmacokinetic (PK) parameters over 28 days of two different dose combinations of the IVRs: E2 at an average daily release rate of 80 ug/day and P4 at a daily release rate of 4mg/day (IVR1), and E2 at a daily release rate of 160 ug/day and P4 at 8 mg/day (IVR2). The results of the PK assessment have been published elsewhere [8]. A referent arm of oral E2 1 mg/day + oral P4 100 mg/day (oral) was also evaluated. The secondary objectives of the study were to assess the safety and acceptability (tolerability and usability) of each IVR, and the results of these objectives are reported herein.
Discussion
This study examined the safety and acceptability of two different IVRs in a small group of women. Vaginal rings have been evaluated as treatments for VMS or vaginal symptoms associated with menopause (i.e. VWA) [9-22]. The rings used in this study were segmented so that release of each active ingredient occurs from separate regions of the ring. They were designed to be similar in mechanical properties to those of NuvaRing® (Organon, Jersey City, NJ, USA). Both IVRs are composed of the same EVA thermoplastic material and have similar dimensions.
The majority of women (25/33, 75.8%) experienced at least one TEAE. It was more common for the TEAEs to be attributed to the study product in the IVR2 group. However, one of the 12 IVR2 women accounted for 26 of the 47 reported TEAEs in that group. Overall, the IVR1 and IVR2 safety results related to the levels of exposure to the two active ingredients, E2 and P4. Both hormones have a long history of postmenopausal use administered by several routes. Bleeding/spotting and breast tenderness are common adverse events when E2 and P4 were administered by vaginal rings [15]. These complaints occurred early in the trial (the first 1-2 months). In this study, there were reports of vaginal bleeding and spotting in all three groups with a slightly higher number in the IVR groups (see Table 4). This is a common occurrence on the initiation of combined E2/P4 therapy as noted earlier. Breast tenderness was noted in the IVR1 (1/10 participants) and IVR2 (2/12 participants) groups but neither group reported breast pain.
The decrease in vaginal pH following the administration of the IVRs and orally administered E2 and P4 was consistent with the use of E2 in a postmenopausal population [23].
In general, vaginal rings composed of EVA are well tolerated [24-27]. The women using IVR1 and IVR2 reported good tolerability, as summarized in Tables 5 and 6. This finding is important in that IVR1 and IVR2 are segmented rings. Each segment has somewhat different mechanical properties as opposed to NuvaRing®, which is a uniform coaxially extruded, single-welded IVR [28].
In conclusion, both IVR1 (E2 80 ug/day + P4 4 mg/day) and IVR2 (E2 160 g/day + P4 8 mg/day) were safe and well tolerated in healthy postmenopausal women. TEAE profiles were comparable to the referent oral regimen. IVR1 and IVR2 rings have shown good safety and tolerability (acceptability/useability) profiles in this phase 1 trial. Since the number of women in this study was small, additional studies in larger groups need to be undertaken to prove their usefulness in clinical practice. These vaginal rings may prove to be another tool in the treatment repertoire for women with postmenopausal symptoms.
M. L. Hull, B. Stuckey, K. Hartman, N. Zack, A. Thurman & D. R. Friend
ABSTRACT
Objective: This study aimed to evaluate the safety and acceptability of two fixed-dose 28-day vaginal ring formulations of 17p-estradiol (E2) and progesterone (P4) to treat vasomotor symptoms (VMS) and the genitourinary syndrome of menopause.
Design: DARE HRT1-001 was the first-in-woman study of 28-day exposure to two 28-day intravaginal rings (IVRs) designed to release 80 ug/day E2-+4mg/day P4 (IVR1) or 160pg/day E2+8mg/day P4 (IVR2) compared with oral E2 1mg/day + oral P4 100 mg/day. To assess safety, participants completed a daily diary to record treatment-emergent adverse events (TEAEs). To determine acceptability, at the end of treatment, IVR users completed a questionnaire assessing tolerability and usability.
Results: Enrolled women (n = 34) were randomized to use IVR1 (n=10), IVR2 (n=12), or oral (n=12). Thirty-one participants (IVR1 =10, IVR2= 10, oral = 11) completed the study. The TEAE profile of those in the IVR groups was similar to the referent oral regimen. TEAEs related to the study product were more common with IVR2 use. Endometrial biopsies were not performed unless endometrial thickness was >4mm or for clinically significant postmenopausal bleeding. One IVR1 participant had an endometrial stripe increase from 4mm at the screening to 8 mm at the end of treatment. The biopsy indicated no evidence of plasma cells or endometritis and no evidence of atypia, hyperplasia, or malignancy. Two other endometrial biopsies were performed for postmenopausal bleeding with similar findings. There were no clinically meaningful laboratory or vital sign abnormalities or trends identified in observed values or changes from baseline. Pelvic speculum examination identified no clinically significant abnormalities in any participant at any visit. Tolerability and usability data demonstrated that both IVRs were generally highly acceptable.
Conclusions: Both IVR1 and IVR2 were safe and well tolerated in healthy postmenopausal women. TEAE profiles were comparable to the referent oral regimen.
Introduction
The advent of menopause is associated with many symptoms, the most common of which are vasomotor symptoms (VMS) such as hot flashes and night sweats. Other significant symptoms include vaginal dryness, dyspareunia, sleep disturbance, and arthralgia [1]. Menopause is associated with a reduction in estrogen levels. Lower levels of estrogen cause thinning of the vaginal epithelium, reduced vaginal elasticity, and an increase in connective tissue with eventual fibrotic changes. Decreased estrogen levels are also associated with a reduction in vaginal blood flow and lubrication [2]. These physiological changes can lead to vulvovaginal atrophy (VVA) and symptoms of vaginal dryness, vaginal and/or vulvar irritation/itching, dysuria, vaginal pain associated with sexual activity, and vaginal bleeding associated with sexual activity.
Hormone therapy (local and systemic) is accepted as an effective treatment for the management of both VMS and symptomatic VVA. The use of estrogen for the treatment of symptoms of menopause is advocated by several professional medical organizations [3,4].
Although estrogen is the most effective treatment for VMS, unopposed treatment (estrogen alone without a progestogen) is associated with an increased risk of endometrial hyperplasia and carcinoma in women with an intact uterus. A meta-analysis of 30 studies showed a relative risk of cancer of 2.3 (95% confidence interval 2.1-2.5) among women using estrogen without a progestogen [5]. This risk is reduced by the addition of progestogens, with the incidence of endometrial cancer under combined treatment being no different from that in untreated women [6]. Furthermore, a Cochrane Review noted a greater effect on reducing hot flash severity following treatment with estrogen and progestogens than with estrogen alone [7].
DARE-HRT1 is an ethylene vinyl acetate (EVA) copolymer intravaginal ring (IVR) designed to release bioidentical 17festradiol (E2) and progesterone (P4) over 28 days of use and is being developed for the following indications: treatment of moderate-to-severe VMS associated with menopause in women with an intact uterus; and reduction in the incidence of symptomatic VVA in women requiring treatment for VMS due to menopause.
*To understand the safety, tolerability, and usability of these IVRs, a phase 1 clinical study (DARE-HRT1-001) was conducted in Australia. The primary objectives of the study were to describe the pharmacokinetic (PK) parameters over 28 days of two different dose combinations of the IVRs: E2 at an average daily release rate of 80 ug/day and P4 at a daily release rate of 4mg/day (IVR1), and E2 at a daily release rate of 160 ug/day and P4 at 8 mg/day (IVR2). The results of the PK assessment have been published elsewhere [8]. A referent arm of oral E2 1 mg/day + oral P4 100 mg/day (oral) was also evaluated. The secondary objectives of the study were to assess the safety and acceptability (tolerability and usability) of each IVR, and the results of these objectives are reported herein.
Discussion
This study examined the safety and acceptability of two different IVRs in a small group of women. Vaginal rings have been evaluated as treatments for VMS or vaginal symptoms associated with menopause (i.e. VWA) [9-22]. The rings used in this study were segmented so that release of each active ingredient occurs from separate regions of the ring. They were designed to be similar in mechanical properties to those of NuvaRing® (Organon, Jersey City, NJ, USA). Both IVRs are composed of the same EVA thermoplastic material and have similar dimensions.
The majority of women (25/33, 75.8%) experienced at least one TEAE. It was more common for the TEAEs to be attributed to the study product in the IVR2 group. However, one of the 12 IVR2 women accounted for 26 of the 47 reported TEAEs in that group. Overall, the IVR1 and IVR2 safety results related to the levels of exposure to the two active ingredients, E2 and P4. Both hormones have a long history of postmenopausal use administered by several routes. Bleeding/spotting and breast tenderness are common adverse events when E2 and P4 were administered by vaginal rings [15]. These complaints occurred early in the trial (the first 1-2 months). In this study, there were reports of vaginal bleeding and spotting in all three groups with a slightly higher number in the IVR groups (see Table 4). This is a common occurrence on the initiation of combined E2/P4 therapy as noted earlier. Breast tenderness was noted in the IVR1 (1/10 participants) and IVR2 (2/12 participants) groups but neither group reported breast pain.
The decrease in vaginal pH following the administration of the IVRs and orally administered E2 and P4 was consistent with the use of E2 in a postmenopausal population [23].
In general, vaginal rings composed of EVA are well tolerated [24-27]. The women using IVR1 and IVR2 reported good tolerability, as summarized in Tables 5 and 6. This finding is important in that IVR1 and IVR2 are segmented rings. Each segment has somewhat different mechanical properties as opposed to NuvaRing®, which is a uniform coaxially extruded, single-welded IVR [28].
In conclusion, both IVR1 (E2 80 ug/day + P4 4 mg/day) and IVR2 (E2 160 g/day + P4 8 mg/day) were safe and well tolerated in healthy postmenopausal women. TEAE profiles were comparable to the referent oral regimen. IVR1 and IVR2 rings have shown good safety and tolerability (acceptability/useability) profiles in this phase 1 trial. Since the number of women in this study was small, additional studies in larger groups need to be undertaken to prove their usefulness in clinical practice. These vaginal rings may prove to be another tool in the treatment repertoire for women with postmenopausal symptoms.
