Trial Outcomes & Findings for Safety and Pharmacokinetics of Dapivirine Vaginal Ring in Post-menopausal Women (NCT NCT02010593)

NCT ID: NCT02010593

Last Updated: 2022-11-03

Results Overview

Evidence of Grade 2 or higher genital, genitourinary and reproductive system AEs as defined by the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, Dec 2004 (Clarification dated August 2009), Addendum 1, (Female Genital Grading Table for Use in Microbicide Studies) judged to be related to study product. Evidence of Grade 3 or higher AEs as defined by the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, Dec 2004 (Clarification dated August 2009). DAIDS severity grades are defined as follows: * Grade 1 = mild * Grade 2 = moderate * Grade 3 = severe * Grade 4 = potentially life-threatening * Grade 5 = death

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

96 participants

Primary outcome timeframe

over 12-week period of use

Results posted on

2022-11-03

Participant Flow

Trial staff pre-screened potential participants at either on-site or off-site locations. During these interactions, staff explained the trial to participants, ascertained elements of presumptive eligibility. Process info was recorded and stored in the absence of written IC from participants, provided the info was collected in such a manner that it could not be linked to participant identifiers. Participants were recruited at 3 medical centres between 23 Dec 2013 and 31 Dec 2014.

Two hundred participants provided written informed consent and were subsequently screened. Of these, 96 participants met recruitment criteria and were randomized.

Participant milestones

Participant milestones
Measure	Dapivirine Vaginal Ring Safety study of a vaginal ring containing Dapivirine in a postmenopausal female population Dapivirine Vaginal Ring: Dapivirine, a non-nucleoside reverse-transcriptase inhibitor (NNRTI), is a substituted amino- pyrimidine (DAPY) derivative with potent antiviral activity against HIV-1. Dapivirine is chemically described as 4-\[\[4-\[(2,4,6-trimethylphenyl)amino\]-2- pyrimidinyl\]amino\]benzonitrile.6 The dapivirine matrix VR is a flexible ring containing 25 mg of drug substance dispersed in a platinum-catalyzed-cured silicone matrix. Dapivirine is known to be well-suited for delivery via VR	Placebo The placebo VR is a flexible, platinum-catalyzed-cured matrix ring, identical to Dapivirine Ring-004, containing no active-drug Placebo Vaginal Ring: The placebo VR is a flexible, platinum-catalyzed-cured silicone matrix ring, identical to dapivirine Ring-004, containing no active drug.
Overall Study STARTED	72	24
Overall Study COMPLETED	70	22
Overall Study NOT COMPLETED	2	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Dapivirine Vaginal Ring Safety study of a vaginal ring containing Dapivirine in a postmenopausal female population Dapivirine Vaginal Ring: Dapivirine, a non-nucleoside reverse-transcriptase inhibitor (NNRTI), is a substituted amino- pyrimidine (DAPY) derivative with potent antiviral activity against HIV-1. Dapivirine is chemically described as 4-\[\[4-\[(2,4,6-trimethylphenyl)amino\]-2- pyrimidinyl\]amino\]benzonitrile.6 The dapivirine matrix VR is a flexible ring containing 25 mg of drug substance dispersed in a platinum-catalyzed-cured silicone matrix. Dapivirine is known to be well-suited for delivery via VR	Placebo The placebo VR is a flexible, platinum-catalyzed-cured matrix ring, identical to Dapivirine Ring-004, containing no active-drug Placebo Vaginal Ring: The placebo VR is a flexible, platinum-catalyzed-cured silicone matrix ring, identical to dapivirine Ring-004, containing no active drug.
Overall Study Lost to Follow-up	1	0
Overall Study Physician Decision	1	0
Overall Study Unable to adhere to visit schedule	0	2

Baseline Characteristics

Safety and Pharmacokinetics of Dapivirine Vaginal Ring in Post-menopausal Women

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Dapivirine Vaginal Ring n=72 Participants Safety study of a vaginal ring containing Dapivirine in a postmenopausal female population Dapivirine Vaginal Ring: Dapivirine, a non-nucleoside reverse-transcriptase inhibitor (NNRTI), is a substituted amino- pyrimidine (DAPY) derivative with potent antiviral activity against HIV-1. Dapivirine is chemically described as 4-\[\[4-\[(2,4,6-trimethylphenyl)amino\]-2- pyrimidinyl\]amino\]benzonitrile.6 The dapivirine matrix VR is a flexible ring containing 25 mg of drug substance dispersed in a platinum-catalyzed-cured silicone matrix. Dapivirine is known to be well-suited for delivery via VR	Placebo n=24 Participants The placebo VR is a flexible, platinum-catalyzed-cured matrix ring, identical to Dapivirine Ring-004, containing no active-drug Placebo Vaginal Ring: The placebo VR is a flexible, platinum-catalyzed-cured silicone matrix ring, identical to dapivirine Ring-004, containing no active drug.	Total n=96 Participants Total of all reporting groups
Age, Customized Age 45 - 65 (inclusive)	57.2 years STANDARD_DEVIATION 4.3 • n=5 Participants	55.3 years STANDARD_DEVIATION 3.0 • n=7 Participants	56.8 years STANDARD_DEVIATION 41.1 • n=5 Participants
Sex: Female, Male Female	72 Participants n=5 Participants	24 Participants n=7 Participants	96 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	71 Participants n=5 Participants	24 Participants n=7 Participants	95 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	22 Participants n=5 Participants	8 Participants n=7 Participants	30 Participants n=5 Participants
Race (NIH/OMB) White	48 Participants n=5 Participants	15 Participants n=7 Participants	63 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Region of Enrollment United States	72 Participants n=5 Participants	24 Participants n=7 Participants	96 Participants n=5 Participants
Main cause of menopause Spontaneous	60 Participants n=5 Participants	18 Participants n=7 Participants	78 Participants n=5 Participants
Main cause of menopause Surgical	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Main cause of menopause Unknown	9 Participants n=5 Participants	3 Participants n=7 Participants	12 Participants n=5 Participants

PRIMARY outcome

Timeframe: over 12-week period of use

Population: Intent-to-Treat: All participants randomized in the trial were included in the primary analysis

Outcome measures

Outcome measures
Measure	Dapivirine Vaginal Ring n=72 Participants Safety study of a vaginal ring containing Dapivirine in a postmenopausal female population Dapivirine Vaginal Ring: Dapivirine, a non-nucleoside reverse-transcriptase inhibitor (NNRTI), is a substituted amino- pyrimidine (DAPY) derivative with potent antiviral activity against HIV-1. Dapivirine is chemically described as 4-\[\[4-\[(2,4,6-trimethylphenyl)amino\]-2- pyrimidinyl\]amino\]benzonitrile.6 The dapivirine matrix VR is a flexible ring containing 25 mg of drug substance dispersed in a platinum-catalyzed-cured silicone matrix. Dapivirine is known to be well-suited for delivery via VR	Placebo n=24 Participants The placebo VR is a flexible, platinum-catalyzed-cured matrix ring, identical to Dapivirine Ring-004, containing no active-drug Placebo Vaginal Ring: The placebo VR is a flexible, platinum-catalyzed-cured silicone matrix ring, identical to dapivirine Ring-004, containing no active drug.
Safety of Dapivirine (25 mg) Administered in a Silicone Elastomer Vaginal Matrix Ring in HIV-uninfected Postmenopausal Women, When Inserted Once Every 4 Weeks During 12 Weeks of Study Product Use DAIDS Grade 2 or higher	6 Participants	3 Participants
Safety of Dapivirine (25 mg) Administered in a Silicone Elastomer Vaginal Matrix Ring in HIV-uninfected Postmenopausal Women, When Inserted Once Every 4 Weeks During 12 Weeks of Study Product Use DAIDS grade 3	4 Participants	0 Participants

SECONDARY outcome

Timeframe: at 12-week visit

Population: Participants who have answered to preference question at the week 12 visit

To evaluate the acceptability, the percentage of participants who at their 12-Week Final Clinic Visit report via acceptability questionnaire that they prefer the ring at least as much as other HIV prevention methods.

Outcome measures

Outcome measures
Measure	Dapivirine Vaginal Ring n=69 Participants Safety study of a vaginal ring containing Dapivirine in a postmenopausal female population Dapivirine Vaginal Ring: Dapivirine, a non-nucleoside reverse-transcriptase inhibitor (NNRTI), is a substituted amino- pyrimidine (DAPY) derivative with potent antiviral activity against HIV-1. Dapivirine is chemically described as 4-\[\[4-\[(2,4,6-trimethylphenyl)amino\]-2- pyrimidinyl\]amino\]benzonitrile.6 The dapivirine matrix VR is a flexible ring containing 25 mg of drug substance dispersed in a platinum-catalyzed-cured silicone matrix. Dapivirine is known to be well-suited for delivery via VR	Placebo n=22 Participants The placebo VR is a flexible, platinum-catalyzed-cured matrix ring, identical to Dapivirine Ring-004, containing no active-drug Placebo Vaginal Ring: The placebo VR is a flexible, platinum-catalyzed-cured silicone matrix ring, identical to dapivirine Ring-004, containing no active drug.
The Percentage of Participants Who Find the Study Vaginal Ring to be as Acceptable	61 Participants	20 Participants

SECONDARY outcome

Timeframe: 12-week period of use

Population: Adherent Participant: based on self report, IP was never out during one month (4 week)

Adherence will be measured by the percentage of women who keep the VR inserted at all times in the vagina over the course of 12 weeks. A participant was considered adherent in one month (4 weeks) by self-reported data, only if the ring was never out during that month and the participant was not on product hold and did not terminate the clinical trial within that month.

Outcome measures

Outcome measures
Measure	Dapivirine Vaginal Ring n=72 Participants Safety study of a vaginal ring containing Dapivirine in a postmenopausal female population Dapivirine Vaginal Ring: Dapivirine, a non-nucleoside reverse-transcriptase inhibitor (NNRTI), is a substituted amino- pyrimidine (DAPY) derivative with potent antiviral activity against HIV-1. Dapivirine is chemically described as 4-\[\[4-\[(2,4,6-trimethylphenyl)amino\]-2- pyrimidinyl\]amino\]benzonitrile.6 The dapivirine matrix VR is a flexible ring containing 25 mg of drug substance dispersed in a platinum-catalyzed-cured silicone matrix. Dapivirine is known to be well-suited for delivery via VR	Placebo n=24 Participants The placebo VR is a flexible, platinum-catalyzed-cured matrix ring, identical to Dapivirine Ring-004, containing no active-drug Placebo Vaginal Ring: The placebo VR is a flexible, platinum-catalyzed-cured silicone matrix ring, identical to dapivirine Ring-004, containing no active drug.
Percentage of Women Who Were Adherent to Daily Study Product Use Based on Self-report Over the 12-week Study Product Use Period Week 0 - 4	58 Participants	22 Participants
Percentage of Women Who Were Adherent to Daily Study Product Use Based on Self-report Over the 12-week Study Product Use Period Week 4 - 8	67 Participants	22 Participants
Percentage of Women Who Were Adherent to Daily Study Product Use Based on Self-report Over the 12-week Study Product Use Period Week 8 - 12	65 Participants	21 Participants

SECONDARY outcome

Timeframe: a 12 week product use period

Population: The PK analysis population included all participants who were randomised to the active IP arm with a detectable concentration in plasma at any time during follow-up. One participant was not included in the PK analysis since she was terminated from the trial early (after Week 4) due to non-compliance. Four of these participants (71) had undetectable dapivirine concentrations in plasma samples in one or more visits: Week 4: 2 x participants Week 8: 1 x participant Week 12: 2 x participants

The PK endpoint is a description of the end of period (28 day post ring insertion) plasma dapivirine concentrations at week 4, 8, and 12 which will be compared to the same results in a recently studied population of premenopausal adult women (MTN-013).

Outcome measures

Outcome measures
Measure	Dapivirine Vaginal Ring n=71 Participants Safety study of a vaginal ring containing Dapivirine in a postmenopausal female population Dapivirine Vaginal Ring: Dapivirine, a non-nucleoside reverse-transcriptase inhibitor (NNRTI), is a substituted amino- pyrimidine (DAPY) derivative with potent antiviral activity against HIV-1. Dapivirine is chemically described as 4-\[\[4-\[(2,4,6-trimethylphenyl)amino\]-2- pyrimidinyl\]amino\]benzonitrile.6 The dapivirine matrix VR is a flexible ring containing 25 mg of drug substance dispersed in a platinum-catalyzed-cured silicone matrix. Dapivirine is known to be well-suited for delivery via VR	Placebo The placebo VR is a flexible, platinum-catalyzed-cured matrix ring, identical to Dapivirine Ring-004, containing no active-drug Placebo Vaginal Ring: The placebo VR is a flexible, platinum-catalyzed-cured silicone matrix ring, identical to dapivirine Ring-004, containing no active drug.
Pharmacokinetics - The Intent is to Determine if the Plasma Dapivirine Concentrations Are Different in Postmenopausal Women Than in Pre-menopausal Adult Women After Placement of Dapivirine Vaginal Rings. Week 12	298.2 picograms/mililiter Standard Deviation 143.2	—
Pharmacokinetics - The Intent is to Determine if the Plasma Dapivirine Concentrations Are Different in Postmenopausal Women Than in Pre-menopausal Adult Women After Placement of Dapivirine Vaginal Rings. Week 4	273.5 picograms/mililiter Standard Deviation 98.2	—
Pharmacokinetics - The Intent is to Determine if the Plasma Dapivirine Concentrations Are Different in Postmenopausal Women Than in Pre-menopausal Adult Women After Placement of Dapivirine Vaginal Rings. Week 8	289.0 picograms/mililiter Standard Deviation 123.8	—

SECONDARY outcome

Timeframe: a 12 week product use period

Population: PK analysis population included all participants who were randomised to active IP arm with a detectable concentration in vaginal fluid at any time during f/u. Results from 36 participants enrolled in dapivirine arm were available for analysis in vaginal fluid sample subset. For 35 participants, detectable dapivirine concentrations were measured in vaginal fluid at any time during f/u. 5 x participants had undetectable dapivirine concentrations in vaginal fluid samples in one or more visits.

The PK endpoint is a description of the end of period (28 day post ring insertion) vaginal fluid dapivirine concentrations at week 4, 8, and 12 which will be compared to the same results in a recently studied population of premenopausal adult women (MTN-013).

Outcome measures

Outcome measures
Measure	Dapivirine Vaginal Ring n=36 Participants Safety study of a vaginal ring containing Dapivirine in a postmenopausal female population Dapivirine Vaginal Ring: Dapivirine, a non-nucleoside reverse-transcriptase inhibitor (NNRTI), is a substituted amino- pyrimidine (DAPY) derivative with potent antiviral activity against HIV-1. Dapivirine is chemically described as 4-\[\[4-\[(2,4,6-trimethylphenyl)amino\]-2- pyrimidinyl\]amino\]benzonitrile.6 The dapivirine matrix VR is a flexible ring containing 25 mg of drug substance dispersed in a platinum-catalyzed-cured silicone matrix. Dapivirine is known to be well-suited for delivery via VR	Placebo The placebo VR is a flexible, platinum-catalyzed-cured matrix ring, identical to Dapivirine Ring-004, containing no active-drug Placebo Vaginal Ring: The placebo VR is a flexible, platinum-catalyzed-cured silicone matrix ring, identical to dapivirine Ring-004, containing no active drug.
Pharmacokinetics - The Intent is to Determine if the Vaginal Fluid Dapivirine Concentrations Are Different in Postmenopausal Women Than in Pre-menopausal Adult Women After Placement of Dapivirine Vaginal Rings. Week 4	64.3 nanogram/miligram Standard Deviation 65.9	—
Pharmacokinetics - The Intent is to Determine if the Vaginal Fluid Dapivirine Concentrations Are Different in Postmenopausal Women Than in Pre-menopausal Adult Women After Placement of Dapivirine Vaginal Rings. Week 8	78.5 nanogram/miligram Standard Deviation 92.2	—
Pharmacokinetics - The Intent is to Determine if the Vaginal Fluid Dapivirine Concentrations Are Different in Postmenopausal Women Than in Pre-menopausal Adult Women After Placement of Dapivirine Vaginal Rings. Week 12	72.1 nanogram/miligram Standard Deviation 80	—

Adverse Events

Dapivirine Vaginal Ring

Serious events: 1 serious events

Other events: 46 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 14 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Dapivirine Vaginal Ring n=72 participants at risk Safety study of a vaginal ring containing Dapivirine in a postmenopausal female population Dapivirine Vaginal Ring: Dapivirine, a non-nucleoside reverse-transcriptase inhibitor (NNRTI), is a substituted amino- pyrimidine (DAPY) derivative with potent antiviral activity against HIV-1. Dapivirine is chemically described as 4-\[\[4-\[(2,4,6-trimethylphenyl)amino\]-2- pyrimidinyl\]amino\]benzonitrile.6 The dapivirine matrix VR is a flexible ring containing 25 mg of drug substance dispersed in a platinum-catalyzed-cured silicone matrix. Dapivirine is known to be well-suited for delivery via VR	Placebo n=24 participants at risk The placebo VR is a flexible, platinum-catalyzed-cured matrix ring, identical to Dapivirine Ring-004, containing no active-drug Placebo Vaginal Ring: The placebo VR is a flexible, platinum-catalyzed-cured silicone matrix ring, identical to dapivirine Ring-004, containing no active drug.
Gastrointestinal disorders Vomiting	1.4% 1/72 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.	0.00% 0/24 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.

Other adverse events

Additional Information

Dr John Steytler

International Partnership for Microbicides

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Dapivirine Vaginal Ring n=72 participants at risk Safety study of a vaginal ring containing Dapivirine in a postmenopausal female population Dapivirine Vaginal Ring: Dapivirine, a non-nucleoside reverse-transcriptase inhibitor (NNRTI), is a substituted amino- pyrimidine (DAPY) derivative with potent antiviral activity against HIV-1. Dapivirine is chemically described as 4-\[\[4-\[(2,4,6-trimethylphenyl)amino\]-2- pyrimidinyl\]amino\]benzonitrile.6 The dapivirine matrix VR is a flexible ring containing 25 mg of drug substance dispersed in a platinum-catalyzed-cured silicone matrix. Dapivirine is known to be well-suited for delivery via VR	Placebo n=24 participants at risk The placebo VR is a flexible, platinum-catalyzed-cured matrix ring, identical to Dapivirine Ring-004, containing no active-drug Placebo Vaginal Ring: The placebo VR is a flexible, platinum-catalyzed-cured silicone matrix ring, identical to dapivirine Ring-004, containing no active drug.
Gastrointestinal disorders Abdominal Pain Lower	5.6% 4/72 • Number of events 4 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.	0.00% 0/24 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.
Gastrointestinal disorders Constipation	2.8% 2/72 • Number of events 2 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.	0.00% 0/24 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.
Gastrointestinal disorders Diarrhoea	4.2% 3/72 • Number of events 3 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.	0.00% 0/24 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.
Infections and infestations Gastroenteritis	2.8% 2/72 • Number of events 2 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.	0.00% 0/24 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.
Infections and infestations Upper respiratory tract infection	8.3% 6/72 • Number of events 6 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.	12.5% 3/24 • Number of events 3 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.
Infections and infestations Urinary tract infection	1.4% 1/72 • Number of events 1 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.	8.3% 2/24 • Number of events 3 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.
Infections and infestations Vulvovaginitis	2.8% 2/72 • Number of events 2 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.	8.3% 2/24 • Number of events 2 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.
Investigations Blood pressure increased	2.8% 2/72 • Number of events 2 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.	0.00% 0/24 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.
Musculoskeletal and connective tissue disorders Back pain	2.8% 2/72 • Number of events 2 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.	0.00% 0/24 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.
Nervous system disorders Headache	2.8% 2/72 • Number of events 2 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.	0.00% 0/24 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.
Reproductive system and breast disorders Cervix haemorrhage uterine	5.6% 4/72 • Number of events 4 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.	4.2% 1/24 • Number of events 1 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.
Reproductive system and breast disorders Dyspareunia	2.8% 2/72 • Number of events 2 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.	0.00% 0/24 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.
Reproductive system and breast disorders Vaginal discharge	11.1% 8/72 • Number of events 8 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.	12.5% 3/24 • Number of events 3 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.
Blood and lymphatic system disorders Anaemia	2.8% 2/72 • Number of events 2 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.	0.00% 0/24 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.
Gastrointestinal disorders Abdominal Discomfort	2.8% 2/72 • Number of events 2 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.	0.00% 0/24 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.
Reproductive system and breast disorders Vaginal erosion	2.8% 2/72 • Number of events 2 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.	0.00% 0/24 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.
Reproductive system and breast disorders Vaginal haemorrhage	5.6% 4/72 • Number of events 4 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.	0.00% 0/24 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.
Reproductive system and breast disorders Vaginal odour	6.9% 5/72 • Number of events 5 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.	0.00% 0/24 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.
Reproductive system and breast disorders Vulvovaginal discomfort	2.8% 2/72 • Number of events 2 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.	0.00% 0/24 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.
Reproductive system and breast disorders Vulvovaginal dryness	2.8% 2/72 • Number of events 2 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.	0.00% 0/24 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.
Reproductive system and breast disorders Vulvovaginal erythema	2.8% 2/72 • Number of events 3 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.	12.5% 3/24 • Number of events 3 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.
Reproductive system and breast disorders Vulvovaginal pruritus	4.2% 3/72 • Number of events 3 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.	4.2% 1/24 • Number of events 1 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.
Gastrointestinal disorders Nausea	2.8% 2/72 • Number of events 2 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.	0.00% 0/24 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.
Gastrointestinal disorders Vomiting	4.2% 3/72 • Number of events 3 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.	0.00% 0/24 • IP 12 weeks + 1 week follow-up All AEs (including deaths and SAE) reported by or observed in enrolled trial participants regardless of severity and presumed relationship to IP was reported in source documents.