Cervical Priming
Conditions
Keywords
Hysteroscopy, Cervical priming, Cervical dilatation, Misoprostol, Endoscopy, uterine
Brief summary
A Phase II, multicenter, double-blind, randomized, placebo-controlled, dose-ranging, study to assess the efficacy and safety of the 100, 200, 400, 800, 1200 and 1600 mcg Misoprostol Vaginal Priming Insert (MVPI) for Women Requiring Cervical Priming prior to an in-office hysteroscopy procedure. Each subject will be randomized to receive one vaginal insert. The study drug will be administered vaginally by a member of the clinical research team (Part I) or insert herself (Part II) 18 - 24 hours prior to the scheduled hysteroscopy clinic visit. The internal os of the cervix will be measured at baseline, just prior to the hysteroscopy and at the follow up visit. The primary outcome measure is change in diameter of the internal cervical os from baseline (pre-treatment) to just prior to the hysteroscopy procedure (post-treatment). The hypothesis is that treatment with the MVPI will soften and dilate the cervix better than placebo.
Detailed description
Prior to the hysteroscopy procedure, study staff will record the type of procedure that will be conducted and the desired cervical dilatation. The study drug will be removed in the office and then a vaginal examination will be performed for signs of irritation or trauma. The diameter of the internal os will then be assessed using Hegar dilators. The diameter of the internal os will be assessed by the largest size of Hegar dilator that can be inserted into the internal os without resistance. If the subject requires further dilatation prior to the procedure, this will be noted; additional dilatation is per clinician preference. The use of a tenaculum to allow insertion of the dilator(s)/ hysteroscope should be recorded. The time of starting and ending the hysteroscopy procedure will be documented. The start time of the hysteroscopy procedure is taken from the time of insertion of the first Hegar dilator to completion of the hysteroscopy procedure. Cervical priming assessment and safety will be recorded. The subject will attend the clinic for follow-up assessments 7 days after the procedure. Adverse events and concomitant medications will be recorded throughout the study. The study will use an adaptive design, beginning with the MVPI 400 mcg and escalating or reducing the dose depending on results seen with a particular dose.
Interventions
DRUGmisoprostol
One vaginal insert containing 100, 200, 400, 800, 1200, 1600 mcg misoprostol administered intravaginally one time and remain in place for 18 - 24 hours prior to the hysteroscopy procedure. An adaptive design will be used to determine whether to escalate or reduce the dose, starting with MVPI 400 mcg.
DRUGplacebo
placebo
Sponsors
Ferring Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Healthy, pre-menopausal women; * Women aged 18 years and above; * Women who are undergoing an in-office procedure requiring uterine access along with a cervical dilatation of at least 5.5 mm; * Women participating in Part 1 of study: Women who have had at least one vaginal delivery of at least 24 weeks gestation; * Women with Pap smear results that do not require further evaluation for at least one year as assessed by the investigator. Note: 1) results must be from a Pap smear obtained within one year of screening; 2) if results are unavailable or not current, a Pap smear must be obtained and results reviewed prior to study inclusion; 3) if a Pap smear is to be performed at screening, subject must have a negative pregnancy test confirmed prior to the Pap smear collection; * Women of child bearing potential: 1) Must have a negative urine pregnancy test at screening and just prior to study drug insertion, if this takes place on a different day from the screening visit; 2) Agree to use a highly effective method of birth control (defined as a low failure rate of less than 1% per year) as follows: implants, injectables, combined oral contraceptives, sexual abstinence from the date of the subject's last menstruation until completion of the follow-up visit, vasectomised partner or barrier method (condom with spermicide). Women in a same sex relationship do not need to meet this criterion if they confirm that there is no possibility of pregnancy; * Women who agree to refrain from vaginal intercourse while the study drug is in place; * Women who agree to refrain from using any of the following from the day of study drug insertion until completion of the follow-up visit: feminine deodorant sprays/products, spermicides\*, douches, condoms\*, tampons, diaphragms or any other pharmaceutical or over the counter vaginal product. Barrier methods of contraception as indicated above (\*) may be resumed following the dilatation procedure; * Women who provide written informed consent.
Exclusion criteria
* Menopausal women; * Women with menstrual periods lasting \>10 days in duration; * Baseline internal cervical os ≥ 3 mm; * Women who have had prior endometrial ablation; * Women who are breastfeeding; * History or current diagnosis of glaucoma; * Women with clinically significant vaginal or cervical abnormality (e.g. symptoms of an infection) that would interfere with conducting study procedures prior to study drug insertion; * Women who are currently undergoing treatment for cancer (basal cell carcinoma is acceptable); * Body Mass Index (BMI) ≥ 50; * Women participating in Part 1 of study: Women with a history of loop electrosurgical excision procedure (LEEP) or cold knife conization without an intervening vaginal delivery; * Women with an intra-uterine device (IUD) in place, had an IUD removed within 30 days of the screening visit or scheduled to have an IUD inserted during the hysteroscopy procedure; * Women using NuvaRing® for contraception; * Known or suspected allergy to misoprostol, other prostaglandins or any of the excipients; * Unable to comply with the protocol.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change in Diameter of the Internal Cervical os From Baseline (Pre-treatment) to Just Prior to the Hysteroscopy Procedure (Post-treatment). | Baseline to 18-24 hours |
Secondary
| Measure | Time frame |
|---|---|
| Percent of Women Requiring Further Dilatation in Order to Allow Uterine Access | 18 - 24 hours |
| Total Procedure Time From Insertion of the First Hegar Dilator to Completion of the Hysteroscopy Procedure; | 18 - 24 hours |
| Physician Assessment of Ease of Cervical Dilation; | 18 - 24 hours |
| Percentage of Participants With Adverse Events | 9 days |
Countries
United States
Participant flow
Recruitment details
Premenopausal women requiring cervical priming prior to an in-office hysterectomy procedure were recruited at 5 sites in the US
Pre-assignment details
Part 1 of the study included only women who had at least one vaginal delivery. There was no restriction on vaginal delivery status in Part 2 of the study. Part 1 participants were included in the MVPI 400 mcg cohort, MVPI 800 mcg cohort and the Placebo cohort. Part 2 participants were included in the MVPI 800 mcg cohort and the Placebo cohort.
Participants by arm
| Arm | Count |
|---|---|
| MVPI 400 Mcg One vaginal insert administered 18 - 24 hours prior to the scheduled hysteroscopy clinic visit. Part 1 participants were included in this arm of the study.
misoprostol : One vaginal insert containing 400 mcg misoprostol administered intravaginally one time and remain in place for 18 - 24 hours prior to the hysteroscopy procedure. | 9 |
| MVPI 800 Mcg One vaginal insert administered 18 - 24 hours prior to the scheduled hysteroscopy clinic visit. Following the initial dose, 400 mcg, the dose was increased to 800 mcg after the 400 mcg group cohort based on safety and efficacy criteria as assessed by the Data and Safety Monitoring Board (DSMB). Part 1 and Part 2 participants were included in this arm of the study. | 25 |
| MVPI Placebo One vaginal insert of placebo administered 18 - 24 hours prior to the scheduled hysteroscopy clinic visit. Part 1 and Part 2 participants were included in this arm of the study.
placebo : placebo | 17 |
| Total | 51 |
Baseline characteristics
| Characteristic | MVPI 800 Mcg | MVPI Placebo | MVPI 400 Mcg | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants | 17 Participants | 9 Participants | 51 Participants |
| Age, Continuous | 41.5 years STANDARD_DEVIATION 6.21 | 42.0 years STANDARD_DEVIATION 5.86 | 40.8 years STANDARD_DEVIATION 6.57 | 41.5 years STANDARD_DEVIATION 6.05 |
| Region of Enrollment United States | 25 participants | 17 participants | 9 participants | 51 participants |
| Sex: Female, Male Female | 25 Participants | 17 Participants | 9 Participants | 51 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 9 | 23 / 25 | 14 / 17 |
| serious Total, serious adverse events | 0 / 9 | 1 / 25 | 0 / 17 |
Outcome results
Primary
Change in Diameter of the Internal Cervical os From Baseline (Pre-treatment) to Just Prior to the Hysteroscopy Procedure (Post-treatment).
Time frame: Baseline to 18-24 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MVPI 400 Mcg | Change in Diameter of the Internal Cervical os From Baseline (Pre-treatment) to Just Prior to the Hysteroscopy Procedure (Post-treatment). | 2.2 mm | Standard Deviation 1.86 |
| MVPI 800 Mcg | Change in Diameter of the Internal Cervical os From Baseline (Pre-treatment) to Just Prior to the Hysteroscopy Procedure (Post-treatment). | 2.3 mm | Standard Deviation 2.21 |
| MVPI Placebo | Change in Diameter of the Internal Cervical os From Baseline (Pre-treatment) to Just Prior to the Hysteroscopy Procedure (Post-treatment). | 1.5 mm | Standard Deviation 1.84 |
Secondary
Percentage of Participants With Adverse Events
Time frame: 9 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MVPI 400 Mcg | Percentage of Participants With Adverse Events | 100 Percentage of participants |
| MVPI 800 Mcg | Percentage of Participants With Adverse Events | 92.0 Percentage of participants |
| MVPI Placebo | Percentage of Participants With Adverse Events | 82.4 Percentage of participants |
Secondary
Percent of Women Requiring Further Dilatation in Order to Allow Uterine Access
Time frame: 18 - 24 hours
Population: A total of 46 subjects (90.2%) did not achieve their target dilatation after study drug removal (MVPI 400: 8 subjects; MVPI 800: 21 subjects; Placebo: 17 subjects). Forty-five subjects had additional dilatation attempted; additional dilatation was not attempted on one subject (MVPI 800) due to a protocol deviation (MVPI 800: 20 subjects).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MVPI 400 Mcg | Percent of Women Requiring Further Dilatation in Order to Allow Uterine Access | Subjects requring additional dilatation | 88.9 percentage of participants |
| MVPI 400 Mcg | Percent of Women Requiring Further Dilatation in Order to Allow Uterine Access | Target Dilation Achieved following 2ndry dilation | 100 percentage of participants |
| MVPI 800 Mcg | Percent of Women Requiring Further Dilatation in Order to Allow Uterine Access | Subjects requring additional dilatation | 84.0 percentage of participants |
| MVPI 800 Mcg | Percent of Women Requiring Further Dilatation in Order to Allow Uterine Access | Target Dilation Achieved following 2ndry dilation | 85.0 percentage of participants |
| MVPI Placebo | Percent of Women Requiring Further Dilatation in Order to Allow Uterine Access | Subjects requring additional dilatation | 100 percentage of participants |
| MVPI Placebo | Percent of Women Requiring Further Dilatation in Order to Allow Uterine Access | Target Dilation Achieved following 2ndry dilation | 100 percentage of participants |
Secondary
Physician Assessment of Ease of Cervical Dilation;
Time frame: 18 - 24 hours
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MVPI 400 Mcg | Physician Assessment of Ease of Cervical Dilation; | Adequate/ Correct Softness | 66.7 percentage of participants |
| MVPI 400 Mcg | Physician Assessment of Ease of Cervical Dilation; | Inadequate | 22.2 percentage of participants |
| MVPI 400 Mcg | Physician Assessment of Ease of Cervical Dilation; | Over Primed/ Too soft | 11.1 percentage of participants |
| MVPI 800 Mcg | Physician Assessment of Ease of Cervical Dilation; | Adequate/ Correct Softness | 48.0 percentage of participants |
| MVPI 800 Mcg | Physician Assessment of Ease of Cervical Dilation; | Inadequate | 36.0 percentage of participants |
| MVPI 800 Mcg | Physician Assessment of Ease of Cervical Dilation; | Over Primed/ Too soft | 16.0 percentage of participants |
| MVPI Placebo | Physician Assessment of Ease of Cervical Dilation; | Inadequate | 47.1 percentage of participants |
| MVPI Placebo | Physician Assessment of Ease of Cervical Dilation; | Over Primed/ Too soft | 0 percentage of participants |
| MVPI Placebo | Physician Assessment of Ease of Cervical Dilation; | Adequate/ Correct Softness | 52.9 percentage of participants |
Secondary
Total Procedure Time From Insertion of the First Hegar Dilator to Completion of the Hysteroscopy Procedure;
Time frame: 18 - 24 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MVPI 400 Mcg | Total Procedure Time From Insertion of the First Hegar Dilator to Completion of the Hysteroscopy Procedure; | 3.26 minutes | Standard Deviation 3.931 |
| MVPI 800 Mcg | Total Procedure Time From Insertion of the First Hegar Dilator to Completion of the Hysteroscopy Procedure; | 3.75 minutes | Standard Deviation 5.888 |
| MVPI Placebo | Total Procedure Time From Insertion of the First Hegar Dilator to Completion of the Hysteroscopy Procedure; | 2.32 minutes | Standard Deviation 1.573 |