Sildenafil Vaginal Gel Co-treatment With Clomiphene Citrate in Infertile Women With Thin Endometrium

• Sponsor: Assiut University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02710981
• Collaborator: (none)
• Enrollment: 42
• Arms: 2
• Duration (Months): 7

Study Details

Study Description

Brief Summary

This is a prospective self controlled clinical trial. Women with clomiphene Citrate failure, and thin endometrium were recruited (N = 42). In their 6th (Clomiphene citrate only) cycle, women continued on Clomiphene citrate 100 mg/ day for 5 days, and had sonographic measurement of their endometrial thickness , and Doppler evaluation of their uterine arteries on the day of HCG administration. In 7th cycle, women (N = 36) were given usual dose of Clomiphene citrate supplemented with sildenafil vagina gel (5 gm, containing 50 mg sildenafil) twice daily from cycle day 8 till the day of HCG injection. Endometrial thickness and uterine artery Doppler were measured on the day of HCG administration.

Condition or Disease	Intervention/Treatment	Phase
Anovulation	Drug: clomiphene citrate; Drug: Sildenafil vaginal gel	N/A

Detailed Description

Study design:

This is a prospective self-controlled clinical trial.

Study subjects:

Investigators counseled and recruited 42 infertile women who had been diagnosed with anovulatory infertility, with normal baseline FSH, LH, and free testosterone levels, patent tubes on hysterosalpingography, and normal male semen analysis.

By the time they were enrolled in the study, all women had already completed 5 ovulatory cycles of Clomiphene citrate induction (in a dose of 100 mg/ day in two divided doses starting from day 3 of the cycle for 5 days) but without conception (clomiphene citrate failure) with thin endometrium (<8mm) in at least 3 cycles. Ovulation was documented sonographically, and with day-21 serum progesterone exceeding 5 ng/ ml in all cases.

Exclusion criteria:

Women with major medical problems, male factor infertility, endocrine abnormalities such as hyperprolactinemia or abnormal thyroid functions, prior ovarian or adnexal surgery, or organic pelvic pathology were not included in the study.

Intervention:

Sixth cycle (Clomiphene citrate only):

Enrolled cases were asked to continue with Clomiphene citrate induction ( at the same dose) for the 6th cycle. A gel base, without medicament (vehicle only), was applied vaginally in a dose of 5 gm twice per day, from cycle day 8 to the day of HCG administration ( when follicular diameter reached 18 mm). Endometrial thickness and Uterine artery Doppler assessment were done in the late proliferative phase ( Day of HCG injection).

Seventh cycle ( Sildenafil vaginal gel and Clomiphene cycle):

Those who didn't conceive on the sixth cycle (41 women) were asked to have an extra (7th) cycle in which they were prescribed the usual dose of Clomiphene citrate in addition to sildenafil vaginal gel. The sildenafil vaginal gel consists of sildenafil acetate as a medicament loaded on an in situ gelling system based on two polymers: Pluronic p-127, and Hydroxy Ethyl Cellulose. The dose was 5 g gel containing 50 mg sildenafil, applied vaginally twice daily from cycle day 8 to Day of HCG injection. The gel was prepared in collaboration with the department of pharmaceutics, faculty of Pharmacy, Assiut University. Sixty grams of gel were prepared in tubes and every patient was given 10 applicators like that used for administration of vaginal antimycotic creams to use them for applying the gel.

Evaluation of the study end points:

On day of HCG injection (main follicular diameter of 18 mm) in the 6th, and 7th cycles, women came for follow up and had transvaginal sonographic assessment of their endometrial thickness. Investigators have measured the maximal distance spanning endometrial- myometrial interphase on each endometrial stripe in a sagittal plane in the fundus of the uterus. In addition, Transvaginal Doppler examination was also done on the same visit to evaluate the pulsatility indices of both uterine arteries. When the leading follicle reached 18 mm in diameter, 5000 IU of HCG was prescribed for IM injection.

Although pregnancy rate was not a primary outcome measure in the study, investigators detected pregnancy in 3 cases in the cohort of 36 cases of infertile women with clomiphene failure in which sildenafil gel was added as an adjuvant. Pregnancy was diagnosed with a B-HCG value above 100 mIU/ml, and confirmed later with ultrasound.

Statistics:

Data were analyzed using SPSS program ver. 17 using Student-t-test and Fisher's exact test for comparing data in the 6th and 7th cycles, as appropriate.

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Effect of Sildenafil Vaginal Gel Co-treatment With Clomiphene Citrate on Endometrial Thickness in Infertile Women With Prior Clomiphene Citrate Failure Due to Thin Endometrium: a Prospective Self-controlled Clinical Trial
• Study Start Date: Jun 1, 2015
• Actual Primary Completion Date: Jan 1, 2016
• Actual Study Completion Date: Jan 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Clomiphene citrate only women with prior 5 ovulatory cycles of Clomiphene citrate induction, but without conception (clomiphene citrate failure), with thin endometrium (<8mm) in at least 3 cycles.	Drug: clomiphene citrate; Clomiphene citrate only arm: Patients received Clomiphene citrate induction ( (in a dose of 100 mg/ day in two divided doses starting from day 3 of the cycle for 5 days) for the 6th cycle. A gel base, without medicament (vehicle only), was applied vaginally in a dose of 5 gm twice per day, from cycle day 8 to the day of HCG injection. Sonographic assessment of endometrial thickness together with Uterine artery Doppler evaluation were done in the late proliferative phase ( Day of HCG injection).; Other Names: clomid only
Experimental: Sildenafil vaginal gel and Clomiphene Women who did not conceive on the Clomiphene citrate only cycle (41 women) were given Clomiphene citrate 100 mg/ day starting from day of the cycle for 5 days, with the addition to sildenafil vaginal gel 5 gm twice daily starting from day 8 of the cycle until day of HCG injection.	Drug: clomiphene citrate; Clomiphene citrate only arm: Patients received Clomiphene citrate induction ( (in a dose of 100 mg/ day in two divided doses starting from day 3 of the cycle for 5 days) for the 6th cycle. A gel base, without medicament (vehicle only), was applied vaginally in a dose of 5 gm twice per day, from cycle day 8 to the day of HCG injection. Sonographic assessment of endometrial thickness together with Uterine artery Doppler evaluation were done in the late proliferative phase ( Day of HCG injection).; Other Names: clomid only ; Drug: Sildenafil vaginal gel; In addition to clomiphene citrate treatment as the previous group, women in the second arm were prescribed sildenafil vaginal gel in a dose of 5 g gel applied vaginally twice daily from cycle day 8 to the day of HCG injection. The sildenafil vaginal gel consists of sildenafil acetate as a medicament loaded on an in situ gelling system based on two polymers: Pluronic p-127, and Hydroxy Ethyl Cellulose.The gel was prepared in collaboration with the department of pharmaceutics, faculty of Pharmacy, Assiut University. Sixty grams of gel were prepared in tubes and every patient was given 10 applicators like that used for administration of vaginal antimycotic creams to use them for applying the gel.; Other Names: Viagra vaginal gel

Outcome Measures

Primary Outcome Measures

1. Endometrial Thickness [Day of HCG administration]

   Transvaginal sonographic measurement of maximal distance spanning endometrial- myometrial interphase on each endometrial stripe in a sagittal plane in the fundus of the uterus

Secondary Outcome Measures

1. Uterine Blood Flow [Day of HCG administration]

   Doppler ultrasound is used to measure the pulsatility index in both uterine arteries. Pulsatility index is a measure of the arterial resistance to blood flow. The higher the value of the pulsatility index, the more resistant the uterine arteries are, and hence the worst the outcome.

2. Clinical Pregnancy Rate [At the end of a 28-day menstrual cycle.]

   Identifying pregnancy through positive urinary HCG test plus sonographic detection of cardiac pulsations

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 40 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Women with clomiphene citrate failure (defined as at least prior 5 ovulatory cycles with clomiphene citrate, with no conception),

• persistently thin endometrium (less than 8 mm in at least 3 cycles).

• normal baseline FSH, LH, and free testosterone levels, patent tubes on hysterosalpingography, and normal male semen analysis

Exclusion Criteria:

• Women with major medical problems,

• male factor infertility,

• endocrine abnormalities such as hyperprolactinemia or abnormal thyroid functions,

• prior ovarian or adnexal surgery, or organic pelvic pathology

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Assiut University

Investigators

• Study Director: Ahmed N. Fetih, M.D., Assiut University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Essam Rashad Abdel-Hafeez Othman, Associate professor, Assiut University
• ClinicalTrials.gov Identifier: NCT02710981
• Other Study ID Numbers: AUH1
• First Posted: Mar 17, 2016
• Last Update Posted: May 5, 2020
• Last Verified: Apr 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Essam Rashad Abdel-Hafeez Othman, Associate professor, Assiut University: Sildenafil vaginal gel; endometrium; clomiphene; anovulation
• Additional relevant MeSH terms: Anovulation; Sildenafil Citrate; Clomiphene; Enclomiphene; Zuclomiphene

Study Results

Participant Flow

Pre-assignment Detail	As this is a self controlled clinical trial, participants in the clomiphene citrate only arm (6th ovulation induction cycle) are the same participant in the clomiphene citrate plus sildenafil vaginal gel arm (7th ovulation induction cycle).

Arm/Group Title	Clomiphene Citrate Only	Clomiphene Citrate Plus Sildenafil Vaginal Gel (7th Ovulation)
Arm/Group Description	Clomiphene citrate only arm: Patients underwent 6th ovulation induction cycle in which women received Clomiphene citrate (in a dose of 100 mg/ day in two divided doses starting from day 3 of the cycle for 5 days). A gel base, without medicament (vehicle only), was applied vaginally in a dose of 5 gm twice per day, from cycle day 8 to the day of HCG injection. Sonographic assessment of endometrial thickness together with Uterine artery Doppler evaluation were done in the late proliferative phase ( Day of HCG injection). Period of this arm is one menstrual cycle (6th induction cycle)	Clomiphene citrate plus sildenafil vaginal gel arm: Women who did not conceive on the 6th cycle ( clomiphene citrate only cycle; 41 women) were offered a 7th cycle in which they were given Clomiphene citrate 100 mg/ day starting from day of the cycle for 5 days, with adding sildenafil vaginal gel 5 gm twice daily starting from cycle day 8 on until day of HCG injection. Sonographic assessment of endometrial thickness together with Uterine artery Doppler evaluation were done in the late proliferative phase ( Day of HCG injection). Period of this arm is the subsequent menstrual cycle (7th induction cycle)
Period Title: 6th Ovulation Induction Cycle (5 Days)
STARTED	42	0
COMPLETED	41	0
NOT COMPLETED	1	0
Period Title: 6th Ovulation Induction Cycle (5 Days)
STARTED	0	41
COMPLETED	0	36
NOT COMPLETED	0	5

Baseline Characteristics

Arm/Group Title	Clomiphene Citrate Only Group (6th Ovulation Induction Cycle)
Arm/Group Description	Infertile women who have completed 5 cycles of clomiphene citrate with successful ovulation, thin endometrium and no pregnancy who are attempting a 6th cycle of clomiphene citrate.
Overall Participants	41
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	41 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	26.8 (2.8)
Sex: Female, Male (Count of Participants)
Female	41 100%
Male	0 0%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (participants) [Number]
Egypt	41 100%
Serum FSH (U/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [U/L]	4.5 (1.5)

Outcome Measures

1. Primary Outcome

Title	Endometrial Thickness
Description	Transvaginal sonographic measurement of maximal distance spanning endometrial- myometrial interphase on each endometrial stripe in a sagittal plane in the fundus of the uterus
Time Frame	Day of HCG administration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Clomiphene Citrate Only Group (6th Ovulation Induction Cycle)	Clomiphene Citrate Plus Sildenafil Vaginal Gel (7th Ovulation)
Arm/Group Description	Infertile women who had undergone 5 cycles of clomiphene citrate ovulation induction with ovulation detected, and no pregnancy due to thin endometrium	Women who did not get pregnant after 6th ovulation induction cycle receive a 7th induction cycle with clomiphene citrate plus sildenafil vaginal gel
Measure Participants	41	36
Mean (Standard Deviation) [millimeter]	6.6 (1.4)	9.3 (3.1)

2. Secondary Outcome

Title	Uterine Blood Flow
Description	Doppler ultrasound is used to measure the pulsatility index in both uterine arteries. Pulsatility index is a measure of the arterial resistance to blood flow. The higher the value of the pulsatility index, the more resistant the uterine arteries are, and hence the worst the outcome.
Time Frame	Day of HCG administration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Clomiphene Citrate Only Group (6th Ovulation Induction Cycle)	Clomiphene Citrate Plus Sildenafil Vaginal Gel (7th Ovulation)
Arm/Group Description	Infertile women who had undergone 5 cycles of clomiphene citrate ovulation induction with ovulation detected, and no pregnancy due to thin endometrium	Women who did not get pregnant after 6th ovulation induction cycle with clomiphene citrate and placebo vaginal gel were offered a 7th cycle in which ovulation was induced with clomiphene citrate plus sildenafil vaginal gel
Measure Participants	41	36
Mean (Standard Deviation) [index]	2.4 (0.8)	1.6 (1.3)

3. Secondary Outcome

Title	Clinical Pregnancy Rate
Description	Identifying pregnancy through positive urinary HCG test plus sonographic detection of cardiac pulsations
Time Frame	At the end of a 28-day menstrual cycle.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Clomiphene Citrate Only Group (6th Ovulation Induction Cycle)	Clomiphene Citrate Plus Sildenafil Vaginal Gel (7th Ovulation
Arm/Group Description	Infertile women who had undergone 5 cycles of clomiphene citrate ovulation induction with ovulation detected, and no pregnancy due to thin endometrium	Women who did not get pregnant after 6th ovulation induction cycle with clomiphene citrate and placebo vaginal gel were offered a 7th ovulation induction cycle with clomiphene citrate and sildenafil vaginal gel
Measure Participants	41	36
Count of Participants [Participants]	0 0%	3 NaN

Adverse Events

Arm/Group Title	Clomiphene Citrate Only Group (6th Ovulation Induction Cycle)		Clomiphene Citrate Plus Sildenafil Vaginal Gel (7th Ovulation)
Arm/Group Description	Infertile women who had undergone 5 cycles of clomiphene citrate ovulation induction with ovulation detected, and no pregnancy due to thin endometrium (N =41)		Women who did not get pregnant after 6th ovulation induction cycle receive a 7th induction cycle with clomiphene citrate plus sildenafil vaginal gel
All Cause Mortality
	Clomiphene Citrate Only Group (6th Ovulation Induction Cycle)		Clomiphene Citrate Plus Sildenafil Vaginal Gel (7th Ovulation)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Clomiphene Citrate Only Group (6th Ovulation Induction Cycle)		Clomiphene Citrate Plus Sildenafil Vaginal Gel (7th Ovulation)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/42 (0%)		0/41 (0%)
Other (Not Including Serious) Adverse Events
	Clomiphene Citrate Only Group (6th Ovulation Induction Cycle)		Clomiphene Citrate Plus Sildenafil Vaginal Gel (7th Ovulation)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/41 (0%)		1/36 (2.8%)
Vascular disorders
Vasodilatory headache	0/41 (0%)	0	1/36 (2.8%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.