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Clomiphene Citrate, Estradiol and Sildenafil for Induction of Ovulation in Unexplained Infertility

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ClinicalTrials.gov Identifier: NCT03755037
Recruitment Status : Completed
First Posted : November 27, 2018
Last Update Posted : November 27, 2018
Sponsor:
Collaborator:
Beni-Suef University
Information provided by (Responsible Party):
Nesreen Abdel Fattah Abdullah Shehata, Beni-Suef University

Brief Summary:
Diagnosis of unexplained infertility is made after the recommended testing fails to reveal any abnormality. The treatment for unexplained infertility is empiric because it does not address a specific defect or functional impairment. The principal treatments for unexplained infertility include expectant observation with timed intercourse and lifestyle changes, clomiphene citrate and intrauterine insemination (IUI), controlled ovarian hyperstimulation (COH) with IUI, and IVF).

Condition or disease Intervention/treatment Phase
Female Infertility Drug: Clomid, Respatio and Ethinyl estradiol Phase 1

Detailed Description:

Clomiphene citrate has been widely used alone, and in combination with intrauterine insemination (IUI), for treatment of unexplained subfertility, The mechanism of action is based on its mixed estrogenic and antiestrogenic properties. Clomiphene is frequently used to treat unexplained female infertility by inducing multifollicular response and correcting potential subtle ovulatory dysfunction .,)The American Society for Reproductive Medicine,2003).

The use of clomiphene citrate decreases the uterine blood flow during the early luteal phase, a periimplantation stage., )The American College of Obstetricians and Gynecologists,1995).

Although ovulation is found in 80% of women with a cumulative effect in 6-8 months, the pregnancy rate can still be very low in these women . The possible causes are the anti-estrogenic effects of CC at the endometrium and cervical mucus level . The endometrial effect is without doubt one of the most important handicaps in infertility treatment. The pregnancy rate can be very low, especially if the endometrial thickness (ET) is <6-8 mm ., )J Turk Ger Gynecol Assoc. ,2012).

Ethinyl E2 reverse the deleterious effect of CC on endometrial development during the follicular phase. Endometrial thickness was dependent on peak E2 concentrations in serum.,(Richard P. Dickey, et.al.,2003).

Sildenafil citrate could lead to an improvement in uterine blood flow and, in conjunction with estrogen, led to the estrogen-induced proliferation of the endometrial lining .

Sildenafil citrate enhances uterine blood flow and increases endometrial thickening . The achieved implantation depends on the blastocyst's ability to infiltrate the endometrium and develop a sustaining blood supply, which requires the following genes to produce the necessary proteins for digesting the endometrial cellular matrix, to regulate cell growth, and to induce angiogenesis (Razieh Dehghani Firouzabadi,et.al.,2013).


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Women with unexplained infertility (n=150) were divided into 3 equal groups. Group 1 received estradiol and clomiphine citrate (cc), group 2 received sildenafil and cc and group 3 cc and placebo.
Masking: Double (Participant, Investigator)
Masking Description: Double blind randomisation
Primary Purpose: Treatment
Official Title: Clomiphine Citrate and Estradiol Versus Clomiphine Citrate and Sildenafil in Comparison With Clomiphine Citrate Alone for Induction of Ovulation in Unexplained Infertility: Double Blind Randomised Trial
Actual Study Start Date : January 31, 2017
Actual Primary Completion Date : April 30, 2018
Actual Study Completion Date : April 30, 2018


Arm Intervention/treatment
Active Comparator: Estradiol and cc

Group 1 received estradiol, cc and placebo simillar to sildenafil for induction of ovulation.

CC 50 mg (clomid) orally twice daily from 3rd day to 7th day of menstrual cycle of the patient then ethinyl estradiol 0.05mg orally twice daily on the 8th day of same cycle till 11th day.

Drug: Clomid, Respatio and Ethinyl estradiol
Drugs were received during the menstrual cycle.

Active Comparator: Sildenafil and cc
Group 2 received CC 50 mg (clomid) orally twice daily from 3rd day to 7th day of menstrual cycle of the patient, sildenafil citrate (Respatio) 20 mg tab orally 3 times daily from8th day of same cycle till 11th day and placebo simillar to estradiol.
Drug: Clomid, Respatio and Ethinyl estradiol
Drugs were received during the menstrual cycle.

Placebo Comparator: Placebo and cc
Group 3 received cc and placebo similar to sildenafil and placebo similar to estradiol with the same doses.
Drug: Clomid, Respatio and Ethinyl estradiol
Drugs were received during the menstrual cycle.




Primary Outcome Measures :
  1. Ultrasound parameters [ Time Frame: at day 14 until day 17 of menstrual cycle ]
    Number of follicles in each ovary and endometrial thickness


Secondary Outcome Measures :
  1. Pregnancy [ Time Frame: at day 21 and 24 of menstrual cycle ]
    A serum pregnancy test was done



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Ages Eligible for Study:   20 Years to 30 Years   (Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   female unexplained infertility patients
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Women whose infertility tests were normal then diagnosed as unexplained infertility.

Exclusion Criteria:

  • Any cause of infertility male factor, tubal or ovarian.
  • Chronic illness as cardiac or renal disease
  • Any contraindication for used drugs

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03755037


Locations
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Egypt
Nesreen Abd El Fattah Abd Allah
Cairo, Egypt, 11412
Sponsors and Collaborators
Nesreen Abdel Fattah Abdullah Shehata
Beni-Suef University

Publications:
1. Alexander Quaas, MD, Ph .D .,and Anuja Dokras, MD . diagnosis and treatment of unexplainrd infertilityRev Obstet Gynecol. 2008 Spring; 1(2): 69-76 2. J Turk Ger Gynecol Assoc.: The effect of administering estrogen to clomiphene citrate stimulated cycles on endometrial thickness and pregnancy rates in unexplained infertility. (2012) . Sep 1;13(3):157-61. 3. Paulus WE, Strehler E, Zhang M, Jelinkova L,El-Danasouri I and Sterzik K. : Benefit of sildenafil citrate in assisted reproductivetherapy. Fertil Steri 2002 Apr;77(4):846-7. 4. Razieh Dehghani Firouzabadi, M.D., Robab Davar, M.D., Farzaneh Hojjat, M.D., and Mohamad Mahdavi, M.D. :effect of sildenafil on endomeerial preparation and outcome of frozen_thawed embryo transfer cycles(. Iran J Reprod Med. 2013 Feb; 11(2): 151-158. 5. Richard P. Dickey, M.D., Ph.D.,):clomiphene citrate for woman with unexplained infertility . pp 261-271 13 May 2015 6. The American Society for Reproductive Medicine. Use of clomiphene citrate in infertile women:. Fertil Steril . Fertil Steril. 2013 Aug;100(2):341-8. doi: 10.1016/j.fertnstert.2013.05.033. Epub 2013 Jun 27.

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Responsible Party: Nesreen Abdel Fattah Abdullah Shehata, Assistant professor, Beni-Suef University
ClinicalTrials.gov Identifier: NCT03755037     History of Changes
Other Study ID Numbers: Beni-Suef 16
First Posted: November 27, 2018    Key Record Dates
Last Update Posted: November 27, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Infertility
Infertility, Female
Genital Diseases, Male
Genital Diseases, Female
Sildenafil Citrate
Citric Acid
Sodium Citrate
Estradiol 3-benzoate
Estradiol 17 beta-cypionate
Clomiphene
Enclomiphene
Zuclomiphene
Estradiol
Polyestradiol phosphate
Ethinyl Estradiol
Anticoagulants
Calcium Chelating Agents
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action
Estrogens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Contraceptive Agents
Reproductive Control Agents
Contraceptive Agents, Female
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors