Clinical trial NCT01672801: Nimodipine to Prevent LH Surge During Ovulation Induction: Blinded Placebo-controlled RCT
Official title: Using Nimodipine, a Calcium Channel Blocker, to Prevent LH Surge in Women Undergoing Controlled Ovarian Stimulation and Intrauterine Insemination: a Double-blinded, Randomized Controlled Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Unexplained Infertility
Polycystic Ovarian Syndrome
Anovulatory
Lead sponsor: Boston IVF
Sponsor class: OTHER
Collaborators: name: Village Fertility Pharmacy
First posted: 2012-08-27
Enrollment: 18
Sex: FEMALE
Minimum age (years): 25
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The main purpose of this study is to test the effectiveness of nimodipine in preventing a luteinizing hormone (LH) surge in women undergoing ovulation induction with clomiphene citrate. It is important to prevent the premature LH surge in controlled ovarian stimulation to allow adequate recruitment of follicles, proper maturation of a dominant follicle before ovulation, and effectively time insemination with semen to allow fertilization of a mature egg to occur.

The investigators are also conducting this study to determine medication side effect profile (including lightheadedness or dizziness from low blood pressure or rapid heart rate, headache, and nausea), patient treatment compliance, and clinical pregnancy (positive pregnancy test and ultrasound evidence of fetal heart rate). Finally, LH and follicle stimulating hormone (FSH) serum levels will be measured to determine effect of nimodipine on these hormones.

As a calcium channel blocker, nimodipine has been shown to block calcium mediated release of gonadotropin releasing hormone in animal and preliminary human studies. The investigators hypothesize that nimodipine, a calcium channel blocker, will prevent or delay the LH surge during controlled ovarian stimulation cycles using clomiphene citrate in subfertile patients undergoing assisted reproduction with intrauterine insemination (IUI).

Detailed description: After enrollment, subjects will be randomized to Placebo Comparator or Active Comparator. All subjects will receive Clomid 100 mg for 5 days for the purpose of ovarian follicle recruitment. Intervention will be initiated once ovarian follicle maturation has been documented (≥1 ovarian follicle size of ≥ 17mm) and the absence of a premature LH surge has been confirmed - this will be classified as intervention day 0. Subjects will receive their assigned comparator (Placebo or Active) according the schedule below:

* Intervention Day 0 - noon / afternoon / bedtime (3 doses)
* Intervention Day 1 - morning / noon / afternoon / bedtime (4 doses)
* Intervention Day 2 - morning (1 dose) Serum hormone levels and ultrasound examination will occur on days 0,1 and 2 for all subjects.

Eligibility criteria: Inclusion Criteria:

* Age 25-40 years at the time of enrollment
* Both ovaries intact by history and ultrasound assessment
* Early follicular phase (day 2-4) serum FSH level \<20 mIU/mL
* Diagnosis of subfertility with a recommended treatment of COH and IUI
* Providing written informed consent in English

Exclusion Criteria:

* Body mass index (BMI) \>38 kg/m2
* Early follicular phase (day 2-4) serum FSH level ≥20 mIU/mL
* History of overstimulated cycle defined as \>3 mature follicles of ≥17 mm
* Abnormal uterine cavity and/or tubal disease (as evidenced by sonohysterogram or hysterosalpingogram)
* Diagnosis of infertility with a clear indication for in-vitro fertilization, such as bilateral tubal occlusion
* Severe male factor infertility: Total Motile Sperm Count \< 2x106 post washing (sperm deemed inadequate for IUI preparation)
* Any ovarian or abdominal abnormality that may interfere with adequate TV ultrasound evaluation
* Absence of one or both ovaries
* Any contraindication to being pregnant or carrying a pregnancy to term
* Unexplained gynecological bleeding
* Any medical condition that would jeopardize the patient or the integrity of the data obtained including:
* Prior reaction or side effects from previous calcium channel blocker use
* Any medical condition that may interfere with the absorption, distribution, metabolism or excretion of nimodipine such as hepatic disease, hypertension, seizure, concurrent infection, depression, reflux (see #12 below).
* Mental health status resulting in cognitive or emotional impairment that would preclude study participation
* The concurrent use of any of the following drugs: \[These medications have been shown to effect the availability of the medication or worsen hypotension symptoms\]
* Antihypertensives (eg. ACE inhibitors, alpha-adrenergic blocking agents,methyldopa, beta-blockers, diuretics, PDE5 inhibitors, and other calcium antagonists)
* Antiepileptics (eg. phenobarbital, phenytoin, carbamazepine or valproic acid)
* Macrolide antibiotics (eg, erythromycin)
* Azole antimycotics (eg, ketoconazole)
* HIV protease inhibitors (eg, ritonavir)
* Antidepressants (eg, nefazodone and fluoxetine)
* Cimetidine
* Patient unable to communicate adequately with the investigators and to comply with the requirements of the study
* Unwillingness to give written informed consent

Primary outcomes:
measure: LH Surge
timeFrame: 7 days
Secondary outcomes:
measure: Number of Participants Experiencing Side Effects
timeFrame: Starting day 0 of intervention to pregnancy test (approximately 15 days)
Other outcomes:
measure: Gonadotropin Levels
timeFrame: Intervention day 0 to ovulation (approximately 1-7 days)
Locations:
city: Waltham
country: United States
facility: Boston IVF
state: Massachusetts
Study officials:
affiliation: Beth Israel Deaconess Medical Center / Boston IVF
name: Alan S Penzias, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chen EC, Javors MA, Norris C, Siler-Khodr T, Schenken RS, King TS. Dependence of 3',5'-cyclic adenosine monophosphate--stimulated gonadotropin-releasing hormone release on intracellular calcium levels and L-type calcium channels in superfused GT1-7 neurons. J Soc Gynecol Investig. 2004 Sep;11(6):393-8. doi: 10.1016/j.jsgi.2004.02.010.
citation: Krsmanovic LZ, Stojilkovic SS, Merelli F, Dufour SM, Virmani MA, Catt KJ. Calcium signaling and episodic secretion of gonadotropin-releasing hormone in hypothalamic neurons. Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8462-6. doi: 10.1073/pnas.89.18.8462.
citation: Nunez L, Villalobos C, Boockfor FR, Frawley LS. The relationship between pulsatile secretion and calcium dynamics in single, living gonadotropin-releasing hormone neurons. Endocrinology. 2000 Jun;141(6):2012-7. doi: 10.1210/endo.141.6.7491.