Anovulatory, Polycystic Ovarian Syndrome, Unexplained Infertility
Conditions
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.
Interventions
DRUGPlacebo
oral administration
DRUGNimodipine
oral administration
Sponsors
Village Fertility Pharmacy
Boston IVF
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
25 Years to 40 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| LH Surge | 7 days | Compare the change between placebo treated and nimodipine treated patients by the presence or absence of an LH surge on intervention Day 1 and Day 2. LH surge will be determined by serum LH levels at least two times the baseline serum LH (baseline serum LH = (cycle day 3 serum \[LH\] + cycle day 7 serum \[LH\])/2). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Side Effects | Starting day 0 of intervention to pregnancy test (approximately 15 days) | Medication side effect profile including: symptomatic hypotension (Note: vital signs will be recorded), symptomatic tachycardia (Note: vital signs will be recorded), headache, nausea. These will be self-reported with constructed questionnaire. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Gonadotropin Levels | Intervention day 0 to ovulation (approximately 1-7 days) | Calculated changes in serum LH, FSH, and estradiol levels between patients in nimodipine and placebo arms |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo All subjects in both arms will receive Clomid 100 mg tablets by mouth for 5 days prior to receiving either placebo comparator or active comparator. Placebo comparator subjects will receive 8 total doses of liquid placebo orally 4 times a day for 8 total doses in pre-filled liquid placebo containing syringes
Placebo: oral administration | 9 |
| Nimodipine All subjects in both arms will receive Clomid 100 mg tablets by mouth for 5 days prior to receiving either placebo comparator or active comparator. Active comparator subjects will receive Nimodipine 30mg liquid orally 4 times a day for 8 total doses in pre-filled syringes
Nimodipine: oral administration | 9 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Screen Failure | 0 | 1 |
Baseline characteristics
| Characteristic | Nimodipine | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 37 years | 35 years | 33 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 17 Participants | 8 Participants |
| Sex: Female, Male Female | 9 Participants | 18 Participants | 9 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 9 |
| other Total, other adverse events | 4 / 9 | 4 / 9 |
| serious Total, serious adverse events | 0 / 9 | 0 / 9 |
Outcome results
Primary
LH Surge
Compare the change between placebo treated and nimodipine treated patients by the presence or absence of an LH surge on intervention Day 1 and Day 2. LH surge will be determined by serum LH levels at least two times the baseline serum LH (baseline serum LH = (cycle day 3 serum \[LH\] + cycle day 7 serum \[LH\])/2).
Time frame: 7 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | LH Surge | 9 Participants |
| Nimodipine | LH Surge | 9 Participants |
Secondary
Number of Participants Experiencing Side Effects
Medication side effect profile including: symptomatic hypotension (Note: vital signs will be recorded), symptomatic tachycardia (Note: vital signs will be recorded), headache, nausea. These will be self-reported with constructed questionnaire.
Time frame: Starting day 0 of intervention to pregnancy test (approximately 15 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants Experiencing Side Effects | 3 Participants |
| Nimodipine | Number of Participants Experiencing Side Effects | 4 Participants |
Other Pre-specified
Gonadotropin Levels
Calculated changes in serum LH, FSH, and estradiol levels between patients in nimodipine and placebo arms
Time frame: Intervention day 0 to ovulation (approximately 1-7 days)