NIMO: Nimodipine to Prevent LH Surge During Ovulation Induction: Blinded Placebo-controlled RCT
Study Details
Study Description
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).
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
N/A |
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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Placebo Comparator: 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 |
Drug: Placebo
oral administration
|
Active Comparator: 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 |
Drug: Nimodipine
oral administration
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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 Outcome Measures
- 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
Eligibility Criteria
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
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Boston IVF | Waltham | Massachusetts | United States | 02451 |
Sponsors and Collaborators
- Boston IVF
- Village Fertility Pharmacy
Investigators
- Principal Investigator: Alan S Penzias, MD, Beth Israel Deaconess Medical Center / Boston IVF
Study Documents (Full-Text)
None provided.More Information
Publications
- 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.
- Krsmanović LZ, Stojilković 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.
- Núñez 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.
- 2012P-000186
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail |
Arm/Group Title | Placebo | Nimodipine |
---|---|---|
Arm/Group Description | 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 | 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 |
Period Title: Overall Study | ||
STARTED | 9 | 9 |
COMPLETED | 9 | 8 |
NOT COMPLETED | 0 | 1 |
Baseline Characteristics
Arm/Group Title | Placebo | Nimodipine | Total |
---|---|---|---|
Arm/Group Description | 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 | 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 | Total of all reporting groups |
Overall Participants | 9 | 9 | 18 |
Age (years) [Mean (Full Range) ] | |||
Mean (Full Range) [years] |
33
|
37
|
35
|
Sex: Female, Male (Count of Participants) | |||
Female |
9
100%
|
9
100%
|
18
100%
|
Male |
0
0%
|
0
0%
|
0
0%
|
Race (NIH/OMB) (Count of Participants) | |||
American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
Asian |
1
11.1%
|
0
0%
|
1
5.6%
|
Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
Black or African American |
0
0%
|
0
0%
|
0
0%
|
White |
8
88.9%
|
9
100%
|
17
94.4%
|
More than one race |
0
0%
|
0
0%
|
0
0%
|
Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
Outcome Measures
Title | LH Surge |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Placebo | Nimodipine |
---|---|---|
Arm/Group Description | 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 | 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 |
Measure Participants | 9 | 9 |
Count of Participants [Participants] |
9
100%
|
9
100%
|
Title | Number of Participants Experiencing Side Effects |
---|---|
Description | 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) |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Placebo | Nimodipine |
---|---|---|
Arm/Group Description | 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 | 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 |
Measure Participants | 9 | 9 |
Count of Participants [Participants] |
3
33.3%
|
4
44.4%
|
Title | Gonadotropin Levels |
---|---|
Description | 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) |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title |
---|
Arm/Group Description |
Adverse Events
Time Frame | ||||
---|---|---|---|---|
Adverse Event Reporting Description | ||||
Arm/Group Title | Placebo | Nimodipine | ||
Arm/Group Description | 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 | 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 | ||
All Cause Mortality |
||||
Placebo | Nimodipine | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/9 (0%) | 0/9 (0%) | ||
Serious Adverse Events |
||||
Placebo | Nimodipine | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/9 (0%) | 0/9 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
Placebo | Nimodipine | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 4/9 (44.4%) | 4/9 (44.4%) | ||
General disorders | ||||
headache | 2/9 (22.2%) | 2 | 3/9 (33.3%) | 3 |
Dizziness | 0/9 (0%) | 0 | 3/9 (33.3%) | 3 |
Acne | 2/9 (22.2%) | 2 | 2/9 (22.2%) | 2 |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE 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.
Results Point of Contact
Name/Title | Alan Penzias |
---|---|
Organization | Boston IVF |
Phone | 781-434-6500 |
apenzias@bostonivf.com |
- 2012P-000186