NIMO: Nimodipine to Prevent LH Surge During Ovulation Induction: Blinded Placebo-controlled RCT

Sponsor
Boston IVF (Other)
Overall Status
Completed
CT.gov ID
NCT01672801
Collaborator
Village Fertility Pharmacy (Other)
18
1
2
19
0.9

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

Study Type:
Interventional
Actual Enrollment :
18 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Treatment
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
Actual Study Start Date :
Sep 1, 2012
Actual Primary Completion Date :
Apr 1, 2014
Actual Study Completion Date :
Apr 1, 2014

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:
  • Nimotop
  • Outcome Measures

    Primary Outcome Measures

    1. 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

    1. 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

    1. 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

    Ages Eligible for Study:
    25 Years to 40 Years
    Sexes Eligible for Study:
    Female
    Accepts 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

    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

    Responsible Party:
    Alan Penzias, Associate Professor of Obstetrics, Gynecology and Reproductive Biology, Boston IVF
    ClinicalTrials.gov Identifier:
    NCT01672801
    Other Study ID Numbers:
    • 2012P-000186
    First Posted:
    Aug 27, 2012
    Last Update Posted:
    Aug 11, 2020
    Last Verified:
    Aug 1, 2020
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Additional relevant MeSH terms:

    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

    1. Primary Outcome
    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%
    2. Secondary Outcome
    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%
    3. Other Pre-specified Outcome
    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

    [Not Specified]

    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
    Email apenzias@bostonivf.com
    Responsible Party:
    Alan Penzias, Associate Professor of Obstetrics, Gynecology and Reproductive Biology, Boston IVF
    ClinicalTrials.gov Identifier:
    NCT01672801
    Other Study ID Numbers:
    • 2012P-000186
    First Posted:
    Aug 27, 2012
    Last Update Posted:
    Aug 11, 2020
    Last Verified:
    Aug 1, 2020