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

Primary Purpose

Unexplained Infertility, Polycystic Ovarian Syndrome, Anovulatory

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Placebo
Nimodipine
Sponsored by
Boston IVF
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Unexplained Infertility

Eligibility Criteria

25 Years - 40 Years (Adult)FemaleAccepts Healthy Volunteers

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

Sites / Locations

  • Boston IVF

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Active Comparator

Arm Label

Placebo

Nimodipine

Arm 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

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

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

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.

Full Information

First Posted
August 22, 2012
Last Updated
August 10, 2020
Sponsor
Boston IVF
Collaborators
Village Fertility Pharmacy
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1. Study Identification

Unique Protocol Identification Number
NCT01672801
Brief Title
Nimodipine to Prevent LH Surge During Ovulation Induction: Blinded Placebo-controlled RCT
Acronym
NIMO
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

2. Study Status

Record Verification Date
August 2020
Overall Recruitment Status
Completed
Study Start Date
September 2012 (Actual)
Primary Completion Date
April 2014 (Actual)
Study Completion Date
April 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Boston IVF
Collaborators
Village Fertility Pharmacy

4. Oversight

Data Monitoring Committee
Yes

5. 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).
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Unexplained Infertility, Polycystic Ovarian Syndrome, Anovulatory

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
18 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Placebo
Arm Type
Placebo Comparator
Arm 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
Arm Title
Nimodipine
Arm Type
Active Comparator
Arm 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. Active comparator subjects will receive Nimodipine 30mg liquid orally 4 times a day for 8 total doses in pre-filled syringes
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
oral administration
Intervention Type
Drug
Intervention Name(s)
Nimodipine
Other Intervention Name(s)
Nimotop
Intervention Description
oral administration
Primary Outcome Measure Information:
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
Secondary Outcome Measure Information:
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)
Other Pre-specified Outcome Measures:
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)

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
25 Years
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alan S Penzias, MD
Organizational Affiliation
Beth Israel Deaconess Medical Center / Boston IVF
Official's Role
Principal Investigator
Facility Information:
Facility Name
Boston IVF
City
Waltham
State/Province
Massachusetts
ZIP/Postal Code
02451
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
15350253
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.
Results Reference
background
PubMed Identifier
1326758
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.
Results Reference
background
PubMed Identifier
10830284
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.
Results Reference
background

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

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