Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT01551368 |
| Other study ID # |
09-0175-A |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
December 2012 |
| Est. completion date |
July 2017 |
Study information
| Verified date |
March 2019 |
| Source |
Mount Sinai Hospital, Canada |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Nimodipine (Nimotop® Bayer Pharmaceuticals Corporation), unlike other calcium channel
blockers is fat soluble and therefore is able to cross the blood-brain barrier1. Gonadotropin
releasing hormone (GnRH) neurons are clustered in the hypothalamus and are dependent on
calcium flux to release GnRH responsible for the release of follicle-stimulating hormone
(FSH) and luteinizing hormone (LH) from the anterior pituitary. In a natural menstrual cycle
a spontaneous LH surge occurs mid-cycle which triggers ovulation. The investigators
hypothesized that nimodipine, by blocking calcium channels, may effectively suppress the
release of GnRH and consequently the natural LH surge.
In this prospective double-blinded randomized study the investigators will evaluate the
efficacy of nimodipine to inhibit the natural LH surge in women undergoing controlled ovarian
stimulation (COS) and intrauterine insemination (IUI). Nimodipine, if successful, may
represent an inexpensive oral medication as an alternative to the currently used GnRH
agonists or GnRH antagonists in assisted reproductive technologies like IVF.
Description:
In reproductive aged women regular ovulatory cycles generate 1-2 mature ovarian follicles
every month. Approximately mid-cycle a natural LH surge is observed and predictably induces
ovulation within 24-36 hours. LH is a hormone produced by the anterior pituitary gland and is
released in response to GnRH. Concurrently GnRH is synthesized and released in a pulsatile
manner from GnRH neurons within the hypothalamus.
One of the essential steps of successful IVF is to ensure the properly timed aspiration of
mature follicles from the ovaries prior to ovulation. If ovulation were to precede aspiration
then the oocytes would have already been released and become unobtainable. Therefore
inhibiting spontaneous ovulation is a crucial component of successful oocyte retrieval. In
the clinical setting of IUI no oocyte retrieval is required, but appropriate timing of
insemination with respect to ovulation is critical.
A premature LH surge and subsequent premature luteinization may occur in up to a third of
ovarian stimulation cycles using gonadotropins (applicable to both IUI and IVF cycles),
making it a major cause of treatment cancellation and having a negative impact on pregnancy
outcomes 2-5. The most commonly used medications to prevent a premature LH surge are GnRH
agonists and more recently GnRH antagonists. They are both commonly administered
subcutaneously on a daily basis and act on the anterior pituitary gland (through different
mechanisms) to inhibit the release of LH. Besides the additional patient cost and burden,
these medications are associated with prolonged treatment protocols and decreased ovarian
response to stimulation.
Nimodipine is a unique calcium channel blocker with lipophilic properties and a greater
affinity for cerebral vasculature, and therefore has the ability to cross the blood-brain
barrier. In a study on mice with induced intracerebral hemorrhage, nimodipine treatment
improved cerebral bloodflow and displayed anti-ischemic effects. Nimodipine has obtained FDA
approval to reduce the severity of neurological deficits in patients who have had a recent
subarachnoid hemorrhage.
On a cellular level nimodipine has been shown to inhibit the pulsatile activity of GnRH gene
expression, an intrinsic property of GnRH neurons that is necessary for proper initiation of
the LH surge. Specifically, nimodipine blocks L-type voltage gated calcium channels which
prevent the influx of extracellular calcium and subsequently the stimulation of GnRH release.
The intrinsic pulsatile secretion of GnRH has been directly associated with the rhythmic
changes in intracellular calcium concentration in GnRH neurons.
Study Objectives and Endpoints
Primary Objective
1. To determine if nimodipine can effectively inhibit the natural LH surge in women
undergoing controlled ovarian stimulation and intrauterine insemination.
Secondary Objectives
2. To determine the medication side effect profile of nimodipine, specifically symptoms of
hypotension, tachycardia, nausea or headache.
3. To determine the treatment compliance rate (nimodipine or placebo).
4. To determine the clinical pregnancy rate for each intervention arm (nimodipine or
placebo) during the COS and IUI treatment cycle.
Primary Endpoint
1. 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 Endpoint
2. Medication side effect profile:
- Symptomatic hypotension [Note: vital signs will not be routinely recorded]
- Symptomatic tachycardia [Note: vital signs will not be routinely recorded]
- Headache
- Nausea (self-reporting; constructed questionnaire)
3. Patient treatment compliance (self-reporting; constructed questionnaire)
4. Clinical Pregnancy (positive BHCG and ultrasound evidence of fetal heart rate)
Study Design
Recruitment / Baseline Assessment The study population will be derived from a pool of
patients referred to TCART (Toronto Centre for Assisted Reproductive Technology; Toronto,
Canada). Patients that have been comprehensively evaluated for infertility and subsequently
recommended to undergo controlled ovarian stimulation and intra-uterine insemination will be
approached and recruited to participate in the study. Patients will be screened and evaluated
for eligibility (based on the inclusion and exclusion criteria) by direct contact from one of
the dedicated study investigators or dedicated research staff.
Randomization Randomization will be computer generated in a block design of 6 patients. Six
corresponding opaque envelopes that enclose the blinded medication will be administered
sequentially to consenting patients. Randomization will be performed at the start of the COH
cycle and consequently the data will be analyzed as an intention-to-treat analysis.
Blinding Procedures Both patients and medical staff will be blinded to the treatment arms.
Both the nimodipine (30 mg po qid) and placebo groups (placebo po qid) will receive 8
identical tablets with the same instructions for self-administration. The capsules will be
only be identified by a unique study number to allow accurate analysis at the end of the
study. A single pharmacy will be responsible for blinding, labeling and packaging the
medication. Only the study coordinator (DN), who will not be involved clinically with study
participants, will remain unblinded.
Interventions
Drug Formulation Nimotop® (Nimodipine) Bayer Pharmaceuticals Corporation. Calcium channel
blocker. 30mg oral soft gelatin capsules.
Dosage Regimen Nimodipine is rapidly absorbed after oral administration reaching a peak
concentration within one hour. It has a half-life of approximately 1-2 hours and a terminal
clearance half-life of 8 hours, and thus requires relatively frequent administration. It is
currently approved for the acute treatment of subarachnoid hemorrhage, with a dosing regimen
of 60mg po q4h for 21 consecutive days. Several pharmacokinetic studies have focused on 30mg
doses three times daily with no evidence of accumulation.
In our study 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. Patients will receive oral
nimodipine 30mg four times daily over a two day period with the following dosing schedule:
- Intervention Day 0 - noon / afternoon / bedtime (3 doses)
- Intervention Day 1 - morning / noon / afternoon / bedtime (4 doses)
- Intervention Day 2 - morning (1 dose)
Washout Period Nimodipine is eliminated almost exclusively in the form of metabolites. Less
than 1% is recovered in the urine as unchanged drug. Over 95% of the medication is bound to
plasma proteins. Nimodipine has a half life of 1-2 hours, with terminal elimination half life
of approximately 8 hours. It should be completely eliminated from the body in about 40 hours.
Contraindications to Nimodipine use
- Hypersensitivity to the active substance or to any of the excipients of Nimodipine.
- The use of Nimodipine in combination with Rifampicin
Precautions to Nimodipine use
- Caution is required in patients with hypotension
- Nimodipine is metabolized by the cytochrome P450 3A4 system, therefore drugs (or
grapefruit juice) that are known to either inhibit or to induce this enzyme should be
taken into account, including:
- Rifampicin
- Quinupristin / Dalfopristin
- Valproic Acid
- Nortryptyline
Secondary Outcome variables:
- Side effects - Nausea, headache, lightheadedness, dizziness, diaphoresis, presyncopal or
palpitations/tachycardia.
- Treatment compliance - Number of tablets taken (out of the prescribed 8 tablets),
appropriate timing of medication (as instructed)
- Clinical pregnancy → positive bHCG serum test 2 weeks post IUI and ultrasound
documentation of a fetal heart rate
Study - Delayed Ovulation Induction and Monitoring:
- Deviating from routine practice, our study protocol will call for a two-day delay in the
hCG injection after the ultrasound detection of a mature ovarian follicle (intervention
day 0). At this time point patients will have already been randomized and blinded to
receive nimodipine 30 mg po qid, or placebo po qid for two days to ideally prevent the
natural LH surge for a further 48 hours.
- During the two day period all study patients (nimodipine or placebo) will continue to be
monitored daily at the clinic (mornings of day 1 and day 2) which will include
transvaginal ultrasound and serum measurements of estradiol, LH and progesterone.
- If during the two day period an LH surge is detected during daily morning monitoring
(eg. on day 1 or on day 2), the standard protocol of ovulation induction and IUI will be
initiated - injection of hCG 250 mcg that same afternoon and two IUIs performed 16 hours
and 40 hours after hCG injection. Participant will discontinue taking their assigned
medication after an LH surge has been detected.
- If an LH surge is not detected during daily monitoring on day 1, the patient will
continue taking their assigned medication and with daily monitoring.
- If an LH surge is not detected during daily monitoring by day 2, ovulation will be
induced that same afternoon (~5 pm) by the injection of hCG 250 mcg followed by a single
IUI 40 hours later.
Safety and Adverse Events Patients undergoing COS and IUI are regularly monitored for optimal
treatment response and timing of IUI. Therefore investigators in this study will also have
the opportunity to closely observe any safety or adverse events associated with the two-day
duration of active intervention (nimodipine 30mg po qid x 48 hours). Specifically all
patients will be asked about medication (nimodipine and placebo) compliance and side effects
experienced during the morning cycle monitoring (day 1 and day 2).
Nimodipine has traditionally been investigated at higher does, frequencies and longer
duration. According to the product monograph1, a dosing regimen of nimodipine 60mg po q4h
resulted in the following side effects: hypotension (3.8%), nausea (1.2%), headache (1.2%)
and bradycardia (1%). Conservative management consisted of discontinuing nimodipine and
generally was effective in reversing the symptoms.
Data Analysis Plan / Statistical Plan Data will be expressed as mean +/- SD or percentage
where applicable. Independent samples will be compared using the Student t test. The
chi-squared test and Fisher exact test will be used for categorical data. A P value of <0.05
will be considered to indicate statistical significance.
Sample Size and Power Sample size calculations were performed using the computer program PS:
Power and sample size calculation by William Dupont. We are planning a study of independent
samples of treatments and controls with a 1:1 randomization. Expert opinion / prior data
suggest that approximately 50% of patients in the placebo arm will have a natural LH surge
detected on day 2 post intervention after a follicular maturation has been reached15. If 20%
of patients in the nimodipine arm have a natural LH surge detected on day 2 post
intervention, then we will need 38 subjects in each of the study arms to reject the null
hypothesis (both groups have equal incidence of natural LH surge on day 2 post intervention)
with a power of 0.8 and a type I error probability of 0.05. We anticipate approximately a 15%
dropout rate leading to a total recruitment of 90 patients (45 per study arm).
