Clinical trial NCT03335163
Conditions: Migraine Migraine;Menstrual Contraception
Sponsor: University of Colorado, Denver
Start date: 2018-03-15; Completion date: 2021-04-22
Enrollment: 48 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A prospective, non-inferiority study to evaluate the pharmacokinetic effect of topiramate on serum Etonogestrel (ENG) levels in contraceptive implant users.

Detailed description:

Arms: arm 1: Healthy women using an ENG implant for at least 12 months and no greater than 36 months will be administered a 6 week titration schedule of topiramate to a max dose of 200mg bid by the final week.
Interventions: intervention 1: Topiramate
Intervention descriptions: intervention 1: Topiramate - Participants will undergo a 6 week titrated regimen of oral topiramate to reach a maximum dose of 400mg per day:

Week 1 - topiramate PO 25mg daily Week 2 - topiramate PO 25mg twice daily Week 3 - topiramate PO 50mg twice daily Week 4 - topiramate PO 100mg twice daily Week 5 - topiramate PO 150mg twice daily Week 6 - topiramate PO 200mg twice daily

Protocol documents:
Prot_SAP_000.pdf: 
Official Title: The effect of topiramate on etonogestrel concentrations in contraceptive implant users 
NCT Number: NCT03335163 
Document date: 12/19/2017 
Principal Investigator: Stephanie Teal, MD and Jeanelle Sheeder, PhD 
 
 


Proposal Narrative 
Objective: To evaluate the pharmacokinetic effect of concomitant topiramate therapy on etonogestrel 
(ENG) contraceptive implant use. 
Specific Aims: 
1. To evaluate the drug-drug interaction between doses of topiramate used for treatment of 
migraines (100-200mg per day) and the ENG contraceptive implant. 
2. To evaluate the drug-drug interaction between doses of topiramate used for treatment of 
epilepsy (400mg per day) and the ENG contraceptive implant. 
3. To characterize whether any pharmacokinetic reductions in serum ENG concentrations reach 
below the level needed to maintain ovulation suppression (<90pg/mL). 
Rationale: 
Topiramate is an anti-epileptic drug initially used for treatment of partial-onset seizures and 
primary generalized tonic-clonic seizures.  However, its main use currently is for migraine prevention: 
topiramate is considered a first-line treatment for migraine prophylaxis, along with B-blockers and 
valproate.1 The majority of patients afflicted by chronic migraines are reproductive age women, most of 
whom need reliable contraception.2 Few women with chronic migraines are candidates for estrogen-
containing contraceptive methods. We have recently cared for several reproductive age women taking 
topiramate and have found no evidence supporting or contraindicating the etonogestrel (ENG) 
contraceptive implant for birth control, and only scant evidence regarding drug-drug interactions 
between topiramate and norethindrone-containing combined oral contraceptives.  As topiramate is a 
Pregnancy Class D drug, definitive evidence of any potential decreased efficacy of the implant is 
imperative.  Conversely, reassuring evidence of stable ENG levels will broaden the contraceptive options 
for women using topiramate.  
Our recent study on the effect of carbamazepine on ENG concentrations in contraceptive 
implant users demonstrated clinically significant reductions in serum ENG concentrations with a median 
decrease of 61% (range 25.4-87.2) and 8/10 participants with concentrations <90pg/mL after the 
intervention.3 These findings added to the limited data on the pharmacokinetic interactions between 
cytochrome P-450 3A4 enzyme inducers (CYP-3A4) and the ENG contraceptive implant, and will likely 
lead to a change in the US Medical Eligibility Criteria (MEC) for Contraceptive Use. In the MEC, 
carbamazepine is lumped into a broad category of “Anticonvulsant therapy” that have known CYP-3A4 
induction properties.4 This category also includes medications such as phenytoin, barbiturates, and 
topiramate. Many of these medications have well documented CYP-3A4 induction properties and 


consistent pharmacokinetic effects with hormonal contraceptives.5 Topiramate is also a CYP-3A4 
inducer, but has far less pharmacokinetic data to support that its induction properties have clinical 
implications. There are only two small published studies that investigated topiramate's pharmacokinetic 
effect on a combined oral contraceptive pill. Both studies found decreases in serum estrogen 
concentrations with concomitant topiramate use, but no significant pharmacokinetic effect of 
topiramate on norethindrone concentrations.6,7 
The data from the norethindrone studies suggest that topiramate’s pharmacokinetic effect on 
hormonal contraceptives differs significantly from carbamazepine, yet the MEC provides identical 
recommendations for these medications.  Because women with chronic migraines already have limited 
contraceptive options, differentiating the actual interactions is crucial. 
 
Research design and methods 
Outcome Measure: Serum etonogestrel concentrations measured at baseline and then repeated after 
participants reach three titrated doses of topiramate: 
• 
Visit 2 = 100mg per day 
• 
Visit 3 = 200mg per day 
• 
Visit 4 = 400mg per day 
Description of Population to be Enrolled: 
We aim to enroll subjects between 18-45 years old based on the following criteria: 
Inclusion Criteria:  Healthy women, who have had an ENG implant for 12-36 months at the time of 
enrollment and will maintain their implant during the study without modifications. 
Exclusion Criteria:  We will exclude women who are taking any known cytochrome P-450 3A4 enzyme 
inducers or inhibitors. We will also exclude women with a body mass index (BMI) <18.5, as underweight 
women may have altered metabolism. We will not have an upper BMI cut-off as studies have shown 
that overweight and obese women have equivalent metabolism and efficacy with the ENG contraceptive 
implant.8,9 
We will also exclude women with any hepatic or renal dysfunction as determined by a comprehensive 
metabolic panel. For purposes of this study, liver function tests will be evaluated and evidence of 
hepatic dysfunction will be defined as an ALT >52 or AST >39, which are beyond the reference range of 
normal values used by the University of Colorado clinical laboratory. Renal function will be assessed by a 
serum creatinine and a value >1.2 will be evidence of renal dysfunction as this is greater than the 
reference range used by the University of Colorado clinical laboratory. 


We will also assess for any history of hepatic or renal disease to screen for diseases such as hepatitis, 
cirrhosis, kidney transplant, etc.  
We will also exclude women with a low serum bicarbonate on screening serum electrolytes due to 
potential increased risk for side-effects from topiramate. We will use a cut-off of bicarbonate <21 for 
purposes of this study as this value is outside the reference range for the University of Colorado clinical 
laboratory. 
Study Design 
We will conduct a prospective, non-inferiority study to evaluate the pharmacokinetic effect of 
topiramate on serum ENG levels in contraceptive implant users. We will enroll healthy women using an 
ENG implant for at least 12 months and no greater than 36 months. Our exclusion and inclusion criteria 
are detailed as above. Interested women will undergo a phone screening prior to scheduling an 
enrollment visit. At the enrollment visit, potential participants will have their vital signs checked in the 
form of a pulse and blood pressure and will have their height and weight measured for purposes of 
calculating a body mass index. We will review each potential participants past medical history and 
current medications to ensure study eligibility. If interested participants meet our non-laboratory 
inclusion and exclusion criteria, then they will undergo informed consent in a private clinic room. 
After the participant has been consented, we will perform a blood draw to obtain whole blood 
and serum. Appropriate blood samples will be sent to the University of Colorado Clinical Laboratory for a 
comprehensive metabolic panel. A blood sample for serum will be centrifuged on location and the 
serum collected for storage in our -80°F freezer. For participants that meet our laboratory exclusion 
criteria, we will ultimately measure a serum baseline ENG concentration from the serum collected at the 
enrollment visit. The research team will then follow-up the comprehensive metabolic panel to 
determine final eligibility based on the criteria discussed above. Eligible participants will then be given 
the options of either returning to our clinic to pick up the first course of the study medication or have 
this first course mailed to them via FedEx. 
Participants will then begin a 6 week titration schedule of topiramate to a max dose of 200mg 
bid by the final week. Women with chronic migraines are typically treated with a dose of 100 or 
200mg/day, which will be achieved in the third and fourth week of titration, respectively. The maximum 
recommended dose of topiramate for treatment of epilepsy is 400mg/day, which will be achieved in the 
sixth and final week of titration. All participants will return at the end of the third week of the 
topiramate titration schedule. We will then draw blood from participants at this third week visit. An 
appropriate blood sample will be sent to the University of Colorado Clinical Laboratory for topiramate 


measurement as a measurement of compliance. Serum obtained from this blood draw will be again 
stored in our -80°F freezer for eventual serum ENG concentration measurement. Participants will also 
undergo screening for adverse events (AEs) and serious adverse events (SAEs) at this follow-up. Any 
participant experiencing an SAE will be removed from the study. Participants will then be given the next 
course of the study medication to continue the titration schedule. 
All participants will return at the end of the fourth and sixth weeks to undergo identical study 
procedures as described for the third week visit. The final course of the study medication will be 
provided at the fourth week visit to continue the titration schedule through to the conclusion of the 
study. A topiramate level will again be measured as a measure of study compliance and serum stored for 
eventual serum ENG concentration measurement. At the conclusion of enrollment, all stored serum 
samples will be de-identified and assigned a random identification number (three letters) so that the 
laboratory is blinded to the timing of samples. We will then ship all samples to a Merck® laboratory for 
serum ENG concentration measurement. Batch analysis will be performed using a liquid 
chromatography mass-spectrometry method that has been previously validated. Participants will serve 
as their own controls for this study. 
Abrupt cessation of topiramate therapy has been associated with increase in seizures in patients 
taking the medication for epilepsy. It is unclear if this risk is present in healthy individuals taking 
topiramate, but we will have participants undergo a gradual withdrawal of topiramate over 1 week after 
the final blood draw (end of 6 weeks). Participants will be given this withdrawal regimen at the final 
blood draw visit and undergo down-titration of their topiramate dose over the course of 1 week. 
Participants who choose to discontinue their participation early will contact the PRA or study physician 
for a custom down-titration schedule or abrupt discontinuation in the case of serious adverse events. 
All participants will be required to use either a back-up non-hormonal method of birth control or 
abstain from intercourse during the study and for 4 weeks after the last dose of topiramate. Topiramate 
has a half-life of 21 hours, and thus, will be eliminated within 1 week of the last dose, but we will allow 
another 3 weeks of buffer to ensure that the ovulation has not occurred and that the contraceptive 
effect of the implant has reinitiated before recommending resuming unprotected intercourse. 
All study visits will occur at the Comprehensive Women's Health Clinic in Lowry. This is our 
Family Planning site for both clinical and research visits. All consent and enrollment processes will be 
conducted in a private clinic room and interested participants will be allowed as much time as needed to 
review the consent and ask any questions regarding the consent and study procedure. 
Treatment: 


Etonogestrel contraceptive implant - All participants will have had an ENG implant for 12-36 months at 
the time of enrollment and will maintain their implant during the study without modifications. 
Topiramate – Participants will undergo a 6 week titrated regimen of oral topiramate to reach a 
maximum dose of 400mg per day, followed by a 7-day withdrawal titration schedule, and 4 week 
abstinence/back-up period: 
Week 1: topiramate PO 25mg daily 
Week 2: topiramate PO 25mg twice daily 
Week 3: topiramate PO 50mg twice daily 
Week 4: topiramate PO 100mg twice daily 
Week 5: topiramate PO 150mg twice daily 
Week 6: topiramate PO 200mg twice daily 
Week 7: withdrawal titration schedule – topiramate PO 100mg twice daily for 2 days, 100mg daily for 2 
days, 50mg daily for 2 days, 25mg daily for 1 day 
Week 8 – 11: abstinence/backup period  
 
Data Analysis Plan 
For this study, non-inferiority was defined as a change in serum ENG concentration that would 
not result in concentrations below the threshold for ovulatory suppression. We chose a non-inferiority 
limit of 30% because this level of decrease from the median published levels (157-207pg/mL) does not 
cross the probably threshold for ovulatory suppression (90pg/mL). Based on the variance findings from 
our carbamazepine study (SD = 67.7), we performed a sample size calculation with an alpha level of 0.05 
and a beta of 0.9 for our non-inferiority limit of 30%. We used a higher beta cut-off to account for the 
use of a statistical sample size calculation based on a normal distribution when serum ENG 
concentrations has a known non-normal distribution. This calculation resulted in a sample size of 27 
women. We will enroll up to 53 women to account for a potential 49% drop-out/non-compliance rate, 
which accounts for an expected 30% intolerance rate for topiramate doses >200mg/day. Given that this 
will be a repeated measures study of non-parametric data, we will use a Friedman test for our analysis. 
We will use a p-value of <0.05 as a cut-off for statistical significance. 
 
 
 
 


Citations 
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