Erenumab (AMG 334) Plus Combined Oral Contraceptive Drug Interaction Study in Healthy Females

Study Overview
=================
Brief Summary
-----------------
A pharmacokinetic drug interaction study of erenumab and an oral contraceptive containing progestin and estrogen.

Detailed Description
-----------------
A pharmacokinetic (PK) drug interaction study of erenumab and an oral contraceptive containing progestin and estrogen. All participants will receive an oral contraceptive containing progestin and estrogen throughout the duration of the study. Participants will also receive a single dose of erenumab, administered by a healthcare provider in cycle 3. Serial PK samples will be collected at specified time points to characterize the PK of the oral contraceptive progestin and estrogen components with and without the presence of erenumab. The study consists of three 28-day cycles and a follow-up period. The first 28 day cycle is an acclimation period when participants initiate oral contraception (Cycle 1). During Cycle 2 and 3 the PK of ethinyl estradiol (EE) and active metabolites of norgestimate (ie, norelgestromin [NGMN] and norgestrel [NG]) will be characterized following the last active dose of oral contraceptive in each cycle (cycle day 21). Erenumab will be given in cycle 3 (cycle day 10); 24-hour PK characterization of norgestimate and EE metabolites will occur 11 days after administration of erenumab, which will maximize the potential for detecting a drug-drug interaction.

Official Title
-----------------
A Multi-Center, Open-label, Pharmacokinetic Drug Interaction Study of AMG 334 and a Combined Oral Contraceptive in Healthy Female Subjects

Conditions
-----------------
Headache, Migraine

Intervention / Treatment
-----------------
* Drug: Erenumab
* Drug: Ethynil Estradiol/Norgestimate Oral Contraceptive


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy female ≥18 to ≤45 years old at the time of enrollment Regular monthly menstrual cycle during the last 12 months Good general health based on a medical history evaluation and physical examination No clinically significant abnormalities in laboratory tests at screening Subject has provided informed consent/assent prior to initiation of any study specific activities/procedures Exclusion Criteria: Intolerance to any recent oral contraceptive in the last three (3) years, Female subjects with a positive serum pregnancy test at screening Female subjects not willing to inform her sexual partner of her participation in the clinical study Use of any over the counter or prescription medications within the 14 days or 5 half lives (whichever is longer) Nicotine use eg cigarettes or equivalent during 12 months prior to day 1 and through the duration of the study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Erenumab + Estrogen/Progestin Contraceptive<br>Participants received a combination oral contraceptive for 3 28-day cycles during the study. A single 140 mg dose of erenumab was administered subcutaneously to the abdomen on day 10 of cycle 3 by a healthcare provider. | Drug: Erenumab<br>* A single dose of erenumab administered in the abdomen.<br>* Other names: Aimovig™;Drug: Ethynil Estradiol/Norgestimate Oral Contraceptive<br>* Ethynil estradiol (EE)/norgestimate combination oral contraceptive is a 28-tablet cycle in which 1 oral tablet is taken daily; each containing 0.250 mg norgestimate and 0.035 mg EE for 21 days, after which a tablet only containing inert ingredients is taken for last 7 days of the 28 day cycle.<br>* Other names: Ortho-Cyclen®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of Ethinyl Estradiol | The pharmacokinetics of ethinyl estradiol (EE) were characterized during cycle 2 following the last active dose of oral contraceptive in the cycle (cycle day 21) without erenumab, and during cycle 3 following the last active dose of oral contraceptive in the cycle (cycle day 21), 11 days after a single dose of erenumab. | Cycle 2, day 21 and cycle 3, day 21 at predose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours post oral contraceptive dose. | 
| Area Under the Plasma Concentration Time Curve From Time 0 to 24 Hours Postdose (AUCtau) for Ethinyl Estradiol | The pharmacokinetics of ethinyl estradiol (EE) were characterized during cycle 2 following the last active dose of oral contraceptive in the cycle (cycle day 21) without erenumab, and during cycle 3 following the last active dose of oral contraceptive in the cycle (cycle day 21), 11 days after a single dose of erenumab. | Cycle 2, day 21 and cycle 3, day 21 at predose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours post oral contraceptive dose. | 
| Maximum Observed Plasma Concentration (Cmax) of Norgestrel | The pharmacokinetics of norgestrel (NG), an active metabolite of norgestimate, were characterized during cycle 2 following the last active dose of oral contraceptive in the cycle (cycle day 21) without erenumab, and during cycle 3 following the last active dose of oral contraceptive in the cycle (cycle day 21), 11 days after a single dose of erenumab. | Cycle 2, day 21 and cycle 3, day 21 at predose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours post oral contraceptive dose. | 
| Area Under the Plasma Concentration Time Curve From Time 0 to 24 Hours Postdose (AUCtau) for Norgestrel | The pharmacokinetics of norgestrel (NG), an active metabolite of norgestimate, were characterized during cycle 2 following the last active dose of oral contraceptive in the cycle (cycle day 21) without erenumab, and during cycle 3 following the last active dose of oral contraceptive in the cycle (cycle day 21), 11 days after a single dose of erenumab. | Cycle 2, day 21 and cycle 3, day 21 at predose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours post oral contraceptive dose. | 
| Maximum Observed Plasma Concentration (Cmax) of Norelgestromin | The pharmacokinetics of norelgestromin (NGMN), an active metabolite of norgestimate, were characterized during cycle 2 following the last active dose of oral contraceptive in the cycle (cycle day 21) without erenumab, and during cycle 3 following the last active dose of oral contraceptive in the cycle (cycle day 21), 11 days after a single dose of erenumab. | Cycle 2, day 21 and cycle 3, day 21 at predose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours post oral contraceptive dose. | 
| Area Under the Plasma Concentration Time Curve From Time 0 to 24 Hours Postdose (AUCtau) for Norelgestromin | The pharmacokinetics of norelgestromin (NGMN), an active metabolite of norgestimate, were characterized during cycle 2 following the last active dose of oral contraceptive in the cycle (cycle day 21) without erenumab, and during cycle 3 following the last active dose of oral contraceptive in the cycle (cycle day 21), 11 days after a single dose of erenumab. | Cycle 2, day 21 and cycle 3, day 21 at predose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours post oral contraceptive dose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Reach the Maximum Concentration (Tmax) of Ethinyl Estradiol | The pharmacokinetics of ethinyl estradiol (EE) were characterized during cycle 2 following the last active dose of oral contraceptive in the cycle (cycle day 21) without erenumab, and during cycle 3 following the last active dose of oral contraceptive in the cycle (cycle day 21), 11 days after a single dose of erenumab. | Cycle 2, day 21 and cycle 3, day 21 at predose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours post oral contraceptive dose. | 
| Time to Reach the Maximum Concentration (Tmax) of Norgestrel | The pharmacokinetics of norgestrel (NG), an active metabolite of norgestimate, were characterized during cycle 2 following the last active dose of oral contraceptive in the cycle (cycle day 21) without erenumab, and during cycle 3 following the last active dose of oral contraceptive in the cycle (cycle day 21), 11 days after a single dose of erenumab. | Cycle 2, day 21 and cycle 3, day 21 at predose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours post oral contraceptive dose. | 
| Time to Reach the Maximum Concentration (Tmax) of Norelgestromin | The pharmacokinetics of norelgestromin (NGMN), an active metabolite of norgestimate, were characterized during cycle 2 following the last active dose of oral contraceptive in the cycle (cycle day 21) without erenumab, and during cycle 3 following the last active dose of oral contraceptive in the cycle (cycle day 21), 11 days after a single dose of erenumab. | Cycle 2, day 21 and cycle 3, day 21 at predose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours post oral contraceptive dose. | 
| Number of Participants With Treatment-emergent Adverse Events | A treatment-related adverse event (AE) is any treatment-emergent AE that per investigator review has a reasonable possibility of being caused by the study drug. A device-related AE is any treatment-emergent AE that per investigator review has a reasonable possibility of being caused by the device (prefilled syringe) used to administer study drug. | From administration of erenumab on study day 66 through the end of the follow-up period on study day 150 (up to 84 days). | 
| Number of Participants Who Developed Anti-erenumab Binding Antibodies | Blood samples were assessed for anti-erenumab binding antibodies. Samples testing positive for binding antibodies were also tested for neutralizing antibodies. | Baseline and day 150 |