Clinical trial NCT03512860: Estetrol (E4)/Drospirenone (DRSP) Drug-drug Interaction (DDI) Study
Official title: An Open-label, Two-way Cross-over Study to Determine the Effect of Multiple Doses of Valproic Acid on the Pharmacokinetics and Safety of a Single Oral Dose of Estetrol/Drospirenone in Healthy Female Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Contraception
Keywords: Estetrol
Drospirenone
Uridine diphosphate glucuronosyltransferase-2B7
Drug-drug interaction
Valproic acid
Lead sponsor: Estetra
Sponsor class: INDUSTRY
Collaborators: name: Quotient Sciences
First posted: 2018-05-01
Enrollment: 24
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: PREVENTION

Brief summary: The present study is designed to determine the effect of valproic acid (VAL), a UGT2B7 inhibiting drug, on the pharmacokinetics (PK) of estetrol (E4)

Detailed description: In the present study, E4/DRSP will be administered alone (Treatment A) and in combination with VAL (Treatment B) following two sequences A-B or B-A.

Eligibility criteria: Inclusion Criteria:

* Healthy premenopausal, aged 18-45 years (inclusive) at the time of signing informed consent.
* For subjects who are sexually active and are of childbearing potential: willing to use a highly effective non-hormonal method of contraception from screening until the follow-up assessment, such as (but not limited to): non-hormonal intra-uterine device (copper IUD), bilateral tubal occlusion, vasectomised partner, or sexual abstinence in a heterosexual relationship; this is acceptable when it is in line with the subject's preferred and usual lifestyle. If a subject is usually not sexually active but becomes active, they, with their partner, must comply with the contraceptive requirements as stated earlier.
* Body weight ≥45 kg, and a body mass index between 18.0 and 30.0 kg/m² (inclusive).
* Negative serum pregnancy test at screening and a negative urine pregnancy test at Day -1.

Exclusion Criteria:

* The use of:

  * any prescription drugs, including oral or vaginal hormonal contraceptives, from 28 days prior to first dose administration until study completion;
  * any herbal medication or dietary supplements acting on cytochrome P450 3A4 (CYP3A4) functions (i.e., St John's Wort), from 28 days prior to first dose administration until study completion;
  * any over-the-counter medication (including paracetamol or dietary supplements (including vitamins and herbal products ), from 14 days prior to first dose administration until study completion. Limited use (i.e., up to 1200 mg/day) of ibuprofen is allowed;
  * any depot progestogen preparations or an injectable hormonal method of contraception, from 6 months prior to the first dose administration until study completion.
* History of hypersensitivity, serious adverse reaction, or existing contraindication to E4, DRSP or VAL, or excipients.

Primary outcomes:
measure: Maximum concentration (Cmax) of E4
timeFrame: 0-168 hr post E4/DRSP dose in both periods 1 and 2 of the two sequences A-B and B-A
measure: Area under the plasma concentration versus time curve from time 0 to the last determined concentration (AUC0-tdlc) of E4
timeFrame: 0-168 hr post E4/DRSP dose in both periods 1 and 2 of the two sequences A-B and B-A
measure: Area under the plasma concentration versus time curve from time 0 to infiny (AUC0-inf) of E4
timeFrame: 0-168 hr post E4/DRSP dose in both periods 1 and 2 of the two sequences A-B and B-A
Secondary outcomes:
measure: Number of subjects with adverse events as a measure of safety and tolerability
timeFrame: The total study duration (between 50 and 86 days)
measure: Cmax of DRSP
timeFrame: 0-168 hr post E4/DRSP dose in both periods 1 and 2 of the two sequences A-B and B-A
measure: Cmax of E4-glucuronide metabolites
timeFrame: 0-168 hr post E4/DRSP dose in both periods 1 and 2 of the two sequences A-B and B-A
measure: AUC0-tdlc of DRSP
timeFrame: 0-168 hr post E4/DRSP dose in both periods 1 and 2 of the two sequences A-B and B-A
measure: AUC0-tdlc of E4-glucuronide metabolites
timeFrame: 0-168 hr post E4/DRSP dose in both periods 1 and 2 of the two sequences A-B and B-A
measure: AUC0-inf of DRSP
timeFrame: 0-168 hr post E4/DRSP dose in both periods 1 and 2 of the two sequences A-B and B-A
measure: AUC0-inf of E4-glucuronide metabolites
timeFrame: 0-168 hr post E4/DRSP dose in both periods 1 and 2 of the two sequences A-B and B-A
Other outcomes:
Locations:
city: Ruddington
country: United Kingdom
facility: Quotient Sciences
state: Nottingham
Study officials:
affiliation: Quotient Sciences
name: Sharan Sidhu
role: PRINCIPAL_INVESTIGATOR
References: