BECONTRA: Effects of combined oral contraceptives on brain and behavior

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Paris Lodron Universitaet Salzburg

Participant type

Pediatric, Healthy volunteers

Age range

0-17 years, 18-64 years

Gender

Female

Therapeutic area

Phenomena and Processes [G] - Reproductive and Urinary Physiological Phenomena [G08]

Trial duration

15 Jul 2020 → ongoing

Decision date (initial)

2024-12-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

European Research Council (ERC)

External identifiers

EU CT number

2024-519260-41-00

EudraCT number

2020-000790-24

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others

The primary objective of this study is to identify and characterize the effects of the most commonly used oral contraceptives (EE/LNG; EE/CMA) on brain structure and function as well as behavior after up to 6 months of treatment and its reversibility upon withdrawal. The influence of age, type of oral contraceptive and other potential determinants of drug response will be analyzed.

Secondary objectives 1

1. A secondary objective is to identify predictors of cognitive, emotional and neuronal off target effects of oral contraceptives, among: - Brain imaging parameters - Steroid hormone levels - Genes related to steroid hormone action and neurotransmission

Conditions and MedDRA coding

Hormonal contraception

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. 14-35 years of age
2. female
3. General interest in the intake of COCs or current use of COCs containing EE/LNG or EE/CMA
4. Regular menstrual cycle for at least 6 months according to the criteria of Fehring et al. (2006), i.e. a cycle duration of 21 to 35 days with a maximum deviation of 7 days between individual cycle lengths.
5. Sufficient German language skills to follow task instructions

Exclusion criteria 8

1. contra-indication for use of EE/LNG or EE/CMA
2. diagnosed psychiatric disorder with known effects on cognition or brain structure/function (e.g. schizophrenia, etc.). Exception: women with mild mood disorders (anxiety, depression) are included as long as no hospitalization occurred in the past 6 months
3. diagnosed neurological disorder with known effects on cognition or brain structure/function (e.g. multiple sclerosis, epilepsy, etc.)
4. diagnosed endocrinological disorder deemed clinically significant by the Investigator at screening (e.g. PCOS, Cushing's syndrome, congenital renal hyperplasia)
5. regular intake of medication that might interfere with the conduct of the study or the interpretation of the results including, but not limited to: 5.1. medication with known interaction potential including but not limited to: A. drugs that can increase intestinal motility and thus reduce the resorption of the IMPs (e.g. metoclopramide) or impact the resorption directly (e.g. active carbon) or reduce entero hepatic circulation (ampicillin, tetracyclin) B. activators of hepatic microsomal enzymes like rifampicin, rifabutin, barbiturates, anticonvulsants (e.g. carbamacepine, phenytoine und topiramat), griseofulvin, barbexaclon, primidon, modafinil, some protease inhibitors (e.g. ritonavir) and St. John’s wort, C. inhibitors of microsomal enzymes like imidazol-antimykotics (e.g. Fluconazol), indinavir or troleandomycin, D. strong or moderate CYP3A4-Inhibitors like azol-antimycotics (e.g. itraconazol, voriconazol, fluconazol), verapamil, macrolide antibiotics (e.g. clarithromycin, erythromycin), diltiazem and grapefruit juice, which can increase plasma levels of estrogen or gestagen or both, BECONTRA Version 7 – 29/July/2024 Page 26 of 57 E. etoricoxib in doses of 60 to 120 mg/d, which can increase plasma ethinylestradiol under combined oral COCs, F. troleandomycin, which can induce intrahepatic cholestasis in co-administration with combined COCs, G. drugs who inhibit sulfatation of ethinylestradiol in enterocytes like ascorbic acid or paracetamol (acetamionophen), H. atorvastatin (increased AUC of ethinylestradiol by 20%). 5.2. drugs that impair cognitive function, including but not limited to hypnotics, benzodiazepines, anti-psychotics, anti-convulsants, anti-depressants, cns active anti-histamines. 5.3. Alcohol or drug abuse 5.4. cognitive stimulants or nootropics. 5.5. medication that might interfere with the conduct of the study or the interpretation of the results otherwise
6. current pregnancy or previous pregnancies
7. for MR group: contra-indication for MRI, including claustrophobia
8. for MR group: brain tissue abnormalities on structural MRI as screened by a neuro-radiologist

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Mood and self-perception (Premenstrual symptoms, Positive and negative affect, depression, Anxiety, Gender Role)
2. Cognition (Face recognition, verbal fluency, navigation, working memory)
3. Brain structure
4. Brain function

Secondary endpoints 5

1. sex hormone levels (estradiol, progesterone, allopregnanolone, testosterone dihydrotestosterone, LH, FSH, Prolactin, SHBG)
2. stress hormone levels (cortisol, ACTH)
3. levels of interventional drugs (Ethinylestradiol, Levonorgestrel, Chlormadinonacetate)
4. Genetic variants (repeat polymorphism or SNP) of steroid hormone receptors (AR, ESR1, ESR2, PGR, MR) targeted by the interventional drugs
5. Genetic variants of genes (repeat polymorphism or SNP) involved in neurotransmitter systems (COMT, MAOA, 5HTT, 5HTR, BDNF) responsive to sex hormones

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Paris Lodron Universitaet Salzburg

Sponsor organisation

Paris Lodron Universitaet Salzburg

Address

Kapitelgasse 4-6

City

Salzburg

Postcode

5020

Country

Austria

Scientific contact point

Organisation

Paris Lodron Universitaet Salzburg

Contact name

Belinda Pletzer

Public contact point

Organisation

Paris Lodron Universitaet Salzburg

Contact name

Belinda Pletzer

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications