NCT Number: NCT07361263
The PHOENIX study aims to investigate whether oral estradiol valerate (EV) and ethinylestradiol (EE) can stimulate oxytocin (OXT) and neurophysin-1 (NP-1) release in humans. The goal is to assess their potential as a safe diagnostic stimulation test for oxytocin deficiency, particularly in patients with arginine vasopressin (AVP) deficiency.
Interested in participating?
Request Info18 year–50 year
All sexes
Interventional
Not applicable
Basel, 4031, Switzerland
Location status: Recruiting
Andi Nikaj, MD
CONTACT
Andi Nikaj, MD
SUB_INVESTIGATOR
Michelle Müller, MD
CONTACT
Michelle Müller, MD
SUB_INVESTIGATOR
Mirjam Christ-Crain, MD
PRINCIPAL_INVESTIGATOR
Ursula Gobrecht-Keller, MD
SUB_INVESTIGATOR
Oxytocin (OXT) and arginine vasopressin (AVP) are hypothalamic peptides involved in water balance and emotional regulation. Patients with AVP-Deficiency (central diabetes insipidus) often experience psychological symptoms such as anxiety and depressed mood, possibly due to coexisting OXT deficiency. Previous research showed that 3,4-Methylenedioxy-N-methylamphetamine (MDMA) can increase plasma OXT in healthy individuals but not in AVP-deficient patients, suggesting a clinically relevant OXT deficiency. However, the side effects of MDMA limit its clinical use as a diagnostic tool. Estrogen is known to stimulate OXT release via estrogen receptor β in the hypothalamus. This study evaluates whether oral estradiol valerate (EV) and ethinylestradiol (EE) can safely and effectively provoke OXT and NP-1 release, offering a potential alternative to MDMA-based tests.
The study consists of two parts:
Part 1 (Proof of Concept): A randomized, double-blind, cross-over trial in healthy adults to compare the stimulatory effects of EV and EE on plasma OXT and NP-1.
Part 2 (Pilot Study): An open-label trial in patients with AVP-Deficiency using the estrogen compound identified as most effective in Part 1, to determine whether OXT and NP-1 responses are blunted compared to healthy controls.
Healthy volunteers accepted: Yes
Only the study team can determine whether someone qualifies for participation.
Inclusion criteria
Part 1
Part 2
Exclusion criteria
Part 1
Part 2
estradiol valerate
estradiol valerate
Time frame: From baseline (0 min) to 300 minutes post-dose.
The primary endpoint is the relative change in plasma oxytocin (OXT) concentrations (pg/mL respectively pM) from baseline to the maximum observed value within 300 minutes after administration of oral estradiol valerate (EV) or ethinylestradiol (EE). Baseline is defined as 100% of the initial pre-dose concentration.
Time frame: From baseline (0 min) to 300 minutes post-dose.
The primary endpoint is the relative change in neurophysin-1 (NP-1) concentrations (pg/mL respectively pM) from baseline to the maximum observed value within 300 minutes after administration of oral estradiol valerate (EV) or ethinylestradiol (EE). Baseline is defined as 100% of the initial pre-dose concentration.
Time frame: From baseline (0 min) to 300 minutes post-dose.
Time frame: From baseline (0 min) to 300 minutes post-dose.
Time frame: From baseline (0 min) to 300 minutes post-dose.
Time frame: From baseline (0 min) to 300 minutes post-dose.
Time course and peak of coagulation marker von Willebrand factor
Time frame: From baseline (0 min) to 300 minutes post-dose.
Time course and peak of coagulation marker Protein S
Time frame: From baseline (0 min) to 300 minutes post-dose.
Time course and peak of coagulation marker D-dimer
Time frame: From baseline (0 min) to 300 minutes post-dose.
Time course and peak of coagulation marker Factor VIII
Time frame: From baseline (0 min) to 300 minutes post-dose.
Time course and peak of coagulation marker Fibrinogen
Time frame: From baseline (0 min) to 300 minutes post-dose.
Peak of coagulation marker von Willebrand factor
Time frame: From baseline (0 min) to 300 minutes post-dose.
Peak of coagulation marker Protein S
Time frame: From baseline (0 min) to 300 minutes post-dose.
Peak of coagulation marker D-dimer
Time frame: From baseline (0 min) to 300 minutes post-dose.
Peak of coagulation marker Factor VIII
Time frame: From baseline (0 min) to 300 minutes post-dose.
Peak of coagulation marker Fibrinogen
Time frame: From baseline (0 min) to 300 minutes post-dose.
Time course of plasma estrogen, testosterone, copeptin, cortisol,Luteinizing Hormone/Follicle-Stimulating Hormone (LH/FSH), and other pituitary hormones.
Time frame: At baseline (0 min), 30, 60, 90, 120, 150, 180, 210, 240, 270 and 300 minutes and 24 hours post-dose.
Changes in subjective feelings assessed by Numeric Rating Scale (NRS). NRS will be repeatedly used to assess subjective alterations in consciousness over time. NRS will be presented as a range from 0 to 10 marked with "not at all" on the left and "extremely" on the right. The following NRS will be used: "any effect", "good effect", "bad effect", "liking", "high", "happy", "fear", "stimulated", "feeling close to others", "concentration", "thinking", "open", and "trust".
Time frame: 300 minutes post-dose.
Participants will be asked to report any adverse events that occur during the sessions or between sessions at the start of the next session. The test requires about 2 minutes.
Time frame: 300 minutes post-dose.
The LC consists of 66 items, yielding a global score measuring physical and general discomfort. The LC list is administered at the beginning and the end of the session with reference to complaints throughout the entire session.
Time frame: Baseline, 90 and 270 minutes post-dose.
This is a questionnaire given to adults to determine the general anxiety levels. Based on responses to 20 items, with scores ranging from 1 ("almost never") to 4 ("almost always"), a total score is calculated. The total trait score (STAI-T) ranges from 20 to 80, with higher scores indicating more pronounced anxiety and scores. The STAI-T evaluates relatively stable aspects of "anxiety proneness," including general states of calmness, confidence, and security. A score above 45/80 indicating clinically significant anxiety symptoms. The state score (STAI-S) evaluates the current state of anxiety, asking how respondents feel "right now," using items that measure subjective feelings of apprehension, tension, nervousness, worry, and activation/arousal of the autonomic nervous system. We will use the STAI-T for the baseline visit and the STAI-S for the treatment visits. The test requires about 5 minutes.
Time frame: Baseline and 270 minutes post-dose.
The EmBody and EmFace subtasks comprise each of 42 stimuli showing body or facial expressions of angry, happy, or neutral affect (14 clips per emotion, half in front view and half in half-profile side view from the left). Stimuli last 1.5 seconds at 24 frames per second and are geometrically and optically standardized to prevent biases induced by ethnic cues (e.g., hair or skin tone) or clothing. Item order is pseudorandom to prevent sequence effects and was determined using the following constraints: the same emotion is shown no more than twice in a row; the same view per emotion is not shown consecutively (i.e., no angry-front, angry-front). The test is performed twice during each treatment visit.
Time frame: At 270 minutes post-dose.
The FERT is used to assess recognition of basic emotions. The task includes 10 neutral faces and 160 faces that express one of four basic emotions (i.e., happiness, sadness, anger, and fear), with pictures morphed between 0% (neutral) and 100% in 10% steps. Two female and two male pictures are used for each of the four emotions. Stimuli are shown in random order for 500 ms and are then replaced by the rating screen where participants have to indicate the correct emotion. The outcome measure is accuracy (proportion correct). The test data is recorded on a computer and processed into scores for each emotion using an established matlab routine according to standard operating procedures (SOP) (clinical pharmacology, Orca DKF). The test is performed once during each treatment visit, exactly 270min after EV/EE administration.
Time frame: 30 minutes pre-dose; 0, 30, 60, 120, 150, 180, 210, 240, 270, 300minutes, 24hours post-dose.
Blood pressure (systolic and diastolic) will be measured at several timepoints during the treatment visit
Time frame: 30 minutes pre-dose; 0, 30, 60, 120, 150, 180, 210, 240, 270, 300minutes, 24hours post-dose.
Heart rate will be measured at several timepoints during the treatment visit
Time frame: 30 minutes pre-dose; 0, 30, 60, 120, 150, 180, 210, 240, 270, 300minutes, 24hours post-dose.
body temperature will be measured at several timepoints during the treatment visit
Time frame: At 0, 180 and 300 minutes post-dose.
Sodium concentration (mmol/l) will be assessed in plasma.
Time frame: At 0, 180 and 300 minutes post-dose.
Sodium concentration (mmol/l) will be assessed in plasma.
Time frame: At 0, 60, 90, 120, 180, 270, 300 minutes and 24 hours post-dose.
Contact information is provided by the study sponsor or research team.
Andi Nikaj, MD
CONTACT
Ursula Gobrecht-Keller, MD
CONTACT
University Hospital, Basel, Switzerland
Other
Plasma Oxytocin in Response to Oral Estradiol Valerate and Ethinylestradiol in Healthy Controls and Patients With AVP-Deficiency
Acronym: PHOENIX
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