Single and Multiple Intravenous Administrations of Estetrol (E4) in Healthy Adult Volunteers

NCT05460065 | Terminated Phase 1 DMC

• 2 other identifiers: MIT-Ne001-C1012021-003781-12
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief Summary

The Sponsor intends to develop an intravenous (i.v.) formulation of E4 for the treatment of neonatal hypoxic-ischemic encephalopathy (NHIE). E4 has not been administered intravenously to humans yet. This single-center, double-blind, placebo-controlled randomized study aims to evaluate the safety, tolerability, and PK of an i.v. E4 solution administered as single-dose or multiple dose to healthy adult volunteers.

Conditions

Safety; Pharmacokinetics

Outcome Measures

Primary Outcomes (54)

• Number of treatment-emergent adverse events (TEAEs) - Cohort A and B

  From Day 1 to End of Study (EoS) (Day 8)/ Early termination (ET)

• Number of treatment-emergent adverse events (TEAEs) - Cohort C

  From Day 1 to EoS (Day 29+7) / ET

• Number of serious adverse events (SAEs) - Cohort A and B

  From Day 1 to EoS (Day 8)/ ET

• Number of serious adverse events (SAEs) - Cohort C

  From Day 1 to EoS (Day 29+7) / ET

• Change from baseline in laboratory safety tests: hematology: hemoglobin - Cohort A and B

  From Day 1 to EoS (Day 8)/ ET

• Change from baseline in laboratory safety tests: hematology: hemoglobin - Cohort C

  From Day 1 to EoS (Day 29+7) / ET

• Change from baseline in laboratory safety tests: hematology: hematocrit - Cohort A and B

  From Day 1 to EoS (Day 8)/ ET

• Change from baseline in laboratory safety tests: hematology: hematocrit - Cohort C

  From Day 1 to EoS (Day 29+7) / ET

• Change from baseline in laboratory safety tests: hematology: red blood cells - Cohort A and B

  From Day 1 to EoS (Day 8)/ ET

• Change from baseline in laboratory safety tests: hematology: red blood cells - Cohort C

  From Day 1 to EoS (Day 29+7) / ET

• Change from baseline in laboratory safety tests: hematology: mean corpuscular volume - Cohort A and B

  From Day 1 to EoS (Day 8)/ ET

• Change from baseline in laboratory safety tests: hematology: mean corpuscular volume - Cohort C

  From Day 1 to EoS (Day 29+7) / ET

• Change from baseline in laboratory safety tests: hematology: mean corpuscular hemoglobin - Cohort A and B

  From Day 1 to EoS (Day 8)/ ET

• Change from baseline in laboratory safety tests: hematology: mean corpuscular hemoglobin - Cohort C

  From Day 1 to EoS (Day 29+7) / ET

• Change from baseline in laboratory safety tests: hematology: mean corpuscular hemoglobin concentration - Cohort A and B

  From Day 1 to EoS (Day 8)/ ET

• Change from baseline in laboratory safety tests: hematology: mean corpuscular hemoglobin concentration - Cohort C

  From Day 1 to EoS (Day 29+7) / ET

• Change from baseline in laboratory safety tests: hematology: differential white blood cells - Cohort A and B

  From Day 1 to EoS (Day 8)/ ET

• Change from baseline in laboratory safety tests: hematology: differential white blood cells - Cohort C

  From Day 1 to EoS (Day 29+7) / ET

• Change from baseline in laboratory safety tests: hematology: thrombocytes - Cohort A and B

  From Day 1 to EoS (Day 8)/ ET

• Change from baseline in laboratory safety tests: hematology: thrombocytes - Cohort C

  From Day 1 to EoS (Day 29+7) / ET

• Change from baseline in laboratory safety tests: biochemistry: urea - Cohort A and B

  From Day 1 to EoS (Day 8)/ ET

• Change from baseline in laboratory safety tests: biochemistry: urea - Cohort C

  From Day 1 to EoS (Day 29+7) / ET

• Change from baseline in laboratory safety tests: biochemistry: sodium - Cohort A and B

  From Day 1 to EoS (Day 8)/ ET

• Change from baseline in laboratory safety tests: biochemistry: sodium - Cohort C

  From Day 1 to EoS (Day 29+7) / ET

• Change from baseline in laboratory safety tests: biochemistry: potassium - Cohort A and B

  From Day 1 to EoS (Day 8)/ ET

• Change from baseline in laboratory safety tests: biochemistry: potassium - Cohort C

  From Day 1 to EoS (Day 29+7) / ET

• Change from baseline in laboratory safety tests: biochemistry: chloride - Cohort A and B

  From Day 1 to EoS (Day 8)/ ET

• Change from baseline in laboratory safety tests: biochemistry: chloride - Cohort C

  From Day 1 to EoS (Day 29+7) / ET

• Change from baseline in laboratory safety tests: biochemistry: calcium - Cohort A and B

  From Day 1 to EoS (Day 8)/ ET

• Change from baseline in laboratory safety tests: biochemistry: calcium - Cohort C

  From Day 1 to EoS (Day 29+7) / ET

• Change from baseline in laboratory safety tests: biochemistry: phosphate - Cohort A and B

  From Day 1 to EoS (Day 8)/ ET

• Change from baseline in laboratory safety tests: biochemistry: phosphate - Cohort C

  From Day 1 to EoS (Day 29+7) / ET

• Change from baseline in laboratory safety tests: biochemistry: creatinine - Cohort A and B

  From Day 1 to EoS (Day 8)/ ET

• Change from baseline in laboratory safety tests: biochemistry: creatinine - Cohort C

  From Day 1 to EoS (Day 29+7) / ET

• Change from baseline in laboratory safety tests: biochemistry: albumin - Cohort A and B

  From Day 1 to EoS (Day 8)/ ET

• Change from baseline in laboratory safety tests: biochemistry: albumin - Cohort C

  From Day 1 to EoS (Day 29+7) / ET

• Change from baseline in laboratory safety tests: biochemistry: magnesium - Cohort A and B

  From Day 1 to EoS (Day 8)/ ET

• Change from baseline in laboratory safety tests: biochemistry: magnesium - Cohort C

  From Day 1 to EoS (Day 29+7) / ET

• Change from baseline in laboratory safety tests: biochemistry: total protein - Cohort A and B

  From Day 1 to EoS (Day 8)/ ET

• Change from baseline in laboratory safety tests: biochemistry: total protein - Cohort C

  From Day 1 to EoS (Day 29+7) / ET

• Change from baseline in laboratory safety tests: biochemistry: lactate dehydrogenase - Cohort A and B

  From Day 1 to EoS (Day 8)/ ET

• Change from baseline in laboratory safety tests: biochemistry: lactate dehydrogenase - Cohort C

  From Day 1 to EoS (Day 29+7) / ET

• Change from baseline in laboratory safety tests: urinalysis: pH - Cohort A and B

  From Day 1 to EoS (Day 8)/ ET

• Change from baseline in laboratory safety tests: urinalysis: pH - Cohort C

  From Day 1 to EoS (Day 29+7) / ET

• Change from baseline in laboratory safety tests: urinalysis: glucose - Cohort A and B

  From Day 1 to EoS (Day 8)/ ET

• Change from baseline in laboratory safety tests: urinalysis: glucose - Cohort C

  From Day 1 to EoS (Day 29+7) / ET

• Change from baseline in laboratory safety tests: urinalysis: protein - Cohort A and B

  From Day 1 to EoS (Day 8)/ ET

• Change from baseline in laboratory safety tests: urinalysis: protein - Cohort C

  From Day 1 to EoS (Day 29+7) / ET

• Change from baseline in laboratory safety tests: urinalysis: white blood cells - Cohort A and B

  From Day 1 to EoS (Day 8)/ ET

• Change from baseline in laboratory safety tests: urinalysis: white blood cells - Cohort C

  From Day 1 to EoS (Day 29+7) / ET

• Change from baseline in laboratory safety tests: urinalysis: blood - Cohort A and B

  From Day 1 to EoS (Day 8)/ ET

• Change from baseline in laboratory safety tests: urinalysis: blood - Cohort C

  From Day 1 to EoS (Day 29+7) / ET

• Change from baseline in laboratory safety tests: hemostasis: prothrombin time - Cohort A and B

  From Day 1 to EoS (Day 8)/ ET

• Change from baseline in laboratory safety tests: hemostasis: prothrombin time - Cohort C

  From Day 1 to EoS (Day 29+7) / ET

Secondary Outcomes (35)

• Observed maximum concentration (Cmax) of E4 and its metabolites (C3- and C16-glucuronides) -Cohort A and B

  From Day 1 (pre-infusion, i.e just prior dosing) to Day 5

• Observed maximum concentration (Cmax) of E4 and its metabolites (C3- and C16-glucuronides) - Cohort C

  From Day 1 (pre-infusion, i.e just prior dosing) to Day 9

• Time of Cmax (Tmax) of E4 and its metabolites (C3- and C16-glucuronides) - Cohort A and B

  From Day 1 (pre-infusion, i.e just prior dosing) to Day 5

• Time of Cmax (Tmax) of E4 and its metabolites (C3- and C16-glucuronides) - Cohort C

  From Day 1(pre-infusion, i.e just prior dosing) to Day 9

• Terminal phase half-life (T1/2) of E4 and its metabolites (C3- and C16-glucuronides) -Cohort A and B

  From Day 1 (pre-infusion, i.e just prior dosing) to Day 5

Study Arms (4)

Cohort A

EXPERIMENTAL

Drug: single E4 28.3 mg

Cohort B

EXPERIMENTAL

Drug: single E4 94.4 mg

Cohort C

EXPERIMENTAL

Drug: multiple E4 94.4 mg

Placebo

PLACEBO COMPARATOR

Drug: Placebo

Interventions

single E4 28.3 mg DRUG

Administration of a single intravenous (i.v.) infusion of estetrol (E4) 28.3 mg (n=6)

Cohort A

single E4 94.4 mg DRUG

Administration of a single i.v. infusion of E4 94.4 mg (n=6)

Cohort B

multiple E4 94.4 mg DRUG

Administration of an i.v. infusion of E4 94.4 mg (or lower dose, depending on single dose results) once a day for 5 consecutive days (n=8)

Cohort C

Placebo DRUG

Cohort A: Single dose of placebo (n=2); Cohort B: Single dose of placebo (n=2); Cohort C: multiple dose of placebo (n=4)

Placebo

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Premenopausal women aged 18-45 years of age who are not taking oral contraceptives or
• Men aged 18-60 years of age who are willing to use adequate contraception from screening until 4 weeks after the last dose of study treatment;
• Body mass index (BMI) \>18.0 kg/m2 and \<30.0 kg/m2, and body weight ≥45.0 kg;
• Continuous non-smokers who have not used tobacco or nicotine-containing products within 3 months prior to screening. Urine cotinine level at screening \<200 ng/mL;
• Able and willing to abstain from tobacco, alcohol-, caffeine-, and xanthine-containing beverages or food (e.g., coffee, tea, cola, chocolate, energy drinks) from 48h (2 days) before each admission to the study site until discharge;
• Normal 12-lead ECG findings as judged by the Investigator at screening and check-in, and evidenced by each criterion listed below:
• Normal sinus rhythm (heart rate between 50 bpm and 100 bpm, inclusive);
• Fridericia-corrected QTc (QTcF) interval ≤450 msec;
• QRS interval ≤120 msec, and confirmed by manual over read if \>120 msec;
• PR interval ≤220 msec
• Good physical and mental health as judged by the Investigator and determined by medical and surgical history, physical examination, vital signs, or laboratory tests performed within 28 days before first study drug administration; For female subjects, physical examination must include breast examination and gynecological examination including a transvaginal ultrasound (TVUS) and a cervical (Papanicolaou \[Pap\]) smear if subject has not undergone one in the previous 18 months;
• Women of child-bearing potential and fertile male subjects with a sexual partner of other sex must be willing to use an adequate double-barrier contraception method from screening until 4 weeks after the last dose of study treatment;
• Capable and willing to give written informed consent (IC);
• Able to understand and comply with the protocol requirements, instructions, and protocol-stated restrictions;
• Venous access sufficient to allow blood sampling as per protocol.

You may not qualify if:

• Renal insufficiency as determined by glomerular filtration rate \[GFR\] \<60 mL/min/1.73 m2;
• History or presence of liver tumors, liver disease or liver injury as indicated by abnormal liver function tests \[alanine transaminase (ALT) or aspartate transaminase (AST) \>2x upper limit of normal (ULN) and bilirubin \>1.5 ULN\]. Any single parameter elevated \>1.5-fold ULN should be re-checked once prior to enrollment/randomization;
• Pregnant or breast-feeding women;
• Menopausal and post-menopausal women. Menopause is defined as at least 12 months of spontaneous amenorrhea without another medical cause;
• Use of estrogen or progestin-containing drug(s). A washout period is required before screening in case of use of:
• vaginal hormonal products (rings, creams, gels): washout of at least 4 weeks;
• transdermal estrogen or estrogen/progestin: washout of at least 4 weeks;
• oral estrogen and/or progestin: washout of at least 4 weeks;
• intrauterine progestin therapy: washout of at least 4 weeks;
• progestin implants or estrogen alone injectable drug therapy: washout of at least 3 months;
• estrogen pellet therapy or progestin injectable drug therapy: washout of at least 6 months.
• Women who have any clinically significant findings found by the Investigator at the breast examination and/or on mammography/ultrasound (performed only if deemed necessary by the Investigator) suspicious of breast malignancy (however, simple cysts confirmed by ultrasound are allowed);
• Women who have a Pap test with atypical squamous cells of undetermined significance (ASC-US or class II) or higher (low-grade squamous intraepithelial lesion \[LSIL\],\] or class III and higher, atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion \[HSIL\] \[ASC-H\], HSIL, dysplastic or malignant cells). Note: ASC-US or class II is allowed if a reflex human papilloma virus (HPV) testing is performed and is negative for high risk oncogene HPV;
• History of venous or arterial thromboembolic disease (e.g., superficial or deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction, angina pectoris, etc.), or first-degree family history of venous thromboembolism (VTE);
• History of known acquired or congenital coagulopathy or abnormal coagulation factors, including known thrombophilia;

Sponsors & Collaborators

• NEURALIS s.a.: lead

Study Sites (1)

MC Comac Medical Ltd

Sofia, 1612, Bulgaria

Location

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 25, 2022
• First Posted: July 15, 2022
• Study Start: April 19, 2022
• Primary Completion: September 13, 2022
• Study Completion: September 13, 2022
• Last Updated: July 4, 2025

Record last verified: 2025-07

Locations

BU (1)