Phase 3 Study on the Efficacy and Safety of Cipepofol vs. Propofol for Induction of General Anesthesia in Adults Undergoing Elective Surgery
- Trial ID
- 2023-507009-32-00
- Protocol
- HSK3486-309
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate that **HSK3486** at a dosage of 0.4/0.2 mg/kg is non-inferior to **propofol** at a dosage of 2.0/1.0 mg/kg in achieving successful induction of **general anesthesia** in adults undergoing elective surgery. This is clinically relevant as it aims to establish an alternative anesthetic agent that could potentially offer similar efficacy to the widely used propofol, thereby expanding the options available for anesthetic induction in surgical procedures.
Secondary objectives include:
- Confirming that HSK3486 0.4/0.2 mg/kg results in statistically significant less injection-site pain compared to propofol 2.0/1.0 mg/kg during the induction of general anesthesia.
- Demonstrating that HSK3486 0.4/0.2 mg/kg provides better anesthetic effects compared to propofol 2.0/1.0 mg/kg without significant cardiac and respiratory depression when used in conjunction with other routinely administered preinduction and maintenance anesthetic agents.
Participants
The clinical trial involves a total of **259 participants** who are undergoing elective surgery requiring endotracheal intubation and inhalation **general anesthesia**. The study population includes both male and female subjects aged 18 years and older, with an **ASA-PS** classification ranging from I to IV, indicating a wide range of general health statuses. Participants were selected based on their need for non-emergency, non-cardiothoracic, and non-intracranial surgeries anticipated to last at least one hour. Key lifestyle considerations include a **BMI** of at least 18 kg/m² and stable vital signs within specified ranges. The trial includes individuals with stable psychiatric or mental disorders and those with managed hypothyroidism, provided their **TSH** levels are within normal limits. Both genders are represented, and the trial includes a vulnerable population, ensuring a comprehensive assessment of the study objectives.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, **controlled** study designed to evaluate the efficacy and safety of HSK3486 Injectable Emulsion compared to **propofol** for the induction of general anesthesia in adults undergoing elective surgery. The trial is categorized as a Phase III study and is not considered low intervention. The primary objective is to demonstrate that HSK3486 is non-inferior to propofol in achieving successful induction of general anesthesia. The trial is expected to commence recruitment on February 1, 2024, and conclude by October 1, 2024.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, health status, and surgical requirements. Eligible participants will be randomized to receive either HSK3486 or propofol. The study will include follow-up visits to monitor the success rate of anesthesia induction, defined by achieving a Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score of ≤1 and requiring one or fewer top-up doses without rescue drugs. Secondary endpoints include the incidence of injection-site pain and maintenance of anesthesia depth without significant cardiac or respiratory depression.
The expected duration of participant involvement is approximately one day, corresponding to the day of surgery and administration of the study drug. Conditions that may lead to early termination from the study include non-compliance with the protocol, withdrawal of consent, or adverse events that compromise participant safety. The trial will ensure strict adherence to the study protocol, with all procedures conducted in compliance with ethical guidelines and regulatory requirements.
Treatment
The clinical trial involves the administration of several **experimental medications** and comparator treatments. The primary experimental medication is **Cipepofol Injectable Emulsion**, which contains the active substance **cipepofol**. This medication is administered as an emulsion for injection, with a dosage of 0.6 mg/kg. The route of administration is intravenous injection, and the maximum treatment period is one day. The trial aims to evaluate the efficacy and safety of Cipepofol for the induction of general anesthesia in adults undergoing elective surgery.
**Propofol** is used as a comparator treatment in this study. It is administered as an emulsion for injection, with a dosage of 2.0 mg/kg for the initial dose, followed by an additional 1.0 mg/kg if needed. The route of administration is intravenous injection, and the maximum treatment period is one day. Propofol serves as the standard-of-care therapy against which the efficacy of Cipepofol is compared.
Additional non-experimental treatments include **Midazolam**, **Rocuronium Bromide**, **Fentanyl**, and **Sevoflurane**. Midazolam is administered intravenously, with a maximum daily dose of 3 mg. Rocuronium Bromide is also administered intravenously, with a maximum daily dose of 0.6 mg/kg. Fentanyl is administered intravenously, with a maximum daily dose of 100 µg. Sevoflurane is administered via inhalation, with a maximum daily dose of 2.0% concentration. These medications are used to support the induction and maintenance of anesthesia as per standard clinical practice.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol. The trial is designed to assess the non-inferiority of Cipepofol compared to Propofol in achieving successful induction of general anesthesia. All medications are administered under controlled conditions, with careful monitoring of patient responses and any adverse events.
Efficacy
The efficacy of the clinical trial will be assessed through both primary and secondary endpoints. The primary endpoint is the success rate of general anesthesia induction, defined by achieving a Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score of ≤1 after administration of the study drug, with one or fewer top-up doses required and no use of rescue drugs. Secondary endpoints include the proportion of subjects experiencing injection-site pain at the time of drug administration, measured using the Numeric Rating Scale (NRS ≥1), and the proportion of subjects who maintain the desired depth of anesthesia for general elective surgery without significant cardiac and respiratory depression within 15 minutes post-initiation of the study drug administration.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Subjects undergoing elective surgery (non emergency, noncardiothoracic, and non intracranial surgery, anticipated to last at least 1 hour) requiring endotracheal intubation and inhalation general anesthesia during the maintenance period. Duration of surgery is defined as time from study drug administration to time of transfer from operating room to recovery room or PACU.
- Males or females, aged ≥18 years old, with ASA-PS I to IV. For ASA-PS IV subjects, clinical status must be optimized at time of preoperative anesthesia evaluation per judgement of the anesthesiologist.
- BMI ≥18 kg/m2.
- Vital signs at screening: RR ≥10 and ≤24 breaths/min; SpO2 ≥92% in ambient air; SBP ≥90 and ≤160 mmHg; DBP ≥55 and ≤100 mmHg; HR ≥55 (or ≥50 if subjects are on beta blockers) and ≤100 beats/min.
- For all women of childbearing potential, negative serum pregnancy test within the screening period and negative urine pregnancy test at baseline (Day 1). Additionally, women of childbearing potential and male subjects with female partners of childbearing potential must agree to use effective contraception from the time of consent until 30 days post study drug administration.
- Capable of understanding the procedures and methods of this study, willing to sign an Informed Consent Form, and able to complete this study in strict compliance with the study protocol.
- Willing to comply with the site’s COVID guidelines and testing requirements as applicable.
- Patients with psychiatric/mental disorders must be considered stable on treatment (e.g., SSRIs, SNRIs, TCAs, MAOIs, psychotherapy) per investigator judgement, and no hospitalizations and urgent care due to the underlying psychiatric pathology for at least 12 months.
- For subjects with known hypothyroidism and/or on thyroid-hormone replacement treatment (i.e., thyroxine), or subjects suspected to have thyroid dysfunction based on clinical laboratory and physical exam, a TSH must drawn and be within normal levels.
Exclusion Criteria
- Contraindications to deep sedation/general anesthesia or a history of adverse reaction to sedation/general anesthesia.
- Known to be allergic to eggs, soy products, opioids and their antidotes, or propofol; subjects having contraindications to propofol, opioids, and their antidotes. In cases where the only previous reaction to opioids was itching or nausea, subjects need not be excluded if the investigator believes the subject is not truly allergic to opioids.
- Medical condition or evidence of increased sedation/general anesthesia risk as follows: a) Cardiovascular disorders: uncontrolled hypertension (SBP >160 mmHg and/or DBP >100 mmHg) with or without antihypertensive therapy (antihypertensive therapy should be stable for 1 month prior to screening), serious arrhythmia (including the subjects with implanted pace makers), unstable heart failure, Adams-Stokes syndrome (i.e., syncope or near syncope due to cardiac arrythmia), unstable angina, myocardial infarction occurring within 6 months prior to screening, history of tachycardia/bradycardia requiring medications, third degree atrioventricular block or QT interval corrected for HR using Fridericia’s formula (QTcF) ≥450ms for males and ≥470ms for females. b) History of severe obstructive lung disease (i.e., forced expiratory volume in 1 second [FEV1] <50% predicted), history of bronchospasm requiring treatment in a hospital emergency room or hospitalization occurring within 3 months prior to screening, developing acute respiratory tract infection within 2 weeks prior to baseline (such as symptoms of fever, shortness of breath, wheezing, nasal congestion, and cough). c) Cerebrovascular disease: subject with a history of serious craniocerebral injury, convulsion, seizure disorder, intracranial hypertension, cerebral aneurysm, or stroke. d) Patients with psychiatric/mental disorders who have not been on a stable treatment regimen (e.g., SSRIs, SNRIs, TCAs, MAOIs, psychotherapy) per investigator judgement, for at least 12 months or who have been hospitalized or had emergent/urgent care due to underlying psychiatric pathology within the last 12 months. e) Uncontrolled clinically significant conditions of liver (e.g., severe hepatic insufficiency defined as Childs- Pugh class C), kidney, gastrointestinal tract, blood system, nervous system, or metabolic system diseases, judged by the investigator to be unsuitable for involvement in the study. f) History of uncontrolled diabetes in the opinion of the investigator. g) History of alcohol abuse within 3 months prior to screening, where alcohol abuse refers to daily alcohol drinking >2 units of alcohol (1 unit = 360 mL of beer or 45 mL of spirit with a strength of 40% or 150 mL of wine). h) History of drug abuse that, in the opinion of the investigator, may confound the interpretation of safety or efficacy in a study subject. i) For subjects with known hypothyroidism and/or on thyroid-hormone replacement treatment (i.e. thyroxine), or subjects suspected to have thyroid disfunction based on clinical laboratory and physical exam who has a TSH value outside the normal range.
- Management risks of respiratory tract and judged by the investigator to be unsuitable for inclusion in the study as follows: a) Asthma must be stable: stable doses of asthma medications for the past 6 months, no requirement for rescue inhalers or oral steroids within past 6 months, not evaluated in emergency department, urgent care, or hospitalized for an asthma attack within past 1 year. b) History (or family history) of malignant hyperthermia. c) Any previous failure of tracheal intubation. d) Judged to have a difficult airway for endotracheal intubation in the opinion of the Investigator based on parameters such as modified Mallampati score (Grade III or IV), neck mobility, short thyromental distance, and/or history of difficult intubation.
- Any medication that has the potential to interact synergistically with propofol or HSK3486, including but not limited to all sedatives and hypnotics (e.g., benzodiazepines and opioids) taken within 5 half-lives prior to Day 1.
- Laboratory parameters measured at screening with the following levels: a) Neutrophil count ≤1.5 x 10^9/L b) Platelet count <80 x 10^9/L c) Hemoglobin <90 g/L (without blood transfusion within 14 days) d) Alanine transaminase and/or aspartate transaminase ≥2.0 x upper limit of normal (ULN) e) Total bilirubin ≥2.0 x ULN f) Severe renal impairment defined by creatinine clearance (CrCl) ≤30 mL/min
- Female subjects with a positive pregnancy test at screening (serum) or baseline (urine); lactating subjects; any subject planning to get pregnant within 1 month after the study (including the male subject’s partner).
- Judged by the investigator to have any other factors that make the subject unsuitable for participation in the study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Poland | Not Recruiting | 01 Feb 2024 | 50 |
 Spain | Not Recruiting | 01 Feb 2024 | 90 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
MIDAZOLAM | Other | PHF00230MIG | INTRAVENOUS ADMINISTRATION | 3 | 1 | SCP3173934 |
PROPOFOL | Other | PHF742 | INTRAVENOUS INJECTION | 2 | 1 | SCP258842 |
ROCURONIUM BROMIDE | Other | PHF675 | INTRAVENOUS ADMINISTRATION | 0.6 | 1 | SCP6166928 |
Cipepofol Injectable Emulsion | Test | EMULSION FOR INJECTION | INTRAVENOUS INJECTION | 0.6 | 1 | PRD10855121 |
FENTANYL | Other | PHF00231MIG | INTRAVENOUS ADMINISTRATION | 100 | 1 | SCP194096 |
SEVOFLURANE | Other | PHF00113MIG | INHALATION USE | 2.0 | 1 | SCP3661382 |
PROPOFOL | Comparator | — | INTRAVENOUS INJECTION | 3 | 1 | SUB10116MIG |