Study Evaluating ISM5411 Administered Orally to Subjects With Active Ulcerative Colitis (BETHESDA)

Official title

A Phase IIa, Multicenter, Randomized, Double-blind, Placebo-controlled, Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Clinical Efficacy of ISM5411 in Adult Patients With Active Ulcerative Colitis

Overview

This is a multicenter, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics and clinical efficacy of ISM5411 in adult patients with active ulcerative colitis.

Detailed description

ISM5411 is a gut-restricted small-molecule prolyl hydroxylase (PHD) inhibitor. It can promote the expression of intestinal mucosal protective genes and maintain the integrity and functions of intestinal barrier together with anti-inflammation. It is expected to become a safe and effective therapy to overcome the shortcomings of traditional simple anti-inflammatory drugs.

Interventions

• Drug ISM5411 tablets
  Dosage Form: Tablet; Frequency of administration: Orally QD.
• Drug ISM5411 tablets
  Dosage Form: Tablet; Frequency of administration: Orally QD.
• Drug ISM5411 tablets
  Dosage Form: Tablet ; Frequency of administration: Orally QD.
• Drug Placebo
  Dosage Form: Tablet; Frequency of administration: Orally QD.

Primary outcome measures

• The rate of treatment-emergent adverse events (TEAEs) in each group. [Time frame: Week1 to Week12.]
• The rate of serious adverse events (SAEs) and adverse events (AEs) leading to discontinuation of treatment in each group. [Time frame: Up to 16 weeks.]
• Changes and comparisons of the following data for each group of subjects: vital signs, physical examination, laboratory test(blood routine, blood chemistry, urinalysis, coagulation function, etc.), ECG(Heart rate, RR, PR, QRS,QT, QTcF ), etc. [Time frame: Up to 16 weeks.]

Secondary outcome measures (10)

• Peak plasma concentration (Cmax) [Time frame: Week1 to Week12.]
• Peak plasma time (Tmax) [Time frame: Week1 to Week12.]
• Area under the plasma concentration-time curve extrapolated from time zero to infinity (AUC0-inf). [Time frame: Week1 to Week12.]
• Area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC0-t). [Time frame: Week1 to Week12.]
• Terminal rate constant (λz) [Time frame: Week1 to Week12.]
• Elimination half-life (t1/2) [Time frame: Week1 to Week12.]
• Apparent volume of distribution (Vz/F) [Time frame: Week1 to Week12.]
• Apparent clearance (CL/F) [Time frame: Week1 to Week12.]
• Mean residence time (MRT) [Time frame: Week1 to Week12.]
• Colonic tissue concentration (Ccolon) [Time frame: Week1 to Week12.]

Eligibility criteria

Inclusion criteria

• Subject who fully understand the content, process and possible adverse events of the study and capable of giving written informed consent form (ICF).
• Female subjects must be nonpregnancy and nonlactating. Subjects (male or female) are willing to take medically approved effective contraceptive measures from the screening period to 3 months after the last administration and have no sperm or egg donation plan during the study period and within 3 months after the last dose.
• Male or female between 18 and 75 years of age (inclusive), at the time of signing the ICF.
• Subject has a diagnosis of ulcerative colitis for at least 3 months prior to colonoscopy during the screening period, and meets the criteria defined in the current protocol.
• If the subjects have concomitant medication defined in the current protocol, they must meet the relevant criteria to be enrolled.
• If the subjects have discontinued medication defined in the current protocol, they must meet the relevant criteria to be enrolled.

Exclusion criteria

• Subjects have suspected or diagnosed Crohn's disease (CD), undefined colitis, ischemic colitis, fulminant colitis, toxic megacolon, radiation colitis, gastrointestinal perforation (other than appendicitis or penetrating injury), diverticular disease associated with colitis, enterophthisis, abdominal abscess or fistula, etc.
• Subjects with previously diagnosed but uneradicated or current gastrointestinal dysplasia.
• Subjects have received surgery for UC or any other type of major intestinal surgery (i.e., surgical procedure requiring general anesthesia) or are likely to require related surgery during the study.
• Subjects have evidence of a pathogenic intestinal infection, or have a Clostridium Difficile infection or other intestinal infection within 30 days prior to the screening endoscopy or have tested positive for Clostridium Difficile toxins or other intestinal pathogens at the screening period.
• Subjects have chronic recurring infection and/or active viral infection that, based on the investigator's clinical assessment, make them an unsuitable candidate for the study.
• Subjects who are unable to take oral medications and/or have an impact on absorption of medication due to severe malnutrition or disease and surgery, etc., or who are currently receiving or plan to receive total parenteral nutrition (TPN) during the study period.
• Subjects who have received the relevant treatments defined in the protocol.
• Subjects with recurrent or disseminated (even if single episode) herpes zoster, or cytomegalovirus infection.
• Subjects who have the risks of tuberculosis defined in the protocol.
• Subjects have any of the infection defined in the protocol.
• Subjects who are known to be allergic to the investigational product or any components of it or who have allergic constitution (allergy to multiple drugs or foods).
• Subjects have unstable or uncontrolled and clinically significant allergic (except for untreated, asymptomatic, seasonal allergies), hematological, endocrine/metabolic, coagulation, immunologic, pulmonary, cardiovascular, hepatic (expect hepatic steatohepatitis), digestion system (expect UC), genitourinary, psychiatric, oncologic or neurological disease or other medical disorder that would make them ineligible for the study.
• Subjects have concomitant illness that in the opinion of the investigator, are likely to require systemic glucocorticosteroid therapy during the study (e.g., moderate to severe asthma).
• Subjects have received major organ surgery (except needle biopsy, tracheotomy, gastrotomy, etc.) or significant trauma within 28 days prior to randomization or is likely to require related surgery during the study.
• Subjects have history of any malignancy within 5 years of screening, except for successfully treated nonmelanoma skin cancer (NMSC), skin basal cell carcinoma, or localized carcinoma in situ of the cervix.
• Any abnormal results defined in the protocol were identified during the screening period.
• Subjects with poorly controlled hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg) despite medication at screening.
• Subjects have a clinically significant abnormal ECG at screening, including QTcF > 450 msec for males and > 470 msec for females.
• Subjects have difficulty in venous blood collection or history of acupuncture syncope reaction or blood phobia.
• Subjects have contraindications to colonoscopy, including but not limited to gastrointestinal fistulas, early post abdominal surgery, severe coagulopathy, large abdominal aneurysms, or any condition that the investigator determines significantly increases the risk of colonoscopy complications.
• Subjects have a history of alcohol or drug abuse within 3 months of screening, according to the judgement of the investigator. Alcohol abuse refers to consuming alcohol at least twice per day or more than 14 units of alcohol per week.
• Subjects have participated in other clinical trials of other drugs or medical devices within 30 days prior to screening period and have already received the investigational product, or are currently participating in another clinical trial of a drug or medical device.
• Subjects are deemed by the investigator to be inappropriate for the study; or have any condition which would confound or interfere with the evaluation of the safety, tolerability, or PK of the investigational drug; or are unable or unwilling to comply with the study protocol.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

China · 28 centers

• Beijing Friendship Hospital, Capital Medical University — Beijing
• The First Affiliated Hospital of Chongqing Medical University — Chongqing
• Guangzhou First People's Hospital — Guangzhou
• The First Affiliated Hospital,Sun Yat-sen University — Guangzhou
• Huizhou First Hospital — Huizhou
• The People's Hospital of Guangxi Zhuang Autonomous Region — Nanning
• The Second Hospital of HeBei Medical University — Shijiazhuang
• The First Affiliated Hospital of Henan University of Science & Technology — Luoyang
• … and 20 more centers

Identifiers

NCT: NCT07265570 · ISM5411-201

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗