Study to Evaluate the Efficacy and Safety of KDS2010 in Overweight or Obese Patients

Официальное название

A Randomized, Double-blind, Placebo-controlled, Dose Finding, Phase 2a Clinical Trial to Evaluate the Efficacy and Safety of KDS2010 in Overweight or Obese Patients

Обзор

This is a randomized, double-blind, placebo-controlled, dose-finding, Phase 2a study designed to evaluate the safety and efficacy of KDS2010 in overweight or obese patients. Based on preliminary efficacy observed in the Phase 1 study, this clinical trial is being conducted in Korea. After a minimum 2-week run-in period, subjects who meet the inclusion and exclusion criteria will be randomized to the treatment group or placebo group at a 2:1 ratio in each stage. Subjects will receive the investigational product for 12 weeks following randomization. The study will be conducted in three stages. Approximately 75 subjects will be enrolled, with 6 subjects in the KDS2010 120 mg group and 3 subjects in the placebo group in Stage 1, 22 subjects in the KDS2010 180 mg group and 11 subjects in the placebo group in Stage 2, and 22 subjects in the KDS2010 240 mg group and 11 subjects in the placebo group in Stage 3. The primary objectives are to assess the efficacy and safety of KDS2010 in overweight or obese patients. Exploratory objectives include evaluating the proportion of subjects achieving a weight reduction of more than 25% from baseline at Week 12 and assessing changes in MAO-B specific activity and adiponectin levels. Based on nonclinical and Phase 1 clinical data, KDS2010 will be administered orally once daily at doses of 120 mg, 180 mg, and 240 mg throughout the study.

Подробное описание

This Phase 2a, randomized, double-blind, placebo-controlled, dose-finding clinical trial is designed to evaluate the efficacy, safety, and pharmacokinetics of KDS2010, a novel, reversible monoamine oxidase-B (MAO-B) inhibitor, in overweight or obese adult patients. The clinical trial is conducted at selected sites in Korea.

The study consists of three stages and will enroll approximately 75 subjects. In Stage 1, 9 subjects were randomized in a 2:1 ratio (KDS2010 120 mg: placebo) to evaluate initial safety and tolerability. Upon completion of the week 13 visit for the last subject in Stage 1, a Safety Review Committee (SRC) assessed cumulative safety data and determined that the study may proceed to Stage 2.

Stage 2 is currently being prepared for subject recruitment and will proceed with 33 subjects randomized in a 2:1 ratio to receive KDS2010 180 mg or placebo. Upon completion of the Week 13 visit for the last ongoing subject in Stage 2, the SRC will review the safety data collected up to that time to determine whether the study may proceed to Stage 3. Stage 3 will proceed with 33 subjects randomized in a 2:1 ratio to receive KDS2010 240 mg or placebo.

All subjects will undergo a 2-week run-in period prior to randomization to confirm eligibility based on adherence to lifestyle modification (documented reduction of ≥500 kcal/day and ≥150 minutes of physical activity per week for ≥50% of the run-in period).

The treatment period consists of 12 weeks of once-daily oral administration of the investigational product (IP), followed by a 1-week post-treatment safety follow-up (week 13). During treatment, subjects will visit the site at Weeks 4, 8, and 12, with a telephone visit at Week 2. Safety follow-up will be conducted by phone at Week 13.

The primary efficacy endpoint is the percentage change in body weight from baseline to Week 12. Secondary efficacy endpoints include the proportion of subjects achieving ≥5%, ≥10%, ≥15%, and ≥20% weight loss and changes in waist circumference, BMI, blood pressure (SBP/DBP), quality of life (IWQOL-Lite-CT), body composition (DEXA), lipid profile, glycemic parameters (HbA1c, fasting glucose, HOMA-IR), and liver steatosis. Exploratory endpoints assess the proportion of subjects with ≥25% weight loss, as well as changes in MAO-B specific activity and adiponectin levels.

Safety will be evaluated through monitoring of adverse events (AEs), laboratory tests, vital signs, ECGs, and psychological assessments, including the Columbia-Suicide Severity Rating Scale (C-SSRS) and Patient Health Questionnaire-9 (PHQ-9). Pharmacokinetic parameters (AUCtau, Cmax,ss, Cmin,ss, Cav,ss, Tmax,ss, t1/2, PTF, etc.) will be measured to assess systemic exposure to KDS2010.

Subjects must be adults aged 19 years or older, have a BMI ≥30 kg/m² or ≥27 kg/m² with at least one weight-related comorbidity, and demonstrate compliance with lifestyle modification during the run-in.

Major exclusion criteria include recent significant weight change (≥5% within 12 weeks), use of anti-obesity drugs or MAO inhibitors, type 1 or 2 diabetes, bariatric surgery, uncontrolled hypertension, hepatic or renal dysfunction, significant psychiatric disorders, or suicidal ideation/attempts.

The total study duration is expected to be approximately 28 months from IRB approval, with individual subject participation lasting up to 17 weeks. This trial aims to evaluate the safety, efficacy, and pharmacokinetics of KDS2010 for future development in the treatment of obesity.

Вмешательства

• Препарат KDS2010
  KDS2010 will be administered orally once daily, two tablets per day, for 12 weeks. Dosage will be 120 mg depending on the assigned group.
• Препарат KDS2010
  KDS2010 will be administered orally once daily, three tablets per day, for 12 weeks. Dosage will be 180 mg depending on the assigned group
• Препарат KDS2010
  KDS2010 will be administered orally once daily, four tablets per day, for 12 weeks. Dosage will be 240mg depending on the assigned group.
• Препарат Placebo
  Placebo matching the investigational product in appearance but containing no active ingredient, administered orally once daily, one tablets per day, for 12 weeks.
• Препарат Placebo
  Placebo matching the investigational product in appearance but containing no active ingredient, administered orally once daily, three tablets per day, for 12 weeks.
• Препарат Placebo
  Placebo matching the investigational product in appearance but containing no active ingredient, administered orally once daily, four tablets per day, for 12 weeks.

Первичные конечные точки

• Percentage Change in Body Weight from Baseline [Срок оценки: Baseline to Week 12]

Вторичные конечные точки (11)

• Proportion of Subjects with ≥5%, ≥10%, ≥15%, and ≥20% weight loss from baseline (%) [Срок оценки: Baseline to Week 12]
• Change from baseline in Waist Circumference [Срок оценки: Screening(Week -4 to -2), Run-in(Week -2), Baseline(Week 0), Week 4, 8, 12]
• Change from baseline in Body Mass Index (BMI) [Срок оценки: Screening(Week -4 to -2), Run-in(Week -2), Baseline(Week 0), Week 4, 8, 12]
• Change from baseline in Systolic and Diastolic Blood Pressure [Срок оценки: Screening(Week -4 to -2), Run-in(Week -2), Baseline(Week 0), Week 4, 8, 12, 13]
• Change from baseline in Impact of Weight on Quality of Life Questionnaire-Lite Clinical Trials version (IWQOL-Lite-CT) Total and Domain Scores [Срок оценки: Baseline(Week 0), Week 12]
• Change from baseline in Body Fat Composition via Dual-energy X-ray absorptiometry (DEXA) Scan [Срок оценки: Baseline(Week 0), Week 12]
• Change from baseline in Lipid Profile [Срок оценки: Screening(Week -4 to -2), Baseline(Week 0), Week 4, 8, 12, 13]
• Change from baseline in Glycemic Parameters: HbA1c (%) [Срок оценки: Screening(Week -4 to -2), Baseline(Week 0), Week 4, 8, 12, 13]
• Change from baseline in Glycemic Parameters: Fasting Glucose (mg/dL) [Срок оценки: Screening(Week -4 to -2), Baseline(Week 0), Week 4, 8, 12, 13]
• Change from baseline in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) [Срок оценки: Baseline(Week 0), Week 12]
• Change from baseline in Liver Steatosis (Abdominal CT) [Срок оценки: Baseline(Week 0), Week 12]

Критерии участия

Критерии включения

• Adult males and females aged 18 years or older (or the legal age of adulthood in the respective country) as of the date of written consent
• Subjects with BMI ≥30 kg/m² or BMI ≥27 kg/m² with at least one weight-related comorbidity (hypertension, dyslipidemia, cardiovascular disease, obstructive sleep apnea) at screening and baseline

• Hypertension: under treatment or have Systolic Blood Pressure (SBP) ≥130 mmHg or Diastolic Blood Pressure (DBP) ≥80 mmHg
• Dyslipidemia: under treatment or LDL > 160 mg/dL or TG > 200 mg/dL or HDL < 40 mg/dL
• Cardiovascular diseases (e.g., ischemic cardiovascular disease, NYHA Class I to III heart failure, Peripheral vascular disease (PVD), Abdominal aortic aneurysm (AAA), etc.)
• Obstructive sleep apnoea
• Subjects who have documented a 500 kcal reduction/day in calorie intake and ≥150 minutes of physical activity/week for ≥50% of the time during the run-in period
• Subjects who have voluntarily provided written consent to participate after being informed about this clinical trial

Критерии исключения

• Subjects with a weight change of 5% or more within 12 weeks before screening
• Subjects with less than 80% or more than 120% compliance during the Run-in period
• Subjects with obesity due to secondary causes (neurological disorders, endocrine disorders, genetic disorders, congenital disorders, etc.)
• Subjects with following medical history,

• Type 1 or Type 2 diabetes
• History of bariatric/metabolic surgery (e.g., adjustable gastric banding, intragastric balloon insertion, sleeve gastrectomy, Roux-en-Y gastric bypass, biliopancreatic diversion, duodenal switch) or planning to undergo such surgery during the study period
• Heart failure classified as NYHA class IV
• Subjects with a medical history of malignant tumors within 5 years prior to screening (however, subjects with successfully treated basal cell carcinoma, squamous cell carcinoma of the skin, thyroid cancer, or other carcinoma in situ, with no recurrence for more than 3 years, may be enrolled at the investigator's discretion)
• Subjects with a medical history of hypersensitivity to MAO inhibitors
• Subjects with a medical history of cerebrovascular disease (e.g., transient ischemic attack, stroke) within 12 weeks prior to baseline, or those hospitalized for unstable angina or congestive heart failure
• Subjects with a history of depressive disorders or psychiatric disorders (e.g., schizophrenia, bipolar disorder, anxiety disorder) within 2 years prior to screening
• Subjects with a history of the following drug administration,

\-- Anti-obesity agents or weight-loss medications (including dietary supplements and herbal medicine) within 12 weeks before screening

• Corticosteroids administered for 2 consecutive weeks or more within 12 weeks before screening (however, topical preparations, including inhalants, are allowed)
• Treatment for hyperthyroidism or hypothyroidism at the time of screening (subjects on a stable dose and regimen for at least 12 weeks may be enrolled at the investigator's discretion)
• MAO inhibitors within 2 weeks before baseline
• Opioid medications (e.g., pethidine, Tramadol, Tapentadol) within 2 weeks before baseline
• Serotonergic drugs within 2 weeks before baseline,

• Selective Serotonin Reuptake Inhibitors (SSRI), ② Serotonin-Norepinephrine Reuptake Inhibitors (SNRI),

• Tricyclic or Tetracyclic antidepressant, ④ Triazolopyridine antidepressant, ⑤ Selective serotonin (5-HT1) agonists (Sumatriptan, etc.), (However, amitriptyline ≤50 mg/day, trazodone ≤100 mg/day, citalopram ≤20 mg/day, sertraline ≤100 mg/day, paroxetine ≤30 mg/day are allowed; long half-life serotonergic drugs (e.g., fluoxetine) require at least a 5-week wash out period before enrollment),
• Lithium, Bupropion, Lamotrigine, Ritonavir, Cyclobenzaprine, or St. John's wort within 2 weeks before baseline
• Hypertension crisis-inducing drugs (e.g., oxymetazoline, phentermine, phenylephrine) within 2 weeks before baseline
• Sympathomimetic agents (e.g., ephedrine, methylphenidate, amphetamine, methamphetamine, lisdexamfetamine) at the time of screening
• Dextromethorphan at the time of screening
• Subjects who meet following criteria based on the tests conducted at Screening

• Glycated hemoglobin (HbA1c) ≥6.5%
• Hepatic impairment (Child-pugh class C)
• AST or ALT > 2.5 X ULN
• Total bilirubin >1.5 X ULN (however, >3.0 mg/dL is acceptable in cases of Gilbert syndrome)
• Severe renal impairment (eGFR <30 mL/min/1.73 m² calculated using the MDRD formula\*),

\* eGFR = 175 X (Serum creatinine)-1.154 X (Age)-0.203 X (0.742 (for females)) X (1.212 (for African Americans))

• TSH >6.0 mIU/L or <0.4 mIU/L,
• Subjects with a lifetime history of suicide attempts
• Subjects with a PHQ-9 score of 10 or higher at screening
• Subjects who answer affirmatively to item 4 or 5 on the C-SSRS at screening
• Pregnant or breastfeeding women
• Females of childbearing potential and males who do not agree to use adequate contraception# until at least 2 weeks after the last dose of the IP or who plan to conceive during the study period,

• Adequate contraception is defined as double contraception using both barrier methods (male condom or female condom) and one of the contraceptive methods ①-③.

• Hormonal contraceptive (oral, injectable, implantable, etc.), ② Implantation of Intrauterine device (IUD) or intrauterine system (IUS), ③ Sterilization procedures or surgeries (bilateral tubal ligation, hysterectomy, vasectomy), ④ Complete abstinence: absolute abstinence is accepted if, in the investigator's judgment, the subject's age, occupation, lifestyle, or sexual orientation ensure compliance with contraception. However, periodic abstinence (calendar method, ovulation method, symptothermal method, etc.) withdrawal, and coitus interruptus are not considered adequate contraceptive methods.,
• Subjects who have participated in another clinical trial and received an investigational drug or device within 4 weeks prior to screening
• Other reasons (such as a medical history of alcohol or substance abuse) that the investigator deems the subject unsuitable for participation in this clinical trial

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

South Korea · 3 центра

• The Catholic University of Korea, St. Vincent's Hospital — Suwon
• Kangbuk Samsung Medical Center — Seoul
• Yonsei University Health System, Severance Hospital — Seoul

Идентификаторы

NCT: NCT07009171 · NB_KDS_OBP2_23 · KCT0010560

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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