Trial on Single/Multiple Ascending Doses for Safety, PK and PD for CBP-0276 in Healthy Subjects

Phase I, double-blind, randomized, placebo-controlled clinical study designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple ascending doses of CBP-0276 in healthy male and female subjects. The study is divided into two parts: Part 1, a Single Ascending Dose (SAD) study, and Part 2, a Multiple Ascending Dose (MAD) study.

The trial intends to evaluate the safety and tolerability of single and multiple doses of CBP-0276, with primary outcomes including the incidence and severity of adverse events, as well as alterations in lab results, vital signs, and ECG readings. The secondary objectives are to evaluate the pharmacokinetics of CLT-0276, its linearity, and the effect of food on the drug's pharmacokinetics. Exploratory objectives include assessing scores from some neurological tests and different clinical biomarkers.

64 healthy subjects (32 in Part 1 and 32 in Part 2), aged 18 to 64 years, with at least 50% being 45 years or older will be included. Key inclusion criteria include being clinically healthy with a BMI between 18.5 and 30.0 kg/m2. Exclusion criteria are strict and include a history of significant diseases, clinically abnormal lab or ECG results, recent use of medications or illegal drugs, and a history of substance abuse.

The study will take place in two research centers in Mexico. The investigational product, CBP-0276, will be administered orally in capsule form. Doses will range from 100 mg to 400 mg, single dose. Part 1 includes four cohorts (S1-S4) where subjects will receive either a single dose of CBP-0276 or a placebo, with one cohort (S2) dedicated to assessing the food effect. Part 2 consists of four cohorts (M1-M4) with multiple doses to evaluate steady-state pharmacokinetics.

Informed Consent will be obtained prior to any study procedures, and information will be kept confidential. Adverse events will be monitored, classified by severity (mild, moderate, or severe), and assessed for causality. Any protocol deviations must be documented and reported to the Sponsor and the Institutional Ethics Committee (IEC). The protocol also specifies procedures for handling pregnancies, with the Principal Investigator required to report any occurrences to the Sponsor and the appropriate regulatory bodies.

Safety Monitoring Committee (SMC), an independent, multidisciplinary group, will oversee the safety of the subjects and advise on whether the study should continue, be modified, or be terminated.

For the safety objective, the incidences of adverse events, alterations in laboratory tests, and alterations in the subjects' 12-lead ECG will be estimated by treatment cohort and total. Adverse events, laboratory abnormalities, and 12-lead ECG abnormalities will be defined according to MedDRA and summarized through frequency tables for each treatment cohort and total by system and preferred system term. The frequency tables will be presented in full and by level of severity. Tolerability will be measured through two times before the occurrence of the first adverse event, laboratory abnormality, or 12-lead ECG abnormality and Event duration time and analyzed through survival analyses; and will be compared between the cohorts through the Kaplan Meier model.

Inclusion criteria

• Clinically healthy subject (male and female) aged ≥ 18 to ≤ 64 years. At least 50% of the population ≥ 45 years old.
• Be able and willing to read, understand, sign, and date the Informed Consent Form prior to entering the study.
• Be in good health at the discretion of the Principal Investigator, as determined by the results of a complete medical history by the physicians at the research site and laboratory tests performed by a certified Clinical Laboratory; Subjects with pre-existing medical conditions must be monitored and on stable doses of medication for a minimum period of 3 months at the screening visit.
• Woman of childbearing potential with negative serum pregnancy test at screening visit.
• Female with any of the following criteria:

• Postmenopausal, defined by cessation of menstruation for at least 12 consecutive months and confirmed by serum FSH levels > 40 mIU/mL and estradiol < 20 pg/mL at the screening visit or surgically sterile (with hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) and not undergoing in vitro fertilization or other fertility treatments.
• Use 2 methods of contraception (one primary or highly effective and one secondary) within 90 days prior to the screening visit and up to at least 90 days after the end-of-study visit.
• Men must either agree to use contraception as described in the "Contraception and Pregnancy Testing" section, or remain abstinent (when it is the subject's usual and preferred lifestyle). They must also agree not to donate sperm for the duration of the study and until at least 90 days after the end-of-study visit.
• Body mass index from ≥ 18.5 to < 30.0 kg/m2 according to the Quetelet index at the screening visit.
• Non-smoker or former smoker, who has not used nicotine-containing products in any form, including nicotine patches or e-cigarettes, for 90 days prior to the Day 1 dose (first period, when applicable) and who has a negative urine cotinine test at the screening visit.
• Be willing to comply with all scheduled visits, treatment plan, lab tests, lifestyle considerations, restrictions, and other study procedures.

Exclusion criteria

Medical history

• Pregnant or breastfeeding women.
• History of cardiac, endocrine, gastrointestinal, hematological, hepatic, immunological, metabolic, urological, pulmonary, neurological, dermatological, psychiatric or renal disease clinically significant or comorbidity of importance at the discretion of the Principal Investigator (or his/her delegate).
• History of allergic reactions, anaphylactic reactions, severe systemic hypersensitivity, or any allergic reaction that, in the opinion of the Principal Investigator or his/her delegate, is likely to be exacerbated by the investigational product.
• History of malignant or ongoing disease, including solid tumors and hematologic malignancies (with the exception of basal cell carcinomas and squamous cell carcinomas that have been completely removed and are considered cured at least 1 year before day 1 [first period, when applicable]).
• Systolic blood pressure in the supine position < 90 mmHg, >140 (18 to 59 years) or >160 (≥ 60 years); diastolic blood pressure > 90 or < 50 mmHg, heart rate >100 or < 40 beats per minute. Orthostatic decrease in systolic blood pressure >20 mmHg, orthostatic decrease in diastolic blood pressure >10 mmHg, or orthostatic increase in heart rate > 30 beats per minute. If any of the parameters are out of range, the measurements should be repeated two more times. Subjects will be excluded if the average of the 3 measurements is outside the corresponding reference range.
• Clinically significant abnormalities (at the discretion of the Principal Investigator or his/her delegate) in the 12-lead electrocardiogram. QT interval corrected using Fridericia's correction method, QTcF > 450 ms for men and > 470 ms for women.
• Elective procedures or surgeries scheduled after signing the Informed Consent Form and until the end-of-study visit.
• History of gastric bypass/bariatric surgery or other gastrointestinal surgery that may affect gastric emptying or absorption of RAP-103 (excluding uncomplicated appendectomy and hernia repair performed at least 90 days prior to the screening visit).
• History of esophagitis and Barrett's esophagus.
• History of cholecystectomy.
• Use of pancreatic enzyme replacement within 30 days prior to the screening visit.

Risk of infection

• History of human immunodeficiency virus or positive result in the HIV detection test (HIV 1-2 antibodies).
• History of hepatitis C infection or positive result in the detection test for antibodies against the hepatitis C virus (HCVAb).
• Current hepatitis B infection (defined as positive for HepBsAg and/or HepBcAb). Subjects with immunity to hepatitis B from prior natural infection (defined as HepBsAg negative, HepBcAb positive, and HepBsAb positive) or vaccination (defined as HepBsAg negative, HepBcAb negative, and HepBsAb positive) are eligible to participate in the study.
• Presence of chronic, recurrent, or severe infection (e.g., pneumonia, sepsis) at the discretion of the Principal Investigator, within 90 days prior to the screening visit and between the screening visit and day -1 (of the first period, when applicable).
• Presence of symptoms of bacterial, fungal or viral infection (including upper respiratory tract infection) within 14 days prior to the screening visit and between screening and day -1 (of the first period, when applicable). Subjects with local fungal infection (e.g., candidiasis, ringworm, tinea pedis) are eligible for reevaluation after successful treatment of the infection.
• Symptoms consistent with SARS-CoV-2 infection, at the discretion of the Principal Investigator or his/her delegate, within 14 days prior to day -1 (of the first period, when applicable), including, but not limited to: temperature >37.5 °C, sore throat, new and persistent cough, shortness of breath, diarrhea, muscle pain, or loss of taste or smell.
• Positive COVID-19 (SARS-CoV-2) test at the screening visit.
• Any immunization or vaccine administered within 30 days prior to day 1 (of the first period, when applicable).

Lab Results

• Abnormal and clinically significant results at the discretion of the Principal Investigator or his/her delegate and Sponsor, in the laboratory tests of the screening visit. Values out of range and determined to be not clinically significant at the discretion of the Principal Investigator or his/her delegate may be repeated on one occasion, the subject may be enrolled if the repeated value is within the normal range.

Pre-medicated and concomitant medications

• Participation in any other investigational study with drugs, biologics, medical devices, or treatment with an investigational product or therapy approved for investigational use within the previous 3 months or 7 half-lives, whichever is greater, at day -1.
• Prior exposure to study treatment or prior participation in studies with CBP-0276
• Use of any prescription or over-the-counter medication (except acetaminophen ≤ 2 g daily, aspirin ≤ 325 mg daily, ibuprofen ≤ 600 mg, and hormonal contraceptives) within 14 days prior to day -1; and unwillingness or inability to refrain from use during study participation.

Other

• History of alcohol or illegal drug abuse, positive urine drug test result at screening visit, positive urine drug test result, and/or positive breath alcohol test result on Day -1 (first period, when applicable), or use of illegal/recreational drugs during the development of the study.
• Habitual alcohol consumption > 14 drinks per week for men and > 7 drinks for women. One drink is equal to 12 ounces (360 mL) of beer, 1.5 ounces (45 mL) of hard liquor, or 5 ounces (150 mL) of wine.
• History or evidence of habitual use of tobacco or nicotine-containing products within 90 days prior to the Day 1 dose (first period, when applicable) and unwillingness to abstain from their use during study participation.
• Abnormal score on the C-SSRS and/or MMSE at the screening visit.
• Receipt of blood products within 2 months prior to the screening visit.
• Blood donation 3 months prior to the screening visit, plasma 2 weeks prior to the screening visit and platelets 6 weeks prior to the screening visit.
• Strenuous physical exercise (e.g., heavy lifting, weight training, calisthenics, and aerobic exercise) within 7 days prior to Day -1 (of the first period, when applicable). Walking at a normal pace is allowed.
• Unwillingness or inability to comply with the requirements of the protocol.
• Other unspecified reasons that, at the discretion of the Principal Investigator or the Sponsor, determine that the subject is not suitable for inclusion.
• Subjects who had been hospitalized in the 7 months prior to the screening visit.