Ensayos clínicos

Inclusion Criteria:

• Individuals aged 18 to 70 years, inclusive, at Screening.
• Clinical diagnosis of IBS-C or IBS-D according to Rome IV criteria at Screening.
• Body mass index (BMI) 18.0 to 40.0 kg/m2, inclusive at Screening.
• Understands the study procedures, is willing and able to comply with the study procedures, and is able to give informed consent.
• Negative test results for alcohol and selected drugs at Screening and Day 1.
• Negative hepatitis panel (including hepatitis B surface antigen [HBsAg] and hepatitis C virus antibody [anti-HCV]) and negative for human immunodeficiency virus (HIV) antibody screens at Screening.
• Subjects with recent (within 6 months of Screening) or ongoing alarm features (unexplained weight loss, nocturnal symptoms, blood mixed with stool) are to have had a diagnostic colonoscopy prior to Screening and after the onset of alarm features (for subjects with alarm features) to exclude non-IBS conditions per the Rome IV diagnostic algorithm for IBS.
• If treated with any of the following medications, dosing must be stable for 90 days prior to Screening and the subject must agree to maintain the same dose of  medication throughout the study:
  • Tricyclic antidepressants, tetracyclic antidepressants (e.g., mirtazapine), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), or anticonvulsants (e.g., pregabalin or gabapentin) for conditions other than IBS pain;
  • Benzodiazepines or non-benzodiazepine hypnotics, administered at bedtime for conditions other than IBS pain.

Exclusion Criteria:

• Pregnant or lactating.
• Structural or metabolic diseases/conditions that affect the gastrointestinal system.
• Diagnosis of IBS-M or unsubtyped IBS (IBS-U).
• Unable to withdraw the following medications that alter GI transit for 72 hours prior to baseline colonic transit assay through the duration of treatment period, with the exception of rescue medicine usage (bisacodyl and loperamide):
  • Stimulant laxatives, osmotic laxatives, magnesium or aluminum-containing antacids, over the counter fiber, stool softeners, probiotics, bismuth subsalicylate, prokinetics;
  • Antibiotics, anticholinergics, antidiarrheals, antiflatulence agents, antispasmodics, chloride channel activators, bile acid sequestrants, cholinomimetics, 5-HT3 antagonists, 5-HT4 agonists, guanylate cyclase C agonists, opioid agonists or antagonists, sodium-proton exchanger NHE3 inhibitors.
    • Note: Low stable doses of thyroid replacement, estrogen replacement, low dose aspirin for cardioprotection, and birth control pills or depot injections are permissible.
• Clinically relevant changes in dietary, lifestyle, or exercise regimen within 30 days prior to Screening and for the duration of the study that may confound efficacy assessments in the clinical judgment of the Investigator (or designee).
• Any colonic or major abdominal surgery (e.g., bariatric surgery [including gastric banding], cholecystectomy, stomach surgery, small-/large-bowel surgery, or abdominal large vessel surgery), except that in IBS-C subjects a history of cholecystectomy more than 6 months prior to Screening is allowed. Procedures such as appendectomy, hysterectomy, caesarean section, or polypectomy are allowed as long as they have occurred at least 3 months prior to Screening.
• History of colorectal cancer, inflammatory bowel disease, diverticulitis, ischemic colitis, microscopic colitis, bile acid diarrhea, or celiac disease.
• History of organic abnormalities of the GI tract, intestinal obstruction, stricture, toxic megacolon, GI perforation, or impaired intestinal circulation (e.g., aortoiliac disease).
• Other GI diseases such as peptic ulceration, GI bleeding, or GI inflammatory disease (e.g., esophagitis, gastritis, or duodenitis) within 6 months prior to Screening. The following conditions will not exclude a subject: acute gastritis that resolved without complication,
• and gastroesophageal reflux disease (GERD).
• Use of any of the following medications within 30 days prior to Screening and for the duration of the study:
  • Opioids;
  • The following are excluded if they are prescribed for IBS pain: tricyclic antidepressants, tetracyclic antidepressants (eg, mirtazapine), SSRIs, SNRIs, anticonvulsants (e.g., pregabalin or gabapentin);
  • Medical or recreational marijuana, tetrahydrocannabinol (THC), cannabidiol (CBD), synthetic cannabinoids, or other cannabis derivatives for any indication;
  • Benzodiazepines, or non-benzodiazepine hypnotics, unless administered at bedtime for conditions other than IBS pain.
• Use of cigarettes or any other nicotine-containing products within 30 days of Screening.
• Prior (within 15 days of Screening) or anticipated concomitant use of GI antibiotics.
• Ongoing treatment with GLP-1 or amylin analogues or agonists.
• Any elective major surgery planned or anticipated at any time during the study.
• History of pancreatitis of any etiology, cholecystitis, or symptomatic gallbladder stone disease within 6 months prior to Screening.
• Have received tube feeding, defined formula diets, or parenteral alimentation within 30 days prior to Screening.
• History of cerebrovascular disease (e.g., stroke, transient ischemic attacks), acute coronary syndrome, myocardial infarction, or unstable angina within 6 months prior to Screening.
• History or presence of:
  • Risk factors for Torsade de Pointes (eg, heart failure, cardiomyopathy, or family history of Long QT Syndrome);
  • Sick sinus syndrome, second or third-degree atrioventricular block, myocardial infarction, pulmonary congestion, symptomatic or significant cardiac arrhythmia, prolonged QT interval corrected by Fridericia's formula (QTcF) interval, or clinically significant conduction abnormalities.
• Clinically significant cardiac history or presence of ECG findings as judged by the Investigator or qualified designee at Screening or Day 1, including each criterion as listed below:
  • Abnormal sinus rhythm (heart rate < 40 or > 100 beats per minute [bpm]);
  • QTcF interval > 470 ms (If there is an abnormal result, ECGs are to be repeated 3 times to obtain a mean QTcF before excluding patient);
  • QRS interval ≥ 110 ms;
  • PR interval ≥ 220 ms.
• Uncontrolled hypertension with an abnormal supine blood pressure defined as a systolic blood pressure (SBP) ≥ 160 mm Hg or a diastolic blood pressure (DBP) ≥ 100 mm Hg, confirmed by at least 1 repeated measurement at Screening.
• Tachycardia defined as a resting heart rate ≥ 120 bpm or bradycardia defined as a resting heart rate of ≤ 40 bpm, confirmed by at least 1 repeated measurement at Screening.
• Hypotension with an abnormal supine blood pressure defined as SBP < 90 mm Hg or DBP < 60 mm Hg, confirmed by at least 1 repeated measurement at Screening.
• Orthostatic hypotension consisting of SBP decrease of ≥ 20 mm Hg or a DBP decrease of ≥ 10 mm Hg approximately 3 minutes after standing from a 5-minute supine position, confirmed by at least 1 repeated measurement at Screening.
• Hepatic dysfunction (history of cirrhosis or abnormal serum alanine aminotransferase [ALT] or aspartate transaminase [AST] > 3 × upper limit of normal [ULN]); total direct bilirubin > 2 × ULN, or alkaline phosphatase > 2 × ULN at Screening.
• Clinically significant renal insufficiency (i.e., serum creatinine > 2.5 mg/dL or estimated glomerular filtration rate [eGFR] ≤ 60 mL/min/1.73 m2) based on CKD-EPI equation at Screening.
• History of insulin-dependent diabetes mellitus.
• Significant history or clinical manifestation of any endocrine, allergic, dermatological, hepatic, renal, hematological, pulmonary, GI, neurological or psychiatric disorder, malignancy (with the exception of treated basal cell carcinomas), or any other condition as determined by the Investigator (or designee), that would prevent the individual from participating in the study due to risk to the scientific validity of study assessments or to personal well-being of the subject.
• History of severe head injury or history of seizures.
• Current suicidal ideation or history of suicide attempt or a hospitalization for a major psychiatric condition within 1 year prior to Screening.
• History of alcohol use disorder or substance use disorder within 2 years of Screening.
• Subjects who do not agree to use a highly effective method of contraception if the possibility of conception exists. Eligible male and female subjects must also agree not to participate in a conception process (ie, actively attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization) during the study and for 30 days after the last dose of study treatment for female subjects and for 90 days after the last dose of study treatment for male subjects. Highly effective methods of contraception include the following:
  • Oral, implantable, transdermal or injectable contraceptives (starting ≥ 60 days before administration of study treatment) in combination with diaphragm with vaginal spermicide, cervical cap with vaginal spermicide, or male condom;
  • Standard intrauterine device (IUD; e.g., Copper T 380A IUD), intrauterine system (IUS; e.g., LNg 20 IUS - progesterone IUD), progesterone implant, or tubal sterilization (≥ 6 months after surgery) in combination with a female condom with spermicide, a diaphragm with vaginal spermicide, cervical cap with vaginal spermicide, or male condom;
  • Post vasectomy and male condom, partner using diaphragm with spermicide, cervical cap with spermicide, estrogen and progesterone oral contraceptives (“the pill”), estrogen and progesterone transdermal patch, vaginal ring, or progesterone
  • injection;
  • Complete sexual abstinence defined as refraining from heterosexual intercourse for the entire period of risk associated with study treatment. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. If a subject who is abstinent at the time of signing the informed consent form (ICF) becomes sexually active they must agree to use contraception as described previously;
  • Females who are surgically sterile (defined as women with documentation of prior hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or postmenopausal (defined as: 12 consecutive months with no menses without an alternative medical cause) are not considered to be of childbearing potential; otherwise women are considered to be of childbearing potential;
  • Male study participant must agree to utilize medically acceptable methods of contraception as described above with female partners of childbearing potential.
• Use of any prescription medications/products or available over the counter (e.g., St John’s wort) which are known to chronically alter drug absorption or elimination processes and/or are known to induce or inhibit cytochrome P450 (CYP) 3A4/5 within 30 days or 5 half-lives (whichever is longer) prior to Screening.
• History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the Investigator or history of severe allergies (e.g., any history of anaphylaxis to medication[s] or allergens and/or asthma requiring hospitalization).
• Identified active infection and/or fever (defined as axillary or forehead temperature ≥ 37.4°C, oral temperature ≥ 37.7°C, or rectal or ear temperature ≥ 38.3°C) at Screening or Day 1.
• Blood donation or significant blood loss within 8 weeks prior to Screening.
• Plasma donation within 7 days prior to Screening.
• Participated in another clinical study (e.g., investigational drug or device study) within 30 days or 5 half-lives (whichever time period is longer) or 6 weeks for biologic therapies prior to Screening.
• Consumption of foods and beverages containing grapefruit or Seville oranges within 14 days prior to Day 1.