Efficacy and Safety of SYN-010 in IBS-C
Condition: Irritable Bowel Syndrome With Constipation
MeSH terms: Irritable Bowel Syndrome; Syndrome; Constipation
Intervention: SYN-010 21 mg; SYN-010 42 mg; Placebo
Intervention description: 21 mg lovastatin will be administered to patients diagnosed with IBS-C to evaluate whether the medication and dose is effective in increasing frequency of completely spontaneous bowel movements. The secondary objectives of the study are to assess the role of lovastatin lactone in increasing overall stool frequency and reducing abdominal pain severity, bloating severity, and rescue medication use. Additional endpoints include improvement in reported adequate relief and the effect of the study drug in lowering exhaled methane levels.; 42 mg lovastatin will be administered to patients diagnosed with IBS-C to evaluate whether the medication and dose is effective in increasing frequency of completely spontaneous bowel movements. The secondary objectives of the study are to assess the role of lovastatin lactone in increasing overall stool frequency and reducing abdominal pain severity, bloating severity, and rescue medication use. Additional endpoints include improvement in reported adequate relief and the effect of the study drug in lowering exhaled methane levels.; A placebo will be administered to patients diagnosed with IBS-C to evaluate whether the medication and dose is effective in increasing frequency of completely spontaneous bowel movements. The secondary objectives of the study are to assess the role of lovastatin lactone in increasing overall stool frequency and reducing abdominal pain severity, bloating severity, and rescue medication use. Additional endpoints include improvement in reported adequate relief and the effect of the study drug in lowering exhaled methane levels.
Intervention MeSH terms: Lovastatin; L 647318; Dihydromevinolin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 59.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Irritable Bowel Syndrome with Constipation; Lovastatin; SYN-010

Summary:

      Irritable bowel syndrome (IBS) is a gastrointestinal (GI) syndrome characterized by chronic
      abdominal pain and altered bowel habits in the absence of any organic cause. The symptoms of
      IBS not only adversely affect a patient's health-related quality of life (QoL), but also
      place a significant financial burden on society due to reduced work productivity and
      increased use of healthcare-related resources. Patients with IBS frequently complain of
      abdominal bloating and increased gas production in the form of flatulence or belching. The
      prevalence in North America and Europe is approximately 10-15%. Irritable bowel syndrome
      affects all ages and genders however there is a 2:1 female predominance in North America.
      Irritable bowel syndrome is classified into 4 subtypes based on stool pattern: IBS with
      constipation (IBS-C), IBS with diarrhea, mixed IBS, and un-subtyped IBS. Irritable bowel
      syndrome with constipation is defined as the presence of hard or lumpy stools with ≥ 25
      percent of bowel movements and loose or watery stools with < 25% of bowel movements.

      SYN-010 is a modified release, oral formulation of lovastatin being developed for the
      treatment of IBS-C. The SYN-010 program is based predominantly on research by Dr. Mark
      Pimentel and collaborators hypothesizing that reduction in intestinal methane (methane)
      production can reverse constipation and improve global symptoms in IBS-C. Methane production
      in humans is due to methanogenic archaea in the intestine, predominantly Methanobrevibacter
      smithii (M. smithii). Methane, the key product of anaerobic respiration of methanogens, had
      been perceived to produce no ill effects in humans aside from gaseous distention. However,
      several research groups worldwide have shown that a significant percentage of patients with
      IBS-C excrete methane, and elevated methane production by methanogens correlates with
      constipation and related symptoms in both IBS-C and chronic idiopathic constipation. A direct
      causative role for methane in IBS-C was demonstrated in a recent case report, wherein a woman
      undergoing fecal microbiota transplantation (FMT) for C. difficile infection unknowingly
      received stool containing a high concentration of methanogens. The FMT recipient rapidly
      developed severe symptoms of IBS-C that were subsequently reversed by ablation of methane
      production.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male or female participants aged between 18 and 65 years inclusive.

          -  Patient must be willing and able to participate in the study for the required
             duration, understand and sign the informed consent (ICF), and be willing to comply
             with all protocol-related visits and procedures.

          -  Patient has had IBS-C symptoms (as defined by Rome III diagnostic criteria) for at
             least 6 months prior to diagnosis.

          -  Patient has an average score of ≥ 3.0 for daily abdominal pain at its worst (11-point
             numerical rating scale [NRS]) during and up to the 17 days immediately before
             randomization (i.e. Pre-treatment Period).

          -  Patient has an average of ≤ 3 CSBMs per week or ≤ 5 SBMs per week during the 17 days
             immediately before randomization (i.e. Pre-treatment Period).

          -  Patient has a breath methane level ≥ 10 ppm on a lactulose breath test administered at
             Screening.

          -  Patient may be on a stable, continuous regimen of fiber or probiotics one month before
             the Screening Visit; however, they must maintain a stable dose regimen through Week
             12.

          -  Patient must agree to refrain from starting a new diet, changing stable dose of
             supplemental fiber, or changing exercise pattern that may affect IBS-C symptoms from
             the time of Screening through the end of the study. If the patient takes food products
             that are strong inhibitors of cytochrome P450 3A (CYP3A) (e.g. grapefruit juice,
             Seville orange juice, St. John's Wort), he/she must agree to refrain from taking these
             from the time of Screening through the end of the study.

          -  Patient must agree to use an acceptable method of contraception from the time of
             signing the ICF to 30 days after the final dose of study drug if the patient is a
             sexually active female of child-bearing potential (defined as any female who has
             experienced menarche and who is NOT permanently sterile or postmenopausal.
             Postmenopausal is defined as 12 consecutive months with no menses without an
             alternative medical cause). Adequate contraceptive measures include: oral
             contraceptives (stable use for two or more cycles before Screening); intrauterine
             device; Depo-Provera®; Norplant® System implants; partner with a vasectomy;
             double-barrier birth control (e.g. use of a condom plus diaphragm or condom plus
             either contraceptive sponge, foam, or jelly); or abstinence. According to drug
             research standards, male patient must agree to use an acceptable method of
             contraception and refrain from donating sperm from the time of signing the ICF to 90
             days after the final dose of study drug.

          -  A female patient of child-bearing potential must be non-pregnant and non-lactating and
             have negative pregnancy tests at the Screening Visit and on Day 1 prior to dosing with
             study drug.

          -  Patients must be able to understand and be willing to sign the written informed
             consent form. A signed informed consent form must be appropriately obtained prior to
             the conduct of any trial-specific procedure.

          -  Willing and able to comply with the protocol, including follow-up visits and
             examinations.

        Exclusion Criteria:

          -  Patient has loose (mushy) or watery stools for > 25% of their bowel movements (BMs)
             during the 12 weeks before Screening or during the Screening and Pre-treatment
             Periods.

          -  Patient has a history of cathartic colon, laxative, or enema abuse.

          -  Patient has a history of ischemic colitis.

          -  Patient has a history of pelvic floor dysfunction.

          -  Patient has a history of bariatric surgery for the treatment of obesity.

          -  Patient has a history of surgery to remove a segment of the gastrointestinal (GI)
             tract at any time before the Screening Visit.

          -  Patient has any history of myopathy, rhabdomyolysis, chronic myalgia, or familial
             history of hereditary muscular disorders.

          -  Patient has been diagnosed with or has a family history of familial adenomatous
             polyposis, hereditary nonpolyposis colorectal cancer, or any other form of familial
             colorectal cancer.

          -  Patient currently has any structural abnormality of the GI tract or a disease or
             condition that can affect GI motility, or any unexplained and clinically significant
             symptoms such as lower GI bleeding, rectal bleeding, heme-positive stool,
             iron-deficiency anemia, weight loss, or systemic signs of infection.

          -  Patient has had any previous surgery involving the abdomen, pelvis, or retroperitoneal
             region during the last 12 months prior to Screening, with the exclusion of
             laparoscopic gallbladder surgery or appendix removal.

          -  Patient has a history of diverticulitis or any chronic condition that could be
             associated with abdominal pain or discomfort and could confound the assessments in the
             study (e.g. inflammatory bowel disease, chronic pancreatitis, polycystic kidney
             disease, ovarian cysts, endometriosis, or lactose intolerance).

          -  Patient has history of severe renal insufficiency defined as an actual or estimated
             glomerular filtration rate of < 30 mL/min/1.73 m2 within the 6 months prior to
             Screening Visit.

          -  Patient has any history of a medical condition or a concomitant medical condition
             that, in the opinion of the investigator, would compromise the patient's ability to
             complete the study safely or could confound the assessments in this study (e.g.
             uncontrolled hypothyroidism).

          -  Patient is known to have elevated liver enzyme levels (aspartate aminotransferase
             [AST], alanine aminotransferase [ALT], alkaline phosphatase [ALP]) or creatine kinase
             levels that are ≥ 1.5 times the upper limit of normal (ULN) that have not been
             resolved within the 4 weeks prior to consent and/or these elevated levels are present
             at the Screening Visit laboratory assessment.

          -  Patient has any abnormal laboratory results, electrocardiogram (ECG) findings, or
             physical examination findings deemed clinically significant by the investigator during
             the Screening Period.

          -  Within 14 days prior to the Screening Visit, patient has used concomitant medications
             that are: (1) moderate-to-strong inhibitors of cytochrome P450 3A (CYP3A) and/or organ
             anion transporting polypeptide (OATP)1B1 (e.g. cyclosporine, verapamil, dronedarone,
             diltiazem, amiodarone, itraconazole, ketoconazole, posaconazole, voriconazole,
             clarithromycin, telithromycin, human immunodeficiency virus protease inhibitors,
             boceprevir, telaprevir, nefazodone, erythromycin, cobicistat-containing products); (2)
             other concomitant medications that are excluded from the lovastatin label (e.g.
             rifampin, colchicine, ranolazine); or (3) metformin or GLP-1 agonists. Patients should
             not take any of these concomitant medications during the treatment phase of the study
             without contacting the investigator.

          -  Patient has hypersensitivity to statins; or has used any statins, fibrates, > 1 g/day
             of niacin, or gemfibrozil within the 3 months prior to the Screening Visit.

          -  Patient reports current chronic or frequent use of drugs known to cause constipation
             (e.g. narcotics) for the 3 months prior to Screening.

          -  Patient has taken over-the-counter IBS treatments (e.g. laxatives) or proton pump
             inhibitors within 3 days prior to the Screening Visit.

          -  Certain drugs used for the treatment of IBS (e.g. low dose tricyclic antidepressants)
             may be allowed at the discretion of the Medical Monitor provided the patient remains
             on a stable dose for one month prior to the Screening Visit and throughout the study
             with the exception of tegaserod, lubiprostone, linaclotide, metoclopramide,
             prucalopride, domperidone, or antibiotics within 2 months prior to the Screening
             Visit. Certain drugs used for the treatment of IBS (e.g. low dose tricyclic
             antidepressants) may be allowed at the discretion of the Medical Monitor provided the
             patient remains on a stable dose for one month prior to the Screening Visit and
             throughout the study with the exception of tegaserod, lubiprostone, linaclotide,
             metoclopramide, prucalopride, domperidone, CandiBactin, Atrantil, Allimax/Allimed
             within 2 weeks prior to the Screening Visit or antibiotics within 2 months prior to
             the Screening Visit.

          -  Patient has used an opioid chronically or frequently within the 3 months prior to the
             Screening Visit and for the duration of the study.

          -  Patient is currently enrolled in, or plans to enroll in, another clinical study or has
             used any investigational drug or device within 1 month before signing the ICF through
             the completion of the study.

          -  Patient has previously participated in a SYN-010 study.

          -  Patient has a history of alcohol or drug abuse within the 12 months prior to the
             Screening Visit.