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Efficacy and Safety of SYN-010 in IBS-C

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ClinicalTrials.gov Identifier: NCT03763175
Recruitment Status : Recruiting
First Posted : December 4, 2018
Last Update Posted : June 19, 2019
Sponsor:
Collaborator:
Synthetic Biologics Inc.
Information provided by (Responsible Party):
Ali Rezaie, Cedars-Sinai Medical Center

Brief 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.


Condition or disease Intervention/treatment Phase
Irritable Bowel Syndrome With Constipation Drug: SYN-010 21 mg Drug: SYN-010 42 mg Drug: Placebo Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Evaluation of the Efficacy and Safety of Single, Daily Oral Doses of SYN-010 Compared to Placebo in Adult Patients With Irritable Bowel Syndrome With Constipation (EASE-DO)
Actual Study Start Date : December 24, 2018
Estimated Primary Completion Date : January 1, 2020
Estimated Study Completion Date : January 1, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Lovastatin

Arm Intervention/treatment
Active Comparator: SYN-010 21 mg
Enrolled subjects will be screened and randomized into the three study arms in a 1:1:1 ratio. 50 subjects with constipation-predominant irritable bowel syndrome (IBS-C) will be administered a 12-week course of lovastatin (21 mg PO QD). Study activities will be the same across all three arms.
Drug: SYN-010 21 mg
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.
Other Name: lovastatin

Active Comparator: SYN-010 42 mg
Enrolled subjects will be screened and randomized into the three study arms in a 1:1:1 ratio. 50 subjects with constipation-predominant irritable bowel syndrome (IBS-C) will be administered a 12-week course of lovastatin (42 mg PO QD). Study activities will be the same across all three arms.
Drug: SYN-010 42 mg
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.
Other Name: lovastatin

Placebo Comparator: Placebo
Enrolled subjects will be screened and randomized into the three study arms in a 1:1:1 ratio. 50 subjects with constipation-predominant irritable bowel syndrome (IBS-C) will be administered a 12-week course of placebo. Study activities will be the same across all three arms.
Drug: Placebo
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.




Primary Outcome Measures :
  1. Change from baseline in the weekly average number of completely spontaneous bowel movements (CSBM) during the 12-week Treatment Period [ Time Frame: After completing 12-week course of SYN-010 ]
    Subjects will record their daily bowel movements throughout the duration of the study. Change in weekly average number of CSBMs will be evaluated by comparing reported values pre- and post-treatment.


Secondary Outcome Measures :
  1. Proportion of overall responders during the 12-week Treatment Period [ Time Frame: After completing 12-week course of SYN-010 ]
    An overall 12-week responder is defined as a patient with a weekly response in at least 50% of the weeks of treatment (6 of 12 weeks). A weekly response is defined as a decrease in the patient's weekly average score for worst abdominal pain in the past 24 hours of at least 30% compared to baseline and a stool frequency increase of 1 or more CSBMs per week compared with baseline.

  2. Proportion of overall stool frequency responders during the 12-week Treatment Period [ Time Frame: After completing 12-week course of SYN-010 ]
    An overall stool frequency responder is defined as a patient with a weekly stool frequency response in at least 50% of the weeks of treatment (6 of 12 weeks). A weekly stool frequency response is defined as a stool frequency increase of 1 or more CSBMs per week compared with baseline, with abdominal pain unchanged or improved compared with baseline.

  3. Proportion of overall abdominal pain intensity responders during the 12-week Treatment Period [ Time Frame: After completing 12-week course of SYN-010 ]
    An overall abdominal pain intensity responder is defined as a patient with a weekly abdominal pain intensity response in at least 50% of the weeks of treatment (6 of 12 weeks). A weekly response abdominal pain intensity response is defined as a decrease in the patient's weekly average score for worst abdominal pain in the past 24 hours of at least 30% compared to baseline, with stool frequency unchanged or improved compared with baseline.

  4. Proportion of overall bloating responders during the 12-week Treatment Period [ Time Frame: After completing 12-week course of SYN-010 ]
    An overall bloating responder is defined as a patient with a weekly bloating response in at least 50% of the weeks of treatment (6 of 12 weeks). A weekly bloating response is defined as a weekly average bloating score of at least 30% improvement compared to baseline, with stool frequency unchanged or improved compared with baseline.

  5. Proportion of patients using rescue medication [ Time Frame: After completing 12-week course of SYN-010 ]
    Subjects will record their use of rescue medication throughout the study period. Proportion of patients using rescue medication after completing the 12-week course of treatment will be compared to those reporting usage at baseline screening period.


Other Outcome Measures:
  1. Proportion of patients with adequate relief [ Time Frame: After completing 12-week course of SYN-010 ]
    Outcome will be assessed by evaluating proportion of patients reporting adequate relief pre- and post-treatment on validated questionnaire.

  2. Change from baseline in the area-under-the-curve (AUC) of breath methane production, based on the 120-minute lactulose breath test. [ Time Frame: After completing 12-week course of SYN-010 ]
    Change in exhaled methane level as a potential predictor of constipation improvement will be evaluated by comparing lactulose breath tests pre- and post-treatment.

  3. Change from baseline in breath methane production based on a single-point breath methane test [ Time Frame: After completing 12-week course of SYN-010 ]
    Change in exhaled methane level as a potential predictor of constipation improvement will be evaluated by comparing single-point breath tests pre- and post-treatment.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03763175


Contacts
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Contact: MAST Program 310.423.0617 GroupMedicineMASTClinical@cshs.org

Locations
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United States, California
Cedars-Sinai Medical Center Recruiting
Los Angeles, California, United States, 90048
Contact: Christine Chang    310-423-7068    christine.chang@cshs.org   
Sponsors and Collaborators
Cedars-Sinai Medical Center
Synthetic Biologics Inc.
Investigators
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Principal Investigator: Ali Rezaie, MD MSc Cedars-Sinai Medical Center

Publications:
Pimentel M, Gunsalus RP, Rao SSC, Zhang H. Methanogens in human health and disease. Am J Gastroenterol. 2012 Jul;1(1) Suppl:28-33.
Mevacor® (lovastatin) tablets. Prescribing information, 2014. Merck & Co., Inc., Whitehouse Station, NJ 08889, USA.
Marsh E, Morales W, Chua KS, Marsh Z, Weitsman S, Wacher V, Kim JH, Pimentel, M. (2015) [Abstract 1771] Lovastatin lactone inhibits methane production in human stool homogenates. Am J Gastroenterol. 110 (Suppl. 1): S753.
Morales W, Marsh E, Yu A, Marsh Z, Weitsman S, Barlow GM, Rezaie A, Chang C, Wacher V, Pimentel, M. (2015) [Abstract Mo 2051] Lovastatin improves stool form in Methanobrevibacter smithii colonized rats with constipation. Gastroenterology 148 (Suppl. 1): S-779-80
Gottlieb K, Wacher V, Sliman J, Coughlin O, McFall H, Rezaie A, Pimentel M. (2016) [Abstract Su1210] SYN-010, a proprietary modified-release formulation of lovastatin lactone, lowered breath methane and improved stool frequency in patients with IBS-C: results of a multi-center randomized double-blind, placebo-controlled Phase 2a trial. Gastroenterology 150 (Suppl. 1): S496-7.
Wacher V, Gottlieb K, Sliman J, Coughlin O, Kokai-Kun, J, McFall H, Pimentel M (2016) [Abstract 562] SYN-010 modified-release lovastatin does not significantly alter lipid parameters at doses that reduce methane and alleviate symptoms in patients suffering irritable bowel syndrome with constipation (IBS-C). Am J Gastroenterol. 111 (Suppl. 1): S256.

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Responsible Party: Ali Rezaie, Director of GI Motility, Cedars-Sinai Medical Center
ClinicalTrials.gov Identifier: NCT03763175     History of Changes
Other Study ID Numbers: 54792
First Posted: December 4, 2018    Key Record Dates
Last Update Posted: June 19, 2019
Last Verified: June 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ali Rezaie, Cedars-Sinai Medical Center:
Irritable Bowel Syndrome with Constipation
Lovastatin
SYN-010
Additional relevant MeSH terms:
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Irritable Bowel Syndrome
Syndrome
Constipation
Disease
Pathologic Processes
Signs and Symptoms, Digestive
Signs and Symptoms
Colonic Diseases, Functional
Colonic Diseases
Intestinal Diseases
Gastrointestinal Diseases
Digestive System Diseases
Lovastatin
L 647318
Dihydromevinolin
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors