Efficacy and Safety of SYN-010 in IBS-C

NCT03763175 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: 54792
• Study Type: interventional
• Target: 59
• Locations: 1 country
• Sites: 1

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.

Conditions

Irritable Bowel Syndrome With Constipation

Keywords

Irritable Bowel Syndrome with Constipation; Lovastatin; SYN-010

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in the Weekly Average Number of Completely Spontaneous Bowel Movements (CSBM) Compared to the 12-week Treatment Period

  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.

  After completing 12-week course of SYN-010

Secondary Outcomes (5)

• Proportion of Overall Responders During the 12-week Treatment Period

  After completing 12-week course of SYN-010

• Proportion of Overall Stool Frequency Responders During the 12-week Treatment Period

  After completing 12-week course of SYN-010

• Proportion of Overall Abdominal Pain Intensity Responders During the 12-week Treatment Period

  After completing 12-week course of SYN-010

• Proportion of Overall Bloating Responders During the 12-week Treatment Period

  After completing 12-week course of SYN-010

• Proportion of Patients Using Rescue Medication

  After completing 12-week course of SYN-010

Other Outcomes (3)

• Proportion of Patients With Adequate Relief

  After completing 12-week course of SYN-010

• Mean Change From Baseline in the Area-under-the-curve (AUC) of Breath Methane Production, Based on the 120-minute Lactulose Breath Test.

  After completing 12-week course of SYN-010

• Change From Baseline in Breath Methane Production Based on a Single-point Breath Methane Test

  After completing course of SYN-010

Study Arms (3)

SYN-010 21 mg

ACTIVE COMPARATOR

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

SYN-010 42 mg

ACTIVE COMPARATOR

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

Placebo

PLACEBO COMPARATOR

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

Interventions

SYN-010 21 mg DRUG

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.

Also known as: lovastatin

SYN-010 21 mg

SYN-010 42 mg DRUG

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.

Also known as: lovastatin

SYN-010 42 mg

Placebo DRUG

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.

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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 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.

Sponsors & Collaborators

• Cedars-Sinai Medical Center: lead
• Theriva Biologics, Inc.: collaborator

Study Sites (1)

Cedars-Sinai Medical Center

Los Angeles, California, 90048, United States

Location

Related Publications (28)

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• Pimentel M, Gunsalus RP, Rao SSC, Zhang H. Methanogens in human health and disease. Am J Gastroenterol. 2012 Jul;1(1) Suppl:28-33.

  BACKGROUND

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• Mevacor® (lovastatin) tablets. Prescribing information, 2014. Merck & Co., Inc., Whitehouse Station, NJ 08889, USA.

  BACKGROUND

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  BACKGROUND

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  BACKGROUND

• 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.

  BACKGROUND

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• Villanueva-Millan MJ, Leite G, Wang J, Morales W, Parodi G, Pimentel ML, Barlow GM, Mathur R, Rezaie A, Sanchez M, Ayyad S, Cohrs D, Chang C, Rashid M, Hosseini A, Fiorentino A, Weitsman S, Chuang B, Chang B, Pichetshote N, Pimentel M. Methanogens and Hydrogen Sulfide Producing Bacteria Guide Distinct Gut Microbe Profiles and Irritable Bowel Syndrome Subtypes. Am J Gastroenterol. 2022 Dec 1;117(12):2055-2066. doi: 10.14309/ajg.0000000000001997. Epub 2022 Sep 6.

  PMID: 36114762 DERIVED

MeSH Terms

Interventions

Lovastatin

Intervention Hierarchy (Ancestors)

Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds

Results Point of Contact

• Title: Director of Clinical Trials
• Organization: MAST Program

GroupMedicineMAST@cshs.org

(310) 423-0617

Study Officials

• Ali Rezaie, MD MSc

  Cedars-Sinai Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of GI Motility

Study Record Dates

• First Submitted: November 30, 2018
• First Posted: December 4, 2018
• Study Start: December 24, 2018
• Primary Completion: October 9, 2020
• Study Completion: October 9, 2020
• Last Updated: July 13, 2022
• Results First Posted: September 5, 2021

Record last verified: 2022-07

Locations

US (1)