Efficacy and Safety of Oral OPS-2071 in Participants With Crohn's Disease Showing Symptoms of Active Inflammation

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effects and safety of OPS-2071 (150, 300, or 600 mg twice a day [BID]) versus placebo, as add-on therapy in participants with Crohn's disease who show symptoms of active inflammation despite being on ongoing treatment.

Detailed Description
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OPS-2071 is a novel agent that is currently being developed for the treatment of Crohn's disease and was previously investigated for the treatment of enteric infection, including those caused by Clostridium difficile. OPS-2071 belongs to the fluoroquinolone family of compounds and has shown anti-inflammatory and potent antibacterial activity in in vitro and in vivo assays. OPS-2071 is anticipated to be effective in the treatment of Crohn's disease due to its unique mode of action. In vitro investigations of OPS-2071 showed a dual mechanism of action, including a potent, broad spectrum antibacterial effect and a strong anti-inflammatory effect that translated into significant attenuation of numerous cytokines, including TNF-alpha (TNF-α) screening.

Official Title
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A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled, Proof-of-Concept Trial to Assess the Efficacy and Safety of Orally Administered OPS-2071 for 12 Weeks in Subjects With Crohn's Disease Showing Symptoms of Active Inflammation Despite Ongoing Treatment

Conditions
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Crohn's Disease

Intervention / Treatment
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* Drug: OPS-2071
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female participants between the ages of 18 and 70 years, inclusive Diagnosis of Crohn's disease localized in the ileum and/or colon, with active mucosal inflammation and visible lesion(s), documented by centrally read ileocolonoscopy and a Simple Endoscopic Score for Crohn's Disease (SES-CD) ≥ 6 (≥ 4 for isolated ileal disease). Participants who do not have an optimal response (daily stool frequency > 3 and pain score > 1) to their current ongoing treatment of biologics (eg, first anti-tumor necrosis factor-alpha [TNF-α] monoclonal antibody), immunosuppressants, low-dose steroids, or 5-aminosalicylic acid (5-ASA) formulations. Participants who are on stable Crohn's disease medications for at least 4 weeks. Participants with a CDAI score between 180 and 450 points, inclusive. Participants who are willing and able to follow the trial protocol and have signed informed consent. Exclusion Criteria: Females who are breast-feeding and/or who have a positive pregnancy test result prior to receiving IMP. Sexually active males or WOCBP who do not agree to practice 2 different methods of birth control or remain abstinent during the trial and for 30 days after the last dose of IMP. If employing birth control, 2 of the following precautions must be used: vasectomy, tubal ligation, intrauterine device, birth control pill, birth control implant, or birth control depot injection. A vaginal diaphragm, condom with spermicide, or sponge with spermicide may also be used as measures to prevent pregnancy, but must be used in combination with at least one of the previous methods. Participants taking any nonsteroidal anti-inflammatory drugs that cannot be stopped or replaced. Use of prednisone or prednisolone > 30 mg/day or budesonide > 9 mg/day within 4 weeks prior to screening; or intravenous steroids within 4 weeks prior to screening. Participants taking antithrombotic drugs. Participants with symptomatic bowel stenosis, fistula, or stoma; or with more than 2 bowel resections. Participants with short bowel syndrome. participants with known existing aortic aneurysm, or who are at risk for an aortic aneurysm, such as participants with peripheral atherosclerotic vascular diseases, uncontrolled hypertension, certain genetic conditions such as Marfan syndrome and Ehlers-Danlos syndrome, and elderly participants (over the age of 70). Participants with known or suspected (family history, unexplained syncope) long QT syndrome or QTcF > 470 msec for females or > 450 msec for males at baseline. Participants with inadequate organ function, as follows: Serum creatinine > 1.5x the upper limit of normal (ULN) Aspartate aminotransferase or alanine aminotransferase levels > 1.5x ULN Total bilirubin > 1.5x ULN. Elevated unconjugated bilirubin related to Gilbert's syndrome is allowed. Use of antibiotics (eg. metronidazole, rifaximin, tinidazole, ciprofloxacin, clarithromycin) within 15 days prior to screening or for greater than 2 months within the past year. A short course (maximum of 5 days) of antibiotics will be permitted during the trial, as needed, for indications other than Crohn's disease. Known hypersensitivity to quinolones or other significant adverse reaction to quinolones. Conditions or circumstances that could prevent completion of the trial according to the judgment of the investigator, including an uncontrolled comorbidity, heart condition, or dysfunction of any other organ; peripheral neuropathy; known arrhythmias, atrial fibrillation, or paroxysmal tachycardia; history of myasthenia gravis; history of drug or alcohol abuse, mental illness, or noncompliance with treatments or visits; or known immune-deficiency. HIV infection, viral hepatitis, prior organ transplant, or malignant disease that is not in remission for at least 3 years, with the exception of basal cell carcinoma. Participants who have used any investigational drug within 2 months prior to screening. Blood donation in the last 2 months. Use of inhibitors of UGT1A1 and UGT1A9 (eg, Silybin, diclofenac, mycophenolic acid, efavirenz, regorafenib) and BCRP (eg, Estrone, 17β-estradiol, flavonoids, herb extracts, gefitinib, imatinib, tamoxifen, novobiocin, nelfinavir, ritonavir, dipyridamole, fumitremorgin C, Ko143, cyclosporine, curcumin, eltrombopag, omeprazole, ivermectin). Participants with a history of treatment failure with 2 or more biologics. Participants with risk factors for tendon rupture (ie, psoriasis, ankylosing spondylitis, competitive athletes, renal failure, diabetes mellitus) or who have a history of tendon rupture and/or ongoing tendinopathy. Participants with systolic blood pressure > 150 mmHg or diastolic blood pressure > 90 mmHg. Participants taking quinidine, procainamide, disopyramide, encainide, flecainide, sotalol, amiodarone, ibutilide, dronedarone, or propafenone.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants are assigned to one of two or more groups in parallel for the duration of the study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OPS-2071 150 mg BID<br>Participants were to receive OPS-2071 150 mg, tablets, orally, twice daily (BID) in the morning and evening (8 to 12 hours apart) with 240 milliliters (mL) of water for up to 12 weeks. | Drug: OPS-2071<br>* OPS-2071 300 mg, tablets, orally, BID.<br>|
| Experimental: OPS-2071 300 mg BID<br>Participants received OPS-2071 300 mg, tablets, orally, BID in the morning and evening (8 to 12 hours apart) with 240 mL of water for up to 6 weeks. | Drug: OPS-2071<br>* OPS-2071 300 mg, tablets, orally, BID.<br>|
| Experimental: OPS-2071 600 mg BID<br>Participants were to receive OPS-2071 600 mg, tablets, orally, BID in the morning and evening (8 to 12 hours apart) with 240 mL of water for up to 12 weeks. | Drug: OPS-2071<br>* OPS-2071 300 mg, tablets, orally, BID.<br>|
| Placebo Comparator: Placebo<br>Participants received OPS-2071-matched placebo, tablets, orally, BID in morning and evening (8 to 12 hours apart) with 240 mL of water for up to 4 weeks. | Drug: Placebo<br>* OPS-2071-matched placebo, tablets, orally, BID.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved Clinical Remission Based on Crohn's Disease Activity Index (CDAI) Score | Clinical remission was defined as CDAI score <150 at Week 12. The CDAI evaluated severity of signs and symptoms of Chron's Disease. Some components of the CDAI were reported by the investigator (physical examination for the presence of an abdominal mass and extraintestinal complications, laboratory results for hematocrit levels, and weight) while other components were determined with data collected in a participant diary (number of liquid or soft stools, number of antidiarrheal medications, abdominal pain score, and general well-being). The index values of 150 and below were associated with quiescent disease; values above that indicated active disease, values >=220 indicated moderate to severe disease, and values above 450 were seen with extremely severe disease. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Endoscopic Response Based on Simple Endoscopic Score for Crohn's Disease (SES-CD) | Endoscopic response was defined as a reduction of the SES-CD by at least 50%, at Week 12. The SES-CD is a total score that indicates endoscopic disease activity status based on endoscopy results regarding the size of ulcers, surface ulceration, affected surface size, and presence of luminal narrowing. Each item is scored from 0-3, with total score from 0-60 . Higher score indicates more severe endoscopic activity. | Week 12 | 
| Change From Baseline in the SES-CD Score at Week 12 | The SES-CD is a total score that indicates endoscopic disease activity status based on endoscopy results regarding the size of ulcers, surface ulceration, affected surface size, and presence of luminal narrowing. Each item is scored from 0-3, with a total score from 0-60. A higher score indicates more severe endoscopic activity. A negative change from baseline indicates improvement. | Baseline (Day 1) and Week 12 | 
| Percentage of Participants With Two-item Participant Reported Outcome (PRO-2) Remission | PRO-2 remission was defined as stool frequency =< 3 times per day and abdominal pain =< 1 at Week 12. The PRO-2 is a symptom control measure based on 2 participant-reported components (stool frequency and abdominal pain) of the CDAI (on an 11-point scale where 0=no pain to 10=worst imaginable pain). A weekly score was calculated for the liquid or soft stool frequency and a separate weekly score was calculated for abdominal pain, in each case based on daily symptom reporting. PRO2 is a composite index consisting of weighted scoring of both variables. PRO2 scores ranges from 0 to approximately 45, higher score indicates higher disease activity. | Week 12 | 
| Percentage of Participants With Clinical Response Based on CDAI Score | Clinical response was defined as at least a 25% decrease in the CDAI score at Week 12. The CDAI evaluated the severity of signs and symptoms of Chron's Disease. Some components of the CDAI were reported by the investigator (physical examination for the presence of an abdominal mass and extraintestinal complications, laboratory results for hematocrit levels, and weight) while other components were determined with data collected in a participant diary (number of liquid or soft stools, number of antidiarrheal medications, abdominal pain score, and general well-being). The index values of 150 and below were associated with quiescent disease; values above that indicated active disease, values >=220 indicated moderate to severe disease, and values above 450 were seen with extremely severe disease. | Week 12 | 
| Percentage of Participants With Endoscopic Remission Based on SES-CD | Endoscopic remission was defined as an SES-CD total score of 0 to 2; or a score of 0 to 4, with no individual subscore greater than 1 at Week 12. The SES-CD is a total score that indicates endoscopic disease activity status based on endoscopy results regarding the size of ulcers, surface ulceration, affected surface size, and presence of luminal narrowing. Each item is scored from 0-3, with a total score from 0-60. A higher score indicates more severe endoscopic activity. | Week 12 | 
| Percentage of Participants With a Decrease in the CDAI Score at Week 12 | Percentage of participants who had a decrease of at least => 100 points in CDAI scores were to be reported. The CDAI evaluated the severity of signs and symptoms of Chron's Disease. Some components of the CDAI were reported by the investigator (physical examination for the presence of an abdominal mass and extraintestinal complications, laboratory results for hematocrit levels, and weight) while other components were determined with data collected in a participant diary (number of liquid or soft stools, number of antidiarrheal medications, abdominal pain score, and general well-being). The index values of 150 and below were associated with quiescent disease; values above that indicated active disease, values >=220 indicated moderate to severe disease, and values above 450 were seen with extremely severe disease. | Week 12 | 
| Percentage of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) and Serious Adverse Event (SAE) | An adverse event (AE) is defined as any untoward medical occurrence in a clinical trial participant and that does not necessarily have a causal relationship with the treatment. An SAE is defined as any fatal; life-threatening; persistently or significantly disabling or incapacitating; required in-patient hospitalization or prolonged hospitalization; a congenital anomaly/birth defect; or other medically significant event that, based upon appropriate medical judgment, may have jeopardized the subject and may have required medical or surgical intervention. A TEAE is defined as an AE that occurred after the administration of investigational medicinal product (IMP). | From the signing of the informed consent form up to early termination (up to approximately 9 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Crohn's disease, Inflammatory bowel disease, Fluoroquinolones, Inflammation, Intestine, Digestive tract, Abdominal pain, Diarrhea