Evaluation of SPH3127 in Patients With Mild-to-Moderate Ulcerative Colitis

Study Overview
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Brief Summary
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SPH3127-US-01 is a multi-center, randomized, double-blind, placebo-controlled study to evaluate the safety, pharmacokinetics, and preliminary efficacy of SPH3127 for the treatment of mild-to-moderate ulcerative colitis.

Detailed Description
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SPH3127-US-01 is a proof-of-concept multi-center, randomized, double-blind, placebo-controlled study to evaluate the safety, pharmacokinetics, and preliminary efficacy of of daily oral administration of SPH3127 or placebo for 8 weeks in patients with mild-to-moderate ulcerative colitis. After meeting all inclusion and exclusion criteria, eligible patients will be randomized to receive SPH3127 (50 mg daily, 50 mg twice daily) or placebo tablets; all patients will take 2 tablets (SPH3127 or placebo) twice a day for 8 weeks. All randomized subjects will have the opportunity to enter an active-treatment extension (50 mg SPH3127 once or twice daily) for an additional 10 months.

Official Title
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A Double-Blind, Placebo-Controlled Trial to Investigate the Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of SPH3127 in Patients With Mild-to-Moderate Ulcerative Colitis

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Drug: SPH3127
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed Informed Consent Form (ICF); Adult males and females ≥ 18 to < 70 years of age on the day of signing the ICF. A diagnosis of UC (documented or confirmed at screening) will be eligible provided they have mild-to-moderate active UC extending ≥ 15 cm from the anal verge. At screening/baseline, a Modified Mayo Clinic Score (MMCS) from 4-9, a rectal bleeding subscore ≥ 1, and a Mayo Clinic Endoscopic Subscale (MCES) score ≥ 2 determined by central reading. Patient has a negative urine drug screen (e.g., amphetamines, barbiturates, benzodiazepines, cannabis, cocaine, opiates, methadone) at Screening. Patient has a negative alcohol breath test at Screening. Female patients who have a negative pregnancy test at Screening and who agree to use adequate birth control methods throughout the entire study (and extension, if applicable) or who is post-menopausal (i.e., amenorrhea ≥ 1 year) or who have been surgically sterilized. Male patients with partners of child-bearing potential who agree to use adequate birth control methods throughout the entire study (and extension, if applicable) or who have been surgically sterilized. Exclusion Criteria: Diagnosis of severe UC, defined as the presence of ≥ 6 bloody stools daily with one or more of the following: (1) oral temperature > 37.8°C or > 100.0°F; (2) pulse > 90 beats/min; (3) hemoglobin concentration < 10.5 g/dL; or erythrocyte sedimentation ratio (ESR) > 30. Patients treated with oral mesalamine >2.4 g/d, systemic steroids or rectal steroids within 4 weeks prior to randomization, rectal mesalamine (within 2 weeks), immunomodulators or immunosuppressant drugs, including, but not limited to, IL-6 inhibitors, TNF inhibitors, anti-IL-1 agents and JAK inhibitors within 5 half-lives prior to randomization, antibiotics, anti-diarrheals (within 2 weeks), drugs blocking the renin-angiotensin system (e.g., direct renin inhibitors, angiotensin converting enzyme inhibitors, or angiotensin II receptor blockers) (within 4 weeks) or administration of any investigational drug (within 4 weeks). Because SPH3127 is a direct renin inhibitor with the potential to reduce blood pressure, other classes of antihypertensives (e.g., calcium channel blockers, beta blockers, diuretics, direct vasodilators, alpha blockers, central α2 antagonists) (within 4 weeks) will also be excluded. Drugs, herbal medicines and substances that inhibit or induce CYP3A4 (e.g., ritonavir, itraconazole, grapefruit juice) (within 2 weeks or 5 half-lives, whichever is longer) will be excluded. History of colectomy or partial colectomy, colorectal dysplasia, Crohn's disease, toxic megacolon, or bleeding disorders. A stool sample positive for enteric pathogens, including Clostridium difficile. Patients with an estimated glomerular filtration rate (eGFR) < 60. Patients with hepatic impairment or history of liver cirrhosis. Serum creatinine > 1.5 times the upper limit of normal, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBIL) or alkaline phosphatase (ALP) > 2 times the upper limit of normal. Serious underlying disease other than UC. Previous participation in clinical trials with SPH3127 Known hypersensitivity to tablet ingredients or history of a significant allergic reaction to any drug as determined by the investigator. Known seropositivity or positive test at screening for an active viral/bacterial infection with: Hepatitis B virus (HBV) (except seropositivity due to HBV vaccination) Hepatitis C virus Human immunodeficiency virus COVID-19 (only active infection excluded) Tuberculosis Known clinically relevant immunological disorders. History of severe allergic or anaphylactic reactions. History of malignancy, unless deemed cured by adequate treatment with no evidence of recurrence for a minimum 3 years before screening; completely eradicated non-melanoma skin cancer (such as basal cell carcinoma or squamous cell carcinoma) is not exclusionary. Clinically relevant abnormalities detected on ECG regarding either rhythm or conduction (e.g., QTcF > 450 ms or a known long QT syndrome). A first-degree heart block or sinus arrhythmia will not be considered a significant abnormality. Low blood pressure at screening (i.e., SBP < 90 mmHg or DBP < 60 mmHg). Clinically relevant abnormalities detected on vital signs prior to dosing. Significant blood loss (including blood donation > 500 mL) or transfusion of any blood product within 12 weeks prior to the IP administration or scheduled transfusion within 4 weeks after the end of the trial. Treatment with any drug known to have a well-defined potential for toxicity to a major organ in the last 3 months preceding the initial investigational product (IP) administration. Concurrent participation, or participation within 30 days prior to the IP administration or 5 half-lives of the investigational drug (whichever is longer), in any drug/device or biologic investigational research trial. Women who are breastfeeding. Vaccination (including influenza and COVID-19) within the last 4 weeks prior to randomization. History of drug or alcohol abuse. Is an investigator, sub-investigator, research assistant, pharmacist, trial coordinator, or other staff of a relative who is directly involved in the conduct of the trial. Any condition or circumstances that in the opinion of the investigator may make a subject unlikely or unable to complete the trial or comply with trial procedures and requirements.

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: randomized, double-blind, placebo-controlled
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo<br>2 placebo tablets, 1 in the morning and 1 in the evening, daily for 8 weeks. After 8 weeks, optional randomization to 1 of 2 SPH3127 daily treatment arms for an additional 10 months | Drug: Placebo<br>* Placebo<br>|
| Experimental: SPH3127 50 mg<br>1 50 mg SPH3127 tablet in the morning and 1 placebo tablet in the evening daily for 8 weeks. After 8 weeks, optional continuation of daily treatment for an additional 10 months. | Drug: SPH3127<br>* SPH3127 - selective renin inhibitor<br>|
| Experimental: SPH3127 100 mg<br>1 50 mg SPH3127 tablet in the morning and 1 50 mg SPH3127 tablet in the evening daily for 8 weeks. After 8 weeks, optional continuation of daily treatment for an additional 10 months. | Drug: SPH3127<br>* SPH3127 - selective renin inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Modified Mayo Clinical Score (MMCS) | The MMCS is a scale with three 4-point domains (stool frequency, rectal bleeding, mucosal appearance at endoscopy). Reductions in score represent clinical improvement. | Screening (baseline) to Day 56 (main study) | 
| Change from baseline in Modified Mayo Clinical Score (MMCS) | The MMCS is a scale with three 4-point domains (stool frequency, rectal bleeding, mucosal appearance at endoscopy). Reductions in score represent clinical improvement. | Screening (baseline) to Day 336 (optional additional 10 months active treatment extension) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Robarts Histopathology Index (RHI) | The RHI is a scale with four 4-point grading domains (chronic inflammatory infiltrate, lamina propria neutrophils, neutrophils in the epithelium, and erosions or ulcerations) for colon tissue samples taken during endoscopy. | Screening (baseline) to Day 56 (main study) | 
| Change from baseline in Robarts Histopathology Index (RHI) | The RHI is a scale with four 4-point grading domains (chronic inflammatory infiltrate, lamina propria neutrophils, neutrophils in the epithelium, and erosions or ulcerations) for colon tissue samples taken during endoscopy. | Screening (baseline) to Day 336 (optional additional 10 months active treatment extension) | 
| Change from baseline in UC-100 score | The UC-100 is a composite score (i.e., 1 + 16 × Mayo Clinical stool frequency subscore [0 to 3] + 6 × Mayo Clinical endoscopic subscore [0 to 3] + 1 × RHI score [0 to 33]), that ranges from 1 (no disease activity) to 100 (severe disease activity) | Screening (baseline) to Day 56 (main study) | 
| Change from baseline in UC-100 score | The UC-100 is a composite score (i.e., 1 + 16 × Mayo Clinical stool frequency subscore [0 to 3] + 6 × Mayo Clinical endoscopic subscore [0 to 3] + 1 × RHI score [0 to 33]), that ranges from 1 (no disease activity) to 100 (severe disease activity) | Screening (baseline) to Day 336 (optional additional 10 months active treatment extension) | 
| Change from baseline in fecal calprotectin | Fecal calprotectin is a biochemical measurement of the protein calprotectin in the stool. Elevated fecal calprotectin indicates the migration of neutrophils to the intestinal mucosa, which occurs during intestinal inflammation caused by inflammatory bowel disease. Reductions in stool calprotectin are a marker of positive clinical activity. | Screening (baseline) to Day 56 (main study) | 
| Incidence and severity of adverse events | The incidence of each reported adverse event (regardless of its relationship to study drug) will be tabulated and classified using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA) classification system. The severity of each adverse event will be graded as mild (event is easily tolerated by the subject and does not affect the patient's usual daily activities), moderate (event causes the subject sufficient discomfort and interferes with the patient's usual daily activities) or severe (event is incapacitating and causes considerable interference with the subject's usual daily activities). | Screening (signing of informed consent form) to Day 56 (main study) | 
| Incidence and severity of adverse events | The incidence of each reported adverse event (regardless of its relationship to study drug) will be tabulated and classified using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA) classification system. The severity of each adverse event will be graded as mild (event is easily tolerated by the subject and does not affect the patient's usual daily activities), moderate (event causes the subject sufficient discomfort and interferes with the patient's usual daily activities) or severe (event is incapacitating and causes considerable interference with the subject's usual daily activities). | Screening (signing of informed consent form) to Day 336 (optional additional 10 months active treatment extension) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mild-to-moderate, selective renin inhibitor