HMPL-004 Maintenance Treatment in Subjects With Mild to Moderate Ulcerative Colitis

Study Overview
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Brief Summary
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A study with an 8 week open label phase study followed by a year long placebo controlled maintenance phase in subjects with active mild to moderate ulcerative colitis (UC), with a modified Mayo Score 4-10 and an endoscopy subscore of 2-3, taking mesalamine (or equivalent) as a concomitant medication. Subjects are required to be in clinical remission or clinical response to enter the year long maintenance phase. This study will help evaluate if HMPL-004 is effective in subjects maintaining clinical remission following successful induction therapy achieving clinical remission or clinical response.

Detailed Description
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A two-phase multi-center study with an open label 8-week induction phase and a randomized, double-blind, placebo controlled maintenance phase to evaluate the efficacy and safety of HMPL-004 for a 52-week maintenance therapy in adults with mild to moderate UC and who have demonstrated a sub-optimal response to mesalamine treatment. The study participants will consist of subjects who have completed either the HMPL-004-03 or HMPL-004-05 induction study, complemented by the enrollment of additional subjects in the open label induction phase who meet the entry criteria of this study. . Subjects entering this maintenance study from one of the HMPL-004 induction studies will have their modified Mayo baseline score from that study as their baseline score for this study. All subjects enrolled in the open label induction phase of the study will be re-evaluated for clinical response and remission after the 8-week open label 2400 mg HMPL-004 treatment period. Clinical responders and remitters will be randomized 2:1 (HMPL-004: placebo) to HMPL-004 1800 mg/day or placebo group for the 52-week maintenance phase of the study.

Official Title
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A Phase III Double Blind, Multi-Center Placebo Controlled Maintenance Trial of HMPL-004 in Subjects With Mild to Moderate Ulcerative Colitis With Clinical Remission or Response From Induction Therapy. (NATRUL-4)

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Drug: HMPL-004
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Completion of induction study HMPL-004-03 or HMPL-004-05 and achieving clinical remission or response with no disruption of study treatment in the transition to HMPL-004-04, or, for the open label induction phase of the study: have active mild to moderate Ulcerative Colitis defined by a modified Mayo Score of 4 to 10 and with endoscopy score activity of 2-3 points confirmed by a full colonoscopy within 2 weeks prior to study. Subjects must be currently receiving mesalamine ≥ 2.4 g/day (or the equivalent) for at least 6 weeks prior to randomization and on a stable dosage for at least 2 weeks prior to entering the screening phase of the study to ensure a stable dose is established at least 2 weeks prior to the endoscopic procedures. Have adequate renal, hepatic and bone marrow function (see exclusion criteria). Age ≥ 18 years All fertile male and female subjects must agree to use one of the following types of contraception: intrauterine device, implantable progesterone device, progesterone intramuscular injection, oral contraceptive which has been started at least one month prior to visit one and continues for the duration of the trial, contraceptive patch, or condom with spermicide. Show evidence of a personally signed and dated informed consent document indicating that the subject (or legally acceptable representative) has been informed of all pertinent aspects of the trial. Exclusion Criteria: Subjects with intolerance to mesalamine (or equivalent medications). Diagnosed with Crohn's disease or with lesions such as fistulas or granulomas on biopsy noted either in history or at baseline endoscope, which would be suspicious for Crohn's disease, or with a diagnosis of indeterminate colitis. Severe disease with a Ulcerative Colitis modified Mayo Clinic score above 10 points at baseline. Positive stool test for pathogens on sample taken within the 2 weeks prior to study entry. Active clostridium difficile (C. diff) infection. Use of Inflammatory Bowel Disease related herbal supplements including supplements containing andrographis or the use of probiotics two weeks prior to study entry or during the study. Toxic megacolon or toxic colitis. Probable requirement for intestinal surgery within 12 weeks after the start of investigational product. Receiving oral or rectal steroids within 1 month prior to study entry. Receiving rectal mesalamine within 1 week prior to study entry. Receiving azathioprine, 6-mercaptopurine, methotrexate, tacrolimus, cyclosporine, or other immunosuppressive therapy at the time of screening or within the preceding 6 weeks. Receiving anti-tumor necrosis factor-α (TNF-α)agents such as infliximab, adalimumab, golimumab, or certolizumab pegol at the time of screening or within the preceding 8 weeks. Receiving other investigational drugs or biologics within 1 month or five half-lives, whichever is longer. Receiving antibiotics within 2 weeks of study entry. Hemoglobin concentration <9 g/dl. White blood cell count (WBC) below 3,000/cm3, or platelets below 100,000/cm3. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and/or alkaline phosphatase >2.5 upper limit of normal. Serum creatinine >1.5 times upper limit of normal. Significant concurrent medical diseases including: active peptic ulcer disease; uncompensated congestive heart disease; myocardial infarction within the last 12 months; unstable angina pectoris; uncontrolled hypertension; and pulmonary disease requiring oxygen therapy. Chronic Hepatitis B or any history of Hepatitis C. Previous colonic surgery except for simple polypectomy. History of cancer within the last 5 years other than resected cutaneous basal and squamous cell carcinomas, and/or in situ cervical cancer. Subjects with a history of or concurrent colonic dysplasia associated with UC, except those with completely excised sporadic colorectal polyps. Women who are pregnant or breast feeding. Subjects known to be seropositive for HIV, or who have had an AIDS defining illness, or a known immunodeficiency disorder. History of alcohol or drug abuse that would interfere with the ability to be compliant with the study procedure. Known allergy to plants of the Acanthaceae family. Unwillingness to participate in the study. Any underlying medical condition that in the Investigator's opinion will make the administration of study drug hazardous to the subject or would obscure the interpretation of Adverse Events.

Ages Eligible for Study
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Minimum Age: 18 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HMPL-004 1800 mg/day<br>Subjects qualifying for entry into the Maintenance Phase of the study were randomized to take an oral dose of HMPL-004 (600 mg TID; total dose 1800 mg/day) daily, for 52 weeks. Those subjects who demonstrated clinical remission or response after completing the HMPL-004-03 Induction Study, or after completing the Open Label Phase of this study, were eligible for enrollment in the Maintenance Phase of this study. | Drug: HMPL-004<br>* Remitters and responders from HMPL-004 Induction study and patients complete the 8-week Open Label Induction Phase will be given HMPL-004 orally three times per day with total daily dose of 1800 mg for 52 weeks.<br>* Other names: Chuan xinlian;|
| Placebo Comparator: Placebo<br>Subjects qualifying for entry into the Maintenance Phase of the study were randomized to take an oral dose of Placebo tablets TID, daily, for 52 weeks. Those subjects who demonstrated clinical remission or response after completing the HMPL-004-03 Induction Study, or after completing the Open Label Phase of this study, were eligible for enrollment in the Maintenance Phase of this study. | Drug: Placebo<br>* Remitters and responders from HMPL-004 Induction study and patients complete the 8-week Open Label Induction Phase will be given Placebo orally three times per day with total daily dose of 1800 mg for 52 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Proportion of Subjects Achieving Clinical Remission | Clinical remission is defined as a modified Mayo Score ≤2 along with no individual score >1 AND rectal bleeding score = 0. | 52 weeks |