A Phase III Trial of HMPL-004 in Patients With Mild to Moderate Active Ulcerative Colitis
Condition: Ulcerative Colitis
MeSH terms: Colitis; Colitis, Ulcerative; Ulcer
Intervention: HMPL-004 1800 mg/day; Placebo; HMPL-004 2400 mg/day
Intervention description: Subjects randomized to the arm of HMPL-004 1800 mg/day will receive HMPL-004 600 mg TID (total dose 1800 mg/day) for 56 days (8 weeks).; Subjects randomized to the arm of Placebo will receive matching Placebo three times daily for 56 days (8 weeks).; Subjects randomized to the arm of HMPL-004 2400 mg/day will receive HMPL-004 800 mg TID (total dose 2400 mg/day) for 56 days (8 weeks).
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: Subjects were randomized according to a stratified blocked randomization schedule generated by an unblinded biostatistician. Stratification was by country/region and modified Mayo Score at screening using an interactive web-based response system (IWRS).
Enrollment: 201.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Ulcerative Colitis,; UC; Patients; active; mild; moderate

Summary:

      A placebo controlled study of two doses of HMPL-004 in patients 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.

      The objective is to evaluate the efficacy and safety of HMPL-004 with mesalamine (mesalamine
      treatment failures). Efficacy will be measured by a comparison of the proportion of patients
      in each treatment group attaining clinical remission at Week 8 as compared to placebo.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients 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 active mild to moderate ulcerative colitis defined by a modified Mayo Score 4-10,
             and with endoscopy score activity of 2-3 points confirmed by centrally read
             colonoscopy (within 2 weeks prior to randomization.

          -  Minimum modified Mayo endoscopy score of >2 at the time of study colonoscopy.

          -  Age ≥ 18 years.

          -  Patients have no prior exposure to HMPL-004.

          -  Have adequate renal, hepatic and bone marrow function (see exclusion criteria).

          -  All fertile male and female subjects must agree to use one of the following types of
             contraception: abstinence, intrauterine device, implantable progesterone device, and
             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 patient (or legally acceptable representative) has been informed of all
             pertinent aspects of the trial

        Exclusion Criteria:

          1. Subjects with intolerance or adverse reactions to mesalamine (or equivalent
             medications).

          2. 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. Subjects with Primary
             Sclerosing Cholangitis (PSC) are excluded..

          3. Severe disease with an ulcerative colitis modified Mayo Clinic score above 10 points
             at baseline.

          4. Positive stool test for pathogens for sample taken within the previous 2 weeks prior
             to study entry.

          5. Active Clostridium difficile (C. diff) infection.

          6. Use of Inflammatory Bowel Disease related herbal supplements including but not limited
             to supplements containing andrographis and probiotics two weeks prior to study entry
             or during the study.

          7. Toxic megacolon or toxic colitis.

          8. Probable requirement for intestinal surgery within 12 weeks after the start of study
             medication.

          9. Receiving oral or rectal steroids within 1 month prior to study entry.

         10. Receiving rectal mesalamine within one week prior to study entry.

         11. Receiving azathioprine, 6-mercaptopurine, methotrexate, tacrolimus, cyclosporine, or
             other immunosuppressive therapy at the time of screening or within the preceding 6
             weeks.

         12. Receiving anti-tumor necrosis factor-α agents such as infliximab, adalimumab,
             golimumab, or certolizumab pegol at the time of screening or within the preceding 8
             weeks.

         13. Receiving other investigational drugs or biologics within 1 month or five half lives.

         14. Receiving antibiotics within 2 weeks of study entry.

         15. Hemoglobin concentration < 9 g/dl.

         16. White blood cell count (WBC) below 3,000/cmm, or platelets below 100,000/cmm.

         17. Serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate
             transaminase (SGPT), alkaline phosphatase >2.5 upper limit of normal.

         18. Serum creatinine >1.5 times upper limit of normal.

         19. 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; pulmonary disease
             requiring oxygen therapy.

         20. Chronic Hepatitis B or any history of Hepatitis C.

         21. Previous colonic surgery except for simple polypectomy or appendectomy. .

         22. History of cancer within the last 5 years other than resected cutaneous basal and
             squamous cell carcinomas, and in situ cervical cancer.

         23. Patients with a history of or concurrent colonic dysplasia associated with UC, except
             those with completely excised sporadic colorectal polyps.

         24. Women who are pregnant or breast feeding.

         25. Patients known to be seropositive for HIV, or who have had an AIDS defining illness,
             or a known immunodeficiency disorder.

         26. Patients with a history of tuberculosis or exposure to tuberculosis, or a history of a
             chest X-ray suspicious for tuberculosis, unless confirmed to be purified protein
             derivative (PPD) skin test negative or latent tuberculosis that has been previously
             treated.

         27. History of alcohol or drug abuse that would interfere with the ability to be compliant
             with the study procedure.

         28. Known allergy to plants of the Acanthaceae family.

         29. Unwillingness to participate in the study.

         30. Any underlying medical condition that in the Investigator's opinion will make the
             administration of study drug hazardous to the patient or would obscure the
             interpretation of adverse events.