E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Ulcerative colitis (UC) is a disease where inflammation develops in the large intestine (the colon and rectum). |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10045365 |
E.1.2 | Term | Ulcerative colitis |
E.1.2 | System Organ Class | 100000004856 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to evaluate the efficacy as defined by the percentage of subjects attaining clinical remission following 8 weeks of induction treatment of HMPL-004 given at a dosing level of either 1800 mg/day or 2400 mg/day as compared with placebo in subjects with mild to moderate ulcerative colitis that currently have a sub-optimal response to their current regimen of mesalamine. |
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E.2.2 | Secondary objectives of the trial |
Secondary endpoints of this study include clinical response and mucosal healing. In this study, each of the colon segments (cecum/ascending, transverse, descending, sigmoid, and rectum) will be reviewed endoscopically and centrally evaluated at the beginning of the study (screening phase) and at end of study to observe the extent of colonic involvement before and after treatment. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) 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.
2) 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 a full colonoscopy within 2 weeks prior to randomization. Activity can be in any of the 5 colon segments.
3) Age ≥ 18 years.
4) Subjects have no prior exposure to HMPL-004.
5) Have adequate renal, hepatic and bone marrow function (see exclusion criteria).
6) All fertile male and female subjects must agree to use one of the following types of contraception: 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.
7) 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 |
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E.4 | Principal 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.
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 IBD related herbal supplements including 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-TNF-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) WBC below 3,000/ cm3, or platelets below 100,000/ cm3.
17) SGOT, 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 any history of Hepatitis C.
21) Previous colonic surgery except for simple polypectomy.
22) History of cancer within the last 5 years other than resected cutaneous basal and squamous cell carcinomas, and in situ cervical cancer.
23) Subjects 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) Subjects known to be seropositive for HIV, or who have had an AIDS defining illness, or a known immunodeficiency disorder.
26) History of alcohol or drug abuse that would interfere with the ability to be compliant with the study procedure.
27) Known allergy to plants of the Acanthaceae family.
28) Unwillingness to participate in the study.
29) 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Clinical remission will be measured by the modified Mayo Score (also known as the Clinical Mayo Score or the disease activity index [DAI]), which serves as the current leading measurement of disease and is used in many of the ulcerative colitis trials. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1) The proportion of subjects with clinical response at Week 8 in each HMPL-004 group compared with the placebo group.
2)The proportion of subjects with mucosal healing at Week 8 in each HMPL-004 group compared with the placebo group.
3) To determine the time to response as measured by the first assessment at which there was a significant difference between the proportion of subjects in either treatment group and placebo who showed a decrease in the partial Mayo Score of ≥ 2 as compared to baseline at Weeks 2, 4, 6 and 8.
4) Decrease in the mean and median modified Mayo Score at baseline and Week 8 in each treatment group. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Week 8
2) Week 8
3) Weeks 2, 4, 6, 8
4) Week 8
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 38 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Bulgaria |
Czech Republic |
Hungary |
Korea, Republic of |
Latvia |
Lithuania |
Poland |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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last visit of the Last Subject (LVLS) |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 13 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |