E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated | |
E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
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 |
To demonstrate the efficacy of GS-4875, compared with placebo control, in achieving Clinical Remission per Modified Mayo Clinic Score (MCS) at Week 10 |
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E.2.2 | Secondary objectives of the trial |
-To demonstrate the efficacy of GS-4875, compared with placebo control, in achieving endoscopic response at Week 10
- To demonstrate the efficacy of GS-4875, compared with placebo control, in achieving MCS Response at Week 10
- To demonstrate the efficacy of GS-4875, compared with placebo control, in achieving MCS Remission at Week 10
- To evaluate GS-4875, as compared with placebo control, in achieving histologic remission at Week 10 |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Intensive PK substudy
Subjects may choose to participate in an optional PK substudy.
Approximately 50 subjects who consent to the optional PK substudy will have additional plasma PK samples at any single visit between Weeks 4 and 10 (inclusive), collected pre-dose, and at 1, 2, 4, 6, 8,
12, and 24 hours after supervised dosing in the clinic.
Genomic Testing
Subjects may choose to participate in genomic testing.
Subjects who provide their additional specific consent for optional genomic research agree to allow an additional blood sample to be collected. This sample should be collected at the Day 1 visit, but may be collected at any time during the study. |
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E.3 | Principal inclusion criteria |
1) Must have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of any study procedures.
2) Males, or non-pregnant, non-lactating females, at least 18 years of age based on the date of the screening visit.
3) UC of at least 3 months duration before randomization confirmed by endoscopy and histology at any time in the past AND a minimum disease extent of 15 cm from the anal verge. Documentation of endoscopy and histology consistent with the diagnosis of UC must be available in the source documents prior to the initiation of screening.
4) Moderately to severely active UC as determined during screening by a centrally read endoscopy score ≥ 2, a Rectal Bleeding subscore ≥ 1, a Stool Frequency subscore ≥ 1 and Physicians Global Assessment (PGA) of ≥ 2 as defined by the Mayo Clinic Score; total MCS must be between 6 and 12, inclusive.
5) Previously demonstrated an inadequate response (primary non-response) or loss of response (secondary non-response) to a TNFα inhibitor (ie, infliximab, adalimumab, golimumab, or biosimilars).
6) May be receiving concomitant therapy for UC at the time of enrollment.
7) A surveillance colonoscopy is required prior to screening in subjects with a history of UC for 8 or more years, if one was not performed in the prior 24 months.
8) Meet the Tuberculosis (TB) screening criteria.
9) Laboratory assessments at screening within the defined parameters.
10) Stool sample test result negative for enteric pathogens
11) Stool sample test result negative for ova and parasites (O&P) unless approved by the medical monitor.
12) Negative HIV antibody test.
13) Negative HBV surface antigen test. Subjects with negative HBsAg test and positive HBV core antibody (HBcAb) test must have a HBV DNA < LLOQ.
14) Negative HCV antibody test or HCV RNA < LLOQ.
15) Negative urine drug screen result. A positive drug screen will exclude subjects unless it can be explained by the use of a medication (prescription or nonprescription) that is being used under the direction of a physician. Cocaine use is exclusionary.
16) Females of childbearing potential must have a negative pregnancy test result at screening and Day 1 prior to randomization.
17) Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must be willing to use protocol specified method(s) of contraception. |
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E.4 | Principal exclusion criteria |
1) Currently displaying clinical signs of acute severe colitis, fulminant colitis, or toxic megacolon.
2) Prior surgery for UC.
3) Subjects who are likely to require any type of major surgery during the study. Cataract surgery, breast surgery without reconstruction, laparoscopic cholecystectomy, laparoscopic tubal ligation and most cutaneous, superficial, endoscopic and arthroscopic procedures can be considered minor surgeries.
4) Have had any major surgery or trauma within 8 weeks prior to randomization.
5) History or evidence of incompletely resected colonic mucosal dysplasia.
6) History of malignancy in the last 5 years except for subjects who have been treated or resected for either non-melanoma skin cancer or cervical carcinoma in situ.
7) History of lymphoproliferative disorder, lymphoma, leukemia, myeloproliferative disorder, or multiple myeloma.
8) Any chronic medical condition (including, but not limited to cardiac or pulmonary disease) or psychiatric problem (including, but not limited to alcohol or drug abuse) that, in the opinion of the investigator or sponsor, would make the subject unsuitable for the study or would prevent compliance with the study protocol.
9) History of immunodeficiency syndrome.
10) Have a stoma or ileoanal pouch.
11) Dependence on total parenteral nutrition.
12) Have a transplanted organ with exception of a corneal transplant.
13) Active clinically significant infection, or any infection requiring hospitalization or treatment with intravenous anti-infectives within 8 weeks of randomization; or any infection requiring oral anti-infective therapy within 6 weeks of randomization.
14) History of opportunistic infection.
15) History of symptomatic herpes zoster within 16 weeks of randomization, or any history of disseminated herpes simplex, disseminated herpes zoster, ophthalmic zoster, or central nervous system zoster.
16) Currently on any chronic systemic (oral or intravenous) anti-infective therapy for chronic infection (such as pneumocystis, cytomegalovirus, herpes zoster, or atypical mycobacteria).
17) Use of prohibited concomitant medications.
18) Administration of a live or attenuated vaccine within 4 weeks of randomization
19) Females who may wish to become pregnant and/or plan to undergo egg donation or egg harvesting for the purpose of current or future fertilization during the course of the study and up to 37 days after last dose of the study drug.
20) Male subjects unwilling to refrain from sperm donation for at least 90 days after last dose of the study drug.
21) Known hypersensitivity to GS-4875, its metabolites, or formulation excipients. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Clinical Remission per Modified MCS, defined as Stool Frequency subscore ≤ 1 and not greater than baseline, Rectal Bleeding subscore of 0, and Endoscopic subscore ≤ 1 at Week 10 |
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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) |
-Endoscopic Response, defined as an Endoscopic subscore ≤ 1 at Week 10
- MCS Response, defined as a decrease from baseline of ≥ 3 points and at least 30% in MCS, in addition to a ≥ 1 point decrease from baseline in the Rectal Bleeding subscore or a Rectal Bleeding subscore ≤ 1 at Week 10
- MCS Remission, defined as a MCS score of ≤ 2 and no individual subscore > 1 at Week 10
- Histologic remission based upon the Geboes Scale where all of the following must be met at Week 10: Grade 0 of ≤ 0.3, Grade 1 of ≤ 1.1, Grade 2a of ≤ 2A.3, Grade 2b of 2B.0, Grade 3 of 3.0, Grade 4 of 4.0, and Grade 5 of 5.0 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
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 | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 61 |
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 |
Australia |
Austria |
Belgium |
Canada |
Czech Republic |
France |
Germany |
Italy |
Poland |
Russian Federation |
Switzerland |
United Kingdom |
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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End of Study is defined as when all subjects have completed treatment plus 30 days follow-up or discontinued from the study |
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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 | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |