A Study Evaluating the Efficacy and Safety of ST-0529 in Subjects With Moderately to Severely Active Ulcerative Colitis

Colitis, Ulcerative Clinical Trial

Official title:

A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of ST-0529 in Subjects With Moderately to Severely Active Ulcerative Colitis

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03844932
• Other study ID #: CYC-202
• Status: Terminated
• Phase: Phase 2
• Start date: January 24, 2019
• Est. completion date: April 14, 2021

Study information

• Verified date: May 2021
• Source: Sublimity Therapeutics Holdco Limited
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Study CYC-202 is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of ST-0529 in subjects with moderately to severely active UC, defined as a score of 5 to 9 on the 3-Component Adapted Mayo Score (comprised of rectal bleeding, stool frequency and endoscopy sub-scores; score range 0-9).

Description:

The study consists of a Screening period, Treatment period and Follow-up. The Screening period is comprised of two separate in-clinic visits, SV1 and SV2. At the initial Screening visit (SV1), subjects will be required to provide written informed consent to participate in the study and will then be assessed for eligibility. Electronic diaries will be provided to subjects at this visit to use for the duration of the study in order to record information relating to their UC disease. Subjects will return to the clinic for their Screening endoscopic assessment (SV2). Ulcerative colitis disease activity for eligibility will be assessed using the 3-Component Adapted Mayo Score. Upon successful completion of the Screening period, subjects will return to the clinic for their Baseline visit. During the Treatment period, subjects will be evaluated in the clinic at Baseline (Day 1), Week 2, Week 4, Week 8, and Week 12 (End of Treatment Period). At Week 6 and Week 10, subjects will be contacted by telephone to assess Adverse Events (AEs), concomitant medication usage and study drug regimen adherence. Subjects who complete the 12-week Treatment period will attend the Week 16 End of Study (EOS) visit. Subjects who discontinue study drug and withdraw or are withdrawn from the study before the Week 12 visit will be requested to return to the clinic as soon as possible to complete an Early Termination (ET) visit.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 235
• Est. completion date: April 14, 2021
• Est. primary completion date: April 14, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Male and female adult subjects 18 to 75 years old, inclusive.

2. Willing to provide written informed consent and to be compliant with the schedule of study visits and protocol assessments.

3. Diagnosis of UC established at least 3 months prior to the Baseline visit, by clinical and endoscopic evidence (colonoscopy or flexible sigmoidoscopy)

4. Moderately to severely active UC defined as the 3-Component Adapted Mayo Score of 5-9, inclusive, with an endoscopic sub-score of = 2 (from central reading), and a rectal bleeding sub-score of = 1, as determined 10 days (± 3 days) prior to Baseline.

5. Evidence of active UC, confirmed histologically (from local read), extending proximal to the rectum with = 15 cm of involved colon.

6. At Screening, a colonoscopy will be required if the subject has had extensive colitis or pancolitis of > 8 years duration or left-sided colitis of > 12 years duration but has not had a colonoscopy within 1 year of the initial screening date. If the subject has had a colonoscopy within 1 year of the initial screening date, a flexible sigmoidoscopy may be used.

7. Subjects presenting at Screening with moderately to severely active UC demonstrating an inadequate response or loss of response or intolerance/medical contraindication to at least one of the following conventional therapies for UC: a. Corticosteroids: i. Signs and symptoms of active disease despite treatment with an adequate dose (e.g., prednisolone > 40 mg/day or equivalent) over a period of 4 weeks for oral therapy or intravenously (IV) for up to 1 week or = 9 mg/day oral budesonide; OR ii. Unable to reduce corticosteroids below the equivalent of prednisolone 10 mg daily orally within 3 months of starting steroids or having experienced a relapse within 3 months of stopping steroids; OR iii. History of, or current intolerance to corticosteroids (including, but not limited to Cushing's syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, infection). b. Immunomodulators: i. Signs and symptoms of active disease despite at least 3 months of treatment with a sufficient dose (oral azathioprine = 1.5 mg/kg or 6-mercaptopurine [6-MP] = 0.75 mg/kg); OR ii. History of, or current dose-limiting toxicity associated with use of the agent (e.g., but not limited to nausea/vomiting, abdominal pain, pancreatitis, liver function test [LFT] abnormalities, lymphopenia, TPMT genetic mutation, infection). c. Anti-tumor necrosis factor (anti-TNF) agents: i. Signs and symptoms of active disease despite treatment with a single anti-TNF agent. Treatment failure is defined as a relapse after an initial response to therapy

as follows:

• Infliximab: At least 4 infusions of at least 5 mg/kg within a 14-week timeframe for induction and maintenance;
• Adalimumab: Induction regimen incorporating 160 mg at Week 0 (four 40 mg injections in one day or two 40 mg injections per day for two consecutive days) and 80 mg at Week 2, followed by maintenance treatment of 40 mg every other week up to at least Week 8;
• Golimumab: Induction regimen incorporating 200 mg subcutaneous (sc) injection at Week 0, followed by 100 mg at Week 2 and then maintenance treatment of 50 mg or 100 mg (weight dependent) every 4 weeks after completion of the induction regimen up to at least Week 12; OR ii. History of, or current intolerance (with an initial response), defined as the presence of clinically significant side-effects, including infusion-related hypersensitivity. d. Vedolizumab: i. Signs and symptoms of active disease despite a history of at least one induction regimen, defined as at least a 14-week (10 weeks in the EU) induction consisting of 300 mg IV at Weeks 0, 2 and 6. OR ii. History of intolerance to vedolizumab including, but not limited to, serious infections, hepatotoxicity, heart failure, allergic reactions, or any other condition that contributed to discontinuation of the agent.

8. Subjects receiving oral corticosteroids for the treatment of UC must be on a stable dose of = 40 mg/day (prednisolone or equivalent), or = 9 mg/day budesonide. This dose must be stable from the initial Screening visit until 1 week after the initiation of study treatment.

9. Subjects receiving oral 5-ASA must be on a stable dose from the initial Screening visit until the end of the study.

10. Subjects willing to cease the use of any therapeutic enema or suppository or foams, other than that required in preparation for study-mandated colonoscopy/flexible sigmoidoscopies, from the initial Screening visit until the end of the study.

11. Subjects willing to cease use of azathioprine or 6-MP from the initial Screening visit until the end of the study.

12. Negative serum pregnancy test in females of childbearing potential at Screening.

13. If female and of childbearing potential, must agree to be sexually abstinent or use one of the following highly effective methods of birth control from the initial

Screening visit until 30 days after the last dose of study drug is administered:

1. Hormonal contraceptives (e.g., combined oral contraceptives, patch, vaginal ring, injectables, and implants);

2. Intrauterine contraceptive system;

3. Surgical sterilization or partner sterile (must have documented proof); AND

One of the following effective methods of birth control:

1. Male/female condom;

2. Cervical cap with spermicide;

3. Diaphragm with spermicide;

4. Contraceptive sponge.

14. Male subjects must be either surgically sterile (must have documented proof), agree to be sexually inactive or use a double-barrier method of birth control (e.g., condom and diaphragm with spermicide, condom with cervical cap and spermicide) from first study drug administration until 90 days after final drug administration. Exclusion Criteria:

If a subject has any of the following criteria, they will be excluded from the study:

1. Subjects without previous treatment for UC.

2. Ulcerative colitis limited to rectum (ulcerative proctitis).

3. Evidence of acute severe colitis with toxic megacolon, abdominal abscess, bowel stricture or bowel perforation.

4. A diagnosis of Crohn's colitis, colitis yet to be classified, ischemic colitis, NSAID-induced colitis, idiopathic colitis (i.e., colitis not consistent with UC) or radiation colitis.

5. Subjects with evidence of pathogenic bowel infection (Clostridium difficile, Escherichia coli, Salmonella, Shigella or Campylobacter).

6. Previous surgery for UC or, in the opinion of the Investigator, will likely require surgery for UC during the study.

7. Any histological evidence of mucosal dysplasia.

8. Subjects with a current or recent history of severe, progressive or uncontrolled cardiac (including uncontrolled hypertension), renal, hepatic, hematological, gastrointestinal, metabolic, endocrine, pulmonary, cardiac or neurological (e.g., history of seizures) disease, abnormal magnesium or potassium levels, hypocholesterolemia, or any other severe co-morbidity that, in the opinion of the Investigator, could confound the study results or put the study subject at unreasonable risk.

9. Malignancies or history of malignancy within 5 years of the initial Screening visit, with the exception of adequately treated or excised non-metastatic basal cell carcinoma or squamous cell carcinoma of the skin.

10. Any of the following laboratory abnormalities during the screening period - if values are initially outside the prescribed limits, the evaluation may be repeated once

within the screening period to determine eligibility:

1. Hemoglobin level < 8.0 g/dL

2. Absolute WBC count < 3.0 × 10^9/L

3. Absolute Lymphocyte count < 0.5 × 10^9/L

4. Absolute neutrophil count < 1.2 × 10^9/L

5. Platelet count < 100 × 10^9/L or >1200 × 10^9/L

6. ALT or AST > 2.0 × ULN

7. Alkaline phosphatase > 2.0 × ULN

8. Serum creatinine > 1.5 × ULN

9. Bilirubin > 1.5 × ULN

11. Subjects with active TB infection or known history of prior treated or untreated TB infection.

12. Subject with a positive serology test result for HIV (HIV type 1 or type 2).

13. Subject with a positive serology test result for active HBV or HCV infection.

14. Treatment with biologic agents for UC within 56 days or 5 half-lives (whichever is greater) prior to the Baseline visit.

15. Treatment with any calcineurin inhibitor (e.g. cyclosporine or tacrolimus) within 28 days prior to the Baseline visit.

16. Treatment with methotrexate or JAK inhibitors (e.g. tofacitinib) from the initial Screening visit until the end of the study.

17. Initiation of treatment with an oral or IV corticosteroid from the initial Screening visit until the end of the study.

18. Use of any strong inhibitors of CYP enzymes (e.g., cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin, fluconazole, ketoconazole, diltiazem, grapefruit juice and HIV antivirals) within 14 days prior to the Baseline visit.

19. Use of strong or moderate P-gp inhibitors (e.g., amiodarone, azithromycin, clarithromycin, itraconazole, ketoconazole, dronedarone, lapatinib, quinidine, ranolazine, verapamil) within 14 days prior to the Baseline visit.

20. Use of any herbal medication for the treatment of UC or which might interfere with CYP enzymes within 14 days prior to the Baseline visit.

21. Subjects vaccinated with a live or live-attenuated vaccine within 14 days of the Baseline visit, or planned vaccination during conduct of the study.

22. Subjects with a QTcF of > 450 ms for males and > 470 ms for females at Screening.

23. A history of risk factors for Torsades de pointes (e.g., history of heart failure, hypokalemia, family history of Long QT Syndrome).

24. Known hypersensitivity to cyclosporine or any excipients contained in ST-0529.

25. History of alcohol or drug abuse in the year prior to the initial Screening visit.

26. Subjects currently breast feeding, pregnant, or unwilling to delay initiation of breast feeding for at least 90 days after the last dose of study drug is administered.

27. Participation in another clinical trial and having received investigational medication within 30 days or within 5 half-lives (whichever is longer) prior to the Baseline visit, or concurrent participation in another clinical trial.

28. Subjects who, in the opinion of the Investigator, are unsuitable for inclusion in the study.

Related Conditions & MeSH terms

• Colitis
• Colitis, Ulcerative
• Ulcer

Intervention

Drug:
• ST-0529
ST-0529 utilizes SmPill® technology to encapsulate the otherwise insoluble cyclosporine in a presolubilized, lipid-based formulation.

Locations

Country	Name	City	State
Belarus	Gomel Regional Clinical Hospital	Gomel
Belarus	Grodno Regional Clinical Hospital	Grodno
Belarus	City Clinical Emergency Hospital	Minsk
Bulgaria	MedConsult Pleven	Pleven
Bulgaria	Medical Center Asklepion	Sofia
Bulgaria	UMBAL Tsaritsa Joanna ISUL	Sofia
Canada	Dalhousie University - Queen Elizabeth II Health Sciences Centre	Halifax	Nova Scotia
Canada	London Health Sciences Centre	London	Ontario
France	CHU Amiens Picardie - Service Hépato-Gastroentérologie	Amiens
France	CHU DE MONTPELLIER - Hôpital St ELOI	Montpellier
France	CHU de Saint-Etienne - Service de Gastro-Entérologie-Hépatologie	Saint-Étienne
France	Hôpital de Brabois Service d'Hépato-Gastro-Entérologie	Vandœuvre-lès-Nancy
Germany	Krankenhaus Walfriede, Akademisches Lehrkrankenhaus der Charite	Berlin
Germany	Medizinische Klinik für Gastroenterologie, Infektiologie, Rheumatologie charite	Berlin
Germany	Agaplesion Markus Krankenhaus Medizinischen Klinik I, Gastroenterologie, Hepatologie, Onkologie, lnfektiologie	Frankfurt
Germany	Universitatsklinikum Freiburg, Medizinische Klinik	Freiburg
Germany	Medizinische Hochschule Hannover, Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Zentrym für Innere Medizin	Hannover
Germany	Klinik für Gastroenterologie, Pulmologie und allg. lnnere Medizin	Köln
Germany	Eugastro GmbH	Leipzig	Saxony
Germany	Universität Leipzig, Klinik f. Gastroenterologie und Rheumatologie	Leipzig
Germany	Gastroenterologische Gemeinschaftspraxis Minden	Minden
Hungary	DRC Gyógyszervizsgáló Központ Kft.	Balatonfüred
Hungary	Semmelweis University	Budapest
Hungary	Semmelweis University, AOK Varosmajori Sziv- es Ergyogyaszati Klinika,	Budapest
Hungary	Bugat Pal Hospital	Gyongyos
Ireland	Mater Misericordiae University Hospital	Dublin
Ireland	St. James's Hospital	Dublin
Israel	Gastroenterology Institute, Emek Medical Center	Afula
Israel	Barzilai Medical Center	Ashkelon
Israel	Clalit Health Services Jerusalem	Jerusalem
Israel	Institute of Gastroenterology, Meir Medical Center	Kfar Saba
Italy	Humanitas Research Hospital, IBD Center	Milan
Italy	A.0.U. di Modena - Policlinico S.C. di Gastroenterologia	Modena
Italy	Fondazione IRCCS Policlinico San Matteo - Medicina Generale I	Pavia
Italy	ASST Rhodense - Ospedale di Rho	Rho
Italy	Fondazione Casa Sollievo della Sofferenza	San Giovanni Rotondo
Poland	Centrum Opieki Zdrowotnej Orkan-med	Ksawerów
Poland	Oddzial Kliniczny Gastroenterologii Ogólnej i Onkologicznej SPZOZ Uniwersytecki Szpital Kliniczny nr 1 im. Norberta Barlickiego UM	Lódz
Poland	Medicome Sp. z o.o.	Oswiecim
Poland	Centrum Medyczne Medyk	Rzeszów
Poland	Endoskopia sp. z o.o.	Sopot
Poland	WIP Warsaw IBD Point Profesor Kierkus	Warszawa
Romania	Colentina Clinical Hospital	Bucharest
Romania	MedLife Grivita	Bucharest
Romania	University Hospital Bucharest	Bucharest
Russian Federation	Federal State Center of Coloproctology	Moscow
Russian Federation	LLC Medical center Healthy family	Novosibirsk
Russian Federation	Military Medical Academy	Saint Petersburg
Russian Federation	North-Western State Medical University n.a. I.I.Mechnikov	Saint Petersburg
Russian Federation	Pavlov First Saint Petersburg State Medical University	Saint Petersburg
Russian Federation	Scientific Research Center Eco-Safety LLC	Saint Petersburg
Russian Federation	Saint-Petersburg State Medical Academy n.a. I.I. Mechnikov of Federal Agency of Healthcare & Social Development	Saint-Petersburg
Russian Federation	Non state Public Health Institution "Railway clinical hospital on station Samara" of joint stock company Russian railways	Samara
Russian Federation	Saratov State Medical University	Saratov
Russian Federation	Siberia State Medical University	Tomsk
Serbia	Clinical Hospital Center "Dr Dragisa Misovic-Dedinje"	Belgrad
Serbia	Clinical Center Zvezdara	Belgrade
Serbia	Clinical-Hospital Centre Bezanijska Kosa - Gastroenterology Department	Belgrade
Serbia	Clinical Center Kragujevac	Kragujevac
Spain	Hospital Universitario Virgen de la Macarena	Sevilla
Ukraine	Chernivtsi Regional Clinical Hospital	Chernivtsi
Ukraine	Ivano-Frankivsk National Medical University, Regional Clinical Hospital	Ivano-Frankivsk
Ukraine	Kharkiv City Clinical Hospital No 2 n.a. prof. O.O.Shalimov	Kharkiv
Ukraine	Kiev City Clinical Hospital No. 1	Kiev
Ukraine	Communal Institution of Kyiv Regional Council "Kyiv Regional Clinical Hospital"	Kyiv
Ukraine	Ukrainian-German Gastroenterology Center "BYK-Kyiv"	Kyiv
Ukraine	Volyn Regional Clinical Hospital	Lutsk
Ukraine	Communal Nonprofit Enterprise "Lviv Clinical Emergency Care Hospital"	Lviv
Ukraine	Communal Nonprofit Entreprise, "Lviv Clinical Emergency Care Hospital", 1st Therapeutic Dpt	Lviv
Ukraine	Communal Nonprofit Enterprise "Odesa Regional Clinical Hospital"	Odesa
Ukraine	Communal Nonprofit Enterprise "Ternopil University Hospital" of Ternopil Regional Council	Ternopil
Ukraine	Municipal Institution "Uzhhorod Central District Hospital"	Uzhhorod
Ukraine	Communal Non-profit Enterprise "Vinnytsia City Clinical Hospital #1"	Vinnytsia
Ukraine	Medical Center "Health Clinic"	Vinnytsia
United Kingdom	Barnsley Hospital NHS Foundation Trust	Barnsley	Yorkshire
United Kingdom	South Eastern Health & Social Care Trust, Ulster Hospital	Belfast	Co Antrim
United Kingdom	Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust	Birmingham	Warwickshire
United Kingdom	Addenbrooke's Hospital	Cambridge	Cambridgeshire
United Kingdom	Royal Liverpool & Broadgreen University Hospitals NHS Trust	Liverpool	Merseyside
United Kingdom	King's College Hospital NHS Foundation Trust	London
United Kingdom	University College London Hospital NHS Foundation Trust	London
United States	University of Chicago	Chicago	Illinois
United States	AGA Clinical Reasearch Associates, LLC	Egg Harbor Township	New Jersey
United States	Baylor College of Medicine	Houston	Texas
United States	Biopharma Informatic, LLC.	Houston	Texas
United States	Advanced Research Institute	Largo	Florida
United States	Advanced Research Institute, Inc.	New Port Richey	Florida
United States	Endoscopic Research Inc	Orlando	Florida
United States	Palmtree Clinical Research Inc	Palm Springs	California

Sponsors (2)

Lead Sponsor	Collaborator
Sublimity Therapeutics Holdco Limited	Dr. Falk Pharma GmbH

Countries where clinical trial is conducted

United States,  Belarus,  Bulgaria,  Canada,  France,  Germany,  Hungary,  Ireland,  Israel,  Italy,  Poland,  Romania,  Russian Federation,  Serbia,  Spain,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Clinical Remission at Week 12	Stool frequency sub-score of = 1 associated with a decrease = 1 point from baseline, rectal bleeding sub-score of 0, and an endoscopic sub-score of = 1 using the 3-Component Adapted Mayo Score.; The 3-Component Adapted Mayo Score is a measure of UC disease ranging from 0 to 9 points and consists of 3 sub-scores, each graded from 0 - 3 with higher scores indicating more severe disease. The sub-scores are stool frequency (0 - 3); rectal bleeding (0 - 3); findings of endoscopy (0 - 3).	Week 12
Secondary	Clinical Response at Week 12	A decrease from baseline in the 3-Component Adapted Mayo Score of = 2 points and = 30%, with an accompanying decrease in the sub-score for rectal bleeding of = 1 point or an absolute sub-score for rectal bleeding of = 1.; The 3-Component Adapted Mayo Score is a measure of UC disease ranging from 0 to 9 points and consists of 3 sub-scores, each graded from 0 - 3 with higher scores indicating more severe disease. The sub-scores are stool frequency (0 - 3); rectal bleeding (0 - 3); findings of endoscopy (0 - 3).	Week 12
Secondary	Endoscopic Healing at Week 12	Endoscopic Healing (I) defined as an endoscopic sub-score of = 1.; The endoscopic sub-score is part of the 3-Component Adapted Mayo score and ranges from 0 - 3, with higher scores indicating more severe disease.	Week 12
Secondary	Corticosteroid-free clinical response at Week 12	Clinical response and achieving a corticosteroid-free status at Week 12 in subjects using oral corticosteroids at the Baseline visit. Clinical response is defined as a decrease from baseline in the 3-Component Adapted Mayo Score of = 2 points and > 30%, with an accompanying decrease in the sub-score for rectal bleeding of = 1 point or an absolute sub-score for rectal bleeding of = 1.	Week 12
Secondary	Corticosteroid-free clinical remission at Week 12	Clinical remission and achieving a corticosteroid-free status at Week 12 in subjects using oral corticosteroids at the Baseline visit. Clinical remission is defined as a stool frequency sub-score of = 1 associated with a decrease = 1 point from baseline, rectal bleeding sub-score of 0, and an endoscopic sub-score of = 1 using the 3-Component Adapted Mayo Score.	Week 12
Secondary	Changes from baseline in individual Adapted Mayo sub-scores at Week 12	The Adapted Mayo Score is a measure of UC disease ranging from 0 to 12 points and consists of 4 sub-scores, each graded from 0 - 3 with higher scores indicating more severe disease. The sub-scores are stool frequency (0 - 3); rectal bleeding (0 - 3); findings of endoscopy (0 - 3); and Physician's Global Assessment [PGA] (0 - 3).	Week 12