Dose-Ranging Phase 2b Study of ABX464 in Moderate to Severe Ulcerative Colitis

Ulcerative Colitis Clinical Trial

Official title:

A Randomized, Double Blind, Placebo Controlled, Parallel Group, Multiple Dose, Induction Study to Evaluate the Safety, Tolerability and Optimal Dose of ABX464 Compared With Placebo in Patients With Moderate to Severe Ulcerative Colitis Who Have Inadequate Response, Loss of Response, or Intolerance With at Least One of the Following Agents: Immunosuppressant Treatment (i.e. Azathioprine, 6-mercaptopurine, Methotrexate), Tumor Necrosis Factor Alpha [TNF-α] Inhibitors, Vedolizumab, JAK Inhibitors and/or Corticosteroid Treatment

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03760003
• Other study ID #: ABX464-103
• Status: Completed
• Phase: Phase 2
• Start date: September 23, 2019
• Est. completion date: April 16, 2021

Study information

• Verified date: July 2021
• Source: Abivax S.A.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Phase IIb study to evaluate the efficacy and the safety of 3 dose-levels of ABX464, administered daily in patients with moderate to severe Ulcerative Colitis.

Description:

This phase IIb study will evaluate the efficacy and the safety of 3 dose-levels of ABX464, administered daily in improving Modified Mayo Score (MMS) in patients with moderate to severe Ulcerative Colitis who have inadequate response, loss of response, or intolerance with at least one of the following agents: immunosuppressant treatment (i.e. azathioprine, 6-mercaptopurine, methotrexate), tumor necrosis factor alpha [TNF-α] inhibitors, vedolizumab, JAK inhibitors and/or corticosteroid treatment .

Eligible patients will be randomized into 4 parallel intervention/treatment groups: 25mg q.d of ABX464, 50mg q.d of ABX464, 100mg q.d of ABX464, or matching placebo and will be treated for 16 weeks.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 254
• Est. completion date: April 16, 2021
• Est. primary completion date: April 1, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• Men or women age 18 - 75 years;

• Diagnosis of moderate to severe active UC (including ulcerative proctitis if proximal extension of disease occurs beyond 10 cm) confirmed by endoscopy and histology at least 12 Weeks prior to screening visit. Moderate to severe active UC defined by Modified Mayo Score (MMS) of 5 to 9 inclusive (on a scale of 0-9). Moderate to severe active UC should be confirmed at screening visit with a centrally read endoscopy sub-score of at least 2 (on a scale of 0-3);

• Patients having either a documented inadequate response, no response, a loss of response, or an intolerance (defined as the occurrence of at least one Adverse Reaction leading to treatment discontinuation) to either immunosuppressant treatment (i.e., azathioprine, 6-mercaptopurine, methotrexate), tumor necrosis factor [TNF] inhibitors, vedolizumab, JAK inhibitors and/or corticosteroid treatment. Inadequate response, no response, loss of response is defined as:

i. Active disease or relapse in spite of thiopurines or methotrexate given at an appropriate dose for at least 3 months (i.e. azathioprine 2-2.5 mg/kg/day or mercaptopurine 1-1.5 mg/kg/day in the absence of leukopenia), and/or ii. Active disease despite corticosteroids treatment (prednisolone up to 0.75 mg/kg/day) over a period of 4 Weeks, and/or iii. Active disease or relapse in spite of adequate treatment (as defined in the SmPC) with tumor necrosis factor [TNF] inhibitors or vedolizumab, and/or iv. Active disease or relapse in spite of adequate treatment with JAK inhibitors over a period of at least 6 Weeks.

• Patients receiving oral corticosteroids must have been on a stable dose of prednisone or prednisone equivalent (=20 mg/day) or on beclomethasone diproprionate (=5mg/day) or on budesonide MMX (=9 mg/day) for at least 2 Weeks prior to the screening visit;

• Topical corticosteroids and topical 5-aminosalicylic acid preparations must have been withdrawn at least 2 Weeks prior to the screening visit;

• Patients who are on oral 5-aminosalicylic acid must have been on a stable dose for at least 4 Weeks prior to the screening visit;

• Patients who are receiving immunosuppressants in the form of azathioprine, 6-mercaptopurine, or methotrexate needed to be on a stable dose for at least 4 Weeks prior to screening visit. Patients taking methotrexate also are advised to take folic acid 1 mg/day (or equivalent) supplementation if there is no contraindication;

• Patients on probiotics (e.g., Culturelle® [Lactobacillus GG, i-Health, Inc.], Saccharomyces boulardii) must be on stable doses for at least 2 Weeks prior to the screening visit;

• Patients on antidiarrheals (e.g., loperamide, diphenoxylate with atropine) must be on stable doses for at least 2 Weeks prior to the screening visit;

• Patients who have received tumor necrosis factor [TNF] inhibitors, vedolizumab or other biologics must have discontinued therapy at least 8 Weeks prior to the screening visit due to lack or insufficient efficacy or intolerance;

• Patients previously treated with cyclosporine, tacrolimus or JAK inhibitors must have discontinued therapy at least 4 Weeks prior to the screening visit due to lack or insufficient efficacy or intolerance;

• Patients previously treated with tube feeding, defined formula diets, or parenteral alimentation/nutrition must have discontinued treatment 3 Weeks before the screening visit and must be able to take, orally, appropriate amount of food (calories) and liquids to maintain body weight;

• Patients with surveillance colonoscopy defined as per ECCO guidelines;

• Patients with the following hematological and biochemical laboratory parameters obtained at screening:

i. Hemoglobin > 9.0 g dL-1; ii. Absolute neutrophil count = 750 mm-3; iii. Platelets = 100,000 mm-3; iv. Total serum creatinine = 1.3 x ULN (upper limit of normal); v. Creatinine clearance > 90 mL min-1 by the Cockcroft-Gault equation within 60 days prior to baseline; vi. Total serum bilirubin < 1.5 x ULN; vii. Alkaline phosphatase, AST (SGOT) and ALT (SGPT) < 2 x ULN;

• Patients are able and willing to comply with study visits and procedures as per protocol;

• Patients should understand, sign and date the written voluntary informed consent form at the screening visit prior to any protocol-specific procedures are performed;

• Patients should be affiliated to a social security regimen (for French sites only);

• Females and males receiving the study treatment (potentially in combination with immunosuppressant) and their partners must agree to use a highly effective contraceptive method during the study and for 6 months after end of study or early termination. Contraception should be in place at least 2 Weeks prior to study participation. Women must be surgically sterile or if of childbearing potential must use a highly effective contraceptive method. Women of childbearing potential (WOCBP) will enter the study after confirmed menstrual period and a negative pregnancy test. Highly effective methods of contraception include true abstinence, intrauterine device (IUD) or hormonal contraception aiming at inhibition of ovulation, intrauterine hormone releasing system, bilateral tubal ligation, vasectomized partner. True abstinence is defined when this is in line with the preferred and usual lifestyle of the patient. In each case of delayed menstrual period (over one month between menstruations) confirmation of absence of pregnancy is required. This recommendation also applies to WOCBP with an infrequent or irregular menstrual cycle. Female and male patients must not be planning pregnancy during the trial and for 6 months post completion of their participation in the trial. In addition, male participants should use condoms and not donate sperm as long as contraception is required.

Exclusion Criteria:

• Patients with Crohn's Disease (CD) or presence or history of fistula, indeterminate colitis (IC), infectious/ischemic colitis or microscopic colitis (lymphocytic and collagenous colitis);

• History of toxic megacolon, abdominal abscess, symptomatic colonic stricture or stoma; history or imminent colectomy, colonic malignancy;

• History or current evidence of colonic dysplasia or adenomatous colonic polyps. Patient with severe gastrointestinal complications; e.g., short bowel syndromes, recent or planned bowel surgery, Ileostomy and/or colostomy, recent bowel perforation;

• History of more than one episode of herpes zoster or a history (single episode) of disseminated zoster;

• Patients with active infections at screening such as infected abdominal abscess, Clostridium difficile (stool antigen and toxin required), CMV (positive IgM), TB and recent infectious hospitalization;

• Patients previously treated with ABX464;

• Acute, chronic or history of clinically relevant pulmonary, cardiovascular, hepatic, pancreatic or renal functional abnormality, encephalopathy, neuropathy or unstable CNS pathology such as seizure disorder, angina or cardiac arrhythmias, active malignancy or any other clinically significant medical problems as determined by physical examination and/or laboratory screening tests and/or medical history;

• Acute, chronic or history of immunodeficiency or autoimmune disease;

• History of malignancy excluding patients considered cured (5 years disease free survivors);

• Serious illness requiring systemic treatment and/or hospitalization within 3 Weeks prior to baseline;

• Pregnant or breast-feeding women;

• Illicit drug or alcohol abuse or dependence;

• Patients who received live vaccine 30 days or fewer before first dose of study treatment and/or who's planning to receive such a vaccine during the study duration;

• Use of any investigational or non-registered product within 3 months or within 5 half-lives preceding baseline, whichever is longer and during the study;

• Any condition, which in the opinion of the investigator, could compromise the patient's safety or adherence to the study protocol.

Related Conditions & MeSH terms

• Colitis
• Colitis, Ulcerative
• Ulcer
• Ulcerative Colitis

Intervention

Drug:
• ABX464 25mg
ABX464 25mg (One capsule of ABX464 25 mg + One capsule of placebo) once daily for 16 weeks
• ABX464 50mg
ABX464 50mg (One capsule of ABX464 50 mg + One capsule of placebo) once daily for 16 weeks
• ABX464 100mg
ABX464 100mg (two capsules of ABX464 50 mg) once daily for 16 weeks
• Placebo
Two capsules of placebo once daily for 16 weeks

Locations

Country	Name	City	State
Austria	Medizinische Universität Innsbruck	Innsbruck
Austria	Klinikum Klagenfurt am Wörthersee	Klagenfurt
Austria	Ordensklinikum Linz GmbH - Barmherzige Schwestern	Linz
Austria	AKH - Medizinische Universität Wien	Vienna
Belarus	Gomel Regional Clinical Hospital	Gomel
Belarus	Minsk city diagnostic center	Minsk
Belarus	Regional Clinical Hospital	Minsk
Belarus	Vitebsk Regional Clinical Hospital	Vitebsk
Belarus	Vitebsk regoinal clinical specialized center	Vitebsk
Belgium	AZ Sint-Lucas	Brugge
Belgium	C. H. U. St-Pierre	Brussels
Belgium	UZA	Edegem
Belgium	Universitair Ziekenhuis Gent	Gent
Belgium	UZ Leuven	Leuven
Canada	Brandon Medical Arts Clinic	Brandon
Canada	South Edmonton Gastroenterology	Edmonton
Canada	LHSC - Victoria Hospital	London
Canada	The Ottawa Hospital - General Campus	Ottawa
Canada	Allen Whey Khye Lim Professional Corporation	Saskatoon
Canada	Mount Sinai Hospital	Toronto
Czechia	Fakultni nemocnice u sv. Anny v Brne	Brno
Czechia	Hepato-Gastroenterologie HK s.r.o.	Hradec Kralove
Czechia	MUDr. GREGAR s.r.o.	Olomouc
Czechia	Fakultni nemocnice Ostrava	Ostrava-Kuncice
Czechia	Nemocnice Na Bulovce	Praha
Czechia	Thomayerova nemocnice	Praha
Czechia	Nemocnice Slany	Slany
France	CHU Amiens - Hopital Sud	Amiens
France	CHU Besançon - Hôpital Jean Minjoz	Besançon
France	CHU Clermont Ferrand - Hôpital d'Estaing	Clermont-Ferrand
France	Hôpital Beaujon	Clichy
France	CHU de Grenoble - Hôpital Nord	Grenoble
France	Centre Hospitalier Départemental Les Oudairies	La Roche-sur-Yon
France	CHU Lille - Hôpital Claude Huriez	Lille
France	Hôpital Nord - CHU Marseille	Marseille
France	Hopital Saint Eloi	Montpellier
France	CHU Nantes - Hôtel Dieu	Nantes
France	CHU Nice - Hôpital de l'Archet 2	Nice
France	CHU Reims - Hôpital Robert Debré	Reims
France	CHU Rennes - Hôpital Pontchaillou	Rennes
France	CHU de Rouen - Hôpital Charles Nicolle	Rouen
France	CHU Saint Etienne - Hôpital Nord	Saint-Étienne
France	CHU Strasbourg - Hôpital Hautepierre	Strasbourg
France	Hopital Rangueil	Toulouse
France	Hôpital de Brabois Adultes	Vandœuvre-lès-Nancy
Germany	Charite Universitaetsmedizin Berlin - Campus Benjamin Franklin	Berlin
Germany	Florence-Nightingale-Krankenhaus-Diakonie Kaiserswerth	Düsseldorf
Germany	Klinikum der Johann Wolfgang Goethe-Universitaet	Frankfurt
Germany	Studiengesellschaft BSF Unternehmergesellschaft haftungsbeschraenkt	Halle
Germany	Universitaetsklinikum Halle (Saale)	Halle
Germany	Medizinische Hochschule Hannover	Hanover
Germany	Johanna-Etienne-Krankenhaus	Neuss
Germany	Tumorzentrum Nordthueringen MVZ GmbH	Nordhausen
Germany	Dr. Tasso Bieler	Riesa
Germany	Universitaetsklinikum Ulm	Ulm
Hungary	DRC Gyogyszervizsgalo Kozpont Kft.	Balatonfured
Hungary	Obudai Egeszsegugyi Centrum Kft.	Budapest
Hungary	Pannonia Maganorvosi Centrum	Budapest
Hungary	Semmelweis Egyetem	Budapest
Hungary	Debreceni Egyetem	Debrecen
Hungary	Vasutegeszsegugyi Kft. - Debreceni Egeszsegugyi Kozpont	Debrecen
Hungary	Petz Aladar Megyei Oktato Korhaz	Gyor
Italy	Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi	Bologna
Italy	Fondazione Poliambulanza Istituto Ospedaliero	Brescia
Italy	Azienda Ospedaliero Universitaria Mater Domini	Catanzaro
Italy	I.R.C.C.S Policlinico San Donato	Milano
Italy	Ospedale Sacro Cuore Don Calabria	Negrar
Italy	Azienda Ospedaliera di Padova	Padova
Italy	Azienda Ospedaliero Universitaria Policlinico Paolo Giaccone	Palermo
Italy	Azienda Ospedaliero Universitaria Pisana (Presidio di Cisanello)	Pisa
Italy	Fondazione Policlinico Universitario Agostino Gemelli IRCCS	Roma
Italy	Istituto Clinico Humanitas	Rozzano
Poland	Szpital Uniwersytecki nr 2 im.dr J. Biziela	Bydgoszcz
Poland	Uniwersyteckie Centrum Kliniczne	Gdansk
Poland	Centrum Medyczne Plejady	Kraków
Poland	Santa Familia Centrum Badan, Profilaktyki i Leczenia	Lodz
Poland	Wojskowy Szpital Kliniczny w Lublinie	Lublin
Poland	Trialmed CRS	Piotrkow Trybunalski
Poland	Centrum Medyczne Grunwald	Poznan
Poland	KO-MED Centra Kliniczne Pulawy	Pulawy
Poland	Gabinet Lekarski Bartosz Korczowski	Rzeszow
Poland	Centrum Zdrowia MDM	Warszawa
Poland	Nzoz Vivamed	Warszawa
Poland	Centrum Zdrowia Tuchow Sp. z o.o.	Wierzchoslawice
Poland	Centrum Badan Klinicznych Piotr Napora Lekarze Spolka Partnerska	Wroclaw
Poland	Centrum Medyczne Oporow	Wroclaw
Poland	LexMedica	Wroclaw
Serbia	Clinical Center " Dr Dragisa Misovic Dedinje"	Belgrad
Serbia	Clinical Center Bezanijska Kosa	Belgrad
Serbia	Clinical Center Zvezdara	Belgrade
Serbia	General Hospital Uzice	Užice
Serbia	General Hospital "Djordje Joanovic"	Zrenjanin
Slovakia	Accout Center s.r.o.	Šahy
Slovakia	Alian s.r.o.	Bardejov
Slovakia	Cliniq s.r.o.	Bratislava
Slovakia	Gastromedic, s.r.o.	Nové Zámky
Slovakia	Gastro I, s.r.o.	Prešov
Slovakia	Endomed, s.r.o.	Vranov Nad Toplou
Slovenia	General Hospital Celje	Celje
Slovenia	University Medical Centre Maribor	Maribor
Slovenia	General Hospital Murska Sobota	Murska Sobota
Spain	Centro Médico Teknon	Barcelona
Spain	Hospital Universitario Reina Sofia	Córdoba
Spain	Hospital Universitario de Gran Canaria Dr. Negrin	Las Palmas De Gran Canaria
Spain	Hospital Quironsalud Malaga	Málaga
Ukraine	CNE Cherkasy Regional Hospital of Cherkasy Regional Council	Cherkasy
Ukraine	I.I.Mechnykov Dnipropetrovsk Regional Clinical Hospital	Dnipro
Ukraine	Central City Clinical Hospital Dept of Theraphy No. 2 SHEI Ivano-Frankivsk NMU	Ivano-Frankivs'k
Ukraine	CHI Kharkiv City Clinical Hospital #13	Kharkiv
Ukraine	CNE Prof. O.O. Shalimov Kharkiv City Clinical Hospital #2 of KCC	Kharkiv
Ukraine	Communal Non-commercial Enterprise of Kharkiv Regional Council Regional Clinical Hospital	Kharkiv
Ukraine	CI Kherson CCH	Kherson
Ukraine	Khmelnytska Regional Hospital	Khmelnytskyi
Ukraine	Communal Institution of Kyiv Regional Council Kyiv Regional Clinical Hospital	Kyiv
Ukraine	Lviv Regional Clinical Hospital D.Halytskyi Lviv NMU	Lviv
Ukraine	Ternopil University Hospital	Ternopil'
Ukraine	A. Novak Transcarpathian Regional Clinical Hospital	Úzhgorod
Ukraine	CCH #1 Vinnytsia M.I. Pyrogov NMU Ch of Propaedeutics of IM	Vinnytsia
Ukraine	M.I. Pyrogov VRCH Dept of Gastroenterology M.I. Pyrogov VNMU	Vinnytsia
Ukraine	MCIC MC LLC Health Clinic	Vinnytsia
Ukraine	CI City Clinical Hospital #6 Dept of Gastroenterology	Zaporizhzhia
Ukraine	CNCE "City Hospital 9" Zaporizhzhia CC	Zaporizhzhia
United Kingdom	Fairfield General Hospital	Bury
United Kingdom	Guy's Hospital	London
United Kingdom	University College London Hospitals	London
United Kingdom	Nottingham University Hospitals Queen's Medical Centre	Nottingham
United States	Central Texas Clinical Research, LLC	Austin	Texas
United States	Atlanta Center for Gastroenterology, P.C	Decatur	Georgia
United States	Southern Star Research Institute, LLC	San Antonio	Texas
United States	UCSD Health System	San Diego	California

Sponsors (1)

Lead Sponsor	Collaborator
Abivax S.A.

Countries where clinical trial is conducted

United States,  Austria,  Belarus,  Belgium,  Canada,  Czechia,  France,  Germany,  Hungary,  Italy,  Poland,  Serbia,  Slovakia,  Slovenia,  Spain,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Modified Mayo Score	Reduction from baseline in Modified Mayo Score	Week 8
Secondary	Clinical remission	Clinical remission, based on the Mayo Scoring system, is defined as stool frequency subscore = 0 or 1 and rectal bleeding subscore = 0 and endoscopy subscore = 0 or 1 (modified to exclude friability).	Week 8 and Week 16
Secondary	Clinical response	Clinical Response is defined as a reduction in Mayo Score of at least 2 points and greater than or equal to 30 percent from baseline with an accompanying decrease in rectal bleeding sub-score of greater than or equal to 1 point or absolute rectal bleeding sub-score of less than or equal to 1 point.	Week 8 and Week 16
Secondary	Endoscopic Improvement	Endoscopic improvement is defined as a Mayo endoscopic sub score of =1 (excluding friability)	Week 8 and Week 16
Secondary	Mucosal healing	Mucosal healing is defined as both endoscopic remission and histological remission (Geboes score < 2.0).	Week 8 and Week 16
Secondary	Stool and rectal bleeding frequency	Assessment of Reduction relative to baseline in stool and rectal bleeding frequency	Every visit
Secondary	Partial Modified Mayo Score	Change from baseline	Every visit
Secondary	Modified Mayo Score	Change from baseline	Week 16
Secondary	Fecal calprotectin	Reduction from baseline in fecal calproctectin	Week 8 and Week 16
Secondary	C Reactive Protein	Reduction from baseline in CRP	Week 8 and Week 16
Secondary	miR-124 expression	Increase in miR-124 expression in Total Blood and rectal tissue	Week 8 and Week 16
Secondary	IBDQ	Scores and changes from baseline i	Week 8 and Week 16
Secondary	Inflammatory Infiltrate	Inflammatory Infiltrate assessment in rectal/colon biopsies	Week 8 and Week 16
Secondary	IL-6, TNFa, IL-1b, IL-10 plasma concentrations	Change relative to baseline	Every visit
Secondary	ABX464 and ABX464-N-Glu	Serum concentration	Every visit (Except D57)
Secondary	Endoscopy Remission	Mayo endoscopic sub score of 0	Week 8 and Week 16
Secondary	Number and rate of all adverse events, causally-related adverse events, SAE and causally-related SAEs classified by severity		Every visit
Secondary	Incidence of treatment-emergent serious adverse event		Every visit
Secondary	Incidence of adverse events leading to investigational medicinal product discontinuation		Every visit
Secondary	Number of clinically-significant laboratory abnormalities		Every visit