Clinical trial NCT03760003: Dose-Ranging Phase 2b Study of ABX464 in Moderate to Severe Ulcerative Colitis
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Ulcerative Colitis
Keywords: ABX464
Refractory patients
Phase 2b
Dose Ranging
Lead sponsor: Abivax S.A.
Sponsor class: INDUSTRY
First posted: 2018-11-30
Enrollment: 254
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, double blind, placebo controlled, parallel groups
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Modified Mayo Score
timeFrame: Week 8
Secondary outcomes:
measure: Clinical remission
timeFrame: Week 8 and Week 16
measure: Clinical response
timeFrame: Week 8 and Week 16
measure: Endoscopic Improvement
timeFrame: Week 8 and Week 16
measure: Mucosal healing
timeFrame: Week 8 and Week 16
measure: Stool and rectal bleeding frequency
timeFrame: Every visit
measure: Partial Modified Mayo Score
timeFrame: Every visit
measure: Modified Mayo Score
timeFrame: Week 16
measure: Fecal calprotectin
timeFrame: Week 8 and Week 16
measure: C Reactive Protein
timeFrame: Week 8 and Week 16
measure: miR-124 expression
timeFrame: Week 8 and Week 16
measure: IBDQ
timeFrame: Week 8 and Week 16
measure: Inflammatory Infiltrate
timeFrame: Week 8 and Week 16
measure: IL-6, TNFα, IL-1b, IL-10 plasma concentrations
timeFrame: Every visit
measure: ABX464 and ABX464-N-Glu
timeFrame: Every visit (Except D57)
measure: Endoscopy Remission
timeFrame: Week 8 and Week 16
measure: Number and rate of all adverse events, causally-related adverse events, SAE and causally-related SAEs classified by severity
timeFrame: Every visit
measure: Incidence of treatment-emergent serious adverse event
timeFrame: Every visit
measure: Incidence of adverse events leading to investigational medicinal product discontinuation
timeFrame: Every visit
measure: Number of clinically-significant laboratory abnormalities
timeFrame: Every visit
Other outcomes:
Locations:
city: San Diego
country: United States
facility: UCSD Health System
state: California
city: Decatur
country: United States
facility: Atlanta Center for Gastroenterology, P.C
state: Georgia
city: Austin
country: United States
facility: Central Texas Clinical Research, LLC
state: Texas
city: San Antonio
country: United States
facility: Southern Star Research Institute, LLC
state: Texas
city: Innsbruck
country: Austria
facility: Medizinische Universität Innsbruck
city: Klagenfurt
country: Austria
facility: Klinikum Klagenfurt am Wörthersee
city: Linz
country: Austria
facility: Ordensklinikum Linz GmbH - Barmherzige Schwestern
city: Vienna
country: Austria
facility: AKH - Medizinische Universität Wien
city: Gomel
country: Belarus
facility: Gomel Regional Clinical Hospital
city: Minsk
country: Belarus
facility: Minsk city diagnostic center
city: Minsk
country: Belarus
facility: Regional Clinical Hospital
city: Vitebsk
country: Belarus
facility: Vitebsk Regional Clinical Hospital
city: Vitebsk
country: Belarus
facility: Vitebsk regoinal clinical specialized center
city: Brugge
country: Belgium
facility: AZ Sint-Lucas
city: Brussels
country: Belgium
facility: C. H. U. St-Pierre
city: Edegem
country: Belgium
facility: UZA
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Leuven
country: Belgium
facility: UZ Leuven
city: Brandon
country: Canada
facility: Brandon Medical Arts Clinic
city: Edmonton
country: Canada
facility: South Edmonton Gastroenterology
city: London
country: Canada
facility: LHSC - Victoria Hospital
city: Ottawa
country: Canada
facility: The Ottawa Hospital - General Campus
city: Saskatoon
country: Canada
facility: Allen Whey Khye Lim Professional Corporation
city: Toronto
country: Canada
facility: Mount Sinai Hospital
city: Brno
country: Czechia
facility: Fakultni nemocnice u sv. Anny v Brne
city: Hradec Kralove
country: Czechia
facility: Hepato-Gastroenterologie HK s.r.o.
city: Olomouc
country: Czechia
facility: MUDr. GREGAR s.r.o.
city: Ostrava-Kunčice
country: Czechia
facility: Fakultni nemocnice Ostrava
city: Praha
country: Czechia
facility: Nemocnice Na Bulovce
city: Praha
country: Czechia
facility: Thomayerova nemocnice
city: Slany
country: Czechia
facility: Nemocnice Slany
city: Amiens
country: France
facility: CHU Amiens - Hopital Sud
city: Besançon
country: France
facility: CHU Besançon - Hôpital Jean Minjoz
city: Clermont-Ferrand
country: France
facility: CHU Clermont Ferrand - Hôpital d'Estaing
city: Clichy
country: France
facility: Hôpital Beaujon
city: Grenoble
country: France
facility: CHU de Grenoble - Hôpital Nord
city: La Roche-sur-Yon
country: France
facility: Centre Hospitalier Départemental Les Oudairies
city: Lille
country: France
facility: CHU Lille - Hôpital Claude Huriez
city: Marseille
country: France
facility: Hôpital Nord - CHU Marseille
city: Montpellier
country: France
facility: Hopital Saint Eloi
city: Nantes
country: France
facility: CHU Nantes - Hôtel Dieu
city: Nice
country: France
facility: CHU Nice - Hôpital de l'Archet 2
city: Reims
country: France
facility: CHU Reims - Hôpital Robert Debré
city: Rennes
country: France
facility: CHU Rennes - Hôpital Pontchaillou
city: Rouen
country: France
facility: CHU de Rouen - Hôpital Charles Nicolle
city: Saint-Étienne
country: France
facility: CHU Saint Etienne - Hôpital Nord
city: Strasbourg
country: France
facility: CHU Strasbourg - Hôpital Hautepierre
city: Toulouse
country: France
facility: Hopital Rangueil
city: Vandœuvre-lès-Nancy
country: France
facility: Hôpital de Brabois Adultes
city: Berlin
country: Germany
facility: Charite Universitaetsmedizin Berlin - Campus Benjamin Franklin
city: Düsseldorf
country: Germany
facility: Florence-Nightingale-Krankenhaus-Diakonie Kaiserswerth
city: Frankfurt
country: Germany
facility: Klinikum der Johann Wolfgang Goethe-Universitaet
city: Halle
country: Germany
facility: Studiengesellschaft BSF Unternehmergesellschaft haftungsbeschraenkt
city: Halle
country: Germany
facility: Universitaetsklinikum Halle (Saale)
city: Hanover
country: Germany
facility: Medizinische Hochschule Hannover
city: Neuss
country: Germany
facility: Johanna-Etienne-Krankenhaus
city: Nordhausen
country: Germany
facility: Tumorzentrum Nordthueringen MVZ GmbH
city: Riesa
country: Germany
facility: Dr. Tasso Bieler
city: Ulm
country: Germany
facility: Universitaetsklinikum Ulm
city: Balatonfured
country: Hungary
facility: DRC Gyogyszervizsgalo Kozpont Kft.
city: Budapest
country: Hungary
facility: Obudai Egeszsegugyi Centrum Kft.
city: Budapest
country: Hungary
facility: Pannonia Maganorvosi Centrum
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Debrecen
country: Hungary
facility: Debreceni Egyetem
city: Debrecen
country: Hungary
facility: Vasutegeszsegugyi Kft. - Debreceni Egeszsegugyi Kozpont
city: Győr
country: Hungary
facility: Petz Aladar Megyei Oktato Korhaz
city: Bologna
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi
city: Brescia
country: Italy
facility: Fondazione Poliambulanza Istituto Ospedaliero
city: Catanzaro
country: Italy
facility: Azienda Ospedaliero Universitaria Mater Domini
city: Milano
country: Italy
facility: I.R.C.C.S Policlinico San Donato
city: Negrar
country: Italy
facility: Ospedale Sacro Cuore Don Calabria
city: Padova
country: Italy
facility: Azienda Ospedaliera di Padova
city: Palermo
country: Italy
facility: Azienda Ospedaliero Universitaria Policlinico Paolo Giaccone
city: Pisa
country: Italy
facility: Azienda Ospedaliero Universitaria Pisana (Presidio di Cisanello)
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
city: Bydgoszcz
country: Poland
facility: Szpital Uniwersytecki nr 2 im.dr J. Biziela
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Kraków
country: Poland
facility: Centrum Medyczne Plejady
city: Lodz
country: Poland
facility: Santa Familia Centrum Badan, Profilaktyki i Leczenia
city: Lublin
country: Poland
facility: Wojskowy Szpital Kliniczny w Lublinie
city: Piotrkow Trybunalski
country: Poland
facility: Trialmed CRS
city: Poznan
country: Poland
facility: Centrum Medyczne Grunwald
city: Pulawy
country: Poland
facility: KO-MED Centra Kliniczne Pulawy
city: Rzeszow
country: Poland
facility: Gabinet Lekarski Bartosz Korczowski
city: Warszawa
country: Poland
facility: Centrum Zdrowia MDM
city: Warszawa
country: Poland
facility: Nzoz Vivamed
city: Wierzchosławice
country: Poland
facility: Centrum Zdrowia Tuchow Sp. z o.o.
city: Wroclaw
country: Poland
facility: Centrum Badan Klinicznych Piotr Napora Lekarze Spolka Partnerska
city: Wroclaw
country: Poland
facility: Centrum Medyczne Oporow
city: Wroclaw
country: Poland
facility: LexMedica
city: Belgrade
country: Serbia
facility: Clinical Center Zvezdara
city: Belgrad
country: Serbia
facility: Clinical Center " Dr Dragisa Misovic Dedinje"
city: Belgrad
country: Serbia
facility: Clinical Center Bezanijska Kosa
city: Užice
country: Serbia
facility: General Hospital Uzice
city: Zrenjanin
country: Serbia
facility: General Hospital "Djordje Joanovic"
city: Bardejov
country: Slovakia
facility: Alian s.r.o.
city: Bratislava
country: Slovakia
facility: Cliniq s.r.o.
city: Nové Zámky
country: Slovakia
facility: Gastromedic, s.r.o.
city: Prešov
country: Slovakia
facility: Gastro I, s.r.o.
city: Vranov Nad Topľou
country: Slovakia
facility: Endomed, s.r.o.
city: Šahy
country: Slovakia
facility: Accout Center s.r.o.
city: Celje
country: Slovenia
facility: General Hospital Celje
city: Maribor
country: Slovenia
facility: University Medical Centre Maribor
city: Murska Sobota
country: Slovenia
facility: General Hospital Murska Sobota
city: Barcelona
country: Spain
facility: Centro Médico Teknon
city: Córdoba
country: Spain
facility: Hospital Universitario Reina Sofia
city: Las Palmas De Gran Canaria
country: Spain
facility: Hospital Universitario de Gran Canaria Dr. Negrin
city: Málaga
country: Spain
facility: Hospital Quironsalud Malaga
city: Cherkasy
country: Ukraine
facility: CNE Cherkasy Regional Hospital of Cherkasy Regional Council
city: Dnipro
country: Ukraine
facility: I.I.Mechnykov Dnipropetrovsk Regional Clinical Hospital
city: Ivano-Frankivs'k
country: Ukraine
facility: Central City Clinical Hospital Dept of Theraphy No. 2 SHEI Ivano-Frankivsk NMU
city: Kharkiv
country: Ukraine
facility: CHI Kharkiv City Clinical Hospital #13
city: Kharkiv
country: Ukraine
facility: CNE Prof. O.O. Shalimov Kharkiv City Clinical Hospital #2 of KCC
city: Kharkiv
country: Ukraine
facility: Communal Non-commercial Enterprise of Kharkiv Regional Council Regional Clinical Hospital
city: Kherson
country: Ukraine
facility: CI Kherson CCH
city: Khmelnytskyi
country: Ukraine
facility: Khmelnytska Regional Hospital
city: Kyiv
country: Ukraine
facility: Communal Institution of Kyiv Regional Council Kyiv Regional Clinical Hospital
city: Lviv
country: Ukraine
facility: Lviv Regional Clinical Hospital D.Halytskyi Lviv NMU
city: Ternopil'
country: Ukraine
facility: Ternopil University Hospital
city: Vinnytsia
country: Ukraine
facility: CCH #1 Vinnytsia M.I. Pyrogov NMU Ch of Propaedeutics of IM
city: Vinnytsia
country: Ukraine
facility: M.I. Pyrogov VRCH Dept of Gastroenterology M.I. Pyrogov VNMU
city: Vinnytsia
country: Ukraine
facility: MCIC MC LLC Health Clinic
city: Zaporizhzhia
country: Ukraine
facility: CI City Clinical Hospital #6 Dept of Gastroenterology
city: Zaporizhzhia
country: Ukraine
facility: CNCE "City Hospital 9" Zaporizhzhia CC
city: Úzhgorod
country: Ukraine
facility: A. Novak Transcarpathian Regional Clinical Hospital
city: Bury
country: United Kingdom
facility: Fairfield General Hospital
city: London
country: United Kingdom
facility: Guy's Hospital
city: London
country: United Kingdom
facility: University College London Hospitals
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals Queen's Medical Centre
Study officials:
affiliation: Universitaire Ziekenhuizen KU Leuven
name: Séverine VERMEIRE, MD
role: PRINCIPAL_INVESTIGATOR
References: