A Study of LY3471851 in Adult Participants With Moderately to Severely Active Ulcerative Colitis (UC)

Colitis, Ulcerative Clinical Trial

— INSTRUCT-UC  

Official title:

An Adaptive Phase 2, Randomized, Double Blind, Placebo Controlled Study of LY3471851 (NKTR 358) in Patients With Moderately to Severely Active Ulcerative Colitis

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04677179
• Other study ID #: 17287
• Secondary ID: J1P-MC-KFAH2020-
• Status: Terminated
• Phase: Phase 2
• Start date: March 22, 2021
• Est. completion date: August 9, 2022

Study information

• Verified date: August 2023
• Source: Nektar Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The reason for this study is to determine if the study drug LY3471851 is safe and effective in adult participants with active ulcerative colitis (UC). The study treatment will last about 52 weeks.

Description:

In stage 1, two doses (high and low) of LY3471851 will be compared to placebo. In stage 2, up to two additional doses (to be confirmed) of LY3471851 will be compared to placebo. LY3471851 (NKTR-358) is a potential first-in-class therapeutic that may address an underlying immune system imbalance in people with many autoimmune conditions. It targets the interleukin (IL-2) receptor complex in the body in order to stimulate proliferation of inhibitory immune cells known as regulatory T cells. By activating these cells, LY3471851 may act to bring the immune system back into balance.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 81
• Est. completion date: August 9, 2022
• Est. primary completion date: August 9, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• Have moderately to severely active ulcerative colitis (UC) as defined by a modified Mayo score (MMS) of 4 to 9 with an endoscopic subscore (ES) =2, with endoscopy performed within 14 days before baseline.
• Have evidence of UC extending proximal to the rectum (with =15 centimeters (cm) of involved colon).
• Have up-to-date colorectal cancer surveillance performed according to local standard.
• Participants are either one of the following:
• Have failed conventional treatments including inability to tolerate oral or intravenous corticosteroids or immunomodulators (6-mercaptopurine or azathioprine or methotrexate), or history of corticosteroid dependence (an inability to successfully taper corticosteroids without return of UC) and neither failed or demonstrated intolerance to advanced therapy (eg, tumor necrosis factor (TNF) antagonists, anti-integrin therapies, anti-IL12/23p40 therapies, Janus kinase (JAK) inhibitor) OR,
• Have failed advanced therapies such as treatment with 1 or more advance therapies (eg, tumor necrosis factor [TNF] antagonists, anti-integrin therapies, anti-IL12/23p40 therapies, Janus kinase [JAK] inhibitor) at doses approved for the treatment of UC with documented history of failure to respond to or tolerate such treatment.
• Have had an established diagnosis of UC of =3 months in duration before baseline which includes endoscopic evidence of UC and a histopathology report that supports a diagnosis of UC. Supportive endoscopy and histopathology reports must be available in the source documents.
• Women of child-bearing potential (WOCBP) must test negative for pregnancy as indicated by a negative serum pregnancy test at the screening visit followed by a negative urine pregnancy test within 24 hours prior to first exposure to study drug.

Exclusion Criteria:

• Have been diagnosed with indeterminant colitis, proctitis (colitis limited to the rectum only; less than 15 centimeter (cm) from the anal verge or Crohn's disease.
• Have received any of the following for treatment of UC: cyclosporine, tacrolimus, mycophenolate mofetil or thalidomide within 2 weeks of screening, rectally administered corticosteroids or 5-aminosalicylic acid treatments within 2 weeks of screening.
• Have had or will need abdominal surgery for UC (for example, subtotal colectomy).
• Have failed 3 or more classes of advanced therapies approved for treatment of UC (eg, tumor necrosis factor [TNF] antagonists, anti-integrin therapies, anti-IL12/23p40 therapies, Janus kinase [JAK] inhibitor).
• Have evidence of toxic megacolon, intra-abdominal abscess, or stricture/stenosis within the small bowel or colon.
• Have any history or evidence of cancer of the gastrointestinal tract
• Have myocardial infarction, unstable ischemic heart disease, stroke or heart failure within 12 months prior to screening.

Related Conditions & MeSH terms

• Colitis
• Colitis, Ulcerative
• Ulcer

Intervention

Drug:
• LY3471851
administered SC
• Placebo
administered SC

Locations

Country	Name	City	State
Argentina	Centro de Educación Médica e Investigaciones Clínicas "Norberto Quirno" CEMIC	Caba	Buenos Aires
Argentina	DOM- Centro de Reumatologia	Caba	Buenos Aires
Argentina	Mautalen Salud e Investigacion-Centro de Osteopatías Médicas	Ciudad Autonoma De Buenos Air	Buenos Aires
Argentina	Centro Médico Privado de Reumatología	Tucumán
Australia	Paratus Clinical Research Brisbane	Albion	Queensland
Australia	Concord Repatriation General Hospital	Concord	New South Wales
Australia	St. Vincent's Hospital	Fitzroy	Victoria
Australia	Mater Adult Hospital Brisbane	South Brisbane	Queensland
Belgium	Université Libre de Bruxelles - Hôpital Erasme	Brussels	Bruxelles-Capitale, Région De
Belgium	AZ Maria Middelares	Gent
Belgium	Centre Hospitalier de Wallonie Picarde - Site Notre Dame	Tournai	Wallonne, Région
Brazil	Upeclin - Unidade de Pesquisa Clínica da Faculdade de Medicina de Botucatu - UNESP	Botucatu	São Paulo
Brazil	Chronos Pesquisa Clínica	Brasília	Distrito Federal
Brazil	HMCP - Hospital e Maternidade Celso Pierro - PUC-Campinas	Campinas	Sao Paulo
Brazil	Nucleo de Pesquisa Clínica do Rio Grande do Sul-NPCRS	Porto Alegre	Rio Grande Do Sul
Brazil	Pesquisare	Santo Andre	Sao Paulo
Brazil	CEMEC - Centro Multidisciplinar de Estudos Clinicos EPP Ltda	São Bernardo do Campo	São Paulo
Brazil	Hepatogastro	Sao Paulo
Brazil	Instituto de Assistencia Medica ao Servidor Publico Estudo Estadual	Sao Paulo	SP
Canada	Gastroenterology and internal medicine research institute	Edmonton	Alberta
Canada	CISSS de la Montérégie - Centre Hôpital Charles-Le Moyne	Greenfield Park	Quebec
Canada	Gastroenterology Research, Nova Scotia Health Authority	Halifax	Nova Scotia
Canada	McGill University	Montreal	Quebec
China	First affiliated Hospital of Sun Yat-Sen University	Guangzhou	Guangdong
China	The Sixth Affiliated Hospital, Sun Yat-Sen University	Guangzhou	Guangdong
China	Sir Run Run Shaw Hospital	Hangzhou	Zhejiang
China	The First Affiliated Hospital of Anhui Medical University	HefeiCity	Anhui
China	The First Affiliated Hospital of Nanchang University	Nanchang	Jiangxi
China	Shanghai Jiaotong University School of Medicine Ruijin Hospital	Shanghai	Shanghai
China	Taian City Central Hospital	Taian	Shandong
China	Tongji Hosp Tongji Med Col Huazhong Univ of Sci & Tech	Wu Han	Hubei
China	Union Hospital Tongji Medical College Huazhong University of Science and Technology	Wuhan	Hubei
Czechia	MUDr. Gregar, s.r.o.	Olomouc
Czechia	PreventaMed, s.r.o.	Olomouc
Czechia	A-Shine	Pilsen	Plzen-mesto
Czechia	I. Interni klinika FN Plzen	Plzen-Lochotin
Czechia	Nemocnice Slaný	Slany
France	CHU De Grenoble Hopital Albert Michallon	Grenoble Cedex 09
France	Centre Hospitalier de Mont de Marsan	Mont-de-Marsan Cedex
Georgia	Acad. F. Todua Medical Center - Research Institute of Clinical Medicine	Tbilisi
Georgia	Medical Center: Medinvestment	Tbilisi
Hungary	Clinexpert SMO	Budapest
Hungary	Óbudai Egészségügyi Centrum	Budapest
Hungary	Bugát Pál Kórház	Gyöngyös
Hungary	CLINFAN Szolgáltató Kft	Szekszard
India	Postgraduate Institute of Medical Education & Research	Chandigarh
India	Apollo Speciality Hospital - Teynampet	Chennai	Tamil Nadu
India	SR Kalla Memorial Gastro & General Hospital	Jaipur	Rajasthan
India	Kingsway Hospital	Nagpur	Maharashtra
India	Midas Multispeciality Hospital Pvt.Ltd.	Nagpur	Maharashtra
India	Shree Giriraj Multispeciality Hospital	Rajkot	Gujarat
India	Gujarat Hospital - Gastro and Vascular Centre	Surat	Gujarat
India	Gandhi Hospital	Telangana
Israel	Soroka Medical Center	Beer Sheva
Israel	Galilee Medical Center - Internal A	Nahariya
Israel	Kaplan Medical Center	Rehovot
Japan	Fukuoka University Chikushi Hospital	Chikushino	Fukuoka
Japan	Sai Gastroenterologist Proctology	Fujiidera	Osaka
Japan	Fukuoka University Hospital	Fukuoka
Japan	Matsuda Hospital	Hamamatsu-shi	Shizuoka-Ken
Japan	Sameshima Hospital	Kagoshima
Japan	Showa University Koto Toyosu Hospital	Koto-ku	Tokyo
Japan	Kyorin University Hospital	Mitaka	Tokyo
Japan	Infusion Clinic	Osaka-shi	Osaka-Fu
Japan	Sapporo Medical University Hospital	Sapporo	Hokkaido
Japan	Tokushukai Sapporo Tokushukai Hospital	Sapporo-shi	Hokkaido
Japan	Center Hospital of the National Center for Global Health and Medicine	Shinjuku-ku	Tokyo-To
Japan	Toyama Prefectural Central Hospital	Toyama
Japan	Yamagata University Hospital	Yamagata
Korea, Republic of	Inje University Haeundae Paik Hospital	Busan
Korea, Republic of	Yonsei University Wonju Severance Christian Hospital	Gangwon-do
Korea, Republic of	Samsung Medical Center	Seoul	Korea
Korea, Republic of	Seoul St. Mary's Hospital	Seoul	Korea
Korea, Republic of	Ajou University Hospital	Suwon-si	Gyeonggi-do
Latvia	Pauls Stradins Clinical Univeristy Hospital	Riga	Riga
Poland	Szpital Miejski Sw. Jana Pawla II	Elblag
Poland	NZOZ Vivamed	Warsaw	Mazowieckie
Poland	WIP Warsaw IBD Point Profesor Kierkus	Warszawa
Poland	ETG Zamosc	Zamosc
Romania	SC Centrul Medical Sana SRL	Bucuresti
Romania	SC Med Life SA	Bucuresti
Romania	Spital Clinic Colentina	Bucuresti
Romania	Spitalul Clinic Judetean de Urgenta Cluj	Cluj-Napoca
Romania	SC Pelican SRL	Oradea	Bihor
Romania	S.C. Materna Care S.R.L.	Timisoara
Russian Federation	Olla-Med	Moscow	Moskva
Russian Federation	Open Joint Stock Company Clinical and Diagnostic Center Euromedservice	Moscow
Russian Federation	Novosibirski Gastrocenter	Novosibirsk	Novosibirskaya Oblast'
Russian Federation	The University Clinic of OSMU	Omsk
Russian Federation	Rostov State Medical University	Rostov-on-Don	Rostovskaya Oblast'
Russian Federation	SPb SBIH "City Mariinskaya Hospital"	Saint-Petersburg
Russian Federation	GOU VPO St-Petersburg SMA n/a Mechnikov Fed. Agen of Health	St. Petersburg
Slovakia	FNsP FDRoosevelta Banska Bystrica	Banska Bystrica
Slovakia	ENDOMED s.r.o.	Kosice
Ukraine	Medical Center of LLC Medical Center Clinic of Family Medicine	Dnipro
Ukraine	Medical Center of Limited Liability Company "Medical Center "Consilium Medical"	Kiev	Kyiv
Ukraine	International Institute of Clinical Trials LLC	Kyiv
Ukraine	Lviv Railway Clinical Hospital	Lviv	Lvivska Oblast
Ukraine	Lviv Regional Endocrinology Dispensary	Lviv	Lvivska Oblast
Ukraine	Communal Enterprise "Odesa Regional Clinical Hospital"	Odesa
Ukraine	A. Novak Transcarpathian Regional Clinical Hospital	Uzhgorod
Ukraine	CCH #1 Vinnytsia M.I. Pyrogov NMU Ch of Propaedeutics of IM	Vinnytsia
Ukraine	Vinnytsia War Veterans Regional Clinical Hospital	Vinnytsia
Ukraine	Diacenter LLC	Zaporizhzhia
United Kingdom	Royal Derby Hospital	Derby	Derbyshire
United Kingdom	Whipps Cross University Hospital	Leytonstone	London
United Kingdom	Guys/St. Thomas Hospital	London	Surrey
United Kingdom	St. George's Hospital	London
United Kingdom	York Hospital	York
United States	Biopharma Informatic, LLC	Houston	Texas
United States	I.H.S. Health, LLC	Kissimmee	Florida
United States	Dedicated Clinical Research	Litchfield Park	Arizona
United States	Atlantic Digestive Health Institute	Morristown	New Jersey
United States	Care Access Research - Ogden	Ogden	Utah
United States	Gastroenterology Associates of Pensacola, PA	Pensacola	Florida
United States	Southern Star Research Institute, LLC	San Antonio	Texas

Sponsors (2)

Lead Sponsor	Collaborator
Nektar Therapeutics	Eli Lilly and Company

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Brazil,  Canada,  China,  Czechia,  France,  Georgia,  Hungary,  India,  Israel,  Japan,  Korea, Republic of,  Latvia,  Poland,  Romania,  Russian Federation,  Slovakia,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants Who Achieved Clinical Remission at Week 12	Clinical remission is defined as achieving a Modified Mayo Score (MMS) sub-score for rectal bleeding=0, stool frequency=0, or stool frequency=1 with = 1 point decrease from baseline, and endoscopy=0 or 1 (excluding friability). The MMS is a scoring system for assessment of UC and is composed of sub-scores of stool frequency (range: 0 to 3, where 0=normal number of stools, 3=5 or more stools more than normal), endoscopy (range: 0 to 3, where 0=normal or inactive disease, 3=severe disease [spontaneous bleeding, ulceration]), rectal bleeding (range: 0 to 3, where 0=no blood seen, 3=blood alone passed). Total MMS score is sum of all sub-scores and ranges from 0 to 9, with higher scores indicating higher disease activity.	Week 12
Secondary	Percentage of Participants Who Achieved Clinical Response at Week 12	Clinical response is defined as a decrease in the MMS of =2 points and =30% decrease from baseline, and a decrease of =1 point in the rectal bleeding sub-score from baseline or a rectal bleeding score of 0 or 1. The MMS is a scoring system for assessment of UC and is composed of sub-scores of stool frequency (range: 0 to 3, where 0=normal number of stools, 3=5 or more stools more than normal), endoscopy (range: 0 to 3, where 0=normal or inactive disease, 3=severe disease [spontaneous bleeding, ulceration]), rectal bleeding (range: 0 to 3, where 0=no blood seen, 3=blood alone passed). Total MMS score is sum of all sub-scores and ranges from 0 to 9, with higher scores indicating higher disease activity.	Week 12
Secondary	Percentage of Participants Who Achieved Endoscopic Remission at Week 12	Endoscopic remission is defined as achieving a MMS sub-score for endoscopy=0 or 1 (excluding friability). The MMS is a scoring system for assessment of UC and is composed of sub-scores of stool frequency (range: 0 to 3, where 0=normal number of stools, 3=5 or more stools more than normal), endoscopy (range: 0 to 3, where 0=normal or inactive disease, 3=severe disease [spontaneous bleeding, ulceration]), rectal bleeding (range: 0 to 3, where 0=no blood seen, 3=blood alone passed). Total MMS score is sum of all sub-scores and ranges from 0 to 9, with higher scores indicating higher disease activity.	Week 12
Secondary	Percentage of Participants Who Achieved Endoscopic Response at Week 12	Endoscopic response is defined as a decrease of =1 point in the MMS endoscopy sub-score from baseline. The MMS is a scoring system for assessment of UC and is composed of sub-scores of stool frequency (range: 0 to 3, where 0=normal number of stools, 3=5 or more stools more than normal), endoscopy (range: 0 to 3, where 0=normal or inactive disease, 3=severe disease [spontaneous bleeding, ulceration]), rectal bleeding (range: 0 to 3, where 0=no blood seen, 3=blood alone passed). Total MMS score is sum of all sub-scores and ranges from 0 to 9, with higher scores indicating higher disease activity.	Week 12
Secondary	Percentage of Participants Who Achieved Symptomatic Remission at Week 12	Symptomatic remission is defined as achieving a MMS sub-score for stool frequency=0, or stool frequency=1 with a decrease of =1 point from baseline, and rectal bleeding =0. The MMS is a scoring system for assessment of UC and is composed of sub-scores of stool frequency (range: 0 to 3, where 0=normal number of stools, 3=5 or more stools more than normal), endoscopy (range: 0 to 3, where 0=normal or inactive disease, 3=severe disease [spontaneous bleeding, ulceration]), rectal bleeding (range: 0 to 3, where 0=no blood seen, 3=blood alone passed). Total MMS score is sum of all sub-scores and ranges from 0 to 9, with higher scores indicating higher disease activity.	Week 12
Secondary	Percentage of Participants Who Achieved Symptomatic Response at Week 12	Symptomatic response is defined as a =30% decrease from baseline in the composite clinical endpoint of the sum of MMS sub-scores of stool frequency and rectal bleeding. The MMS is a scoring system for assessment of UC and is composed of sub-scores of stool frequency (range: 0 to 3, where 0=normal number of stools, 3=5 or more stools more than normal), endoscopy (range: 0 to 3, where 0=normal or inactive disease, 3=severe disease [spontaneous bleeding, ulceration]), rectal bleeding (range: 0 to 3, where 0=no blood seen, 3=blood alone passed). Total MMS score is sum of all sub-scores and ranges from 0 to 9, with higher scores indicating higher disease activity.	Week 12
Secondary	Percentage of Participants Who Achieved Histologic Remission at Week 12	Histologic Remission is defined as Geboes score <2 or subscores = 0 for Grade 2a, 2b, 3, 4, and 5. The Geboes score is a 7-item instrument used to identify histologic changes in UC. The 7 items are Grade 0: Architectural changes (0=No abnormality to 3=Severe diffuse or multifocal abnormalities); Grade 1: Chronic inflammatory infiltrate (0=No increase to 3=Marked increase); Grade 2A: lamina propria eosinophils (0=No increase to 3=Marked increase); Grade 2B: lamina propria neutrophils (0= No increase to 3=Marked increase); Grade 3: Neutrophils in epithelium (0=None to 3=>50% crypts involved); Grade 4: Crypt destruction(0=none to 3=Unequivocal crypt destruction),and Grade 5: Erosion or ulceration:(0=No erosion, ulceration or granulation to 4=Ulcer or granulation tissue). The grade with severe histological observation is considered the Geboes score and ranges from 0 to 4, with higher scores indicating severe disease.	Week 12
Secondary	Percentage of Participants Who Achieved Histologic-Endoscopic Mucosal Healing (HEMH)	HEMH is defined as Geboes score <2 AND endoscopic remission. Geboes score is a 7-item instrument used to identify histologic changes in UC. The 7-items are Grade 0: Architectural changes (0=No abnormality to 3=Severe diffuse or multifocal abnormalities); Grade 1: Chronic inflammatory infiltrate (0=No increase to 3=Marked increase); Grade 2A: lamina propria eosinophils (0=No increase to 3=Marked increase); Grade 2B: lamina propria neutrophils (0= No increase to 3=Marked increase); Grade 3: Neutrophils in epithelium (0=None to 3=>50% crypts involved); Grade 4: Crypt destruction(0=none to 3=Unequivocal crypt destruction),and Grade 5: Erosion or ulceration:(0=No erosion, ulceration or granulation to 4=Ulcer or granulation tissue). The grade with severe histological observation is considered the Geboes score and ranges from 0 to 4, with higher scores indicating severe disease. Endoscopic remission is defined as achieving a MMS sub-score for endoscopy=0 or 1 (excluding friability).	Week 12
Secondary	Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) - Total Score	IBDQ is a 32-item questionnaire that measures four aspects of participants' lives: symptoms directly related to the primary bowel disturbance (10 items), systemic symptoms (5 items), emotional function (12 items), and social function (5 items). Responses are graded on a 7-point Likert scale, where 7 denotes "not a problem at all" and 1 denotes "a very severe problem." The responses are summed to produce a total score ranging from 32 to 224, with higher score indicating a better quality of life. LS Mean was calculated using ANCOVA (analysis of covariance) model with treatment, baseline value, previous advanced therapy failure status (yes/no), baseline corticosteroid use (yes/no), baseline disease activity (MMS: [4 to 6] or [7 to 9]) and region (North America/Europe/Other) as fixed factors.	Baseline, Week 12
Secondary	Pharmacokinetics (PK): Trough Concentration of LY3471851 (Ctrough) at Week 12	C-trough is the concentration of drug in the blood immediately before the next dose was administered.	Predose at week 12

External Links

•   A Study of LY3471851 in Adult Participants With Moderately to Severely Active Ulcerative Colitis (UC) ( INSTRUCT-UC )