Efficacy&Safety of ALTB-168 in Patients With Moderate to Severe Active,Anti-TNF Alpha and/or Anti-integrin Refractory UC (TNF)

Efficacy and Safety of ALTB-168 in Patients With Moderate to Severe Active, Anti-TNF Alpha and/or Anti-integrin Refractory Ulcerative Colitis: a 26-week, Open-label, Multi-center, Phase II Proof of Principle Trial

To evaluate the efficacy and safety of Neihulizumab (ALTB-168) administered intravenously in patients with moderate to severe active ulcerative colitis who are refractory or intolerant to anti-Tumor Necrosis Factor α and/or anti-integrin treatments.

Study Overview

• Status: Terminated
• Conditions: Ulcerative Colitis
• Intervention / Treatment: Biological: ALTB-168

Detailed Description

This is a Phase II, open label, single arm, multiple dose proof of principle study to test the efficacy and safety of Neihulizumab in patients with moderate to severe active ulcerative colitis and who has failed or are intolerant to anti-TNFα and/or anti-integrin therapy. A minimum of 30 patients and a maximum of 40 will be recruited in 1 dosing group. For efficacy evaluation, the primary endpoint is the proportion of patients with clinical response, defined as ≥ 3- point reduction in MCS, a 30% or greater decrease from the baseline score, and with a 1-point or greater decrease of the rectal bleeding subscore or an absolute rectal bleeding score of 0 or 1 at Week 12. Safety assessments will consist of evaluating physical examination, vital signs (blood pressure, heart rate, respiratory rate, body temperature and oxygen saturation), safety laboratory tests, adverse events and tolerability.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2

Contacts and Locations

Study Locations

• Puerto Rico
  • Vega Baja, Puerto Rico, 00694
    • Wellness Clinical Research (WCR)
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Lynn Institute of the Ozarks
  • California
    • Newport Beach, California, United States, 92660
      • Stomach Doctor - Surinder Saini, MD - Fountain Valley
  • Florida
    • Hialeah, Florida, United States, 33016-2202
      • Wellness Clinical Research (WCR)
    • Lake Wales, Florida, United States, 33853
      • Wellness Clinical Research (WCR)
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
    • Chicago, Illinois, United States, 60611
      • Northwestern University Feinberg School of Medicine
  • Maryland
    • Rockville, Maryland, United States, 20850
      • Capitol Research
  • New York
    • New York, New York, United States, 10021
      • Weill Cornell Medical College
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center (UWMC) - Digestive Disease Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients must provide written informed consent;
2. Age 18-75 years;
3. Diagnosis of UC ≥ 12 weeks prior to screening by full colonoscopy (i.e., ≥ 12 weeks after first diagnosis by a physician according to American College of Gastroenterology guidelines);

4. Moderate-to-severe active UC, at time of screening, defined as:

   1. Mayo Clinic Score (MCS) of 6 points or higher, AND
   2. a centrally read MCS endoscopic subscore of grade 2 or higher, AND
   3. MCS rectal bleeding subscore of 1 point or higher, AND
   4. disease extending 15 cm or more from the anal verge;

5. Stable doses of concomitant medications, including :

   1. Stable oral corticosteroids (i.e., ≤ 20 mg/day of prednisone, ≤ 9 mg/day of budesonide) ≥ 2 weeks before D1 dosing; Taper of oral corticosteroids per Investigator's discretion during the study is allowed;
   2. Stable oral 5-amyinosalicylic acid dose ≥ 2 weeks before D1 dosing;
   3. Stable immunosuppressant including azathioprine, mercaptopurine, or methotrexate ≥ 8 weeks before D1 dosing. Patients taking methotrexate also are advised to take folic acid 1 mg/day or equivalent if there is no contraindication;
   4. Stable doses of probiotics ≥ 2 weeks before D1 dosing;
   5. Stable anti-diarrheas ≥ 2 weeks before D1 dosing;
6. Patients must have previously received anti-tumor necrosis factor alpha (anti- TNF alpha and/or anti-integrin therapy for UC and demonstrated an inadequate response, loss of response, or intolerance, and must have discontinued therapy ≥ 8 weeks before D1 dosing;
7. Patients previously treated with cyclosporine or tacrolimus must have discontinued therapy ≥ 4 weeks before D1 dosing;
8. Topical corticosteroids and topical 5-amyinosalicylic acid preparations must have been withdrawn ≥ 2 weeks before D1 dosing;
9. Nonsteroidal anti-inflammatory drugs (NSAIDs) must have been discontinued ≥ 4 weeks before D1 dosing;
10. Tofacitinib or other Janus kinase (JAK) inhibitors must have been discontinued ≥ 2 weeks before D1 dosing;
11. Patients previously treated with tube feeding, defined formula diets, or parenteral alimentation/nutrition must have discontinued treatment 3 weeks before D1 dosing;
12. Females with reproductive potential must have a negative pregnancy test result before enrollment. Men and women with reproductive potential have to be willing to use a highly effective method of contraception from study start to ≥ 3 months after the final dose of the study drug. A highly effective method of birth control is defined as one which results in a low failure rate (less than 1% per year).

Exclusion Criteria:

GI related exclusion criteria:

1. Indeterminate colitis (Inflammatory bowel disease unclassified, IBD-U) or suspected Crohn's disease
2. Any history of colectomy
3. Presence of an ileostomy or colostomy
4. A history or evidence of colonic mucosal dysplasia

5. Short gut syndrome

   General health related exclusion criteria:

6. Pregnant or lactating
7. Inability to comply with study protocol in the opinion of the investigator
8. History of dysplasia or malignancy in recent 5 years, except completely excised basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix
9. Cirrhosis or active alcohol abuse per the judgement of investigator
10. Poorly controlled diabetes (HbA1c > 8.0%)
11. Significant screening ECG abnormalities, including evidence of acute myocardial infarction, complete left bundle branch block, second-degree heart block, or complete heart block
12. Impaired renal function (calculated creatinine clearance < 60 mL/min)
13. Impaired hepatic function in the absence of diagnosis of primary sclerosing cholangitis, serum transaminase > 2.5x Upper Limit Normal (ULN), alkaline phosphatase > 2.5x ULN, or increased total bilirubin judged by the investigator to be clinically significant, or a diagnosis of primary sclerosing cholangitis, serum transaminases > 3x ULN, alkaline phosphatase > 3x ULN, or total bilirubin > 2.5x ULN judged by the investigator to be clinically significant
14. Moderate to severe anemia (Hb < 8g/dL)
15. Thrombocytopenia (platelet count < 75,000/uL)
16. Evidence of current or previous clinically significant disease, medical condition or finding in the medical examination that in the opinion of the investigator, would compromise the safety of the patient or quality of the data
17. Requiring parenteral corticosteroid treatment.
18. Received any investigational product within 1 year.

19. History of drug abuse according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-V) criteria within 12 months prior to screening or positive drug screening tests.

    Infection related exclusion criteria:

20. Human immune deficiency virus (HIV) infection or known HIV-related malignancy.
21. Acute or chronic hepatitis B or C, or carrier status. Patients with anti-HBc Ab but with undetectable anti-HBs Ab should also be excluded.
22. Positive IgM antibody titers in the presence of negative IgG titers to Epstein-Barr virus
23. Positive stool test for ova or parasites, positive stool culture for pathogens, or positive stool toxin assay for Clostridium difficile at screening. Patients with the positive stool toxin assay for C. difficile at screening could be rescreened if they are being treated for C. difficile and a repeat stool toxin assay at least 4 weeks after the completion of treatment is negative with no evidence of recurrence.
24. Intestinal mucosa biopsy positive for cytomegalovirus (CMV) at screening.
25. Positive screening test for latent Mycobacterium tuberculosis (TB) infection. Patients with a history of latent TB infection who received an appropriate and documented course of therapy can be included if the screening examination and a chest x-ray performed ≤ 3 months before screening revealed no evidence of current active infection. If a Quantiferon TB test is indeterminate, the test should be repeated, and if the result is again indeterminate, such patient should be excluded.
26. History of any opportunistic infection ≤ 12 weeks before D1 dosing.
27. Any current or recent (≤ 4 weeks before D1 dosing) symptoms/signs of infection.
28. Received oral antibiotics ≤ 4 weeks before D1 dosing or intravenous antibiotics ≤ 8 weeks before D1 dosing.
29. Received a live attenuated vaccine ≤ 4 weeks before D1 dosing.
30. Neutropenia (absolute neutrophil count < 1,500/uL).
31. Lymphocytopenia (absolute lymphocyte count < 500 /uL).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ALTB-168; intravenous doses of ALTB-168	Biological: ALTB-168; monoclonal antibody; Other Names: Neihulizumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Proportion of Patients With Clinical Response at Week 12	The clinical response is defined as a ≥ 3-point reduction in Mayo Clinic Score, a 30% or greater decrease from the baseline score, and with a 1-point or greater decrease of the rectal bleeding subscore or an absolute rectal bleeding score of 0 or 1, The colonic site with maximum inflammation was determined by Mayo endoscopic subscore (MES) defined as follows: normal (0 points); erythema, decreased vascular pattern, mild friability (1 point); absent vascular pattern, friability, erosions (2 points); and spontaneous bleeding or ulceration (3 points). Lower score means disease improvement.	week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Proportion of Patients With Clinical Response (mITT)	The proportion of patients with clinical response defined as a ≥2-point decrease in partial MCS (pMCS), and with a 1 point or greater decrease of the rectal bleeding subscale or an absolute rectal bleeding score of 0 or 1. The colonic site with maximum inflammation was determined by Mayo endoscopic subscore (MES) defined as follows: normal (0 points); erythema, decreased vascular pattern, mild friability (1 point); absent vascular pattern, friability, erosions (2 points); and spontaneous bleeding or ulceration (3 points). Lower score means disease improvement.	weeks 6,16, 20 and 26
The Proportion of Patients With Clinical Remission	The number of patients with clinical remission, defined as MCS of 2 or lower (or pMCS of 1 or lower) and no subscore higher than 1. The colonic site with maximum inflammation was determined by Mayo endoscopic subscore (MES) defined as follows: normal (0 points); erythema, decreased vascular pattern, mild friability (1 point); absent vascular pattern, friability, erosions (2 points); and spontaneous bleeding or ulceration (3 points). Lower score means disease improvement.	weeks 6,16, 20 and 26
Flexible Sigmoidoscopy Subscore Changes From Baseline	The mean (SD) observed flexible sigmoidoscopy subscore change from baseline (CFB). Baseline is defined as the last available assessment prior to the first administration of the study drug. The sigmoidoscopic improvement is defined as any decrease in Mayo Clinic Score (MCS) endoscopic subscore, at Weeks 12 and 26. MCS range is 1-3. The colonic site with maximum inflammation was determined by Mayo endoscopic subscore (MES) defined as follows: normal (0 points); erythema, decreased vascular pattern, mild friability (1 point); absent vascular pattern, friability, erosions (2 points); and spontaneous bleeding or ulceration (3 points). Lower score means disease improvement.	Baseline, week 12- and week 26 after the first treatment
The Number of Patients With Mucosal Healing	The mucosal healing is defined as an absolute subscore for endoscopy of 0 or 1 The colonic site with maximum inflammation was determined by Mayo endoscopic subscore (MES) defined as follows: normal (0 points); erythema, decreased vascular pattern, mild friability (1 point); absent vascular pattern, friability, erosions (2 points); and spontaneous bleeding or ulceration (3 points). Lower score means disease improvement.	at 12- and 26-week after the first treatment
Change of Histological Activity Grade From Baseline Using the Geboes System	The number of patients with histological activity Geboes Score ≤ 3.1 (worst of both rectum and sigmoid colon). The original Geboes grade system is from Grade 0 to Grade 5. The following are the grades: Grade 0: Architectural changes Grade 1: Chronic inflammatory infiltrate Grade 2A: Eosinophils in lamina propria Grade 2B: Neutrophils in lamina propria Grade 3: Neutrophils in epithelium Grade 4:Crypt destruction Grade 5: Erosions and ulcerations	at 12- and 26-week after the first treatment
The Number of Patients With Histological Healing	The histological healing is defined as histological grade = 0	at 12- and 26-week after the first treatment
Change of Inflammatory Bowel Disease Questionnaire (IBDQ) Score From Baseline	Number of Participants with a Clinically Significant Difference in the Inflammatory Bowel Disease Questionnaire (IBDQ) Score From Baseline, to Week 12 and Week 26. The IBDQ is a questionnaire used for an assessment of Health Related Quality of Life (HRQoL) in patients with the Inflammatory Bowel Disease (IBD). The IBDQ has a possible score range of 32 (minimum) to 224 (maximum), where a higher score indicates better HRQoL. A difference of 16 points from Baseline Assessment (Baseline Score) to Week 12, and Baseline Assessment (Baseline Score) to Week 26, is considered clinically significant. The outcome measure is assessed by comparing each patient's change in individual IBDQ score from Baseline to Week 12, and from Baseline to Week 26. Patients who achieved the 16 point difference (improvement of the IBDQ score from the baseline indicating the Clinically Significant Difference) are included as responders to the treatment.	at 12- and 26-week after the first treatment
The Number of Patients With Inflammatory IBDQ Response	The Inflammatory Bowel Disease Questionnaire (IBDQ) has a possible score range of 32 (minimum) to 224 (maximum), where a higher score indicates better Health Related Quality of Life (HRQoL). A difference of 16 points from Baseline to Week 12 and Baseline to Week 26, is considered clinically significant. The outcome measure will be assessed by comparing each patient's change in individual IBDQ score from Baseline to Week 12, and from Baseline to Week 26, to assess whether a response was seen.	at 12- and 26-week after the first treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
CRP Changes From Baseline (CFB) (Exploratory)	Change in biomarkers of CRP (C-reactive protein). C-reactive protein (CRP) is a biomarker produced by your liver in response to inflammation. Normal CRP value is below 1 mg/L. 1-3 mg/L is in the "yellow zone", indicating some inflammation >3 mg/L is in the "red zone", meaning there is significant inflammation	Am 4, Weeks 4, 9, 12, 16, 20, 26; Am 1-3 weeks 4,8,12,16,20, 26
Changes in Fecal Calprotectin (CFB) - Exploratory Biomarker	Faecal calprotectin changes from the baseline at Week 4, 9, 12, 16, 20, and 26 were measured. Baseline is defined as the last available assessment prior to the first administration of the study drug. Faecal calprotectin is measured as mcg/g, so the results come back as a numeric value. A level under 50 is considered to be 'normal'. A level between 50 and 100, coupled with digestive symptoms, means IBS is likely. Lower level means improvement.	Am 4, Weeks 4, 9, 12, 16, 20, 26; Am 1-3 weeks 4,8,12,16,20, 26

Collaborators and Investigators

• Sponsor: AltruBio Inc.
• Investigators: Study Director: Shih-Yao Lin, MD, PhD, AltruBio Inc.; Principal Investigator: David T Rubin, MD, University of Chicago

Study record dates

Study Major Dates

• Study Start (Actual): May 4, 2018
• Primary Completion (Actual): April 6, 2020
• Study Completion (Actual): June 1, 2020

Study Registration Dates

• First Submitted: September 27, 2017
• First Submitted That Met QC Criteria: September 27, 2017
• First Posted (Actual): September 29, 2017

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: January 3, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Ulcerative Colitis
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Inflammatory Bowel Diseases; Ulcer; Colitis; Colitis, Ulcerative
• Other Study ID Numbers: 2017.008.01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No