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

Study Overview
=================
Brief Summary
-----------------
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.

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.

Official Title
-----------------
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

Conditions
-----------------
Ulcerative Colitis

Intervention / Treatment
-----------------
* Biological: ALTB-168


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must provide written informed consent and to be compliant with the schedule of study visits and protocol assessments. Age 18-75 years, inclusive, at Screening Diagnosis of UC establised ≥ 12 weeks prior to Screening by standard clinical and edoscopic evidence and corroborated by a histopathology report (i.e., ≥ 12 weeks after first diagnosis by a physician according to American College of Gastroenterology guidelines). Moderate-to-severe active UC, at time of Screening, defined as a modified Mayo Score (mMS) of 4-9, inclusive, with an endoscopic subscore of ≥ 2 (from central reading), and a rectal bleeding (RB) subscore of ≥ 1. Evidence of active UC, extending proximal to the rectum with ≥ 15 cm of involved colon. Stable doses of concomitant medications, including: (1) Subjects receiving oral corticosteroids for the treatment of UC must be on a stable dose of ≤ 20 mg/day (prednisone or equivalent), or ≤ 9 mg/day budesonide. This dose must be stable from 4 weeks prior to Screening until the end of the Induction Phase. (2) Subjects receiving oral 5-aminosalicylic acid (5-ASA) must be on a stable dose from 4 weeks prior to Screening until the end of study. (3) Subjects receiving immunosuppressants (azathioprine, 6-mercaptopurine [6-MP] or methotrexate) must be on a stable dose for 4 weeks prior to Screening until the end of study treatment. Subjects taking methotrexate are also advised to take folic acid 5 mg/week (or equivalent) if there is no contraindication. (4) Subjects receiving probiotics must be on a stable dose for ≥ 2 weeks prior to Screening until the end of study. (5) Subjects receiving an anti-diarrhetic must be on a stable dose for ≥ 2 weeks prior to Screening until the end of study. 7. Previous treatment with at least one biologic therapy that demonstrated an inadequate response and/or loss of response. 8. Negative pregnancy test during Screening and Day 1 (V0) in females of childbearing potential. 9. Females with reproductive potential must be sexually abstinent or be willing to use a highly effective method of contraception from study start to ≥ 3 months after the final dose of the study drug. Highly effective methods of contraception include: Hormonal contraceptives (e.g., combined oral contraceptives, patch, vaginal ring, injectables, and implants); male partner should use a condom; Intrauterine device or system; or Surgical sterilization or partner sterile (must have documented proof). 10. Male subjects must be either surgically sterile (must have documented proof), agree to be sexually abstinent, 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 to ≥ 3 months after the final dose administration. 11. Male subjects must agree to refrain from donating sperm from first study drug administration to ≥ 3 months after final dose administration. Exclusion Criteria: If a subject meets any of the following criteria, they will be excluded from the study: Diagnosis of Crohn's colitis, colitis yet to be classified, ischemic colitis, nonsteroidal anti-inflammatory drug (NSAID)-induced colitis, idiopathic colitis (i.e., colitis not consistent with UC), or radiation-induced colitis. Ulcerative colitis limited to the rectum (ulcerative proctitis). Presence of short bowel syndrome. History of colectomy, or presence of an ileostomy or colostomy. History of, or active colonic mucosal dysplasia. Treatment with any intravenous (IV) corticosteroid or rectal therapy during the Screening period. Treatment with any calcineurin inhibitor (e.g., cyclosporine, tacrolimus) within 4 weeks prior to Screening. Treatment with NSAIDs within 4 weeks prior to Screening. Short-term use (<7 days) of NSAIDs for non-UC related symptoms is allowed. Treatment with tofacitinib or other Janus Kinase (JAK) inhibitors within 4 weeks prior to Screening. Treatment with sphingosine-1-phosphate receptor (S1PR) modulators within 4 weeks prior to Screening. Biologic therapy within 56 days or 5 half-lives (whichever is longer) prior to Screening. Confirmation of undetectable or non-therapeutic serum levels, as assessed by the Investigator, will allow for eligibility. Tube feeding, defined formula diets, or parenteral alimentation/nutrition within 3 weeks of first dosing. Treatment with oral antibiotics within 4 weeks prior to Screening or IV antibiotics within 8 weeks prior to Screening. Vaccination with a live or live-attenuated vaccine within 4 weeks prior to Screening. History of dysplasia or malignancy in the past 5 years, except completely excised basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix. 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, or any other severe co-morbidity that, in the opinion of the Investigator, could confound the study results or put the subject at unreasonable risk. Significant screening electrocardiogram (ECG) abnormalities, including evidence of acute myocardial infarction, complete left bundle branch block, second-degree heart block, or complete heart block. For males, a QTc interval (Fridericia's correction) of >450 ms, and for females, a QTc interval (Fridericia's correction) of >470 ms. Any of the following laboratory abnormalities during the Screening period. If values are initially outside prescribed limits, the evaluation may be repeated once within the Screening period to determine eligibility: Calculated creatinine clearance < 60 mL/min Serum transaminases > 2.0x Upper Limit Normal (ULN) Alkaline phosphatase (ALP) > 2.0x ULN Bilirubin > 1.5x ULN; does not apply to subjects with Gilbert's Syndrome (Meulengracht Syndrome) Hemoglobin < 8g/dL Platelets < 75,000/μL Absolute neutrophil count < 1,500/ μL Absolute lymphocyte count < 800/ μL 20. Human immune deficiency virus (HIV) infection or known HIV-related malignancy. 21. Acute or chronic hepatitis B (HBV) or hepatitis C (HCV), or carrier status. Subjects with anti-HBc (hepatitis B core) antibodies (Ab) but with undetectable anti-HBs (hepatitis B surface) Ab should be excluded. 22. Positive immunoglobulin M (IgM) Ab titers in the presence of negative immunoglobulin G (IgG) Ab titers to Epstein-Barr virus (EBV). 23. Positive stool test for ova or parasites, positive stool culture for pathogens, or positive stool toxin assay for Clostridium difficile at Screening. Subjects with the positive stool toxin assay for Clostridium difficile at Screening may be eligible to be re-screened following discussion with the Sponsor and/or Medical Monitor. 24. Active cytomegalovirus (CMV) infection at Screening, as assessed by the Investigator. 25. Positive QuantiFERON® TB test at Screening for latent Mycobacterium tuberculosis (TB) infection. If a QuantiFERON® TB test is indeterminate, the test should be repeated. If the result is again indeterminate, the subject should be excluded. Subjects with a history of latent TB infection who received or are receiving an appropriate and documented course of therapy can be included if the screening examination and a chest x-ray performed within 3 months prior to Screening revealed no evidence of current active infection. 26. History of any opportunistic infection within 12 weeks of first dosing. 27. Any current or recent symptoms/signs of infection, except nasopharyngitis, within 4 weeks of first dosing. 28. Cirrhosis or active alcohol abuse, per the judgment of the Investigator. 29. 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 a positive drug screening test. 30. Currently breast feeding, or pregnant. 31. Known hypersensitivity or intolerance to ALTB-268 or any of its excipients. 32. Participation in another clinical trial AND having received investigational medication within 30 days or 5 half-lives (whichever is longer) prior to Screening or having used an investigational device treatment within 30 days prior to Screening. Concurrent participation in an observational or long-term follow-up study and not actively receiving an investigational drug or device treatment may be eligible for participation in this study. 33. Inability to comply with the study protocol, in the opinion of the Investigator.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ALTB-168<br>intravenous doses of ALTB-168 | Biological: ALTB-168<br>* monoclonal antibody<br>* 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Ulcerative Colitis