A Randomized, Placebo-controlled ,Double-blind, Phase IIa Assessment of the Safety of Foralumab, an Oral Anti-CD3 Antibody, in Patients With Nonalcoholic Steatohepatitis (NASH) and Type 2 Diabetes Mellitus (T2DM)
Overview
- Phase
- Phase 2
- Intervention
- placebo
- Conditions
- NASH - Nonalcoholic Steatohepatitis
- Sponsor
- Tiziana Life Sciences LTD
- Primary Endpoint
- Abnormal physical findings
- Status
- Withdrawn
- Last Updated
- 6 years ago
Overview
Brief Summary
This is a randomized, placebo-controlled, four-arm, double-blind study. Subjects will be randomized (1:1:1:1) to receive either a daily oral placebo solution or a daily oral dose of 0.5 mg, 2.5 mg or 5.0 mg Foralumab Solution for 30 consecutive days. Subjects will record adverse events and daily administration of study medication in a subject diary. This will serve as a measure of compliance and record of safety and tolerability. Subjects will be followed up for 30 days following completion of treatment.
Study visits performed on Days 14, 30 and 60 of the study, will monitor metabolic parameters (body mass index [BMI] and waist circumference), serum lipid profiles, immunological markers (c-reactive protein [CRP] and an array of cytokines), hepatic enzymes and functions (13C-methacetin breath test [MBT]) and liver steatosis/fibrosis, which will be compared to baseline levels (Day 1).
The safety and tolerability of the treatment regimen will be determined by monitoring vital signs, laboratory values, adverse events and physical findings throughout the study. In addition, its efficacy will be established upon either reduced Day 30 serum alanine aminotransferase (ALT) levels, reduced hemoglobin A1c (HbA1c) or improved homeostasis model assessment (HOMA) or HOMA of insulin resistance (HOMA-IR) scores as compared to baseline (Day 1). In addition, to assess the efficacy of the tested Foralumab Solution regimen in improving overall subject status, a battery of exploratory metabolic, immunologic and hepatic markers will be evaluated on Days 30 and 60.
Detailed Description
A randomized, placebo-controlled, double-blind, phase IIa study for assessment of the safety of Foralumab, an oral anti-CD3 antibody, in patients with nonalcoholic steatohepatitis (NASH) and type 2 diabetes mellitus (T2DM). This is a randomized, placebo-controlled, four-arm, double-blind study. Subjects will be randomized (1:1:1:1) to receive either a daily oral placebo solution or a daily oral dose of 0.5 mg, 2.5 mg or 5.0 mg Foralumab Solution for 30 consecutive days. Subjects will record adverse events and daily administration of study medication in a subject diary. This will serve as a measure of compliance and record of safety and tolerability. Subjects will be followed up for 30 days following completion of treatment. Study visits performed on Days 14, 30 and 60 of the study, will monitor metabolic parameters (body mass index \[BMI\] and waist circumference), serum lipid profiles, immunological markers (c-reactive protein \[CRP\] and an array of cytokines), hepatic enzymes and functions (13C-methacetin breath test \[MBT\]) and liver steatosis/fibrosis, which will be compared to baseline levels (Day 1). The safety and tolerability of the treatment regimen will be determined by monitoring vital signs, laboratory values, adverse events and physical findings throughout the study. In addition, its efficacy will be established upon either reduced Day 30 serum alanine aminotransferase (ALT) levels, reduced hemoglobin A1c (HbA1c) or improved homeostasis model assessment (HOMA) or HOMA of insulin resistance (HOMA-IR) scores as compared to baseline (Day 1). In addition, to assess the efficacy of the tested Foralumab Solution regimen in improving overall subject status, a battery of exploratory metabolic, immunologic and hepatic markers will be evaluated on Days 30 and 60. Primary: To assess the safety and tolerability of the tested Foralumab Solution regimen in subjects with both T2DM and NASH/NAFLD Secondary: To assess the efficacy of the tested Foralumab Solution regimen in improving serum ALT levels, HbA1c, HOMA or HOMA-IR scores in subjects with both T2DM and NASH/NAFLD. Exploratory: To assess the efficacy of the tested Foralumab Solution regimen in improving overall subject status, as measured by a battery of metabolic, immunologic and hepatic markers. 48 adult subjects (≥18 years) with T2DM and who meet the inclusion criteria for NASH or NAFLD 2a Up to 25 Foralumab (TZLS-0401) is a fully human IgG1 monoclonal antibody directed against the CD3-epsilon (or CD3ε) antigen expressed on the surface of a type of white blood cell called T-cells, or T-lymphocytes. The Fc region of the antibody is mutated to reduce the cytokine release syndrome associated with parenteral administration of anti CD3. When administered orally, Foralumab is not absorbed and induces a signal at the level of the gut immune system to promote regulatory T cells systemically. A once-daily oral dose of Foralumab solution (0.5, 2.5 or 5.0 mg) or placebo solution will be taken in the morning on an empty stomach for 30 consecutive days. Group A will receive placebo solution for 30 days (n=12) Group B will receive 0.5 mg Foralumab Solution daily for 30 days (n=12) Group C will receive 2.5 mg Foralumab Solution daily for 30 days (n=12) Group D will receive 5.0 mg Foralumab Solution daily for 30 days (n=12) A single 20 mg omeprazole pill will be concomitantly administered daily.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Age ≥ 18 years
- •Provision of written informed consent
- •Diagnosis of T2DM
- •HbA1c \< 9.0 while on standard of care
- •Historical histology-based confirmation of NASH within 12 months prior to screening OR
- •Diagnosis of NAFLD based on all the following:
- •Presentation of at least one other parameter of the metabolic syndrome from the following list of three:
- •(i) hypertension \[≥130/85 mmHg or regularly taking an antihypertensive\], (ii) dyslipidemia with high serum triglycerides \[≥150 mg/dL or regularly taking medicines to lower high triglyceride levels\] or low serum HDL \[\<50 mg/dL for women and \<40 mg/dL for men\], (iii) obesity (BMI \> 30 kg/m2) or central obesity \[waistline measurement ≥ 89 cm for women and ≥ 102 cm for men\])
- •ALT \> 40 IU
- •Fat fraction \>10% in MRI performed during screening or up to 3 months prior to screening.
Exclusion Criteria
- Not provided
Arms & Interventions
Group A
Group A will receive placebo solution for 30 consecutive days
Intervention: placebo
Group A
Group A will receive placebo solution for 30 consecutive days
Intervention: Omeprazole 20mg
Group B
Group B will receive 0.5 mg Foralumab Solution daily for 30 consecutive days
Intervention: Foralumab
Group B
Group B will receive 0.5 mg Foralumab Solution daily for 30 consecutive days
Intervention: Omeprazole 20mg
Group C
Group B will receive 2.5 mg Foralumab Solution daily for 30 consecutive days
Intervention: Foralumab
Group C
Group B will receive 2.5 mg Foralumab Solution daily for 30 consecutive days
Intervention: Omeprazole 20mg
Group D
Group B will receive 5.0 mg Foralumab Solution daily for 30 consecutive days
Intervention: Foralumab
Group D
Group B will receive 5.0 mg Foralumab Solution daily for 30 consecutive days
Intervention: Omeprazole 20mg
Outcomes
Primary Outcomes
Abnormal physical findings
Time Frame: 30 days after last dose
Incidence, severity, and duration for all adverse events (AEs), and abnormal laboratory and physical findings up until 30 days after last dose
severity and duration for all adverse events
Time Frame: 30 days after last dose
Incidence, severity, and duration for all adverse events (AEs), and abnormal laboratory and physical findings up until 30 days after last dose
Abnormal laboratory findings
Time Frame: 30 days after last dose
Incidence, severity, and duration for all adverse events (AEs), and abnormal laboratory and physical findings up until 30 days after last dose
Secondary Outcomes
- Change ALT levels(Day 30 versus Day 1 serum ALT levels)
- Change in HbA1c levels(Day 30 versus Day 1)
- change in HOMA/HOMA-IR scores(Day 30 versus Day 1)